[The influencing factors on the spinal sagittal alignment and global balance status of degenerative thoracolumbar kyphosis].

Objective: To explore the effect of degenerative thoracolumbar kyphosis (DTLK) on the sagittal alignment of the spine, as well as the impact on spinal parameters and imbalance secondary to thoracolumbar kyphosis. Methods: A case-control study. A total of 128 DTLK patients who aged over 50 years [thoracolumbar kyphosis (TLK)>15°] treated in Peking University People's Hospital from January 2018 to December 2021 (DTLK group) were retrospectively included in this study. Other 73 contemporaneous patients with lumbar spinal stenosis or disc herniation without thoracolumbar kyphosis (TLK=0°±15°) were enrolled into the control group. The following parameters were obtained on spine X-ray: TLK, thoracic kyphosis (TK), lumbar lordosis (LL) and sagittal vertical axis (SVA). In addition, the osteoporosis (OP) was evaluated by dual-emission X-ray absorptiometry (DXA), and the L5/S1 disc signal grading (Pfirrmann grading) was evaluated on MRI. Based on the age, the Lafage formula SVA=2× (age-55)+25 was used to distinguish balance/imbalance, and the DTLK patients were divided into balanced and an imbalanced group, the characteristics and influencing factors of the loss of sagittal balance in this population were clarified, and the interaction among various parts of the spine under a state of balance was analyzed too. Results: The TK (30.0°±13.5° vs 24.2°±7.4°) and TLK (26.6°±9.7° vs 6.0°±6.6°) in the DTLK group were both larger than those in control group while LL was smaller (34.4°±17.7° vs 44.2°±10.3°) (all P<0.001). TK was correlated to TLK (r=0.234, P=0.008) and LL (r=0.539, P<0.001) in DTLK group. LL loss was positively correlated to L5/S1 disc signal reduction (r=0.253, P=0.044). LL loss [RR=1.04(1.01-1.08)] and OP [RR=3.97(1.09, 14.50)] were influencing factors for the occurrence of imbalance in DTLK patients. The influencing factors for TK in DTLK balance group were LL (ß=0.572, P<0.001) and age (ß=0.351, P=0.045). The positive influencing factor for TK in imbalanced group is LL (ß=0.209, P=0.015), and the impact is weaker than balanced group. Conclusions: Loss of LL and osteoporosis are more likely to cause imbalance and kyphosis in DTLK patients. In DTLK balance group, the proximal spine is regulated by lumbar spine, and the synergistic effect between the two parts maintains balance.

[Comparable study of alternative-level and all-level Arch mini-plate fixation for unilateral open-door laminoplasty].

Objectives: To compare the clinical effect of alternative-level and all-level Arch mini-plate fixation in patients undergoing unilateral open-door laminoplasty. Methods: Clinical data of 134 patients administrated in the Peking University International Hospital for multistage cervical spondylotic myelopathy from March 2015 to March 2019 were reviewed retrospectively. There were 63 males and 71 females with an average age of (62±8) years and a mean disease course of (18±7) months (3-37 months). All the patients underwent posterior cervical unilateral open-door laminoplasty with Arch titanium plate fixation. All the patients were divided into two groups according to the different amount of titanium plates used during operation as follow: group A, Arch plates were fixed at the door sides of C3, C5 and C7 (n=68) and group B, Arch plates were fixed at the door sides of C3, C4, C5, C6 and C7 (n=66). Operation time, intraoperative blood loss, postoperative hospitalization days and the cost of consumables, the Japanese orthopaedic association (JOA) score, cervical dysfunction index (NDI), the rates of improved JOA score, cervical curvature index, C2-7 Cobb angle, cervical range of motion, sagittal diameter of vertebral canal, opening angle of laminar, hinges bone healing and surgery related complications (axial symptoms, C5 nerve root palsy, screw loosening, laminar re-closing, cervical kyphosis, etc.) were recorded and compared between the two groups. Results: There was no complications during the operation, and the mean follow-up was (20±8) months (14-48 months). There was no statistically significant difference between the two groups in terms of gender, age, course of disease and compression segments (all P>0.05). There was no statistically significant differences between the two groups in operation time, intraoperative blood loss and postoperative hospital stay too (all P>0.05). The cost of consumables in group A was (34 970±1 325) yuan, and it was (57 450±2 161) yuan in group B, the difference between the two groups was statistically significant (P<0.01). The JOA and NDI score were significantly improved 3 months and 1 year after operation in both groups (both P<0.05). The sagittal diameter of each segment of the spinal canal at C3, C4, C5, C6 and C7 were all significantly increased in both groups 3 months and 1 year after surgery (all P<0.05). The C2-7 Cobb angle and cervical curvature index were all significantly reduced in both groups 3 months and 1 year after surgery (all P<0.05). The cervical range of motion in both groups was significantly reduced 3 months and 1 year after surgery compared with that before surgery (both P<0.05). The range of motion of the cervical spine in group A was significantly higher than that in group B (P<0.05). The opening angles of C4 and C6 segment lamina in group A 3 months and 1 year after operation were significantly lower than those in group B (all P<0.05). At 3 months after the operation, the hinges healing rate of C4 and C6 in group B was significantly better than that of group A (both P<0.05). At 1 year after the operation, there was no difference in the hinges healing rate of C4 and C6 in the two groups (both P>0.05). There was no statistically significant difference in postoperative complications between the two groups (P>0.05). Conclusions: The safety and early clinical efficacy of alternative-level and all-level Arch titanium plate fixation in posterior cervical unilateral open-door laminoplasty are comparable, alternative-level fixation can effectively reduce the cost of hospitalization. The open Angle loss and lower early hinges healing rate of the non-fixed segment in the alternative-level fixed group does not lead to laminar re-closing in early period of post operation.

