Interaction of aluminium and gallium with human lymphocytes: the role of transferrin

Aluminium-transferrin (Al-Tf) and gallium-transferrin caused a dose-dependent decrease in proliferation of human peripheral blood lymphocytes cultured for 3 days with phytohaemagglutinin (PHA). Addition of apotransferrin reduced the inhibitory effect. Al added as AlCl3 or aluminium citrate had no effect, and there was no significant difference in the response of cells from renal failure patients with or without high serum Al levels or controls. Lymphocytes cultured in the presence of Al-Tf showed a dose-dependent uptake of Al, whereas uptake from aluminium citrate was low and not dose-dependent. Uptake from AlCl3 was very high but probably involved a nonspecific uptake mechanism. Levels of Al in freshly isolated lymphocytes were approximately 1.6 ng/10(6) cells, there being no difference between cells from patients and controls. It is concluded that Al, when bound to transferrin, may have a detrimental effect on lymphocyte function and might contribute to the decreased immune responsiveness of renal failure patients on haemodialysis. However, lymphocyte Al levels are probably not useful as a marker of Al overload in such patients.     

高危型HPV筛查与TCT 联合检查在宫颈癌筛查中的临床应用

目的:探究液基薄层细胞学检测(TCT)与高危人乳头瘤病毒(HR-HPV)筛查联合检查在宫颈癌(CC)筛查中的临床价值。方法:选择2013年4月~2015年4月期间我院就诊疑似CC患者318例为研究对象;研究对象均进行HR-HPV筛查、TCT检查及阴道镜下病理活检,评价三种筛查结果的临床应用价值。结果:318例可疑CC患者中,病理学诊断炎症患者162例(50.94%),宫颈上皮内瘤样变(CIN)患者151例(47.48%),鳞癌(SCC)患者5例(1.57%);HR-HPV、TCT及HPV+TCT联合对诊断结果与病理诊断的符合率分别为78.30%、85.22%和99.37%;HR-HPV与TCT单独检测的符合率随患者病情进展呈现升高趋势(P0.05);TCT、HR-HPV检测单独进行诊断的敏感度、特异度均低于联合诊断(P0.05);HR-HPV与TCT联合检测诊断CC的敏感度为98.71%、特异度100%。结论:TCT检查HR-HPV筛查联合检查CC的敏感性、特异性及准确性高,为CC筛查的有效方式,值得在临床应用推广。     

吐温80 在深部脏器肿瘤热化疗中的应用研究

目的：研究热增敏剂吐温80在深部肿瘤热化疗中的临床应用疗效。方法：采用吐温80合并热化疗综合治疗晚期肿瘤118例,并与同时期未采用吐温80的热化疗组98例进行比较。膀胱癌复发5例,伴腹水、腹膜转移7例。小剂量化疗用5-FU、丝裂霉素、顺铂等行膀胱灌注或腹腔注射,吐温80浓度为0．2％。肿瘤射频热疗机,f：41MHz。平均随访时间36个月。结果：复发性膀胱癌完全缓解率达60％,血尿消失,3例在12～34月随访期间膀胱镜检查未复发;伴腹水者完全缓解率达85．7％（CR6／7）,中位生存期8．5月,腹痛、腹胀、便血等消失。治疗未引起恶心、呕吐等明显的消化道症状,肝、肾和骨髓功能损害。结论：在肿瘤的热化疗中。合用吐温80不仅可以降低化疗药物的剂量,而且降低热疗时的温度,减少毒副作用,改善症状和体征。     

Effect of parathyroid hormone and thyrocalcitonin on the cell membrane Na, K-ATP-ase of rat brain and kidney]

The influence of parathyroid hormone (PH) and thyrocalcitonine (TCT) on the enzymatic activity of ATP-ase systems of the membrane specimens of the cerebral cortex and renal cortex was investigated in experiments on rats. It was found that parathyroid hormone increased the activity of Na, K-ATP-ase and Ca-activated ATP-ase transport of the membranes in the brain and the kidneys both in vivo and in vitro. TCT caused analogous, but less expressed changes of the ATP-ase activity. Both hormones showed no influence on the Mg-ATP-ase activity of the both organs. It is supposed that the PH hormone influenced the membrane structures with the ATP-ase activity directly, while the action of TCT on them was mediated.     

