Ultrastructural changes of the internal limiting membrane removed during indocyanine green assisted peeling versus conventional surgery for idiopathic macular epiretinal membrane

Résumé : Introduction : L'objectif de cette étude était d'une part d'évaluer les caractéristiques histologiques des fragments cellulaires rétiniens attachés à la limitante interne après vitrectomie et pelage d'une membrane epirétinienne, et d'autre part de mettre en évidence des différences histologiques entre les cas opérés avec ou sans l'aide d'ICG dilué dans du glucose 5%. Méthodes Nous avons examiné rétrospectivement l'histologie de 88 spécimens de membranes épimaculaires contenant la limitante interne de la rétine, qui ont été enlevés chirurgicalement entre 1995 et 2003. L'analyse histologique a centré principalement l'attention sur la présence et les caractéristiques des fragments cellulaires rétiniens attachés à la limitante interne. L'analyse statistique a comparé les résultats entre le groupe I (chirurgie conventionnelle sans l'aide de l'ICG) et le groupe II (chirurgie à l'aide de l'ICG). Résultats Soixante et onze patients ont eu une vitrectomie sans l'aide de l'ICG (groupe I) et 17 avec l'aide de l'ICG (groupe II). Le nombre de débris de cellules de Müller à la surface rétinienne de la limitante interne était plus important dans le groupe I (sans ICG) que dans le groupe II (avec ICG) (40.8% versus 11.8% ; p = 0.024). Des larges fragments cellulaires rétiniens attachés à la limitante interne ont été plus fréquemment observés dans le groupe I (sans ICG) que dans le groupe II (avec ICG) (63.4% versus 23.5%; p= 0.003). Dans cinq (7%) cas du groupe I, de gros éléments cellulaires rétiniens ont été mis en évidence (des axones neuraux ou des vaisseaux sanguins). De tels éléments n'ont pas été retrouvés dans les spécimens du groupe II (avec ICG). Conclusions L'utilisation de l'ICG dilué dans du glucose 5% pour faciliter le pelage d'une membrane épimaculaire et notamment l'ablation de la limitante interne de la rétine semble diminuer de manière significative le nombre et la taille des débris des cellules de Muller adhérents à la face rétinienne de la membrane limitante interne de la rétine. Cette observation suggère que l'utilisation per-opératoire d'ICG dilué dans du glucose 5% facilite l'ablation de la limitante interne pendant la chirurgie de la membrane epirétinienne en diminuant l'adhérence de la limitante interne à la rétine.

