Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases

Prostate and mammary cancer bone metastases can be osteoblastic or osteolytic, but the mechanisms determining these features are unclear. Bone morphogenetic and Wnt proteins are osteoinductive molecules. Their activity is modulated by antagonists such as noggin and dickkopf-1. Differential expression analysis of bone morphogenetic and Wnt protein antagonists in human prostate and mammary cancer cell lines showed that osteolytic cell lines constitutively express in vitro noggin and dickkopf-1 and at least one of the osteolytic cytokines parathyroid hormone-related protein, colony-stimulating factor-1, and interleukin-8. In contrast, osteoinductive cell lines express neither noggin nor dickkopf-1 nor osteolytic cytokines in vitro. The noggin differential expression profile observed in vitro was confirmed in vivo in prostate cancer cell lines xenografted into bone and in clinical samples of bone metastasis. Forced noggin expression in an osteoinductive prostate cancer cell line abolished the osteoblast response induced in vivo by its intraosseous xenografts. Basal bone resorption and tumor growth kinetics were marginally affected. Lack of noggin and possibly dickkopf-1 expression by cancer cells may be a relevant mechanism contributing to the osteoblast response in bone metastases. Concomitant lack of osteolytic cytokines may be permissive of this effect. Noggin is a candidate drug for the adjuvant therapy of bone metastasis.     

A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant

Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.     

ISSLS PRIZE IN BIOENGINEERING SCIENCE 2018: dynamic imaging of degenerative spondylolisthesis reveals mid-range dynamic lumbar instability not evident on static clinical radiographs

Purpose

Degenerative spondylolisthesis (DS) in the setting of symptomatic lumbar spinal stenosis is commonly treated with spinal fusion in addition to decompression with laminectomy. However, recent studies have shown similar clinical outcomes after decompression alone, suggesting that a subset of DS patients may not require spinal fusion. Identification of dynamic instability could prove useful for predicting which patients are at higher risk of post-laminectomy destabilization necessitating fusion. The goal of this study was to determine if static clinical radiographs adequately characterize dynamic instability in patients with lumbar degenerative spondylolisthesis (DS) and to compare the rotational and translational kinematics in vivo during continuous dynamic flexion activity in DS versus asymptomatic age-matched controls.

Methods

Seven patients with symptomatic single level lumbar DS (6 M, 1 F; 66 ± 5.0 years) and seven age-matched asymptomatic controls (5 M, 2 F age 63.9 ± 6.4 years) underwent biplane radiographic imaging during continuous torso flexion. A volumetric model-based tracking system was used to track each vertebra in the radiographic images using subject-specific 3D bone models from high-resolution computed tomography (CT). In vivo continuous dynamic sagittal rotation (flexion/extension) and AP translation (slip) were calculated and compared to clinical measures of intervertebral flexion/extension and AP translation obtained from standard lateral flexion/extension radiographs.

Results

Static clinical radiographs underestimate the degree of AP translation seen on dynamic in vivo imaging (1.0 vs 3.1 mm; p = 0.03). DS patients demonstrated three primary motion patterns compared to a single kinematic pattern in asymptomatic controls when analyzing continuous dynamic in vivo imaging. 3/7 (42%) of patients with DS demonstrated aberrant mid-range motion.

Conclusion

Continuous in vivo dynamic imaging in DS reveals a spectrum of aberrant motion with significantly greater kinematic heterogeneity than previously realized that is not readily seen on current clinical imaging.

Level of evidence

Level V data

Graphical abstract

These slides can be retrieved under Electronic Supplementary Material.

