Impaired defense of core temperature in aged humans during mild cold stress

Aged humans often exhibit an impaired defense of core temperature during cold stress. However, research documenting this response has typically used small subject samples and strong cold stimuli. The purpose of this study was to determine the responses of young and older subjects, matched for anthropometric characteristics, during mild cold stress. Thirty-six young (YS; 23 +/- 1 years, range 18-30) and 46 older (OS; 71 +/- 1 years, range 65-89) subjects underwent a slow transient cold air exposure from a thermoneutral baseline, during which esophageal (T(es)) and mean skin temperatures (T(sk)), O(2) consumption, and skin blood flow (SkBF; laser-Doppler flowmetry) were measured. Cold exposure was terminated at the onset of visible sustained shivering. Net metabolic heat production (M(net)), heat debt, predicted change in midregion temperature (DeltaT(mid)), and tissue insulation (I(t)) were calculated. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial pressure and expressed as percent change from baseline (DeltaCVC(%base)). There were no baseline group differences for T(es), but OS M(net) was lower (OS: 38.0 +/- 1.1; YS: 41.9 +/- 1.1 W . m(-2), P < 0.05). T(es) was well maintained in YS but fell progressively in OS (P < 0.01 for all timepoints after 35 min). The skin vasoconstrictor response to mild cold stress was attenuated in OS (42 +/- 3 vs. 53 +/- 4 DeltaCVC(%base), P < 0.01). There were no group differences for T(sk) or I(t), while M(net) remained lower in OS (P < 0.05). The DeltaT(mid) did not account for the drop in T(es) in OS. Healthy aged humans failed to maintain T(es); however, the mechanisms underlying this response are not clear.     

Influence of cold and warm acclimation on neuronal responses in the lower brain stem

Neurons in two lower brain stem areas, the nucleus raphe magnus and the subcoeruleus region, have been shown to be part of the thermoafferent system. It is concluded from microcut experiments in unanaesthetized guinea pigs that inhibition of shivering caused by nucleus raphe magnus stimulation is mediated partly by ascending and partly by descending efferents of the nucleus raphe magnus. Electrical stimulation of the subcoeruleus area caused excitatory metabolic responses. Interruption of the ascending efferents of the subcoeruleus area did not prevent the metabolic activation. It is concluded that the excitatory responses are partly mediated by descending efferents of the subcoeruleus area. The descending pathways project mainly to motoneurone pools and to dorsal horn cells. In cold-acclimated guinea pigs, the average maximum activity of bell-shaped subcoeruleus cold-responsive units was reduced significantly in comparison with cold-responsive neurons in animals acclimated to normal room temperature. Furthermore, peak activity of warm-responsive units in the nucleus raphe magnus was larger in cold-acclimated animals than in animals acclimated to normal room temperature. These neuronal changes may contribute via descending lower loops and via ascending upper loops to long-term slope reduction of metabolic cold defence and shivering threshold displacements.     

Pioglitazone does not affect vascular or inflammatory responses after endotoxemia in humans.

PPARgamma agonists have been proposed to exert more than metabolic benefits, particularly by anti-inflammatory mechanisms. We hypothesized that pioglitazone might modulate inflammatory and vascular responses to lipopolysaccharide (LPS). In a placebo-controlled parallel-group study in 18 healthy male subjects, the E. coli endotoxin model of inflammation (20 IU/kg i. v.) was employed to test the effect of 60 mg pioglitazone over nine days on inflammatory cytokines. Macrovascular function and microvascular blood flow were assessed by brachial artery ultrasound and retinal blood flow parameters, respectively. Pioglitazone increased brachial artery diameter by 5.6% but had no effect on other outcome parameters under resting conditions. LPS increased cytokine levels to peak concentrations of 91.3+/-22.5 ng/ml (IL-6), 261.4+/-60.0 ng/ml (TNFalpha), and 524.5+/-15.3 ng/ml (VCAM-1). The endotoxin caused microvascular vasodilation and increased retinal white blood cell flux, while baseline brachial artery diameter remained unchanged. Pioglitazone had no effect on inflammatory cytokine or adhesion molecule release but mitigated LPS-induced hypotension (p<0.05). Neither brachial artery function nor microvascular blood flow was altered by pioglitazone. In conclusion, acute immune reactions to LPS are not affected by pioglitazone, which exerts subtle vascular effects alone and during endotoxemia. The anti-inflammatory properties of short-term pioglitazone to endotoxins in healthy subjects are therefore limited.     

