Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells

Cell stress may give rise to insuperable growth arrest, which is defined as cellular senescence. Stenotic kidney (STK) ischemia and injury induced by renal artery stenosis (RAS) may be associated with cellular senescence. Mesenchymal stem cells (MSCs) decrease some forms of STK injury, but their ability to reverse senescence in RAS remains unknown. We hypothesized that RAS evokes STK senescence, which would be ameliorated by MSCs. Mice were studied after 4 weeks of RAS, RAS treated with adipose tissue‐derived MSCs 2 weeks earlier, or sham. STK senescence‐associated β‐galactosidase (SA‐β‐Gal) activity was measured. Protein and gene expression was used to assess senescence and the senescence‐associated secretory phenotype (SASP), and staining for renal fibrosis, inflammation, and capillary density. In addition, senescence was assessed as p16+ and p21+ urinary exosomes in patients with renovascular hypertension (RVH) without or 3 months after autologous adipose tissue‐derived MSC delivery, and in healthy volunteers (HV). In RAS mice, STK SA‐β‐Gal activity increased, and senescence and SASP marker expression was markedly elevated. MSCs improved renal function, fibrosis, inflammation, and capillary density, and attenuated SA‐β‐Gal activity, but most senescence and SASP levels remained unchanged. Congruently, in human RVH, p21+ urinary exosomes were elevated compared to HV, and only slightly improved by MSC, whereas p16+ exosomes remained unchanged. Therefore, RAS triggers renal senescence in both mice and human subjects. MSCs decrease renal injury, but only partly mitigate renal senescence. These observations support exploration of targeted senolytic therapy in RAS.     

The human urinary proteome reveals high similarity between kidney aging and chronic kidney disease

Aging induces morphological changes of the kidney and reduces renal function. We analyzed the low molecular weight urinary proteome of 324 healthy individuals from 2–73 years of age to gain insight on human renal aging. We observed age‐related modification of secretion of 325 out of over 5000 urinary peptides. The majority of these changes were associated with renal development before and during puberty, while 49 peptides were related to aging in adults. We therefore focussed the remainder of the study on these 49 peptides. The majority of these 49 peptides were also markers of chronic kidney disease, suggesting high similarity between aging and chronic kidney disease. Blinded evaluation of samples from healthy volunteers and diabetic nephropathy patients confirmed both the correlation of biomarkers with aging and with renal disease. Identification of a number of these aging‐related peptides led us to hypothesize that reduced proteolytic activity is involved in human renal aging. Finally, among the 324 supposedly healthy individuals, some had urinary aging‐related peptide excretion patterns typical of an individual significantly older than their actual age. In conclusion, these aging‐related biomarkers may allow noninvasive detection of renal lesions in healthy persons and show high resemblance between human aging and chronic kidney disease. This similarity has to be taken into account when searching for biomarkers of renal disease.     

Effect of the functional state of the internal organs on the pharmacokinetics of benzylpenicillin in angina]

The levels of benzylpenicillin on its intramuscular administration in doses of 100000 or 200000 units, as well as the renal and hepatic functions and the antibiotic binding by the host protein components were studied in 44 angina patients and 29 healthy persons. The benzylpenicillin levels were always markedly higher in the angina cases than those in the healthy persons. The ratio of the free and protein bound fractions of the antibiotic in the above groups was practically the same. At the same time the amount of benzylpenicillin excreted with the urine was higher in the angina patients than in the healthy persons approximately by 2 times. The study of the function of the internal organs revealed a marked decrease in the daily diuresis in all the angina patients and microhematuria in the 1/4 of the cases. The impairment of the renal function was determined by the laboratory methods practically in all the patients. On the basis of the data obtained it was concluded that the increased benzylpenicillin levels in the angina cases were connected with a decreased capacity for inactivating this substance by the liver enzymatic systems due to the changed function of this organ. The fact of the increased antibiotics levels in the host is considered as a positive phenomenon providing inhibition of the disease causative agents resistant to usual concentrations of the drug.     