ROLES OF ACID-SENSING ION CHANNELS (ASICS) IN PERIPHERAL NEUROPEPTIDE SECRETION AND PAIN

Acid-sensing ion channels (ASICs) are non-voltage-gated sodium channels activated by an extracellular acidification. They are widely expressed in neurons of the central and peripheral nervous system. ASICs have a role in learning, the expression of fear, in neuronal death after cerebral ischemia, and in pain sensation. Tissue damage leads to the release of inflammatory mediators. There is a subpopulation of sensory neurons which are able to release the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). Neurogenic inflammation refers to the process whereby peripheral release of the neuropeptides CGRP and SP induces vasodilation and extravasation of plasma proteins, respectively. Our laboratory has previously shown that calcium-permeable homomeric ASIC1a channels are present in a majority of CGRP- or SP-expressing small diameter sensory neurons. In the first part of my thesis, we tested the hypothesis that a local acidification can produce an ASIC-mediated calcium-dependant neuropeptide secretion. We have first verified the co-expression of ASICs and CGRP/SP using immunochemistry and in-situ hybridization on dissociated rat dorsal root ganglion (DRG) neurons. We found that most CGRP/SP-positive neurons also expressed ASIC1a and ASIC3 subunits. Calcium imaging experiments with Fura-2 dye showed that an extracellular acidification can induce an increase of intracellular Ca2+ concentration, which is essential for secretion. This increase of intracellular Ca2+ concentration is, at least in some cells, ASIC-dependent, as it can be prevented by amiloride, an ASIC antagonist, and by Psalmotoxin (PcTx1), a specific ASIC1a antagonist. We identified a sub-population of neurons whose acid-induced Ca2+ entry was completely abolished by amiloride, an amiloride-resistant population which does not express ASICs, but rather another acid-sensing channel, possibly transient receptor potential vanilloïde 1 (TRPV1), and a population expressing both H+-gated channel types. Voltage-gated calcium channels (Cavs) may also mediate Ca2+ entry. Co-application of the Cavs inhibitors (ω-conotoxin MVIIC, Mibefradil and Nifedipine) reduced the Ca2+ increase in neurons expressing ASICs during an acidification to pH 6. This indicates that ASICs can depolarise the neuron and activate Cavs. Homomeric ASIC1a are Ca2+-permeable and allow a direct entry of Ca2+ into the cell; other ASICs mediate an indirect entry of Ca2+ by inducing a membrane depolarisation that activates Cavs. We showed with a secretion assay that CGRP secretion can be induced by extracellular acidification in cultured rat DRG neurons. Amiloride and PcTx1 were not able to inhibit the secretion at acidic pH, but BCTC, a TRPV1 inhibitor was able to decrease the secretion induced by an extracellular acidification in our in vitro secretion assay. In conclusion, these results show that in DRG neurons a mild extracellular acidification can induce a calcium-dependent neuropeptide secretion. Even if our data show that ASICs can mediate an increase of intracellular Ca2+ concentration, this appears not to be sufficient to trigger neuropeptide secretion. TRPV1, a calcium channel whose activation induces a sustained current - in contrary of ASICs - played in our experimental conditions a predominant role in neurosecretion. In the second part of my thesis, we focused on the role of ASICs in neuropathic pain. We used the spared nerve injury (SNI) model which consists in a nerve injury that induces symptoms of neuropathic pain such as mechanical allodynia. We have previously shown that the SNI model modifies ASIC currents in dissociated rat DRG neurons. We hypothesized that ASICs could play a role in the development of mechanical allodynia. The SNI model was performed on ASIC1a, -2, and -3 knock-out mice and wild type littermates. We measured mechanical allodynia on these mice with calibrated von Frey filaments. There were no differences between the wild-type and the ASIC1, or ASIC2 knockout mice. ASIC3 null mice were less sensitive than wild type mice at 21 day after SNI, indicating a role for ASIC3. Finally, to investigate other possible roles of ASICs in the perception of the environment, we measured the baseline heat responses. We used two different models; the tail flick model and the hot plate model. ASIC1a null mice showed increased thermal allodynia behaviour in the hot plate test at three different temperatures (49, 52, 55°C) compared to their wild type littermates. On the contrary, ASIC2 null mice showed reduced thermal allodynia behaviour in the hot plate test compared to their wild type littermates at the three same temperatures. We conclude that ASIC1a and ASIC2 in mice can play a role in temperature sensing. It is currently not understood how ASICs are involved in temperature sensing and what the reason for the opposed effects in the two knockout models is.

Biomarqueurs associés à la dyspnée et douleurs thoraciques: quelle utilité clinique [Biomarkers associated with dyspnea and chest pain: which cinical utility?].

Dyspnea and chest pain are typical reasons for consultations. biomarkers (CRP, procalcitonin, NT-proBNP, troponins, D-dimers) can have an interest for the diagnosis, the prognosis and the follow-up of several pathologies. There are however numerous pitfalls and limitations between the discovery of a biomarker and the utility in clinical practice. It is essential to always estimate a pre-test probability based on an attentive history and a careful physical examination, to know the intrinsic and extrinsic qualities of a test, and to determine a threshold of care. A biomarker should be used only if it modifies the patient's care and if it brings him a benefit compared to the patient who has no biomarker.

Idiopathic sclerochoroidal calcification: new observations.

Two cases of idiopathic sclerochoroidal calcification are reported with follow-up of two and ten years. In addition we have reviewed 102 cases of choroidal osteoma, including six misleading case reports which actually described idiopathic sclerochoroidal calcification and not choroidal osteoma. Clinical manifestation and the angiographic features of idiopathic sclerochoroidal calcification are outlined. The differential diagnosis of intraocular deposition of calcium salts is discussed in detail.

Automatic Prediction of Facial Trait Judgments: Appearance vs. Structural Models

Evaluating other individuals with respect to personality characteristics plays a crucial role in human relations and it is the focus of attention for research in diverse fields such as psychology and interactive computer systems. In psychology, face perception has been recognized as a key component of this evaluation system. Multiple studies suggest that observers use face information to infer personality characteristics. Interactive computer systems are trying to take advantage of these findings and apply them to increase the natural aspect of interaction and to improve the performance of interactive computer systems. Here, we experimentally test whether the automatic prediction of facial trait judgments (e.g. dominance) can be made by using the full appearance information of the face and whether a reduced representation of its structure is sufficient. We evaluate two separate approaches: a holistic representation model using the facial appearance information and a structural model constructed from the relations among facial salient points. State of the art machine learning methods are applied to a) derive a facial trait judgment model from training data and b) predict a facial trait value for any face. Furthermore, we address the issue of whether there are specific structural relations among facial points that predict perception of facial traits. Experimental results over a set of labeled data (9 different trait evaluations) and classification rules (4 rules) suggest that a) prediction of perception of facial traits is learnable by both holistic and structural approaches; b) the most reliable prediction of facial trait judgments is obtained by certain type of holistic descriptions of the face appearance; and c) for some traits such as attractiveness and extroversion, there are relationships between specific structural features and social perceptions.