Ebselen ameliorates renal ischemia–reperfusion injury via enhancing autophagy in rats

Renal ischemia–reperfusion (I/R) injury is one of the most common causes of chronic kidney disease (CKD). It brings unfavorable outcomes to the patients and leads to a considerable socioeconomic burden. The study of renal I/R injury is still one of the hot topics in the medical field. Ebselen is an organic selenide that attenuates I/R injury in various organs. However, its effect and related mechanism underlying renal I/R injury remains unclear. In this study, we established a rat model of renal I/R injury to study the preventive effect of ebselen on renal I/R injury and further explore the potential mechanism of its action. We found that ebselen pretreatment reduced renal dysfunction and tissue damage caused by renal I/R. In addition, ebselen enhanced autophagy and inhibited oxidative stress. Additionally, ebselen pretreatment activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The protective effect of ebselen was suppressed by autophagy inhibitor wortmannin. In conclusion, ebselen could ameliorate renal I/R injury, probably by enhancing autophagy, activating the Nrf2 signaling pathway, and reducing oxidative stress.

     

Calcitonin, an enigmatic hormone: does it have a function?

This editorial presents our view of the status of thyroidal calcitonin (TCT) in mammalian physiology. The discovery of calcitonin (CT) enabled the development of a valuable therapeutic agent but the early experiments most likely misled us with regard to its physiological significance. These early purported roles for TCT, first as an agent important in blood calcium regulation and later as an agent to prevent hypercalcemia, are no longer considered as physiological functions. While large supraphysiological doses of CT have an effect on the morphology and function of osteoclasts, it is unlikely that these effects of CT are important in the normal physiology of osteoclasts or bone remodeling. It is surprising that 38 years after the discovery of TCT there is no consensus as to its role in normal mammalian physiology. This editorial concerns three possibilities with respect to TCT: 1) the hormone is vestigial; 2) the hormone plays a role in water metabolism, ionic concentrations, and/or acid-base balance, actions that may not involve calcium metabolism at all; and 3) TCT acts to store phosphate postprandially on bone surfaces as a labile calcium-phosphate colloid, an action that may provide calcium needed for use in non-feeding periods or to reduce postprandial loss of phosphate when dietary phosphate is limited. Also discussed are recent publications indicating that CT synthesized in non-thyroidal tissues (NTCT) may have paracrine actions.     

TCT、HPV检测在宫颈锥切术后复发中的预测价值

目的:评估薄层液基细胞学检查(thinprep cytologic test,TCT)和人乳头瘤病毒(human papillomavirus,HPV)检测在宫颈锥切术后复发中的预测价值。方法:随访531例病理诊断为子宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)Ⅱ-Ⅲ级接受宫颈锥切术的患者,分别于术后3、6个月及术后每6-12月随访1次,以TCT及HPV检测作为随访的检测指标,若二者有一项异常,行阴道镜下活组织检查,病理证实存在子颈上皮内瘤变Ⅰ-Ⅲ级者视为复发。采用敏感度、特异度、阳性预测值、阴性预测值表示TCT、HPV检测性能。结果:531例患者中10%(54例)的患者出现不同级别的病变复发。TCT在术后预测病变复发的灵敏度77%,特异度72%;HPV在术后预测病变复发的灵敏度95%,特异度60%,TCT联合HPV预测病变复发的灵敏度100%,特异性80%。术后HPV负荷量100 RLU/PC者较HPV负荷量100 RLU/PC者而言术后病变复发的风险增高,差别有统计学意义(P0.01),术后HPV负荷量100 RLU/PC是锥切术后病变复发的高危因素。结论:使用细胞学联合HPV检测是有效的预测宫颈锥切术后病变复发的方法,术后高HPV负荷量与病变复发相关,并可对术后复发高风险人群进行分流,临床需严密随访。     

