Inhibition of sphingosine 1-phosphate protects mice against chondrocyte catabolism and osteoarthritis.

OBJECTIVE: Cartilage loss observed in osteoarthritis (OA) is prevented when osteoclasts in the subchondral bone are inhibited in mice. Here, we investigated the role of the osteoclast secretome and of the lipid mediator sphingosine 1-phosphate (S1P) in chondrocyte metabolism and OA. MATERIALS AND METHODS: We used SphK1LysMCre and wild type mice to assess the effect of murine osteoclast secretome in chondrocyte metabolism. Gene and protein expressions of matrix metalloproteinase (Mmp) were quantified in chondrocytes and explants by RT-qPCR and Western blots. SphK1LysMCre mice or wild type mice treated with S1P2 receptor inhibitor JTE013 or anti-S1P neutralizing antibody sphingomab are analyzed by OA score and immunohistochemistry. RESULTS: The osteoclast secretome increased the expression of Mmp3 and Mmp13 in murine chondrocytes and cartilage explants and activated the JNK signaling pathway, which led to matrix degradation. JTE013 reversed the osteoclast-mediated chondrocyte catabolism and protected mice against OA, suggesting that osteoclastic S1P contributes to cartilage damage in OA via S1P/S1P2 signaling. The activity of sphingosine kinase 1 (SphK1) increased with osteoclast differentiation, and its expression was enhanced in subchondral bone of mice with OA. The expression of Mmp3 and Mmp13 in chondrocytes was low upon stimulation with the secretome of Sphk1-lacking osteoclasts. Cartilage damage was significantly reduced in SphK1LysMCre mice, but not the synovial inflammation. Finally, intra-articular administration of sphingomab inhibited the cartilage damage and synovial inflammation. CONCLUSIONS: Lack of S1P in myeloid cells and local S1P neutralization alleviates from osteoarthritis in mice. These data identify S1P as a therapeutic target in OA.

[A phenomenological approach of treatment-resistant depressions]. / Une approche clinico-phénoménologique des dépressions résistantes.

BACKGROUND: Hospital practitioners are regularly facing treatment-resistant depression, which may be defined according to the clinical picture or according to the therapeutic strategy. There are different levels of resistance and different levels of evidence for this resistance. Indeed, the notions of relative and absolute resistance describe the adequacy of assigned treatment. It thus seems necessary to specify the psychopathology of treatment-resistant depression and to highlight the endogeneity phenomenon in order to solve this problem. OBJECTIVE: Our work addresses the concept of endogeneity (previously clarified by Hubertus Tellenbach) and will consider its implications in the management of treatment-resistant depression. We attempt to demonstrate that the phenomenological approach is an interesting tool in clinical practice through the highlight of endogenous characteristics. METHOD: The first step consists in specifying the endogenous phenomena: abolition of rhythms, loss of the forward-looking deployment, overall impression, and reversibility, spatial and temporal characteristics from the phenotype. Our phenomenological approach continues by exploring the false resistances. Hence, we take into account anxious comorbidity, medical comorbidity, addictions, personality disorders and the hypothesis of a bipolar diathesis. First of all, it is difficult to show the patient in which way their behaviour results in stagnation. Indeed, it could strengthen the internal move that leads to an imperious necessity to cope with the surroundings. The psychotherapeutic help is elaborated by specifically highlighting the pathogenic situations whilst also taking into account the difficulties of an authentic therapeutic alliance. RESULTS: Our approach emphasizes the endogeneity phenomenon in depression, permitting the search for an optimal therapeutic strategy. It also provides assistance in resolving false resistance or what is apparent. In cases of endogenous depression, therapeutic orientation favours pharmacological and instrumental strategies (brain stimulation). If elements of self-understanding can be given to the patient, they must show that the rigid way in which the patient appropriates the daily reports is more stressful than the choice. Therefore, the psychotherapeutic help must take into account the situation and the individual vulnerability so as to develop a suitable care.

[Clinical evaluation of the Pascal dynamic contour tonometer]. / Evaluation clinique du tonomètre dynamique de contour Pascal.

