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Transdermal drug delivery is suitable for low-molecular-weight drugs with specific lipophilicity, like fentanyl, which is widely used for cancer-induced pain management. However, fentanyl's transdermal therapy displays high intra-individual variability. Factors like skin characteristics at application sites and ambient temperature contribute to this variation. In this study, we developed a physics-based digital twin of the human body to cope with this variability and propose better adapted setups. This twin includes an in-silico skin model for drug penetration, a pharmacokinetic model, and a pharmacodynamic model. Based on the results of our simulations, applying the patch on the flank (side abdominal area) showed a 15.3 % higher maximum fentanyl concentration in the plasma than on the chest. Additionally, the time to reach this maximum concentration when delivered through the flank was 19.8 h, which was 10.3 h earlier than via the upper arm. Finally, this variation led to an 18 % lower minimum pain intensity for delivery via the flank than the chest. Moreover, the impact of seasonal changes on ambient temperature and skin temperature by considering the activity level was investigated. Based on our result, the fentanyl uptake flux by capillaries increased by up to 11.8 % from an inactive state in winter to an active state in summer. We also evaluated the effect of controlling fentanyl delivery by adjusting the temperature of the patch to alleviate the pain to reach a mild pain intensity (rated three on the VAS scale). By implementing this strategy, the average pain intensity decreased by 1.1 points, and the standard deviation for fentanyl concentration in plasma and average pain intensity reduced by 37.5 % and 33.3 %, respectively. Therefore, our digital twin demonstrated the efficacy of controlled drug release through temperature regulation, ensuring the therapy toward the intended target outcome and reducing therapy outcome variability. This holds promise as a potentially useful tool for physicians., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

To determine whether using nicotine exacerbates exertional heat strain through an increased metabolic heat production (H prod ) or decreased skin blood flow (SkBF), 10 nicotine-naïve trained males [37 ± 12 yr; peak oxygen consumption (V̇o 2peak ): 66 ± 10 mL·min -1 ·kg -1 ] completed four trials at 20°C and 30°C following overnight transdermal nicotine (7 mg·24 h -1 ) and placebo use in a crossover, double-blind design. They cycled for 60 min (55% V̇o 2peak ) followed by a time trial (∼75% V̇o 2peak ) during which measures of gastrointestinal (T gi ) and mean weighted skin ([Formula: see text] sk ) temperatures, SkBF, H prod , and mean arterial pressure (MAP) were made. The difference in ΔT gi between nicotine and placebo trials was greater during 30°C (0.4 ± 0.5°C) than 20°C (0.1 ± 0.7°C), with [Formula: see text] sk higher during nicotine than placebo trials (0.5 ± 0.5°C, P = 0.02). SkBF became progressively lower during nicotine than placebo trials ( P = 0.01) and progressively higher during 30°C than 20°C trials ( P < 0.01); MAP increased from baseline ( P < 0.01) and remained elevated in all trials. The difference in H prod between 30°C and 20°C trials was lower during nicotine than placebo ( P = 0.01) and became progressively higher during 30°C than 20°C trials with exercise duration ( P = 0.03). Mean power output during the time trial was lower during 30°C than 20°C trials (24 ± 25 W, P = 0.02), and although no effect of nicotine was observed ( P > 0.59), two participants (20%) were unable to complete their 30°C nicotine trials as one reached the ethical limit for T gi (40.0°C), whereas the other withdrew due to "nausea and chills" (T gi = 39.7°C). These results demonstrate that nicotine use increases thermal strain and risk of exertional heat exhaustion by reducing SkBF. NEW & NOTEWORTHY In naïve participants, acute nicotine use exerts a hyperthermic effect that increases the risk of heat exhaustion during exertional heat strain, which is driven by a blunted skin blood flow response. This has implications for 1 ) populations that face exertional heat strain and demonstrate high nicotine use (e.g., athletes and military, 25%-50%) and 2 ) study design whereby screening and exclusion for nicotine use or standardization of prior use (e.g., overnight abstinence) is encouraged.

Cold exposure increases blood pressure (BP) and salivary flow rate (SFR). Increased cold-induced SFR would be hypothesized to enhance oral nitrate delivery for reduction to nitrite by oral anaerobes and to subsequently elevate plasma [nitrite] and nitric oxide bioavailability. We tested the hypothesis that dietary nitrate supplementation would increase plasma [nitrite] and lower BP to a greater extent in cool compared with normothermic conditions. Twelve males attended the laboratory on four occasions. Baseline measurements were completed at 28°C. Subsequently, participants ingested 140 mL of concentrated nitrate-rich (BR; ∼13 mmol nitrate) or nitrate-depleted (PL) beetroot juice. Measurements were repeated over 3 h at either 28°C (Norm) or 20°C (Cool). Mean skin temperature was lowered compared with baseline in PL-Cool and BR-Cool. SFR was greater in BR-Norm, PL-Cool, and BR-Cool than PL-Norm. Plasma [nitrite] at 3 h was higher in BR-Cool (592 ± 239 nM) versus BR-Norm (410 ± 195 nM). Systolic BP (SBP) at 3 h was not different between PL-Norm (117 ± 6 mmHg) and BR-Norm (113 ± 9 mmHg). SBP increased above baseline at 1, 2, and 3 h in PL-Cool but not BR-Cool. These results suggest that BR consumption is more effective at increasing plasma [nitrite] in cool compared with normothermic conditions and blunts the rise in BP following acute cool air exposure, which might have implications for attenuating the increased cardiovascular strain in the cold. NEW & NOTEWORTHY Compared with normothermic conditions, acute nitrate ingestion increased plasma [nitrite], a substrate for oxygen-independent nitric oxide generation, to a greater extent during cool air exposure. Systolic blood pressure was increased during cool air exposure in the placebo condition with this cool-induced blood pressure increase attenuated after acute nitrate ingestion. These findings improve our understanding of environmental factors that influence nitrate metabolism and the efficacy of nitrate supplementation to lower blood pressure.

This study aimed to explore how natural menstrual cycle phases and dosage of oral hormonal contraceptives (OC) influence the diurnal rhythm of distal skin temperature (DST) under real-life conditions. Participants were 41 healthy females (23.9 ± 2.48 y), comprising 27 females taking monophasic hormonal oral contraceptives (OC users) and 14 females with menstrual cycles (non-OC users). Wrist DST was continuously recorded and averaged over two consecutive 24-hour days during (pseudo)follicular and (pseudo)luteal menstrual phases. Diurnal rhythm characteristics, i.e. acrophase and amplitude, describing timing and strength of the DST rhythm, respectively, were calculated using cosinor analysis. Results show that non-OC users experienced earlier diurnal DST maximum (acrophase, p  = 0.019) and larger amplitude ( p  = 0.016) during the luteal phase than during the follicular phase. This was observed in most (71.4%) but not all individuals. The OC users showed no differences in acrophase or amplitude between pseudoluteal and pseudofollicular phases. OC users taking a higher dosage of progestin displayed a larger amplitude for DST rhythm during the pseudoluteal phase ( p  = 0.009), while estrogen dosage had no effect. In conclusion, monophasic OC cause changes in diurnal DST rhythm, similar to those observed in the luteal phase of females with menstrual cycles, suggesting that synthetic progestins act in a similar manner on skin thermoregulation as progesterone does.

Purpose: Cold-induced vasodilation (CIVD) is an oscillatory rise in blood flow to glabrous skin that occurs in cold-exposed extremities. Dietary flavanols increase bioavailable nitric oxide, a proposed mediator of CIVD through active vasodilation and/or withdrawal of sympathetic vascular smooth muscle tone. However, no studies have examined the effects of flavanol intake on extremity skin perfusion during cold exposure. We tested the hypothesis that acute and 8-day flavanol supplementation would augment CIVD during single-digit cold water immersion (CWI)., Methods: Eleven healthy adults (24 ± 6 years; 10 M/1F) ingested cocoa flavanols (900 mg/day) or caffeine- and theobromine-matched placebo for 8 days in a double-blind, randomized, crossover design. On Days 1 and 8, CIVD was assessed 2 h post-treatment. Subjects immersed their 3rd finger in warm water (42 °C) for 15 min before CWI (4 °C) for 30 min, during which nail bed and finger pad skin temperature were measured., Results: Flavanol ingestion had no effect on CIVD frequency (Day 1, Flavanol: 3 ± 2 vs. Placebo: 3 ± 2; Day 8, Flavanol: 3 ± 2 vs. Placebo: 3 ± 1) or amplitude (Day 1, Flavanol: 4.3 ± 1.7 vs. Placebo: 4.9 ± 2.6 °C; Day 8, Flavanol: 3.9 ± 1.9 vs. Placebo: 3.9 ± 2.0 °C) in the finger pad following acute or 8-day supplementation (P > 0.05). Furthermore, average, nadir, and apex finger pad temperatures during CWI were not different between treatments on Days 1 or 8 of supplementation (P > 0.05). Similarly, no differences in CIVD parameters were observed in the nail bed following supplementation (P > 0.05)., Conclusion: These data suggest that cocoa flavanol ingestion does not alter finger CIVD. Clinical Trial Registration Clinicaltrials.gov Identifier: NCT04359082. April 24, 2020., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Context: Psidium guajava L. (Myrtaceae) leaf contains a wide variety of bioactive compounds that contribute valuable effects on human well-being., Objective: This study investigates the influence of guava leaf extract-menthol toner on thermoregulation, including perspiration, skin temperature, and recovery heart rate., Materials and Methods: This randomised, placebo-controlled clinical trial assessed the effects of the guava leaf extract-menthol toner and placebo with a 1-week washout period. Sixty-four participants were enrolled. The participants exercised on a treadmill until a 75% heart rate reserve was achieved for 5 min, followed by a 5 min post-exercise rest period. The skin temperature and heart rate were then measured before 5 mL of the testing product was sprayed to specific areas of the body, left it for 30 sec before wiped off. Post-exercise perspiration and skin temperatures were collected by sweat patches and measured by the Skin-thermometer ST500, respectively. A 20 min heart rate monitoring period started 10 min after the exercise and measured every 2 min intervals., Results: Use of the toner significantly reduced post-exercise perspiration to approximately half of the baseline and placebo use values ( p  < 0.05). Furthermore, relative heart rate changes showed no significant differences among the tests ( p  > 0.05). Skin temperature was also unaffected ( p  > 0.05)., Discussion and Conclusion: Guava leaf extract-menthol toner reduced perspiration by astringent effects but did not influence heat dissipation and did not affect cardiovascular mechanism compared to the controls. Additional cleaning with guava leaf extract-menthol toner could offer better hygiene after a workout.