Effect of cold air inhalation on core temperature in exercising subjects under heat stress

Whether increasing respiratory heat loss (RHL) during exercise under heat stress can contain elevation of rectal temperature (Tre) was examined. Eight men cycled twice at 45-50% their maximum work rate until exhaustion at ambient temperature and relative humidity of 38 degrees C and 90-95%, respectively. They inspired either cold (3.6 degrees C) or ambient air in random sequence. When subjects breathed cold air during 23 min of exercise, a ninefold increase in RHL was observed vs. similar work during hot air inhalation (32.81 vs. 3.46 W). Respiratory frequency (f) and rate of rise in Tre decreased significantly (P less than or equal to 0.004 and P less than or equal to 0.002, respectively). The rise in skin temperature in each inhalant gas condition was accompanied by a parallel almost equal increase in core temperature above basal (delta Tre) for equivalent gains in skin temperature. The increase in tidal volume and decreased f in the cold condition allowed more effective physical conditioning of cold inspirate gas in the upper airways and aided RHL. Cold air inhalation also produced a significant (P less than or equal to 0.05) decrease in heart rate vs. hot air inhalation in the final stages of exercise. Insignificant changes in O2 consumption and total body fluid loss were found. These data show that cold air inhalation during exercise diminishes elevation of Tre and suggest that both the intensity and duration of work can thus be extended. The importance of the physical exchange of heat energy and any physiological mechanisms induced by the cold inspirate in producing the changes is undetermined.     

Glucocorticoid-treatment does not influence the synthesis of thromboxane B2 and bicyclo-PGE2 in humans

It has been reported that the anti-inflammatory action of glucocorticoids is due to the inhibition of phospholipases. Consequently, after high-dose steroid treatment in humans a decrease in cyclooxygenase products should be expected. In 15 patients (10 males, 5 females, 29-62 y) undergoing 6-methyl-prednisolone-treatment (40-80 mg daily) for various clinical reasons and in 5 healthy volunteers (4 male, 1 female, 28-37 y) receiving 500 mg 6-methyl-prednisolone daily for 3 days plasma- and serum-thromboxane B2 (TXB2), as well as bicyclo-prostaglandin E2 (bicyclo-PGE2) were monitored over 3 weeks. In the entire follow-up period, however, no significant change in either serum- or plasma-TXB2 or bicyclo-PGE2 could be measured in either, patients and volunteers, under glucocorticoid-treatment. These findings indicate that even high-dose glucocorticoid-treatment does not affect the serum- and plasma-metabolites of the eicosanoids examined. It is concluded that in humans a significant inhibition of phospholipases by glucocorticoids and subsequently reduced formation of cyclooxygenase products seems to be rather unlikely.     

Testosterone does not influence opiate binding sites in the male rat brain

It has been reported previously that castration produces testosterone-reversible increases in the density of 3H-naltrexone binding sites in the male rat brain. Unfortunately, we were unable to replicate these observations in a comprehensive series of studies. Specifically, we found that castration failed to produce changes in the Kd or Bmax of opiate binding sites in whole male rat brain, or in the hypothalamus, utilizing 3H-dihydromorphine (a mu receptor ligand), 3H-D-alanine, D-leucine enkephalin (delta) or 3H-naltrexone (ubiquitous). Furthermore, we found that the relative proportion of mu and delta binding sites in brain was unchanged by castration. The reasons for the discrepancy between the present results and those previously reported are unclear, but it appears that the provocative hypothesis that testosterone influences opioid receptors in brain must be carefully reevaluated.     