[Comparison of percutaneous pedicle screw placement under O-arm navigation with traditional percutaneous pedicle screw placement in patients with thoracolumbar fractures without neurological symptoms].

Objective: To investigate the accuracy and clinical efficacy of percutaneous pedicle screw placement under O-arm navigation and traditional fluoroscopy in patients with thoracolumbar fractures without neurological symptoms. Methods: From July 2016 to July 2018, 72 patients with thoracolumbar fractures in Peking University International Hospital without neurological symptoms were divided into two groups, group A and group B. In group A, 36 patients underwent the surgery of percutaneous pedicle screw implantation under traditional fluoroscopy and 168 pedicle screws were inserted. In group B, 36 patients underwent the surgery of percutaneous pedicle screw implantation under O-arm guided fluoroscopy and 164 pedicle screws were inserted by the same surgeon. The general condition, operation condition, radiation dose, fluoroscopy time of single screw, screw placement time and accuracy, visual analogue score (VAS) score, Oswestry dysfunction index (ODI), kyphosis Cobb's angle, anterior edge height of 1 week and 6 months after surgery were compared. The data were compared with paired t test between the two groups. Results: There was no significant differences between the two groups in general condition, intraoperative blood loss, length of hospital stay, VAS, ODI, kyphosis Cobb's angle, and anterior edge height of the injured vertebra (all P>0.05). The operation time was (99±14) min in group A and (75±10) min in group B, the average screw setting time was (15.8±2.6) min in group A and (11.8±3.3) min in group B, the fluoroscopy time of each screw was (38.0±2.0) s in group A and (28.5±2.8) s in group B, the radiation dose of each surgery was (563±163) cGy/cm(2) in group A and (378±70) cGy/cm(2) in group B; the above-mentioned data of group A were all superior to those in group B and the differences between the two groups were all statistically significant (t=8.48, 5.73, 16.30, 6.25, all P<0.05). Rampersaud grading in group A was better than group B, and the differences between the two groups was statistically significant(χ(2)=12.2, P<0.05). Conclusion: The O-arm navigation system could not only provide high-definition navigation images and achieve high-precision navigation operations, which is more accurate than traditional pedicle screws placement, but also contribute to the reconstruction of spinal stability and reduce radiation dose, pedicle screws placement and operating time.

[The expression of VHL/HIF signaling pathway in the erythroid progenitor cells with chronic mountain sickness].

Objective: To investigate the expression and interaction of VHL/HIF-α pathways including HIF-1α, HIF-2α as well as VHL in erythroid progenitor cells of bone marrow from chronic mountain sickness (CMS) patients. Methods: A total of 25 patients with CMS and 21 healthy controls were recruited for this study. The CD71(+)CD235a(+) cells in bone marrow mononuclear cells, marked as erythroid progenitor cells, were isolated using MACS separation technology. The expression levels of HIF-1α, HIF-2α and VHL in erythroid progenitor cells were detected by Western blotting and real-time fluorescence quantitative PCR. Results: The mRNA levels of HIF-2α were higher in erythroid progenitor cells of CMS than in healthy controls [1.68 (0.81, 2.22) vs 0.98 (0.60, 1.19), P<0.05], while HIF-1α and VHL mRNA levels were similar between the two groups (P>0.05). Spearman analyses indicated that HIF-2α mRNA was positively associated with hemoglobin (Hb) levels in the erythroid progenitor cells of CMS (ρ=0.504, P<0.05). Furthermore, the mRNA level of HIF-2α was correlated with the mRNA level of VHL in the erythroid progenitor cells of CMS (ρ=0.647, P<0.05).The protein levels of HIF-2α in the erythroid progenitor cells of CMS were higher than that of healthy controls [0.94(0.68, 3.30) vs 0.59(0.30, 0.88), P<0.05], but the protein levels of HIF-1α and VHL were similar between the two groups (P>0.05). Conclusions: The abnormal increased expression of HIF-2α in the erythroid progenitor cells of CMS patients leads to the abnormal expression of hypoxia sensitive genes downstream, participating in the occurrence and development of CMS.

