Glucocorticoid safety for treating rheumatoid arthritis

Introduction: Glucocorticoids (GCs) are often used in the treatment of rheumatoid arthritis and many other inflammatory diseases. Besides strong favorable effects on disease activity, GCs can cause (serious) side effects as well.

Areas covered: Side effects of GCs that are ranked as most important by rheumatologists as well as by patients are bone loss and fractures, cardiovascular events, hypertension, and diabetes mellitus. In evaluating these side effects, confounding by indication is a disturbing factor: not only the use of GCs can increase the risk of several side effects, but so can the activity of the underlying disease, which in turn is related to the amount of GCs that is prescribed to the patient.

Expert opinion: Generally, side effects predominantly occur in patients with a high disease activity and when used in high doses and for a long period of time. For these patients, caution and monitoring are most warranted. However, monitoring is not only recommended in patients with a high disease activity, and high-dose or long-term use of GCs, but in all GC users, since side effects may also occur in patients treated with low-dose GCs. When detecting possible negative effects in time, they might be managed and serious damage due to side effects might hopefully be prevented.     

Papillary squamotransitional cell carcinoma of the vagina

A case of a papillary squamotransitional cell carcinoma (PSTCC) of the vagina with a follow-up of 3 years is presented here. The characteristics of this case support a squamous rather than urothelial origin of this rare entity. Unlike its counterparts in the cervix uteri, the clinical behavior of vaginal PSTCC is more favorable than squamous cell carcinoma. Histological and clinical features are compared to those of previously described cases of vaginal and cervical PSTCC.     

Self-limitation of intravenous tocolysis with beta2-adrenergic agonists is mediated through receptor G protein uncoupling

Tocolysis with a beta-adrenergic receptor agonist is the most common approach to premature labor management after the 25th wk of pregnancy. However, prolonged treatment is associated with a marked loss of efficacy. The biochemical mechanisms involved remain unclear. This study was undertaken to investigate the effect of fenoterol on beta-adrenergic receptor signal transduction in human myometrium. Myometrial biopsy specimens were obtained from 40 women at cesarean section between the 25th and 34th wk of pregnancy. Nineteen patients had received no tocolysis (controls, group I) and 21 had been treated with fenoterol (<48 h in 10, group II; > or = 48 h in 11, group III). As methods we used membrane preparation, adenylyl cyclase assay and cAMP RIA. Adenylyl cyclase activity was determined by the measurement of cAMP levels to evaluate signal transduction after stimulation of beta-adrenergic receptors with isoproterenol, G protein with GTP, and adenylyl cyclase with forskolin. The functional activity of GTP-binding regulatory proteins (G(s)) and adenylyl cyclase was not altered by fenoterol treatment. In the control group, the increase in adenylyl cyclase activity in response to GTP plus isoproterenol was greater than in response to GTP alone. The increase was reduced by 50% in group II and was insignificant in group III. There was no correlation between gestational age and basal adenylyl cyclase activity. Intravenous tocolysis with the beta2-adrenergic receptor agonist fenoterol leads to complete desensitization of the beta-adrenergic receptor system. In addition to the known reduction in receptor number (down-regulation) as underlying mechanism, uncoupling of the receptor from the stimulatory G protein G(s) was identified.     

Preoperative diagnosis of bile duct strictures--comparison of intraductal ultrasonography with conventional endosonography

BACKGROUND: The accuracy of intraductal ultrasonography (IDUS) and endoscopic ultrasonography (EUS) were compared in diagnosing biliary obstruction and in predicting surgical resectability. METHODS: Fifty-six patients with biliary obstruction were investigated preoperatively with both conventional EUS and IDUS. The ultrasonographic miniprobe was inserted into the bile duct system through the working channel of the duodenoscope during endoscopic retrograde cholangiopancreatography (ERCP). Conventional endosonography was performed with echoendoscopes in a standard technique. Images of endoluminal ultrasonography were prospectively reviewed and compared with intraoperative findings and resection specimen analyses. RESULTS: IDUS exceeded EUS in terms of accuracy (IDUS, 89.1%; EUS, 75.6%; P < 0.002), sensitivity (IDUS, 91.1%; EUS, 75.7%; P < 0.002), specificity (IDUS, 80%; EUS, 75%; NS), and T-staging (IDUS, 77.7%; EUS, 54.1%; P < 0.001). In bile duct carcinomas the accuracy rate for lymph node staging using IDUS (60%) is comparable with that using EUS (62.5%). In pancreatic carcinomas, however, lymph node staging using IDUS (13.3%) is significantly (P < 0.002) inferior to EUS (69.2%). Endoluminal ultrasonography may predict the potential resectability of bile duct tumors (IDUS, 81.8%; EUS, 75.6%; P < 0.002). CONCLUSIONS: IDUS proved to be accurate in preoperative diagnosing and T-staging of malignant biliary strictures, whereas it is not suitable for lymph node staging. IDUS using miniprobes during ERCP exceeds conventional EUS in terms of depiction of bile duct obstruction, diagnostic accuracy, and sensitivity and in the prediction of surgical tumor resectability. Additionally, different to EUS, IDUS can conveniently be performed during ERCP in one and the same session.     

