Abstract Interaction between hypoxia and coagulation is important given the increased risk of thrombotic diseases in chronically hypoxic patients who reside at sea level and in residents at highaltitude. Hypoxia alters the proteome of platelets favouring a prothrombotic phenotype, but studies of activation and consumption of speciﬁc coagulation factors in hypoxic humans have yielded con ﬂicting results. We tested blood from 63 healthy lowland volunteers acclimatizing to highaltitude (5,200 m) using thromboelastometry and assays of plateletfunction to examine the effects of hypoxia on haemostasis. Using data from two separate cohorts of patients following identical ascent pro ﬁles, we detected a signiﬁcant delay in clot formation, but increased clot strength by day 7 at 5,200 m. The latter ﬁnding may be accounted for by the signi ﬁcant rise in platelet count and ﬁbrinogen concentration that occurred duringacclimatization. Plateletfunction assays revealed evidence of platelet hyper-reactivity, with shortened PFA-100 closure times and increased platelet aggregation in response to adenosine diphosphate. Post-expedition results were consistent with the normal- ization of coagulation following descent to sea level. These robust ﬁndings indicate that hypoxia increases platelet reactivity and, with the exception of the paradoxical delay in thromboelastometry clotting time, suggest a prothrombotic phenotype at altitude. Further work to elucidate the mechanism of platelet activation in hypoxia will be important and could impact upon the management of patients with acute or chronic hypoxic respiratory diseases who are at risk of thrombotic events.
tional changes to cells, leading to myocardial cell dam- age . Zhang K, et al.  study confirmed, with en- hanced of myocardial injuries, the increased levels of Malondialdehyde (MDA), lactate dehydrogenase (LDH) and interleukin 6 (IL-6), the LOB (Chrysoeriol7-O- [-D-glucuronopyran-osyl-(1 → 2)-O–D-glucuronopy- ranoside]) can decreased plasma levels of MDA, LDH, IL-6, suggesting that the LOB could be a potential the- rapeutic agent for myocardial ischemia/reperfusion (I/R) injury and hypoxia/reoxygenation (H/R) injury. 3) Cal- cium overload: anaerobic glycolysis may enhance myo- cardial hypoxia, causing intracellular acidosis. As the extracellular pH gradually returns to normal after the restoration of normal oxygenation, intracellular and ex- tracellular formation of transmembrane pH gradients may result in enhanced sodium and hydrogen exchange, increasing the intracellular Na concentration. Since the cells generate less ATP after reoxygenation, the cell membrane and sarcoplasmic reticulum calcium and so- dium pump functions may be reduced, leading to intra- cellular calcium overload. The increase in the intracellu- lar calcium concentration can further activate endothelial cells, promoting OFR generation, and leading to further damage [16,17]. But Li Q  study shows that endocan- nabinoids can suppresses calcium overload through inhi- bition of INCX during perfusion with simulated ischemic solution; the effects may be mediated by CB2 receptor via PTX-sensitive Gi/o proteins. 4) Highaltitude hypoxia stress induced myocardial injury, restore oxygen after myocardial injury has not been fully restored, or restore later than other functions. Hu J, et al.  study show that simple plateau hypoxia exposure endothelin (ET)-1 α concentrations gradually increased whereas HIF-1 ex- pression in myocardial cells was significantly higher (P < 0.01). There was low pressure hypoxia exposure after myocardial mitochondria numbers were reduced during the initial phase of acute stress response to hypoxia and cellular injury but, later, mitochondrial numbers were restored to normal values. Plasma VEGF concentrations increased under exposure group hypoxia in low pressure hypoxia exposure, which were significantly higher than those of control group. Therefore Hu concluded that high-altitude hypoxia exposure: a) induced HIF-1 α ex- pression; b) prompted adaptation/acclimatization after initial stress and cellular injury; and c) enhanced VEGF expression. The mechanism of HADAR and hypoxia- reoxygenation injury on the body is extremely complex and requires further in-depth studies in order to more fully elucidate them.
Because the diagnosis of highaltitude de-acclimatization syndrome has not been standardized, it is vital to formulate diagnostic criteria. Our study demonstrated that highaltitude de-acclimatization syndrome is different from other highaltitude diseases. The latter often has typical symptoms and signs while the former does not have specific symptoms; instead, it has a series of non-specific symptoms such as dizziness, fatigue, weakness, sleepiness, diarrhea, cough, palpitation, chest tightness, vertigo, hair loss, increased appetite, and weight gain . Physical examination shows no specific signs but may demonstrate some abnormal changes. First, the RBC, Hb, and Hct are higher than those of plain natives, and the Plt count is lower than that of plain natives . Second, the plateau migrants experience cardiac abnormities, such as abnormal ventricular diastole, increased pulmonary arterial pressure, ventricular hypertrophy, and decreased left ventricular contraction. Right ventricu- lar hypertrophy and increased RVOT and RVID/LVID are major changes experienced by this population - . Third, an examination of the urinary system may reveal proteinuria and increased microalbuminuria. Fourth, a chest X-ray examination could show an increased cardiothoracic ratio. Fifth, these patients may have low blood and pulse pressure . Other tests, such as liver and kidney function, ECG, serum enzyme, and hu- moral immune function, cannot detect specific changes. Therefore, the diagnosis of highaltitude de-acclimati- zation syndrome should be based on clinical symptoms, signs, and other examination results such as heart, lung, and hematological examinations.