[The expressions of VEGF and VEGFR signaling pathway in the bone marrow mononuclear cells with chronic mountain sickness].

Objective: This study was aimed at investigating the levels and relationships of vascular endothelial growth factor (VEGF) and its receptor(VEGFR) in the bone marrow mononuclear cells (MNC) of chronic mountain sickness (CMS). Methods: A total of 34 patients with CMS and 30 controls residing at altitudes of 3 000-4 500 m were recruited for this study. The levels of VEGF, VEGFR1 and VEGFR2 in bone marrow MNC were detected by flow cytometry technique and RT-qPCR. Results: The percentage of VEGFR2 positive cells in the bone marrow MNC of CMS were higher than that of the controls[20.7% (8.1%, 67.6%) vs 8.1% (2.2%, 14.9%), P<0.05], but that of VEGFR1-positive and VEGF-positive were similar in CMS and controls. The mRNA levels of VEGFR2 were higher in the bone marrow MNC of CMS than in the controls[1.7(1.0, 5.1) vs 1.0(0.4, 2.7), P<0.05], while VEGF and VEGFR1 mRNA levels were similar between the two groups. The percentage of VEGFR2 positive cells in CMS were significantly correlated with hemoglobin (r=0.453, P=0.007) and the percentage of VEGF-positive cells (r=0.373, P=0.030). Conclusions: Bone marrow MNC of CMS may show enhanced activity of the VEGF-VEGFR2 pathway, and it appears to be involved in the pathogenesis of CMS.

[Study on apoptosis, cytochrome C and mitochondrial membrane potential in CD71(+) nucleated erythrocytes in patients with chronic mountain sickness].

Objective: To investigate the changes of CD71(+) nucleated erythrocyte apoptosis, cytochrome C (Cyt-C) and mitochondrial membrane potential (MMP) in bone marrow of chronic mountain sickness (CMS). Methods: 14 patients with CMS and 15 patients with simple old fracture were divided into CMS group and control group, respectively.Bone marrow mononuclear cells (BMMNC) were separated, marked with CD71 monoclonal antibody and stained with Annexin V-FITC/PI.Then the apoptotic index of CD71(+) nucleated erythrocytes was determined by flow cytometry.CD71(+) nucleated erythrocytes were sorted out by magnetic column separation, and Cyt-C mRNA was detected by RT-qPCR, MMP was detected by JC-1 staining flow cytometry. Results: The apoptotic index of CD71(+) nucleated erythrocytes was (1.9±1.4)% in the CMS group, and was (3.2±1.5)% in the control group, with significant difference between the two groups (P<0.05). The expression of Cyt-C mRNA was (0.72±0.14) in the CMS group, and was (1.00±0.15) in the control group, with significant difference between the two groups (P<0.01). The MMP was (5.0±2.2) in the CMS group, and was (3.3±0.9) in the control group, with significant difference between the two groups (P<0.05). The apoptotic index of CD71(+) nucleated erythrocytes was negatively correlated with hemoglobin in CMS group (r=-0.569, P=0.034). But there was no significant correlation among apoptosis index, MMP and Cyt-C mRNA. Conclusions: The apoptosis index of CD71(+) nucleated erythrocytes decreased in CMS patients, which was negatively correlated with the level of hemoglobin, indicating that the decline of apoptosis index of CD71(+) nucleated erythrocytes may be related to the accumulation of red blood cells in CMS.The MMP increased and Cyt-C mRNA expression decreased in CD71(+) nucleated erythrocytes of CMS patients, which suggests that the change of mitochondrial pathway of apoptosis might be involved in the down-regulation of CD71(+) nucleated erythrocytes apoptosis in CMS patients.But there was no significant correlation among CD71(+) nucleated erythrocyte apoptosis index, MMP and Cyt-C mRNA levels, which indicates that the mechanism of CD71(+) nucleated erythrocytes apoptosis is complex in CMS.

Living altitude influences endurance exercise performance change over time at altitude.

