Activation of the MAP kinase pathway induces apoptosis in the Merkel cell carcinoma cell line UISO

Merkel cell carcinoma (MCC) is a rare but highly aggressive tumor of the skin. Recently, we have shown that MCC cells in situ are characterized by a complete absence of mitogen-activated protein kinase (MAPK) pathway signaling, which is preserved in the MCC cell line UISO. Here we present data suggesting that silencing of the MAPK pathway is essential for the survival of MCC cells. Activation of the MAPK pathway could be achieved by inducing a regulatable form of the c-Raf-1 kinase domain in UISO cells. Consequently, MAPK signaling led to morphological changes, loss of actin stress fibers, and induction of apoptosis, which could be prevented by the MAP kinase kinase-specific inhibitor U0126. Hence, despite the fact that activation of the MAPK pathway contributes to oncogenesis in many cancers, it seems to be a negative selection factor for MCC cells. Since ERK phosphorylation was also inducible by the Raf-activating pharmacological agent ZM336372, these results provide new perspectives for potential therapeutics for this highly aggressive tumor.     

The dual EGF/VEGF receptor tyrosine kinase inhibitor AEE788 inhibits growth of human hepatocellular carcinoma xenografts in nude mice

We investigated the effect of AEE788, a novel dual receptor tyrosine kinase inhibitor of the EGF and the VEGF receptor, for treatment of human HCC cell lines and in a subcutaneous xenograft model. Cell viability and apoptosis of HepG2 and Hep3B cells incubated with 0.1-100 microM AEE788 were quantified. In vivo, HepG2 cells were xenografted to NMRI mice and animals were treated orally with 50 mg/kg AEE788 3x/week. Immunohistochemistry and quantitative Western blotting was performed for pathway analysis in vitro and in vivo. AEE788 reduced growth and induced apoptosis of HCC cells by disrupting mitochondrial transmembrane potentials and inhibiting MAPK phosphorylation. In the xenografts, AEE788 lead to a reduced tumor growth by reducing proliferation and vascularisation. Except for a reversible skin reaction and weight loss, no signs of toxicity were observed. AEE788 is a promising new option for the treatment of HCC.     

Pulse wave analysis: a preliminary study of a novel technique for the prediction of pre-eclampsia

Objective  To investigate whether first-trimester arterial pulse wave analysis (PWA) can predict pre-eclampsia.
Design  This was a prospective screening study.
Setting  The Homerton University Hospital, a London teaching hospital.
Population  Two hundred and ten low-risk women with a singleton pregnancy were analysed.
Methods  Radial artery pulse waveforms were measured between the 11⁺⁰ and 13⁺⁶ weeks of gestation and the aortic waveform derived by applying a generalised transfer function. Augmentation pressure (AP) and augmentation index at heart rate of 75 beats per minute (AIx-75), measures of arterial stiffness, were calculated. The multiple of the gestation-specific median in controls for AP and AIx-75 were calculated. Logistic regression models were developed and their predictive ability assessed using the area under the receiver operator curve.
Main outcome measures  Prediction of pre-eclampsia by AIx-75.
Results  Fourteen (6.7%) women developed pre-eclampsia, and 196 remained normotensive. Eight of the 14 women developed pre-eclampsia before 34 weeks of gestation (early-onset pre-eclampsia). For a false-positive rate of 11%, AIx-75 had a detection rate of 79% for all cases of pre-eclampsia and 88% for early-onset pre-eclampsia.
Conclusion  First-trimester arterial PWA can play a significant role in understanding the pathophysiology of pre-eclampsia and may play a role in early screening.     

难治性乳糜泻

乳糜泻是一种自身免疫性疾病．由对小麦、黑麦和大麦中的麸质发生持久不耐所致。存在乳糜泻遗传易感性的个体会发生近端小肠慢性炎症、固有层和上皮内淋巴细胞浸润以及隐窝增生和绒毛萎缩。大多数乳糜泻患者遵循无麸质饮食（GFD）后,其临床症状和组织病理学均有所改善。难治性乳糜泻（RCD）是乳糜泻的一种罕见并发症,患者严格执行GFD但症状仍持续或复发：RCD患者预后差,可能死于严重吸收不良或发展为肠病相关T细胞淋巴瘤（EATL）。     

The value of contrast‐enhanced color doppler ultrasound in the detection of vascularization of finger joints in patients with rheumatoid arthritis

Objective

A prospective study was performed to assess the usefulness of contrast‐enhanced color Doppler ultrasound (CDUS) in the evaluation of intraarticular vascularization of finger joints in patients with rheumatoid arthritis (RA).