Ultrasound studies in varicocele

Renal function, the anatomic and functional status of the vena cava inferior, renal arteries and veins, and spermatic veins were evaluated in healthy individuals and patients with varicocele before and 12 months after laparoscopic ligation of the left spermatic vein. The renal vessels were assessed by color Doppler ultrasonography and renal function was examined by complex radionuclide study with 99mTc-pentatech. There were no significant changes in the diameter of renal arteries and vena cava inferior and the right arterial blood flow velocities in healthy individuals and patients. No difference were found in the diameter of renal veins and in the blood flow velocity in renal arteries and veins. The enlarged renal veins and decreased mean blood flow velocity in the left renal vein in healthy persons and patients with varicocele and lower blood flow in the left renal artery than in the right one indicate left-sided renal hypertension that is attributable to left renal vein overload due to a great variety of collaterals and to compression at the site of "a forcepts". At the same time 12-month postoperative ultrasonic, Doppler and complex radionuclide studies revealed no significant changes in the diameter and blood flow velocity in the left renal vein.     

Magnetic resonance tomography in the diagnosis of aneurysm and coarctation of the thoracic aorta]

MR-tomography (MRT) was performed in 25 patients with aneurysms and in 11 with coarctation of the thoracic aorta. For investigations a device with a resistive magnet (the force of a field--0.23 T) was used simultaneously with ECG. MRT revealed all cases of aortic dissection (10 patients) and one case with a false-positive result. Oblique sections in the direction of the thoracic aorta were used to assess the state of the aortic arch branches. Comparison of MRT and x-ray computerized tomography has shown that the diagnostic value of both methods was almost equal, however MRT was a safer method and easier to use. MRT was shown to be a method of choice for diagnosis of aneurysms and coarctations of the thoracic aorta but cannot be a substitution for aortography.     

Serum antibodies of periodontitis patients compared to the lipopolysaccharides of Porphyromonas gingivalis and Fusobacterium nucleatum

Serum antibody titers against the lipopolysaccharides (LPSs) of Porphyromonas gingivalis and Fusobacterium nucleatum were compared between 9 periodontitis patients and 24 healthy persons. The IgG titers against the LPSs of P. gingivalis ATCC 33277(T) and W50 were clearly higher in the patients than in the healthy persons. However, IgM titers against the LPSs of P. gingivalis strains were relatively low, and no significant difference was observed between the patients and healthy persons. On the other hand, IgG and IgM titers against the LPS of Fusobacterium nucleatum JCM 8532(T) in some patients were significantly higher than those in the healthy persons, although the difference in IgG titers was not large compared to that of the LPS of P. gingivalis. These results suggest that the antibody measurement of patients' sera against the LPS of periodontal bacteria can be applied for the diagnosis of periodontitis.     

Elevated oxidative stress and endothelial dysfunction in right coronary artery of right ventricular hypertrophy

Remodeling of right coronary artery (RCA) occurs during right ventricular hypertrophy (RVH) induced by banding of the pulmonary artery (PA). The effect of RVH on RCA endothelial function and reactive oxygen species (ROS) in vessel wall remains unclear. A swine RVH model (n = 12 pigs) induced by PA banding was used to study RCA endothelial function and ROS level. To obtain longitudinal coronary hemodynamic and geometric data, digital subtraction angiography was used during the progression of RVH. Blood flow in the RCA increased by 82% and lumen diameter of RCA increased by 22% over a 4-wk period of RVH. The increase in blood flow and the commensurate increase in diameter resulted in a constant wall shear stress in RCA throughout the RVH period. ROS was elevated by ～100% in RCA after 4 wk of PA banding. The expressions of p47(phox), NADPH oxidase (NOX1, NOX2, and NOX4) were upregulated in the range of 20-300% in RCA of RVH. The endothelial function was compromised in RCA of RVH as attributed to insufficient endothelial nitric oxide synthase cofactor tetrahydrobiopterin. In vivo angiographic analysis suggests an increased basal tone in the RCA during RVH. In conclusion, stretch due to outward remodeling of RCA during RVH (at constant wall shear stress), similar to vessel stretch in hypertension, appears to induce ROS elevation, endothelial dysfunction, and an increase in basal tone.     

