神经肽CRH作为急性高原低氧应激损伤的生物标志分子研究
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摘要
我国西部的青藏高原,最突出的自然环境特征就是低氧,随着西部大开发战略的实施,日益增多的援建移民、旅游、探险、军事换防等,使得每年有数百万人进入青藏高原,面临高原低氧损伤的危险。急性高原反应和急性高原病(AMS)是人体快速暴露于高原低氧环境后产生的各种生理反应和低氧性疾病,常见的症状有头痛,恶心呕吐,全身乏力,头晕和睡眠障碍等。急性高原病是人类到达高原的主要挑战,AMS的发病率随着所到达的高度升高而显著升高,在1850米到2750米时有25%的发病率,在3000米时有42%的发病率,而在6000米的时候发病率高达75%。如果AMS得不到及时正确的治疗,可能会发展成为严重的危及生命的高原肺水肿(HAPE)和脑水肿(HACE)。AMS极大地限制了人们在高原的活动。研究AMS的发病机制,预警预测AMS发生的风险具有重大的现实意义,然而目前AMS的发病机制尚未完全清楚,人们试图研究探索快速有效地预测AMS,提出低氧通气反应,心率变异率,最大运动后的氧饱和度的变化等指标来预测AMS的发生,但都不能有效地预测其发生。我们实验室以前的研究发现高原低氧促进神经肽促肾上腺皮质激素释放激素(CRH)在下丘脑的分泌及其1型受体(CRHR1)的过度表达,在脑-内分泌-免疫网络低氧损伤调节过程中起核心主导的作用,所以我们提出CRH可能成为预测急性高原低氧应激损伤的生物标志分子,证明血浆和唾液CRH水平过度增高与发生AMS相关,通过检测唾液CRH水平变化程度,可以预测人们到达高原后可能发生AMS的潜在风险性。
本研究分为实验动物研究和人类研究两部分。在动物实验中,成年大鼠被置于低压氧舱中分别模拟2,5,和7km不同海拔高度高原低氧8小时以及海拔7km高原低氧2,8和24小时不同时间,研究大鼠下丘脑和外周血液CRH和皮质酮水平的相应变化,分析下丘脑和血浆CRH线性相关性。还研究了大鼠脑CRHR1和CRHR2受体基因的表达变化模式,探讨了CRHR1在低氧脑细胞损伤中的作用。在以人类为对象的研究中,令志愿者进行自行车功量仪运动和登高跑运动两种平原耗竭运动模拟低氧,检测运动前后血浆和唾液中CRH和皮质醇水平,测定心率,氧饱和度,以及血清和唾液中的乳酸脱氢酶(LDH)水平；此外,志愿者进入3600和5500海拔的青藏高原现场,结合Lake Louise Score AMS标准,进行AMS问卷调查,根据临床AMS症状和发病率以及血浆、唾液CRH水平的相关变化,计算分析了CRH和发生AMS风险间的相关性。提出了应用检测唾液CRH水平预测发生高原AMS风险的方法。
研究结果
1低氧强度和时间依赖性地增加大鼠脑PVN区CRH的分泌
低氧显著性降低大鼠脑PVN和ME处CRH蛋白水平,升高大鼠垂体CRH水平,这个变化呈现低氧强度和时间变化依赖的关系。低氧显著性增加大鼠脑PVN区CRH mRNA的表达,随着低氧强度的增加,CRH mRNA的表达也增加。
2低氧强度和时间依赖性地升高大鼠血浆CRH和皮质酮水平及相关性分析
低氧诱导大鼠血浆CRH水平升高,低氧后CRH水平的变化呈现低氧强度和时间依赖的关系。低氧诱导大鼠血浆皮质酮水平升高,皮质酮水平的变化同样呈现低氧强度和时间依赖的变化。
3低氧升高大鼠血浆CRH与中枢CRH分泌增加的相关性分析
低氧升高大鼠血浆CRH水平和低氧刺激PVN区CRH释放相关,下丘脑CRH水平与血浆CRH水平呈负相关。血浆CRH水平与皮质酮水平呈正相关。
4低氧刺激大鼠不同脑区和垂体CRHR1和CRHR2受体的不同表达模式
低氧后大鼠皮层、海马、杏仁中央核、PVN和蓝斑区CRHR1mRNA表达升高,在7km高原低氧8小时达到峰值,低氧24小时后开始回落。大鼠垂体CRHR1mRNA表达模式相同。大鼠皮层、海马、杏仁中央核、蓝斑区和垂体CRHR2mRNA表达降低,而下丘脑PVN区CRHR2mRNA的表达与CRHR1mRNA的表达模式相似的升高。
CRHR1mRNA和CRHR2mRNA在不同脑区的相对表达水平不同,其中在皮层,杏仁核,蓝斑CRHR1mRNA的表达水平是CRHR2mRNA的3-5倍,而海马,PVN和垂体中CRHR1和CRHR2mRNA的表达水平相近。低氧后,CRHR1和CRHR2mRNA表达水平差异显著,7km海拔低氧8小时后最为明显,其中在皮层,杏仁中央核和蓝斑区两型受体表达水平相差8倍,而海马,PVN区和垂体两型受体相差2倍。
5低氧过度激活大鼠脑皮层CRHRl与皮层细胞凋亡相关
大鼠皮层促凋亡基因(bim, bnip3, bax) mRNA表达水平在5km高原低氧8小时和7km高原低氧2和8小时后显著升高,而抗凋亡基因bcl-2mRNA在2km高原低氧8小时后升高,5和7km高原低氧8小时后下降。凋亡蛋白caspase-3的活性在7km高原低氧8和24小时后都有显著升高。HE和TUNEL染色发现,7km高原低氧8小时后,大鼠皮层细胞肿胀,间隙加大,凋亡细胞显著增加。而预先使用CRHR1拮抗剂CP154,526处理后,能显著降低低氧诱导的凋亡基因bim和bax的表达升高,下调凋亡蛋白caspase-3的活性,降低凋亡细胞数目。
6急性耗竭运动诱导人体低氧生理反应
志愿者登高跑运动后,心率由86±10/分钟升高到177±16/分钟,唾液LDH活性由199.7±112.7U/L升高到468.7±279.9U/L,而血清LDH活性没有显著变化,同时动脉血氧饱和度从98%±1%降低到93%±3%。自行车功量仪运动后心率从82±11/min升高到166±18/min,唾液LDH活性从156.7±92.5U/L升高到294±187.6U/L,而血清LDH活性没有明显变化,动脉血氧饱和度同样从98%±1%降低到94%±1%。
7急性耗竭运动和高原低氧诱导人体唾液和血液CRH水平升高
检测健康人体唾液CRH和皮质醇水平存在明显的昼夜节律,唾液CRH水平在清晨7：00最高,中午11：00下降,在下午15：00和19：00保持一个稳定的水平,夜间23：00时降低到最低水平,唾液皮质醇的变化趋势和唾液CRH相同。
耗竭运动低氧诱导唾液和血浆CRH和皮质醇水平显著升高,在登高跑运动后,唾液和血浆CRH水平分别从25.25±6.41pg/ml和39.82±7.87pg/ml升高到35.78±8.51pg/ml和54.37±9.31pg/ml,唾液和血浆皮质醇水平分别从1.62±0.54ng/ml和6.5±1.51ng/ml升高到3.52±1.22ng/ml和10.8±2.58ng/ml.自行车功量仪运动后,唾液CRH和皮质醇水平分别从5.68±6.15pg/ml和1.96±0.53ng/ml升高到40.21±10.1pg/ml和4.11±1.12ng/ml。
志愿者在快速到达青藏高原3.6和5.5km后,唾液和血浆CRH分别从17.97±4.46pg/ml和43.71±9.1pg/ml升高到53.04±16.06pg/ml和106.7±31.7pg/ml,唾液和血浆皮质醇分别从1.87±0.51ng/ml和11.43±2.76ng/ml升高到3.84±0.99ng/ml和1.72±5.81ng/ml。
急性耗竭运动和高原低氧暴露前后,唾液和血浆CRH都有很好的线性相关性。在耗竭运动前后,唾液和血浆CRH水平的相关系数分别是0.9336和0.9086。而高原现场低氧暴露前后,唾液和血浆CRH水平的相关系数分别是0.8410和0.8142。此外,在急性耗竭运动后CRH水平和皮质醇水平也有很好的相关性,其相关系数是0.9228和0.9437,而志愿者暴露于高原环境低氧后,CRH水平和皮质醇水平无明显相关性。
8高原低氧AMS和血液、唾液高CRH水平相关
人类志愿者分别从平原快速到达海拔3.6km和5.5km高度的青藏高原,到达高原后,使用AMS评分量表(Lake Louise Score)测定了个体AMS症状(AMS症状：包括头痛,恶心呕吐,全身无力,头昏和失眠)。在3.6km组,AMS的发病率是28.6%(63人中有18人发病),其中50.7%的志愿者出现头疼,6.2%出现恶心呕吐,41.2%出现全身无力,49.2%出现头昏,17.4%的志愿者出现失眠。而在5.5km组,AMS发病率是50%(48人中有24人发病),其中头痛,恶心呕吐,全身无力,头昏和失眠的发生率分别是50%,37.5%,41.7%,39.6%和21.7%。根据AMS评分量表将志愿者分为AMS发病组和AMS未发病组,其中AMS发病组的血浆和唾液CRH水平比AMS未发病组高40%,而血浆皮质醇没有显著差异。
9唾液CRH基础水平可预测进入高原后发生AMS的风险性
无论3.6km组中唾液和血浆基础CRH,还是5.5km组的血浆基础CRH都可以预测AMS的发生,ROC曲线下的面积(Area under curve,AUC)可以用来衡量预测的准确性,3种样本的AUC分别是0.7292,0.6和0.7236。从ROC曲线上我们也得出了最佳预测诊断阈值。基础血浆CRH水平大于或等于50.33pg/ml的志愿者中有83%(12人当中有10人)在到达3.6km海拔高度的高原环境后发生AMS；而唾液中CRH水平的阈值为21pg/ml,血浆和唾液中CRH水平存在线性相关,血浆CRH在50.33pg/ml时对应的唾液CRH值为20.8pg/ml.在另一组到达5.5km海拔高度的高原环境的志愿者中,基础血浆CRH水平在大于或等于49.16pg/ml有81%(16人当中有13人)发生AMS。
结论
高原低氧高度和时间依赖性地刺激大鼠下丘脑PVN区CRH合成和分泌,上调不同脑区和垂体CRHR1mRNA的表达,抑制CRHR2mRNA的表达,激活皮层细胞促凋亡基因bnip3, bim, bax的表达和caspase-3活性的增加,当轻度低氧时,促进抗凋亡基因bcl-2的表达,严重低氧则抑制bcl-2的表达,诱导皮层细胞凋亡增加,CRHR1拮抗剂可逆转低氧诱导的细胞凋亡,提示低氧脑损伤与CRHR1的过度激活有关。低氧强度和时间依赖性的增加大鼠血浆CRH的水平,而与脑CRH水平呈负相关,与大鼠血浆皮质酮水平呈正相关,提示血浆CRH来源于下丘脑中枢的分泌,CRH以及CRHR1是低氧应激下脑损伤HPA的标志分子。
人体耗竭运动诱导机体低氧,升高血浆和唾液CRH及皮质醇水平,唾液CRH水平和血浆CRH水平有很好的线性相关,由于动物实验证明唾液腺不含CRH神经元,提示唾液CRH来源于血液循环。此外,高原低氧暴露后血浆和唾液CRH同时升高,发生AMS的志愿者中具有高的CRH水平,提示高水平的CRH可能与AMS发生相关。唾液和血浆CRH可作为中枢CRH/CRHR1激活的标志分子和AMS的发生密切相关,提示特异的CRHR1抑制剂可能成为治疗或预防AMS的一种选择。此外,由于CRH和CRHR1过度激活与脑损伤有关,可被视为监视AMS的一种生物标志分子,提示通过检测唾液中CRH的水平,可以预测个体应对低氧应激损伤的能力,并预测AMS的风险。
Hypoxia is the most significant geographical feature of the Qinghai-Tibet Plateau in west China. Every year, millions of people enter the Qinghai-Tibet Plateau with the demand of travel, adventure, plateau search and rescue, and national defense. Acute mountain sickness (AMS) is a common feature of acute altitude illness while people rapid ascent to altitudes above3000m without sufficient time to acclimatize, and common symptoms includes headache, nausea, vomiting, fatigue, dizziness, and sleep disorders. Acute mountain sickness is the major challenge for people to reach the plateau, and the incidence of AMS correlates with the arrival altituede. At1850m to2750m, the incidence of AMS is25%,42%at3000m, and up to75%at6000m. If AMS is treated improper, life threaten high altitude cerebral edema (HACE) could occur. AMS can sharply limit recreation and work at high altitude, and have brought great difficulties to the staff in Yushu earthquake rescue operations. Understand AMS pathogenesis to early warn and forecast the risk of AMS occurred is very important, however, the pathogenesis of AMS is currently not yet entirely clear, and a lot of research have done on AMS prediction, hypoxic ventilatory response, heart rate variability rate, the change of the oxygen saturation after maximum workload exercise were proposed to predict the occurrence of AMS, but the results are not particularly desirable. Base our previous work on modulation mechanism of brain-endocrine-immune network under hypoxia, here we report the corticotrophin releasing factor (CRH) and its type1receptors (CRHR1), as biomarkers, are associated with AMS and could be used for prediction of AMS through monitoring salivary CRH levels. In animal studies adult rats were put in a hypobaric chamber to simulate high-altitude hypoxia at2,5, and7km for8hours and7km for2,8and24hours. The brain and plasma samples from rats were collected for evaluation of CRH, CRHR1mRNA, CRHR2mRNA and corticosterone levels respectively. And the plasma and saliva were collected for evaluation of CRH and cortisol level. The CRH and CRHR1mRNA, and cortisol/corticosterone were assayed with specific kits and real-time qPCR respectively. Volunteers are arranged to do exercise by bicycle and climbing up stairways in the Zhejiang University campus as and are ascent from lowland to high-altitude (3.6and5.5km), CRH levels were tested in plasma and saliva and AMS questionnaires were tested in all of these volunteers before and after these exercise. The LDH and O2saturation in both serum and saliva were evaluated. The linear correlation coefficients for levels of CRH among the brain, plasma, and saliva were analyzed. Double-blunted analysis was applied.
Results
1Hypoxia stimulated CRH release and CRH mRNA expression via intensity and time dependent manners
We found CRH levels in PVN and ME significantly decreased while those in pituitary significantly increased in a dose and time dependent manner. CRH mRNA expression in PVN was significantly increased with ascent at altitude of2,5and7km and peaked at8hours, then returned to control level for24hours at altitude of7km hypoxia.
2Hypoxia elicited increase of CRH and corticosterone levels in rat plasma via intensity and time dependent manners
Hypobaric hypoxia enhances CRH and corticosterone levels in plasma in a dose dependent manner. Plasma CRH significantly increased with ascent to altitude of5and7km for8hours, while plasma corticosterone increased at altitude of2,5and7km. Extreme altitude (7km) increased plasma CRH and corticosterone levels reached the highest levels at24hours.
3Elavation of CRH under hypoxia correlated with increase release of PVN CRH The increase of plasma CRH was positively correlated with increased plasma corticosterone, but the plasma CRH level negatively correlated with PVN CRH contents.
4Hypobaric hypoxia activates CRHR1mRNA expression in various brain regions and pituitary
CRHR1mRNA expressions were sharply and dose dependently enhanced with ascent to altitude of5and7km in cortex, hippocampus, CeA, PVN, and LC as well as in pituitary, in the meantime, CRHR2mRNA expressions were decreased in cortex, CeA, and pituitary, while unchanged in hippocampus and LC, but increased in PVN. All increased or decreased expressions were removed24hours later except for in pituitary.
There were different expression amount of CRHR1mRNA and CRHR2mRNA in brain regions. In cortex, CeA and LC, the expression amounts of CRHR1mRNA were about four times larger than CRHR2mRNA, but in hippocampus, PVN and pituitary, the expression amounts of CRHR1mRNA were close to CRHR2mRNA. After7km hypoxia for8hours, the expression amounts of CRHR1mRNA in cortex, CeA and LC were about eight folds higher than CRHR2mRNA, and the ratio in hippocampus, PVN and pituitary was about two.
5Over-activated CRHR1was involved in hypoxia induced rat cortex cell apoptosis
The pro-apoptosis genes bnip3, bax and bim significantly increased in cerebral cortex at altitude of7km for8hours but not at altitude of2or5km. Moreover, anti-apoptosis gene bcl-2was significant increased only at2km for8hours.The severe hypoxia (7km) caused peak expression of pro-apoptotic genes bnip3, bim, and bax mRNA at8hours following turn down, while bcl-2mRNA was kept unchanged at all time points. Moreover, cell swelling in cerebral cortex were presented by HE staining, and increased numbers of apoptotic cells in cortex were also presented by TUNEL staining.
Hypoxia up-regulated bax and bim mRNA expression at altitude of7km for8and24hours were reversed by the CP-154,526treatment, while hypoxia-induced bnip3mRNA expression did not. The bcl-2mRNA expression was not up-regulated by altitude of7km and also not affected by CP-154,526. As result, caspase-3activity in cerebral cortex was increased at altitude of7km for8and24hours and the increase was abolished by pretreatment of CP-154,526.
6Acute exercises led to temportary hypoxia in humans
We found that in climbing stairs group, HR was significantly increased from86±10/min to177±16/min, salivary LDH activity was significantly increased from199.7±112.7U/L to468.7±279.9U/L, but serum LDH activity was unchanged. The saturated O2was significantly decreased from98%±1%to93%±3%. In cycling group, HR and salivary LDH activity were increased from82±11/min and156.7±92.5U/L to166±18/min and294±187.6U/L, however serum LDH activity was unchanged, while the saturated O2was decreased from98%±1%to94%±1%.
7Intensive exercise and high altitude hypoxia both elevated CRH and cortisol levels in plasma and saliva
We first determined the circadian rhythm of CRH and cortisol release through measuring salivary CRH and cortisol in volunteers at regular life status. Saliva samples were collected once per～4hours intervals setting at7:00,11:00,15:00,19:00, and23:00hours. The CRH circadian rhythm was shown that the peak reached at7:00am and the nadir occurred at23:00pm as well as a similar level of CRH kept at11:00,15:00, and19:00pm.
The CRH and cortisol levels in saliva and plasma both significantly elevated after exercises. In climbing stairs group, CRH in saliva and plasma increased from25.25±6.41pg/ml and39.82±7.87pg/ml to35.78±8.51pg/ml and54.37±9.31pg/ml, respectively; cortisol in saliva and plasma increased from from1.62±0.54ng/ml and6.5±1.51ng/ml to3.52±1.22ng/ml and10.8±2.58pg/ml, respectively. Similarly in cycling exercise, saliva CRH and cortisol increased from25.68±6.15pg/ml and1.96±0.53ng/ml to40.21±10.1pg/ml and4.11±1.12pg/ml, respectively.
After the volunteers fast ascended to Lhasa at altitude of3.6km, CRH in plasma and salivary were significantly increased from43.71±9.1pg/ml and17·97±4·46pg/ml to106.7±31.7pg/ml and53.04±16.06pg/ml, respectively. Cortisol level also increased from11.43±2.76ng/ml to21.72±5.81ng/ml in plasma and from1.87±0.51ng/ml to3.84±0.99ng/ml in saliva, respectively.
8High CRH level is associated with occurrence of AMS at high-altitude
Two groups of volunteers were ascended to altitude of3.6km in Lhasa or5.5km respectively. In3.6km group, AMS developed in28.6%(18in63) volunteers, while50.7%(24in48) in5.5km group. We divide volunteers into AMS goup and No AMS group. AMS group has a high level of CRH in plasma and saliva, and also much higher amplify rate of CRH increase compared with No AMS group at high-altitude of3.6km, while cortisol level change was not statistically significant. The CRH level in plasma and saliva was also positively correlated with AMS score at altitude of3.6km, respectively; however, the basal CRH level in plasma and saliva was not correlated. Furthermore, there was no correlation between AMS score and cortisol level was shown either at sea level or at altitude of3.6km.
9Basal CRH could be used to predict risk of AMS
We are able to predict individual risk of AMS when arrive at high altitude from their basal CRH level. In volunteers who had above50.33pg/ml plasma CRH at sea level,83%(10out of12) of them developed AMS after ascent to3.6km high altitude, and when monitoring in saliva, the threshold value was21pg/ml. In another group volunteers who ascended to5.5km high altitude,81%(13out of16) of them who had above49-16pg/ml basal plasma CRH level developed AMS at5.5km.