Dynamic flux of microvesicles modulate parasite–host cell interaction of Trypanosoma cruzi in eukaryotic cells

Extracellular vesicles released from pathogens may alter host cell functions. We previously demonstrated the involvement of host cell‐derived microvesicles (MVs) during early interaction between Trypanosoma cruzi metacyclic trypomastigote (META) stage and THP‐1 cells. Here, we aim to understand the contribution of different parasite stages and their extracellular vesicles in the interaction with host cells. First, we observed that infective host cell‐derived trypomastigote (tissue culture‐derived trypomastigote [TCT]), META, and noninfective epimastigote (EPI) stages were able to induce different levels of MV release from THP‐1 cells; however, only META and TCT could increase host cell invasion. Fluorescence resonance energy transfer microscopy revealed that THP‐1‐derived MVs can fuse with parasite‐derived MVs. Furthermore, MVs derived from the TCT–THP‐1 interaction showed a higher fusogenic capacity than those from META– or EPI–THP‐1 interaction. However, a higher presence of proteins from META (25%) than TCT (12%) or EPI (5%) was observed in MVs from parasite–THP‐1 interaction, as determined by proteomics. Finally, sera from patients with chronic Chagas disease at the indeterminate or cardiac phase differentially recognized antigens in THP‐1‐derived MVs resulting only from interaction with infective stages. The understanding of intracellular trafficking and the effect of MVs modulating the immune system may provide important clues about Chagas disease pathophysiology.     

Splint renal function after captopril in unilateral renal artery stenosis.

The renal extraction ratios of 131I-sodium iodohippurate (131I-Hippuran) and 125I-thalamate were greatly reduced on the affected side by 50 mg captopril in seven out of 14 patients with unilateral renal artery stenosis. With long term captopril 150 mg daily the uptake of 99mTc-diethylenetriaminepenta-acetic acid by the affected kidney, which was determined by scintillation camera renography, became almost zero in these seven patients, indicating severe reduction of the glomerular filtration rate. Function of the affected kidney returned on discontinuing treatment. The reduced extraction of sodium iodohippurate probably reflected a shortened plasma transit time through the kidney due to intrarenal vasodilatation. The reduced extraction of thalamate reflected a low filtration fraction, suggesting that the vasodilatation was, at least in part, at the level of the postglomerular arterioles. Captopril had little effect on the contralateral kidney and on the kidneys of 17 patients with essential hypertension, and serum creatinine concentrations showed minor changes. Radioisotope renography should be performed after beginning captopril treatment in patients with renal artery stenosis. This is also recommended for patients given captopril as a third line drug when renal artery stenosis has not been excluded. Hypertension is these patients is often severe and difficult to control. Renal artery disease is not rare in this difficult group and finding seriously impaired renal function on one side during captopril treatment may be diagnostic.     

TCT、阴道镜下活检和LEEP对CIN诊断价值的比较

目的：评价TCT检查、阴道镜活检和LEEP活检在宫颈上皮内瘤变（ClN）诊断中的价值,比较其差异。方法：对324例经TCT加阴道镜下活检诊断为CIN的患者进一步行LEEP,采用对比研究TCT、阴道镜下活检和IEEP活检病理结果。结果：TCT检查与阴道镜活检诊断结果的完全符合率为65．1％,TCT结果与LEEP活检病理学诊断结果的完全符合率为69．4％,诊断过度11．4％,诊断不足18．5％。阴道镜下宫颈活检结果与LEEP活检病理学诊断结果的完全符合率为68．2％,诊断过度21．9％,诊断不足9-3％,后两种方法的诊断结果差异有统计学意义（P〈O．01）。结论：TCT是辅助诊断CIN的有效方法;单独阴道镜下活检诊断CIN的准确性尚不够理想,阴道镜下活检不能替代LEEP活检;TCT诊断CIN者在初次治疗时可用LEEP一次完成诊断和治疗。     