Background: Thyroid hormones are essential for the full thermogenic response of brown adipose tissue (BAT) and have been implicated in dermal temperature regulation. Nevertheless, persistent cold-intolerance exists among a substantial proportion of hypothyroid patients on adequate levothyroxine (LT4) substitution., Materials and Methods: To assess if skin temperature and activation of BAT during treatment with liothyronine (LT3) differs from that of LT4 treatment, fifty-nine female hypothyroid patients with residual symptoms on LT4 or LT4/LT3 combination therapy were randomly assigned in a non-blinded crossover study to receive monotherapy with LT4 or LT3 for 12 weeks each. Change in supraclavicular (SCV) skin temperature overlying BAT, and sternal skin temperature not overlying BAT, during rest and cold stimulation were assessed by infrared thermography (IRT). In addition, abundance of exosomal miR-92a, a biomarker of BAT activation, was estimated as a secondary outcome., Results: Cold stimulated skin temperatures decreased less with LT3 vs . LT4 in both SCV (mean 0.009°C/min [95% CI: 0.004, 0.014]; P <0.001) and sternal areas (mean 0.014°C/min [95% CI: 0.008, 0.020]; P <0.001). No difference in serum exosomal miR-92a abundance was observed between the two treatment groups., Conclusion: LT3 may reduce dermal heat loss. Thermography data suggested increased BAT activation in hypothyroid patients with cold-intolerance. However, this finding was not corroborated by assessment of the microRNA biomarker of BAT activation., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03627611., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bjerkreim, Hammerstad, Gulseth, Berg, Lee-Ødegård, Rangberg, Jonassen, Budge, Morris, Law, Symonds and Eriksen.)

The aim of the study was to explore the correlations between peripheral perfusion, mean arterial pressure and the dose-rate of norepinephrine (NE) infused for the treatment of septic shock. The study is retrospective analysis of data acquired prospectively on 57 patients during the first 24 hours after the occurrence of the shock. Clinical and haemodynamic characteristics, skin perfusion parameters (capillary refill time [CRT], mottling score and temperature gradients) and the dose rate of NE infusion were collected. Negative correlations between mean arterial pressure (MAP) and temperature gradients (core-to-toe: P = .03, core-to-index: P = .04) were found and abnormal CRT was associated with lower MAP (P = .02). The dose rate of NE was negatively correlated with temperature gradients (core-to-toe: P = .02, core-to-index: P = .01, forearm-to-index: P = .008) in the overall population. In patients receiving NE for at least 12 hours, the NE dose rate positively was correlated with the mottling score (P = .006), temperature gradients (core-to-toe: P = .04, forearm-to-index: P = .02, core-to-index: P = .005) and CRT (P = .001). The dose of NE administrated was associated with 14-days mortality (odds ration [OR] = 1.21 [1.06-1.38], P = .006) and with 28-days mortality (OR = 1.17 [1.01-1.36], P = 0.04). In conclusion, the study described the presence of correlations between peripheral perfusion and MAP and between peripheral perfusion and the dose rate of NE infusion., (© 2021 John Wiley & Sons Australia, Ltd.)

The majority of women experience vasomotor symptoms (VMS), such as hot flashes and night sweats, during the menopausal transition. Recent evidence strongly suggests a connection between neurokinin 3 (NK3) receptor signaling and VMS associated with menopause. The NK3 receptor antagonist fezolinetant is currently in phase 3 development for treatment of moderate to severe VMS associated with menopause. We investigated the pharmacological effects of repeated administration of fezolinetant on levels of sex hormones and gonadotropins, neuronal activity in the hypothalamus, and skin temperature as an index of hot flash-like symptoms in ovariectomized rats as a model of menopause. Ovariectomized rats exhibited several typical menopausal symptoms: hyperphagia, increased body weight, significantly decreased plasma estradiol levels, increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and significantly increased skin temperature. Increased c-Fos expression (an indirect marker of neuronal activity) in median preoptic nucleus (MnPO) hypothalamic neurons was also observed in ovariectomized rats. Repeated oral administration of fezolinetant (1-10 mg/kg, twice daily) for 1 week dose-dependently reduced plasma LH levels without affecting estradiol or FSH levels, inhibited the activation of MnPO neurons, and attenuated hot flash-like symptoms. In addition, fezolinetant dose-dependently reduced hyperphagia and weight gain in ovariectomized rats. These preclinical findings suggest that fezolinetant attenuates hot flash-like symptoms via inhibition of neuronal activity in the MnPO of ovariectomized rats and provides further support for the ongoing clinical development of fezolinetant for the treatment of VMS associated with menopause., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: The etiology of vasopressor-induced digital necrosis is poorly understood, but the skin changes resemble those of frostbite, and it is known from experience that patients taking vasopressors have decreased digital temperatures. We aimed to examine the effects of norepinephrine use on surface temperatures of the distal extremities because there have been no studies examining this relation., Methods: Surface temperatures of all digits, palms, and soles were measured using an infrared thermometer in patients receiving different rates of norepinephrine infusion in the intensive care unit and compared with those not receiving any vasopressors., Results: A total of 101 measurements from 41 unique individuals were obtained. Temperature gradients between the core and the fingertips were consistently more pronounced in those receiving norepinephrine compared with those not receiving norepinephrine and increased with increasing rates of norepinephrine infusion, except with high-dose norepinephrine. Temperature gradients were more pronounced in the toes., Conclusions: Norepinephrine use was associated with greater core-to-fingertip temperature gradients and were more pronounced in the toes compared with the fingers.

Despite the need for safe and effective postoperative analgesia in neonates, research regarding pain management in neonatal rodents is relatively limited. Here, we investigate whether sustained release buprenorphine (Bup SR) effectively attenuates thermal hypersensitivity in a neonatal rat model of incisional pain. Male and female postnatal day 3 Sprague Dawley rat pups (n = 34) were randomly assigned to one of four treatment groups: 1) saline (control), 0.1 mL, once subcutaneously (SC); 2) buprenorphine HCl (Bup HCl), 0.05 mg/kg, once SC; 3) low dose Bup SR (low-SR), 0.5 mg/kg, once SC; 4) high dose Bup SR (high-SR), 1 mg/kg, once SC. Pups were anesthetized with sevoflurane and a 0.5-cm long skin incision was made over the left lateral thigh. The underlying muscle was dissected and closed using surgical glue. Thermal hypersensitivity testing was performed at 24 h prior to surgery and subsequently at 1, 4, 8, 24, and 48 h post-surgery using an infrared diode laser. Thermal hypersensitivity was attenuated at 1 h post-surgery in the Bup HCl group, while it was attenuated through the entire postoperative period in both low-SR and high-SR groups. This data suggests that a single dose of low-SR (0.5 mg/kg) or high-SR (1 mg/kg) effectively attenuates thermal hypersensitivity for at least 8 h in neonatal rat pups., Competing Interests: The authors have declared that no competing interests exist.

Anesthesia is frequently used to facilitate physiological monitoring during interventional animal studies. However, its use may induce cardiovascular (central and peripheral), respiratory, and thermoregulatory depression, confounding results in anesthetized animals. Despite the wide utility of guinea pigs as a translational platform, anesthetic protocols remain unstandardized for extended physiological studies in this species. Therefore, optimizing an anesthetic protocol that balances stable anesthesia with intact cardiorespiratory and metabolic function is crucial. To achieve this, 12 age and sex-matched juvenile Dunkin Hartley guinea pigs underwent extended anesthesia (≤150 min) with either (a) isoflurane (ISO: 1.5%), or (b) isoflurane + N 2 O (ISO+ N 2 O: 0.8% +70%), in this randomized cross-over designed study. Cardiovascular (HR, SBP, peripheral microvascular blood flow), respiratory (respiratory rate, SpO 2 ), and thermal (T re and T sk ) measures were recorded continuously throughout anesthesia. Blood gas measures pre- and post- anesthesia were performed. Incorporation of 70% N 2 O allowed for significant reductions in isoflurane (to 0.8%) while maintaining an effective anesthetic depth for prolonged noninvasive physiological examination in guinea pigs. ISO+N 2 O maintained heart rate, peripheral blood flow, respiratory rate, and thermoregulatory function at levels closest to those of conscious animals, especially in females; however, it did not fully rescue anesthesia-induced hypotension. These results suggest that for studies requiring prolonged physiological examination (≤150 min) in guinea pigs, 0.8% isoflurane with a 70% N 2 O adjuvant provides adequate anesthesia, while minimizing associated cardiorespiratory depression. The preservation of cardiorespiratory status is most marked throughout the first hour of anesthesia., (© 2021 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Fasting increases ghrelin that is a peptide hormone with two circulating isoforms, acyl and des-acyl ghrelin. We reported that fasting or des-acyl ghrelin facilitates behavioral thermoregulation in the cold in rats assessed by tail-hiding behavior that was the indicator of rats' thermoregulatory behavior in the cold; however, the effect of acyl-ghrelin on the same process remains to be elucidated. We investigated the effect of acyl-ghrelin on thermoregulatory behavior in the cold in rats. The animals received an intraperitoneal saline or 24 μg acyl-ghrelin injection and were exposed to 27 °C or 15 °C for 2 h, while their body temperature, tail skin temperature, and tail-hiding behavior were constantly monitored. cFos immunoreactive (cFos-IR) cells in the median preoptic area, medial preoptic area, paraventricular nucleus (PVN), and arcuate nucleus were counted. Body temperature and the duration of thermoregulatory behavior did not show a significant difference between the acyl-ghrelin-treated and control groups at 15 °C; however, tail skin temperature in the acyl-ghrelin-treated group was higher than that in the control group. The number of cFos-IR cells in the PVN was greater in the control group than that in the acyl-ghrelin-treated group at 27 °C. These results indicate that acyl-ghrelin did not affect behavioral thermoregulation but might affect tail skin temperature in rats in the cold., (Copyright © 2020 Elsevier B.V. All rights reserved.)