Conclusions
In rat study, hypobaric altitude-hypoxia produced a lowered O2level-dependent increase of CRH release and CRH mRNA expression in the PVN and upregulation of CRHR1mRNA expression in various brain region and pituitary as well as activation of apoptotic genes mRNA of binip3, bim, bax, and caspase-3activity but biphase of bcl-2in cortex. All these were associated with activation of CRHRl. This hypoxia enhanced plasma CRH levels were negatively correlated with brain CRH, but positively with plasma corticosterone in rats. In human, the exercises mimic hypoxia increased CRH and corticosterone levels in both plasma and saliva. This increased plasma CRH correlated with increased salivary CRH. In addition, volunteers with high plasma CRH at lowland developed the AMS by rapid ascent to Tibet high-altitude. The CRH level in both plasma and saliva reflect an activation of CRH neurons in the brain during high-altitude hypoxia that correlates with occurrence of AMS and acute brain injury through the CRHRl pathway, a specific CRHR1antagonist, therefore, may be a choice for therapy or prevention of AMS. Additionally, since over-activated CRH is associated with brain injury, it could be treated as a biomarker for AMS to monitor and predict an individual susceptibility to hypoxia and for AMS by salivary CRH level test.
本研究分为实验动物研究和人类研究两部分。在动物实验中,成年大鼠被置于低压氧舱中分别模拟2,5,和7km不同海拔高度高原低氧8小时以及海拔7km高原低氧2,8和24小时不同时间,研究大鼠下丘脑和外周血液CRH和皮质酮水平的相应变化,分析下丘脑和血浆CRH线性相关性。还研究了大鼠脑CRHR1和CRHR2受体基因的表达变化模式,探讨了CRHR1在低氧脑细胞损伤中的作用。在以人类为对象的研究中,令志愿者进行自行车功量仪运动和登高跑运动两种平原耗竭运动模拟低氧,检测运动前后血浆和唾液中CRH和皮质醇水平,测定心率,氧饱和度,以及血清和唾液中的乳酸脱氢酶(LDH)水平；此外,志愿者进入3600和5500海拔的青藏高原现场,结合Lake Louise Score AMS标准,进行AMS问卷调查,根据临床AMS症状和发病率以及血浆、唾液CRH水平的相关变化,计算分析了CRH和发生AMS风险间的相关性。提出了应用检测唾液CRH水平预测发生高原AMS风险的方法。
研究结果
1低氧强度和时间依赖性地增加大鼠脑PVN区CRH的分泌
低氧显著性降低大鼠脑PVN和ME处CRH蛋白水平,升高大鼠垂体CRH水平,这个变化呈现低氧强度和时间变化依赖的关系。低氧显著性增加大鼠脑PVN区CRH mRNA的表达,随着低氧强度的增加,CRH mRNA的表达也增加。
2低氧强度和时间依赖性地升高大鼠血浆CRH和皮质酮水平及相关性分析
低氧诱导大鼠血浆CRH水平升高,低氧后CRH水平的变化呈现低氧强度和时间依赖的关系。低氧诱导大鼠血浆皮质酮水平升高,皮质酮水平的变化同样呈现低氧强度和时间依赖的变化。
3低氧升高大鼠血浆CRH与中枢CRH分泌增加的相关性分析
低氧升高大鼠血浆CRH水平和低氧刺激PVN区CRH释放相关,下丘脑CRH水平与血浆CRH水平呈负相关。血浆CRH水平与皮质酮水平呈正相关。
4低氧刺激大鼠不同脑区和垂体CRHR1和CRHR2受体的不同表达模式
低氧后大鼠皮层、海马、杏仁中央核、PVN和蓝斑区CRHR1mRNA表达升高,在7km高原低氧8小时达到峰值,低氧24小时后开始回落。大鼠垂体CRHR1mRNA表达模式相同。大鼠皮层、海马、杏仁中央核、蓝斑区和垂体CRHR2mRNA表达降低,而下丘脑PVN区CRHR2mRNA的表达与CRHR1mRNA的表达模式相似的升高。
CRHR1mRNA和CRHR2mRNA在不同脑区的相对表达水平不同,其中在皮层,杏仁核,蓝斑CRHR1mRNA的表达水平是CRHR2mRNA的3-5倍,而海马,PVN和垂体中CRHR1和CRHR2mRNA的表达水平相近。低氧后,CRHR1和CRHR2mRNA表达水平差异显著,7km海拔低氧8小时后最为明显,其中在皮层,杏仁中央核和蓝斑区两型受体表达水平相差8倍,而海马,PVN区和垂体两型受体相差2倍。
5低氧过度激活大鼠脑皮层CRHRl与皮层细胞凋亡相关
大鼠皮层促凋亡基因(bim, bnip3, bax) mRNA表达水平在5km高原低氧8小时和7km高原低氧2和8小时后显著升高,而抗凋亡基因bcl-2mRNA在2km高原低氧8小时后升高,5和7km高原低氧8小时后下降。凋亡蛋白caspase-3的活性在7km高原低氧8和24小时后都有显著升高。HE和TUNEL染色发现,7km高原低氧8小时后,大鼠皮层细胞肿胀,间隙加大,凋亡细胞显著增加。而预先使用CRHR1拮抗剂CP154,526处理后,能显著降低低氧诱导的凋亡基因bim和bax的表达升高,下调凋亡蛋白caspase-3的活性,降低凋亡细胞数目。
6急性耗竭运动诱导人体低氧生理反应
志愿者登高跑运动后,心率由86±10/分钟升高到177±16/分钟,唾液LDH活性由199.7±112.7U/L升高到468.7±279.9U/L,而血清LDH活性没有显著变化,同时动脉血氧饱和度从98%±1%降低到93%±3%。自行车功量仪运动后心率从82±11/min升高到166±18/min,唾液LDH活性从156.7±92.5U/L升高到294±187.6U/L,而血清LDH活性没有明显变化,动脉血氧饱和度同样从98%±1%降低到94%±1%。
7急性耗竭运动和高原低氧诱导人体唾液和血液CRH水平升高
检测健康人体唾液CRH和皮质醇水平存在明显的昼夜节律,唾液CRH水平在清晨7：00最高,中午11：00下降,在下午15：00和19：00保持一个稳定的水平,夜间23：00时降低到最低水平,唾液皮质醇的变化趋势和唾液CRH相同。
耗竭运动低氧诱导唾液和血浆CRH和皮质醇水平显著升高,在登高跑运动后,唾液和血浆CRH水平分别从25.25±6.41pg/ml和39.82±7.87pg/ml升高到35.78±8.51pg/ml和54.37±9.31pg/ml,唾液和血浆皮质醇水平分别从1.62±0.54ng/ml和6.5±1.51ng/ml升高到3.52±1.22ng/ml和10.8±2.58ng/ml.自行车功量仪运动后,唾液CRH和皮质醇水平分别从5.68±6.15pg/ml和1.96±0.53ng/ml升高到40.21±10.1pg/ml和4.11±1.12ng/ml。
志愿者在快速到达青藏高原3.6和5.5km后,唾液和血浆CRH分别从17.97±4.46pg/ml和43.71±9.1pg/ml升高到53.04±16.06pg/ml和106.7±31.7pg/ml,唾液和血浆皮质醇分别从1.87±0.51ng/ml和11.43±2.76ng/ml升高到3.84±0.99ng/ml和1.72±5.81ng/ml。
急性耗竭运动和高原低氧暴露前后,唾液和血浆CRH都有很好的线性相关性。在耗竭运动前后,唾液和血浆CRH水平的相关系数分别是0.9336和0.9086。而高原现场低氧暴露前后,唾液和血浆CRH水平的相关系数分别是0.8410和0.8142。此外,在急性耗竭运动后CRH水平和皮质醇水平也有很好的相关性,其相关系数是0.9228和0.9437,而志愿者暴露于高原环境低氧后,CRH水平和皮质醇水平无明显相关性。
8高原低氧AMS和血液、唾液高CRH水平相关
人类志愿者分别从平原快速到达海拔3.6km和5.5km高度的青藏高原,到达高原后,使用AMS评分量表(Lake Louise Score)测定了个体AMS症状(AMS症状：包括头痛,恶心呕吐,全身无力,头昏和失眠)。在3.6km组,AMS的发病率是28.6%(63人中有18人发病),其中50.7%的志愿者出现头疼,6.2%出现恶心呕吐,41.2%出现全身无力,49.2%出现头昏,17.4%的志愿者出现失眠。而在5.5km组,AMS发病率是50%(48人中有24人发病),其中头痛,恶心呕吐,全身无力,头昏和失眠的发生率分别是50%,37.5%,41.7%,39.6%和21.7%。根据AMS评分量表将志愿者分为AMS发病组和AMS未发病组,其中AMS发病组的血浆和唾液CRH水平比AMS未发病组高40%,而血浆皮质醇没有显著差异。
9唾液CRH基础水平可预测进入高原后发生AMS的风险性
无论3.6km组中唾液和血浆基础CRH,还是5.5km组的血浆基础CRH都可以预测AMS的发生,ROC曲线下的面积(Area under curve,AUC)可以用来衡量预测的准确性,3种样本的AUC分别是0.7292,0.6和0.7236。从ROC曲线上我们也得出了最佳预测诊断阈值。基础血浆CRH水平大于或等于50.33pg/ml的志愿者中有83%(12人当中有10人)在到达3.6km海拔高度的高原环境后发生AMS；而唾液中CRH水平的阈值为21pg/ml,血浆和唾液中CRH水平存在线性相关,血浆CRH在50.33pg/ml时对应的唾液CRH值为20.8pg/ml.在另一组到达5.5km海拔高度的高原环境的志愿者中,基础血浆CRH水平在大于或等于49.16pg/ml有81%(16人当中有13人)发生AMS。
结论
高原低氧高度和时间依赖性地刺激大鼠下丘脑PVN区CRH合成和分泌,上调不同脑区和垂体CRHR1mRNA的表达,抑制CRHR2mRNA的表达,激活皮层细胞促凋亡基因bnip3, bim, bax的表达和caspase-3活性的增加,当轻度低氧时,促进抗凋亡基因bcl-2的表达,严重低氧则抑制bcl-2的表达,诱导皮层细胞凋亡增加,CRHR1拮抗剂可逆转低氧诱导的细胞凋亡,提示低氧脑损伤与CRHR1的过度激活有关。低氧强度和时间依赖性的增加大鼠血浆CRH的水平,而与脑CRH水平呈负相关,与大鼠血浆皮质酮水平呈正相关,提示血浆CRH来源于下丘脑中枢的分泌,CRH以及CRHR1是低氧应激下脑损伤HPA的标志分子。
人体耗竭运动诱导机体低氧,升高血浆和唾液CRH及皮质醇水平,唾液CRH水平和血浆CRH水平有很好的线性相关,由于动物实验证明唾液腺不含CRH神经元,提示唾液CRH来源于血液循环。此外,高原低氧暴露后血浆和唾液CRH同时升高,发生AMS的志愿者中具有高的CRH水平,提示高水平的CRH可能与AMS发生相关。唾液和血浆CRH可作为中枢CRH/CRHR1激活的标志分子和AMS的发生密切相关,提示特异的CRHR1抑制剂可能成为治疗或预防AMS的一种选择。此外,由于CRH和CRHR1过度激活与脑损伤有关,可被视为监视AMS的一种生物标志分子,提示通过检测唾液中CRH的水平,可以预测个体应对低氧应激损伤的能力,并预测AMS的风险。
Hypoxia is the most significant geographical feature of the Qinghai-Tibet Plateau in west China. Every year, millions of people enter the Qinghai-Tibet Plateau with the demand of travel, adventure, plateau search and rescue, and national defense. Acute mountain sickness (AMS) is a common feature of acute altitude illness while people rapid ascent to altitudes above3000m without sufficient time to acclimatize, and common symptoms includes headache, nausea, vomiting, fatigue, dizziness, and sleep disorders. Acute mountain sickness is the major challenge for people to reach the plateau, and the incidence of AMS correlates with the arrival altituede. At1850m to2750m, the incidence of AMS is25%,42%at3000m, and up to75%at6000m. If AMS is treated improper, life threaten high altitude cerebral edema (HACE) could occur. AMS can sharply limit recreation and work at high altitude, and have brought great difficulties to the staff in Yushu earthquake rescue operations. Understand AMS pathogenesis to early warn and forecast the risk of AMS occurred is very important, however, the pathogenesis of AMS is currently not yet entirely clear, and a lot of research have done on AMS prediction, hypoxic ventilatory response, heart rate variability rate, the change of the oxygen saturation after maximum workload exercise were proposed to predict the occurrence of AMS, but the results are not particularly desirable. Base our previous work on modulation mechanism of brain-endocrine-immune network under hypoxia, here we report the corticotrophin releasing factor (CRH) and its type1receptors (CRHR1), as biomarkers, are associated with AMS and could be used for prediction of AMS through monitoring salivary CRH levels. In animal studies adult rats were put in a hypobaric chamber to simulate high-altitude hypoxia at2,5, and7km for8hours and7km for2,8and24hours. The brain and plasma samples from rats were collected for evaluation of CRH, CRHR1mRNA, CRHR2mRNA and corticosterone levels respectively. And the plasma and saliva were collected for evaluation of CRH and cortisol level. The CRH and CRHR1mRNA, and cortisol/corticosterone were assayed with specific kits and real-time qPCR respectively. Volunteers are arranged to do exercise by bicycle and climbing up stairways in the Zhejiang University campus as and are ascent from lowland to high-altitude (3.6and5.5km), CRH levels were tested in plasma and saliva and AMS questionnaires were tested in all of these volunteers before and after these exercise. The LDH and O2saturation in both serum and saliva were evaluated. The linear correlation coefficients for levels of CRH among the brain, plasma, and saliva were analyzed. Double-blunted analysis was applied.
Results
1Hypoxia stimulated CRH release and CRH mRNA expression via intensity and time dependent manners
We found CRH levels in PVN and ME significantly decreased while those in pituitary significantly increased in a dose and time dependent manner. CRH mRNA expression in PVN was significantly increased with ascent at altitude of2,5and7km and peaked at8hours, then returned to control level for24hours at altitude of7km hypoxia.
2Hypoxia elicited increase of CRH and corticosterone levels in rat plasma via intensity and time dependent manners
Hypobaric hypoxia enhances CRH and corticosterone levels in plasma in a dose dependent manner. Plasma CRH significantly increased with ascent to altitude of5and7km for8hours, while plasma corticosterone increased at altitude of2,5and7km. Extreme altitude (7km) increased plasma CRH and corticosterone levels reached the highest levels at24hours.
3Elavation of CRH under hypoxia correlated with increase release of PVN CRH The increase of plasma CRH was positively correlated with increased plasma corticosterone, but the plasma CRH level negatively correlated with PVN CRH contents.
4Hypobaric hypoxia activates CRHR1mRNA expression in various brain regions and pituitary
CRHR1mRNA expressions were sharply and dose dependently enhanced with ascent to altitude of5and7km in cortex, hippocampus, CeA, PVN, and LC as well as in pituitary, in the meantime, CRHR2mRNA expressions were decreased in cortex, CeA, and pituitary, while unchanged in hippocampus and LC, but increased in PVN. All increased or decreased expressions were removed24hours later except for in pituitary.
There were different expression amount of CRHR1mRNA and CRHR2mRNA in brain regions. In cortex, CeA and LC, the expression amounts of CRHR1mRNA were about four times larger than CRHR2mRNA, but in hippocampus, PVN and pituitary, the expression amounts of CRHR1mRNA were close to CRHR2mRNA. After7km hypoxia for8hours, the expression amounts of CRHR1mRNA in cortex, CeA and LC were about eight folds higher than CRHR2mRNA, and the ratio in hippocampus, PVN and pituitary was about two.
5Over-activated CRHR1was involved in hypoxia induced rat cortex cell apoptosis
The pro-apoptosis genes bnip3, bax and bim significantly increased in cerebral cortex at altitude of7km for8hours but not at altitude of2or5km. Moreover, anti-apoptosis gene bcl-2was significant increased only at2km for8hours.The severe hypoxia (7km) caused peak expression of pro-apoptotic genes bnip3, bim, and bax mRNA at8hours following turn down, while bcl-2mRNA was kept unchanged at all time points. Moreover, cell swelling in cerebral cortex were presented by HE staining, and increased numbers of apoptotic cells in cortex were also presented by TUNEL staining.
Hypoxia up-regulated bax and bim mRNA expression at altitude of7km for8and24hours were reversed by the CP-154,526treatment, while hypoxia-induced bnip3mRNA expression did not. The bcl-2mRNA expression was not up-regulated by altitude of7km and also not affected by CP-154,526. As result, caspase-3activity in cerebral cortex was increased at altitude of7km for8and24hours and the increase was abolished by pretreatment of CP-154,526.
6Acute exercises led to temportary hypoxia in humans
We found that in climbing stairs group, HR was significantly increased from86±10/min to177±16/min, salivary LDH activity was significantly increased from199.7±112.7U/L to468.7±279.9U/L, but serum LDH activity was unchanged. The saturated O2was significantly decreased from98%±1%to93%±3%. In cycling group, HR and salivary LDH activity were increased from82±11/min and156.7±92.5U/L to166±18/min and294±187.6U/L, however serum LDH activity was unchanged, while the saturated O2was decreased from98%±1%to94%±1%.
7Intensive exercise and high altitude hypoxia both elevated CRH and cortisol levels in plasma and saliva
We first determined the circadian rhythm of CRH and cortisol release through measuring salivary CRH and cortisol in volunteers at regular life status. Saliva samples were collected once per～4hours intervals setting at7:00,11:00,15:00,19:00, and23:00hours. The CRH circadian rhythm was shown that the peak reached at7:00am and the nadir occurred at23:00pm as well as a similar level of CRH kept at11:00,15:00, and19:00pm.
The CRH and cortisol levels in saliva and plasma both significantly elevated after exercises. In climbing stairs group, CRH in saliva and plasma increased from25.25±6.41pg/ml and39.82±7.87pg/ml to35.78±8.51pg/ml and54.37±9.31pg/ml, respectively; cortisol in saliva and plasma increased from from1.62±0.54ng/ml and6.5±1.51ng/ml to3.52±1.22ng/ml and10.8±2.58pg/ml, respectively. Similarly in cycling exercise, saliva CRH and cortisol increased from25.68±6.15pg/ml and1.96±0.53ng/ml to40.21±10.1pg/ml and4.11±1.12pg/ml, respectively.
After the volunteers fast ascended to Lhasa at altitude of3.6km, CRH in plasma and salivary were significantly increased from43.71±9.1pg/ml and17·97±4·46pg/ml to106.7±31.7pg/ml and53.04±16.06pg/ml, respectively. Cortisol level also increased from11.43±2.76ng/ml to21.72±5.81ng/ml in plasma and from1.87±0.51ng/ml to3.84±0.99ng/ml in saliva, respectively.
8High CRH level is associated with occurrence of AMS at high-altitude
Two groups of volunteers were ascended to altitude of3.6km in Lhasa or5.5km respectively. In3.6km group, AMS developed in28.6%(18in63) volunteers, while50.7%(24in48) in5.5km group. We divide volunteers into AMS goup and No AMS group. AMS group has a high level of CRH in plasma and saliva, and also much higher amplify rate of CRH increase compared with No AMS group at high-altitude of3.6km, while cortisol level change was not statistically significant. The CRH level in plasma and saliva was also positively correlated with AMS score at altitude of3.6km, respectively; however, the basal CRH level in plasma and saliva was not correlated. Furthermore, there was no correlation between AMS score and cortisol level was shown either at sea level or at altitude of3.6km.
9Basal CRH could be used to predict risk of AMS
We are able to predict individual risk of AMS when arrive at high altitude from their basal CRH level. In volunteers who had above50.33pg/ml plasma CRH at sea level,83%(10out of12) of them developed AMS after ascent to3.6km high altitude, and when monitoring in saliva, the threshold value was21pg/ml. In another group volunteers who ascended to5.5km high altitude,81%(13out of16) of them who had above49-16pg/ml basal plasma CRH level developed AMS at5.5km.
