Dithiocarbamates are teratogenic to developing zebrafish through inhibition of lysyl oxidase activity

Dithiocarbamates (DTCs) are a class of compounds that are extensively used in agriculture as pesticides. As such, humans and wildlife are undoubtedly exposed to these chemicals. Although DTCs are thought to be relatively safe due to their short half lives, it is well established that they are teratogenic to vertebrates, especially to fish. In zebrafish, these teratogenic effects are characterized by distorted notochord development and shortened anterior to posterior axis. DTCs are known copper (Cu) chelators but this does not fully explain the observed teratogenic effects. We show here that DTCs cause malformations in zebrafish that highly resemble teratogenic effects observed by direct inhibition of a group of cuproenzymes termed lysyl oxidases (LOX). Additionally, we demonstrate that partial knockdown of three LOX genes, lox, loxl1 and loxl5b, sensitizes the developing embryo to DTC exposure. Finally, we show that DTCs directly inhibit zebrafish LOX activity in an ex vivo amine oxidase assay. Taken together, these results provide the first evidence that DTC induced teratogenic effects are, at least in part, caused by direct inhibition of LOX activity.     

The pre-B cell receptor and its role in proliferation and Ig heavy chain allelic exclusion

The pre-B cell receptor (pre-BCR) is composed of the immunoglobulin (Ig) heavy (microH) chain and the surrogate light chain encoded by VpreB and lambda5. The pre-BCR has been implicated in precursor B cell proliferation, differentiation and IgH chain allelic exclusion. B cell development in mice lacking the transmembrane form of microH chain is blocked at the precursor B cell stage: the cells cannot proliferate or differentiate further and the IgH locus is allelically included. In mice lacking lambda5, the precursor B cells, although unable to proliferate, can nonetheless differentiate, whereas the IgH locus is allelically excluded. It was, therefore, postulated that microH chain together with VpreB could form a pre-BCR-like receptor that would allow IgH allelic exclusion but not proliferation. In mice lacking both VpreB genes, precursor B cells do not proliferate but are able to differentiate. Surprisingly, the IgH locus is allelically excluded. This suggests that microH chains find other partner proteins to signal allelic exclusion.     

Comparison of four reconstruction methods after total sacrectomy: A finite element study

Background

After total sacrectomy, it is mandatory to reconstruct the continuity between the lumbar spine and the pelvis. Only few biomechanical analyses exist which compare different reconstructions. Therefore, the aim of this study was to compare the lumbo-pelvic motion and the relative risk of implant breakage for four different reconstructions after total sacrectomy.

Method

Finite element analyses were performed for four general different reconstructions after total sacrectomy: sacral-rod reconstruction, four-rod reconstruction, bilateral fibular flaps reconstruction, and improved compound reconstruction. The rotations between L5 vertebra and ilium, the L5 shift-down displacement, and the maximum von Mises stress in the implants were calculated and evaluated for flexion, extension, lateral bending and axial rotation.

Findings

The decreasing order of the rotations between L5 vertebra and ilium as well as of the L5 shift-down displacement for the studied reconstruction methods was four-rod reconstruction > sacral-rod reconstruction > bilateral fibular flaps reconstruction > improved compound reconstruction. The decreasing order of the maximum von Mises stress in the implants was sacral-rod reconstruction > four-rod reconstruction > bilateral fibular flaps reconstruction > improved compound reconstruction.

Interpretation

From the mechanical point of view, improved compound reconstruction is superior to the other methods studied here as it shows the highest stability and the lowest maximum von Mises stress. However, clinical aspects must also be regarded when choosing a reconstruction method for a specific patient.     

Bedside prediction rule for infections after pediatric cardiac surgery

Purpose  

Infections after pediatric cardiac surgery are a common complication, occurring in up to 30% of cases. The purpose of this study was to develop a bedside prediction rule to estimate the risk of a postoperative infection.     

Evaluation of a new simple treatment for positional sleep apnoea patients

Obstructive sleep apnoea syndrome is a common clinical problem. Positional sleep apnoea syndrome, defined as having a supine apnoea-hypopnoea index of twice or more compared to the apnoea-hypopnoea index in the other positions, occurs in 56% of obstructive sleep apnoea patients. A limited number of studies focus on decreasing the severity of sleep apnoea by influencing sleep position. In these studies an object was strapped to the back (tennis balls, squash balls, special vests), preventing patients from sleeping in the supine position. Frequently, this was not successful due to arousals while turning from one lateral position to the other, thereby disturbing sleep architecture and sleep quality. We developed a new neck-worn device which influences sleep position by offering a vibration when in supine position, without significantly reducing total sleep time. Thirty patients with positional sleep apnoea were included in this study. No side effects were reported. The mean apnoea-hypopnoea index dropped from 27.7 ± 2.4 to 12.8 ± 2.2. Seven patients developed an overall apnoea-hypopnoea index below 5 when using the device in ON modus. We expect that positional therapy with such a device can be applied as a single treatment in many patients with mild to moderate position-dependent obstructive sleep apnoea, while in patients with a more severe obstructive sleep apnoea such a device could be used in combination with other treatment modalities.     

Intervention mapping for the development of a strategy to implement the insurance medicine guidelines for depression

Background  

This article describes the development of a strategy to implement the insurance medicine guidelines for depression. Use of the guidelines is intended to result in more transparent and uniform assessment of claimants with depressive symptoms.     

Positive remodeling at 3 year follow up is associated with plaque free coronary wall segment at baseline: A serial IVUS study

Aims

At present it is unknown what limits the arterial remodeling process during atherosclerotic plaque formation. In healthy arteries remodeling is regulated by the shear stress induced response by the endothelium. As endothelium at the plaque site is assumed to be dysfunctional, we tested the hypothesis that plaque free wall (PFW) determines vascular remodeling during atherosclerotic plaque build-up.

Methods & results

66 human coronary ROIs (38 patients) were studied at baseline and at 3 years follow up applying intravascular ultrasound (IVUS). From the IVUS images the lumen and external elastic membrane contours were delineated to assess wall thickness (WT), vessel area (VA), Plaque Area (PA) and plaque burden (PA/VA*100%). WT < 0.5 mm was defined as normal and determined the arc of the PFW (0–360°). Positive remodeling was defined as relative difference of VA over time >5%. At baseline, IVUS-PFW was inversely related to plaque burden (p < 0.05). Positive remodeling was most frequently observed in ROIs with IVUS-PFW > 180° (i.e. larger than half of the circumference) compared to PFW < 180° (55% vs. 12%, p < 0.05). Accordingly, plaques with IVUS-PFW > 180° at baseline had the largest change in VA (1.1 ± 2.1 vs. −0.4 ± 0.6 mm², p < 0.05) with an odds ratio of 9.2 to develop positive remodeling.

Conclusions

Our serial IVUS data show that IVUS-PFW is a determinant of vascular remodeling. ROIs with PFW > 180 at baseline had the highest probability to undergo positive remodeling.