核医学肾动态显像和血清Cys C在评价肾积水患者肾功能中的临床应用

目的:探讨核医学肾动态显像和血清胱抑素C(Cys C)在评价肾积水患者肾功能中的临床应用。方法:选择2014年1月至2015年1月我院收治的肾积水患者70例,依据肾积水程度将患者分为轻度积水组(21例)、中度积水组(26例)、重度积水组(23例)三组,选择同期我院体检中心的健康成人20例作为对照组,所有研究对象分别通过肾动态显像和双血浆法测量肾小球率过滤(GFR),分别记为I-GFR和rGFR,采用酶联免疫吸附法和血生化分析仪分别检测血清Cys C和尿素氮(BUN)、血肌酐(SCr)。结果:各组各指标比较差异均有统计学意义(均P0.05),肾积水患者r-GFR、I-GFR显著低于对照组患者,Cys C、BUN、SCr均显著高于对照组患者,差异有统计学意义(均P0.05);不同程度患者r-GFR、Cys C和SCr差异有统计学意义(均P0.05),其中,重度积水组中度积水组轻度积水组,差异有统计学意义(均P0.05);重度积水组I-GFR和BUN均高于轻度积水组和中度积水组,差异有统计学意义(均P0.05);rGFR和I-GFR与肾积水程度呈负相关(r=-0.967、-0.754,P=0.000、0.000),Cys C、BUN和SCr与肾积水程度呈正相关(r=0.883、0.627、0.671,P=0.000、0.002、0.001)。结论:核医学肾动态显像在评价轻度肾积水患者肾功能时更敏感,而血清Cys C在区分中、重度肾积水患者时更加准确,上述两指标作为替代双血浆法的检测方法在临床上应该互为补充,方能使诊断更加准确。     

三维斑点追踪技术对慢性肾功能不全患者左心室收缩功能和右心室功能的评估价值研究

摘要 目的：探讨慢性肾功能不全患者应用三维斑点追踪技术对其左心室收缩功能和右心室功能的评估价值。方法：选择我院收治的慢性肾功能不全患者82例,根据患者肾功能将其分为轻度慢性肾功能不全组[慢性肾脏病（CKD） 2期,47例],中-重度慢性肾功能不全组（CKD 3~5期,35例）,另选取同期医院体检的健康志愿者30例作为对照组,应用二维超声及三维斑点追踪技术检测各组心脏指标,比较三组二维超声指标、三维斑点追踪技术指标,应用受试者工作特征（ROC）曲线分析三维斑点追踪技术对患者左心室收缩功能和右心室功能的评估价值。结果：中-重度慢性肾功能不全组室间隔舒张末期厚度（IVSTd）、肺动脉收缩压（PASP）显著高于轻度慢性肾功能不全组、对照组,右心室面积变化分数（RVFAC）、组织运动三尖瓣环位移（TAPSE）、左心室射血分数（LVEF）显著低于轻度慢性肾功能不全组、对照组（P<0.05）。中-重度慢性肾功能不全组左室整体圆周收缩期峰值应变（LGCS）、左室整体纵向收缩期峰值应变（LGLS）、右室整体圆周收缩期峰值应变（RGCS）右室整体纵向收缩期峰值应变（RGLS）、显著高于轻度慢性肾功能不全组、对照组,左室整体径向收缩期峰值应变（LGRS）、三维左室射血分数（3D-LVEF）、右室整体径向收缩期峰值应变（RGRS）、三维右室射血分数（3D-RVEF）显著低于轻度慢性肾功能不全组、对照组（P<0.05）。ROC曲线分析显示,三维斑点追踪技术对慢性肾功能不全患者左心室收缩功能和右心室功能的评估价值较高。结论：三维斑点追踪技术可以准确检测心脏的纵向运动、圆周运动、径向运动,为临床早期发现慢性肾功能不全患者的心脏功能异常提供依据。     

Visual classification of erythrocytes in blood smears from normal subjects and patients