The ventilatory response to exercise and hypoxia is complex and not completely understood. In spite of this limitation, hypoxemia, which stimulates the carotid body, effects an increase in ventilation. This response is proportional to the individual’s inherent hypoxia ventilation response (HVR) (Schoene et al., 1984; Schoene et al., 1990), to the altitude and to the state of acclimatization incurred by a sojourn at highaltitude. Although the actual increase in the sensitivity of the carotid body to hypoxemia during the course of acclimation is not fully understood, it appears that each individual’s HVR, as measured at sea level, is roughly proportional to the ventilatory response to exercise at highaltitude (Schoene et al., 1984; Schoene et al., 1990). In other words, subjects with a low HVR at rest measured at sea level have a relatively more blunted ventilatory response to exercise at highaltitude than those with a high HVR, and vice versa. A large ventilatory response to exercise conveys a greater respiratory alkalosis and higher arterial oxygen saturation and may confer a better climbing performance at very high altitudes (Schoene et al., 1984) (Fig. 2). However, individuals with very large HVRs may incur a greater work of breathing at extreme altitude. Thus, there may be a trade-off between increased arterial blood Ventilation
specific training prior to ascent. These impairments pose a significant risk to personnel safety in a HA environment, particularly when performing tasks that requires cognitive vigilance.
Normal cerebral function, a critical determinant of cognitive function 9 , is dependent upon oxygen supply. 10 At HA, the partial pressure of oxygen (PO 2 ) decreases, leading to reduced oxygen availability, and hypoxemia 10 at the expense of critical organs such as the brain. This results in a compensatory increase in cerebral blood flow (CBF), 10-12 to offset drops in blood oxygen saturation. A primary signaling molecule that may help regulate blood flow in this setting is nitric oxide (NO). NO is released from the vascular endothelium and acts to relax vascular smooth muscle, eliciting vasodilation and increased blood flow. 13 In addition to its central role as a regulator of blood flow, 14 NO ensures optimal hyperemic response to neural activity (neurovascular coupling between central and cerebrovasculature), 15 and is necessary for hypoxia-induced cerebral vasodilation. 16 Moreover, NO appears to play an integral role in adaptation to HA. 14 Specifically, NO production is elevated following acclimatization to HA, 14 and HA natives have been shown to have drastically greater levels of circulating NO products compared to lowlanders, which was further associated with increased blood flow. 17 These chronic and acclimatization-based adaptations most likely serve to increase oxygen delivery 18 and may be related to the improvement in cognitive function with acclimatization. 19,20 Some
The entire subjects were treated with three months yogic exercise. The entire lots of students were again evaluated physiologically [(Cardiovascular measurement: Blood Pressure (BP), VO2 Max (TLC) and Pulse Rate (PR)] with standard equipments. The educators were trained and explained to the level of acclimatization of their understanding. The researcher took all possible precautions to prevent any error or injury to the participants. The participants were not only motivated personally by the scholars but also took voluntary consent of them.
LDH activity has been extensively studied for years. The activities vary greatly among organs and tissues, and respond differently under hypoxic conditions. During hypoxia or moderate intensity exercise, LDH in skeletal muscle catalyzes the conversion of pyruvate to lactate. The lactate produced likely exits from muscles through monocarboxylate transport protein (Stanley et al., 1988) and is subsequently used as the primary fuel source for the mitochondrial TCA cycle of heart (Schurr, 2006). Nevertheless, skeletal muscle is not only responsible for the lactate production but also for the removal of lactate from the circulation (Drury and Wick, 1956). It seems lactate is a crucial fuel for mitochondrial respiration in skeletal muscles (Schurr, 2006). This regulation, which may contribute to the energy supply of skeletal muscle, is a reasonable explanation of the often observed down-
Poly phenol oxidase activity varied from 0.093 to 0.023 units/min/mg protein with respect to invitro derived plants, where as 0.076 to 0.023 units/min/mg protein in case of control. PPO levels were high in the invitro derived plants compare to control indicating PPO is required for acclimatization which is supported by previous reports where highest PPO expression levels are usually associated with young tissues (leaves, flowers, fruits, tubers) and in meristematic regions, which are particularly vulnerable to diseases and insect pests, and gene expression generally declines during development and maturation of plant tissues . Polyphenol oxidase (PPO; EC 220.127.116.11) catalyses the oxidation of polyphenols and the hydroxylation of monophenols  and lignification of plant cells. Recent studies have indicated that phenol-oxidizing enzymes may participate in response to the defense reaction and hypersensitivity in inducing resistance of plants to biotic and abiotic stress [15, 16] (shown in table 3 and graph 2).