For sea level based endurance athletes who compete at low and moderate altitudes, adequate time for acclimatization to altitude can mitigate performance declines. We asked whether it is better for the acclimatizing athlete to live at the specific altitude of competition or at a higher altitude, perhaps for an increased rate of physiological adaptation. After 4 wk of supervised sea level training and testing, 48 collegiate distance runners (32 men, 16 women) were randomly assigned to one of four living altitudes (1,780, 2,085, 2,454, or 2,800 m) where they resided for 4 wk. Daily training for all subjects was completed at a common altitude from 1,250 to 3,000 m. Subjects completed 3,000-m performance trials on the track at sea level, 28 and 6 days before departure, and at 1,780 m on days 5, 12, 19, and 26 of the altitude camp. Groups living at 2,454 and 2,800 m had a significantly larger slowing of performance vs. the 1,780-m group on day 5 at altitude. The 1,780-m group showed no significant change in performance across the 26 days at altitude, while the groups living at 2,085, 2,454, and 2,800 m showed improvements in performance from day 5 to day 19 at altitude but no further improvement at day 26 The data suggest that an endurance athlete competing acutely at 1,780 m should live at the altitude of the competition and not higher. Living ∼300-1,000 m higher than the competition altitude, acute altitude performance may be significantly worse and may require up to 19 days of acclimatization to minimize performance decrements.

Sea-level haemoglobin concentration is associated with greater exercise capacity in Tibetan males at 4200 m.

NEW FINDINGS: What is the topic of this review? Recent developments link relatively lower hemoglobin concentration in Tibetans at high altitude to exercise capacity and components of oxygen transport. What advances does it highlight? Haemoglobin concentration (ranging from 15.2 to 22.9 g dl(-1) ) in Tibetan males was negatively associated with peak oxygen (O2 ) uptake per kilogram, cardiac output and muscle O2 diffusion conductance. Most variance in the peak O2 uptake per kilogram of Tibetan males was attributed to cardiac output, muscle diffusional conductance and arterial partial pressure of CO2 . The mechanisms underlying these differences in oxygen transport in Tibetans require additional analyses. Despite residence at >4000 m above sea level, many Tibetan highlanders, unlike Andean counterparts and lowlanders at altitude, exhibit haemoglobin concentration ([Hb]) within the typical sea-level range. Genetic adaptations in Tibetans are associated with this relatively low [Hb], yet the functional relevance of the lower [Hb] remains unknown. To address this, we examined each major step of the oxygen transport cascade [ventilation (VE), cardiac output (QT) and diffusional conductance in lung (DL) and muscle (DM)] in Tibetan males at maximal exercise on a cycle ergometer. Ranging from 15.2 to 22.9 g dl(-1) , [Hb] was negatively associated with peak O2 uptake per kilogram (r = -0.45, P < 0.05) and both cardiac output (QT/kg: r = -0.54, P < 0.02) and muscle O2 diffusion conductance (DM/kg: r = -0.44, P < 0.05) but not ventilation, arterial partial pressure of O2 or pulmonary diffusing capacity. Most variance in peak O2 uptake per kilogram was attributed to QT, DM and arterial partial pressure of CO2 (r(2)  = 0.90). In summary, lack of polycythaemia in Tibetans is associated with increased exercise capacity, which is explained by elevated cardiac, muscle and, to a small extent, ventilatory responses rather than pulmonary gas exchange. Whether lower [Hb] is the cause or result of these changes in O2 transport or is causally unrelated will require additional study.

Low haemoglobin concentration in Tibetan males is associated with greater high-altitude exercise capacity.

Tibetans living at high altitude have adapted genetically such that many display a low erythropoietic response, resulting in near sea-level haemoglobin (Hb) concentration. We hypothesized that absence of the erythropoietic response would be associated with greater exercise capacity compared to those with high [Hb] as a result of beneficial changes in oxygen transport. We measured, in 21 Tibetan males with [Hb] ranging from 15.2 g dl(-1) to 22.9 g dl(-1) (9.4 mmol l(-1) to 14.2 mmol l(-1) ), [Hb], ventilation, volumes of O2 and CO2 utilized at peak exercise (V̇O2 and V̇CO2), heart rate, cardiac output and arterial blood gas variables at peak exercise on a cycle ergometer at ∼4200 m. Lung and muscle O2 diffusional conductances were computed from these measurements. [Hb] was related (negatively) to V̇O2 kg(-1) (r = -0.45, P< 0.05), cardiac output kg(-1) (QT kg(-1) , r = -0.54, P < 0.02), and O2 diffusion capacity in muscle (DM kg(-1) , r = -0.44, P<0.05), but was unrelated to ventilation, arterial partial pressure of O2 (PaO2) or pulmonary diffusing capacity. Using multiple linear regression, variance in peak V̇O2 kg(-1) was primarily attributed to QT, DM, and PCO2 (R(2) = 0.88). However, variance in pulmonary gas exchange played essentially no role in determining peak V̇O2. These results (1) show higher exercise capacity in Tibetans without the erythropoietic response, supported mostly by cardiac and muscle O2 transport capacity and ventilation rather than pulmonary adaptations, and (2) support the emerging hypothesis that the polycythaemia of altitude, normally a beneficial response to low cellular PO2, may become maladaptive if excessively elevated under chronic hypoxia. The cause and effect relationships among [Hb], QT, DM, and PCO2 remain to be elucidated.