Erythrocytes on specially prepared and coloured blood smears can be classified not only by idcture analysis but also by phase contrast microscopy. Parameters of change for the peripheral zone area and pallor area (phase contrast value PW and index of erythrocyte changes Ev-I) serve as classificators of visual technique. 449 blood smears of the same number of male and female grown-up persons, whose diagnosis was unknown at the time of evaluation, were used for evaluation. In 145 cases these were healthy test persons in clinical and laboratory respect (group I). 163 test persons were ill, but without any malignous neoplasias (group II), and in 141 patients an ensured malignous neoplasia could be found (group III). From those 308 test persons or patients respectively in group I + II 11 blood smears were falsely classified as positive (= 3.6%). In 5 from 141 cases in group III blood smears were falsely evaluated as negative (= 3.6%). The findings were statistically ensured by the t-test. Clinical parameters of evaluation gained with visual techniques of classification are in accordance with those gained with automatic picture analysis. The reasons for the good separating ability of PW and Ev-I are discussed. Visual techniques of classification are suitable for institutions of all grades of equipment.     

Magnetic resonance tomography, computed tomography and ultrasonic diagnosis of hemangiomas of the liver

The paper is concerned with the potentialities of modern radiation methods in the diagnosis of liver hemangiomas. USI, CT, angiography and MR-tomography (MRT) were used for investigation of 64 patients with liver hemangiomas. The diagnostic potentialities and the role of each of the above methods in the diagnostic algorithm in liver hemangiomas were studied. The results of the investigation have shown that MRT possesses a higher informative value than USI and CT in the diagnosis of liver hemangiomas and can even replace angiography in the verification of diagnosis.     

A computer-assisted study of the effect of gravitation on the functional state of the lungs

Gravitation influence on lung function was investigated in 115 patients and 21 healthy persons. Changing of an examinee's position from vertical into a horizontal one causes changes in lung function in health and disease. Characteristic features of lung function were determined for each group of examinees in order to improve the diagnosis and differential diagnosis of bronchial cancer and nonspecific chronic pulmonary diseases with a similar x-ray picture. A study of pulmonary ventilation and blood supply of the lungs in vertical and horizontal postures in Hodgkin's disease patients led to a conclusion that irradiation of patients seemed more effective in a phase of deep breath. It made it possible to reduce radiation exposure of healthy parts in a zone to be irradiated.     

Allicin in garlic protects against coronary endothelial dysfunction and right heart hypertrophy in pulmonary hypertensive rats

We recently reported that coronary endothelial cell (CEC) dysfunction may contribute to the development of right ventricular (RV) hypertrophy (RVH) in monocrotaline (MCT)-induced pulmonary hypertensive rats. This present study investigated whether preservation of CEC function with garlic and its active metabolite allicin could abrogate RVH. Rats were fed with 1% raw garlic (RG)-supplemented diet 1 day or 3 wk before and 1 day after MCT injection, and changes in RV pressure (RVP), RVH, and CEC function were assessed 3 wk after MCT administration. In all cases, RG feeding significantly inhibited the development of RVP and RVH in these MCT rats. However, similar treatments with either boiled garlic (BG) or aged garlic (AG), which do not contain the active allicin metabolite, were ineffective. CEC function, assessed with acetylcholine-induced dilation as well as N(omega)-nitro-l-arginine methyl ester-induced constriction, revealed marked attenuation in right, but not left, coronary arteries of the MCT rats. This is consistent with our earlier report. Feeding of RG, but not BG or AG, preserved the CEC function and prevented the exaggerated vasoconstrictory responses of the MCT coronary arteries. There was no change in the coronary dilatory responses to a nitric oxide donor sodium nitroprusside. Further testings of vasoactivity to garlic extracts showed that only RG, but not BG or AG, elicited a potent, dose-dependent dilation on the isolated coronaries. Taken together, these findings show that the protective effect of garlic against the development of RVP and RVH in MCT-treated rats is probably mediated via its active metabolite allicin action on coronary endothelial function and vasoreactivity.     