This study showed that a reduced platelet count, accompanied by lower mean platelet volume in the surgically treated horses, occurs concomitantly with a prolonged closure time (CT). CT measurement with the PFA-100® (PlateletFunction Analyzer-100) using ADP as a platelet agonist allows rapid as- sessment of the adhesion and aggregation capac- ity of platelets in horses. Our finding confirms the results of Segura et al. (2005) who evaluated the usefulness of the PFA-100® for platelet func- tion assessment in healthy and acetyl-salicylic acid (ASA)-treated horses. Our reference interval for CT-ADP in clinically healthy horses is 81–116 s and is similar to Segura et al. (2005). However, our data are not in agreement with those of Monreal et al. (2000) showing activation of coagulation and the fibrinolytic system in the course of acute horse colic. This can be explained by the different gas- trointestinal (GI) status of the animals in the two studies. Sampling time relative to surgery has a marked effect on subsequent findings. Therefore, comparison of studies is only possible after stand- ardisation of sampling time and clear definition of the GI pathologies. Furthermore, interpretation of observed CT changes after colic surgery should account for possible effects of other therapeutic agents used concurrently, especially NSAID as well as the progressive reduction in platelet count.
spectral identification confirmed continuing prostacyclin biosynthesis during aspirin therapy. Recovery of prostacyclin biosynthesis was incomplete 5 d after drug administration was discontinued. To relate aspirin intake to indices of thromboxane biosynthesis and plateletfunction, volunteers received 20 mg aspirin daily followed by 2,600 mg aspirin daily, each dose for 7 d in sequential weeks. Increasing aspirin dosage inhibited Tx-M excretion from 70 to 98% of pretreatment control values; platelet TxB2 formation from 4.9 to 0.5% and further inhibited plateletfunction. An extended study was performed to relate aspirin intake to both thromboxane and prostacyclin generation over a wide range of doses. Aspirin, in the range of 20 to 325 mg/d, resulted in a dose-dependent decline in both Tx-M and PGI-M excretion. At doses of 325-2,600 mg/d Tx-M excretion ranged from 5 to 3% of control values while PGI-M remained at 37-23% of control. 3 d […]
sedimentation and WU-test). However, hyperlipidemia revealed a variable influence on the tests examined. Some of the available tests apparently sensitive to show platelet activation reflect the increase in triglycerides (TG), such as the sedimentation index. ADP-induced platelet aggregatory activity in count adjusted washed isolated platelet samples during postprandial hyperlipidemia indicates mildly enhanced platelet activity, but does not seem to induce significant changes in aggregation. In patients with severe hypertriglyceridemia (> 400 mg/dl fasting) changes in plateletfunction are more pronounced due to delayed decay and may last up to 16 hours paralleling TG reaching the prevalue. The overwhelming majority of plateletfunction tests do not significantly respond to postprandial hyperlipidemia. The correlation between the tests applied is poor. For standardization purpose, platelet aggregation tests, aimed to examine proaggregatory capacity in atherosclerosis, should only be performed at the same time of the day after a fasting period > 6 hours. The great variation in preanalytical work-up on comparison of various tests, large number of platelet tests available and their respective potential value are discussed.