New Findings: What is the central question of this study? Does dietary nitrate supplementation with beetroot juice attenuate thermoregulatory and cardiovascular strain in older adults during severe heat stress? What is the main finding and its importance? A 7-day nitrate supplementation regimen lowered resting mean arterial pressure in thermoneutral conditions. During heat stress, core and mean skin temperatures, vasodilatory responses, sweat loss, heart rate and left ventricular function were unchanged, and mean arterial pressure was only transiently reduced, post-supplementation. These data suggest nitrate supplementation with beetroot juice does not mitigate thermoregulatory or cardiovascular strain in heat-stressed older individuals., Abstract: This study tested the hypothesis that dietary nitrate supplementation with concentrated beetroot juice attenuates thermoregulatory and cardiovascular strain in older individuals during environmental heat stress. Nine healthy older individuals (six females, three males; aged 67 ± 5 years) were exposed to 42.5 ± 0.1°C and 34.0 ± 0.5% relative humidity conditions for 120 min before (CON) and after 7 days of dietary nitrate supplementation with concentrated beetroot juice (BRJ; 280 ml, ∼16.8 mmol of nitrate daily). Core and skin temperatures, body mass changes (indicative of whole-body sweat loss), skin blood flow and cutaneous vascular conductance, forearm blood flow and vascular conductance, heart rate, arterial blood pressures and indices of cardiac function were measured. The 7-day beetroot juice regimen increased plasma nitrate/nitrite levels from 27.4 ± 15.2 to 477.0 ± 102.5 μmol l -1 (P < 0.01) and lowered resting mean arterial pressure from 90 ± 7 to 83 ± 10 mmHg at baseline under thermoneutral conditions (P = 0.02). However, during subsequent heat stress, no differences in core and skin temperatures, skin blood flow and vascular conductance, forearm blood flow and vascular conductance, whole-body sweat loss, heart rate, and echocardiographic indices of systolic function and diastolic filling were evident following nitrate supplementation (all P > 0.05). Mean arterial pressure was lower in BRJ vs. CON during heat stress (treatment-by-time interaction: P = 0.02). Overall, these findings suggest that dietary nitrate supplementation with concentrated beetroot juice does not attenuate thermoregulatory or cardiovascular strain in older individuals exposed to severe ambient heat stress., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Introduction: This study assessed the influence of High (H, 4.13%), Medium (M, 2.0%) and Low (L, 0.1%) doses of menthol on temperature perception and regulation, compared to a Placebo Condition (P)., Method: Sixteen participants underwent the aforementioned conditions on four separate days. During each test participants rested supine (Environmental conditions: 30 °C, 50% rh) for 30-min before 40 mL of L, M, H or P gel was applied to the anterior upper body, then rested 30-min thereafter. Primary measures included thermal sensation (TS), thermal comfort (TC), irritation (IRR), rectal temperature (Tre), and skin temperature (chest, forearm, thigh, calf), and EMG (trapezius, pectoralis major, sternocleidomastoid). The area under the curve (AUC) from minute 30 to 60 was compared between conditions using relevant non/parametric tests (alpha level = 0.05)., Results: A cooling trend in Tre was observed following Placebo gel application, but this significantly (p < 0.05) reversed into a heat storage response in M and H. Both TS and TC significantly differed by condition (p < 0.001) in a dose-dependent manner, with L, M, and H doses eliciting significantly cooler sensations and more discomfort than P (p < 0.05). Irritation significantly differed by condition (p < 0.01) in a dose-dependent manner, with L and M eliciting significantly greater irritation than P (p < 0.01). No other differences were observed., Conclusions: Menthol exerts perceptual and thermoregulatory effects independent of skin temperature. A menthol dose-dependent perceptual cooling effect was evident with possible saturation at the moderate dose. A dose-dependent alteration in deep body temperature was also evident., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC 0-4 h at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC 0-3 h at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer., (© 2020, The American College of Clinical Pharmacology.)

A computational model was developed to better understand the impact of elevated skin temperatures on transdermal drug delivery and dermal clearance. A simultaneous heat and mass transport model with emphasis on transdermal delivery system (TDS) applications was developed to address transient and steady-state temperature effects on dermal absorption. The model was tested using representative data from nicotine TDS applied to human skin either in vitro or in vivo. The approximately 2-fold increase of nicotine absorption with a 10°C increase in skin surface temperature was consistent with a 50-65 kJ/mol activation energy for diffusion in the stratum corneum, with this layer serving as the primary barrier for nicotine absorption. Incorporation of a dermal clearance component into the model revealed efficient removal of nicotine via the dermal capillaries at both normal and elevated temperatures. Two-compartment pharmacokinetic simulations yielded systemic drug concentrations consistent with the human pharmacokinetic data. Both in vitro skin permeation and in vivo pharmacokinetics of nicotine delivered from a marketed TDS under normal and elevated temperatures can be satisfactorily described by a simultaneous heat and mass transfer computational model incorporating realistic skin barrier properties and dermal clearance components.

Introduction: During cold exposure, an increase in sympathetic nerve activity evokes vasoconstriction (VC) of cutaneous vessels to minimize heat loss. In older adults, this reflex VC response is impaired thereby increasing their susceptibility to excess heat loss and hypothermia. Because L-tyrosine, the amino acid substrate necessary for catecholamine production, has been shown to augment reflex VC in age skin, we hypothesize that oral ingestion of L-tyrosine will attenuate the decline in core temperature (Tc) during whole-body cooling in older adults., Methods: In a randomized, double-blind design, nine young (25 ± 3 yr) and nine older (72 ± 8 yr) participants ingested either 150 mg·kg of L-tyrosine or placebo before commencing 90 min of whole-body cooling to decrease skin temperature to approximately 29.5°C. Esophageal temperature and forearm laser Doppler flux (LDF) were measured continuously throughout the protocol to provide an index of Tc and skin blood flow, respectively. The change in esophageal temperature (ΔTES) was the difference in temperature at the end of cooling subtracted from baseline. Cutaneous vascular conductance (CVC) was calculated as CVC = LDF/mean arterial pressure and expressed as a percent change from baseline (%ΔCVCBASELINE)., Results: Oral tyrosine ingestion augmented the cutaneous VC response to cooling in older adults (placebo, 14.4 ± 2.0; tyrosine, 32.7% ± 1.7% ΔCVCBASELINE; P < 0.05). Additionally, tyrosine improved Tc maintenance throughout cooling in older adults (placebo, -0.29 ± 0.07; tyrosine, -0.07 ± 0.07 ΔTES; P < 0.05). Both the cutaneous VC and Tc during cooling were similar between young and older adults supplemented with tyrosine (P > 0.05)., Conclusions: These results indicate that L-tyrosine supplementation improves Tc maintenance in response to acute cold exposure in an older population.

Ischemic colitis is resulted from an inadequate blood supply to a segment or entire colon. Polydeoxyribonucleotide (PDRN), extracted from salmon sperm, has been reported to exert anti-inflammatory and anti-ischemic effects through the adenosine A 2A receptor (A 2A R). We investigated whether PDRN possesses therapeutic effectiveness on ischemic colitis rats. Ischemic colitis was induced by selective devascularization. The skin temperature on the ischemic colitis-induced region was determined. To assess the colonic damage score and collagen deposition, colonic tissue sections were stained with hematoxylin and eosin (H&E), and Masson trichrome staining was performed. Western blot analysis for A 2A R, vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), tumor necrosis factor- α (TNF- α ), interleukin-1 β (IL-1 β ), and IL-6, Bax, Bcl-2, and extracellular signal-regulated kinase 1/2 (ERK1/2) was performed. Skin temperature was increased and mucosal damage and collagen deposition were observed in the affected colonic tissues in the ischemic colitis rats. Expressions of inflammatory cytokines (TNF- α , IL-1 β , and IL-6) and inflammatory mediator (COX-2) were upregulated in the ischemic colitis rats. Apoptosis was increased by decreasing the ratio of Bcl-2 to Bax and by suppressing the phosphorylated form of ERK1/2 expression in the ischemic colitis rats. Treatment with PDRN alleviated mucosal damage reduced the expressions of inflammatory cytokines and COX-2 and inhibited apoptosis in the ischemic colitis rats. PDRN treatment more enhanced the expressions of A 2A R and VEGF in the ischemic colitis rats. PDRN showed therapeutic effectiveness on ischemic colitis by increasing VEGF expression and inhibiting inflammatory cytokines and COX-2 through enhancing A 2A R expression., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Sung-Eun Kim et al.)

