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Rationale We previously showed that early calcification of atherosclerotic plaques associates with macrophage accumulation. Chronic renal disease (CRD) and mineral imbalance accelerates calcification and the subsequent release of matrix vesicles (MVs) — precursors of microcalcification. Objective We tested the hypothesis that macrophage-derived MVs contribute directly to microcalcification. Methods and Results Macrophages associated with regions of calcified vesicular structures in human carotid plaques (n=136 patients). In vitro, macrophages released MVs with high calcification and aggregation potential. MVs expressed exosomal markers (CD9 and TSG101), and contained S100A9 and annexin V (Anx5). Silencing S100A9 in vitro and genetic deficiency in S100A9−/− mice reduced MV calcification, while stimulation with S100A9 increased calcification potential. Externalization of phosphatidylserine (PS) after Ca/P stimulation and interaction of S100A9 and Anx5, indicated that a PS-Anx5-S100A9 membrane complex facilitates hydroxyapatite nucleation within the macrophage-derived MV membrane. Conclusions Our results support the novel concept that macrophages release calcifying MVs enriched in S100A9 and Anx5, which contribute to accelerated microcalcification in CRD.

In humans, evaporative heat loss from eccrine sweat glands is critical for thermoregulation during exercise and/or exposure to hot environmental conditions, particularly when environmental temperature is greater than skin temperature. Since the time of the ancient Greeks, the significance of sweating has been recognized, whereas our understanding of the mechanisms and controllers of sweating has largely developed during the past century. This review initially focuses on the basic mechanisms of eccrine sweat secretion during heat stress and/or exercise along with a review of the primary controllers of thermoregulatory sweating (i.e., internal and skin temperatures). This is followed by a review of key nonthermal factors associated with prolonged heat stress and exercise that have been proposed to modulate the sweating response. Finally, mechanisms pertaining to the effects of heat acclimation and microgravity exposure are presented.

Long-term exposure to pyschostimulants and opioids induced neuronal plasticity. Accumulating evidence suggests that astrocytes actively participate in synaptic plasticity. We show here that a glial modulator propentofylline (PPF) dramatically diminished the activation of astrocytes induced by drugs of abuse, such as methamphetamine (METH) and morphine (MRP). In vivo treatment with PPF also suppressed both METH-and MRP-induced rewarding effects. On the other hand, intra-nucleus accumbens (N.Acc.) administration of astrocyte-conditioned medium (ACM) aggravated the development of rewarding effects induced by METH and MRP via the Janus kinase/signal transducers and activators of transcription (Jak/STAT) pathway, which modulates astrogliosis and/or astrogliogenesis. Furthermore, ACM, but not METH itself, clearly induced the differentiation of multipotent neuronal stem cells into glial fibrillary acidic protein-positive astrocytes, and this effect was reversed by cotreatment with the Jak/STAT inhibitor AG490. Intra-cingulate cortex (CG) administration of ACM also enhanced the rewarding effect induced by METH and MRP. In contrast to ACM, intra-N.Acc. administration of microglia-conditioned medium failed to affect the rewarding effects of METH and MRP in mice. These findings suggest that astrocyte-, but not microglia-, related soluble factors could amplify the development of rewarding effect of METH and MRP in the N.Acc. and CG. The present study provides direct evidence that astrocytes may, at least in part, contribute to the synaptic plasticity induced by drugs of abuse during the development of rewarding effects induced by psychostimulants and opioids.

