Changes in cerebrovascular reactivity in healthy adults after acute exposure to high altitude.

OBJECTIVE: To study changes in the cerebrovascular reactivity (CVR) at different altitude area in healthy adults. SUBJECTS AND METHODS: CVR was tested using transcranial Doppler combined with CO2 inhalation, near-infrared spectroscopy (NIRS) was used to detect the regional cerebral oxygen saturation (rScO2). Blood samples were collected, and the vasoactive substances in serum were detected using the enzyme-linked immunosorbent assay. In this study, 59 healthy adults were divided into 3 groups: low altitude group, medium altitude group and high altitude group. All the indicators in low altitude group were tested at 24h before departure and after arrival from Beijing (at an altitude of 44.4 m) to Xining (at a medium altitude of 2200 m). Then, after resting for 48h, all the indicators were tested at 24h and 48h after arrival from Xining (at a medium altitude of 2200 m) to Yushu Jiegu town (at a high altitude of 3700 m) together with those at the medium altitude. Intergroup comparisons were made for the subjects in the three altitudes. RESULTS: There was an increase in the CVR in low altitude group after acute exposure to high altitude, and the difference was significant (CVR: 1.94re was vs. 0.91±0.53, p<0.001); the CVR index was increased, and the difference was significant [cerebrovascular reserve index (CVRI): 3.65he CVR vs. 1.37e CVR, p<0.001]; the rScO2 level was decreased with the increase of altitude, and the difference was significant [(66.78±4.61)% vs. (70.29±4.52)%, p<0.001]. The levels of vasoactive substances in low altitude group were decreased after acute exposure to high altitude compared with those before exposure: NO: [(79.14±9.54) µmol/L vs. (58.01±9.93) µmol/L, p<0.001]; serum eNOS level was increased, and the difference was significant [(77.23±6.20) pg/ml vs. (65.07±9.82) pg/ml, p<0.001]; EPO: [(84.68±13.16) pg/ml vs. (65.01±5.92) pg/ml, p<0.001]; VEGF: [(71.91±11.62) pg/ml vs. (54.92±11.86) pg/ml, p<0.001]; sFlt: [(384.18±42.73) pg/ml vs. (320.62±78.96) pg/ml, p<0.001]. There was also an increase in CVR in medium altitude group after acute exposure to high altitude, and the difference was significant [CVR: 2.00±0.79 vs. 0.91±0.66, p<0.001]; the difference of CVRI was significant [3.83±0.67 vs. 1.67±0.87, p<0.001]; rScO2 was slightly decreased with the increase of altitude, and the difference was not statistically significant [(67.53±4.61) % vs. (69.63±5.59) %, p<0.001]. Before exposure to high altitude area, the levels of NO, NOS, EPO, VEGF, and sFlt in low and medium altitude groups were higher than those in high altitude group. CVR level of subjects at different altitudes was negatively related to the ScO2 (r=-0.91) but positively related to NO and NOS levels (rs=0.89, r=0.75); CVR was moderately related to VEGF and EPO (rs=0.45, r=0.42). rScO2 was positively related to RBC, HB and VEGF levels (r=0.89, r=0.75, rs=0.86), but had a moderately negative correlation with NO and NOS levels (rs=-0.52, r=-0.57). CONCLUSIONS: After subjects at a low altitude are exposed to high altitude rapidly, CVR is increased, RBC and vasoactive substances in serum, such as NO, eNOS, and EPO, are dramatically increased, VEGF is increased first and then decreased, sFlt-1 level is increased gradually, and rScO2 level is gradually decreased with the increase of altitude, indicating the local brain anoxia of subjects at a high altitude.

[Pulmonary surfactant protein adenosine triphosphate-binding-cassette-A3 gene composite mutations in infant congenital interstitial lung disease: report of a case and review of literature].