Background: Cold hypersensitivity in the hands and feet (CHHF) is a common complaint in Asian female population especially in Korea. Due to the symptoms of CHHF the quality of individual's daily life can be degraded. Ucha-Shinki-Hwan (UCHA) is widely used in the treatment of various diseases including CHHF by harmonizing Yin and Yang, and improving the vitality of whole body. However, the efficacy of UCHA as a treatment option of CHHF has not been assessed in trials. Thus, we aimed to investigate the efficacy and safety of UCHA in Korean women with CHHF through this trial., Methods: This study will be an exploratory, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Korean women aged 19 to 59 years who complaint with CHHF will be enrolled from 5 university affiliated Korean medicine hospitals. A total of 164 subjects will be randomly assigned to a treatment group (UCHA) or a placebo group at a 1:1 ratio. The subjects will receive 2.5 g of either UCHA or placebo three times a day for 8 weeks. The primary outcome will be evaluated with the visual analog scale score of CHHF. The secondary outcome measures will be changes in skin temperature in extremities as measured by using a thermometer and the Korean version of the World Health Organization Quality of Life Scale Abbreviated Version., Discussion: This study will be the first trial to explore the efficacy and safety of UCHA for CHHF patient. This will provide meaningful clinical information on herbal medicine treatment of CHHF and a clinical evidence for planning a full randomized clinical trial., Disclosures and Acknowledgments: The authors report no competing interests., Trial Registration: This study is registered at ClinicalTrials.gov, ID: NCT03790033. Registered on (31 December 2018) PROTOCOL VERSION:: The final approved version of the trial protocol is V1.3. (25 January 2019).

Certain individuals tend to suffer from a cold sensation-particularly in the lower extremities-despite most people not suffering from the same sensation. In Japan, this phenomenon is called "hie-sho" and reduces quality of life for several people, particularly women. A previous study has shown that a standardized oligomerized-polyphenol from Litchi chinensis fruit extract (OPLFE) reportedly causes a significant increase in body surface temperature. The present study aimed to investigate whether supplementation with OPLFE affected peripheral circulation and cold sensitivity. This randomized, double-blind, placebo-controlled trial was performed including 25 participants (age, 45.0±10.4 y; 3 males and 22 females) who were assigned to consume OPLFE, mixed plant extract with OPLFE, or placebo capsules for 14 d. Participants were instructed to relax for 60 min in a temperature-controlled room prior to obtaining measurements. Changes in skin temperature and peripheral blood flow of the middle finger were assessed immediately before and 1, 5, 10, 20, and 30 min after immersion in cold water (10ºC). Participants' height, weight, skin temperature, and blood flow in peripheral tissue were measured; furthermore, their "hie-sho" was measured using the Visual Analog Scale (VAS). Skin temperature and blood flow in peripheral tissue increased in the OPLFE and mixed plant extract with OPLFE groups on day 14 compared with those on day 1. In addition, cold sensitivity in these two groups significantly improved between day 1 and day 14. These findings suggest that OPLFE improves "hie-sho" by increasing peripheral blood flow and skin temperature.

Benzodiazepines are important therapeutic drugs, but they are often abused and co-abused with opioids. Clinical evidence suggests that benzodiazepines can inhibit respiration, and when combined with the respiratory-depressive effects of opioids, may increase likelihood of death. In this study we used oxygen sensors coupled with high-speed amperometry and multi-site thermorecording to examine how intravenous (iv) midazolam, a potent benzodiazepine, modulates the brain hypoxic and temperature effects of iv heroin in freely-moving rats. Oxygen levels and brain temperature were assessed with high temporal resolution in the nucleus accumbens (NAc), an important structure in the motivational-reinforcement circuit. When administered alone, midazolam (2 mg/kg) modestly decreased NAc temperature but had no evident effects on oxygen levels in this structure. In contrast, heroin (0.4 mg/kg) induced a strong decrease in NAc oxygen that was followed by a weaker, rebound-like oxygen increase. Midazolam pretreatment did not affect heroin-induced brain hypoxia but potentiated the initial hypothermia induced by heroin. However, co-administration of these drugs potentiated the heroin-induced oxygen decrease and enhanced heroin-induced brain hypothermia. Co-administration of heroin and midazolam also resulted in enhanced locomotor inhibition and loss of motor control. This effect caused some rats to collapse, resulting in nose and mouth occlusion, which caused a secondary hypoxic phase. These results could have important implications for human drug users, as the combined use of benzodiazepines with potent opioids not only results in sustained brain hypoxia but creates conditions of loss of motor control which could result in asphyxia and death. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'., (Published by Elsevier Ltd.)

According to the literature, the arteriovenous anastomoses in the peripheral parts (ex. hands and feet) respond thermal stimulation susceptibly. Thus, the feet are sensitive to cold stimulation. The aim of the present study was to investigate the effect of menstrual cycle on skin temperature (T sk ) of the foot during menthol application in young women. T sk and partial cutaneous blood flow in the foot, tympanic temperature, blood pressure, heart rate, thermal sensation and pleasantness during the preovulatory (P), luteal (L), and menstrual (M) phases during menthol application in young women using thermography, laser Doppler flowmetry, a digital blood pressure monitor, and VAS scale were examined at 25 °C. After application of the 0.5% menthol solution to the right foot, the measurements were continued for 20 min. The T sk of the second and third right toes in the P phase were lower than that in the L phase. The T sk of the little right toe in the P phase was lower than that in the L and M phases. No significant differences were observed in the T sk of the dorsum of right foot, cutaneous Laser-Doppler flow in the right great toe, tympanic temperature, blood pressure, heart rate, thermal sensation and pleasantness among the phases. The menstrual cycle phase did not affect T sk in the dorsum of the foot, but it affected T sk in some toes during menthol application., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To compare the antinociceptive, sedative and cardiovascular effects of dexmedetomidine pharmacopuncture at Governing Vessel 1 (GV 1) with dexmedetomidine intramuscular (IM) administration., Study Design: Randomized, masked crossover design., Animals: A group of eight healthy female cats., Methods: Cats were randomly administered either dexmedetomidine (0.005 mg kg -1 ; Dex-IM) IM or at acupuncture point GV 1 (Dex-P) separated by 1 week. Prior to and up to 120 minutes posttreatment, skin temperature (ST), thermal threshold (TT), heart rate (HR), respiratory rate (f R ), sedation, muscle relaxation and auditory response scores were recorded. Parametric data were analyzed using a two-way repeated measures anova followed by Tukey's test for multiple comparisons. Nonparametric data were analyzed using a Friedman test followed by Dunn's multiple comparisons test, and Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons. Significance was set at p ≤ 0.05., Results: There were no differences within or between treatments for ST, f R and auditory response. TT was significantly higher at 30-90 minutes in Dex-P (p ≤ 0.0285) than baseline. TT was significantly higher at 60-90 minutes for Dex-P than for Dex-IM (p ≤ 0.0252). HR was significantly lower at 10-75 minutes in Dex-P (p ≤ 0.0378) and at 5-75 minutes in Dex-IM (p ≤ 0.0132) than baseline. Compared with baseline, sedation scores were higher at 25 minutes (p = 0.0327) and 30 minutes (p = 0.0327), and muscle relaxation scores were higher at 25 minutes (p = 0.0151) and 35 minutes (p = 0.0151) in Dex-P. There were no differences in HR, sedation and muscle relaxation scores between treatments., Conclusions and Clinical Relevance: Dex-P increased thermal antinociception compared with Dex-IM at the same dose of dexmedetomidine in cats. This antinociceptive effect must be evaluated under clinical situations., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate thermal antinociception from intravenous (IV) administration of hydromorphone alone or followed by butorphanol or naloxone in cats., Study Design: Randomized, controlled, masked, crossover design., Animals: A group of eight adult female cats., Methods: Cats were administered six treatments of two IV injections 30 minutes apart: treatments S-S, two 0.9% saline; H-S, hydromorphone (0.1 mg kg -1 ) and saline; H-LB, hydromorphone and butorphanol (0.02 mg kg -1 ); H-MB, hydromorphone and butorphanol (0.1 mg kg -1 ); H-HB, hydromorphone and butorphanol (0.2 mg kg -1 ); H-N, hydromorphone and naloxone (0.04 mg kg -1 ). Skin temperature (ST), thermal threshold (TT) and sedation score (SS) were recorded before (baseline) and for 8 hours after the first injection. Percentage maximum possible effect (%MPE), thermal excursion (TE), TT, SS and ST were compared using two-way repeated measures anova or Friedman test followed by Tukey's or Dunn's multiple comparisons test when appropriate. Significance was set at p ≤ 0.05., Results: Data from seven cats were analyzed. There were no significant differences among treatments in baseline values, SS and within S-S over time. Compared with respective 0.5 hour values following hydromorphone administration, %MPE was significantly lower at 4-8 hours for H-S; at 3-8 hours for H-LB; at 4-8 hours for H-MB; at 6-8 hours for H-HB and at 1-8 hours for H-N. Compared with respective 0.5 hour values, TE was significantly lower at 4-8 hours for H-S; at 3-8 hours for H-LB; at 2 and 4-8 hours for H-MB; at 6 and 8 hours for H-HB and at 1-8 hours for H-N., Conclusions and Clinical Relevance: Butorphanol and naloxone reduced hydromorphone-induced thermal antinociception. Butorphanol preserved hydromorphone antinociceptive properties better than naloxone. Butorphanol is recommended during non-life-threatening scenarios as a partial reversal agent for hydromorphone in cats., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Panic attacks (PAs) are episodes of intense fear or discomfort that are accompanied by a variety of both psychological and somatic symptoms. Panic induction in preclinical models (e.g. rats) has largely been assayed through flight and avoidance behavioral tests and cardiorespiratory activity. Yet, the literature pertaining to PAs shows that thermal sensations (hot flushes/heat sensations and chills) are also a common symptom during PAs in humans. Considering that temperature alterations are objectively measurable in rodents, we hypothesized that select panicogenic drugs and stimuli induce consistent changes in thermoregulation related to hot flushes and chills. Specifically, we challenged male rats with intraperitoneal injections of the GABAergic inverse agonist FG-7142; the α2 adrenoceptor antagonist yohimbine; the serotonin agonist D-fenfluramine, and 20% CO2 (an interoceptive homeostatic challenge). We assayed core body temperature and tail skin temperature using implanted radiotelemetry probes and tail thermistors/thermal imaging camera, respectively, and found that all challenges elicited rapid, high-amplitude (~7-9°C) increase in tail skin temperature and delayed decreases (~1-3°C) in core body temperature. We propose that thermal sensations such as these may be an additional indicator of a panic response in rodents and humans, as these panicogenic compounds or stimuli are known to precipitate PAs in persons with panic disorder.

