CYLD deletion triggers nuclear factor-κB-signaling and increases cell death resistance in murine hepatocytes

AIM:To analyze the role of CYLD for receptor-mediated cell death of murine hepatocytes in acute liver injury models.METHODS:Hepatocyte cell death in CYLD knockout mice(CYLD-/-)was analyzed by application of liver injury models for CD95-(Jo2)and tumor necrosis factor(TNF)-α-[D-Gal N/lipopolysaccharide(LPS)]induced apoptosis.Liver injury was assessed by measurement of serum transaminases and histological analysis.Apoptosis induction was quantified by cleaved PARP staining and Western blotting of activated caspases.Nuclear factor(NF)-κB,ERK,Akt and jun amino-terminal kinases signaling were assessed.Primary Hepatocytes were isolated by two step-collagenase perfusion and treated with recombinant TNF-αand with the CD95-ligand Jo2.Cell viability was analyzed by MTT-assay.RESULTS:Livers of CYLD-/-mice showed increased anti-apoptotic NF-κB signaling.In both applied liver injury models CYLD-/-mice showed a significantly reduced apoptosis sensitivity.After D-Gal N/LPS treatment CYLD-/-mice exhibited significantly lower levels of alanine aminotransferase(ALT)(295 U/L vs 859 U/L,P<0.05)and aspartate aminotransferase(AST)(560 U/L vs 1025 U/L,P<0.01).After Jo injection CYLD-/-mice showed 2-fold lower ALT(50 U/L vs 110 U/L,P<0.01)and lower AST(250 U/L vs 435 U/L,P<0.01)serumlevels compared to WT mice.In addition,isolated CYLD-/-primary murine hepatocytes(PMH)were less sensitive towards death receptor-mediated apoptosis and showed increased levels of Bcl-2,XIAP,c IAP1/2,survivin and c-FLIP expression upon TNF-and CD95-receptor triggering,respectively.Inhibition of NF-κB activation by the inhibitor of NF-κB phosphorylation inhibitor BAY 11-7085 inhibited the expression of antiapoptotic proteins and re-sensitized CYLD-/-PMH towards TNF-and CD95-receptor mediated cell death.CONCLUSION:CYLD is a central regulator of apoptotic cell death in murine hepatocytes by controlling NF-κB dependent anti-apoptotic signaling.     

Myelin-based inhibitors of oligodendrocyte myelination: clues from axonal growth and regeneration

The differentiation of and myelination by oligodendrocytes (OLs) are exquisitely regulated by a series of intrinsic and extrinsic mechanisms. As each OL can make differing numbers of myelin segments with variable lengths along similar axon tracts, myelination can be viewed as a graded process shaped by inhibitory/inductive cues during development. Myelination by OLs is a prime example of an adaptive process determined by the microenvironment and architecture of the central nervous system (CNS). in this review, we discuss how myelin formation by OLs may be controlled by the heterogeneous microenvironment of the CNS. Then we address recent findings demonstrating that neighboring OLs may compete for available axon space, and highlight our current understanding of myelin-based inhibitors of axonal regeneration that are potentially responsible for the reciprocal dialogue between OLs and determine the numbers and lengths of myelin internodes. Understanding the mechanisms that control the spatiotemporal regulation of myelinogenic potential during development may provide valuable insight into therapeutic strategies for promoting remyelination in an inhibitory microenvironment.     

Immediate allergic cross‐reactivity to levobupivacaine and ropivacaine

Allergic reactions to amide local anaesthetic agents are rare. We report the case of a 74‐year‐old man who suffered anaphylaxis, presenting with cardiovascular collapse, immediately after receiving regional anaesthesia on two separate occasions, the first involving the use of levobupivacaine and the second using ropivacaine. Skin testing revealed positive reactions to both levobupivacaine and ropivacaine, and negative reactions to articaine and lidocaine. Severe allergic reactions can be caused by the amide local anaesthetic drugs, levobupivacaine and ropivacaine.     

