Immunomodulatory drugs increase endothelial tissue factor expression in vitro

Introduction

Immunomodulatory compounds such as thalidomide (THL) and lenalidomide (LEN) represent treatment options for multiple myeloma. Venous thromboembolism is a potential complication of immunomodulatory treatment in myeloma patients. The optimal thromboprophylactic strategy to prevent this drug-induced hypercoagulable state is debated. It is the aim of this study to investigate i) the effect of immunomodulatory treatment on endothelial cell tissue factor (TF) expression and function, ii) the regulation of the observed TF activity, and iii) the modulating effect of low molecular weight heparin and aspirin on TF activity in vitro.

Materials and methods

These aims were addressed in an in vitro culture model, human umbilical vein endothelial cells, using TF activity and antigen assays as well flow cytometry, real time PCR and electron microscopy.

Results

At THL and LEN concentrations resembling those observed in myeloma patients in vivo and in the presence of tumor necrosis factor-α (TNFα) we observed significantly increased TF activity in human umbilical vein endothelial cells in vitro. Concordant changes were detected for tissue factor mRNA and TF whole cell antigen. Dalteparin and a mixture of monoclonal anti-TF antibodies inhibited TF activity by 100% and more than 80% respectively, while aspirin's inhibitory effect was only approximately 30%. In the presence of TNFα we detected the generation of endothelial cell-derived microparticles which expressed TF activity.

Conclusions

Our in vitro data support the hypothesis that THL and LEN induce a hypercoagulable state through increased endothelial TF expression.     

Contribution of the primary motor cortex to motor imagery: a subthreshold TMS study

Motor imagery (MI) mostly activates the same brain regions as movement execution (ME) including the primary motor cortex (Brodmann area 4, BA4). However, whether BA4 is functionally relevant for MI remains controversial. The finding that MI tasks are impaired by BA4 virtual lesions induced by transcranial magnetic stimulation (TMS) supports this view, though previous studies do not permit to exclude that BA4 is also involved in other processes such as hand recognition. Additionally, previous works largely underestimated the possible negative consequences of TMS-induced muscle twitches on MI task performance. Here we investigated the role of BA4 in MI by interfering with the function of the left or right BA4 in healthy subjects performing a MI task in which they had to make laterality judgements on rotated hand drawings. We used a subthreshold repetitive TMS protocol and monitored electromyographic activity to exclude undesirable effects of hand muscle twitches. We found that BA4 virtual lesions selectively increased reaction times in laterality judgments on hand drawings, leaving unaffected a task of equal difficulty, involving judgments on letters. Interestingly, the effects of virtual lesions of left and right BA4 on MI task performance were the same irrespective of the laterality (left/right) of hand drawings. A second experiment allowed us to rule out the possibility that BA4 lesions affect visual or semantic processing of hand drawings. Altogether, these results indicate that BA4 contribution to MI tasks is specifically related to the mental simulation process and further emphasize the functional coupling between ME and MI.     

Malignant transformation of oral lichen planus by a chronic inflammatory process. Use of topical corticosteroids to prevent this progression?

Background: Oral lichen planus is a potentially malignant disorder with a capacity, although low, for malignant transformation. Of all the factors related to the process of malignant transformation, it is believed that the chronic inflammatory process plays a key role in the development of oral cancer. This inflammatory process is capable of providing a microenvironment based on different inflammatory cells and molecules that affect cellular growth, proliferation and differentiation. Objectives: The objectives of our study are: to review the available evidence about the possible relationship between the chronic inflammatory process present in oral lichen planus and its malignant transformation, to discuss the potential therapeutic implications derived from this relationship and to study the role that topical corticosteroids play in the control of oral lichen planus inflammation and its possible progression to malignant transformation. Conclusion: The maintenance of a minimum dose of topical corticosteroids could prevent the inflammatory progression of oral lichen planus to oral cancer.     

Does an intracanal composite anchorage replace posts?

Objectives

This study aims to assess the effectiveness of an intracanal composite anchorage to replace conventionally cemented titanium or bonded glass fibre posts.

Materials and methods

Post space preparation was performed up to depths of 6 mm (groups 1 and 2) and 3 mm (group 3) in root filled mandibular premolars. In group 1, titanium posts were cemented with zinc phosphate cement. Glass fibre posts were adhesively cemented in group 2 using a dual-cure composite resin. In group 3, intracanal anchorage was solely performed with a dual-cure composite. All teeth were restored with standardised direct composite crowns without a ferrule. After thermo-mechanical loading, static load was applied until failure. Fracture patterns were assessed, and a microscopic analysis was performed to analyse the occurrence of additional cracks.