Objective: To report a case of the pulmonary surfactant protein(SP) adenosine triphosphate-binding-cassette-A3 (ABCA3) gene mutations in infant congenital interstitial lung disease(ILD), and review the related literature, to investigate the relationships of ABCA3 gene mutation associated with ILD in infants. Method: A 6-months-old boy was hospitalized in the department of Pediatrics of the First Affiliated Hospital of Guangzhou Medical University. The clinical, radiological, histological information from transbronchial lung biopsy (TBLB) and genetic testing in this case was analyzed; 12 reports retrieved on literature search at Pubmed, OVID databases from 2004 to 2015 by using the ABCA3 as keyword were reviewed and analyzed. Result: (1)The patient, a 6-months-old boy, had progressive tachypnea and dyspnea since 4 months old. Physical examination on admission revealed respiratory rate of 78 times/min , heart rate of 187 times/min, SpO2 0.93(mask oxygen-inspiration with 6 L/min), scattered fine moist crackles could be heard over the both lungs, clubbing fingers were found. High-resolution computed tomography(HRCT) revealed diffuse ground-glass opacity, interlobular and intralobular septal thickening. Lung biopsies showed evidences of the alveolar cavity atelectatic changes and interstitial fibrosis. SP-A and SP-B were negative in immunohistochemical stainting. SP-related gene sequence analysis found that there was compound heterozygous missense mutation of ABCA3 gene in c. 1942A>G, c.2701-33G>C and c. 991-105C>A. (2)The review of related literature found that totally 12 cases were reported. The main manifestations were progressive tachypnea and dyspnea, age of onset was between birth and 4 years of age. The imaging characteristics of chest HRCT revealed diffuse infiltration or diffuse ground-glass pattern in the lung. PROGNOSIS: 6 cases died, and 6 cases survived, including 4 cases with pulmonary function disturbance to different degrees; 12 cases had ABCA3 gene mutations, 9 cases had composite ABCA3 gene mutations, in 11 cases the mutation occured in the exon of coding region, in 1 case in the intron, 9 cases had heterozygous mutations, 3 cases had homozygous mutations. Conclusion: The main phenotypes of ABCA3 mutation associated with ILD were full term neonatal respiratory distress syndrome or progressive tachypnea or dyspnea unexplained in infants. The chest HRCT showed two diffuse pulmonary interstitial changes. ABCA3 mutation mainly was multi-site composite mutations and heterozygous mutations in the exon of coding region.

Testosterone therapy delays cardiomyocyte aging via an androgen receptor-independent pathway

The testicular feminized (Tfm) mouse carries a nonfunctional androgen receptor (AR) and reduced circulating testosterone levels. We used Tfm and castrated mice to determine whether testosterone modulates markers of aging in cardiomyocytes via its classic AR-dependent pathway or conversion to estradiol. Male littermates and Tfm mice were divided into 6 experimental groups. Castrated littermates (group 1) and sham-operated Tfm mice (group 2, N = 8 each) received testosterone. Sham-operated Tfm mice received testosterone in combination with the aromatase inhibitor anastrazole (group 3, N = 7). Castrated littermates (group 4) and sham-operated untreated Tfm mice (group 5) were used as controls (N = 8 and 7, respectively). An additional control group (group 6) consisted of age-matched non-castrated littermates (N = 8). Cardiomyocytes were isolated from the left ventricle, telomere length was measured by quantitative PCR and expression of p16INK4α, retinoblastoma (Rb) and p53 proteins was detected by Western blot 3 months after treatment. Compared with group 6, telomere length was short (P < 0.01) and expression of p16INK4α, Rb and p53 proteins was significantly (P < 0.05) up-regulated in groups 4 and 5. These changes were improved to nearly normal levels in groups 1 and 2 (telomere length = 0.78 ± 0.05 and 0.80 ± 0.08; p16INK4α = 0.13 ± 0.03 and 0.15 ± 0.04; Rb = 0.45 ± 0.05 and 0.39 ± 0.06; p53 = 0.16 ± 0.04 and 0.13 ± 0.03), but did not differ between these two groups. These improvements were partly inhibited in group 3 compared with group 2 (telomere length = 0.65 ± 0.08 vs 0.80 ± 0.08, P = 0.021; p16INK4α = 0.28 ± 0.05 vs 0.15 ± 0.04, P = 0.047; Rb = 0.60 ± 0.06 vs 0.39 ± 0.06, P < 0.01; p53 = 0.34 ± 0.06 vs 0.13 ± 0.03, P = 0.004). In conclusion, testosterone deficiency contributes to cardiomyocyte aging. Physiological testosterone can delay cardiomyocyte aging via an AR-independent pathway and in part by conversion to estradiol.

Testosterone therapy delays cardiomyocyte aging via an androgen receptor-independent pathway.