Objetive: To evaluate Neosaxitoxin (NeoSTX) as a local anesthetic drug, for pain control during and after piglet castration., Study Design: Prospective, randomized and double-blind study., Animals: 24 commercial hybrids, males, 23-day-old piglets., Methods: The piglets were randomized into two groups: a Lidocaine group and a NeoSTX group. One minute before castration, they were injected intra-scrotally with a single dose of Lidocaine (20 mg, in 1 mL) and NeoSTX (0.1 μg, in 1 mL), respectively., Results: NeoSTX does not generate vasoconstriction or scrotal contraction, unlike Lidocaine, where a decrease in temperature and scrotal size is observed within 5 min after the procedure. After 24 h, wound inflammation, as measured by scrotal size, was lower in the NeoSTX group. No significant difference could be shown between the vocalizations and facial expressions of pain of both groups during the castration procedure., Conclusions: A single dose of NeoSTX is safe and effective for pain management during and after piglet castration. NeoSTX treated piglets were less affected by castration than those in the Lidocaine group, thus reducing piglet stress and enhancing the quality of piglet convalescence., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The dorsal hippocampus has a central role in modulating cardiovascular responses and behavioral adaptation to stress. The dorsal hippocampus also plays a key role in stress-associated mental disorders. The endocannabinoid system is widely expressed in the dorsal hippocampus and modulates defensive behaviors under stressful conditions. The endocannabinoid anandamide activates cannabinoid type 1 receptors and is metabolized by the fatty acid amide hydrolase enzyme., Aims: We sought to verify whether cannabinoid type 1 receptors modulate stress-induced cardiovascular changes, and if pharmacological fatty acid amide hydrolase inhibition in the dorsal hippocampus would prevent the cardiovascular responses and the delayed anxiogenic-like behavior evoked by restraint stress in rats via cannabinoid type 1 receptors., Methods: Independent groups received intra-dorsal-hippocampal injections of N-(piperidin-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-hpyrazole-3-carboxamide (AM251; cannabinoid type 1 receptor antagonist/inverse agonist, 10-300 pmol) and/or cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597; fatty acid amide hydrolase inhibitor, 10 pmol) before the restraint stress session. Cardiovascular response during restraint stress or later behavioral parameters were evaluated., Results: Acute restraint stress altered the cardiovascular response, characterized by increased heart rate and mean arterial pressure, as well as decreased tail cutaneous temperature. It also induced a delayed anxiogenic-like effect, evidenced by reduced open arm exploration in the elevated plus maze 24 h after stress. AM251 exacerbated the stress-induced cardiovascular responses after injection into the dorsal hippocampus. In contrast, local injection of URB597 prevented the cardiovascular response and the delayed (24 h) behavioral consequences of restraint stress, effects attenuated by pretreatment with AM251., Conclusion: Our data corroborate previous results indicating that the hippocampal endocannabinoid system modulates the outcome of stress exposure and suggest that this could involve modulation of the cardiovascular response during stress exposure.

Plasma pharmacokinetic profiles and the anti-inflammatory efficacy of meloxicam were determined when administered subcutaneously (SC) or intramuscularly (IM) to sheep. Merino ewes were initially injected with 0.1 mL of oil of turpentine into a forelimb to induce inflammation, followed by either 1.0 mg/kg or 2.0 mg/kg of meloxicam administered either SC or IM (n = 6 per treatment group) or followed by no meloxicam administration (control) (n = 4). Ewes were examined to determine skin temperature, limb circumference, limb sensitivity and signs of lameness at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24 and 48 h following treatment, with blood collected at these time-points to quantify meloxicam plasma concentrations. Skin temperature of ewes dosed with meloxicam at 1.0 mg/kg SC and 2.0 mg/kg IM at 12 h and 1.0 mg/kg SC at 24 were significantly different to the controls (P < 0.05). Limb circumferences of ewes dosed with 1.0 mg/kg IM were significantly different to controls at 10 h and 12 h (P < 0.05). All meloxicam treatment groups resulted in reduced limb sensitivity compared to controls at 6 h, with the 1.0 and 2.0 mg/kg IM treatments significantly different at 12 h (P < 0.05) and 1.0 and 2.0 mg/kg SC groups, significantly different to controls at 48 h (P < 0.05). No significant difference in lameness scores were detected over 48 h. The 1.0 mg/kg IM treatment had a significantly greater plasma meloxicam concentration than the 1.0 mg/kg SC treatment over 0.5 to 4 h (P < 0.001). Both 1.0 mg/kg SC and IM treatments demonstrated elimination half-lives (mean ± SD) of 10.82 ± 2.46 and 12.63 ± 2.37 h, respectively. Meloxicam at all doses provided some anti-inflammatory and analgesic effects from 6 to 48 h; however no route could be distinguished as more efficacious than the others., Competing Interests: The authors have declared that no competing interests exist.

Aim: To investigate whether mineralocorticoid (MC) antagonism enhances brown adipose tissue (BAT) function in humans., Materials and Methods: In a randomized double-blind, cross-over designed trial, 10 healthy adults (two men, eight women) underwent 2 weeks of spironolactone (100 mg/d) treatment and placebo, with an intervening 2-week wash-out period. BAT function was assessed in response to cooling and to a mixed meal. Metabolic activity was measured by fluoro-deoxyglucose (FDG) uptake (maximal standardized uptake value, SUV max ) using PET-CT. Thermogenic activity was measured by skin temperatures overlying supraclavicular (SCL) BAT depots using infrared thermography. Postprandial metabolism was measured by energy production rate (EPR) and lipid synthesis using indirect calorimetry., Results: During cooling, BAT metabolic activity (SUV 6.30 ± 2.16 vs 3.98 ± 1.34; P < 0.05) and volume (54.9 ± 22.8 vs 21.6 ± 11.8 cm 3 ; P < 0.05) were significantly higher, and mean SCL temperature decreased by a smaller degree (-0.3°C°± 0.2°C vs -0.9°C ± 0.2°C; P = 0.05) with spironolactone treatment. A mixed meal increased SCL temperature and EPR. The postprandial rise in SCL temperature (+0.4°C ± 0.1°C vs +0.1°C ± 0.1°C; P < 0.05) but not in EPR was greater during spironolactone treatment. Postprandial lipid synthesis occurred in three participants with placebo but in none with spironolactone treatment (P = 0.06)., Conclusion: MC antagonism enhanced human BAT function in response to cooling and to a meal during which lipid synthesis was suppressed. As postprandial EPR comprises energy dissipated as heat and energy required to store nutrients, the reduction in lipid synthesis during MC antagonism is a probable consequence of concurrent stimulation of BAT thermogenesis. The shift in energy usage from storage to heat dissipation indicates that MC antagonists may have therapeutic benefit for obesity., (© 2018 John Wiley & Sons Ltd.)