Oligoanalgesia in the emergency department: short-term beneficial effects of an education program on acute pain.

STUDY OBJECTIVE: Acute pain is the most frequent complaint in emergency department (ED) admissions, but its management is often neglected, placing patients at risk of oligoanalgesia. We evaluate the effect of the implementation of guidelines for pain management in ED patients with pain at admission or anytime during their stay in our ED. METHODS: This prospective pre-post intervention cohort study included data collection both before and after guideline implementation. Consecutive adult patients admitted with acute pain from any cause or with pain at any time after admission were enrolled. The quality of pain management was evaluated according to information in the ED medical records by using a standardized collection form, and its impact on patients was recorded with a questionnaire at discharge. RESULTS: Two hundred forty-nine and 192 patients were included during pre- and postintervention periods. Pain was documented in 61% and 76% of nurse and physician notes, respectively, versus 78% and 85% after the intervention (difference 17%/9%; 95% confidence interval [CI] 8% to 26%/2% to 17%, respectively). Administration of analgesia increased from 40% to 63% (difference 23%; 95% CI 13% to 32%) and of morphine from 10% to 27% (difference 17%; 95% CI 10% to 24%). Mean doses of intravenous morphine increased from 2.4 mg (95% CI 1.9 to 2.9 mg) to 4.6 mg (95% CI 3.9 to 5.3 mg); administration of nonsteroidal antiinflammatory drugs and acetaminophen increased as well. There was a greater reduction of visual analogue scale score after intervention: 2.1 cm (95% CI 1.7 to 2.4 cm) versus 2.9 cm (95% CI 2.5 to 3.3 cm), which was associated with improved patient satisfaction. CONCLUSION: Education program and guidelines implementation for pain management lead to improved pain management, analgesia, and patient satisfaction in the ED.

Premature epiphyseal closure in an adolescent treated by retinoids for acne: An unusual cause of anterior knee pain

Introduction.- Retinoids are effective and widely used for the treatment of severe acne. Their use can be, however, associated with numerous side effects. For example, some rare cases of premature epiphyseal closure were reported.Observation.- A sixteen-year-old soccer player consulted for bilateral progressive anterior knee pain, since two months, evoking a femoro-patellar origin. After physiotherapy, the pain decreases on the right but remained on the left. The history taking brought out the use of isotretinoin for more than 6 months (0.5 mg/kg). Magnetic resonance imaging (MRI) findings showed an irregularity of the growth plate and an important metaphyso-epiphyseal oedema, more marked on the left. The diagnosis of retinoid induced premature ephysieal closure was retained. The treatment was stopped, with a resolution of symptoms within two months. The control MRI of the left knee present persisting small sequelar thumbprint-like growth plate lesion. Eighteen months later, neither limb-length discrepancy nor static disorder was noticed.Discussion.- Premature epiphyseal closure is a rare complication of retinoid treatment of acne. Retinoids induce an invasion of the growth plate by osteoclasts and a decrease in proteoglycans synthesis. The knee seems the most involved joint. The clinical presentation is aspecific, sometimes lightly symptomatic. A careful pharmacological history and an appropriate imaging are necessary. MRI is now the gold standard. It shows an irregularity of the growth plate with an oedema on both sides. In chronic phase, a thumbprint-like image may persist. The symptoms resolution arises in few weeks after the treatment interruption. A single case of static disorder was reported until now. The small size of the growth plate interruptions, insufficient to lead to a growth disorder if the medicament is stopped early enough, explains probably it. This complication being rare, a radiological follow-up of the young patients treated by retinoids is not proposed.

Unraveling dynamics of human physical activity patterns in chronic pain conditions.

Chronic pain is a complex disabling experience that negatively affects the cognitive, affective and physical functions as well as behavior. Although the interaction between chronic pain and physical functioning is a well-accepted paradigm in clinical research, the understanding of how pain affects individuals' daily life behavior remains a challenging task. Here we develop a methodological framework allowing to objectively document disruptive pain related interferences on real-life physical activity. The results reveal that meaningful information is contained in the temporal dynamics of activity patterns and an analytical model based on the theory of bivariate point processes can be used to describe physical activity behavior. The model parameters capture the dynamic interdependence between periods and events and determine a 'signature' of activity pattern. The study is likely to contribute to the clinical understanding of complex pain/disease-related behaviors and establish a unified mathematical framework to quantify the complex dynamics of various human activities.