MARS (Molecular Adsorbent Recycling System) as a novel hepatic detoxification procedure until orthotopic liver transplantation]

MARS (Molecular Adsorbent Recycling System) as a novel hepatic detoxification procedure until orthotopic liver transplantation.We report the case of a 30-year-old man who was admitted because of acute liver failure due to longstanding ethanol abuse. On conservative treatment liver function progressively deteriorated and the patient was listed for orthotopic liver transplantation. Because of a rapidly progressive and clinically severe hepatic encephalopathy together with increasing bilirubin levels (maximum 39 mg/dl) we began intermittent extracorporeal detoxification with the Molecular Adsorbent Recycling System (MARS). Under MARS therapy serum bilirubin decreased significantly (to 20 mg/dl after three cycles) and encephalopathy improved rapidly until the patient was completely oriented. No effect of MARS on liver function could be demonstrated. MARS treatment was successfully continued until a cadaver liver became available after 48 days and the patient was transplanted in good clinical and neurological condition and without complications. MARS represents a novel detoxification technique which, in patients with acute liver failure, can successfully replace hepatic detoxification until orthotopic liver transplantation can be performed.     

Anti-tumour activity of phosphoinositide-3-kinase antagonist AEZS 126 in models of triple-negative breast cancer

Purpose

Of more than one million global cases of breast cancer diagnosed each year, a high percentage are characterized as triple-negative, lacking the oestrogen, progesterone and Her2/neu receptors. The incidence exceeds the incidence of malignancies like CML by far. Lack of effective therapies, younger age at onset and early metastatic spread have contributed to the poor prognosis and outcomes associated with these malignancies.

Methods

Here, we investigate the ability of the PI3K/AKT inhibitor AEZS 126 to selectively target the triple-negative breast cancer (TNBC) cell proliferation and survival in vitro by MTT-assays and FACS-based analysis. Furthermore, the mechanism of cytotoxicity is analysed by FACS-based assays and Western blots.

Results

AEZS 126 showed good anti-tumour activity in in vitro models of TNBC as well as in MCF-7 cells. Main mechanism of cytotoxicity seems to be programmed cell death after an incubation time of 72 h, which could be abrogated by co-incubation with z-VAD-fmk in MCF-7 and MDA-MB468 cells. In HCC1806 cells, addition of necrostatin-1 has only slightly protective effects, but in HCC1937 cells, the addition of necrostatin-1 has the same protective effect as co-incubation with z-VAD-fmk, and this observation argues for cell death caused by apoptosis and necroptosis in this cell line.

Conclusion

We demonstrated the highly efficient anti-tumour activity of AEZS 126 in in vitro models of TNBC. Due to the good anti-tumour activity and the expected favourable toxicity profile, AEZS 126 in combination with chemotherapy seems to be a promising candidate for clinical testing in TNBC especially in the basal-like subgroup of TNBC.     

Variations in radiation sensitivity and repair among different hematopoietic stem cell subsets following fractionated irradiation

The radiation dose-survival of various hematopoietic cell subsets in murine bone marrow (BM) was determined in the cobblestone area forming cell (CAFC) assay under conditions of single-, split-, and multiple- dose irradiation. A greater recovery in cell survival with decreasing dose per fraction, or increasing fraction number, was observed for primitive CAFC day-28 and day-35 than for CAFC day-6 and day-12 (colony- forming unit (CFU)-granulocyte macrophage and CFU-spleen day-12 equivalents). Linear quadratic (LQ) model analysis of CAFC survival data provided an estimate of the alpha/beta ratio that is an inverse index of the fractionation effect and is known to be lower for late than for acutely responding tissues. This analysis gave decreasing alpha/beta ratios with increasing primitiveness of the CAFC subset. These values were found to be comparatively low (about 4 Gy) for CAFC day-28 and day-35 and are in general agreement with previous studies on long-term repopulation in vivo. In contrast, alpha/beta ratios of CAFC day-6 and day-12 were relatively high (above 6 Gy) and are consistent with values obtained from acute marrow failure. Delayed harvesting of BM after a single dose of 6 Gy showed little evidence of proliferative repopulation over 1 week and hence the differential dose-sparing effect of fractionation among the CAFC subsets appears to be mostly attributable to the influence of sublethal damage repair. These results require a reevaluation of previous notions of marrow stem cell radiosensitivity and repair based on acute marrow lethality (LD50/30) or spleen colony (CFU-S) data, especially when applied to fractionated total body irradiation effects on long-term repopulating stem cells in a BM transplant setting.     

开通闭塞冠状动脉策略的全球性研究GUSTO-Ⅲ(亚组研究)

治疗方案 患者按2:1比例随机分配。或接受reteplase 1000万 U静脉注射、30min后再次静脉注射;或接受alteplase加速化滴注治疗,90min内剂量