Attenuation of host NO production by MAMPs potentiates development of the host in the squid-vibrio symbiosis

Bacterial pathogens typically upregulate the host's production of nitric oxide synthase (NOS) and nitric oxide (NO) as antimicrobial agents, a response that is often mediated by microbe-associated molecular patterns (MAMPs) of the pathogen. In contrast, previous studies of the beneficial Euprymna scolopes/Vibrio fischeri symbiosis demonstrated that symbiont colonization results in attenuation of host NOS/NO, which occurs in high levels in hatchling light organs. Here, we sought to determine whether V. fischeri MAMPs, specifically lipopolysaccharide (LPS) and the peptidoglycan derivative tracheal cytotoxin (TCT), attenuate NOS/NO, and whether this activity mediates the MAMPs-induced light organ morphogenesis. Using confocal microscopy, we characterized levels of NOS with immunocytochemistry and NO with a NO-specific fluorochrome. When added exogenously to seawater containing hatchling animals, V. fischeri LPS and TCT together, but not individually, induced normal NOS/NO attenuation. Further, V. fischeri mutants defective in TCT release did not. Experiments with NOS inhibitors and NO donors provided evidence that NO mediates apoptosis and morphogenesis associated with symbiont colonization. Attenuation of NOS/NO by LPS and TCT in the squid-vibrio symbiosis provides another example of how the host's response to MAMPs depends on the context. These data also provide a mechanism by which symbiont MAMPs regulate host development.     

Cells lacking the fumarase tumor suppressor are protected from apoptosis through a hypoxia-inducible factor-independent, AMPK-dependent mechanism

Loss-of-function mutations of the tumor suppressor gene encoding fumarase (FH) occur in individuals with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). We found that loss of FH activity conferred protection from apoptosis in normal human renal cells and fibroblasts. In FH-defective cells, both hypoxia-inducible factor 1α (HIF-1α) and HIF-2α accumulated, but they were not required for apoptosis protection. Conversely, AMP-activated protein kinase (AMPK) was activated and required, as evidenced by the finding that FH inactivation failed to protect AMPK-null mouse embryo fibroblasts (MEFs) and AMPK-depleted human renal cells. Activated AMPK was detected in renal cysts, which occur in mice with kidney-targeted deletion of Fh1 and in kidney cancers of HLRCC patients. In Fh1-null MEFs, AMPK activation was sustained by fumarate accumulation and not by defective energy metabolism. Addition of fumarate and succinate to kidney cells led to extracellular signal-regulated kinase 1/2 (ERK1/2) and AMPK activation, probably through a receptor-mediated mechanism. These findings reveal a new mechanism of tumorigenesis due to FH loss and an unexpected pro-oncogenic role for AMPK that is important in considering AMPK reactivation as a therapeutic strategy against cancer.     

薄层液基细胞学检查在宫颈普查中应用的临床分析

目的:评价薄层液基细胞学检查在宫颈普查中应用的临床价值。方法:选择经薄层液基细胞学门诊普查妇女520例,其中经TCT检查结果提示ASCUS以上的妇女76例,均进一步采取阴道镜下宫颈活检病理检查,将TCT检查结果与阴道镜下宫颈活检病理检查结果对比分析。结果:TCT检查结果具有较高的检出率及符合率,HSIL组、SCC组与LSIL组符合率比较,差异具有统计学意义(P<0.05)。结论:TCT检查作为妇科宫颈普查的方法,具有检出率及符合率高的优点;检查结果为HSIL或SCC时,应引起临床极高度重视。     

The Lescol(R) Intervention Prevention Study (LIPS): a double-blind,placebo-controlled,randomized trial of the long-term effects of fluvastatin after successful transcatheter therapy in patients with coronary heart disease