The strength of this cohort study is that it involves a large sample size with paired data obtained on both hypothermia and subsequent normothermia. The study included patients with cardiac arrest, which increased the external validity for study of critically ill patients. Moreover, there was a small time frame for each sampling and the each blood sample was analysed simultaneously. The advantage of ROTEM® compared to plasma-based conventional coagulation tests, such as APTT and INR, is that ROTEM® is performed in whole blood and thereby, is superior for reflection of in vivo coagulation. ROTEM® re- sults are performed quickly, and the results are more suit- able for targeted haemostatic treatment in bleeding patients . However, ROTEM® has a limited capability to detect antithrombotic treatment, and as platelet func- tion is not reflected in the ROTEM® analysis, it is import- ant to supplement it with platelet aggregation tests such as the Multiplate®Analyzer. The agonists used in the present study were sensitive to the use of ADP inhibitors and acetysalicylic acid . Hence, the use of both these Table 5 The difference in Multiplate®Analyzer measurements performed at 33 °C and 37 °C in 40 cardiac arrest patients
The consequences of inhibiting the metabolism of prostaglandin G2 to thromboxane A2 in man were studied by using an inhibitor of thromboxane synthase, 4-[2-(IH-imidazol-1- yl)ethoxy] benzoic acid hydrochloride (dazoxiben). Single doses of 25, 50, 100, and 200 mg of dazoxiben were administered to healthy volunteers at 2-wk intervals in a randomized, placebo-controlled, double-blind manner. Serum thromboxane B2 and aggregation studies in whole blood and platelet-rich plasma were measured before dosing and at 1, 4, 6, 8, and 24 h after dosing. Both serum thromboxane B2 and the platelet aggregation response to arachidonic acid (1.33 mM) were reversibly inhibited in a dose-dependent manner. Aggregation induced by 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (0.4 and 4.0
Apart from unique electronic properties, the mechani- cal behavior of nanotubes also has provided interest be- cause nanotubes are seen as the ultimate carbon fiber, which can be used as reinforcements in advanced com- posite technology. Early theoretical work and recent ex- periments on individual nanotubes (mostly MWNT’s, Multi Wall Nano Tubes) have confirmed that nanotubes are one of the stiffest materials ever made. Whereas car- bon-car- bon covalent bonds are one of the strongest in nature, a structure based on a perfect arrangement of these bonds oriented along the axis of nanotubes would pro- duce an exceedingly strong material. Traditional carbon fibers show high strength and stiffness, but fall far short of the theoretical, in-plane strength of graphite layers by an order of magnitude. Nanotubes come close to being the best fiber that can be made from graphite.
There is a growing interest in picosatellite projects, in particular CubeSats, whose modest size and standardized launcher interface lowers costs for launch and deployment into orbit. CubeSat missions are typically restricted to Low Earth Orbits (LEO) because of deorbiting requirements. They can be deployed at an altitude where orbit decay due to atmospheric drag can be guaranteed because they characteristically do not accommodate a propulsion system to perform orbital maneuvers. This is due to their small size and simple design which are hard to combine with the complexity of a propulsion system. Moreover, CubeSats are typically launched as a secondary payload together with a significantly larger and more expensive spacecraft. Due to launch safety considerations, storing propellant on the CubeSat would be a hazard for the main payload.
The proteasome inhibiter bortezomib has been successfully used to treat patients with relapsed multiple myeloma; however, many of these patients become thrombocytopenic, and it is not clear how the proteasome influences platelet production. Here we determined that pharmacologic inhibition of proteasome activity blocks proplatelet formation in human and mouse megakaryocytes. We also found that megakaryocytes isolated from mice deficient for PSMC1, an essential subunit of the 26S proteasome, fail to produce proplatelets. Consistent with decreased proplatelet formation, mice lacking PSMC1 in platelets (Psmc1 fl/fl Pf4-Cre mice) exhibited severe thrombocytopenia and died shortly after birth. The failure to produce proplatelets in proteasome-inhibited megakaryocytes was due to upregulation and hyperactivation of the small GTPase, RhoA, rather than NF-kB, as has been previously suggested. Inhibition of RhoA or its downstream target, Rho-associated protein kinase (ROCK), restored megakaryocyte proplatelet formation in the setting of proteasome inhibition in vitro. Similarly, fasudil, a ROCK inhibitor used clinically to treat cerebral vasospasm, restored platelet counts in adult mice that were made
For T1DM, no specific recommendations regarding the type or the amount of exercise exist, and according to the ADA, “all levels of physical activity can be performed by people with T1DM who do not have complications and are in good blood glucose control”. (7) Given the emphasis on a healthy and active lifestyle and an increasing popularity of leisure activities in the mountains, a growing number of subjects with diabetes participating in activities at altitude -such as trekking, hiking and skiing- is expected. Stays at altitudes up to 2500m are well tolerated by most people including the majority of subjects with diabetes. (8) However, altitude (i.e. hypobaric hypoxia: a lower partial oxygen pressure in inhaled ambient air causing a lower arterial oxygen pressure) can affect many organs and regulatory systems in the body, potentially leading to medical problems, especially at higher elevations and in case of rapid ascents. Hypoxemia, acute mountain sickness, altitude related anorexia, equipment failure or inaccuracy due to freezing and hypoxia are all factors that can complicate activities at altitude. (9-12) Specific diabetes related problems at altitude include: the loss of glycemic control due to hypoxia induced increments in gluco-counter regulatory hormones, the inaccuracy of blood glucose meters due to cold and/or the use of oxygen for its chemical reaction, the potential freezing of insulin resulting in the loss of its therapeutic potency, the theoretical risk of diabetic keto-acidosis due to the prophylactic use of acetazolamide for acute mountain sickness, the hypoxia induced loss of appetite and reduced food intake, potentially causing hypoglycemia, and the remoteness and scarcity of medical care.