Correlation between carbonic anhydrase IX (CA-9), XII (CA-12) and hypoxia inducible factor-2α (HIF-2α) in breast cancer.

Hypoxia inducible factor 2α (HIF-2α) can trigger the expression of several genes related to many aspects of tumor progress under hypoxia. As an independent factor, the role of HIF-2α is different from other hypoxia-mediated elements, including HIF-1α. Carbonic anhydrase (CA) were also regarded as important enzymes that involve in the tumor microenvironment pH. To find clinical-pathological features of breast cancer in plateau and explore the impact of CAIX, XII (CA-9, CA-12) and HIF-2α on patients with breast cancer. Clinical data were collected and summarized in 94 patients with breast cancer. The expression of HIF-2α, CA-9 and CA-12 were detected, using immunohistochemistry of specimens. The relation between expressions and clinical-pathology was analyzed. Under normoxia, hypoxia, and after being pretreated with the JNK inhibitor SP600125, HIF- 2α, CA-9 and CA-12 expressions were detected, and adhesion and invasion assays were performed in MCF-7 cells and HIF- 2α shRNA cells, respectively. There are higher expressions of HIF-2α in tumor classification 2 and clinical stage 2 (P < 0.05). High expression of CA-12 was observed in clinical stage 2 (P < 0.05). CA-9 expression is significantly correlated with CA-12 expression (r = 0.376, P = 0.0001). HIF-2α expression is not correlated with both CA-9 expression (P = 0.21) and CA-12 expression (P = 0.27). Breast cancer cells in vitro showed that HIF-2α, CA-9 or CA-12 had an increase expression under hypoxia (1% O2). CA-9 or CA-12 expression was observed in HIF-2α shRNA cells. JNK inhibitor SP 600125 reduced the HIF-2α expression and inhibited the adhesion and invasion of breast cancer cell. Slight inhibition effect on CA-9 and CA-12 expression was found. In conclusion, HIF-2α, CA-9 and CA-12 are important hypoxia responsive elements in breast cancer. HIF-2α was involved in metastasis and invasion of breast cancer cells under hypoxia, by the involvement of c-Jun NH2-terminal kinase (JNK) signal pathway. CA-9 and CA-12 may tend to be regulated by HIF-1α more often than by HIF-2α under hypoxia.

Defining the "dose" of altitude training: how high to live for optimal sea level performance enhancement.

Chronic living at altitudes of ∼2,500 m causes consistent hematological acclimatization in most, but not all, groups of athletes; however, responses of erythropoietin (EPO) and red cell mass to a given altitude show substantial individual variability. We hypothesized that athletes living at higher altitudes would experience greater improvements in sea level performance, secondary to greater hematological acclimatization, compared with athletes living at lower altitudes. After 4 wk of group sea level training and testing, 48 collegiate distance runners (32 men, 16 women) were randomly assigned to one of four living altitudes (1,780, 2,085, 2,454, or 2,800 m). All athletes trained together daily at a common altitude from 1,250-3,000 m following a modified live high-train low model. Subjects completed hematological, metabolic, and performance measures at sea level, before and after altitude training; EPO was assessed at various time points while at altitude. On return from altitude, 3,000-m time trial performance was significantly improved in groups living at the middle two altitudes (2,085 and 2,454 m), but not in groups living at 1,780 and 2,800 m. EPO was significantly higher in all groups at 24 and 48 h, but returned to sea level baseline after 72 h in the 1,780-m group. Erythrocyte volume was significantly higher within all groups after return from altitude and was not different between groups. These data suggest that, when completing a 4-wk altitude camp following the live high-train low model, there is a target altitude between 2,000 and 2,500 m that produces an optimal acclimatization response for sea level performance.

Current concept of chronic mountain sickness: pulmonary hypertension-related high-altitude heart disease.