BACKGROUND: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) inhibit atherosclerosis and reduce both morbidity and mortality in patients with coronary heart disease. No randomised prospective study, however, has investigated the long-term effect of statins on clinical outcomes in patients who have undergone first successful transcatheter therapy. METHODS: The Lescol((R)) Intervention Prevention Study (LIPS) is a double-blind randomized trial designed to compare the effect of fluvastatin (Lescol) with that of placebo on the time which patients with serum cholesterol >/= 3.5 mmol/l and < 7.0 mmol/l (135-270 mg/dl) remain free of major adverse cardiac events (MACE) after successful first transcatheter therapy (TCT). Patients, aged 18-80 years inclusive, will be randomized in a 1 : 1 ratio to receive fluvastatin, 40 mg, or placebo, twice daily for three to five years. The primary endpoint is the survival time during which patients remain MACE free after first TCT. Secondary endpoints are the incidence of MACE, noncardiac death, hospitalization for other atherosclerotic diseases, changes in serum lipid concentrations and anginal status. SUMMARY: LIPS is unique because it is the first study that will investigate whether MACE can be prevented or reduced by fluvastatin in patients who have undergone successful first transcatheter therapy for coronary heart disease.     

Simple and direct detection of Staphylococcus aureus in milk by a tube coagulase test

A tube coagulase test (TCT) is described as a simple and non-expensive system for detection of Staphylococcus aureus directly in milk. The procedure is characterized by mixing milk samples with rabbit citrate plasma followed by incubation at 37 °C for clot formation. The tube coagulase test demonstrated 91·5% accuracy, 88·5% sensitivity and 100% specificity for the direct recognition of Staph. aureus in milk samples from quarters with subclinical mastitis, when compared with plating of milk on blood agar. The TCT has the potential to detect other coagulase positive staphylococci in milk. It is concluded that TCT may be of use to veterinary practitioners with limited laboratory facilities, or to dairy farmers as a simple diagnostic test on site.     

Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin

Tracheal cytotoxin (TCT) was originally described as the minimal effector that was able to reproduce the cytotoxic response of Bordetella pertussis on ciliated epithelial cells. This molecule triggers pleiotropic effects such as immune stimulation or slow-wave sleep modulation. Further characterization identified TCT as a specific diaminopimelic acid (DAP)-containing muropeptide, GlcNAc-(anhydro)MurNAc-L-Ala-D-Glu-mesoDAP-D-Ala. Here, we show that the biological activity of TCT depends on Nod1, an intracellular sensor of bacterial peptidoglycan. However, Nod1-dependent detection of TCT was found to be host specific, as human Nod1 (hNod1) poorly detected TCT, whereas mouse Nod1 (mNod1) did so efficiently. More generally, hNod1 required a tripeptide (L-Ala-D-Glu-mesoDAP) for efficient sensing of peptidoglycan, whereas mNod1 detected a tetrapeptide structure (L-Ala-D-Glu-mesoDAP-D-Ala). In murine macrophages, TCT stimulated cytokine secretion and NO production through Nod1. Finally, in vivo, injection of the tetrapeptide structure in mice triggered a transient yet strong release of cytokines into the bloodstream and the maturation of macrophages, in a Nod1-dependent manner. This study thereby identifies Nod1 as the long sought after sensor of TCT in mammals.     

Improvement and initial in vivo application of the radioimmunoassay of rat thyrocalcitonin.