Results

Group 2 revealed a significantly higher median fracture value (408 N) than groups 1 and 3, while no difference was detected between group 1 (290 N) and group 3 (234 N) (p?=?.1417). In group 3, the more favourable fracture patterns were observed. However, the majority of teeth within this fracture category revealed additional minor cracks of the root.

Conclusions

Within the limitations of this study, adhesive intracanal anchorage to a depth of 3 mm with resin composite only has the same fracture resistance as titanium posts conventionally cemented to a depth of 6 mm. Even teeth with repairable main fractures exhibited additional dentinal cracks on the root.

Clinical relevance

Additional dentinal root cracks in the teeth with repairable main fractures may considerably impair their longevity.     

A Proactive Approach to High Risk Delirium Patients Undergoing Total Joint Arthroplasty

Background

Delirium is a common complication among elderly patients undergoing total joint arthroplasty (TJA). Its incidence has been reported from 4% to 53%. The Centers for Medicare and Medicaid Services consider delirium following TJA a “never-event.” The purpose of this study is to evaluate a simple perioperative protocol used to identify delirium risk patients and prevent its incidence following TJA.

Downstaging prior to liver transplantation for hepatocellular carcinoma: advisable but at the price of an increased risk of cancer recurrence – a retrospective study

The use of downstaging prior to liver transplantation for hepatocellular carcinoma (HCC) still needs refinement. This study included patients with HCC listed for transplantation according to the Total Tumour Volume (TTV) ≤115 cm³ and alpha fetoprotein (AFP) ≤400 ng/ml criteria, with and without previous downstaging. Overall, 455 patients were listed, and 286 transplanted. Post‐transplant follow‐up was 38.5 ± 1.7 months. Patients downstaged to TTV115/AFP400 (n = 29) demonstrated similar disease‐free survivals (DFS, 74% vs. 80% at 5 years, P = 0.949), but a trend to more recurrences (14% vs. 5.8%, P = 0.10) than those always within TTV115/AFP400 (n = 257). Similarly, patients downstaged to Milan criteria (n = 80) demonstrated similar DFS (76% vs. 86% at 5 years, P = 0.258), but more recurrences (11% vs. 1.7%, P = 0.001) than those always within Milan (n = 177). Among patients downstaged to Milan, those originally beyond TTV115/AFP400 (n = 27) had similar outcomes as those originally beyond Milan, but within TTV115/AFP400 (n = 53). However, the likelihood of being within Milan at transplant was lower for patients with more advanced original HCCs (P < 0.0001). Overall, despite an expected increase in post‐transplant HCC recurrence, similar survivals can be achieved with and without downstaging, using the TTV115/AFP400 transplantation criteria, and including patients with advanced original HCCs. Downstaging should continue to be performed.     

Bax phosphorylation association with nucleus and oligomerization after neonatal Hypoxia–ischemia

Neonatal hypoxia–ischemia (HI) is a common occurrence in preterm and low‐birth‐weight infants, and the incidence of low‐birth‐weight and preterm births is increasing. Characterization of brain injury after HI is of critical importance in developing new treatments that more accurately target the injury. After severe HI, neuronal cells undergo necrosis and secondary apoptosis of the surrounding cells as a result of neuroinflammation. We sought to characterize the biochemical pathways associated with cell death after HI. Bax, a cell death signaling protein, is activated after HI and translocates to the nucleus, endoplasmic reticulum, and mitochondria. The translocation patterns of Bax affect the resultant cell death phenotype (necrotic or apoptotic) observed. Although Bax is known to oligomerize once it is activated, less is known about the factors that control its translocation and oligomerization. We hypothesize that Bax kinase‐specific phosphorylation determines its oligomerization and intracellular localization. Using well‐established in vivo and in vitro models of neonatal HI, we characterized Bax oligomerization and multiorganelle translocation. We found that HI‐dependent phosphorylation of Bax determines its oligomerization status and multiorganelle localization, and, ultimately, the cell death phenotype observed. Understanding the mechanisms of Bax translocation will aid in the rational design of therapeutic strategies that decrease the trauma resulting from HI‐associated inflammation. © 2013 Wiley Periodicals, Inc.