Conclusions
In rat study, hypobaric altitude-hypoxia produced a lowered O2level-dependent increase of CRH release and CRH mRNA expression in the PVN and upregulation of CRHR1mRNA expression in various brain region and pituitary as well as activation of apoptotic genes mRNA of binip3, bim, bax, and caspase-3activity but biphase of bcl-2in cortex. All these were associated with activation of CRHRl. This hypoxia enhanced plasma CRH levels were negatively correlated with brain CRH, but positively with plasma corticosterone in rats. In human, the exercises mimic hypoxia increased CRH and corticosterone levels in both plasma and saliva. This increased plasma CRH correlated with increased salivary CRH. In addition, volunteers with high plasma CRH at lowland developed the AMS by rapid ascent to Tibet high-altitude. The CRH level in both plasma and saliva reflect an activation of CRH neurons in the brain during high-altitude hypoxia that correlates with occurrence of AMS and acute brain injury through the CRHRl pathway, a specific CRHR1antagonist, therefore, may be a choice for therapy or prevention of AMS. Additionally, since over-activated CRH is associated with brain injury, it could be treated as a biomarker for AMS to monitor and predict an individual susceptibility to hypoxia and for AMS by salivary CRH level test.
引文
Askew, E. W. (2002). "Work at high altitude and oxidative stress:antioxidant nutrients." Toxicology 180(2):107-119.
Bailey, D. M., S. Taudorf, R. M. Berg, C. Lundby, J. McEneny, I. S. Young, K. A. Evans, P. E. James, A. Shore, D. A. Hullin, J. M. McCord, B. K. Pedersen and K. Moller (2009). "Increased cerebral output of free radicals during hypoxia:implications for acute mountain sickness?" Am J Physiol Regul Integr Comp Physiol 297(5): R1283-1292.
Bale, T. L. and W. W. Vale (2004). "CRF and CRF receptors:role in stress responsivity and other behaviors." Annu Rev Pharmacol Toxicol 44:525-557.
Beall, C. M., K. Song, R. C. Elston and M. C. Goldstein (2004). "Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m." Proc Natl Acad Sci U S A 101(39):14300-14304.
Buckley, T. M. and A. F. Schatzberg (2005). "On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep:normal HPA axis activity and circadian rhythm, exemplary sleep disorders." J Clin Endocrinol Metab 90(5): 3106-3114.
Chen, X. Q., F. P. Kong, Y. Zhao and J. Z. Du (2012). "High-altitude hypoxia induces disorder of the brain-endocrine-immune network though activation of corticotrophin-releasing factor and its type-1 receptors." Zhongguo Ying Yong Sheng Li Xue Za Zhi 28(6):481-487.
Chen, X. Q., N. Y. Xu, J. Z. Du, Y. Wang and C. Duan (2005). "Corticotropin-releasing factor receptor subtype 1 and somatostatin modulating hypoxia-caused downregulated mRNA of pituitary growth hormone and upregulated mRNA of hepatic insulin-like growth factor-I of rats." Mol Cell Endocrinol 242(1-2):50-58.
De Souza, E. B. (1995). "Corticotropin-releasing factor receptors:physiology, pharmacology, biochemistry and role in central nervous system and immune disorders." Psychoneuroendocrinology 20(8):789-819.
Erecinska, M. and I. A. Silver (2001). "Tissue oxygen tension and brain sensitivity to hypoxia." Respir Physiol 128(3):263-276.
Erzurum, S. C., S. Ghosh, A. J. Janocha, W. Xu, S. Bauer, N. S. Bryan, J. Tejero, C. Hemann, R. Hille, D. J. Stuehr, M. Feelisch and C. M. Beall (2007). "Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans." Proc Natl Acad Sci U S A 104(45):17593-17598.
Fan, J. M., X. Q. Chen, H. Jin and J. Z. Du (2009). "Gestational hypoxia alone or combined with restraint sensitizes the hypothalamic-pituitary-adrenal axis and induces anxiety-like behavior in adult male rat offspring." Neuroscience 159(4): 1363-1373.
Galard, R., R. Catalan, J. M. Castellanos and J. M. Gallart (2002). "Plasma corticotropin-releasing factor in depressed patients before and after the dexamethasone suppression test." Biol Psychiatry 51(6):463-468.
Graham, J. and D. Potyk (2005). "Age and acute mountain sickness:examining the data." J Am Geriatr Soc 53(4):735.
Hackett, P. H. and R. C. Roach (2001). "High-altitude illness." N Engl J Med 345(2): 107-114.
Hackett, P. H. and R. C. Roach (2004). "High altitude cerebral edema." High Alt Med Biol 5(2):136-146.
Honigman, B., M. K. Theis, J. Koziol-McLain, R. Roach, R. Yip, C. Houston, L. G. Moore and P. Pearce (1993). "Acute mountain sickness in a general tourist population at moderate altitudes." Ann Intern Med 118(8):587-592.
Huang, H. H., C. Y. Tseng, J. S. Fan, D. H. Yen, W. F. Kao, S. C. Chang, T. B. Kuo, C. I. Huang and C. H. Lee (2010). "Alternations of heart rate variability at lower altitude in the predication of trekkers with acute mountain sickness at high altitude." Clinical journal of sport medicine 20(1):58-63.
Imray, C., A. Wright, A. Subudhi and R. Roach (2010). "Acute mountain sickness: pathophysiology, prevention, and treatment." Prog Cardiovasc Dis 52(6):467-484.
Karinen, H., J. Peltonen and H. Tikkanen (2008). "Prevalence of acute mountain sickness among Finnish trekkers on Mount Kilimanjaro, Tanzania:an observational study." High Alt Med Biol 9(4):301-306.
Karinen, H. M., J. E. Peltonen, M. Kahonen and H. O. Tikkanen (2010). "Prediction of acute mountain sickness by monitoring arterial oxygen saturation during ascent." High Alt Med Biol 11(4):325-332.
Karinen, H. M., A. Uusitalo, H. Vaha-Ypya, M. Kahonen, J. E. Peltonen, P. K. Stein, J. Viik and H. O. Tikkanen (2012). "Heart rate variability changes at 2400 m altitude predicts acute mountain sickness on further ascent at 3000-4300 m altitudes." Front Physiol3:336.
Leone, M. and G Bussone (1993). "A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement." Cephalalgia 13(5):309-317.
Lu, X. J., X. Q. Chen, J. Weng, H. Y. Zhang, D. T. Pak, J. H. Luo and J. Z. Du (2009). "Hippocampal spine-associated Rap-specific GTPase-activating protein induces enhancement of learning and memory in postnatally hypoxia-exposed mice." Neuroscience 162(2):404-414.
Owens, M. J. and C. B. Nemeroff (1991). "Physiology and pharmacology of corticotropin-releasing factor." Pharmacol Rev 43(4):425-473.
Pavlov, E. P., S. M. Harman, G P. Chrousos, D. L. Loriaux and M. R. Blackman (1986). "Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men." J Clin Endocrinol Metab 62(4):767-772.
Richardson, A., R. Twomey, P. Watt and N. Maxwell (2008). "Physiological responses to graded acute normobaric hypoxia using an intermittent walking protocol." Wilderness Environ Med 19(4):252-260.
Rivier, C, M. Brownstein, J. Spiess, J. Rivier and W. Vale (1982). "In vivo corticotropin-releasing factor-induced secretion of adrenocorticotropin, beta-endorphin, and corticosterone." Endocrinology 110(1):272-278.
Roach R. C., B. P., Oelz O., Hackett P. H. (1992). The Lake Louise acute mountain sickness scoring system. Hypoxia and Molecular Medicine. H. C. S. Sutton J. R., Coates G. Queen City Press, Burlington, VT.
Roach, R. C., E. R. Greene, R. B. Schoene and P. H. Hackett (1998). "Arterial oxygen saturation for prediction of acute mountain sickness." Aviat Space Environ Med 69(12):1182-1185.
Stevens, S. L., T. E. Shaw, E. Dykhuizen, N. S. Lessov, J. K. Hill, W. Wurst and M. P. Stenzel-Poore (2003). "Reduced cerebral injury in CRH-Rl deficient mice after focal ischemia:a potential link to microglia and atrocytes that express CRH-R1." J Cereb Blood Flow Metab 23(10):1151-1159.
Tache, Y., V. Martinez, L. Wang and M. Million (2004). "CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity:implications for irritable bowel syndrome." Br J Pharmacol 141(8):1321-1330.
Turnbull, A. V. and C. L. Rivier (1999). "Regulation of the hypothalamic-pituitary-adrenal axis by cytokines:actions and mechanisms of action." Physiol Rev 79(1):1-71.
Vale, W., J. Spiess, C. Rivier and J. Rivier (1981). "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin." Science 213(4514):1394-1397.
Vardy, J., J. Vardy and K. Judge (2006). "Acute mountain sickness and ascent rates in trekkers above 2500 m in the Nepali Himalaya." Aviat Space Environ Med 77(7): 742-744.
Wang, T. Y, X. Q. Chen, J. Z. Du, N. Y Xu, C. B. Wei and W. W. Vale (2004). "Corticotropin-releasing factor receptor type 1 and 2 mRNA expression in the rat anterior pituitary is modulated by intermittent hypoxia, cold and restraint." Neuroscience 128(1):111-119.
Woods, D. R., J. Begley, M. Stacey, C. Smith, C. J. Boos, T. Hooper, A. Hawkins, P. Hodkinson, N. Green and A. Mellor (2012). "Severe acute mountain sickness, brain natriuretic peptide and NT-proBNP in humans." Acta Physiol (Oxf) 205(3): 349-355.
Wu, T. Y., S. Q. Ding, J. L. Liu, M. T. Yu, J. H. Jia, Z. C. Chai, R. C. Dai, S. L. Zhang, B. Y Li, L. Pan, B. Z. Liang, J. Z. Zhao, T. Qi de, Y F. Sun and B. Kayser (2007). "Who should not go high:chronic disease and work at altitude during construction of the Qinghai-Tibet railroad." High Alt Med Biol 8(2):88-107.
Xu, J. F., X. Q. Chen and J. Z. Du (2006). "CRH receptor type 1 mediates continual hypoxia-induced changes of immunoreactive prolactin and prolactin mRNA expression in rat pituitary." Horm Behav 49(2):181-189.
Xu, J. F., X. Q. Chen, J. Z. Du and T. Y Wang (2005). "CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats."Peptidees 26(4):639-646.
You,H.,X.Li,T.Pei,Q.Huang,F.Liu and Y Gao(2012)."Predictive value of basal exhaled nitric oxide and carbon monoxide for acute mountain sickness." Wilderness Environ Med 23(4):316-324.
Bale, T. L. and W. W. Vale (2004). "CRF and CRF receptors:role in stress responsivity and other behaviors." Annu Rev Pharmacol Toxicol 44:525-557.
Chen, X. Q., J. Dong, C. Y. Niu, J. M. Fan and J. Z. Du (2007). "Effects of hypoxia on glucose, insulin, glucagon, and modulation by corticotropin-releasing factor receptor type 1 in the rat." Endocrinology 148(7):3271-3278.
Chen, X. Q., J. Z. Du and Y. S. Wang (2004). "Regulation of hypoxia-induced release of corticotropin-releasing factor in the rat hypothalamus by norepinephrine." Reeul Pept 119(3):221-228.
Corwin, E. J. (2008). Handbook of pathophysiology. Philadelphia, Wolters Kluwer Health/Lippincott Williams & Wilkins.
Cuello, A. C. (1983). Brain microdissection techniques. Chichester England; New York, Wiley.
De Souza, E. B. (1995). "Corticotropin-releasing factor receptors:physiology, pharmacology, biochemistry and role in central nervous system and immune disorders." Psvchoneuroendocrinology 20(8):789-819.
Miller, D. B. and J. P. O'Callaghan (2002). "Neuroendocrine aspects of the response to stress." Metabolism 51(6 Suppl 1):5-10.
Owens, M. J. and C. B. Nemeroff (1991). "Physiology and pharmacology of corticotropin-releasing factor." Pharmacol Rev 43(4):425-473.
Pavlov, E. P., S. M. Harman, G P. Chrousos, D. L. Loriaux and M. R. Blackman (1986). "Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men." J Clin Endocrinol Metab 62(4):767-772.
Paxinos, G. and C. Watson (1998). The rat brain in stereotaxic coordinates. San Diego, Academic Press.
Piazza, J. R., D. M. Almeida, N. O. Dmitrieva and L. C. Klein (2010). "Frontiers in the use of biomarkers of health in research on stress and aging." J Gerontol B Psychol Sci Soc Sci 65(5):513-525.
Rivier, C., M. Brownstein, J. Spiess, J. Rivier and W. Vale (1982). "In vivo corticotropin-releasing factor-induced secretion of adrenocorticotropin, beta-endorphin, and corticosterone." Endocrinology 110(1):272-278.
Sasaki, A., S. Sato, O. Murakami, M. Go, M. Inoue, Y. Shimizu, K. Hanew, N. Andoh, I. Sato, N. Sasano and et al. (1987). "Immunoreactive corticotropin-releasing hormone present in human plasma may be derived from both hypothalamic and extrahypothalamic sources." J Clin Endocrinol Metab 65(1):176-182.
Sumitomo, T., T. Suda, N. Tomori, F. Yajima, Y. Nakagami, T. Ushiyama, H. Demura and K. Shizume (1987). "Immunoreactive corticotropin-releasing factor in rat plasma." Endocrinology 120(4):1391-1396.
Turnbull, A. V. and C. L. Rivier (1999). "Regulation of the hypothalamic-pituitary-adrenal axis by cytokines:actions and mechanisms of action." Physiol Rev 79(1):1-71.
Vale, W., J. Spiess, C. Rivier and J. Rivier (1981). "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin." Science 213(4514):1394-1397.
Wang, T. Y, X. Q. Chen, J. Z. Du, N. Y Xu, C. B. Wei and W. W. Vale (2004). "Corticotropin-releasing factor receptor type 1 and 2 mRNA expression in the rat anterior pituitary is modulated by intermittent hypoxia, cold and restraint." Neuroscience 128(1):111-119.
Xu, J. F., X. Q. Chen and J. Z. Du (2006). "CRH receptor type 1 mediates continual hypoxia-induced changes of immunoreactive prolactin and prolactin mRNA expression in rat pituitary." Horm Behav 49(2):181-189.
Xu, J. F., X. Q. Chen, J. Z. Du and T. Y. Wang (2005). "CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats." Peptides 26(4):639-646.
Bale, T. L., A. Contarino, G W. Smith, R. Chan, L. H. Gold, P. E. Sawchenko, G F. Koob, W. W. Vale and K. F. Lee (2000). "Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress." Nat Genet 24(4):410-414.
Bale, T. L. and W. W. Vale (2004). "CRF and CRF receptors:role in stress responsivity and other behaviors." Annu Rev Pharmacol Toxicol 44:525-557.
Chalmers, D. T., T. W. Lovenberg and E. B. De Souza (1995). "Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain:comparison with CRF1 receptor mRNA expression." J Neurosci 15(10):6340-6350.
Chen, X. Q., F. P. Kong, Y. Zhao and J. Z. Du (2012). "High-altitude hypoxia induces disorder of the brain-endocrine-immune network though activation of corticotrophin-releasing factor and its type-1 receptors." Zhongguo Ying Yong Sheng Li Xue Za Zhi 28(6):481-487.
Coste, S. C., R. A. Kesterson, K. A. Heldwein, S. L. Stevens, A. D. Heard, J. H. Hollis, S. E. Murray, J. K. Hill, G A. Pantely, A. R. Hohimer, D. C. Hatton, T. J. Phillips, D. A. Finn, M. J. Low, M. B. Rittenberg, P. Stenzel and M. P. Stenzel-Poore (2000). "Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2." Nat Genet 24(4):403-409.
Cuello, A. C. (1983). Brain microdissection techniques. Chichester England; New York, Wiley.
Dautzenberg, F. M., G J. Kilpatrick, R. L. Hauger and J. Moreau (2001). "Molecular biology of the CRH receptors--in the mood." Peptides 22(5):753-760.
Heinrichs, S. C. and E. B. De Souza (1999). "Corticotropin-releasing factor antagonists, binding-protein and receptors:implications for central nervous system disorders." Baillieres Best Pract Res Clin Endocrinol Metab 13(4):541-554.
Imaki, T., M. Naruse, S. Harada, N. Chikada, J. Imaki, H. Onodera, H. Demura and W. Vale (1996). "Corticotropin-releasing factor up-regulates its own receptor mRNA in the paraventricular nucleus of the hypothalamus." Brain Res Mol Brain Res 38(1):166-170.
Imray, C., A. Wright, A. Subudhi and R. Roach (2010). "Acute mountain sickness: pathophysiology, prevention, and treatment." Prog Cardiovasc Dis 52(6):467-484.
Lovenberg, T. W., D. T. Chalmers, C. Liu and E. B. De Souza (1995). "CRF2 alpha and CRF2 beta receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues." Endocrinology 136(9):4139-4142.
Maiti, P., S. B. Singh, S. Muthuraju, S. Veleri and G Ilavazhagan (2007). "Hypobaric hypoxia damages the hippocampal pyramidal neurons in the rat brain." Brain Res 1175:1-9.
Paxinos, G and C. Watson (1998). The rat brain in stereotaxic coordinates. San Diego, Academic Press.
Potter, E., S. Sutton, C. Donaldson, R. Chen, M. Perrin, K. Lewis, P. E. Sawchenko and W. Vale (1994). "Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary." Proc Natl Acad Sci U S A 91(19): 8777-8781.
Rybnikova, E., N. Sitnik, T. Gluschenko, E. Tjulkova and M. O. Samoilov (2006). "The preconditioning modified neuronal expression of apoptosis-related proteins of Bcl-2 superfamily following severe hypobaric hypoxia in rats." Brain Res 1089(1): 195-202.
Sanchez, M. M., L. J. Young, P. M. Plotsky and T. R. Insel (1999). "Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain." J Comp Neurol 408(3):365-377.
Silverman, A. J., A. Hou-Yu and W. P. Chen (1989). "Corticotropin-releasing factor synapses within the paraventricular nucleus of the hypothalamus." Neuroendocrinology 49(3):291-299.
Smith, G. W., J. M. Aubry, F. Dellu, A. Contarino, L. M. Bilezikjian, L. H. Gold, R. Chen, Y. Marchuk, C. Hauser, C. A. Bentley, P. E. Sawchenko, G. F. Koob, W. Vale and K. F. Lee (1998). "Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development." Neuron 20(6):1093-1102.
Stevens, S. L., T. E. Shaw, E. Dykhuizen, N. S. Lessov, J. K. Hill, W. Wurst and M. P. Stenzel-Poore (2003). "Reduced cerebral injury in CRH-R1 deficient mice after focal ischemia:a potential link to microglia and atrocytes that express CRH-R1." J Cereb Blood Flow Metab 23(10):1151-1159.
Timpl, P., R. Spanagel, I. Sillaber, A. Kresse, J. M. Reul, G. K. Stalla, V. Blanquet, T. Steckler, F. Holsboer and W. Wurst (1998). "Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1." Nat Genet 19(2):162-166.
Titus, A. D., B. S. Shankaranarayana Rao, H. N. Harsha, K. Ramkumar, B. N. Srikumar, S. B. Singh, S. Chattarji and T. R. Raju (2007). "Hypobaric hypoxia-induced dendritic atrophy of hippocampal neurons is associated with cognitive impairment in adult rats." Neuroscience 145(1):265-278.
Wallace, M. G., K. D. Hartle, W. M. Snow, N. L. Ward and T. L. Ivanco (2007). "Effect of hypoxia on the morphology of mouse striatal neurons." Neuroscience 147(1): 90-96.
Wang, M. J., S. Z. Lin, J. S. Kuo, H. Y. Huang, S. F. Tzeng, C. H. Liao, D. C. Chen and W. F. Chen (2007). "Urocortin modulates inflammatory response and neurotoxicity induced by microglial activation." J Immunol 179(9):6204-6214.
Xu, J. F., X. Q. Chen, J. Z. Du and T. Y. Wang (2005). "CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats." Peptides 26(4):639-646.
Yang, Y, E. Hahm, Y. Kim, J. Kang, W. Lee, I. Han, P. Myung, H. Kang, H. Park and D. Cho (2005). "Regulation of IL-18 expression by CRH in mouse microglial cells." Immunol Lett 98(2):291-296.
Bale, T. L. and W. W. Vale (2004). "CRF and CRF receptors:role in stress responsivity and other behaviors." Annu Rev Pharmacol Toxicol 44:525-557.