Previously we reported a homologous radioimmunoassy for rat thyrocalcitonin (TCT) which was sensitive enough (2--3 ng/ml serum) to measure TCT in thyroid venous blood or thyroid gland extracts but could not detect TCT in peripheral blood even after provocative challenge with iv calcium. In the present study chicken antisera to rat TCT were developed which were sufficiently sensitive (120--240 pg/ml serum) to permit initial evaluation of changes in TCT in rat peripheral blood. The following results were observed: (1) Basal serum TCT in young male Holtzman rats was undetectable, being less than 120--240 pg/ml; (2) induction of marked hypercalcemia by iv calcium increased TCT to approximately 1000--3000 pg/ml within 5 min; (3) thyroid cautery increased TCT to approximately 1000 pg/ml in 5--15 min; (4) calcium gavage (12.2 mg Ca/100 g) produced modest hypercalcemia in 30--60 min and increased serum TCT to approximately 500 pg/ml; (5) injection of isoproterenol raised serum TCT detectably; (6) injection of large doses of gastrin or pentagastrin did not produce detectable increases in TCT 5 or 30 min later. The results show that suitable antisera to rat TCT can be developed in chickens and applied to the measurement, by radioimmunoassay, of elevated circulating levels of TCT in the rat.     

Do the HLA-A2 genes prevent tumor development? A hypothesis

The statistical evaluation of the results of 22 HLA antigen typing in 132 patients with tumors (Wilms' tumor, neuroblastoma, germinative testicular non-seminoma-like tumors, benign teratomata) which are probably of common origin during early embryogenesis showed a substantial, after correction of p an insignificant decrease of HLA-A2 frequency against 301 controls. The lower frequency of HLA-A2 was also found in some other tumors. A hypothesis on the protective action of HLA-A2 against tumor development was proposed. The mechanism of this phenomenon may utilize the enhancing effect of HLA-A2 gene on the membrane and humoral immune reactivity of the organism, thus presenting an analogy of HLA-A2 effect on the survival of renal graft and transfused thrombocytes.     

Primary structure of the peptidoglycan-derived tracheal cytotoxin of Bordetella pertussis

The etiological agent of whooping cough, Bordetella pertussis, destroys the ciliated epithelial cells lining the large airways of infected individuals. This cytopathology can be reproduced in respiratory epithelium by tracheal cytotoxin (TCT), a small peptidoglycan-related molecule purified from the culture supernatant of growing B. pertussis organisms. Using fast atom bombardment mass spectrometry, we analyzed the positive- and negative-ion spectra of the purified, biologically active material and assigned a mass of 921 daltons to TCT. Analysis of fragment ions in these spectra as well as the spectra of the methyl ester and acetylated derivatives of TCT unambiguously defined the primary structure of TCT as N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramylalanyl-gamma- glutamyldiaminopimelylalanine. TCT is therefore identical with the ciliostatic anhydropeptidoglycan monomer released by Neisseria gonorrhoeae and with the neurologically active slow-wave sleep-promoting factor FSu. These and other structurally related glycopeptides containing muramic acid thus form a family of molecules with remarkably diverse biological activities.     

Normolipidaemic Activity of Liposomal-Encapsulated Superoxide Dismutase in Rats

To determine the regulatory effects of superoxide dismutase (SOD) on lipid metabolism a simple model of hyperlipidaemia induced by a hypercholesterolaemic (HCT) diet in rat was used. In animals fed a HCT diet, triglyceride (TG) were increased by 126%, total cholesterol (TCT) by 40%, very low density lipoprotein (VLDL) by 124% and the TCT/HDL ratio by 82%. The procedure would therefore appear to model some of the risk factors of atherogenesis.

In animals fed a hypercholesterolemic diet, liposomal Cu-SOD (200μg/kg i. m. every two days; 1000 μg/kg i. m./day) decreased TG by 29 and 49%, TCT by 14 and 36%, TCT/HDL ratio by 32 and 60%, VLDL by 52 and 55% respectively and increased high density lipoprotein cholesterol (HDL-C) by 17 and 46% respectively.

The present experiments show therefore that the administration of liposomal SOD has a marked effect on lipid parameters (particularly TCT and TG) and might therefore reduce the atherogenic risk by increasing HDL and decreasing VLDL and cholesterol atherogenicity ratio (CAR).