Osteocalcin does not influence acute or chronic inflammation in human vascular cells

Some human observational studies have suggested an anti-inflammatory role of osteocalcin (OCN). An inflammatory protocol using interferon-γ and tumor necrosis factor-α (10 ng/ml) was employed to examine the acute (24 hr) and chronic (144 hr) effects of uncarboxylated OCN (ucOCN) in commercial, primary, subcultured human aortic endothelial cells (HAEC), and human smooth muscle cells (HASMCs). The inflammatory protocol increased phosphorylation of intracellular signaling proteins (CREB, JNK, p38, ERK, AKT, STAT3, STAT5) and increased secretion of adhesion markers (vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemoattractant protein-1) and proinflammatory cytokines (interleukin-6 [IL-6], IL-8). After acute inflammation, there were no additive or reductive effects of ucOCN in either cell type. Following chronic inflammation, ucOCN did not affect cell responses, nor did it appear to have any pro- or anti-inflammatory effects when administered acutely or chronically on its own in either cell type. Additionally, ucOCN did not affect lipopolysaccharide (LPS)-induced acute inflammation in HAECs or HASMCs. The findings of this study do not support a causal role for OCN within the models of vascular inflammation chosen. Further confirmatory studies are warranted.     

The influence of kainic acid on core temperature and cytokine levels in the brain

Excitotoxic brain injury is associated with hyperthermia, and there are data showing beneficial effects of hypothermia on neurodegeneration and that hyperthermia facilitates the neurodegeneration. Cytokines are inflammatory proteins that seem to be involved in the neuroinflammation associated with epilepsy. Core temperature changes caused by the epileptogenic glutamate analogue kainic acid (KA) were investigated in relation to changes in levels of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), and the endogenous interleukin-1 receptor antagonist (IL-1ra). The temperature was measured every 10 min during the first hour, and at 90 and 120 min, and hourly until 8 h after KA-injection (10 mg/kg). The cytokines were measured in the hypothalamus, a site of temperature regulation, and in hippocampus, cerebellum, and frontal cortex. KA induced a brief hypothermia followed by hyperthermia. IL-1beta levels were increased after KA-administration in all brain regions examined and, excepting hippocampus, returned to baseline levels at 24 h. The hippocampal IL-1ra levels were significantly increased at 24 h, whereas no changes in IL-6 levels were observed. The changes in IL-1beta levels and in ratios between the levels of the three cytokines, may account for some of the temperature changes and the behavioural manifestations induced by KA.     

Urine temperature as an index for the core temperature of industrial workers in hot or cold environments

Workers working in hot or cold environments are at risk for heat stroke and hypothermia. In Japan, 1718 people including 47 workers died of heat stroke in 2010 (Ministry of Health Labour and Welfare, Japan 2011). While the American Conference of Governmental Industrial Hygienists (ACGIH) recommendation lists the abnormal core temperature of workers as a criterion for halting work, no method has been established for reliably measuring core temperatures at workplaces. ISO 9886 (Ergonomics-evaluation of thermal strain by physiological measurements. ISO copyright office, Geneva, pp 3–14; 2004) recognizes urine temperature as an index of core temperature only at normal temperature. In this study we ascertained whether or not urine temperature could serve as an index for core temperature at temperatures above and below the ISO range. We measured urine temperature of 31 subjects (29.8 ± 11.9 years) using a thermocouple sensor placed in the toilet bowl at ambient temperature settings of 40, 20, and 5˚C, and compared them with rectal temperature. At all ambient temperature settings, urine temperature correlated closely with rectal temperature exhibiting small mean bias. Urine temperature changed in a synchronized manner with rectal temperature at 40˚C. A Bland and Altman analysis showed that the limits of agreement (mean bias ± 2SD) between rectal and urine temperatures were −0.39 to +0.15˚C at 40˚C (95%CI −0.44 to +0.20˚C) and −0.79 to +0.29˚C at 5˚C (−0.89 to +0.39˚C). Hence, urine temperature as measured by the present method is a practical surrogate index for rectal temperature and represents a highly reliable biological monitoring index for assessing hot and cold stresses of workers at actual workplaces.     

MFGE8 does not influence chorio-retinal homeostasis or choroidal neovascularization in vivo

Purpose

Milk fat globule-epidermal growth factor-factor VIII (MFGE8) is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP) in MFGE8 was studied in two exsudative or “wet” Age-related Macular Degeneration (AMD) groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV) in mice.

Methods

The distribution of the SNP (rs4945 and rs1878326) of MFGE8 was analyzed in two groups of patients with “wet” AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8 ^+/− mice expressing ß-galactosidase. Aged Mfge8 ^+/− and Mfge8 ^−/− mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser-induced CNV.

Results

rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8^−/− mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser-induced CNV. In contrast, the Bruch''s membrane (BM) was slightly but significantly thicker in Mfge8^−/− mice as compared to controls.