Open image in new window

     

Oral mucoceles: A clinical,histopathological and immunohistochemical study

The aim of study was to evaluate the clinicopathological features of oral mucoceles and the immunohistochemical expression of cellular and extracellular matrix components in these lesions. One hundred cases of oral mucoceles were examined for clinicopathological features. The expression of mast cell tryptase, CD68, MMP-1 (matrix metalloproteinase-1), MMP-9 (matrix metalloproteinase-9) and CD34 was investigated immunohistochemically in 32 cases. The lesions arose as nodules or blisters of variable color. The mean age was 23.2 years and a higher male frequency was observed. The most common locations were the lower lip (92%), followed by the floor of the mouth (7%), and palate (1%). The lesion size ranged from 0.4 to 3.0 cm. Unusual histopathological findings as superficial mucoceles (n = 16, 16%), pseudopapillary projections (n = 3, 3%), epithelioid histiocytes (n = 4, 4%), multinucleated giant cells (n = 1, 1%) and myxoglobulosis (n = 9, 9%) were also seen. Mast cells and CD68-positive macrophages, MMP-1, MMP-9 and CD34-positive blood vessels were seen in all cases. A significant association was seen between mast cells and MMP-1 (p = 0.03) and between macrophages and MMP-1 (p = 0.01). This study provided important insight into the demographic and histopathological occurrence of oral mucoceles. The tissue remodeling seen in these lesions mainly involved the migration and interaction of mast cells, macrophages and MMP-1.     

Development and Testing of a Hybrid Measure of Muscle Strength in Juvenile Dermatomyositis for Use in Routine Care

Objective

To develop and test a hybrid measure of muscle strength for juvenile dermatomyositis (JDM), which is based on the combination of the Manual Muscle Testing in 8 muscles (MMT‐8) and the Childhood Myositis Assessment Scale (CMAS) but is more comprehensive than the former and more feasible than the latter.

Methods

The hybrid MMT‐8/CMAS (hMC) is composed of all 8 items of the MMT‐8 and 3 items of the CMAS: time of head lift, assessment of abdominal muscles, and floor rise. The score ranges 0–100, with 100 indicating normal muscle strength. Validation procedures were conducted using 3 large multinational patient samples, including a total of 810 JDM patients.

Results

The hMC revealed face and content validity, good construct validity, excellent test–retest reliability (intraclass correlation coefficient = 0.99), and internal consistency (Cronbach's α = 0.94), strong responsiveness to clinical change over time (standardized response mean = 0.8 among patients judged as improved by the caring physician), and satisfactory capacity to discriminate patients judged as being in the states of inactive disease or low, moderate, or high disease activity by the physician (P < 0.001) or patients whose parents were satisfied or not satisfied with the illness course (P < 0.001).

Conclusion

The hMC was found to possess good measurement properties in a large population of patients with a wide range of disease activity and severity. The new tool, which is primarily intended for use in routine clinical care, should be further tested in other populations of patients evaluated prospectively.

     

Chronic Alcohol Consumption Leads to a Tissue Specific Expression of Uncoupling Protein-2

Uncoupling proteins (UCPs) are anion channels that can decouple the mitochondrial respiratory chain. "Mild uncoupling" of internal respiration reduces free radical production and oxidative cell stress. Chronic alcohol consumption is a potent inducer of oxidative stress in multiple tissues and regulates UCP-2 and -4 expression in the brain. To analyse the impact of chronic alcohol intake on UCP-2 expression in tissues with high endogenous UCP-2 contents, male Wistar rats (n=34) were treated with a 12-week 5% alcohol diet. In the lungs and the spleen of rats with a chronic alcohol diet cytochrome c release from mitochondria was significantly increased. Both organs did not show any altered gene and protein expression of UCP-2. Different to cerebral tissue chronic alcohol consumption has no regulatory effect on UCP-2 gene and protein expression in organs with a high endogenous UCP-2 content. Therefore, chronic alcohol consumption leads to a tissue specific expression of UCP-2.     

Remote Usability Testing and Satisfaction with a Mobile Health Medication Inquiry System in CKD

Background and objectives

Inappropriate medication use is common in the care of patients with CKD. The feasibility of a simple mobile health tool designed to advise patients on safe medication usage in CKD was examined.

