PGE2 Signaling Through the EP4 Receptor on Fibroblasts Upregulates RANKL and Stimulates Osteolysis

Periprosthetic osteolysis is the most common cause of aseptic loosening in total joint arthroplasty. The role of inflammatory mediators such as prostaglandin E2 (PGE2) and osteoclast promoting factors including RANKL in the pathogenesis of osteolysis has been well characterized. However, the PGE2 receptor (EP1, EP2, or EP4), and cell type in which it is expressed, which is responsible for PGE2 induction of RANKL during wear debris–induced osteolysis, has yet to be elucidated. To address this, we used mice genetically deficient in these EP receptors to assess PGE2 and wear debris responses in vitro and in vivo. Wear debris–induced osteolysis and RANKL expression were observed at similar levels in WT, EP1^?/?, and EP2^?/? mice, indicating that these receptors do not mediate PGE2 signals in this process. A conditional knockout approach was used to eliminate EP4 expression in FSP1⁺ fibroblasts that are the predominant source of RANKL. In the absence of EP4, fibroblasts do not express RANKL after stimulation with particles or PGE2, nor do they exhibit high levels of osteoclasts and osteolysis. These results show that periprosthetic fibroblasts are important mediators of osteolysis through the expression of RANKL, which is induced after PGE2 signaling through the EP4 receptor.     

The value of using verbs in Medline searches

New findings are continuously identified thanks to novel diagnostic procedures, among others in medical imaging. It would be useful to retrieve these new findings from literature. The aim of this work is to investigate if using verbs in MEDLINE queries can improve the retrieval of findings. Verbs used in the field of findings were selected: 'to show' (an examination shows a finding) and 'to confirm' (a finding confirms a diagnosis). For each of these verbs, semantically close verbs were researched on the WordNet website. Then, the extent to which adding these verbs to a query about various radiological pathologies can improve findings retrieval in Medline citations was studied. This method has been tested on two sets of MEDLINE citations regarding the diagnostic imaging of musculo-skeletal disorders. Using appropriate verbs in Medline queries enhances the precision from 53% to 61% and from 53% to 74%, respectively, in our first and second test set. A recall of 74% and 83% was reached in our two experiments. Using relevant verbs can be a rather simple way to improve the retrieval of findings related to diseases and diagnostic procedures from Medline citations.     

Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease

OBJECTIVE: To determine the prevalence and characteristics of moderate to severe pulmonary hypertension (PH) in patients with systemic sclerosis (SSc) with and without interstitial lung disease (ILD). METHODS: We retrospectively studied clinical and functional characteristics of 197 consecutive patients with SSc who had undergone a screening echocardiography to detect PH. RESULTS: Moderate to severe PH was suspected in 36 patients (18.3%) and confirmed in 32 who underwent right heart catheterization. The prevalence of PH did not differ between patients with limited and patients with diffuse cutaneous SSc. PH was detected in 12/67 (17.9%) patients without ILD vs 24/110 (21.8%) patients with ILD (p not significant). In patients with ILD, a lower PaO2 appeared as the unique independent factor significantly associated with PH, regardless of the extent of fibrosis. In 3 patients out of 9 (33.3%) with ILD and significantly restrictive disease, PH was out of proportion to the degree of fibrosis. In patients with no ILD, a higher grade of dyspnea appeared as the unique independent factor associated with PH. In patients with no ILD, altered DLCO was the sole indicator of the pulmonary function tests associated with PH (best cutoff value 72%). DLCO correlated with systolic pulmonary arterial pressure only in patients with no ILD. CONCLUSION: Prevalence of moderate to severe PH was similar in SSc patients with and those without ILD. In patients with ILD, a lower PaO2 was the unique independent indicator associated with PH. In some patients with severe ILD, PH was out of proportion to the degree of fibrosis. A linear correlation between DLCO and systolic pulmonary arterial pressure was observed only in patients without ILD. All these indicators should assist identification of patients with or without ILD requiring diagnostic procedures for PH before annual screening.     