The testicular feminized (Tfm) mouse carries a nonfunctional androgen receptor (AR) and reduced circulating testosterone levels. We used Tfm and castrated mice to determine whether testosterone modulates markers of aging in cardiomyocytes via its classic AR-dependent pathway or conversion to estradiol. Male littermates and Tfm mice were divided into 6 experimental groups. Castrated littermates (group 1) and sham-operated Tfm mice (group 2, N = 8 each) received testosterone. Sham-operated Tfm mice received testosterone in combination with the aromatase inhibitor anastrazole (group 3, N = 7). Castrated littermates (group 4) and sham-operated untreated Tfm mice (group 5) were used as controls (N = 8 and 7, respectively). An additional control group (group 6) consisted of age-matched non-castrated littermates (N = 8). Cardiomyocytes were isolated from the left ventricle, telomere length was measured by quantitative PCR and expression of p16INK4α, retinoblastoma (Rb) and p53 proteins was detected by Western blot 3 months after treatment. Compared with group 6, telomere length was short (P < 0.01) and expression of p16INK4α, Rb and p53 proteins was significantly (P < 0.05) up-regulated in groups 4 and 5. These changes were improved to nearly normal levels in groups 1 and 2 (telomere length = 0.78 ± 0.05 and 0.80 ± 0.08; p16INK4α = 0.13 ± 0.03 and 0.15 ± 0.04; Rb = 0.45 ± 0.05 and 0.39 ± 0.06; p53 = 0.16 ± 0.04 and 0.13 ± 0.03), but did not differ between these two groups. These improvements were partly inhibited in group 3 compared with group 2 (telomere length = 0.65 ± 0.08 vs 0.80 ± 0.08, P = 0.021; p16INK4α = 0.28 ± 0.05 vs 0.15 ± 0.04, P = 0.047; Rb = 0.60 ± 0.06 vs 0.39 ± 0.06, P < 0.01; p53 = 0.34 ± 0.06 vs 0.13 ± 0.03, P = 0.004). In conclusion, testosterone deficiency contributes to cardiomyocyte aging. Physiological testosterone can delay cardiomyocyte aging via an AR-independent pathway and in part by conversion to estradiol.

Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors.

OBJECTIVE: The goals were to critically review all complications resulting within 30 days after craniotomies performed for excision of intra-axial brain tumors relative to factors likely to affect complication rates and to assess the value of these data in predicting the risk of surgical morbidity, particularly for surgery in eloquent brain regions. METHODS: Neurosurgical outcomes were studied for 327 patients who underwent 400 craniotomies for removal of intra-axial parenchymal brain neoplasms in a 21-month period. Tumors removed included gliomas (206 tumors) and metastases (194 tumors) located both supratentorially (358 tumors) and infratentorially (42 tumors). RESULTS: The major complication incidence was 13%, and the operative mortality rate was 1.7%. The overall morbidity rate was 32%, but more types of complications were considered than in previous studies. The major neurological morbidity rate was 8.5%. Based on pre- versus postoperative (at 4 wk) Karnofsky Performance Scale scores, 9% of patients deteriorated neurologically, 32% improved, and 58% showed no change. The median postoperative hospital stay was 5 days. Tumors were defined as Grade I, II, or III based on their location relative to brain function, and this tumor functional grade was the most important variable affecting the incidence of any neurological deficit. Patients with tumors in eloquent (Grade III) or near-eloquent (Grade II) brain areas incurred more neurological deficits than did patients with tumors in noneloquent areas (Grade I). Neither repeat surgery for recurrent disease nor extent of surgical resection affected outcome significantly. Although most tumors in this study, including those in eloquent regions, were removed by gross total resection, this did not lead to more major neurological deficits. Regional complications (at the surgical sites) and systemic complications (medical) were more prevalent among older patients (age >60 yr) with lower preoperative Karnofsky Performance Scale scores (< or = 50) and posterior fossa masses. We showed how our data can be used to predict the total risk of surgical morbidity for a given patient, to facilitate patient counseling and surgical decision-making. CONCLUSION: The finding that gross total resections could be performed in eloquent brain regions with an acceptable level of neurological impairment suggested that the mere presence of a tumor in eloquent brain does not automatically contraindicate surgery. Our results have practical risk-predictive value, and they should aid in the construction of subsequent outcome studies, because we have identified the key areas to monitor.

Prognostic significance of proteolytic enzymes in human brain tumors.

Proteases and their inhibitors have been shown to play roles in tumor invasion and metastasis in a number of experimental models. Recently, relative increases in the amounts of urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor samples have been correlated with poorer, pathological grade, shorter disease-free interval, and shorter survival. To date, all studies investigating the prognostic significance of proteases and their inhibitors have been limited to extracranial cancer. In this article, we review the literature and present our data on the prognostic significance of proteases in human brain tumors. High levels of uPA were seen in malignant glioma and metastatic tumors (n = 82), whereas normal levels of uPA were found in low-grade gliomas. Analysis with magnetic resonance imaging (MRI) demonstrated a significant correlation between high levels of uPA and necrosis and edema (n = 50; P < 0.05). Similarly, patients with high levels of uPA had shorter survival than did patients with low levels of uPA. Tissue-type plasminogen activator (tPA), which was virtually absent in glioblastoma multiforme (GBM), colon lung, and breast metastasis, was found in normal quantities in anaplastic astrocytoma (AA), low-grade glioma (LGG), and meningioma. Melanoma had significantly more tPA activity than normal brain did. A reverse correlation was found between tPA and MRI findings of necrosis, enhancement, and edema. Similarly, patients with no detectable tPA activity had shorter survival than did patients with detectable tPA activity. We conclude that high levels of uPA and absent tPA activity correlate with histologically malignant brain tumors, aggressive characteristics, and shorter survival.