Brancaccio, P., G. Lippi and N. Maffulli (2010). "Biochemical markers of muscular damage." Clin Chem Lab Med 48(6):757-767.
Buckley, T. M. and A. F. Schatzberg (2005). "On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep:normal HPA axis activity and circadian rhythm, exemplary sleep disorders." J Clin Endocrinol Metab 90(5): 3106-3114.
Cai, A. and P. M. Wise (1996). "Age-related changes in the diurnal rhythm of CRH gene expression in the paraventricular nuclei." Am J Physiol 270(2 Pt 1):E238-243.
Dautzenberg, F. M. and R. L. Hauger (2002). "The CRF peptide family and their receptors:yet more partners discovered." Trends Pharmacol Sci 23(2):71-77.
Dempsey, J. A. and P. D. Wagner (1999). "Exercise-induced arterial hypoxemia." J Appl Physiol 87(6):1997-2006.
Florio, P., M. C. Zatelli, F. M. Reis, E. C. degli Uberti and F. Petraglia (2007). "Corticotropin releasing hormone:a diagnostic marker for behavioral and reproductive disorders?" Front Biosci 12:551-560.
Hellhammer, D. H., S. Wust and B. M. Kudielka (2009). "Salivary cortisol as a biomarker in stress research." Psychoneuroendocrinology 34(2):163-171.
Kirschbaum, C. and D. H. Hellhammer (1994). "Salivary cortisol in psychoneuroendocrine research:recent developments and applications." Psychoneuroendocrinology 19(4):313-333.
Kling, M. A., A. Roy, A. R. Doran, J. R. Calabrese, D. R. Rubinow, H. J. Whitfield, Jr., C. May, R. M. Post, G. P. Chrousos and P. W. Gold (1991). "Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing's disease and major depression:potential clinical implications." J Clin Endocrinol Metab 72(2):260-271.
Kwak, S. P., M. I. Morano, E. A. Young, S. J. Watson and H. Akil (1993). "Diurnal CRH mRNA rhythm in the hypothalamus:decreased expression in the evening is not dependent on endogenous glucocorticoids." Neuroendocrinology 57(1):96-105.
Liu, J. and Y. Duan (2012). "Saliva:a potential media for disease diagnostics and monitoring." Oral Oncol 48(7):569-577.
Mastorakos, G, E. A. Bouzas, P. B. Silver, G Sartani, T. C. Friedman, C. C. Chan, R. R. Caspi and G P. Chrousos (1995). "Immune corticotropin-releasing hormone is present in the eyes of and promotes experimental autoimmune uveoretinitis in rodents." Endocrinology 136(10):4650-4658.
Mastorakos, G, M. A. Magiakou and G P. Chrousos (1995). "Effects of the immune/inflammatory reaction on the hypothalamic-pituitary-adrenal axis." Ann N Y Acad Sci 771:438-448.
Nagler, R. M., S. Lischinsky, E. Diamond, I. Klein and A. Z. Reznick (2001). "New insights into salivary lactate dehydrogenase of human subjects." J Lab Clin Med 137(5):363-369.
Nemeroff, C. B., E. Widerlov, G. Bissette, H. Walleus, I. Karlsson, K. Eklund, C. D. Kilts, P. T. Loosen and W. Vale (1984). "Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients." Science 226(4680):1342-1344.
Pfaffe, T., J. Cooper-White, P. Beyerlein, K. Kostner and C. Punyadeera (2011). "Diagnostic potential of saliva:current state and future applications." Clin Chem 57(5):675-687.
Powers, R. E., L. C. Walker, E. B. DeSouza, W. W. Vale, R. G Struble, P. J. Whitehouse and D. L. Price (1987). "Immunohistochemical study of neurons containing corticotropin-releasing factor in Alzheimer's disease." Synapse 1(5):405-410.
Roy, A., D. Pickar, S. Paul, A. Doran, G P. Chrousos and P. W. Gold (1987). "CSF corticotropin-releasing hormone in depressed patients and normal control subjects." Am J Psychiatry 144(5):641-645.
Sasaki, A., S. Sato, O. Murakami, M. Go, M. Inoue, Y. Shimizu, K. Hanew, N. Andoh, I. Sato, N. Sasano and et al. (1987). "Immunoreactive corticotropin-releasing hormone present in human plasma may be derived from both hypothalamic and extrahypothalamic sources." J Clin Endocrinol Metab 65(1):176-182.
Sasaki, A., O. Shinkawa, A. N. Margioris, A. S. Liotta, S. Sato, O. Murakami, M. Go, Y. Shimizu, K. Hanew and K. Yoshinaga (1987). "Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor, and delivery." J Clin Endocrinol Metab 64(2):224-229.
Watts, A. G., S. Tanimura and G. Sanchez-Watts (2004). "Corticotropin-releasing hormone and arginine vasopressin gene transcription in the hypothalamic paraventricular nucleus of unstressed rats:daily rhythms and their interactions with corticosterone." Endocrinology 145(2):529-540.
Whitehouse, P. J., W. W. Vale, R. M. Zweig, H. S. Singer, R. Mayeux, M. J. Kuhar, D. L. Price and E. B. De Souza (1987). "Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy." Neurology 37(6):905-909.
Arlt, J., H. Jahn, M. Kellner, A. Strohle, A. Yassouridis and K. Wiedemann (2003). "Modulation of sympathetic activity by corticotropin-releasing hormone and atrial natriuretic peptide." Neuropeptides 37(6):362-368.
Austin, D. and J. Sleigh (1995). "Prediction of acute mountain sickness." BMJ 311(7011):989-990.
Bailey, D. M., S. Taudorf, R. M. Berg, C. Lundby, J. McEneny, I. S. Young, K. A. Evans, P. E. James, A. Shore, D. A. Hullin, J. M. McCord, B. K. Pedersen and K. Moller (2009). "Increased cerebral output of free radicals during hypoxia:implications for acute mountain sickness?" Am J Physiol Regul Integr Comp Physiol 297(5): R1283-1292.
Bale, T. L. and W. W. Vale (2004). "CRF and CRF receptors:role in stress responsivity and other behaviors." Annu Rev Pharmacol Toxicol 44:525-557.
Bartsch, P., E. R. Swenson, A. Paul, B. Julg and E. Hohenhaus (2002). "Hypoxic ventilatory response, ventilation, gas exchange, and fluid balance in acute mountain sickness." High Alt Med Biol 3(4):361-376.
Basnyat, B. and D. R. Murdoch (2003). "High-altitude illness." Lancet 361(9373): 1967-1974.
Bernardi, L., A. Schneider, L. Pomidori, E. Paolucci and A. Cogo (2006). "Hypoxic ventilatory response in successful extreme altitude climbers." Eur Respir J 27(1): 165-171.
Bourbia, N., O. B. Ansah and A. Pertovaara (2010). "Corticotropin-releasing factor in the rat amygdala differentially influences sensory-discriminative and emotional-like pain response in peripheral neuropathy." J Pain 11(12):1461-1471.
Buckley, T. M. and A. F. Schatzberg (2005). "On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep:normal HPA axis activity and circadian rhythm, exemplary sleep disorders." J Clin Endocrinol Metab 90(5): 3106-3114.
Burtscher, M., C. Szubski and M. Faulhaber (2008). "Prediction of the susceptibility to AMS in simulated altitude." Sleep Breath 12(2):103-108.
Carskadon, M. and W. Dement (2000). Normal human sleep:an overview. Principles and practice of sleep medicine. M. H. Kryger, T. Roth and W. C. Dement. Philadelphia, Saunders:15-25.
Chen, X. Q., F. P. Kong, Y. Zhao and J. Z. Du (2012). "High-altitude hypoxia induces disorder of the brain-endocrine-immune network though activation of corticotrophin-releasing factor and its type-1 receptors." Zhongguo Ying Yong Sheng Li Xue Za Zhi 28(6):481-487.
Compte-Torrero, L., J. Botella de Maglia, A. de Diego-Damia, L. Gomez-Perez, P. Ramirez-Galleymore and M. Perpina-Tordera (2005). "[Changes in spirometric parameters and arterial oxygen saturation during a mountain ascent to over 3000 meters]." Arch Bronconeumol 41(10):547-552.
Duplain, H., L. Vollenweider, A. Delabays, P. Nicod, P. Bartsch and U. Scherrer (1999). "Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema." Circulation 99(13):1713-1718.
Ehlers, C. L., T. K. Reed and S. J. Henriksen (1986). "Effects of corticotropin-releasing factor and growth hormone-releasing factor on sleep and activity in rats." Neuroendocrinology 42(6):467-474.
Fu, Y. and V. Neugebauer (2008). "Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior." J Neurosci 28(15):3861-3876.
Fukudo, S. (2007). "Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation." J Gastroenterol 42 Suppl 17:48-51.
Graham, J. and D. Potyk (2005). "Age and acute mountain sickness:examining the data." J Am Geriatr Soc 53(4):735.
Hackett, P. H., D. Rennie, S. E. Hofmeister, R. F. Grover, E. B. Grover and J. T. Reeves (1982). "Fluid retention and relative hypoventilation in acute mountain sickness." Respiration 43(5):321-329.
Hainsworth, R., M. J. Drinkhill and M. Rivera-Chira (2007). "The autonomic nervous system at high altitude." Clin Auton Res 17(1):13-19.
Hohenhaus, E., A. Paul, R. E. McCullough, H. Kucherer and P. Bartsch (1995). "Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema." Eur Respir J 8(11):1825-1833.
Holsboer, F., U. von Bardeleben and A. Steiger (1988). "Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man." Neuroendocrinology 48(1):32-38.
Huang, H. H., C. Y. Tseng, J. S. Fan, D. H. Yen, W. F. Kao, S. C. Chang, T. B. Kuo, C. I. Huang and C. H. Lee (2010). "Alternations of heart rate variability at lower altitude in the predication of trekkers with acute mountain sickness at high altitude." Clinical journal of sport medicine 20(1):58-63.
Imray, C., A. Wright, A. Subudhi and R. Roach (2010). "Acute mountain sickness: pathophysiology, prevention, and treatment." Prog Cardiovasc Dis 52(6):467-484.
Kanazawa, M., M. Hongo and S. Fukudo (2011). "Visceral hypersensitivity in irritable bowel syndrome." J Gastroenterol Hepatol 26 Suppl 3:119-121.
Kao, W. F., C. C. Kuo, T. F. Hsu, H. Chang, Y. Y. Sung, D. H. Yen, J. K. Wu and C. H. Lee (2002). "Acute mountain sickness in Jade Mountain climbers of Taiwan." Aviat Space Enyiron Med 73(4):359-362.
Karinen, H. M., J. E. Peltonen, M. Kahonen and H. O. Tikkanen (2010). "Prediction of acute mountain sickness by monitoring arterial oxygen saturation during ascent." High Alt Med Biol 11(4):325-332.
Karinen, H. M., A. Uusitalo, H. Vaha-Ypya, M. Kahonen, J. E. Peltonen, P. K. Stein, J. Viik and H. O. Tikkanen (2012). "Heart rate variability changes at 2400 m altitude predicts acute mountain sickness on further ascent at 3000-4300 m altitudes." Front Phvsiol 3:336.
Kimura, M., P. Muller-Preuss, A. Lu, E. Wiesner, C. Flachskamm, W. Wurst, R Holsboer and J. M. Deussing (2010). "Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep." Mol Psychiatry 15(2):154-165.
King, A. B. and S. M. Robinson (1972). "Ventilation response to hypoxia and acute mountain sickness." Aerosp Med 43(4):419-421.
La, J. H., T. S. Sung, H. J. Kim, T. W. Kim, T. M. Kang and I. S. Yang (2008). "Peripheral corticotropin releasing hormone mediates post-inflammatory visceral hypersensitivity in rats." World J Gastroenterol 14(5):731-736.
Lariviere, W. R., P. Fiorenzani, I. Ceccarelli, C. Massafra, G. Sorda, C. Di Canio and A. M. Aloisi (2011). "Central CRH administration changes formalin pain responses in male and female rats." Brain Res 1383:128-134.
Leone, M. and G Bussone (1993). "A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement." Cephalalgia 13(5):309-317.
Luks, A. M. and E. R. Swenson (2011). "Pulse oximetry at high altitude." High Alt Med Biol 12(2):109-119.
Mason, N. P., P. W. Barry, A. J. Pollard, D. J. Collier, N. A. Taub, M. R. Miller and J. S. Milledge (2000). "Serial changes in spirometry during an ascent to 5,300 m in the Nepalese Himalayas." High Alt Med Biol 1(3):185-195.
Mimassi, N., F. Lancien, D. Mabin, C. Delarue, J. M. Conlon and J. C. Le Mevel (2003). "Induction of bradycardia in trout by centrally administered corticotropin-releasing-hormone (CRH)." Brain Res 982(2):211-218.
Moore, L. G., G. L. Harrison, R. E. McCullough, R. G. McCullough, A. J. Micco, A. Tucker, J. V. Weil and J. T. Reeves (1986). "Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness." J Appl Physiol 60(4): 1407-1412.
Nijsen, M. J., G Croiset, R. Stam, A. Bruijnzeel, M. Diamant, D. de Wied and V. M. Wiegant (2000). "The role of the CRH type 1 receptor in autonomic responses to corticotropin- releasing hormone in the rat." Neuropsychopharmacology 22(4): 388-399.
Raadsheer, F. C., W. J. Hoogendijk, F. C. Stam, F. J. Tilders and D. F. Swaab (1994). "Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients." Neuroendocrinology 60(4):436-444.
Richardson, A., R. Twomey, P. Watt and N. Maxwell (2008). "Physiological responses to graded acute normobaric hypoxia using an intermittent walking protocol." Wilderness Enyiron Med 19(4):252-260.
Roach R. C, B. P., Oelz O., Hackett P. H. (1992). The Lake Louise acute mountain sickness scoring system. Hypoxia and Molecular Medicine. H. C. S. Sutton J. R., Coates G Queen City Press, Burlington, VT.
Roach, R. C., E. R. Greene, R. B. Schoene and P. H. Hackett (1998). "Arterial oxygen saturation for prediction of acute mountain sickness." Aviat Space Environ Med 69(12):1182-1185.
Sagami, Y., Y. Shimada, J. Tayama, T. Nomura, M. Satake, Y. Endo, T. Shoji, K. Karahashi, M. Hongo and S. Fukudo (2004). "Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome." Gut 53(7):958-964.
Saito, S., H. Shimada, T. Imai, Y. Futamata and K. Yamamori (1995). "Estimation of the degree of acclimatization to high altitude by a rapid and simple physiological examination." Int Arch Occup Environ Health 67(5):347-351.
Saito, S., K. Tanobe, M. Yamada and F. Nishihara (2005). "Relationship between arterial oxygen saturation and heart rate variability at high altitudes." Am J Emerg Med 23(1):8-12.
Savourey, G., J. C. Launay, Y. Besnard, A. Guinet-Lebreton, A. Alonso, F. Sauvet and C. Bourrilhon (2007). "Normo or hypobaric hypoxic tests:propositions for the determination of the individual susceptibility to altitude illnesses." Eur J Appl Physiol 100(2):193-205.
Savourey, G., C. Moirant, J. Eterradossi and J. Bittel (1995). "Acute mountain sickness relates to sea-level partial pressure of oxygen." Eur J Appl Physiol Occup Physiol 70(6):469-476.
Schirlo, C., V. Pavlicek, A. Jacomet, J. S. Gibbs, E. Koller, O. Oelz, M. Seebauer and J. Kohl (2002). "Characteristics of the ventilatory response in subjects susceptible to high altitude pulmonary edema during acute and prolonged hypoxia." High Alt Med Bioi 3(3):267-276.
Sevre, K., B. Bendz, E. Hanko, A. R. Nakstad, A. Hauge, J. I. Kasin, J. D. Lefrandt, A. J. Smit, I. Eide and M. Rostrup (2001). "Reduced autonomic activity during stepwise exposure to high altitude." Acta Physiol Scand 173(4):409-417.
Sutton, J. R., A. C. Bryan, G. W. Gray, E. S. Horton, A. S. Rebuck, W. Woodley, I. D. Rennie and C. S. Houston (1976). "Pulmonary gas exchange in acute mountain sickness." Ayiat Space Enyiron Med 47(10):1032-1037.
Tache, Y, V. Martinez, L. Wang and M. Million (2004). "CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity:implications for irritable bowel syndrome." Br J Pharmacol 141(8):1321-1330.
Theoharides, T. C. (1999). Treatment of stress-induced migraine headache with a corticotropin releasing hormone blocker, Google Patents.
West, J. B. (2000). "Human limits for hypoxia. The physiological challenge of climbing Mt. Everest." Ann N Y Acad Sci 899:15-27.
Wilson, M. H., C. H. Imray and A. R. Hargens (2011). "The headache of high altitude and microgravity--similarities with clinical syndromes of cerebral venous hypertension." High Alt Med Biol 12(4):379-386.
Woods, D. R., J. Begley, M. Stacey, C. Smith, C. J. Boos, T. Hooper, A. Hawkins, P. Hodkinson, N. Green and A. Mellor (2012). "Severe acute mountain sickness, brain natriuretic peptide and NT-proBNP in humans." Acta Physiol (Oxf) 205(3): 349-355.
You, H., X. Li, T. Pei, Q. Huang, F. Liu and Y. Gao (2012). "Predictive value of basal exhaled nitric oxide and carbon monoxide for acute mountain sickness." Wilderness Enyiron Med 23(4):316-324.
Zuzewicz, K., B. Biernat, G. Kempa and K. Kwarecki (1999). "Heart rate variability in exposure to high altitude hypoxia of short duration." Int J Occup Saf Ergon 5(3): 337-346.
Aeberli, I., A. Erb, K. Spliethoff, D. Meier, O. Gotze, H. Fruhauf, M. Fox, G. S. Finlayson, M. Gassmann, K. Berneis, M. Maggiorini, W. Langhans and T. A. Lutz (2013). "Disturbed eating at high altitude:influence of food preferences, acute mountain sickness and satiation hormones." Eur J Nutr 52(2):625-635.
Ashina, M., L. Bendtsen, R. Jensen, R. Ekman and J. Olesen (1999). "Plasma levels of substance P, neuropeptide Y and vasoactive intestinal polypeptide in patients with chronic tension-type headache." Pain 83(3):541-547.
Austin, D. and J. Sleigh (1995). "Prediction of acute mountain sickness." BMJ 311(7011):989-990.
Bailey, D. M. and B. Davies (2001). "Acute mountain sickness; prophylactic benefits of antioxidant vitamin supplementation at high altitude." High Alt Med Biol 2(1): 21-29.
Bartsch, P., E. R. Swenson, A. Paul, B. Julg and E. Hohenhaus (2002). "Hypoxic ventilatory response, ventilation, gas exchange, and fluid balance in acute mountain sickness." High Alt Med Biol 3(4):361-376.
Basnyat, B. and D. R. Murdoch (2003). "High-altitude illness." Lancet 361(9373): 1967-1974.
Baumgartner, R. W., I. Spyridopoulos, P. Bartsch, M. Maggiorini and O. Oelz (1999). "Acute mountain sickness is not related to cerebral blood flow:a decompression chamber study." J Appl Physiol 86(5):1578-1582.
Beidleman, B. A., S. R. Muza, C. S. Fulco, A. Cymerman, M. N. Sawka, S. F. Lewis and G. S. Skrinar (2008). "Seven intermittent exposures to altitude improves exercise performance at 4300 m." Med Sci Sports Exerc 40(1):141-148.
Bernardi, L., A. Schneider, L. Pomidori, E. Paolucci and A. Cogo (2006). "Hypoxic ventilatory response in successful extreme altitude climbers." Eur Respir J 27(1): 165-171.
Bernhard, W. N., L. M. Schalick, P. A. Delaney, T. M. Bernhard and G. M. Barnas (1998). "Acetazolamide plus low-dose dexamethasone is better than acetazolamide alone to ameliorate symptoms of acute mountain sickness." Aviat Space Environ Med 69(9):883-886.
Buckley, T. M. and A. F. Schatzberg (2005). "On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep:normal HPA axis activity and circadian rhythm, exemplary sleep disorders." J Clin Endocrinol Metab 90(5): 3106-3114.
Burtscher, M., C. Szubski and M. Faulhaber (2008). "Prediction of the susceptibility to AMS in simulated altitude." Sleep Breath 12(2):103-108.