肾脏肿瘤患者CT灌注参数与肾功能生化检测指标的相关性研究

目的:探讨肾脏肿瘤患者CT灌注参数与肾功能生化检测指标的相关性。方法:选取河北省第六人民医院2013年3月至2018年1月期间收治的35例肾脏肿瘤患者作为观察组,另选取同期来我院体检的35例健康者作为对照组,均对两组受试者实施CT灌注成像,获取等效血容量(Equiv BV)、表面渗透性(Ps)、血流量(BF)等CT灌注参数,并检测两组受试者血尿素氮(BUN)、血肌酐(Scr)、总胆固醇(TC)、甘油三酯(TG)等肾功能生化指标,对比两组受试者上述指标检测结果,采用Pearson相关分析CT灌注参数与肾功能生化指标的相关性。结果:与对照组相比,观察组CT灌注参数Equiv BV、Ps、BF均降低,肾功能生化指标BUN、Scr、TC、TG水平均升高,有统计学差异(P0.05)。Pearson相关分析结果显示,CT灌注参数Equiv BV、Ps、BF与肾功能生化指标TC、BUN均呈负相关(P0.05),与Scr、TG无相关性(P0.05)。结论:肾脏肿瘤患者的CT灌注参数Equiv BV、Ps、BF均较低,BUN、Scr、TC、TG水平均较高,且CT灌注参数与BUN、TC水平呈负相关性,可作为评估肾脏肿瘤患者肾功能的辅助方法。     

Atrial natriuretic peptide in kidney of renal disease patients and healthy persons

Regulation of renal excretion of atrial natriuretic peptide (ANP) was studied in kidney disease patients and healthy kidney donors. The measured ANP concentration in the patient's plasma did not correlate with their creatinine clearance (Ccr), while the fractional excretion of ANP (FEANP) significantly correlated with Ccr. FEANP in healthy persons is less than 1%. In the healthy donors of kidneys for transplantation, approximately 80% of the plasma ANP from the renal artery appeared in the renal vein. From these results, this high recovery of ANP in the veins does not appear to be adequately explained by its degradation in the renal arterioles and nephrons. The FEANP from kidney disease patients significantly correlated with FENa, FEK and FEP, but not with FECa and FEMg. The manner of ANP handling in the nephron may possibly differ from that of Ca or Mg.     

Microbeam radiation therapy: Clinical perspectives

Microbeam radiation therapy (MRT), a novel form of spatially fractionated radiotherapy (RT), uses arrays of synchrotron-generated X-ray microbeams (MB). MRT has been identified as a promising treatment concept that might be applied to patients with malignant central nervous system (CNS) tumours for whom, at the current stage of development, no satisfactory therapy is available yet. Preclinical experimental studies have shown that the CNS of healthy rodents and piglets can tolerate much higher radiation doses delivered by spatially separated MBs than those delivered by a single, uninterrupted, macroscopically wide beam. High-dose, high-precision radiotherapies such as MRT with reduced probabilities of normal tissue complications offer prospects of improved therapeutic ratios, as extensively demonstrated by results of experiments published by many international groups in the last two decades. The significance of developing MRT as a new RT approach cannot be understated. Up to 50% of cancer patients receive conventional RT, and any new treatment that provides better tumour control whilst preserving healthy tissue is likely to significantly improve patient outcomes.     

Strain and sex differences in the cardiopulmonary adaptation of rats to high altitude

On chronic exposure to hypoxia, the commercially available Hilltop (H) strain of male Sprague-Dawley rats develops severe pulmonary hypertension, right ventricular hypertrophy (RVH), and polycythemia. These signs of chronic mountain sickness are associated with a high mortality rate. In contrast, the Madison (M) strain of Sprague-Dawley rats remains healthy with significantly less severe cardiopulmonary and hematological responses. Breeding experiments under locally controlled conditions were undertaken to determine if the differences between the two strains were genetically determined and to look for possible sex differences. Following 30 to 50 days exposure to a simulated altitude of 18,000 ft, the first generation of male H rats exhibited a higher right ventricular peak systolic pressure (RVPP), a more pronounced RVH, and a greater degree of polycythemia than the male M rats. The H rats had a mortality rate of 40% in contrast to a rate of 0% in the male M rats. The first generation of female H rats also developed a higher RVPP, a greater RVH, and more severe polycythemia than that in the female M rats. There were no differences in RVPP or RVH between the males and females of either strain. Females of both strains tolerated the hypoxic exposure with a 0% mortality rate. The data suggest that the differences between the males of H and M strains in their cardiopulmonary and hematological responses and in their susceptibilities to chronic hypoxia are genetic in nature. They further suggest that the female resistance to hypoxia is not due to milder cardiopulmonary responses. Perhaps female rats tolerate RVH better than male rats, at least of the H strain.     