PURPOSE: The Pascal dynamic contour tonometer (DCT) was designed to measure IOP independently of corneal properties. This study aimed at 1) assessing the intra- and interindividual variability of DCT IOP measurements, the differences between DCT and applanation tonometry IOP measurements (APL), and their correlations with central corneal thickness (CCT); 2) analyzing the variability of the ocular pulse amplitude (OPA) and its correlations with age, blood pressure (BP), cardiac beat pulse (CP), diagnosis of glaucoma, IOP, and severity of glaucomatous visual field (VF) defects. METHODS: Twenty-five normal subjects (25 eyes), 14 patients with ocular hypertension (27 eyes), and 54 glaucomatous patients (104 eyes) were included in this prospective study. In the first 12 normal subjects, three consecutive IOP measurements were taken by three different observers using DCT, directly followed by three measurements with APL by the same observer. In the following 13 subjects, the reverse sequence was followed. In the other group, the IOP measurements (three DCT and three APLs) were taken by the same observer. Only DCT measurements with quality levels 1-3 were considered for analysis. RESULTS: In the normal group, DCT IOP measurement variability varied between 4.4%-7.3% (intraobserver variation coefficient) and 8% (interobserver variation coefficient). DCT IOP measurement was not influenced by the sequence of measurements or the observer. DCT overestimated IOP by a mean of 2.2 mmHg compared with APL (p<0.001). The 95% limits of agreement for each subject tested with both tonometers ranged from -0.5 mmHg to +6.3 mmHg. IOP APL and DCT measurements were strongly correlated. Both DCT and APL were not correlated with CCT. OPA ranged from 1.2 mmHg to 6.6 mmHg (mean, 3.1+/-1.2 mmHg) and was comparable between the three observers. Intraobserver OPA variability ranged from 7.6% to 9.5%. The interobserver OPA variability coefficient was 8.8%. OPA was only correlated with systolic BP (p<0.05). In glaucomatous patients, the correlation between DCT and APL IOP measurements was highly significant (r=0.860, p<0.001). DCT overestimated IOP by a mean 2 mmHg compared with APL (p<0.001). IOP differences between both tonometers were not influenced by the sequence of measurements. Unlike APL, DCT was not or only slightly influenced by CCT (p=0.07 for DCT; p=0.001 for APL). The mean difference between IOP DCT and APL was larger in thin corneas (<520 microm): 2.8+/-3.1 mmHg versus 0.8+/-2.3 mmHg in thick corneas (580 microm) (p=0.001). OPA was not correlated with age. It was positively correlated with IOP (p<0.001), systolic BP (p=0.047), and MD (mean deviation) (p=0.018). It was negatively correlated with diastolic BP (p=0.003), cardiac frequency (p<0.001), severity of glaucomatous VF defects (p=0.002), and PSD (pattern standard deviation) (p=0.008). It was significantly higher in the OHT subgroup and significantly lower in the NTG subgroup (p<0.05). In both groups, the IOP difference between DCT and APL was not correlated with age (p>0.05). CONCLUSIONS: IOP measurements with the Pascal(R) DCT and APL correlated well and were reproducible. DCT IOP measurement variability was slightly higher than APL with relatively wide 95% limits of agreement. Considering the entire study population, DCT overestimated IOP by a mean 2.0 mmHg compared with APL. DCT was independent of CCT, especially in thin corneas. The DCT does not appear to be clinically advantageous over the Goldmann tonometer in the IOP measurement in thick corneas. Therefore an IOP follow-up by APL tonometry and pachymetry appeared to be mandatory for the interpretation of the true IOP. Interindividual OPA variations were high, as was measurement variability. OPA was correlated with BP, cardiac frequency, IOP, diagnosis of glaucoma, and severity of glaucomatous VF defects. These must be considered in the clinical interpretation of this parameter.

In vivo gene silencing in solid tumors by targeted electrically mediated siRNA delivery.