High-altitude heart disease, a form of chronic mountain sickness, has been well established in both Tibet and Qinghai provinces of China, although little is known regarding this syndrome in other countries, particularly in the West. This review presents a general overview of high-altitude heart disease in China and briefly summarizes the existing data with regard to the prevalence, clinical features, and pathophysiology of the illness. The definition of high-altitude heart disease is right ventricular enlargement that develops primarily (by high-altitude exposure) to pulmonary hypertension without excessive polycythemia. The prevalence is higher in children than adults and in men than women, but is lower in both sexes of Tibetan high-altitude residents compared with acclimatized newcomers, such as Han Chinese. Clinical symptoms consist of headache, dyspnea, cough, irritability, and sleeplessness. Physical findings include a marked cyanosis, rapid heart and respiratory rates, edema of the face, liver enlargement, and rales. Most patients have complete recovery on descent to a lower altitude, but symptoms recur with a return to high altitude. Right ventricular enlargement, pulmonary hypertension, and remodeling of pulmonary arterioles are hallmarks of high-altitude heart disease. It is hoped that this information will assist in understanding this type of chronic mountain sickness, facilitate international exchange of data, and stimulate further research into this poorly understood condition.

Atrial natriuretic peptide and red cell 2,3-diphosphoglycerate in patients with chronic mountain sickness.

BACKGROUND: Individuals with chronic mountain sickness (CMS) show severe hypoxemia, excessive polycythemia, and marked pulmonary hypertension. The pathophysiologic mechanisms of CMS are still not completely understood. METHODS: We determined plasma atrial natriuretic peptide (ANP), red cell 2,3-diphosphoglycerate (2,3-DPG), hematocrit, hemoglobin, and arterialized ear lobe blood gas values in 13 patients with CMS (9 Hans, 4 Tibetans) and 18 control Han Chinese men of similar age, height, and weight who had been living at 4300 m on the Tibetan plateau of Qinghai Province, China, for approximately 14 years. RESULTS: A significantly higher level of ANP was found in the CMS patients compared to the non-CMS patients (113.4+/-5.5 pg/mL vs 87.6+/-4.7 pg/mL, P < .01), and the levels of ANP correlated positively with the hemoglobin concentration (r = 0.8282, P < .01). The 2,3-DPG levels in the CMS patients were significantly increased compared to the non-CMS subjects (5.23+/-0.16 mmol/L vs 4.40+/-0.12 mmol/L, P < .01), and the 2,3-DPG concentrations in the CMS patients were negatively correlated with their PaO2 values (r = -0.7898, P < .01). The CMS patients had significantly higher PaCO2 levels, lower pH values, lower PaO2 levels, and greater alveolar-arterial oxygen differences (PAO2 - PaO2) compared to the non-CMS subjects. CONCLUSIONS: These findings suggest that overproduction of ANP and 2,3-DPG at high altitudes may play an important role in the pathophysiology of chronic mountain sickness.

Pulmonary artery remodeling modifies pulmonary hypertension during exercise in severe emphysema.

To clarify the relation between the vessel remodeling and the physiology of pulmonary circulation in chronic obstructive pulmonary disease (COPD), we studied the pulmonary hemodynamics at rest and during exercise (25W) and the morphology of pulmonary arteries with external diameters of 100-200 microm in ten patients with severe emphysema. The wall thickness (WT) was defined as the intima plus media. The percent WT of the external diameter (% WT) in emphysema (36.0 +/- 4.3%) was significantly increased compared with that (22.6 +/- 3.3%) in five control lungs. The % WT was not related to pulmonary arterial pressure (Ppa) at rest, but was highly correlated with exercise Ppa (r = 0.721, P = 0.02) and with deltaPpa (Ppa during exercise-Ppa at rest) (r = 0.899, P = 0.0004). These findings suggest that pulmonary artery remodeling leads to reduced recruitability and distensibility of pulmonary vessels and is closely related to exercise pulmonary hypertension.

Hypoxia-induced pulmonary blood redistribution in subjects with a history of high-altitude pulmonary edema.

BACKGROUND: Pulmonary hypertension has been suggested to play an important role in development of high-altitude pulmonary edema (HAPE), and individual susceptibility has been suggested to be associated with enhanced pulmonary vascular response to hypoxia. We hypothesized that much greater pulmonary vasoconstriction would be induced by acute alveolar hypoxia in HAPE-susceptible (HAPE-s) subjects and that changes in pulmonary blood flow distribution could be demonstrated by radionuclide study. METHODS AND RESULTS: We performed ventilation-perfusion scintigraphy in 8 HAPE-s subjects and 5 control subjects while each was in the supine position and acquired functional images of pulmonary blood flow and ventilation under separate normoxic and hypoxic (arterial oxygen saturation, 70%) conditions. We also measured acceleration time/right ventricular ejection time (AcT/RVET) with Doppler echocardiography under each condition in both groups. Moreover, we assayed human leukocyte antigen (HLA) alleles serologically in the HAPE-s group. Pulmonary blood flow was significantly shifted from the basal lung region to the apical lung region under hypoxia in HAPE-s subjects, although no significant change in regional ventilation was observed. With Doppler echocardiography, HAPE-s subjects showed increased pulmonary arterial pressure during hypoxia compared with control subjects. The magnitude of cephalad redistribution of lung blood flow was significantly higher in the HLA-DR6-positive than in HLA-DR6-negative HAPE-s subjects. CONCLUSIONS: These findings suggest that acute hypoxia induces much greater cephalad redistribution of pulmonary blood flow that results from exaggerated vasoconstriction in the basal lung in HAPE-s subjects. Furthermore, pulmonary vascular hyperreactivity to hypoxia may be associated with HLA-DR6.