Methods

We investigated 198 finger joints in 46 patients with RA, and 80 finger joints in 10 healthy volunteers. Joints with varying levels of clinical activity of inflammation were classified as being active, moderately active, or inactive. CDUS was performed with a high‐frequency multi‐D linear array transducer. A microbubble‐based ultrasound (US) contrast agent (Levovist; Schering, Berlin, Germany) was intravenously infused. Doppler findings were rated on the basis of both unenhanced and contrast‐enhanced CDUS images.

Results

Healthy joints showed no intraarticular vascularization on either unenhanced or contrast‐enhanced CDUS. Unenhanced CDUS detected intraarticular vascularization in 7 (8%) of 83 inactive joints, in 31 (52%) of 60 moderately active joints, and in 32 (58%) of 55 active joints. Contrast‐enhanced CDUS detected intraarticular vascularization in 41 (49%) of 83 joints with inactive RA, in 59 (98%) of 60 joints with moderately active RA, and in all 55 joints with active RA. Detection of intraarticular vascularization was improved by administration of the microbubble‐based US contrast agent (P < 0.001). Contrast‐enhanced CDUS demonstrated differences in intraarticular vascularization between joints with inactive RA and those with active RA (P < 0.001), between joints with inactive RA and those with moderately active RA (P < 0.001), and between joints with moderately active RA and those with active RA (P < 0.001).

Conclusion

The use of a microbubble‐based US contrast agent significantly improved the detection of intraarticular vascularization in the finger joints of patients with RA. This technique seems to be a useful adjunct in the assessment of disease activity.

     

肝移植治疗原发性肝细胞癌的临床研究进展

肝细胞肝癌行肝脏移植的指征、效果及相关问题一直存在争论. 本文我们收集并分析近年国内外文献,对肝癌肝移植的受体选择、影响预后/复发的因素、过渡性治疗以及术后注意的问题等相关问题进行探讨. 笔者认为在肝癌患者拟行肝移植治疗之前,严格、合理选择病例,结合围手术期辅助治疗,肝癌肝移植可以获得满意的疗效和较高的生活质量.     

Disruption of the silver and non-silver coated sewing cuff of a new generation bileaflet valve prosthesis during aortic valve replacement: report on four cases.

OBJECTIVES: New generation bileaflet valve prostheses with a silver-coated sewing cuff like the St Jude Medical (SJM((R)) Regent) model are designed to offer a larger valvular orifice as well as a better resistance to postoperative prosthetic endocarditis, at the expense of a smaller sewing cuff. METHODS AND RESULTS: We report on four cases of aortic valve replacement where during the implantation procedure the fixation cuff disrupted, leading to the exchange of all four valve prostheses. This happened three times with silver- coated sewing cuffs and after withdrawal of the silver- coated cuff prostheses from the market, once with a non silver- coated sewing cuff. This was due to the arbitrary cutting of the cuff fixation suture at the ventricular side of the prosthesis, although the implantation was performed according to the recommendations of the company. This problem didn't occur previously, using other models of the same manufacturer, although the sewing cuff had been fixed in the same technique. CONCLUSION: Fixation of smaller sewing cuffs of mechanical valve prostheses with a critically exposed fixation suture at the ventricular side of the prosthesis represents a significant risk for disruption during the implantation process through cut off by chance. We recommend meticulous inspection of the sewing cuff for signs of disruption before seating the valve into position. During follow-up particular attention should be paid to valve dislodgement and leakage. The company was informed and advised by us to modify the fixation of the prosthetic annulus of the SJM((R)) Regent valve, which has led to an alternative cuff design, called the SJM Flex cuff.     

The postreperfusion syndrome is associated with acute kidney injury following donation after brain death liver transplantation

Acute kidney injury (AKI) is frequently observed after donation after brain death (DBD) liver transplantation (LT) and associated with impaired recipient survival and chronic kidney disease. Hepatic ischemia/reperfusion injury (IRI) is suggested to be an important factor in this process. The postreperfusion syndrome (PRS) is the first manifestation of severe hepatic IRI directly after reperfusion. We performed a retrospective study on the relation between hepatic IRI and PRS and their impact on AKI in 155 DBD LT recipients. Severity of hepatic IRI was measured by peak postoperative AST levels and PRS was defined as >30% decrease in MAP ≥1 min within 5 min after reperfusion. AKI was observed in 39% of the recipients. AKI was significantly more observed in recipients with PRS (53% vs. 32%; P = 0.013). Median peak AST level was higher in recipients with PRS (1388 vs. 771 U/l; P < 0.001). Decrease in MAP after reperfusion correlated well with both severity of AKI (P = 0.012) and hepatic IRI (P < 0.001). Multiple logistic regression identified PRS as an independent factor for postoperative AKI (OR 2.28; 95% CI 1.06–4.99; P = 0.035). In conclusion, PRS reflects severe hepatic IRI and predicts AKI after DBD LT. PRS immediately after reperfusion is an early warning sign and creates opportunities to preserve postoperative renal function.