Study objectives were to determine the effects of chromium (Cr) propionate (Cr propionate 0.04%; 0.5 g/kg of feed to deliver 200 parts per billion Cr/d; KemTRACE Cr, Kemin Industries, Inc., Des Moines, IA) on growth performance, metabolism, and health biomarkers in heat-stressed and nutrient-restricted pigs. Crossbred barrows (n = 96; 105 ± 1 kg BW) were enlisted in an experiment conducted in two replicates, blocked by initial BW, and randomly assigned to one of six dietary-environmental treatments: (i) thermoneutral (TN) and fed ad libitum a control diet (TNCtl), (ii) TN and fed ad libitum a Cr supplemented diet (TNCr), (iii) TN and pair-fed a control diet (PFCtl), (iv) TN and pair-fed a Cr supplemented diet (PFCr), (v) heat stress (HS) and ad libitum fed a control diet (HSCtl), or (vi) HS and ad libitum fed a Cr supplemented diet (HSCr). The study consisted of three experimental periods (P). During P0 (5 d), all pigs were housed in TN conditions (21.3 ± 0.1 °C, 56.8 ± 0.3% relative humidity [RH]) and fed the control diet ad libitum. During P1 (5 d), pigs were fed their respective dietary treatments ad libitum and kept in TN conditions. During P2 (35 d), HSCtl and HSCr-treated pigs were fed ad libitum and exposed to progressive cyclical HS conditions (27 to 31 °C, 50 ± 0.3% RH), while TNCtl, TNCr, PFCtl, and PFCr pigs remained in TN conditions and were fed ad libitum or pair-fed to their respective HSCtl and HSCr counterparts to eliminate the confounding effects of dissimilar feed intake. Overall, HS pigs had increased (P < 0.01) rectal temperature, skin temperature, and respiration rate (0.3 °C, 3.8 °C, and 32 breaths per minute, respectively) relative to TN pigs. Overall, HS decreased ADFI and ADG (20 and 21%, respectively; P < 0.01) compared with TN controls. Final BW tended to be increased in HSCr (2.7 kg, P = 0.06) compared with HSCtl pigs. Similarly, ADG tended to be increased during P2 in HSCr relative to HSCtl-treatment (0.77 vs. 0.72 kg/d; P = 0.10). There were no effects of Cr on most production parameters, but ADFI tended to be increased in Cr relative to Ctl-fed pigs (3.19 vs. 3.09 kg/d; P = 0.08). No effects of Cr supplementation were detected on circulating glucose, insulin, NEFA, cholesterol, triglycerides, or lipopolysaccharide binding protein. However, blood neutrophils were increased in HSCr (37%; P < 0.01) relative to HSCtl pigs. In summary, these results suggest Cr supplementation may benefit growth performance during HS., (© The Author(s) 2018. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We investigated thermoregulatory and cardiovascular responses at rest in a temperate (20°C) and in a warm (30°C) environment (40% RH) without and with the application of capsaicin on the skin. We hypothesized that regardless of environmental temperature, capsaicin application would stimulate heat loss and concomitantly deactivate heat conservation mechanisms, thus resulting in rectal temperature (Tre) and mean blood pressure decline due to excitation of heat-sensitive TRPV1. Ten male subjects were exposed, while seated, for 30 minutes to 20.8 ± 1.0°C or to 30.6 ± 1.1°C: without (NCA) and with (CA) application of capsaicin patches on the skin. Thermoregulatory (Tre, proximal-distal skin temperature gradient) and cardiovascular variables (modelflow technique) as well as oxygen uptake were continuously measured. The area under the curve for Tre decline at 20°C was smaller in CA (-2.1 ± 1.3 a.u.) than in NCA (-0.6 ± 1.1 a.u., P < 0.01, r = 0.8). Likewise, at 30°C it was smaller in CA (-2.2 ± 2.1 a.u.) compared to NCA (-0.8 ± 2.0 a.u., P = 0.02, r = 0.7). Local vasomotor tone and oxygen uptake, were significantly lower by 36.7% ± 94.2% and 12.3% ± 12.3%, respectively, with capsaicin compared to NCA (P = 0.05 and P < 0.01, respectively). Additionally, in 30°C CA mean arterial pressure was lower by 10.7% ± 5.9%, 8.9% ± 5.9%, and 10.6% ± 7.0% compared to 30°C NCA, 20°C NCA, and 20°C CA, respectively (P < 0.01, P = 0.02, and P < 0.01, respectively, d = 1.4-1.8). In conclusion, capsaicin application on the skin induced vasodilation and Tre decline. At 30°C CA, thermal responses were accompanied by arterial hypotension most likely due to the interactive effects of both stressors (warm environment and capsaicin) on cutaneous vascular regulation., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: To quantify acute energy expenditure, supraclavicular skin temperature and cardiovascular responses to four doses of the β3-adrenoceptor agonist, mirabegron., Materials and Methods: A total of 17 individuals (11 men, six women) participated in this ascending-dose study, receiving single 50-, 100-, 150- and 200-mg doses of mirabegron on four separate days with 3 to 14 days wash-out between each dose. All variables were measured each visit from baseline to 180 minutes post mirabegron treatment. To determine brown adipose tissue (BAT) thermogenic efficacy at each dose, energy expenditure and supraclavicular skin temperature were compared from baseline to 180 minutes post mirabegron treatment. To examine safety, changes in cardiovascular variables at 100, 150 and 200 mg were compared with the standard clinical dose of 50 mg., Results: Energy expenditure significantly increased after the 100- (35.6 ± 5.4 kJ/h) and 200-mg (35.6 ± 13.1 kJ/h) doses (P ≤ 0.05), and trended towards an increase after 150 mg (24.1 ± 13.6 kJ/h). Supraclavicular skin temperature increased after 50- (0.22 ± 0.1°C), 100- (0.30 ± 0.1°C) and 150-mg mirabegron doses (0.29 ± 0.1°C; P ≤ 0.05). The change in systolic blood pressure was greater after 150- (7.1 ± 1.3 mm Hg) and 200-mg doses (9.3 ± 1.9 mm Hg) than after the 50-mg dose (2.2 ± 1.3 mm Hg; P ≤ 0.05). The change in heart rate was greater after 200 mg (9.0 ± 2.2 bpm) compared with 50 mg (2.9 ± 1.4 bpm; P ≤ 0.05)., Conclusions: A 100-mg dose of mirabegron increases energy expenditure and supraclavicular skin temperature in a β3-adrenoceptor-specific manner, without the off-target elevations in blood pressure or heart rate observed at higher doses., (© 2018 John Wiley & Sons Ltd.)

Roasted barley extract (RBE) is a traditional Japanese beverage. Previously, we reported the effects of RBE containing cyclo(d-Phe-l-Pro) on blood flow in animals and humans and investigated rapid skin temperature recovery from cold-water immersion in women. The present randomized, double-blind study investigated the effects of RBE containing cyclo(d-Phe-l-Pro) on men's and women's skin temperature in excessively air-cooled conditions. Participants felt cold in the test room (25.5±0.5ºC). They ingested an RBE or placebo beverage and remained in the air-conditioned room for 100 min. Skin temperature of the left foot was measured every 5 min using infrared thermography. We evaluated effect of RBE administration by paired t-test. The skin temperature of the RBE group remained higher than that of the placebo group. The skin temperature changes 100 min after RBE or placebo ingestion were -3.67±1.14ºC and -4.59±0.89ºC, respectively in all participants. We also did subclass analysis focusing on men or women. In a previous study, RBE efficacy for skin temperature in men was not clearly demonstrated. RBE consumption was also effective not only in female participants but also in male participants. The skin temperature changes 100 min after RBE or placebo ingestion were -3.65±0.64ºC and -4.55±0.32ºC, respectively in male participants. Therefore, RBE containing cyclo(d-Phe-l-Pro) prevented skin temperature decreases in excessively air-cooled conditions in both men and women.

The present study describes the hair growth-promoting effects of sodium thiosulfate (STS), a widely used compound, in mice. STS accelerated hair growth in the "telogen model", suggesting that it stimulates telogen hair follicles to reenter the anagen phase of hair growth. In the same model, STS potentiated hair growth in an additive manner with minoxidil (MXD), a drug used for the treatment of androgenic alopecia. Furthermore, in the "anagen model", STS promoted hair growth, probably by promoting hair follicle proliferation. Since STS elevated the skin surface temperature, its hair growth-promoting activity may be partly due to vasorelaxation, similar to MXD. In addition, STS is known to generate a gaseous mediator, H 2 S, which has vasorelaxation and anti-inflammatory/anti-oxidative stress activities. Therefore, STS and/or provisionally its metabolite, H 2 S, may aid the hair growth process. Collectively, these results suggest that salts of thiosulfate may represent a novel and beneficial remedy for hair loss.

Objective: To evaluate the efficacy of the non-steroidal anti-inflammatory drug, meloxicam, in alleviating pain and inflammation and on production-related variables in a model of sterile acute inflammation in sheep., Methods: Groups of 12 mature Merino ewes received 0, 0.5, 1.0 or 1.5 mg/kg meloxicam subcutaneously 90 min before injection of 0.1 mL turpentine subcutaneously on the anterior aspect of the proximal phalanx of a forelimb. Pain- and inflammation-related variables were assessed at -18, 3, 6, 9, 12, 24, 48 and 72 h relative to meloxicam administration. Daily feed intake and body weight change 7 days later were also assessed. Pain-related variables measured were weight borne on each forelimb, lameness score, time each forelimb was raised in a 20-s interval and tolerance to a noxious mechanical stimulus. Inflammation-related variables measured were skin temperature, limb circumference, body temperature, plasma haptoglobin concentration and peripheral blood leucocyte parameters., Results: Meloxicam was effective in improving all pain-related variables. A dose-dependent response was seen between 0 and 1.0 mg/kg, with no additional benefit provided by 1.5 mg/kg. At a dose rate of 1.0 mg/kg, meloxicam improved weight borne on the turpentine-treated limb by 14%, reduced the time the treated limb was held in a non-weight-bearing posture by 46%, reduced the lameness score by 58% and improved tolerance to pressure by 52%. No significant effects of meloxicam on inflammatory variables or appetite were observed., Conclusions: Using a validated pain model, the data suggested that 1.0 mg/kg meloxicam provided significant analgesic benefits to sheep., (© 2019 Australian Veterinary Association.)

Objective: To analyze the short-term thermogenic effects of footbaths with warm water alone (WA) versus when combined with medicinal powders., Design: Randomized controlled trial with cross-over., Interventions and Outcomes: Seventeen healthy volunteers (mean age 22.1 years, SD = 2.4; 11 female) received three footbaths with WA or WA combined with mustard (MU) or ginger (GI) in a randomized order. Self-perceived warmth (Herdecke warmth perception questionnaire) and actual skin temperatures (thermography) were assessed before (t0), immediately after footbaths (t1), and 10 minutes later (t2). The primary outcome was perceived warmth in the feet. Secondary outcomes were warmth perception in the face, hands and overall, as well as actual skin temperature in the feet, face, and hands., Results: Perceived warmth at the feet (primary outcome) increased significantly (all p's < .001) for MU and GI at t1 as well as for GI at t2 when compared to t0 with high effect sizes. At t2, GI differed significantly from WA (p < .001) and MU (p = .048). With regards to the secondary measures of outcome, no significant effects were seen for perceived warmth at the face or hands. Overall warmth was significantly higher at t1 compared to t0 (p = .01). Thermography assessments of skin temperature at the feet at t1 increased after all conditions (p < .001). No effects were seen in the face. At the hands, temperature decreased at t1 (p = .02) and t2 compared to t0 (p < .001)., Conclusion: The present study provides preliminary evidence that mustard and ginger increase warmth perception at the feet more than warm water alone, with only the effects for GI enduring at the brief follow-up., (Copyright © 2018. Published by Elsevier Ltd.)