Carlsten, C., E. R. Swenson and S. Ruoss (2004). "A dose-response study of acetazolamide for acute mountain sickness prophylaxis in vacationing tourists at 12,000 feet (3630 m)." High Alt Med Biol 5(1):33-39.
Carskadon, M. and W. Dement (2000). Normal human sleep:an overview. Principles and practice of sleep medicine. M. H. Kryger, T. Roth and W. C. Dement. Philadelphia, Saunders:15-25.
Chen, H. C., W. L. Lin, J. Y. Wu, S. H. Wang, T. F. Chiu, Y. M. Weng, T. Y. Hsu and M. H. Wu (2012). "Change in oxygen saturation does not predict acute mountain sickness on Jade Mountain." Wilderness Environ Med 23(2):122-127.
Chen, X. Q., F. P. Kong, Y. Zhao and J. Z. Du (2012). "High-altitude hypoxia induces disorder of the brain-endocrine-immune network though activation of corticotrophin-releasing factor and its type-1 receptors." Zhongguo Ying Yong Shene Li Xue Za Zhi 28(6):481-487.
Chow, T., V. Browne, H. L. Heileson, D. Wallace, J. Anholm and S. M. Green (2005). "Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness:a randomized, placebo-controlled trial." Arch Intern Med 165(3):296-301.
Compte-Torrero, L., J. Botella de Maglia, A. de Diego-Damia, L. Gomez-Perez, P. Ramirez-Galleymore and M. Perpina-Tordera (2005). "[Changes in spirometric parameters and arterial oxygen saturation during a mountain ascent to over 3000 meters]." Arch Bronconeumol 41(10):547-552.
Ding, H., Q. Liu, M. Hua, M. Ding, H. Du, W. Zhang, Z. Li and J. Zhang (2011). "Polymorphisms of hypoxia-related genes in subjects susceptible to acute mountain sickness." Respiration 81(3):236-241.
Duplain, H., L. Vollenweider, A. Delabays, P. Nicod, P. Bartsch and U. Scherrer (1999). "Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema." Circulation 99(13):1713-1718.
Ehlers, C. L., T. K. Reed and S. J. Henriksen (1986). "Effects of corticotropin-releasing factor and growth hormone-releasing factor on sleep and activity in rats." Neuroendocrinology 42(6):467-474.
Ferrazzini, G, M. Maggiorini, S. Kriemler, P. Bartsch and O. Oelz (1987). "Successful treatment of acute mountain sickness with dexamethasone." Br Med J (Clin Res Ed) 294(6584):1380-1382.
Fukudo, S. (2007). "Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation." J Gastroenterol 42 Suppl 17:48-51.
Gertsch, J. H., B. Basnyat, E. W. Johnson, J. Onopa and P. S. Holck (2004). "Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers:the prevention of high altitude illness trial (PHAIT)." BMJ 328(7443): 797.
Gertsch, J. H., T. B. Seto, J. Mor and J. Onopa (2002). "Ginkgo biloba for the prevention of severe acute mountain sickness (AMS) starting one day before rapid ascent." High Alt Med Biol 3(1):29-37.
Hackett, P. H., D. Rennie, S. E. Hofmeister, R. F. Grover, E. B. Grover and J. T. Reeves (1982). "Fluid retention and relative hypoventilation in acute mountain sickness." Respiration 43(5):321-329.
Hackett, P. H., D. Rennie and H. D. Levine (1976). "The incidence, importance, and prophylaxis of acute mountain sickness." Lancet 2(7996):1149-1155.
Hackett, P. H. and R. C. Roach (1987). "Medical therapy of altitude illness." Ann Emerg Med 16(9):980-986.
Hackett, P. H. and R. C. Roach (2001). "High-altitude illness." N Engl J Med 345(2): 107-114.
Hackett, P. H. and R. C. Roach (2004). "High altitude cerebral edema." High Alt Med Biol 5(2):136-146.
Hackett, P. H., R. C. Roach, R. A. Wood, R. G. Foutch, R. T. Meehan, D. Rennie and W. J. Mills, Jr. (1988). "Dexamethasone for prevention and treatment of acute mountain sickness." Aviat Space Enyiron Med 59(10):950-954.
Hainsworth, R., M. J. Drinkhill and M. Rivera-Chira (2007). "The autonomic nervous system at high altitude." Clin Auton Res 17(1):13-19.
Hall, D. P., I. J. MacCormick, A. T. Phythian-Adams, N. M. Rzechorzek, D. Hope-Jones, S. Cosens, S. Jackson, M. G. Bates, D. J. Collier and D. A. Hume (2013). "Network analysis reveals distinct clinical syndromes underlying acute mountain sickness." arXiv preprint arXiv:1303.6525.
Hillebrand, J. J., D. de Wied and R. A. Adan (2002). "Neuropeptides, food intake and body weight regulation:a hypothalamic focus." Peptides 23(12):2283-2306.
Hohenhaus, E., A. Paul, R. E. McCullough, H. Kucherer and P. Bartsch (1995). "Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema." Eur Respir J 8(11):1825-1833.
Holsboer, F., U. von Bardeleben and A. Steiger (1988). "Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man." Neuroendocrinology 48(1):32-38.
Honigman, B., M. K. Theis, J. Koziol-McLain, R. Roach, R. Yip, C. Houston, L. G. Moore and P. Pearce (1993). "Acute mountain sickness in a general tourist population at moderate altitudes." Ann Intern Med 118(8):587-592.
Houston, C. S. (1989). "Incidence of acute mountain sickness at intermediate altitudes." JAMA 261(24):3551-3552.
Huang, H. H., C. Y. Tseng, J. S. Fan, D. H. Yen, W. F. Kao, S. C. Chang, T. B. Kuo, C. I. Huang and C. H. Lee (2010). "Alternations of heart rate variability at lower altitude in the predication of trekkers with acute mountain sickness at high altitude." Clinical journal of sport medicine 20(1):58-63.
Huang, S. Y, L. G. Moore, R. E. McCullough, R. G. McCullough, A. J. Micco, C. Fulco, A. Cymerman, M. Manco-Johnson, J. V. Weil and J. T. Reeves (1987). "Internal carotid and vertebral arterial flow velocity in men at high altitude." J Appl Physiol 63(1):395-400.
Imray, C. (2012). "Acetazolamide for the prophylaxis of acute mountain sickness." BMJ 345:e7077.
Imray, C., A. Wright, A. Subudhi and R. Roach (2010). "Acute mountain sickness: pathophysiology, prevention, and treatment." Prog Cardiovasc Dis 52(6):467-484.
Jafarian, S., F. Gorouhi, A. Taghva and J. Lotfi (2008). "High-altitude sleep disturbance: results of the Groningen Sleep Quality Questionnaire survey." Sleep Med 9(4): 446-449.
Jensen, J. B., A. D. Wright, N. A. Lassen, T. C. Harvey, M. H. Winterborn, M. E. Raichle and A. R. Bradwell (1990). "Cerebral blood flow in acute mountain sickness." J Appl Physiol 69(2):430-433.
Johnson, T. S., P. B. Rock, C. S. Fulco, L. A. Trad, R. F. Spark and J. T. Maher (1984). "Prevention of acute mountain sickness by dexamethasone." N Engl J Med 310(11): 683-686.
Kallenberg, K., D. M. Bailey, S. Christ, A. Mohr, R. Roukens, E. Menold, T. Steiner, P. Bartsch and M. Knauth (2007). "Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness." J Cereb Blood Flow Metab 27(5):1064-1071.
Kanazawa, M., M. Hongo and S. Fukudo (2011). "Visceral hypersensitivity in irritable bowel syndrome." J Gastroenterol Hepatol 26 Suppl 3:119-121.
Kao, W. F., C. C. Kuo, T. F. Hsu, H. Chang, Y. Y. Sung, D. H. Yen, J. K. Wu and C. H. Lee (2002). "Acute mountain sickness in Jade Mountain climbers of Taiwan." Aviat Space Environ Med 73(4):359-362.
Karinen, H., J. Peltonen and H. Tikkanen (2008). "Prevalence of acute mountain sickness among Finnish trekkers on Mount Kilimanjaro, Tanzania:an observational study." High Alt Med Biol 9f41:301-306.
Karinen, H. M., J. E. Peltonen, M. Kahonen and H. O. Tikkanen (2010). "Prediction of acute mountain sickness by monitoring arterial oxygen saturation during ascent." High Alt Med Biol 11(4):325-332.
Karinen, H. M., A. Uusitalo, H. Vaha-Ypya, M. Kahonen, J. E. Peltonen, P. K. Stein, J. Viik and H. O. Tikkanen (2012). "Heart rate variability changes at 2400 m altitude predicts acute mountain sickness on further ascent at 3000-4300 m altitudes." Front Physiol 3:336.
Kayser, B., L. Dumont, C. Lysakowski, C. Combescure, G. Haller and M. R. Tramer (2012). "Reappraisal of acetazolamide for the prevention of acute mountain sickness:a systematic review and meta-analysis." High Alt Med Biol 13(2):82-92.
King, A. B. and S. M. Robinson (1972). "Ventilation response to hypoxia and acute mountain sickness." Aerosp Med 43(4):419-421.
La, J. H., T. S. Sung, H. J. Kim, T. W. Kim, T. M. Kang and I. S. Yang (2008). "Peripheral corticotropin releasing hormone mediates post-inflammatory visceral hypersensitivity in rats." World J Gastroenterol 14(5):731-736.
Leadbetter, G, L. E. Keyes, K. M. Maakestad, S. Olson, M. C. Tissot van Patot and P. H. Hackett (2009). "Ginkgo biloba does--and does not--prevent acute mountain sickness." Wilderness Enyiron Med 20(1):66-71.
Leaf, D. E. and D. S. Goldfarb (2007). "Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness." J Appl Physiol 102(4): 1313-1322.
Leone, M. and G Bussone (1993). "A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement." Cephalalgia 13(5):309-317.
Loeppky, J. A., M. Icenogle, P. Scotto, R. Robergs, H. Hinghofer-Szalkay and R. C. Roach (1997). "Ventilation during simulated altitude, normobaric hypoxia and normoxic hypobaria." Respir Physiol 107(3):231-239.
Low, E. V., A. J. Avery, V. Gupta, A. Schedlbauer and M. P. Grocott (2012). "Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness:systematic review and meta-analysis." BMJ 345:e6779.
Luks, A. M. and E. R. Swenson (2011). "Pulse oximetry at high altitude." High Alt Med Biol 12(2):109-119.
Lyons, T. P., S. R. Muza, P. B. Rock and A. Cymerman (1995). "The effect of altitude pre-acclimatization on acute mountain sickness during reexposure." Aviat Space Environ Med 66(10):957-962.
Macinnis, M. J., E. A. Carter, M. S. Koehle and J. L. Rupert (2012). "Exhaled nitric oxide is associated with acute mountain sickness susceptibility during exposure to normobaric hypoxia." Respir Physiol Neurobiol 180(1):40-44.
Mairer, K., M. Gobel, M. Defrancesco, M. Wille, H. Messner, A. Loizides, M. Schocke and M. Burtscher (2012). "MRI evidence:acute mountain sickness is not associated with cerebral edema formation during simulated high altitude." PLoS One 7(11):e50334.
Mason, N. P., P. W. Barry, A. J. Pollard, D. J. Collier, N. A. Taub, M. R. Miller and J. S. Milledge (2000). "Serial changes in spirometry during an ascent to 5,300 m in the Nepalese Himalayas." High Alt Med Biol 1(3):185-195.
Moore, L. G., G. L. Harrison, R. E. McCullough, R. G. McCullough, A. J. Micco, A. Tucker, J. V. Weil and J. T. Reeves (1986). "Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness." J Appl Physiol 60(4): 1407-1412.
Moraga, F. A., A. Flores, J. Serra, C. Esnaola and C. Barriento (2007). "Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollague (3696 m) in northern Chile." Wilderness Environ Med 18(4):251-257.
Morocz, I. A., G P. Zientara, H. Gudbjartsson, S. Muza, T. Lyons, P. B. Rock, R. Kikinis and F. A. Jolesz (2001). "Volumetric quantification of brain swelling after hypobaric hypoxia exposure." Exp Neurol 168(1):96-104.
Pollard, A. J. (1992). "Altitude induced illness." BMJ 304(6838):1324-1325.
Roach R. C., B. P., Oelz O., Hackett P. H. (1992). The Lake Louise acute mountain sickness scoring system. Hypoxia and Molecular Medicine. H. C. S. Sutton J. R., Coates G Queen City Press, Burlington, VT.
Roach, R. C., E. R. Greene, R. B. Schoene and P. H. Hackett (1998). "Arterial oxygen saturation for prediction of acute mountain sickness." Aviat Space Environ Med 69(12):1182-1185.
Roach, R. C., C. S. Houston, B. Honigman, R. A. Nicholas, M. Yaron, C. K. Grissom, J. K. Alexander and H. N. Hultgren (1995). "How well do older persons tolerate moderate altitude?" West J Med 162(1):32-36.
Sagami, Y., Y. Shimada, J. Tayama, T. Nomura, M. Satake, Y. Endo, T. Shoji, K. Karahashi, M. Hongo and S. Fukudo (2004). "Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome." Gut 53(7):958-964.
Saito, S., H. Shimada, T. Imai, Y. Futamata and K. Yamamori (1995). "Estimation of the degree of acclimatization to high altitude by a rapid and simple physiological examination." Int Arch Occup Environ Health 67(5):347-351.
Saito, S., K. Tanobe, M. Yamada and F. Nishihara (2005). "Relationship between arterial oxygen saturation and heart rate variability at high altitudes." Am J Emerg Med 23(1):8-12.
Sanders, D. B., T. Kelley and D. Larson (2000). "The role of nitric oxide synthase/nitric oxide in vascular smooth muscle control." Perfusion 15(2):97-104.
Savourey, G., J. C. Launay, Y. Besnard, A. Guinet-Lebreton, A. Alonso, F. Sauvet and C. Bourrilhon (2007). "Normo or hypobaric hypoxic tests:propositions for the determination of the individual susceptibility to altitude illnesses." Eur J Appl Physiol 100(2):193-205.
Savourey, G., C. Moirant, J. Eterradossi and J. Bittel (1995). "Acute mountain sickness relates to sea-level partial pressure of oxygen." Eur J Appl Physiol Occup Physiol 70(6):469-476.
Schirlo, C., V. Pavlicek, A. Jacomet, J. S. Gibbs, E. Koller, O. Oelz, M. Seebauer and J. Kohl (2002). "Characteristics of the ventilatory response in subjects susceptible to high altitude pulmonary edema during acute and prolonged hypoxia." High Alt Med Biol 3(3):267-276.
Schneider, M., D. Bernasch, J. Weymann, R. Holle and P. Bartsch (2002). "Acute mountain sickness:influence of susceptibility, preexposure, and ascent rate." Med Sci Sports Exerc 34(12):1886-1891.
Schoch, H. J., S. Fischer and H. H. Marti (2002). "Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain." Brain 125(Pt 11):2549-2557.
Schommer, K., N. Wiesegart, C. Dehnert, H. Mairbaurl and P. Bartsch (2011). "No correlation between plasma levels of vascular endothelial growth factor or its soluble receptor and acute mountain sickness." High Alt Med Biol 12(4):323-327.
Schoonman, G G, P. S. Sandor, A. C. Nirkko, T. Lange, T. Jaermann, U. Dydak, C. Kremer, M. D. Ferrari, P. Boesiger and R. W. Baumgartner (2008). "Hypoxia-induced acute mountain sickness is associated with intracellular cerebral edema:a 3 T magnetic resonance imaging study." J Cereb Blood Flow Metab 28(1): 198-206.
Severinghaus, J. W. (1995). "Hypothesis:angiogenesis cytokines in high altitude cerebral oedema." Acta Anaesthesiol Scand Suppl 107:177-178.
Severinghaus, J. W., H. Chiodi, E. I. Eger,2nd, B. Brandstater and T. F. Hornbein (1966). "Cerebral blood flow in man at high altitude. Role of cerebrospinal fluid pH in normalization of flow in chronic hypocapnia." Circ Res 19(2):274-282.
Sevre, K., B. Bendz, E. Hanko, A. R. Nakstad, A. Hauge, J. I. Kasin, J. D. Lefrandt, A. J. Smit, I. Eide and M. Rostrup (2001). "Reduced autonomic activity during stepwise exposure to high altitude." Acta Physiol Scand 173(4):409-417.
Sutton, J. R., A. C. Bryan, G W. Gray, E. S. Horton, A. S. Rebuck, W. Woodley, I. D. Rennie and C. S. Houston (1976). "Pulmonary gas exchange in acute mountain sickness." Aviat Space Environ Med 47(10):1032-1037.
Swenson, E. R. and L. J. Teppema (2007). "Prevention of acute mountain sickness by acetazolamide:as yet an unfinished story." J Appl Physiol 102(4):1305-1307.
Tache, Y., V. Martinez, L. Wang and M. Million (2004). "CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity:implications for irritable bowel syndrome." Br J Pharmacol 141(8):1321-1330.
Theoharides, T. C. (1999). Treatment of stress-induced migraine headache with a corticotropin releasing hormone blocker, Google Patents.
Tissot van Patot, M. C., G Leadbetter, L. E. Keyes, J. Bendrick-Peart, V. E. Beckey, U. Christians and P. Hackett (2005). "Greater free plasma VEGF and lower soluble VEGF receptor-1 in acute mountain sickness." J Appl Physiol 98(5):1626-1629.
Vale, W., J. Spiess, C. Rivier and J. Rivier (1981). "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin." Science 213(4514):1394-1397.
Van Osta, A., J. J. Moraine, C. Melot, H. Mairbaurl, M. Maggiorini and R. Naeije (2005). "Effects of high altitude exposure on cerebral hemodynamics in normal subjects." Stroke 36(3):557-560.
van Patot, M. C., G Leadbetter,3rd, L. E. Keyes, K. M. Maakestad, S. Olson and P. H. Hackett (2008). "Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness." High Alt Med Biol 9(4):289-293.
Van Roo, J. D., M. P. Lazio, C. Pesce, S. Malik and D. M. Courtney (2011). "Visual analog scale (VAS) for assessment of acute mountain sickness (AMS) on Aconcagua." Wilderness Environ Med 22(1):7-14.
Vardy, J., J. Vardy and K. Judge (2006). "Acute mountain sickness and ascent rates in trekkers above 2500 m in the Nepali Himalaya." Aviat Space Environ Med 77(7): 742-744.
Wagner, D. R., J. R. Knott and J. P. Fry (2012). "Oximetry fails to predict acute mountain sickness or summit success during a rapid ascent to 5640 meters." Wilderness Environ Med 23(2):114-121.
Webb, J. D., M. L. Coleman and C. W. Pugh (2009). "Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing." Cell Mol Life Sci 66(22): 3539-3554.
West, J. B. (2000). "Human limits for hypoxia. The physiological challenge of climbing Mt. Everest." Ann N Y Acad Sci 899:15-27.
West, J. B. (2003). "Improving oxygenation at high altitude:acclimatization and O2 enrichment." High Alt Med Biol 4(3):389-398.
West, J. B. (2008). "The Qinghai-Tibet railway." High Alt Med Biol 9(1):1-2.
Wille, M., H. Gatterer, K. Mairer, M. Philippe, H. Schwarzenbacher, M. Faulhaber and M. Burtscher (2012). "Short-term intermittent hypoxia reduces the severity of acute mountain sickness." Scand J Med Sci Sports 22(5):e79-85.
Wille, M., K. Mairer, H. Gatterer, M. Philippe, M. Faulhaber and M. Burtscher (2012). "Changes in cardiac autonomic activity during a passive 8 hour acute exposure to 5 500 m normobaric hypoxia are not related to the development of acute mountain sickness." Int J Sports Med 33(3):186-191.
Wilson, M. H., S. Newman and C. H. Imray (2009). "The cerebral effects of ascent to high altitudes." Lancet Neurol 8(2):175-191.
Windsor, J. S. (2012). "Pulse oximetry and predicting acute mountain sickness:are we asking the right questions?" Wilderness Environ Med 23(2):112-113.
Wu, T. Y., S. Q. Ding, J. L. Liu, M. T. Yu, J. H. Jia, Z. C. Chai, R. C. Dai, S. L. Zhang, B. Y. Li, L. Pan, B. Z. Liang, J. Z. Zhao, T. Qi de, Y. F. Sun and B. Kayser (2007). "Who should not go high:chronic disease and work at altitude during construction of the Qinghai-Tibet railroad." High Alt Med Biol 8(2):88-107.