Conclusions

Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8^−/− mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD.     

AT1 receptor antagonism does not influence early radiation-induced changes in microglial activation or neurogenesis in the normal rat brain

Blockers of the renin-angiotensin-aldosterone system (RAAS) ameliorate cognitive deficits and some aspects of brain injury after whole-brain irradiation. We investigated whether treatment with the angiotensin II type 1 receptor antagonist L-158,809 at a dose that protects cognitive function after fractionated whole-brain irradiation reduced radiation-induced neuroinflammation and changes in hippocampal neurogenesis, well-characterized effects that are associated with radiation-induced brain injury. Male F344 rats received L-158,809 before, during and after a single 10-Gy dose of radiation. Expression of cytokines, angiotensin II receptors and angiotensin-converting enzyme 2 was evaluated by real-time PCR 24 h, 1 week and 12 weeks after irradiation. At the latter times, microglial density and proliferating and activated microglia were analyzed in the dentate gyrus of the hippocampus. Cell proliferation and neurogenesis were also quantified in the dentate subgranular zone. L-158,809 treatment modestly increased mRNA expression for Ang II receptors and TNF-α but had no effect on radiation-induced effects on hippocampal microglia or neurogenesis. Thus, although L-158,809 ameliorates cognitive deficits after whole-brain irradiation, the drug did not mitigate the neuroinflammatory microglial response or rescue neurogenesis. Additional studies are required to elucidate other mechanisms of normal tissue injury that may be modulated by RAAS blockers.     

Cellular phone use does not acutely affect blood pressure or heart rate of humans

A recent study raised concern about increase of resting blood pressure after a 35 min exposure to the radiofrequency (RF) field emitted by a 900 MHz cellular phone. In this randomized, double blind, placebo controlled crossover trial, 32 healthy subjects were submitted to 900 MHz (2 W), 1800 MHz (1 W) cellular phone exposure, and to sham exposure in separate sessions. Arterial blood pressure (arm cuff method) and heart rate were measured during and after the 35 min RF and sham exposure sessions. We evaluated cardiovascular responses in terms of blood pressure and heart rate during controlled breathing, spontaneous breathing, head-up tilt table test, Valsalva manoeuvre and deep breathing test. Arterial blood pressure and heart rate did not change significantly during or after the 35 min RF exposures at 900 MHz or 1800 MHz, compared to sham exposure. The results of this study indicate that exposure to a cellular phone, using 900 MHz or 1800 MHz with maximal allowed antenna powers, does not acutely change arterial blood pressure and heart rate.     

Pregnancy in goats does not influence intake of novel or familiar foods with or without toxins

Some hypothesize that mammals decrease intake of foods that contain toxins during pregnancy to protect the fetus. We conducted a longitudinal study of feeding behavior to determine if pregnancy-related changes in food selection and intake occurred in goats. Goats eat modest amounts of toxic plants, some of which contain teratogenic or abortifacient compounds, but it is not known if pregnant and non-pregnant goats differ in food selection. The embryo is susceptible to toxins during all stages of pregnancy, but especially so during organogenesis early in pregnancy. Thus, we hypothesized that food selection and intake by pregnant versus non-pregnant goats may differ during various stages of pregnancy. We examined the following predictions that stem from this hypothesis: relative to non-pregnant goats, pregnant goats may alter selection of familiar foods that contain toxins, and of familiar and unfamiliar foods that do not contain toxins. We fed 14 plants with known or probable teratogenic properties during two pregnancies. We also offered beet pulp containing 0.5% LiCl during one pregnancy to test for increased sensitivity to toxins. In addition, we offered novel foods several times during one pregnancy to test for increased food neophobia or neophyllia. Finally, we measured intake of the basal ration by pregnant and non-pregnant goats daily throughout both pregnancies. Both pregnant and non-pregnant goats ate modest amounts of the plants with toxins and of beet pulp with LiCl. Both groups limited intake of novel foods and beet pulp with LiCl to the same degree. Finally, pregnant and non-pregnant goats did not differ in intake (per kg MBW) of the basal ration—dry matter, energy, or protein—in either pregnancy. Thus, the data do not support the notion that goats experienced pregnancy-related changes in food selection or intake.     