Background: This study aims to evaluate the safety, efficacy, and feasibility of a full randomized clinical trial of Ojeok-san in Korean female patients with cold hypersensitivity in the hands and feet., Methods: This study is a multicenter, double-blinded, randomized, placebo-controlled, two-arm, parallel-group pilot clinical trial. A total of 60 participants will be enrolled and randomly assigned to the Ojeok-san treatment group or the placebo control group, in a 1:1 ratio using an Internet-based randomization system. Each group will be administered Ojeok-san or placebo three times per day for 8 weeks. The primary outcome will be the mean change in the Visual Analog Scale scores of cold hypersensitivity in the hands from baseline to week 8. Secondary outcomes will include the mean changes in the skin temperature of the extremities, recovery rate of the skin temperature of hands after cold stress test, and the score of Korean version of the WHO Quality of Life Scale abbreviated version., Discussion: The findings of this study should provide meaningful information for a further large-scale, randomized controlled trial to confirm the safety and efficacy of Ojeok-san on cold hypersensitivity in the hands and feet in female patients., Trial Registration: ClinicalTrials.gov, ID: NCT03083522 . Registered on 20 March 2017.

New Findings: What is the central question of this study? Does folic acid supplementation alleviate thermoregulatory and cardiovascular strain of older adults during exposure to extreme heat and humidity? What is the main finding and its importance? Folic acid supplementation for 6 weeks did not affect whole-limb blood flow/vasodilatation, core and skin temperatures, heart rate, blood pressure and cardiac output. Thus, 6 weeks of folic acid supplementation does not alleviate thermoregulatory or cardiovascular strain of healthy older adults exposed to extreme heat and humidity., Abstract: Folic acid supplementation reverses age-related reductions in cutaneous vasodilatation during passive heating. However, it is unknown if folic acid supplementation alleviates thermoregulatory and cardiovascular strain experienced by older adults during heat exposure. We evaluated the effect of folic acid supplementation on thermoregulatory and cardiovascular responses of nine healthy older adults (61-72 years, 3 males/6 females) exposed to extreme heat and humidity. Participants rested at 42°C while relative humidity was increased from 30% to 70% in 2% increments every 5 min. The protocol was performed before (CON) and after (FOLIC) 6 weeks of folic acid supplementation (5 mg day -1 ). Local cutaneous vascular conductance (CVC, laser-Doppler flowmetry), forearm vascular conductance (FVC, Doppler ultrasound), mean skin and oesophageal temperatures, heart rate, blood pressure and cardiac output were measured. Folic acid supplementation increased fasting serum folate concentrations (P < 0.01). Absolute CVC was greater throughout the protocol following supplementation (CON: 1.29 ± 0.16 units mmHg -1 vs. FOLIC: 1.65 ± 0.24 units mmHg -1 , P < 0.01). However, normalized CVC (CON: 54 ± 8% vs. FOLIC: 59 ± 7%, P = 0.22), FVC (CON: 3.47 ± 0.76 ml mmHg -1 vs. FOLIC: 3.40 ± 0.56 ml mmHg -1 , P = 0.93), mean skin (P = 0.81) and oesophageal (CON: 36.87 ± 0.28°C vs. folic: 36.90 ± 0.25°C, P = 0.98) temperatures, heart rate (CON: 83 ± 10 beats min -1 vs. FOLIC: 84 ± 8 beats min -1 , P = 0.64), blood pressure (P = 0.71) and cardiac output (P = 0.20) were unaffected by folic acid supplementation. These results demonstrate that 6 weeks of folic acid supplementation does not alleviate thermoregulatory or cardiovascular strain of healthy older adults exposed to extreme heat and humidity., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

We evaluated the effects of intracerebroventricular administration (ICV) of brain estrogen and progesterone on menopausal symptoms and their effects on the secretion of follicle-stimulating hormone(FSH) and luteinizing hormone (LH) in estrogen-deficient rats. Three weeks after ovariectomy (OVX) or sham operation, OVX rats were given ICV infusions of either 17β-estradiol (4 μg/day; ICV-E), progesterone(0.8 μg/day; ICV-P), or vehicle (control) for 4 wk. OVX rats in the positive-control group were orally provided 150 μg 17β-estradiol·kg body wt -1 ·day -1 . Sham rats had ICV vehicle infusion (normal-control). Serum 17β-estradiol levels of ICV-E and ICV-P groups were higher than the control group but much lower than the normal- and positive-control groups. Tail skin temperature was higher in the control group than the other groups. Serum FSH and LH levels were much higher in the control group than positive- and normal-control groups, but ICV-E and ICV-P lowered the levels similar to the normal-control treatment. ICV-E and ICV-P prevented the decreased energy expenditure in OVX rats. Homeostasis model assessment estimate of insulin resistance was lowered in the descending order of the control, positive-control, ICV-P, ICV-E, and normal-control treatments. The decreased bone mineral density was prevented by the positive-control, ICV-E, and ICV-P treatments. The control group exhibited decreased short-term memory and spatial memory compared with the other groups. Surprisingly, the control group exhibited a decreased richness of the gut microbiome compared with normal-control group, and ICV-E protected against the decrease the most. In conclusion, small amounts of brain estrogen and, to some extent, progesterone improved menopausal symptoms by decreasing serum FSH levels and maintaining the diversity of the gut microbiome in estrogen-deficient rats.

Roasted barley extract (RBE), also known as mugi-cha, is a well-known healthy non-caffeinated beverage, and its health functionality has been widely reported. Our previous clinical study showed that RBE affects the cutaneous blood flow and skin temperature after cold-water immersion and that cyclo(d-Phe-l-Pro) is responsible for its effect. In this study, we investigated whether cyclo(d-Phe-l-Pro)-containing RBE prevents the decrease in the cutaneous blood flow and skin temperature. Subjects remained in the air-conditioned room while ingesting RBE or a placebo. We measured the cutaneous blood flow and skin temperature. We evaluated the effect of RBE administration by two-way repeated measures analysis of variance. A total of 15 subjects were enrolled. The change in cutaneous blood flow in the RBE and placebo groups was -0.79 ± 0.38 and -2.03 ± 0.35 mL min -1 100 g -1 , respectively ( p value of 0.041). The change in the skin temperature in the RBE and placebo groups was -1.85 ± 0.35 and -3.02 ± 0.30 °C, respectively ( p value of <0.001). We also did subclass analysis with cold-feeling subjects. For the seven subjects who had cold sensation, the change in the cutaneous blood flow in the RBE and placebo groups was -0.48 ± 0.58 and -2.56 ± 0.48 mL min -1 100 g -1 , respectively ( p value of 0.008). The change in the skin temperature in the RBE and placebo groups was -1.46 ± 0.74 and -2.89 ± 0.39 °C, respectively ( p value of 0.009). Thus, RBE containing cyclo(d-Phe-l-Pro) prevents the decrease in the cutaneous blood flow and skin temperature under air conditioning.

Anxiety- and stress-related disorders can be debilitating psychiatric conditions in humans. To prevent or ameliorate these conditions, reliable animal models are needed to evaluate the effects of anxiolytic drugs. Previously, we found that a mixture of three pyrazine analogues (P-mix) that were present at high levels in wolf urine induced fear-related responses in mice, rats and deer. A change in cutaneous temperature was shown to be induced by acute stress simultaneously with changes in heart rate, arterial pressure and freezing behavior, raising the possibility that cutaneous temperature could be used as an index of stress. In the present study, using infrared thermography, we showed that exposure of mice to P-mix induced a decrease in cutaneous temperature. We then examined the dose-dependent effects of an anxiolytic drug, etizolam (0-20 mg/kg), on the temperature decrease. Pre-administration of etizolam (5 mg/kg or higher) inhibited the P-mix-induced decrease in cutaneous temperature. Exposure to P-mix induced Fos-immunoreactivity, a marker of neuronal excitation, at the mouse amygdala and hypothalamus, and etizolam (5 mg/kg) attenuated that immunoreactivity. The present results suggested that the measurement of cutaneous P-mix-induced temperature changes in mice could be used as an animal model for evaluating the effects of anxiolytic drugs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: To investigate the effects of black cohosh and estrogen on the temperature in ovariectomized rats, the core body temperature (CBT) and tail-skin temperature (TST) were simultaneously monitored and the relationship between these two temperatures was explored., Methods: Twenty-four female Sprague-Dawley rats aged 8 weeks were randomly divided into four groups: sham-operated (SHAM), ovariectomized (OVX), OVX treated with estradiol valerate (OVX + E), and OVX treated with isopropanolic black cohosh extract (OVX + ICR). Rats were sham-operated or ovariectomized and were implanted with telemetry transmitters with dual thermistor probes. Two weeks after surgery, the animals were treated with drugs for 4 weeks. During the last week of the treatments, the dynamic temperature profiles of the CBT and TST were collected., Results: The average CBT and TST, TST fluctuation frequency, and the average amplitude fluctuation were significantly higher in OVX than in SHAM rats. In addition, dramatic fluctuations of TST in OVX rats occurred at the time points of the day when the CBTs were lower in OVX rats than in SHAM rats. Treatment of OVX rats with estradiol valerate or isopropanolic black cohosh extract markedly decreased the average CBT and TST, TST fluctuation frequency, and the average amplitude fluctuation. Moreover, CBT was found to be significantly higher, while TST was lower in OVX + E than in OVX + ICR rats., Conclusions: Both black cohosh and estradiol treatments ameliorated the abnormal thermoregulation in OVX rats. In particular, black cohosh reduced CBT better than estradiol and estradiol reduced TST better than black cohosh.