Endothelin receptor blockade attenuates air embolization-induced pulmonary hypertension in sheep.

We investigated the effects of two types of endothelin receptor antagonists on pulmonary hypertension induced by pulmonary air embolization in awake sheep. We prepared awake sheep with indwelling catheters inserted in blood vessels for continuous monitoring of pulmonary artery pressure, left atrial pressure and systemic arterial pressure. Cardiac output was measured every 30 min. The study consisted of two experiments, one with FR139317 (100 microg/kg/min; (R)2-[(R)-2-[(S)-2-[1-(hexahydro-1H-azepinyl)]-carbonyl]amino-4-++ +methy l-pentanoyl]amino-3-[3-(1-methyl-1H-indolyl)]propionyl)amino-3-(2-pyr idyl)propionic acid), a selective endothelin ET(A) receptor antagonist, and the other with TAK-044 (100 microg/kg/h; cyclo[D-alpha-aspartyl-3-[(4-phenylpiperazin-yl)carbonyl]-L-alanyl -L- alpha- aspartyl-D-2-(2-thienyl) glycyl-L-leucyl-D-tryptophyl] disodium salt), an endothelin ET(A) and ET(B) receptor antagonist. In the paired experiments, air was continuously (4.06 ml/min) infused into the main pulmonary artery for 3 h after the baseline pressures were stabilized. Sheep were treated or not treated with FR139317 or TAK-044. Pulmonary artery pressure was significantly higher than the baseline pressure after the start of air infusion. Both FR139317 and TAK-044 significantly attenuated the increase in pulmonary artery pressure during air embolization. Plasma endothelin -1 levels in both pulmonary and systemic arteries were equally and significantly increased after the start of air infusion. The results indicate that endothelin-1 release is attributable to the development of pulmonary hypertension during the course of air embolization in awake sheep.

Pharmacokinetic characteristics of the novel anticancer agent CPT-11 and its active metabolite in plasma and lung lymph fluid following intravenous administration to sheep.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11, 100286-90-6) is one of the most promising novel anticancer agents, especially for lung cancer. 7-Ethyl-10-hydroxycamptothecin (SN-38), an active metabolic of CPT-11, has much stronger cytotoxicity than CPT-11. The present study was designed to evaluate the distribution and behavior of CPT-11 and SN-38 in lung lymph circulation following intravenous infusion. Awake sheep with chronically instrumented lung lymph fistulas were prepared. The concentrations of CPT-11 and SN-38 in plasma and lung lymph fluid were measured after intravenous infusion of 100 mg/body of CPT-11 for 90 min. SN-38 constantly showed higher lymph to plasma concentration ratios than those of CPT-11, and the % area under the curve (AUC) ratio of SN-38/CPT-11 in lymph fluid was significantly higher than that in plasma. These data indicated that SN-38 distributed in lung tissue moved more easily into lung lymph fluid than CPT-11, and might be more rapidly metabolized in lung tissue than plasma. CPT-11 may have favorable therapeutic effects on intrathoracic malignancies such as lung cancer and lymph metastasis.

Blunted hypoxic pulmonary vasoconstrictive response in the rodent Ochotona curzoniae (pika) at high altitude.