RNA interference (RNAi)-mediated gene silencing approaches appear very promising for therapies based on the targeted inhibition of disease-relevant genes. The major hurdle to the therapeutic development of RNAi strategies remains, however, the efficient delivery of the RNAi-inducing molecules, the short interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs), to the target tissue. With respect to cancer treatment the development of efficient delivery methods into solid tumors appears as a critical issue. However, very few studies have addressed this problem. In this study we have investigated the contribution of electrically mediated delivery of siRNA into murine tumors stably expressing an enhanced green fluorescent protein (EGFP) target reporter gene. The silencing of EGFP gene expression was quantified over time by fluorescence imaging in the living animal. Our study indicates that electric field can be used as an efficient method for siRNA delivery and associated gene silencing into cells of solid tumors in vivo.

[Clinical evaluation of the dynamic rebound tonometer Icare]. / Evaluation clinique du tonomètre dynamique Icare.

PURPOSE: The Icare dynamic tonometer (impact or Rebound tonometry) is a new tonometer based on making a moving object collide with an eye and on monitoring the motion parameters of this object following contact. The purpose of this study was to assess intra- and interobserver variability of IOP measurements with the Icare and their correlations with Goldmann applanation tonometry (GAT) and central corneal thickness (CCT). MATERIAL AND METHODS: A prospective study including three groups of patients: group 1 (50 normal subjects), group 2 (50 patients with OHT or POAG and GAT IOP>22 mmHg), and group 3 (38 glaucomatous patients with GAT IOP< or =22 mmHg). In group 1, three consecutive IOP measurements were taken by three distinct observers with Icare followed by three GAT measurements by the same clinician. In group 2, the same procedure was followed from patients 1 to 25 and the reverse sequence from patients 25 to 50 after a 10-min break. In group 3, only one clinician took three GAT measurements followed by three Icare measurements after a 10-min break to exclude a tonographic effect in eyes with statistically normal-range IOPs. RESULTS: : In group 1, intraobserver variability was about 6% for each observer (NS). There was no learning curve effect. The interobserver variation coefficient was 6.4%. Icare overestimated IOP compared to GAT (mean difference, 1.5-2.2 mmHg) (p<0.001). Icare IOP was 23.4 mmHg for observer 1 when GAT was 22 mmHg (95% individual CI, 18-28.9 mmHg). In group 2, intraobserver variation coefficients of the IOP ranged from 5% to 5.4% (NS). Icare overestimated IOP by mean 0.84 mmHg compared with GAT. In group 3, mean IOP was not different between Icare and GAT. Icare IOP of 20.7 mmHg corresponded to a value of 22 mmHg using GAT. In this group, correlations between CCT and IOP measurements were higher for Icare than for GAT (p=0.062). CONCLUSION: Icare measures IOP in an unanesthetized sitting patient in a very brief time. Patient's minimal cooperation is needed. As long as the device is correctly positioned, the learning curve is short. Icare gives reproducible IOP measurements. Intra- and interobserver variability of IOP measurements are close to those of GAT. Icare overestimates IOP measurements an average 1.5 mmHg compared with GAT. Whatever the IOP level, Icare IOP measurements are well correlated with GAT. To a greater extent than for GAT, the reliability of IOP measurements is influenced by CCT. This tonometer can be used as a screening device for ocular hypertension as long as CCT measurements can be taken.

[Vitreo-retinal pediatric surgery: epidemiologic factors, etiology and prognosis]. / Chirurgie vitréo-rétinienne pédiatrique: facteurs épidémiologiques, étiologiques et pronostiques.

The features of pediatric vitreoretinal surgery are different from those of the adult population. In order to identify those differences, our retrospective study, dealing with a consecutive series of 2230 patients who underwent vitreoretinal surgery, analyzes several parameters for the 43 young patients (under 19 years old) (2%). Two main results can be withdrawn from the study. First, trauma is a major cause of vitreoretinal surgery in children (30% of the cases), proportionally much more frequent than in adults. Second, patient's age is the only factor that significantly influences the surgical prognosis, with a success rate of 35% under the age of 10 years, and 73% above this age (p < 0.05). We conclude that pediatric vitreoretinal surgery has a more guarded prognosis compared to the one performed in the adult population.