Aim: To investigate the effect of glucocorticoids on brown adipose tissue (BAT) function in humans., Materials and Methods: In a randomized double-blind cross-over design, 13 healthy adults underwent 1 week of oral prednisolone treatment (15 mg/d) and placebo with an intervening 2-week wash-out period. BAT function was assessed in response to cooling (19°C) and to a standardized meal, by measuring fluoro-deoxyglucose (FDG) uptake using positron emission tomography-computed tomography and skin temperatures overlying the supraclavicular (SCL) BAT depots using infrared thermography. Postprandial energy and substrate metabolism was assessed by indirect calorimetry., Results: During cooling, prednisolone significantly reduced BAT FDG uptake (standardized uptake value, SUV max, 6.1 ± 2.2 vs 3.7 ± 1.2; P < .05) and SCL temperature (-0.45 ± 0.1 vs -1.0 ± 0.1°C; P < .01) compared to placebo. Postprandially, prednisolone significantly blunted the rise in SCL temperature (+0.2 ± 0.1 vs -0.3 ± 0.1°C; P < .05), enhanced energy production (+221 ± 17 vs +283 ± 27 kcal/d; P < .01) and lipid synthesis (+16.3 ± 3.2 vs +23.6 ± 4.9 mg/min; P < .05). The prednisolone-induced reduction in SCL temperature significantly correlated with the reduction in FDG uptake (r = 0.65, P < .05), while the increase in energy production significantly correlated with the increase in lipogenesis (r = 0.6, P < .05)., Conclusion: Prolonged exposure to glucocorticoid suppresses the function of human BAT. The enhancement of energy production and lipogenesis in the face of reduced dissipation of energy as heat suggests that glucocorticoids channel energy towards fat storage after nutrient intake. This is a novel mechanism of glucocorticoid-induced obesity., (© 2017 John Wiley & Sons Ltd.)

Roasted barley extract (RBE, "Mugicha") is a traditional Japanese beverage reported to improve blood viscosity and affect food functionality. RBE is suggested to contain 2,5-diketopiperazines, which are the functional component with neuroprotective and immunostimulatory effects that are produced in food through roasting. In this study, we investigated the effects of RBE on blood circulation, both clinically and in rats. At first, we confirmed five 2,5-diketopiperazine derivatives in RBE by LC-MS analysis. Secondarily, we revealed that RBE affects blood flow in the rat tail and compared the efficacy on rat tail blood flow among five 2,5-diketopiperazines in RBE. Especially, cyclo(d-Phe-l-Pro) was the most effective in increasing blood flow in the rat tail. We also researched the mechanism of cyclo(d-Phe-l-Pro) with rat aorta study. As a result, we confirmed that cyclo(d-Phe-l-Pro) has an effect on vasodilatation through the release of nitric oxide in the vascular endothelium. Finally, we also confirmed that RBE affects cutaneous blood flow and increases skin temperature in humans.

This study verified the occurrence of dental sensitivity in patients submitted to a 35% hydrogen peroxide based product (Whiteness HP Maxx 35% - FGM), skin cold sensation threshold (SCST) and its influence on dental sensitivity. Sixty volunteers were divided into 4 groups (n = 15), according to SCST (low: GI and GIII, and high: GII and IV) and bleaching treatment (hydrogen peroxide: GI and GII, and placebo: GIII and GIV). SCST was determined in the inner forearm for 6 different times using a neurosensory analyzer, the TSA II (Medoc Advanced Medical Systems, Ramat Yishai, Northern District, Israel). Dental sensitivity measurements were performed 10 different times using a thermal stimulus and an intraoral device attached to TSA II, positioned in the buccal surface of the upper right central incisor. Spontaneous dental sensitivity was also determined using the Visual Analogue Scale (VAS). Data were submitted to Student's t-test and Pearson's Correlation Test (α=0.05). SCST remained the same during bleaching treatment. Distinct responses of dental sensitivity were found in patients with low and high SCST during the first and third bleaching session (p≤0.05). The teeth submitted to the bleaching treatment became more sensitive to cold than those treated with placebo. Moreover, data obtained with TSA and VAS presented moderate correlation. Bleaching treatment increased dental sensitivity and skin cold sensation threshold might represent a determining factor in this occurrence, since low and high SCST patients had different responses to the thermal stimulus in the teeth.

The risk of surgical site infections (SSIs) after total knee arthroplasty (TKA) can never be eliminated. Antimicrobial sutures containing triclosan have been used to decrease SSIs, but whether triclosan-coated sutures are effective with TKA is unclear. Between 2011 and 2012, 102 patients randomly assigned to a triclosan or a control group were prospectively assessed. The incidence of SSI within 3 months of surgery, length of hospital stay, pain scale, functional scores, wound condition, and serum inflammatory markers during hospitalization and within 3 months postoperatively were compared. At the final follow-up, there were 2 patients with superficial infections (3.9%) in the control group but none in the triclosan group. Lower serum IL-6 was detected in the triclosan group at 4 weeks and 3 months. The local skin temperature of the knees-recorded at 3 months using infrared thermography-was lower in the triclosan group than in the control group. More precise analytical measurements are needed to investigate local and systemic complications, especially in the early subclinical stage. This prospective, randomized, open-label clinical trial is in the public registry: ClinicalTrials.gov (NCT02533492).

The bed nucleus of the stria terminalis (BNST) constitutes an important component of neural substrates of physiological and behavioral responses to aversive stimuli, and it has been implicated on cardiovascular responses evoked by stress. Nevertheless, the local neurochemical mechanisms involved in BNST control of cardiovascular responses during aversive threats are still poorly understood. Thus, the aim of the present study was to assess the involvement of activation in the BNST of the neuronal isoform of the enzyme nitric oxide synthase (nNOS), as well as of signaling mechanisms related to nitric oxide effects such as soluble guanylate cyclase (sGC) and protein kinase G (PKG) on cardiovascular responses induced by an acute session of restraint stress in male rats. We observed that bilateral microinjection of either the nonselective NOS inhibitor Nω-Nitro-L-arginine methyl ester (L-NAME), the selective nNOS inhibitor Nω-Propyl-L-arginine (NPLA) or the sGC inhibitor 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) into the BNST enhanced the tachycardic response and decreased the drop in tail cutaneous temperature evoked by acute restraint stress, but without affecting the increase on blood pressure. Bilateral BNST treatment with the selective PKG inhibitor KT5823 also facilitated the heart rate increase and decreased the drop in cutaneous temperature, in addition to enhancing the blood pressure increase. Taken together, these results provide evidence that NO released from nNOS and activation of sGC and PKG within the BNST play an inhibitory influence on tachycardia to stress, whereas this signaling mechanism mediates the sympathetic-mediated cutaneous vasoconstriction., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Objective: To evaluate the anti-inflammatory effectiveness of celecoxib and its effect on the rehabilitation of joint function after total knee arthroplasty., Methods: 72 patients presented between 2016 and 2017 and were divided into two groups. The experimental group was given 200 mg celecoxib twice daily with tramadol hydrochloride 50 mg twice daily (as required); the control group was given tramadol hydrochloride 50 mg twice daily for 6 weeks from the first day after total knee arthroplasty. Skin temperature around the knee was measured 1 day before surgery, on postoperative days 1 and 3, and at weeks 1, 2, and 6. Inflammatory markers (white blood cell count, C-reactive protein, erythrocyte sedimentation rate, and interleukin-6) were measured preoperatively, on postoperative day 3, and at weeks 1 and 6. Knee Society Score was recorded preoperatively and at postoperative weeks 1, 2, and 6., Results: Except for preoperative skin temperature, the recorded skin temperatures of the experimental group were significantly different compared to those of the control group (p = 0.001, 0.024, 0.030, 0.041, 0.047, respectively). Levels of C-reactive protein were significantly different at the 1st and the 6th week after surgery, differing by 19.3 ± 4.64 mg/L (p < 0.001) and 2.6 ± 0.92 mg/L (p = 0.006). Levels of interleukin-6 showed a significant difference of 6.61 ± 2.36 pg/mL (p = 0.007) at the 1st week after surgery. Until the 6th week after surgery, the erythrocyte sedimentation rate in the experimental group and the control group differed by 17 ± 4.6 mm/h (p = 0.001)., Conclusions: Celecoxib has a significant inhibitory effect on postoperative aseptic inflammation., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

The adaptogen Rhodiola rosea (RR) may mitigate stress responses and have beneficial effects on endurance capacity (EC) and mental performance. Heat acclimation (HA) improves EC in the heat, but the potential impact of RR on the HA process is unknown. Therefore, our intent was to determine if RR has a positive impact on HA. Twenty male subjects (age, 22.5 ± 3.0 years) completed 2 EC tests involving walking (6 km·h -1 ) until volitional exhaustion in a climate chamber (air temperature, 42 °C; relative humidity, 18%) before (H1) and after (H2) an 8-day HA period. One group (SHR; n = 10) ingested standardised extract SHR-5 of RR (a single daily dose of 432 mg), while a second group (PLC; n = 10) administered a placebo prior to each HA session. Efficacy of HA was evaluated on the basis of changes that occurred from H1 to H2 in the time to exhaustion (TTE), exercise heart rate (HR), core and skin temperatures (T c , T sk ), stress hormones, ratings of perceived exertion (RPE) and fatigue (RPF), and thermal sensation (TS). HA significantly increased TTE (133.1 ± 44.1 min in H1; 233.4 ± 59.8 min in H2; p < 0.0001) and decreased (p < 0.0001) HR, T c , T sk , stress hormones as well as RPE, RPF, and TS. However, the magnitude of all these changes was similar (p > 0.05) in the SHR and PLC groups. These results suggest that the use of RR during HA has no beneficial performance, physiological, or perceptual effects in young healthy males.