It is presently unclear how the fast and slow components of pulmonary oxygen uptake (VO(2)) kinetics would be altered by body posture during heavy exercise [i.e., above the lactate threshold (LT)]. Nine subjects performed transitions from unloaded cycling to work rates representing moderate (below the estimated LT) and heavy exercise (VO(2) equal to 50% of the difference between LT and peak VO(2)) under conditions of upright and supine positions. During moderate exercise, the steady-state increase in VO(2) was similar in the two positions, but VO(2) kinetics were slower in the supine position. During heavy exercise, the rate of adjustment of VO(2) to the 6-min value was also slower in the supine position but was characterized by a significant reduction in the amplitude of the fast component of VO(2), without a significant slowing of the phase 2 time constant. However, the amplitude of the slow component was significantly increased, such that the end-exercise VO(2) was the same in the two positions. The changes in VO(2) kinetics for the supine vs. upright position were paralleled by a blunted response of heart rate at 2 min into exercise during supine compared with upright heavy exercise. Thus the supine position was associated with not only a greater amplitude of the slow component for VO(2) but also, concomitantly, with a reduced amplitude of the fast component; this latter effect may be due, at least in part, to an attenuated early rise in heart rate in the supine position.

Ten older (aged 64-76 years) and ten younger (aged 20-24 years) healthy men were exposed to a standard heat stress [by placing the lower legs and feet in a water bath at 42 degrees C while sitting in a controlled environment (ambient temperature 35 degrees C and 45% relative humidity) for 60 min]. During passive heating, the rectal temperature of the older men was significantly greater (P < 0.05) and mean skin temperature was lower (P < 0.001), compared to the younger men. Skin blood flow by laser Doppler flowmetry (LDF) was significantly lower on the chest and thigh for the older men (P < 0.001), but forehead LDF did not differ between the groups. The percentages of total LDF in the older men to total LDF in the younger men for the last 30 min were 99%, 58% and 50% on the forehead, chest and thigh, respectively. The age-related differences in LDF responses mirrored cutaneous vascular conductances (CVC), since no group and time effects were observed in mean arterial blood pressure during the test. During the last 30 min the local sweat rates (msw) on the back and thigh were significantly lower for the older men (P < 0.02), but not on forehead, chest and forearm, although the older men had lower msw during the first 30 min exposure regardless of site (P < 0.03). The percentages of total msw in the older men to total msw in the younger men during the last 30 min were 105%, 99%, 63%, 106% and 88% on the forehead, chest, thigh, forearm, and back, respectively. During the latter half of the exposure, the older men had similar LDF, CVC and msw on the forehead, lower LDF and CVC and a similar msw on the chest, and lower LDF, CVC and msw on the thigh, compared to the younger men. These results suggest firstly that regional differences exist in the age-related decrement of cutaneous vasodilatation as well as sweat gland function, secondly that the age-related decrement in cutaneous vascular function may precede a decrement in sweat gland function, and thirdly that the successive decrements may develop sequentially from the lower limbs to the upper body, and head.

The venoarteriolar response causes vasoconstriction to skin and muscle via local mechanisms secondary to venous congestion. The purpose of this project was to investigate whether this response occurs through α‐adrenergic mechanisms. In supine individuals, forearm skin blood flow was monitored via laser‐Doppler flowmetry over sites following local administration of terazosin (α1‐antagonist), yohimbine (α2‐antagonist), phentolamine (non‐selective α‐antagonist) and bretylium tosylate (inhibits neurotransmission of adrenergic nerves) via intradermal microdialysis or intradermal injection. In addition, skin blood flow was monitored over an area of forearm skin that was locally anaesthetized via application of EMLA (2.5 % lidocaine (lignocaine) and 2.5 % prilocaine) cream. Skin blood flow was also monitored over adjacent sites that received the vehicle for the specified drug. Each trial was performed on a minimum of seven subjects and on separate days. The venoarteriolar response was engaged by lowering the subject's arm from heart level such that the sites of skin blood flow measurement were 34 ± 1 cm below the heart. The arm remained in this position for 2 min. Selective and non‐selective α‐adrenoceptor antagonism and presynaptic inhibition of adrenergic neurotransmission did not abolish the venoarteriolar response. However, local anaesthesia blocked the venoarteriolar response without altering α‐adrenergic mediated vasoconstriction. These data suggest that the venoarteriolar response does not occur through adrenergic mechanisms as previously reported. Rather, the venoarteriolar response may due to myogenic mechanisms associated with changes in vascular pressure or is mediated by a non‐adrenergic, but neurally mediated, local mechanism.

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