Perception of foot temperature in young women with cold constitution: analysis of skin temperature and warm and cold sensation thresholds

To examine the disease state of cold constitution, physiological measurements of the foot were conducted by investigating thermal sensations under an environmental condition of 25 degrees C-26 degrees C (neutral temperature) in 29 young women with and without cold constitution. The subjects were classified into 3 groups according to their experiences with cold constitution: cold constitution, intermediate, and normal groups. Foot skin temperature was measured by thermography. Thermal sensations were measured on the dorsum of the left foot using a thermal stimulator. Cold and warm spots on the dorsum of the right foot were ascertained. Thermal stimulation was delivered by a copper probe. No significant differences in foot skin temperature among these 3 groups were identified as measured in a laboratory under neutral temperature conditions. However, the mean warm sensation threshold was +6.3+/-1.09 degrees C (mean+/-SEM) for the cold constitution group (n=14), +3.4+/-2.10 degrees C (mean+/-SEM) for the intermediate group (n=7), and -0.25+/-1.96 degrees C (mean+/-SEM) for the normal group (n=6). The difference was significant between the cold constitution and normal groups. No significant differences among the 3 groups were found in the cold sensation threshold. This may be attributable to the distribution of thermal receptors and to chronically reduced blood flow in subcutaneous tissues, where the skin temperature receptors responsible for temperature sensation are located.     

Thermoregulatory and respiratory responses in asthmatic and nonasthmatic subjects breathing cold and warm air during exercise in the cold

1.

The effects of whole-body exposure to ambient temperature of −15 °C on thermoregulatory and respiratory responses in asthmatic and nonasthmatic subjects were investigated. The subjects were exposed to inhalation of cold dry and warm humid air during 30 min submaximal exercise.     

Evaluation of two cold thermoregulatory models for prediction of core temperature during exercise in cold water.

Cold thermoregulatory models (CTM) have primarily been developed to predict core temperature (T(core)) responses during sedentary immersion. Few studies have examined their efficacy to predict T(core) during exercise cold exposure. The purpose of this study was to compare observed T(core) responses during exercise in cold water with the predicted T(core) from a three-cylinder (3-CTM) and a six-cylinder (6-CTM) model, adjusted to include heat production from exercise. A matrix of two metabolic rates (0.44 and 0.88 m/s walking), two water temperatures (10 and 15 degrees C), and two immersion depths (chest and waist) were used to elicit different rates of T(core) changes. Root mean square deviation (RMSD) and nonparametric Bland-Altman tests were used to test for acceptable model predictions. Using the RMSD criterion, the 3-CTM did not fit the observed data in any trial, whereas the 6-CTM fit the data (RMSD less than standard deviation) in four of eight trials. In general, the 3-CTM predicted a rapid decline in core temperature followed by a plateau. For the 6-CTM, the predicted T(core) appeared relatively tight during the early part of immersion, but was much lower during the latter portions of immersion, accounting for the nonagreement between RMSD and SD values. The 6-CTM was rerun with no adjustment for exercise metabolism, and core temperature and heat loss predictions were tighter. In summary, this study demonstrated that both thermoregulatory models designed for sedentary cold exposure, currently, cannot be extended for use during partial immersion exercise in cold water. Algorithms need to be developed to better predict heat loss during exercise in cold water.     

Herbivory damage does not indirectly influence the composition or excretion of aphid honeydew

Recent research has shown that extrafloral nectar secretion by plants, which also attracts ants, is a defense inducible by herbivory damage. Our research addresses the question of whether plants can manipulate the honeydew secretions of homopterans as an inducible defense in response to herbivory in the same manner as extrafloral nectaries. We investigated changes in honeydew composition and excretion rate by the facultatively ant-attended aphid Chaitophorus saliniger Shinji (Homoptera: Aphididae) depending on the presence or absence of herbivory by caterpillars (Clostera anastomosis L.; Lepidoptera: Notodontidae) on their host plant, the willow Salix gilgiana Seemen. Our results found no evidence to suggest that herbivory damage to the aphids host plant causes significant changes in aphid population growth, honeydew droplet volume, volume of honeydew excreted per aphid per hour, or composition of three abundant sugars in aphid honeydew as a result of herbivory damage to the aphids host plant, suggesting that, in this particular system, the plant is not manipulating the aphids honeydew output for its own benefit.