To investigate the possible mechanisms of adaptation to chronic hypoxia in the pulmonary circulation, we made direct measurements of pulmonary arterial pressure (Ppa) in 10 awake pika rodents that were transported to Xining, People's Republic of China (altitude 2,260 m) after being captured at 4,300 m and in 10 Wistar rats in a decompression chamber (simulated altitudes of 4,300 and 5,000 m) in Xining. Ppa was obtained at 1 h of exposure to each simulated altitude. The histology and immunohistochemistry of the lung tissues were also studied. Ppa in the pikas after the 4,300- and 5,000-m altitude exposures did not significantly increase, whereas in the rats Ppa rose significantly. Mean changes in Ppa from 2,260 to 4,300 and 5,000 m were 1.48 +/- 0.49 and 4.80 +/- 0.67 mmHg in the pikas and 10.38 +/- 3.36 and 19.10 +/- 2.28 mmHg in the rats. The ratio of right ventricular to left ventricular plus septal weight in the pikas and rats was 0.22 and 0.45, respectively. The pikas maintained levels of Hb, hematocrit, and 2,3-diphosphoglycerate lower than those of the rats. The percent wall thickness of the small pulmonary arteries in the pikas and rats was 9.22 and 27.21%, respectively, and it was well correlated with the degree of Ppa in both groups. Mast cells were observed in the lungs of the rats (7.1 +/- 0.33 cells/mm2) but not in the pikas. There was highly positive staining for mast cell tryptase and transforming growth factor-beta around pulmonary vessels in the rats, whereas no demonstrable reaction was observed in the pikas. We conclude that the pika has adapted to high altitude by losing hypoxic pulmonary vasoconstriction and thin-walled pulmonary arterioles.

Exercise performance of Tibetan and Han adolescents at altitudes of 3,417 and 4,300 m.

The difference was studied between O2 transport in lifelong Tibetan adolescents and in newcomer Han adolescents acclimatized to high altitude. We measured minute ventilation, maximal O2 uptake, maximal cardiac output, and arterial O2 saturation during maximal exercise, using the incremental exercise technique, at altitudes of 3,417 and 4,300 m. The groups were well matched for age, height, and nutritional status. The Tibetans had been living at the altitudes for a longer period than the Hans (14.5 +/- 0.2 vs. 7.8 +/- 0.8 yr at 3,417 m, P < 0.01; and 14.7 +/- 0.3 vs. 5.3 +/- 0.7 yr at 4,300 m, P < 0.01, respectively). At rest, Tibetans had significantly greater vital capacity and maximal voluntary ventilation than the Hans at both altitudes. At maximal exercise, Tibetans compared with Hans had higher maximal O2 uptake (42.2 +/- 1.7 vs. 36.7 +/- 1.2 ml . min-1 . kg-1 at 3,417 m, P < 0.01; and 36.8 +/- 1.9 vs. 30.0 +/- 1. 4 ml . min-1 . kg-1 at 4,300 m, P < 0.01, respectively) and greater maximal cardiac output (12.8 +/- 0.3 vs. 11.4 +/- 0.2 l/min at 3,417 m, P < 0.01; 11.5 +/- 0.5 vs. 10.0 +/- 0.5 l/min at 4,300 m, P < 0. 05, respectively). Although the differences in arterial O2 saturation between Tibetans and Hans were not significant at rest and during mild exercise, the differences became greater with increases in exercise workload at both altitudes. We concluded that exposure to high altitude from birth to adolescence resulted in an efficient O2 transport and a greater aerobic exercise performance that may reflect a successful adaptation to life at high altitude.

Low pulmonary diffusing capacity in subjects with acute mountain sickness.

This study was conducted to investigate whether the changes in the pulmonary diffusing capacity found in individuals with acute mountain sickness (AMS) reflect the early stage of high-altitude pulmonary edema (HAPE). We measured the pulmonary diffusion capacity for carbon monoxide (DCO) by the single-breath method, arterialized capillary blood gas, and spirometry in a group of 32 healthy subjects (24 men, eight women) at an altitude of 2,260 m and after ascent to 4,700 m. Twelve subjects (10 men, two women) had symptoms of AMS (AMS group) by the second day after arrival at 4,700 m, but none had clinical signs of pulmonary or cerebral edema. In the non-AMS group, almost all subjects exhibited an increase in DCO at 2,260 to 4,700 m (delta DCO, 10.7 +/- 1.25 mL/min/mm Hg), while the degree of increase in DCO in the AMS group (n = 12) was significantly lower (delta DCO, 1.26 +/- 1.74 mL/min/mm Hg) than that of the non-AMS group (p < 0.01). In four of the 12 subjects with AMS who had a high AMS score, DCO decreased from 38.4 +/- 4.5 to 33.2 +/- 5.3 mL/min/mm Hg (delta DCO, -5.84 +/- 1.1 mL/min/mm Hg). The AMS group showed significantly lower vital capacity, forced expiratory flow during the middle half of FVC, PaO2, and a greater alveolar-arterial oxygen pressure difference at 4,700 m compared with the non-AMS group. DCO showed a significant negative correlation with AMS score (r = -0.885) and a positive correlation with PaO2 (r = 0.757) at 4,700 m. These results suggest that the decreased pulmonary diffusing capacity in subjects with AMS reflects the presence of pulmonary gas exchange abnormality, which is probably due to subclinical interstitial edema of the lung.