You, H., X. Li, T. Pei, Q. Huang, F. Liu and Y. Gao (2012). "Predictive value of basal exhaled nitric oxide and carbon monoxide for acute mountain sickness." Wilderness Environ Med 23(4):316-324.
Zuzewicz, K., B. Biernat, G. Kempa and K. Kwarecki (1999). "Heart rate variability in exposure to high altitude hypoxia of short duration." Int J Occup Saf Ergon 5(3): 337-346.
Bailey, D. M., S. Taudorf, R. M. Berg, C. Lundby, J. McEneny, I. S. Young, K. A. Evans, P. E. James, A. Shore, D. A. Hullin, J. M. McCord, B. K. Pedersen and K. Moller (2009). "Increased cerebral output of free radicals during hypoxia:implications for acute mountain sickness?" Am J Physiol Regul Integr Comp Physiol 297(5): R1283-1292.
Bale, T. L. and W. W. Vale (2004). "CRF and CRF receptors:role in stress responsivity and other behaviors." Annu Rev Pharmacol Toxicol 44:525-557.
Beall, C. M., K. Song, R. C. Elston and M. C. Goldstein (2004). "Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m." Proc Natl Acad Sci U S A 101(39):14300-14304.
Buckley, T. M. and A. F. Schatzberg (2005). "On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep:normal HPA axis activity and circadian rhythm, exemplary sleep disorders." J Clin Endocrinol Metab 90(5): 3106-3114.
Chen, X. Q., F. P. Kong, Y. Zhao and J. Z. Du (2012). "High-altitude hypoxia induces disorder of the brain-endocrine-immune network though activation of corticotrophin-releasing factor and its type-1 receptors." Zhongguo Ying Yong Sheng Li Xue Za Zhi 28(6):481-487.
Chen, X. Q., N. Y. Xu, J. Z. Du, Y. Wang and C. Duan (2005). "Corticotropin-releasing factor receptor subtype 1 and somatostatin modulating hypoxia-caused downregulated mRNA of pituitary growth hormone and upregulated mRNA of hepatic insulin-like growth factor-I of rats." Mol Cell Endocrinol 242(1-2):50-58.
De Souza, E. B. (1995). "Corticotropin-releasing factor receptors:physiology, pharmacology, biochemistry and role in central nervous system and immune disorders." Psychoneuroendocrinology 20(8):789-819.
Erecinska, M. and I. A. Silver (2001). "Tissue oxygen tension and brain sensitivity to hypoxia." Respir Physiol 128(3):263-276.
Erzurum, S. C., S. Ghosh, A. J. Janocha, W. Xu, S. Bauer, N. S. Bryan, J. Tejero, C. Hemann, R. Hille, D. J. Stuehr, M. Feelisch and C. M. Beall (2007). "Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans." Proc Natl Acad Sci U S A 104(45):17593-17598.
Fan, J. M., X. Q. Chen, H. Jin and J. Z. Du (2009). "Gestational hypoxia alone or combined with restraint sensitizes the hypothalamic-pituitary-adrenal axis and induces anxiety-like behavior in adult male rat offspring." Neuroscience 159(4): 1363-1373.
Galard, R., R. Catalan, J. M. Castellanos and J. M. Gallart (2002). "Plasma corticotropin-releasing factor in depressed patients before and after the dexamethasone suppression test." Biol Psychiatry 51(6):463-468.
Graham, J. and D. Potyk (2005). "Age and acute mountain sickness:examining the data." J Am Geriatr Soc 53(4):735.
Hackett, P. H. and R. C. Roach (2001). "High-altitude illness." N Engl J Med 345(2): 107-114.
Hackett, P. H. and R. C. Roach (2004). "High altitude cerebral edema." High Alt Med Biol 5(2):136-146.
Honigman, B., M. K. Theis, J. Koziol-McLain, R. Roach, R. Yip, C. Houston, L. G. Moore and P. Pearce (1993). "Acute mountain sickness in a general tourist population at moderate altitudes." Ann Intern Med 118(8):587-592.
Huang, H. H., C. Y. Tseng, J. S. Fan, D. H. Yen, W. F. Kao, S. C. Chang, T. B. Kuo, C. I. Huang and C. H. Lee (2010). "Alternations of heart rate variability at lower altitude in the predication of trekkers with acute mountain sickness at high altitude." Clinical journal of sport medicine 20(1):58-63.
Imray, C., A. Wright, A. Subudhi and R. Roach (2010). "Acute mountain sickness: pathophysiology, prevention, and treatment." Prog Cardiovasc Dis 52(6):467-484.
Karinen, H., J. Peltonen and H. Tikkanen (2008). "Prevalence of acute mountain sickness among Finnish trekkers on Mount Kilimanjaro, Tanzania:an observational study." High Alt Med Biol 9(4):301-306.
Karinen, H. M., J. E. Peltonen, M. Kahonen and H. O. Tikkanen (2010). "Prediction of acute mountain sickness by monitoring arterial oxygen saturation during ascent." High Alt Med Biol 11(4):325-332.
Karinen, H. M., A. Uusitalo, H. Vaha-Ypya, M. Kahonen, J. E. Peltonen, P. K. Stein, J. Viik and H. O. Tikkanen (2012). "Heart rate variability changes at 2400 m altitude predicts acute mountain sickness on further ascent at 3000-4300 m altitudes." Front Physiol3:336.
Leone, M. and G Bussone (1993). "A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement." Cephalalgia 13(5):309-317.
Lu, X. J., X. Q. Chen, J. Weng, H. Y. Zhang, D. T. Pak, J. H. Luo and J. Z. Du (2009). "Hippocampal spine-associated Rap-specific GTPase-activating protein induces enhancement of learning and memory in postnatally hypoxia-exposed mice." Neuroscience 162(2):404-414.
Owens, M. J. and C. B. Nemeroff (1991). "Physiology and pharmacology of corticotropin-releasing factor." Pharmacol Rev 43(4):425-473.
Pavlov, E. P., S. M. Harman, G P. Chrousos, D. L. Loriaux and M. R. Blackman (1986). "Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men." J Clin Endocrinol Metab 62(4):767-772.
Richardson, A., R. Twomey, P. Watt and N. Maxwell (2008). "Physiological responses to graded acute normobaric hypoxia using an intermittent walking protocol." Wilderness Environ Med 19(4):252-260.
Rivier, C, M. Brownstein, J. Spiess, J. Rivier and W. Vale (1982). "In vivo corticotropin-releasing factor-induced secretion of adrenocorticotropin, beta-endorphin, and corticosterone." Endocrinology 110(1):272-278.
Roach R. C., B. P., Oelz O., Hackett P. H. (1992). The Lake Louise acute mountain sickness scoring system. Hypoxia and Molecular Medicine. H. C. S. Sutton J. R., Coates G. Queen City Press, Burlington, VT.
Roach, R. C., E. R. Greene, R. B. Schoene and P. H. Hackett (1998). "Arterial oxygen saturation for prediction of acute mountain sickness." Aviat Space Environ Med 69(12):1182-1185.
Stevens, S. L., T. E. Shaw, E. Dykhuizen, N. S. Lessov, J. K. Hill, W. Wurst and M. P. Stenzel-Poore (2003). "Reduced cerebral injury in CRH-Rl deficient mice after focal ischemia:a potential link to microglia and atrocytes that express CRH-R1." J Cereb Blood Flow Metab 23(10):1151-1159.
Tache, Y., V. Martinez, L. Wang and M. Million (2004). "CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity:implications for irritable bowel syndrome." Br J Pharmacol 141(8):1321-1330.
Turnbull, A. V. and C. L. Rivier (1999). "Regulation of the hypothalamic-pituitary-adrenal axis by cytokines:actions and mechanisms of action." Physiol Rev 79(1):1-71.
Vale, W., J. Spiess, C. Rivier and J. Rivier (1981). "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin." Science 213(4514):1394-1397.
Vardy, J., J. Vardy and K. Judge (2006). "Acute mountain sickness and ascent rates in trekkers above 2500 m in the Nepali Himalaya." Aviat Space Environ Med 77(7): 742-744.
Wang, T. Y, X. Q. Chen, J. Z. Du, N. Y Xu, C. B. Wei and W. W. Vale (2004). "Corticotropin-releasing factor receptor type 1 and 2 mRNA expression in the rat anterior pituitary is modulated by intermittent hypoxia, cold and restraint." Neuroscience 128(1):111-119.
Woods, D. R., J. Begley, M. Stacey, C. Smith, C. J. Boos, T. Hooper, A. Hawkins, P. Hodkinson, N. Green and A. Mellor (2012). "Severe acute mountain sickness, brain natriuretic peptide and NT-proBNP in humans." Acta Physiol (Oxf) 205(3): 349-355.
Wu, T. Y., S. Q. Ding, J. L. Liu, M. T. Yu, J. H. Jia, Z. C. Chai, R. C. Dai, S. L. Zhang, B. Y Li, L. Pan, B. Z. Liang, J. Z. Zhao, T. Qi de, Y F. Sun and B. Kayser (2007). "Who should not go high:chronic disease and work at altitude during construction of the Qinghai-Tibet railroad." High Alt Med Biol 8(2):88-107.
Xu, J. F., X. Q. Chen and J. Z. Du (2006). "CRH receptor type 1 mediates continual hypoxia-induced changes of immunoreactive prolactin and prolactin mRNA expression in rat pituitary." Horm Behav 49(2):181-189.
Xu, J. F., X. Q. Chen, J. Z. Du and T. Y Wang (2005). "CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats."Peptidees 26(4):639-646.
You,H.,X.Li,T.Pei,Q.Huang,F.Liu and Y Gao(2012)."Predictive value of basal exhaled nitric oxide and carbon monoxide for acute mountain sickness." Wilderness Environ Med 23(4):316-324.
Bale, T. L. and W. W. Vale (2004). "CRF and CRF receptors:role in stress responsivity and other behaviors." Annu Rev Pharmacol Toxicol 44:525-557.
Chen, X. Q., J. Dong, C. Y. Niu, J. M. Fan and J. Z. Du (2007). "Effects of hypoxia on glucose, insulin, glucagon, and modulation by corticotropin-releasing factor receptor type 1 in the rat." Endocrinology 148(7):3271-3278.
Chen, X. Q., J. Z. Du and Y. S. Wang (2004). "Regulation of hypoxia-induced release of corticotropin-releasing factor in the rat hypothalamus by norepinephrine." Reeul Pept 119(3):221-228.
Corwin, E. J. (2008). Handbook of pathophysiology. Philadelphia, Wolters Kluwer Health/Lippincott Williams & Wilkins.
Cuello, A. C. (1983). Brain microdissection techniques. Chichester England; New York, Wiley.
De Souza, E. B. (1995). "Corticotropin-releasing factor receptors:physiology, pharmacology, biochemistry and role in central nervous system and immune disorders." Psvchoneuroendocrinology 20(8):789-819.
Miller, D. B. and J. P. O'Callaghan (2002). "Neuroendocrine aspects of the response to stress." Metabolism 51(6 Suppl 1):5-10.
Owens, M. J. and C. B. Nemeroff (1991). "Physiology and pharmacology of corticotropin-releasing factor." Pharmacol Rev 43(4):425-473.
Pavlov, E. P., S. M. Harman, G P. Chrousos, D. L. Loriaux and M. R. Blackman (1986). "Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men." J Clin Endocrinol Metab 62(4):767-772.
Paxinos, G. and C. Watson (1998). The rat brain in stereotaxic coordinates. San Diego, Academic Press.
Piazza, J. R., D. M. Almeida, N. O. Dmitrieva and L. C. Klein (2010). "Frontiers in the use of biomarkers of health in research on stress and aging." J Gerontol B Psychol Sci Soc Sci 65(5):513-525.
Rivier, C., M. Brownstein, J. Spiess, J. Rivier and W. Vale (1982). "In vivo corticotropin-releasing factor-induced secretion of adrenocorticotropin, beta-endorphin, and corticosterone." Endocrinology 110(1):272-278.
Sasaki, A., S. Sato, O. Murakami, M. Go, M. Inoue, Y. Shimizu, K. Hanew, N. Andoh, I. Sato, N. Sasano and et al. (1987). "Immunoreactive corticotropin-releasing hormone present in human plasma may be derived from both hypothalamic and extrahypothalamic sources." J Clin Endocrinol Metab 65(1):176-182.
Sumitomo, T., T. Suda, N. Tomori, F. Yajima, Y. Nakagami, T. Ushiyama, H. Demura and K. Shizume (1987). "Immunoreactive corticotropin-releasing factor in rat plasma." Endocrinology 120(4):1391-1396.
Turnbull, A. V. and C. L. Rivier (1999). "Regulation of the hypothalamic-pituitary-adrenal axis by cytokines:actions and mechanisms of action." Physiol Rev 79(1):1-71.
Vale, W., J. Spiess, C. Rivier and J. Rivier (1981). "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin." Science 213(4514):1394-1397.
Wang, T. Y, X. Q. Chen, J. Z. Du, N. Y Xu, C. B. Wei and W. W. Vale (2004). "Corticotropin-releasing factor receptor type 1 and 2 mRNA expression in the rat anterior pituitary is modulated by intermittent hypoxia, cold and restraint." Neuroscience 128(1):111-119.
Xu, J. F., X. Q. Chen and J. Z. Du (2006). "CRH receptor type 1 mediates continual hypoxia-induced changes of immunoreactive prolactin and prolactin mRNA expression in rat pituitary." Horm Behav 49(2):181-189.
Xu, J. F., X. Q. Chen, J. Z. Du and T. Y. Wang (2005). "CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats." Peptides 26(4):639-646.
Bale, T. L., A. Contarino, G W. Smith, R. Chan, L. H. Gold, P. E. Sawchenko, G F. Koob, W. W. Vale and K. F. Lee (2000). "Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress." Nat Genet 24(4):410-414.
Bale, T. L. and W. W. Vale (2004). "CRF and CRF receptors:role in stress responsivity and other behaviors." Annu Rev Pharmacol Toxicol 44:525-557.
Chalmers, D. T., T. W. Lovenberg and E. B. De Souza (1995). "Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain:comparison with CRF1 receptor mRNA expression." J Neurosci 15(10):6340-6350.
Chen, X. Q., F. P. Kong, Y. Zhao and J. Z. Du (2012). "High-altitude hypoxia induces disorder of the brain-endocrine-immune network though activation of corticotrophin-releasing factor and its type-1 receptors." Zhongguo Ying Yong Sheng Li Xue Za Zhi 28(6):481-487.
Coste, S. C., R. A. Kesterson, K. A. Heldwein, S. L. Stevens, A. D. Heard, J. H. Hollis, S. E. Murray, J. K. Hill, G A. Pantely, A. R. Hohimer, D. C. Hatton, T. J. Phillips, D. A. Finn, M. J. Low, M. B. Rittenberg, P. Stenzel and M. P. Stenzel-Poore (2000). "Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2." Nat Genet 24(4):403-409.
Cuello, A. C. (1983). Brain microdissection techniques. Chichester England; New York, Wiley.
Dautzenberg, F. M., G J. Kilpatrick, R. L. Hauger and J. Moreau (2001). "Molecular biology of the CRH receptors--in the mood." Peptides 22(5):753-760.
Heinrichs, S. C. and E. B. De Souza (1999). "Corticotropin-releasing factor antagonists, binding-protein and receptors:implications for central nervous system disorders." Baillieres Best Pract Res Clin Endocrinol Metab 13(4):541-554.
Imaki, T., M. Naruse, S. Harada, N. Chikada, J. Imaki, H. Onodera, H. Demura and W. Vale (1996). "Corticotropin-releasing factor up-regulates its own receptor mRNA in the paraventricular nucleus of the hypothalamus." Brain Res Mol Brain Res 38(1):166-170.
Imray, C., A. Wright, A. Subudhi and R. Roach (2010). "Acute mountain sickness: pathophysiology, prevention, and treatment." Prog Cardiovasc Dis 52(6):467-484.
Lovenberg, T. W., D. T. Chalmers, C. Liu and E. B. De Souza (1995). "CRF2 alpha and CRF2 beta receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues." Endocrinology 136(9):4139-4142.
Maiti, P., S. B. Singh, S. Muthuraju, S. Veleri and G Ilavazhagan (2007). "Hypobaric hypoxia damages the hippocampal pyramidal neurons in the rat brain." Brain Res 1175:1-9.
Paxinos, G and C. Watson (1998). The rat brain in stereotaxic coordinates. San Diego, Academic Press.
Potter, E., S. Sutton, C. Donaldson, R. Chen, M. Perrin, K. Lewis, P. E. Sawchenko and W. Vale (1994). "Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary." Proc Natl Acad Sci U S A 91(19): 8777-8781.
Rybnikova, E., N. Sitnik, T. Gluschenko, E. Tjulkova and M. O. Samoilov (2006). "The preconditioning modified neuronal expression of apoptosis-related proteins of Bcl-2 superfamily following severe hypobaric hypoxia in rats." Brain Res 1089(1): 195-202.
Sanchez, M. M., L. J. Young, P. M. Plotsky and T. R. Insel (1999). "Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain." J Comp Neurol 408(3):365-377.
Silverman, A. J., A. Hou-Yu and W. P. Chen (1989). "Corticotropin-releasing factor synapses within the paraventricular nucleus of the hypothalamus." Neuroendocrinology 49(3):291-299.
Smith, G. W., J. M. Aubry, F. Dellu, A. Contarino, L. M. Bilezikjian, L. H. Gold, R. Chen, Y. Marchuk, C. Hauser, C. A. Bentley, P. E. Sawchenko, G. F. Koob, W. Vale and K. F. Lee (1998). "Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development." Neuron 20(6):1093-1102.
Stevens, S. L., T. E. Shaw, E. Dykhuizen, N. S. Lessov, J. K. Hill, W. Wurst and M. P. Stenzel-Poore (2003). "Reduced cerebral injury in CRH-R1 deficient mice after focal ischemia:a potential link to microglia and atrocytes that express CRH-R1." J Cereb Blood Flow Metab 23(10):1151-1159.
Timpl, P., R. Spanagel, I. Sillaber, A. Kresse, J. M. Reul, G. K. Stalla, V. Blanquet, T. Steckler, F. Holsboer and W. Wurst (1998). "Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1." Nat Genet 19(2):162-166.
Titus, A. D., B. S. Shankaranarayana Rao, H. N. Harsha, K. Ramkumar, B. N. Srikumar, S. B. Singh, S. Chattarji and T. R. Raju (2007). "Hypobaric hypoxia-induced dendritic atrophy of hippocampal neurons is associated with cognitive impairment in adult rats." Neuroscience 145(1):265-278.
Wallace, M. G., K. D. Hartle, W. M. Snow, N. L. Ward and T. L. Ivanco (2007). "Effect of hypoxia on the morphology of mouse striatal neurons." Neuroscience 147(1): 90-96.
Wang, M. J., S. Z. Lin, J. S. Kuo, H. Y. Huang, S. F. Tzeng, C. H. Liao, D. C. Chen and W. F. Chen (2007). "Urocortin modulates inflammatory response and neurotoxicity induced by microglial activation." J Immunol 179(9):6204-6214.
Xu, J. F., X. Q. Chen, J. Z. Du and T. Y. Wang (2005). "CRF receptor type 1 mediates continual hypoxia-induced CRF peptide and CRF mRNA expression increase in hypothalamic PVN of rats." Peptides 26(4):639-646.
Yang, Y, E. Hahm, Y. Kim, J. Kang, W. Lee, I. Han, P. Myung, H. Kang, H. Park and D. Cho (2005). "Regulation of IL-18 expression by CRH in mouse microglial cells." Immunol Lett 98(2):291-296.
Bale, T. L. and W. W. Vale (2004). "CRF and CRF receptors:role in stress responsivity and other behaviors." Annu Rev Pharmacol Toxicol 44:525-557.
Brancaccio, P., G. Lippi and N. Maffulli (2010). "Biochemical markers of muscular damage." Clin Chem Lab Med 48(6):757-767.
Buckley, T. M. and A. F. Schatzberg (2005). "On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep:normal HPA axis activity and circadian rhythm, exemplary sleep disorders." J Clin Endocrinol Metab 90(5): 3106-3114.
Cai, A. and P. M. Wise (1996). "Age-related changes in the diurnal rhythm of CRH gene expression in the paraventricular nuclei." Am J Physiol 270(2 Pt 1):E238-243.