[Simulation and dissimulation in ophthalmology]. / Simulation et dissimulation en ophtalmologie.

Simulation is defined when a patient desires a given condition to such an extent that he either initiates the symptoms through physical means of direct harm to his eyes (positive simulation) or imitates the symptoms even though he is healthy and otherwise free of pathology (dissimulation or negative simulation). We show that diagnosing simulation may be done during the ophthalmologic consultation when in doubt of the patient's condition. These simple tests are accessible to all and do not require sophisticated material.

Passive derivation of basic walker-assisted gait characteristics from measured forces and moments.

This work describes a method that passively assesses basic walker-assisted gait characteristic, including heel strikes, toe-off events, as well as stride time, double support and right & left single support phases using only force-moment measurements from the walker's handles. The passively derived gait characteristics were validated against motion capture gait analysis and showed good correlations. This research is part of an effort that aims to identify user intent, from measuring forces and moments exerted on the handles of the walker as well as from perceiving the environment, and to incorporate identified intent into a passive shared steering control system for the walker. The primary focus of the work leading to This work is to identify the double support phase, and to engage the steering control at the beginning of this phase to maximize the user's stability. However, the application of the method presented and the instrumented walker can be extended to longitudinal outside the lab Gait assessment.

[About two cases of uterine rupture outside of labour: consequences of an unnoticed previous perforation]. / A propos de deux cas de rupture utérine en dehors du travail: conséquences d'une perforation antérieure non notifiée.

The uterine mute perforation following uterine evacuation of pregnancy exists; the obstetrical consequences of these are quite unknown. We report 2 cases of pregnancy complicated by uterine rupture and defect after uterine mute perforation. The physical signs are late and misleading. The notion of perforation during the instrumental evacuation of pregnancy must be mentioned for an adequate follow-up. Management thus remains essentially preventive.

[Endometrioid adenofibroma of the ovary. An anatomo-clinical case report]. / Adénofibrome endométrioïde de l'ovaire. A propos d'un cas anatomoclinique.

Endometrioid adenofibromas are rare tumours of the ovary characterised by proliferation of endometrial type glands without any particular atypical cell structure, within a dense and thick stroma. We report a case of such a tumour which showed an outline of stromal luteinisation.

[Massive fibroma of the round ligament developing as an extraperitoneal abdominal mass]. / Volumineux fibrome du ligament rond à développement abdominal mais extra-péritonéal.

The authors report the exceptionally rare case of a huge myofibroma of the round ligament. The localization of the myoma was very unusual. It developed from the inguinal insertion of the round ligament; and the fibroma had grown in the abdominal wall between muscle and the peritoneum. Consequently the mass was both abdominal and extra-peritoneal. To our knowledge, such an association has never before been described. In the case described here, the mass was asymptomatic and the patient presented because of her increasing abdominal size. Examination revealed an abdominal mass that almost reached the umbilicus and resembled a four months pregnancy. Ultrasonography showed that the uterus was normal. The mass was a 15 cm by 15 cm tumour of heterogenous structure. As the ovaries were not visualized it was impossible to decide whether the tumour was ovarian, intestinal or peritoneal. Laparotomy was performed with a preliminary diagnosis of a solid ovarian tumour. It was then possible to localize the mass accurately and to define it. Histological examination showed that it was a leiomyoma. Tumours of the round ligament are very uncommon. Among these tumours leiomyomas are the most frequent. Endometriotic tumours come next. Various very rare tumours can also be found. Leiomyoma of the round ligament may arise from each portion of the ligament: abdominal, inguinal or Labium Majus. But both abdominal and extra-peritoneal development from the inguinal insertion of the ligament is rare. They are usually single, and unilateral, and are found by chance.(ABSTRACT TRUNCATED AT 250 WORDS)

[Launois-Bensaude disease. Apropos of 2 new cases]. / Maladie de Launois-Bensaude. A propos de deux nouveaux cas.

Data relating to Launois-Bensaude disease are reviewed and two cases reported. Both patients were dyspneic, one of them presenting preoperative trachea deviation, a complication reported in only about 2% of cases documented in the literature. Dissection of these non-encapsulated fatty tumors is difficult and can lead to complications, but surgical excision remains the only possible treatment.