Clinical significance of oxidation and acetylation genetic polymorphism in patients with hyperthyreosis

INTRODUCTION: The relationship between genetically determined polymorphic oxidation and acetylation and susceptibility to some disease was aroused much interest. The aim of our study was to evaluate whether patients with hyperthyreosis differ from healthy persons in their ability to oxidize sparteine and acetylate sulphadimidine as model drugs. Oxidation and acetylation were estimated in 48 patients with hiperthyreosis. MATERIAL AND METHODS: The control group consisted of 160 healthy volunteers for comparison of oxidation phenotype and 60 healthy volunteers for comparison of acetylation phenotype. The phenotyping of oxidation revealed two distinct populations among 40 patients with hyperthyreosis: 38 persons (95%) were extensive metabolizers (EM) of sparteine and 2 persons (5%) was poor metabolizers (PM). In 160 healthy persons (91.2%) were EM and 14 persons (8.8%) were PM. The difference between frequency distribution of PM and EM in healthy persons and in patients with hyperthyreosis was not statistically significant. RESULTS: The phenotyping of acetylation showed among 48 patients with hyperthyreosis 8 persons (13%) were rapid acetylators (RA) and 40 persons (87%) were slow acetylators (SA). In 60 healthy volunteers the phenotype of rapid acetylation was observed in 31 persons (51%) and slow acetylation in 29 persons (49%). Relative risk (odds ratio) of development of thyroid diseases was 5.34 times higher for SA in comparison to RA. The prevalence of SA among patients with hyperthyreosis in comparison to healthy volunteers was statistically significant (p < 0.0002). CONCLUSIONS: The results of our study may suggest that slow acetylation phenotype is associated with increased risk of the development of hyperthyreosis.     

Detection by proton nuclear magnetic resonance of elevated lactate concentration in serums from patients with malignant tumors.

Proton nuclear magnetic resonance (1H-NMR) spectra of the serum specimens from patients with malignant tumors were compared with those from presumably healthy persons. We found that 87% of serum specimens from the patients yielded a common proton signal, which was ascribed to the methyl protons of lactic acid; whereas only 9% of serum specimens from the healthy persons tested gave this signal. On the basis of these results we concluded that the lactate level in the serum can be used as a criterion for the diagnosis of cancer in humans and that the determination of lactate concentration in the serum is easily performed by means of 1H-NMR.     

Avidity of immunoglobulin G to rubella virus in post-vaccination and post-infection immunity

Comparative evaluation of avidity of IgG to rubella virus in vaccinated persons, in patients with rubella or other exanthematous illness, and in healthy persons revealed similar patterns in post-vaccination and post-infection immunity. Virus specific low avidity IgG (index of avidity < or =30%) were detected in patients with rubella during 7 weeks after symptoms appeared as well as in vaccinated persons which were tested 6 weeks after vaccination. Low avidity antibodies in sera were detected in 96% of patients with rubella and in 75% of vaccinated persons which were not immune before immunization. Live attenuated vaccines Ervevax, Priorix, and MMR-II had similar ability to induce low avidity IgG to rubella virus. Increase of low avidity antibodies concentration was noted after immunization of children with low levels of antibodies before vaccination. After immunization of persons with high avidity antibodies in serum, index of avidity remained above threshold. Anamnestic high avidity IgG (index of avidity 51-100%) were detected in majority of immune healthy persons (96.4%) as well as in patients with exanthematous illnesses not related to rubella infection (93.6%). ELISA test-systems for detection of low avidity IgG to rubella virus allow to obtain reliable information about seroconversion rate and characteristics of immune response in vaccines. Detection of low avidity IgG in serum obtained 5-6 weeks after immunization points to primary immune response, whereas identification of high avidity antibodies reveals already immune persons.