Dautzenberg, F. M. and R. L. Hauger (2002). "The CRF peptide family and their receptors:yet more partners discovered." Trends Pharmacol Sci 23(2):71-77.
Dempsey, J. A. and P. D. Wagner (1999). "Exercise-induced arterial hypoxemia." J Appl Physiol 87(6):1997-2006.
Florio, P., M. C. Zatelli, F. M. Reis, E. C. degli Uberti and F. Petraglia (2007). "Corticotropin releasing hormone:a diagnostic marker for behavioral and reproductive disorders?" Front Biosci 12:551-560.
Hellhammer, D. H., S. Wust and B. M. Kudielka (2009). "Salivary cortisol as a biomarker in stress research." Psychoneuroendocrinology 34(2):163-171.
Kirschbaum, C. and D. H. Hellhammer (1994). "Salivary cortisol in psychoneuroendocrine research:recent developments and applications." Psychoneuroendocrinology 19(4):313-333.
Kling, M. A., A. Roy, A. R. Doran, J. R. Calabrese, D. R. Rubinow, H. J. Whitfield, Jr., C. May, R. M. Post, G. P. Chrousos and P. W. Gold (1991). "Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing's disease and major depression:potential clinical implications." J Clin Endocrinol Metab 72(2):260-271.
Kwak, S. P., M. I. Morano, E. A. Young, S. J. Watson and H. Akil (1993). "Diurnal CRH mRNA rhythm in the hypothalamus:decreased expression in the evening is not dependent on endogenous glucocorticoids." Neuroendocrinology 57(1):96-105.
Liu, J. and Y. Duan (2012). "Saliva:a potential media for disease diagnostics and monitoring." Oral Oncol 48(7):569-577.
Mastorakos, G, E. A. Bouzas, P. B. Silver, G Sartani, T. C. Friedman, C. C. Chan, R. R. Caspi and G P. Chrousos (1995). "Immune corticotropin-releasing hormone is present in the eyes of and promotes experimental autoimmune uveoretinitis in rodents." Endocrinology 136(10):4650-4658.
Mastorakos, G, M. A. Magiakou and G P. Chrousos (1995). "Effects of the immune/inflammatory reaction on the hypothalamic-pituitary-adrenal axis." Ann N Y Acad Sci 771:438-448.
Nagler, R. M., S. Lischinsky, E. Diamond, I. Klein and A. Z. Reznick (2001). "New insights into salivary lactate dehydrogenase of human subjects." J Lab Clin Med 137(5):363-369.
Nemeroff, C. B., E. Widerlov, G. Bissette, H. Walleus, I. Karlsson, K. Eklund, C. D. Kilts, P. T. Loosen and W. Vale (1984). "Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients." Science 226(4680):1342-1344.
Pfaffe, T., J. Cooper-White, P. Beyerlein, K. Kostner and C. Punyadeera (2011). "Diagnostic potential of saliva:current state and future applications." Clin Chem 57(5):675-687.
Powers, R. E., L. C. Walker, E. B. DeSouza, W. W. Vale, R. G Struble, P. J. Whitehouse and D. L. Price (1987). "Immunohistochemical study of neurons containing corticotropin-releasing factor in Alzheimer's disease." Synapse 1(5):405-410.
Roy, A., D. Pickar, S. Paul, A. Doran, G P. Chrousos and P. W. Gold (1987). "CSF corticotropin-releasing hormone in depressed patients and normal control subjects." Am J Psychiatry 144(5):641-645.
Sasaki, A., S. Sato, O. Murakami, M. Go, M. Inoue, Y. Shimizu, K. Hanew, N. Andoh, I. Sato, N. Sasano and et al. (1987). "Immunoreactive corticotropin-releasing hormone present in human plasma may be derived from both hypothalamic and extrahypothalamic sources." J Clin Endocrinol Metab 65(1):176-182.
Sasaki, A., O. Shinkawa, A. N. Margioris, A. S. Liotta, S. Sato, O. Murakami, M. Go, Y. Shimizu, K. Hanew and K. Yoshinaga (1987). "Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor, and delivery." J Clin Endocrinol Metab 64(2):224-229.
Watts, A. G., S. Tanimura and G. Sanchez-Watts (2004). "Corticotropin-releasing hormone and arginine vasopressin gene transcription in the hypothalamic paraventricular nucleus of unstressed rats:daily rhythms and their interactions with corticosterone." Endocrinology 145(2):529-540.
Whitehouse, P. J., W. W. Vale, R. M. Zweig, H. S. Singer, R. Mayeux, M. J. Kuhar, D. L. Price and E. B. De Souza (1987). "Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy." Neurology 37(6):905-909.
Arlt, J., H. Jahn, M. Kellner, A. Strohle, A. Yassouridis and K. Wiedemann (2003). "Modulation of sympathetic activity by corticotropin-releasing hormone and atrial natriuretic peptide." Neuropeptides 37(6):362-368.
Austin, D. and J. Sleigh (1995). "Prediction of acute mountain sickness." BMJ 311(7011):989-990.
Bailey, D. M., S. Taudorf, R. M. Berg, C. Lundby, J. McEneny, I. S. Young, K. A. Evans, P. E. James, A. Shore, D. A. Hullin, J. M. McCord, B. K. Pedersen and K. Moller (2009). "Increased cerebral output of free radicals during hypoxia:implications for acute mountain sickness?" Am J Physiol Regul Integr Comp Physiol 297(5): R1283-1292.
Bale, T. L. and W. W. Vale (2004). "CRF and CRF receptors:role in stress responsivity and other behaviors." Annu Rev Pharmacol Toxicol 44:525-557.
Bartsch, P., E. R. Swenson, A. Paul, B. Julg and E. Hohenhaus (2002). "Hypoxic ventilatory response, ventilation, gas exchange, and fluid balance in acute mountain sickness." High Alt Med Biol 3(4):361-376.
Basnyat, B. and D. R. Murdoch (2003). "High-altitude illness." Lancet 361(9373): 1967-1974.
Bernardi, L., A. Schneider, L. Pomidori, E. Paolucci and A. Cogo (2006). "Hypoxic ventilatory response in successful extreme altitude climbers." Eur Respir J 27(1): 165-171.
Bourbia, N., O. B. Ansah and A. Pertovaara (2010). "Corticotropin-releasing factor in the rat amygdala differentially influences sensory-discriminative and emotional-like pain response in peripheral neuropathy." J Pain 11(12):1461-1471.
Buckley, T. M. and A. F. Schatzberg (2005). "On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep:normal HPA axis activity and circadian rhythm, exemplary sleep disorders." J Clin Endocrinol Metab 90(5): 3106-3114.
Burtscher, M., C. Szubski and M. Faulhaber (2008). "Prediction of the susceptibility to AMS in simulated altitude." Sleep Breath 12(2):103-108.
Carskadon, M. and W. Dement (2000). Normal human sleep:an overview. Principles and practice of sleep medicine. M. H. Kryger, T. Roth and W. C. Dement. Philadelphia, Saunders:15-25.
Chen, X. Q., F. P. Kong, Y. Zhao and J. Z. Du (2012). "High-altitude hypoxia induces disorder of the brain-endocrine-immune network though activation of corticotrophin-releasing factor and its type-1 receptors." Zhongguo Ying Yong Sheng Li Xue Za Zhi 28(6):481-487.
Compte-Torrero, L., J. Botella de Maglia, A. de Diego-Damia, L. Gomez-Perez, P. Ramirez-Galleymore and M. Perpina-Tordera (2005). "[Changes in spirometric parameters and arterial oxygen saturation during a mountain ascent to over 3000 meters]." Arch Bronconeumol 41(10):547-552.
Duplain, H., L. Vollenweider, A. Delabays, P. Nicod, P. Bartsch and U. Scherrer (1999). "Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema." Circulation 99(13):1713-1718.
Ehlers, C. L., T. K. Reed and S. J. Henriksen (1986). "Effects of corticotropin-releasing factor and growth hormone-releasing factor on sleep and activity in rats." Neuroendocrinology 42(6):467-474.
Fu, Y. and V. Neugebauer (2008). "Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior." J Neurosci 28(15):3861-3876.
Fukudo, S. (2007). "Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation." J Gastroenterol 42 Suppl 17:48-51.
Graham, J. and D. Potyk (2005). "Age and acute mountain sickness:examining the data." J Am Geriatr Soc 53(4):735.
Hackett, P. H., D. Rennie, S. E. Hofmeister, R. F. Grover, E. B. Grover and J. T. Reeves (1982). "Fluid retention and relative hypoventilation in acute mountain sickness." Respiration 43(5):321-329.
Hainsworth, R., M. J. Drinkhill and M. Rivera-Chira (2007). "The autonomic nervous system at high altitude." Clin Auton Res 17(1):13-19.
Hohenhaus, E., A. Paul, R. E. McCullough, H. Kucherer and P. Bartsch (1995). "Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema." Eur Respir J 8(11):1825-1833.
Holsboer, F., U. von Bardeleben and A. Steiger (1988). "Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man." Neuroendocrinology 48(1):32-38.
Huang, H. H., C. Y. Tseng, J. S. Fan, D. H. Yen, W. F. Kao, S. C. Chang, T. B. Kuo, C. I. Huang and C. H. Lee (2010). "Alternations of heart rate variability at lower altitude in the predication of trekkers with acute mountain sickness at high altitude." Clinical journal of sport medicine 20(1):58-63.
Imray, C., A. Wright, A. Subudhi and R. Roach (2010). "Acute mountain sickness: pathophysiology, prevention, and treatment." Prog Cardiovasc Dis 52(6):467-484.
Kanazawa, M., M. Hongo and S. Fukudo (2011). "Visceral hypersensitivity in irritable bowel syndrome." J Gastroenterol Hepatol 26 Suppl 3:119-121.
Kao, W. F., C. C. Kuo, T. F. Hsu, H. Chang, Y. Y. Sung, D. H. Yen, J. K. Wu and C. H. Lee (2002). "Acute mountain sickness in Jade Mountain climbers of Taiwan." Aviat Space Enyiron Med 73(4):359-362.
Karinen, H. M., J. E. Peltonen, M. Kahonen and H. O. Tikkanen (2010). "Prediction of acute mountain sickness by monitoring arterial oxygen saturation during ascent." High Alt Med Biol 11(4):325-332.
Karinen, H. M., A. Uusitalo, H. Vaha-Ypya, M. Kahonen, J. E. Peltonen, P. K. Stein, J. Viik and H. O. Tikkanen (2012). "Heart rate variability changes at 2400 m altitude predicts acute mountain sickness on further ascent at 3000-4300 m altitudes." Front Phvsiol 3:336.
Kimura, M., P. Muller-Preuss, A. Lu, E. Wiesner, C. Flachskamm, W. Wurst, R Holsboer and J. M. Deussing (2010). "Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep." Mol Psychiatry 15(2):154-165.
King, A. B. and S. M. Robinson (1972). "Ventilation response to hypoxia and acute mountain sickness." Aerosp Med 43(4):419-421.
La, J. H., T. S. Sung, H. J. Kim, T. W. Kim, T. M. Kang and I. S. Yang (2008). "Peripheral corticotropin releasing hormone mediates post-inflammatory visceral hypersensitivity in rats." World J Gastroenterol 14(5):731-736.
Lariviere, W. R., P. Fiorenzani, I. Ceccarelli, C. Massafra, G. Sorda, C. Di Canio and A. M. Aloisi (2011). "Central CRH administration changes formalin pain responses in male and female rats." Brain Res 1383:128-134.
Leone, M. and G Bussone (1993). "A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement." Cephalalgia 13(5):309-317.
Luks, A. M. and E. R. Swenson (2011). "Pulse oximetry at high altitude." High Alt Med Biol 12(2):109-119.
Mason, N. P., P. W. Barry, A. J. Pollard, D. J. Collier, N. A. Taub, M. R. Miller and J. S. Milledge (2000). "Serial changes in spirometry during an ascent to 5,300 m in the Nepalese Himalayas." High Alt Med Biol 1(3):185-195.
Mimassi, N., F. Lancien, D. Mabin, C. Delarue, J. M. Conlon and J. C. Le Mevel (2003). "Induction of bradycardia in trout by centrally administered corticotropin-releasing-hormone (CRH)." Brain Res 982(2):211-218.
Moore, L. G., G. L. Harrison, R. E. McCullough, R. G. McCullough, A. J. Micco, A. Tucker, J. V. Weil and J. T. Reeves (1986). "Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness." J Appl Physiol 60(4): 1407-1412.
Nijsen, M. J., G Croiset, R. Stam, A. Bruijnzeel, M. Diamant, D. de Wied and V. M. Wiegant (2000). "The role of the CRH type 1 receptor in autonomic responses to corticotropin- releasing hormone in the rat." Neuropsychopharmacology 22(4): 388-399.
Raadsheer, F. C., W. J. Hoogendijk, F. C. Stam, F. J. Tilders and D. F. Swaab (1994). "Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients." Neuroendocrinology 60(4):436-444.
Richardson, A., R. Twomey, P. Watt and N. Maxwell (2008). "Physiological responses to graded acute normobaric hypoxia using an intermittent walking protocol." Wilderness Enyiron Med 19(4):252-260.
Roach R. C, B. P., Oelz O., Hackett P. H. (1992). The Lake Louise acute mountain sickness scoring system. Hypoxia and Molecular Medicine. H. C. S. Sutton J. R., Coates G Queen City Press, Burlington, VT.
Roach, R. C., E. R. Greene, R. B. Schoene and P. H. Hackett (1998). "Arterial oxygen saturation for prediction of acute mountain sickness." Aviat Space Environ Med 69(12):1182-1185.
Sagami, Y., Y. Shimada, J. Tayama, T. Nomura, M. Satake, Y. Endo, T. Shoji, K. Karahashi, M. Hongo and S. Fukudo (2004). "Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome." Gut 53(7):958-964.
Saito, S., H. Shimada, T. Imai, Y. Futamata and K. Yamamori (1995). "Estimation of the degree of acclimatization to high altitude by a rapid and simple physiological examination." Int Arch Occup Environ Health 67(5):347-351.
Saito, S., K. Tanobe, M. Yamada and F. Nishihara (2005). "Relationship between arterial oxygen saturation and heart rate variability at high altitudes." Am J Emerg Med 23(1):8-12.
Savourey, G., J. C. Launay, Y. Besnard, A. Guinet-Lebreton, A. Alonso, F. Sauvet and C. Bourrilhon (2007). "Normo or hypobaric hypoxic tests:propositions for the determination of the individual susceptibility to altitude illnesses." Eur J Appl Physiol 100(2):193-205.
Savourey, G., C. Moirant, J. Eterradossi and J. Bittel (1995). "Acute mountain sickness relates to sea-level partial pressure of oxygen." Eur J Appl Physiol Occup Physiol 70(6):469-476.
Schirlo, C., V. Pavlicek, A. Jacomet, J. S. Gibbs, E. Koller, O. Oelz, M. Seebauer and J. Kohl (2002). "Characteristics of the ventilatory response in subjects susceptible to high altitude pulmonary edema during acute and prolonged hypoxia." High Alt Med Bioi 3(3):267-276.
Sevre, K., B. Bendz, E. Hanko, A. R. Nakstad, A. Hauge, J. I. Kasin, J. D. Lefrandt, A. J. Smit, I. Eide and M. Rostrup (2001). "Reduced autonomic activity during stepwise exposure to high altitude." Acta Physiol Scand 173(4):409-417.
Sutton, J. R., A. C. Bryan, G. W. Gray, E. S. Horton, A. S. Rebuck, W. Woodley, I. D. Rennie and C. S. Houston (1976). "Pulmonary gas exchange in acute mountain sickness." Ayiat Space Enyiron Med 47(10):1032-1037.
Tache, Y, V. Martinez, L. Wang and M. Million (2004). "CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity:implications for irritable bowel syndrome." Br J Pharmacol 141(8):1321-1330.
Theoharides, T. C. (1999). Treatment of stress-induced migraine headache with a corticotropin releasing hormone blocker, Google Patents.
West, J. B. (2000). "Human limits for hypoxia. The physiological challenge of climbing Mt. Everest." Ann N Y Acad Sci 899:15-27.
Wilson, M. H., C. H. Imray and A. R. Hargens (2011). "The headache of high altitude and microgravity--similarities with clinical syndromes of cerebral venous hypertension." High Alt Med Biol 12(4):379-386.
Woods, D. R., J. Begley, M. Stacey, C. Smith, C. J. Boos, T. Hooper, A. Hawkins, P. Hodkinson, N. Green and A. Mellor (2012). "Severe acute mountain sickness, brain natriuretic peptide and NT-proBNP in humans." Acta Physiol (Oxf) 205(3): 349-355.
You, H., X. Li, T. Pei, Q. Huang, F. Liu and Y. Gao (2012). "Predictive value of basal exhaled nitric oxide and carbon monoxide for acute mountain sickness." Wilderness Enyiron Med 23(4):316-324.
Zuzewicz, K., B. Biernat, G. Kempa and K. Kwarecki (1999). "Heart rate variability in exposure to high altitude hypoxia of short duration." Int J Occup Saf Ergon 5(3): 337-346.
Aeberli, I., A. Erb, K. Spliethoff, D. Meier, O. Gotze, H. Fruhauf, M. Fox, G. S. Finlayson, M. Gassmann, K. Berneis, M. Maggiorini, W. Langhans and T. A. Lutz (2013). "Disturbed eating at high altitude:influence of food preferences, acute mountain sickness and satiation hormones." Eur J Nutr 52(2):625-635.
Ashina, M., L. Bendtsen, R. Jensen, R. Ekman and J. Olesen (1999). "Plasma levels of substance P, neuropeptide Y and vasoactive intestinal polypeptide in patients with chronic tension-type headache." Pain 83(3):541-547.
Austin, D. and J. Sleigh (1995). "Prediction of acute mountain sickness." BMJ 311(7011):989-990.
Bailey, D. M. and B. Davies (2001). "Acute mountain sickness; prophylactic benefits of antioxidant vitamin supplementation at high altitude." High Alt Med Biol 2(1): 21-29.
Bartsch, P., E. R. Swenson, A. Paul, B. Julg and E. Hohenhaus (2002). "Hypoxic ventilatory response, ventilation, gas exchange, and fluid balance in acute mountain sickness." High Alt Med Biol 3(4):361-376.
Basnyat, B. and D. R. Murdoch (2003). "High-altitude illness." Lancet 361(9373): 1967-1974.
Baumgartner, R. W., I. Spyridopoulos, P. Bartsch, M. Maggiorini and O. Oelz (1999). "Acute mountain sickness is not related to cerebral blood flow:a decompression chamber study." J Appl Physiol 86(5):1578-1582.
Beidleman, B. A., S. R. Muza, C. S. Fulco, A. Cymerman, M. N. Sawka, S. F. Lewis and G. S. Skrinar (2008). "Seven intermittent exposures to altitude improves exercise performance at 4300 m." Med Sci Sports Exerc 40(1):141-148.
Bernardi, L., A. Schneider, L. Pomidori, E. Paolucci and A. Cogo (2006). "Hypoxic ventilatory response in successful extreme altitude climbers." Eur Respir J 27(1): 165-171.
Bernhard, W. N., L. M. Schalick, P. A. Delaney, T. M. Bernhard and G. M. Barnas (1998). "Acetazolamide plus low-dose dexamethasone is better than acetazolamide alone to ameliorate symptoms of acute mountain sickness." Aviat Space Environ Med 69(9):883-886.
Buckley, T. M. and A. F. Schatzberg (2005). "On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep:normal HPA axis activity and circadian rhythm, exemplary sleep disorders." J Clin Endocrinol Metab 90(5): 3106-3114.
Burtscher, M., C. Szubski and M. Faulhaber (2008). "Prediction of the susceptibility to AMS in simulated altitude." Sleep Breath 12(2):103-108.
Carlsten, C., E. R. Swenson and S. Ruoss (2004). "A dose-response study of acetazolamide for acute mountain sickness prophylaxis in vacationing tourists at 12,000 feet (3630 m)." High Alt Med Biol 5(1):33-39.
Carskadon, M. and W. Dement (2000). Normal human sleep:an overview. Principles and practice of sleep medicine. M. H. Kryger, T. Roth and W. C. Dement. Philadelphia, Saunders:15-25.