The Copeland resurfacing humeral head implant does not restore humeral head anatomy. A retrospective study

Purpose

Recently, there has been concern that the Copeland resurfacing humeral head implant (RHHI) leaves the shoulder joint overstuffed. The purpose of this study was in a selected cohort of patients operated with a Copeland RHHI (1) to evaluate the Length of the Gleno-Humeral Offset (LGHO), (2) to assess the patient-reported quality of life and functional outcome measured by Western Ontario Osteoarthritis of the Shoulder Index (WOOS) and (3) to determine the number of revisions in the cohort.

Methods

Pre- and postoperative radiographs were retrieved from 71 of 91 possible patients operated with a Copeland RHHI from 2005 to 2009. The cohort consisted of 30 males and 41 females at a mean age of 61 (38–89) years. One radiologist measured the LGHO and performed double measurements. The WOOS score 1 year after surgery and the number of revisions from all patients operated with a Copeland RHHI in Denmark was requested from the Danish Shoulder Arthroplasty Registry.

Results

The mean LGHO was 4.99 ± 0.53 cm before surgery and 5.39 ± 0.58 cm after surgery, (p < 0.001). 95 % limits of agreement for measurements of LGHO were ± 0.11 cm. One year after surgery, the WOOS score was 67 for the cohort and 64 for all patients operated with a Copeland RHHI in Denmark. 13 of 71 RHHI in the cohort were revised.

Conclusion

The Copeland RHHI causes significantly increased LGHO and leads to overstuffing in the shoulder joint. The WOOS score in the cohort was comparable to that for all other Danish patients operated with a Copeland RHHI.     

Arthroscopically assisted stabilization of acute high-grade acromioclavicular joint separations in a coracoclavicular Double-TightRope technique: V-shaped versus parallel drill hole orientation

Background

The arthroscopically assisted Double-TightRope technique has recently been reported to yield good to excellent clinical results in the treatment of acute, high-grade acromioclavicular dislocation. However, the orientation of the transclavicular–transcoracoidal drill holes remains a matter of debate.

Hypothesis

A V-shaped drill hole orientation leads to better clinical and radiologic results and provides a higher vertical and horizontal stability compared to parallel drill hole placement.

Study design

This was a cohort study; level of evidence, 2b.

Methods

Two groups of patients with acute high-grade acromioclavicular joint instability (Rockwood type V) were included in this prospective, non-randomized cohort study. 15 patients (1 female/14 male) with a mean age of 37.7 (18–66) years were treated with a Double-TightRope technique using a V-shaped orientation of the drill holes (group 1). 13 patients (1 female/12 male) with a mean age of 40.9 (21–59) years were treated with a Double-TightRope technique with a parallel drill hole placement (group 2). After 2 years, the final evaluation consisted of a complete physical examination of both shoulders, evaluation of the Subjective Shoulder Value (SSV), Constant Score (CS), Taft Score (TF) and Acromioclavicular Joint Instability Score (ACJI) as well as a radiologic examination including bilateral anteroposterior stress views and bilateral Alexander views.

Results

After a mean follow-up of 2 years, all patients were free of shoulder pain at rest and during daily activities. Range of motion did not differ significantly between both groups (p > 0.05). Patients in group 1 reached on average 92.4 points in the CS, 96.2 % in the SSV, 10.5 points in the TF and 75.9 points in the ACJI. Patients in group 2 scored 90.5 points in the CS, 93.9 % in the SSV, 10.5 points in the TF and 84.5 points in the ACJI (p > 0.05). Radiographically, the coracoclavicular distance was found to be 13.9 mm (group 1) and 13.4 mm (group 2) on the affected side and 9.3 mm (group 1) and 9.4 mm (group 2) on the contralateral side. The distance of neither the affected side nor the contralateral side differed significantly between both groups (p > 0.05). In group 1, eight patients (53 %) and in group 2 four patients (31 %) revealed signs of dynamic posterior instability (p > 0.05). Clavicular drill hole enlargement was found to be equally distributed in group 1, whereas group 2 displayed a cone-shaped form.

Conclusion

The Double-TightRope technique yields good to excellent clinical results in both V-shaped and parallel drill hole placement. Partial recurrent vertical and horizontal instability represents a problem in both techniques. So far, no significant differences regarding clinical or radiologic results have been found. Long-term results are needed to reveal possible advantages in terms of clinical and radiologic acromioclavicular stability.