[Technique and supervision of home assisted ventilation (author's transl)]. / Technique et surveillance de la ventilation assistée à domicile (V.A.D.).

Based on data obtained from 260 patients ventilated through a mouth-piece, several notions concerning equipment and supervision requirements have become clear.--In our opinion, the indications should not be reserved for extremely severe patients; in their case cardiac complications are constant in spite of usual treatment. These patients, most often respiratory encephalopathic, are not very receptive to the "directions for use" of home assisted ventilation.--On the contrary, chronic hypoxia-hypercapnia, whatever its origin, accompanied by slight or transitory cardiac signs, has much more chance of being treated successfully.--The adaptation of the patient to the respirator before his release from the hospital must be worked out until a clinical and biological improvement can be obtained, at the risk of probable failure.--Supervision at home should disclose any alteration in the patient's clinical condition. It can only be carried out by the conjoined visits of the practicing doctor, nurse, technician, etc. The contacts between the practicing doctor and the hospital physician should be frequent. The ideal solution is systematic visits to the hospital.

Bipolar fixation of fractures of the distal end of the radius.

The frequency fo secondary displacement in fractures of the distal end of the radius is very high and varies from 40 to 60% in various series. This results from the void in the epiphysis after reduction due to crushing of the cancellous bone. Secondary displacement can be easily avoided by the bipolar fixation method. This method is quite simple. Two strong Kirschner wires are driven into the radius and into the first metacarpal, and then incorporated in the cast after the reduction of the fracture. In this study we have followed 102 out of 250 patients treated by this method. The number of secondary displcements has been negligible. The functional results are excellent and we did not find any untoward effects attributable to our technique.

[Bronchopulmonary "tumouriet" Rare aetiology of an isolated rounded opacity (author's transl)]. / "Tumorlet" broncho-pulmonaire. Etiologie exceptionnelle d'une opacité arrondie isolée.

In the case described, the onset of haemoptysis led to the discovery of a rounded opacity at the left base. All investigations being negative, thoracotomy was performed. The diagnosis could then be made by histology. Bronchopulmonary "tumourlets" are rarely seen (184 cases) masses of epithelial cells which are usually discovered by chance within areas of altered pulmonary tissue. Forms with clinical or radiological manifestations are extremely rare, only 4 other cases having been described. The pathogenesis of these tumours has been the object of recent ultrastructural studies which have shown the relationship which exists between "tumourlet" and carcinoid tumour. It would thus seem reasonable to classify "tumourlets" amongst the tumours of the diffuse endocrine system. The authors nevertheless feel that it would be premature to name them as bronchial carcinoids of tumourlet type. The concept of "tumourlet" as a separate entity should be retained.

[Pulmonary fibrosis due to bleomycin]. / Les fibroses pulmonaires à la bléomycine.

Being little myelotoxic, Bleomycin (BLM) is more and more used in association with other anti-neoplastic drugs; its pulmonary toxicity is not to be overlooked and here is a recall of the risks of pulmonary fibrosis during treatment by BLM. This review is based on a personal experience of 45 cases, of which 6 were cases of respiratory insufficiency. It derived also from a study of the literature which expressed the frequency of respiratory accidents in figures varying from 2 to 94% according to the criteria of tolerance used by the authors. BLM toxicity for the pulmonary tract being important some precautions should be taken in its use: specially supervising aged patients or those with a pastpathological respiratory story; it should particularly concern the functional side, using CO ductance to trace the first signs of toxicity A total dose of 450 mg should not be exceeded.

Benign paroxysmal positional vertigo and rotatory-induced nystagmus.

The study of 25 cases of 'benign paroxysmal position vertigo' showed us that irrigation of the ear opposed to the injured side inhibited this nystagmus. In these patients, it is difficult, not to say impossible, to provoke rotatory nystagmus, either by the caloric test (Brünings position II) or by the rotatory test in frontal plane. The significance of these observation is discussed and ascribed to a central compensation system.