Chen, H. C., W. L. Lin, J. Y. Wu, S. H. Wang, T. F. Chiu, Y. M. Weng, T. Y. Hsu and M. H. Wu (2012). "Change in oxygen saturation does not predict acute mountain sickness on Jade Mountain." Wilderness Environ Med 23(2):122-127.
Chen, X. Q., F. P. Kong, Y. Zhao and J. Z. Du (2012). "High-altitude hypoxia induces disorder of the brain-endocrine-immune network though activation of corticotrophin-releasing factor and its type-1 receptors." Zhongguo Ying Yong Shene Li Xue Za Zhi 28(6):481-487.
Chow, T., V. Browne, H. L. Heileson, D. Wallace, J. Anholm and S. M. Green (2005). "Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness:a randomized, placebo-controlled trial." Arch Intern Med 165(3):296-301.
Compte-Torrero, L., J. Botella de Maglia, A. de Diego-Damia, L. Gomez-Perez, P. Ramirez-Galleymore and M. Perpina-Tordera (2005). "[Changes in spirometric parameters and arterial oxygen saturation during a mountain ascent to over 3000 meters]." Arch Bronconeumol 41(10):547-552.
Ding, H., Q. Liu, M. Hua, M. Ding, H. Du, W. Zhang, Z. Li and J. Zhang (2011). "Polymorphisms of hypoxia-related genes in subjects susceptible to acute mountain sickness." Respiration 81(3):236-241.
Duplain, H., L. Vollenweider, A. Delabays, P. Nicod, P. Bartsch and U. Scherrer (1999). "Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema." Circulation 99(13):1713-1718.
Ehlers, C. L., T. K. Reed and S. J. Henriksen (1986). "Effects of corticotropin-releasing factor and growth hormone-releasing factor on sleep and activity in rats." Neuroendocrinology 42(6):467-474.
Ferrazzini, G, M. Maggiorini, S. Kriemler, P. Bartsch and O. Oelz (1987). "Successful treatment of acute mountain sickness with dexamethasone." Br Med J (Clin Res Ed) 294(6584):1380-1382.
Fukudo, S. (2007). "Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation." J Gastroenterol 42 Suppl 17:48-51.
Gertsch, J. H., B. Basnyat, E. W. Johnson, J. Onopa and P. S. Holck (2004). "Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers:the prevention of high altitude illness trial (PHAIT)." BMJ 328(7443): 797.
Gertsch, J. H., T. B. Seto, J. Mor and J. Onopa (2002). "Ginkgo biloba for the prevention of severe acute mountain sickness (AMS) starting one day before rapid ascent." High Alt Med Biol 3(1):29-37.
Hackett, P. H., D. Rennie, S. E. Hofmeister, R. F. Grover, E. B. Grover and J. T. Reeves (1982). "Fluid retention and relative hypoventilation in acute mountain sickness." Respiration 43(5):321-329.
Hackett, P. H., D. Rennie and H. D. Levine (1976). "The incidence, importance, and prophylaxis of acute mountain sickness." Lancet 2(7996):1149-1155.
Hackett, P. H. and R. C. Roach (1987). "Medical therapy of altitude illness." Ann Emerg Med 16(9):980-986.
Hackett, P. H. and R. C. Roach (2001). "High-altitude illness." N Engl J Med 345(2): 107-114.
Hackett, P. H. and R. C. Roach (2004). "High altitude cerebral edema." High Alt Med Biol 5(2):136-146.
Hackett, P. H., R. C. Roach, R. A. Wood, R. G. Foutch, R. T. Meehan, D. Rennie and W. J. Mills, Jr. (1988). "Dexamethasone for prevention and treatment of acute mountain sickness." Aviat Space Enyiron Med 59(10):950-954.
Hainsworth, R., M. J. Drinkhill and M. Rivera-Chira (2007). "The autonomic nervous system at high altitude." Clin Auton Res 17(1):13-19.
Hall, D. P., I. J. MacCormick, A. T. Phythian-Adams, N. M. Rzechorzek, D. Hope-Jones, S. Cosens, S. Jackson, M. G. Bates, D. J. Collier and D. A. Hume (2013). "Network analysis reveals distinct clinical syndromes underlying acute mountain sickness." arXiv preprint arXiv:1303.6525.
Hillebrand, J. J., D. de Wied and R. A. Adan (2002). "Neuropeptides, food intake and body weight regulation:a hypothalamic focus." Peptides 23(12):2283-2306.
Hohenhaus, E., A. Paul, R. E. McCullough, H. Kucherer and P. Bartsch (1995). "Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema." Eur Respir J 8(11):1825-1833.
Holsboer, F., U. von Bardeleben and A. Steiger (1988). "Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man." Neuroendocrinology 48(1):32-38.
Honigman, B., M. K. Theis, J. Koziol-McLain, R. Roach, R. Yip, C. Houston, L. G. Moore and P. Pearce (1993). "Acute mountain sickness in a general tourist population at moderate altitudes." Ann Intern Med 118(8):587-592.
Houston, C. S. (1989). "Incidence of acute mountain sickness at intermediate altitudes." JAMA 261(24):3551-3552.
Huang, H. H., C. Y. Tseng, J. S. Fan, D. H. Yen, W. F. Kao, S. C. Chang, T. B. Kuo, C. I. Huang and C. H. Lee (2010). "Alternations of heart rate variability at lower altitude in the predication of trekkers with acute mountain sickness at high altitude." Clinical journal of sport medicine 20(1):58-63.
Huang, S. Y, L. G. Moore, R. E. McCullough, R. G. McCullough, A. J. Micco, C. Fulco, A. Cymerman, M. Manco-Johnson, J. V. Weil and J. T. Reeves (1987). "Internal carotid and vertebral arterial flow velocity in men at high altitude." J Appl Physiol 63(1):395-400.
Imray, C. (2012). "Acetazolamide for the prophylaxis of acute mountain sickness." BMJ 345:e7077.
Imray, C., A. Wright, A. Subudhi and R. Roach (2010). "Acute mountain sickness: pathophysiology, prevention, and treatment." Prog Cardiovasc Dis 52(6):467-484.
Jafarian, S., F. Gorouhi, A. Taghva and J. Lotfi (2008). "High-altitude sleep disturbance: results of the Groningen Sleep Quality Questionnaire survey." Sleep Med 9(4): 446-449.
Jensen, J. B., A. D. Wright, N. A. Lassen, T. C. Harvey, M. H. Winterborn, M. E. Raichle and A. R. Bradwell (1990). "Cerebral blood flow in acute mountain sickness." J Appl Physiol 69(2):430-433.
Johnson, T. S., P. B. Rock, C. S. Fulco, L. A. Trad, R. F. Spark and J. T. Maher (1984). "Prevention of acute mountain sickness by dexamethasone." N Engl J Med 310(11): 683-686.
Kallenberg, K., D. M. Bailey, S. Christ, A. Mohr, R. Roukens, E. Menold, T. Steiner, P. Bartsch and M. Knauth (2007). "Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness." J Cereb Blood Flow Metab 27(5):1064-1071.
Kanazawa, M., M. Hongo and S. Fukudo (2011). "Visceral hypersensitivity in irritable bowel syndrome." J Gastroenterol Hepatol 26 Suppl 3:119-121.
Kao, W. F., C. C. Kuo, T. F. Hsu, H. Chang, Y. Y. Sung, D. H. Yen, J. K. Wu and C. H. Lee (2002). "Acute mountain sickness in Jade Mountain climbers of Taiwan." Aviat Space Environ Med 73(4):359-362.
Karinen, H., J. Peltonen and H. Tikkanen (2008). "Prevalence of acute mountain sickness among Finnish trekkers on Mount Kilimanjaro, Tanzania:an observational study." High Alt Med Biol 9f41:301-306.
Karinen, H. M., J. E. Peltonen, M. Kahonen and H. O. Tikkanen (2010). "Prediction of acute mountain sickness by monitoring arterial oxygen saturation during ascent." High Alt Med Biol 11(4):325-332.
Karinen, H. M., A. Uusitalo, H. Vaha-Ypya, M. Kahonen, J. E. Peltonen, P. K. Stein, J. Viik and H. O. Tikkanen (2012). "Heart rate variability changes at 2400 m altitude predicts acute mountain sickness on further ascent at 3000-4300 m altitudes." Front Physiol 3:336.
Kayser, B., L. Dumont, C. Lysakowski, C. Combescure, G. Haller and M. R. Tramer (2012). "Reappraisal of acetazolamide for the prevention of acute mountain sickness:a systematic review and meta-analysis." High Alt Med Biol 13(2):82-92.
King, A. B. and S. M. Robinson (1972). "Ventilation response to hypoxia and acute mountain sickness." Aerosp Med 43(4):419-421.
La, J. H., T. S. Sung, H. J. Kim, T. W. Kim, T. M. Kang and I. S. Yang (2008). "Peripheral corticotropin releasing hormone mediates post-inflammatory visceral hypersensitivity in rats." World J Gastroenterol 14(5):731-736.
Leadbetter, G, L. E. Keyes, K. M. Maakestad, S. Olson, M. C. Tissot van Patot and P. H. Hackett (2009). "Ginkgo biloba does--and does not--prevent acute mountain sickness." Wilderness Enyiron Med 20(1):66-71.
Leaf, D. E. and D. S. Goldfarb (2007). "Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness." J Appl Physiol 102(4): 1313-1322.
Leone, M. and G Bussone (1993). "A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement." Cephalalgia 13(5):309-317.
Loeppky, J. A., M. Icenogle, P. Scotto, R. Robergs, H. Hinghofer-Szalkay and R. C. Roach (1997). "Ventilation during simulated altitude, normobaric hypoxia and normoxic hypobaria." Respir Physiol 107(3):231-239.
Low, E. V., A. J. Avery, V. Gupta, A. Schedlbauer and M. P. Grocott (2012). "Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness:systematic review and meta-analysis." BMJ 345:e6779.
Luks, A. M. and E. R. Swenson (2011). "Pulse oximetry at high altitude." High Alt Med Biol 12(2):109-119.
Lyons, T. P., S. R. Muza, P. B. Rock and A. Cymerman (1995). "The effect of altitude pre-acclimatization on acute mountain sickness during reexposure." Aviat Space Environ Med 66(10):957-962.
Macinnis, M. J., E. A. Carter, M. S. Koehle and J. L. Rupert (2012). "Exhaled nitric oxide is associated with acute mountain sickness susceptibility during exposure to normobaric hypoxia." Respir Physiol Neurobiol 180(1):40-44.
Mairer, K., M. Gobel, M. Defrancesco, M. Wille, H. Messner, A. Loizides, M. Schocke and M. Burtscher (2012). "MRI evidence:acute mountain sickness is not associated with cerebral edema formation during simulated high altitude." PLoS One 7(11):e50334.
Mason, N. P., P. W. Barry, A. J. Pollard, D. J. Collier, N. A. Taub, M. R. Miller and J. S. Milledge (2000). "Serial changes in spirometry during an ascent to 5,300 m in the Nepalese Himalayas." High Alt Med Biol 1(3):185-195.
Moore, L. G., G. L. Harrison, R. E. McCullough, R. G. McCullough, A. J. Micco, A. Tucker, J. V. Weil and J. T. Reeves (1986). "Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness." J Appl Physiol 60(4): 1407-1412.
Moraga, F. A., A. Flores, J. Serra, C. Esnaola and C. Barriento (2007). "Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollague (3696 m) in northern Chile." Wilderness Environ Med 18(4):251-257.
Morocz, I. A., G P. Zientara, H. Gudbjartsson, S. Muza, T. Lyons, P. B. Rock, R. Kikinis and F. A. Jolesz (2001). "Volumetric quantification of brain swelling after hypobaric hypoxia exposure." Exp Neurol 168(1):96-104.
Pollard, A. J. (1992). "Altitude induced illness." BMJ 304(6838):1324-1325.
Roach R. C., B. P., Oelz O., Hackett P. H. (1992). The Lake Louise acute mountain sickness scoring system. Hypoxia and Molecular Medicine. H. C. S. Sutton J. R., Coates G Queen City Press, Burlington, VT.
Roach, R. C., E. R. Greene, R. B. Schoene and P. H. Hackett (1998). "Arterial oxygen saturation for prediction of acute mountain sickness." Aviat Space Environ Med 69(12):1182-1185.
Roach, R. C., C. S. Houston, B. Honigman, R. A. Nicholas, M. Yaron, C. K. Grissom, J. K. Alexander and H. N. Hultgren (1995). "How well do older persons tolerate moderate altitude?" West J Med 162(1):32-36.
Sagami, Y., Y. Shimada, J. Tayama, T. Nomura, M. Satake, Y. Endo, T. Shoji, K. Karahashi, M. Hongo and S. Fukudo (2004). "Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome." Gut 53(7):958-964.
Saito, S., H. Shimada, T. Imai, Y. Futamata and K. Yamamori (1995). "Estimation of the degree of acclimatization to high altitude by a rapid and simple physiological examination." Int Arch Occup Environ Health 67(5):347-351.
Saito, S., K. Tanobe, M. Yamada and F. Nishihara (2005). "Relationship between arterial oxygen saturation and heart rate variability at high altitudes." Am J Emerg Med 23(1):8-12.
Sanders, D. B., T. Kelley and D. Larson (2000). "The role of nitric oxide synthase/nitric oxide in vascular smooth muscle control." Perfusion 15(2):97-104.
Savourey, G., J. C. Launay, Y. Besnard, A. Guinet-Lebreton, A. Alonso, F. Sauvet and C. Bourrilhon (2007). "Normo or hypobaric hypoxic tests:propositions for the determination of the individual susceptibility to altitude illnesses." Eur J Appl Physiol 100(2):193-205.
Savourey, G., C. Moirant, J. Eterradossi and J. Bittel (1995). "Acute mountain sickness relates to sea-level partial pressure of oxygen." Eur J Appl Physiol Occup Physiol 70(6):469-476.
Schirlo, C., V. Pavlicek, A. Jacomet, J. S. Gibbs, E. Koller, O. Oelz, M. Seebauer and J. Kohl (2002). "Characteristics of the ventilatory response in subjects susceptible to high altitude pulmonary edema during acute and prolonged hypoxia." High Alt Med Biol 3(3):267-276.
Schneider, M., D. Bernasch, J. Weymann, R. Holle and P. Bartsch (2002). "Acute mountain sickness:influence of susceptibility, preexposure, and ascent rate." Med Sci Sports Exerc 34(12):1886-1891.
Schoch, H. J., S. Fischer and H. H. Marti (2002). "Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain." Brain 125(Pt 11):2549-2557.
Schommer, K., N. Wiesegart, C. Dehnert, H. Mairbaurl and P. Bartsch (2011). "No correlation between plasma levels of vascular endothelial growth factor or its soluble receptor and acute mountain sickness." High Alt Med Biol 12(4):323-327.
Schoonman, G G, P. S. Sandor, A. C. Nirkko, T. Lange, T. Jaermann, U. Dydak, C. Kremer, M. D. Ferrari, P. Boesiger and R. W. Baumgartner (2008). "Hypoxia-induced acute mountain sickness is associated with intracellular cerebral edema:a 3 T magnetic resonance imaging study." J Cereb Blood Flow Metab 28(1): 198-206.
Severinghaus, J. W. (1995). "Hypothesis:angiogenesis cytokines in high altitude cerebral oedema." Acta Anaesthesiol Scand Suppl 107:177-178.
Severinghaus, J. W., H. Chiodi, E. I. Eger,2nd, B. Brandstater and T. F. Hornbein (1966). "Cerebral blood flow in man at high altitude. Role of cerebrospinal fluid pH in normalization of flow in chronic hypocapnia." Circ Res 19(2):274-282.
Sevre, K., B. Bendz, E. Hanko, A. R. Nakstad, A. Hauge, J. I. Kasin, J. D. Lefrandt, A. J. Smit, I. Eide and M. Rostrup (2001). "Reduced autonomic activity during stepwise exposure to high altitude." Acta Physiol Scand 173(4):409-417.
Sutton, J. R., A. C. Bryan, G W. Gray, E. S. Horton, A. S. Rebuck, W. Woodley, I. D. Rennie and C. S. Houston (1976). "Pulmonary gas exchange in acute mountain sickness." Aviat Space Environ Med 47(10):1032-1037.
Swenson, E. R. and L. J. Teppema (2007). "Prevention of acute mountain sickness by acetazolamide:as yet an unfinished story." J Appl Physiol 102(4):1305-1307.
Tache, Y., V. Martinez, L. Wang and M. Million (2004). "CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity:implications for irritable bowel syndrome." Br J Pharmacol 141(8):1321-1330.
Theoharides, T. C. (1999). Treatment of stress-induced migraine headache with a corticotropin releasing hormone blocker, Google Patents.
Tissot van Patot, M. C., G Leadbetter, L. E. Keyes, J. Bendrick-Peart, V. E. Beckey, U. Christians and P. Hackett (2005). "Greater free plasma VEGF and lower soluble VEGF receptor-1 in acute mountain sickness." J Appl Physiol 98(5):1626-1629.
Vale, W., J. Spiess, C. Rivier and J. Rivier (1981). "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin." Science 213(4514):1394-1397.
Van Osta, A., J. J. Moraine, C. Melot, H. Mairbaurl, M. Maggiorini and R. Naeije (2005). "Effects of high altitude exposure on cerebral hemodynamics in normal subjects." Stroke 36(3):557-560.
van Patot, M. C., G Leadbetter,3rd, L. E. Keyes, K. M. Maakestad, S. Olson and P. H. Hackett (2008). "Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness." High Alt Med Biol 9(4):289-293.
Van Roo, J. D., M. P. Lazio, C. Pesce, S. Malik and D. M. Courtney (2011). "Visual analog scale (VAS) for assessment of acute mountain sickness (AMS) on Aconcagua." Wilderness Environ Med 22(1):7-14.
Vardy, J., J. Vardy and K. Judge (2006). "Acute mountain sickness and ascent rates in trekkers above 2500 m in the Nepali Himalaya." Aviat Space Environ Med 77(7): 742-744.
Wagner, D. R., J. R. Knott and J. P. Fry (2012). "Oximetry fails to predict acute mountain sickness or summit success during a rapid ascent to 5640 meters." Wilderness Environ Med 23(2):114-121.
Webb, J. D., M. L. Coleman and C. W. Pugh (2009). "Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing." Cell Mol Life Sci 66(22): 3539-3554.
West, J. B. (2000). "Human limits for hypoxia. The physiological challenge of climbing Mt. Everest." Ann N Y Acad Sci 899:15-27.
West, J. B. (2003). "Improving oxygenation at high altitude:acclimatization and O2 enrichment." High Alt Med Biol 4(3):389-398.
West, J. B. (2008). "The Qinghai-Tibet railway." High Alt Med Biol 9(1):1-2.
Wille, M., H. Gatterer, K. Mairer, M. Philippe, H. Schwarzenbacher, M. Faulhaber and M. Burtscher (2012). "Short-term intermittent hypoxia reduces the severity of acute mountain sickness." Scand J Med Sci Sports 22(5):e79-85.
Wille, M., K. Mairer, H. Gatterer, M. Philippe, M. Faulhaber and M. Burtscher (2012). "Changes in cardiac autonomic activity during a passive 8 hour acute exposure to 5 500 m normobaric hypoxia are not related to the development of acute mountain sickness." Int J Sports Med 33(3):186-191.
Wilson, M. H., S. Newman and C. H. Imray (2009). "The cerebral effects of ascent to high altitudes." Lancet Neurol 8(2):175-191.
Windsor, J. S. (2012). "Pulse oximetry and predicting acute mountain sickness:are we asking the right questions?" Wilderness Environ Med 23(2):112-113.
Wu, T. Y., S. Q. Ding, J. L. Liu, M. T. Yu, J. H. Jia, Z. C. Chai, R. C. Dai, S. L. Zhang, B. Y. Li, L. Pan, B. Z. Liang, J. Z. Zhao, T. Qi de, Y. F. Sun and B. Kayser (2007). "Who should not go high:chronic disease and work at altitude during construction of the Qinghai-Tibet railroad." High Alt Med Biol 8(2):88-107.
You, H., X. Li, T. Pei, Q. Huang, F. Liu and Y. Gao (2012). "Predictive value of basal exhaled nitric oxide and carbon monoxide for acute mountain sickness." Wilderness Environ Med 23(4):316-324.
Zuzewicz, K., B. Biernat, G. Kempa and K. Kwarecki (1999). "Heart rate variability in exposure to high altitude hypoxia of short duration." Int J Occup Saf Ergon 5(3): 337-346.