Musculoskeletal tumours: preliminary experience with perfusion MRI

PURPOSE: Our study aimed to assess the role of magnetic resonance imaging (MRI) in the characterisation of musculoskeletal tumours and to identify specific perfusion patterns for the different tumours. MATERIALS AND METHODS: Between January 2003 and September 2005, we evaluated the conventional and perfusion MRIs of 39 patients with musculoskeletal tumours. Dynamic MRI was performed with a 1.5-T and 1.0-T MRI unit before and after the intravenous administration of contrast material, using dedicated phased-array coils appropriate for the region to be studied and fast and ultrafast consecutive sequences. Postprocessing was done on an independent workstation (Advantage Windows, GE Medical System), with Functool (GE) software, which allowed a quantitative evaluation of enhancement as a function of time. The results were compared with the histopathological diagnoses obtained by biopsy or surgery. RESULTS: The lesions identified in the 39 patients included 23 soft tissue tumours (12 benign, 11 malignant) and 16 bone tumours (ten benign, six malignant). Comparing the time-intensity diagrams of lesions of the same histological type, we found typical enhancement patterns for some bone tumours only, especially for bone, cartilaginous, fibrohistiocytic and pseudoinflammatory lesions. No typical enhancement pattern could be detected for any of the histological types of soft tissue tumour. Analysis of the slope of the time-intensity curves has a sensitivity and specificity of 64%-58% for soft tissue tumours and 86%-67% for bone tumours in determining the biological aggressiveness of the lesions. CONCLUSIONS: Perfusion MRI had moderate sensitivity and specificity in the differential diagnosis between lesions with high or low biological activity. Only in a few cases was it possible to find some correlation between perfusion patterns and lesion histology. The slope values should therefore be used in combination with conventional spin-echo images and other imaging and clinical data in order to narrow the field of the possible differential diagnoses and reliably predict the nature of the lesion.     

Source localization of scalp-EEG interictal spikes in posterior cortex epilepsies investigated by HR-EEG and SEEG

Purpose:   To determine the validity of scalp-electroencephalography (EEG)-interictal spike (IIS) source localization in posterior cortex epilepsies (PCE).
Methods:   Eleven patients with drug-resistant PCE were studied with high-resolution EEG (HR-EEG) and stereoelectroencephalography (SEEG). Sixty-four scalp channels, a realistic head model, and different algorithms [multiple signal classification (MUSIC) and equivalent current dipoles] were used. Results were compared to intracerebral SEEG recordings. For SEEG, a semiautomatic detection of intracerebral IIS was used, allowing a classification of intracerebral IIS into one of three groups: Medial, lateral, and mediolateral.
Results:   In the medial group (two patients), scalp-EEG IIS were usually absent for one patient whereas for the other, scalp-EEG was misleading. Indeed, scalp-EEG IIS had a posterior projection, predominantly contralateral to the source. In the lateral group (two patients), scalp-EEG IIS were subcontinuous and accurately localized. In the mediolateral group (seven patients), intracerebral interictal distribution was complex and bilateral for four of seven patients. Source localizations were able to determine only a part, whether lateral or medial, of the intracerebral interictal distribution.
Discussion:   The accuracy of scalp-EEG IIS source localization is dependant on the type of intracerebral interictal distribution. In the most frequent type of PCE, patients proved to have a complex interictal distribution between both medial and lateral cortices, and source localizations always  underestimated intracerebral IIS. In cases where intracranial sources were quite focal, surface EEG sources were localized with accuracy, even in medial occipital lobe structures.     

PINK1-dependent recruitment of Parkin to mitochondria in mitophagy

Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARK2/Parkin mutations cause autosomal recessive forms of Parkinson''s disease. Upon a loss of mitochondrial membrane potential (ΔΨ_m) in human cells, cytosolic Parkin has been reported to be recruited to mitochondria, which is followed by a stimulation of mitochondrial autophagy. Here, we show that the relocation of Parkin to mitochondria induced by a collapse of ΔΨ_m relies on PINK1 expression and that overexpression of WT but not of mutated PINK1 causes Parkin translocation to mitochondria, even in cells with normal ΔΨ_m. We also show that once at the mitochondria, Parkin is in close proximity to PINK1, but we find no evidence that Parkin catalyzes PINK1 ubiquitination or that PINK1 phosphorylates Parkin. However, co-overexpression of Parkin and PINK1 collapses the normal tubular mitochondrial network into mitochondrial aggregates and/or large perinuclear clusters, many of which are surrounded by autophagic vacuoles. Our results suggest that Parkin, together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy. Thus by impairing this process, mutations in either Parkin or PINK1 may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson''s disease.     

Post-traumatic tarsal tunnel syndrome: interest of muscular MRI

INTRODUCTION: Tarsal tunnel syndrome is a compressive neuropathy of the tibial nerve with multiple causes. This syndrome is difficult to diagnose and can be missed because of its subjective symptomatology. OBSERVATION: In our patient, suspected post-traumatic tarsal tunnel syndrome was confirmed at MRI. This case highlights muscle signal anomalies caused by their denervation in the tibial nerve territory. CONCLUSION: MRI can provide supplementary information to the electromyography (EMG) and contribute to positive and etiologic diagnosis of peripheral nerve lesions.