Therapeutic effects of an androgenic preparation on myocardial ischemia and cardiac function in 62 elderly male coronary heart disease patients.

The elevated estradiol/testosterone (E2/T) ratio had been proved to be a risk factor for coronary heart disease (CHD) in elderly men. We conducted a randomized placebo controlled crossover study on the effects of a new androgenic preparation "Andriol" in 62 elderly men with CHD over a period of 2.5 months. The results showed significant differences between Andriol- and placebo-treated groups at the end of this period: in the former, serum T level was elevated significantly (P < 0.001), E2 level was unchanged (P > 0.05), E2/T ratio was reduced (P < 0.05), angina pectoris (AP) was relieved (total effective rate, 77.4%), and myocardial ischemia in ECG and Holter recordings were improved (total effective rate, respectively 68.8% and 75%). Doppler echocardiography showed that 12 parameters of cardiac function were unchanged in both groups. No obvious side effect was found in those who took Andriol.

Plasma fibrinolytic profile in patients with brain tumors.

Changes in the fibrinolytic and coagulation values measured preoperatively in brain tumor patients have not been done systematically using individual rather than global assays. Such measurements can provide meaningful information on the status of tumor-host interactions and could potentially help in predicting thromboembolic and hemorrhagic tendencies. A complete fibrinolytic profile including total fibrinolytic activity (TFA), tissue plasminogen activator (t-PA), plasmin inhibitor (PI), plasminogen activator inhibitor (PAI), protein C (PC) and plasminogen (PLG) was obtained preoperatively in 114 brain tumor patients. PLG and PI did not show much variation among the groups. TFA was slightly reduced (15%) in patients with malignant brain tumors. t-PA, however, was abnormally low in several patients and in almost 40% of patients with brain metastasis. PAI was above the upper limit of normal in approximately 50% of the patients but particularly in glioma, glioblastoma and metastasis patients. Finally, mean PC was abnormally increased in the glioblastoma and metastasis groups (p less than 0.001). This is the first study that has measured protein C in brain tumor patients. In conclusion, plasma fibrinolytic levels show marked changes in a substantial number of brain tumor patients prior to surgery--suggesting an ongoing tumor-host interaction.

The relationship between the capillary structure and hemorrhage in gliomas.

A 48-year-old man was admitted with the sudden onset of symptoms of stroke caused by hemorrhage in an oligodendroglioma. Despite surgery and antiedema treatment, the patient died. Histological evaluation revealed an oligodendroglioma with calcified capillaries of the retiform type. To further investigate this phenomenon, a total of 160 gliomas were reviewed: 90 glioblastomas multiforme, 30 oligodendrogliomas, and 40 astrocytomas. Sufficient data were available for clinical evaluation in 100 cases. Of these, 5% (two oligodendrogliomas and three glioblastomas multiforme) were related to clinically significant hemorrhages. Of the remaining cases, microhemorrhages were found in 53.0% of the glioblastomas, in 56.7% of the oligodendrogliomas, and in 10.0% of the astrocytomas. In each case reviewed, the capillaries were assigned to one of three groups: axial, retiform, or glomeruloid. Statistical analysis revealed a significant association between hemorrhages and retiform capillaries in all three types of tumors, except that in oligodendrogliomas the statistical significance held true when calcification of the capillaries was also present. Glomeruloid-type capillaries were only weakly associated with hemorrhages, and no association was found for axial capillaries. A large-scale prospective study is necessary to more precisely assess the role of each of the three types of capillaries in hemorrhages of gliomas. Based on data available so far, patients with glial tumors with retiform capillaries, confirmed on biopsy, should be carefully monitored to exclude possible intratumoral hemorrhage.

[Chemotherapy combined with selective resection in small cell lung cancer--analysis of 239 patients].

From 1957 to 1976, 143 patients with small cell lung cancer (SCLC) were treated with surgical resection followed by chemotherapy. The 5 year survival rates were 38.7%, 8.7% and 3.5% in stages I, II and III. The prognostic factors were clinical stage and chemotherapy. 4 stage I and 1 stage II patients without chemotherapy have survived for more than 5 years. It seems to suggest that SCLC in stage I be indicated for surgery. 4 stage III have survived for more than 5 years, all of whom had received postoperative chemotherapy for more than 4 courses. From 1980 to 1982, 96 patients with SCLC were treated, 37 of whom by chemotherapy combined with surgery. 11/37 patients were alive for more than 2 years, 7 for more than 3 years and 4 for more than 4 years. In the preoperative chemotherapy followed by selective resection plus postoperative chemotherapy group (13 patients), the mean survival time was 22.7 months, but in the postoperative chemotherapy group (24 patients), it was 11.0 months. It indicates that full-dose chemotherapy before and after operation may be superior to the postoperative chemotherapy alone.