Design, setting, participants, & measurements

Participants with predialysis CKD (defined as eGFR<60 ml/min per 1.73 m²) in the Safe Kidney Care Cohort Study were recruited for home usability testing of a novel medication inquiry system between January and September of 2013. Testing was through two mobile platforms: (1) short messaging service text or (2) personal digital assistant (e.g., iPod Touch). Twenty participants (one half assigned to one device and one half assigned to the other device) were enrolled and received an in-center tutorial on device usage before the end of the study visit. Participants were subsequently mailed three sample pill bottles with the name of randomly selected medications and asked to input these medications into the medication inquiry system. The medication inquiry system response options were as follows: (1) safe in CKD, (2) not safe in CKD, (3) use with caution/speak with your health care provider, or (4) error message (for an incorrectly inputted medication). Participants were asked to record the response issued by the medication inquiry system for each medication sent for usability testing. A user satisfaction survey was administered after completion of the protocol.

Results

All participants owned a mobile telephone, but few owned a smartphone. Of 60 total medication queries, there were only three recorded errors, two of which occurred in the short messaging service texting group. Overall satisfaction with the application was high, with slightly higher satisfaction noted in the personal digital assistant group compared with the short messaging service group.

Conclusions

The mobile health medication inquiry system application had general ease of use and high acceptance across two platforms among individuals representative of the CKD population. Tailored mobile health technology may improve medication safety in CKD.     

Intraoperative simulation of remnant liver function during anatomic liver resection with indocyanine green clearance (LiMON) measurements

Objective

Post-hepatectomy liver failure (PHLF) is the major cause of death following liver resection. The aim of this study was to evaluate the feasibility of an intraoperative simulation of post-resection liver function.

Methods

Intraoperative liver function was measured by indocyanine green (ICG) clearance using the LiMON™ technology. In 20 patients undergoing anatomic liver resection, ICG plasma disappearance rate (PDR (%/min) and ICG retention at 15 min (R₁₅) (%) were measured immediately after the induction of anaesthesia (t₀), after selective arterial and portovenous inflow trial clamping (TC) of the resected liver segments (t₁), after the completion of resection (t₂) and before the closure of the abdominal cavity (t₃).

Results

The median baseline (t₀) PDR was 16.5%/min. Trial clamping of the inflow (t₁) resulted in a significant reduction in PDR to 10.5%/min. Results under TC were similar to those obtained after resection (t₂) (median PDR: 10.5%/min). Linear regression modelling showed that post-resection liver volume could be accurately predicted by TC of liver inflow (P < 0.0001), but not by determining the resected liver volume. Simulated post-resection liver function under TC correlated well with PHLF and length of hospital stay.

Conclusions

Intraoperative ICG clearance measurements allow real-time monitoring of intraoperative liver function during surgery. Trial clamping of arterial and portovenous inflow accurately predicts immediate post-resection liver function. The intraoperative measurement of liver function and simulation of post-resection liver function may help to avoid PHLF.     

Understanding the cognitive underpinnings of functional impairments in early dementia: a review

Objectives: Early dementia is marked by cognitive and functional impairments, and although studies indicate an association between these, detailed analyses exploring this relationship are rare. It is crucial to understand how specific cognitive deficits underlie functional deficits to develop successful cognitive interventions. This paper reviews the evidence of impairment in everyday functioning and in working, long-term and prospective memory in early dementia. Findings are evaluated with respect to the relationship between cognitive and functional impairments.

Methods: From the literature searches, 17 studies on everyday functioning and 40 studies on memory were obtained. Studies were only included if patients had an official diagnosis and were in the early stages of dementia.

Results: Complex instrumental activities of daily living were subject to greater impairment than basic activities of daily living. In particular, early dementia patients struggle with finance tasks; a deficit linked to impaired working memory. Regarding cognition, long-term memory is the earliest form of memory to decline as is well recognised. Evidence also indicates deficits in working and prospective memory, with inconsistent evidence about impairments of the former. A major limitation of the literature is a lack of studies assessing individual everyday activities and the associated error patterns that might occur.

Conclusion: This review critically assesses the status of translational research for everyday activities in early dementia, an area with critical implications for cognitive-based rehabilitation. Further research is required into the detailed assessment of individual everyday activity and specific memory deficits, in order to effectively map cognitive functions onto functional performance.