Retrospective analysis of complications of immunosuppressive therapies (steroidsand immunosuppressive therapies) in pediatric uveitis

Purpose¦The purpose of this study is to analyze the incidence rate of side effects occurring during systemic therapy (corticosteroids, methotrexate, azathioprine, cyclosporine A or biologic agents) of auto-immune uveitis.¦Material and methods¦Retrospective study including 23 / 71 patients aged between 0-16 years old presenting with a chronic non-infectious uveitis. All children were treated in the Jules-Gonin Eye Hospital and paediatric rheumatology unit of the CHUV (Centre Hospitalier Universitaire Vaudois) between January 2000 and December 31st 2010. Side effects were reported as minor (without subsequent change in systemic medication), moderate (associated with a change in systemic dosage or class of immunosuppressive therapy or in the presence of Cushingoid face or weight gain) or severe (hospitalization or life threatening).¦Results¦52% of boys and 48% of girls are present in the cohort with a mean age at the first visit of 8.1 years (1.7-15.6). Intermediate uveitis consisted of the commonest aetiology with 8 patients (35%), juvenile idiopathic arthritis (JIA) in 7 (30%), Behçet's disease in 3 (13%) and others in 5 (22%). The overall length of therapy was longer for prednisone (26.6 ± 5.4 patient / year), but was similar between methotrexate (22.1 ± 5.4 patient / year) and azathioprine (15.2 patient / year). Moderate side effects were respectively 64% for corticosteroids therapy, 54% with methotrexate and 14% with azathioprine. One severe and one moderate side effect were observed with anti-TNFα respectively stage III anaphylactic shock and pain during injection associated with a redness of the site of injection and limping after the injection.¦Discussion¦Immunomodulating agents allow a rapid decrease in corticosteroid therapy, but one severe side effect was observed with anti-TNFa agents. These agents are considered in most countries as third line therapeutic agents.

Juvenile arthritis patients report favorable subjective outcomes of hip arthroplasty despite poor standard outcome scores.

We evaluated midterm patient-reported outcomes and satisfaction with total hip arthroplasty in patients who had severe juvenile idiopathic arthritis. Thirty-one patients (49 hips), with a mean age of 29 years (range, 16-43 years), reported low hip pain and stiffness at follow-up (mean, 7 years; range, 3-17 years). Up to 92% were satisfied with their ability to perform various activities; 96% were satisfied with pain relief. A mean postoperative flexion arc of 96° was observed. Final 36-Item Short Form Health Survey, EuroQol in 5 dimensions, Western Ontario and McMaster Universities Arthritis Index, and Harris Hip scores were lower than reference populations, particularly for mobility, physical functioning, and social functioning subscores. Young adults with end-stage hip involvement and severe longstanding juvenile idiopathic arthritis expressed high satisfaction with total hip arthroplasty, which improved range of motion, pain, and stiffness, despite poor performance on widely used outcome measures.

Nouveautés dans la physiopathologie, le diagnostic et le traitement de la douleur neuropathique [New concepts in the pathophysiology, diagnosis and treatment of neuropathic pain].

We here summarize five articles bringing new advances in our knowledge on neuropathic pain and put them into perspective with our current understanding. The first uses a mechanism-based approach with a capsaicin test to stratify patients suffering from painful diabetic neuropathy before starting a topical clonidine treatment. The second reviews disinhibition as a critical mechanism and a promising target for chronic pain. The third evokes neuroglial interactions and its implication regarding the interplay between injuries in childhood and hypersensitivity in adulthood. The last articles remind us that interventional therapies, not always very invasive, have a future potential in the therapy of frequent conditions such as head pain disorders.

Upregulation of the GABA transporter GAT-1 in the gracile nucleus in the spared nerve injury model of neuropathic pain.

Neuropathic pain is a major health issue and is frequently accompanied by allodynia (painful sensations in response to normally non-painful stimulations), and unpleasant paresthesia/dysesthesia, pointing to alterations in sensory pathways normally dedicated to the processing of non-nociceptive information. Interestingly, mounting evidence indicate that central glial cells are key players in allodynia, partly due to changes in the astrocytic capacity to scavenge extracellular glutamate and gamma-aminobutyric acid (GABA), through changes in their respective transporters (EAAT and GAT). In the present study, we investigated the glial changes occurring in the dorsal column nuclei, the major target of normally innocuous sensory information, in the rat spared nerve injury (SNI) model of neuropathic pain. We report that together with a robust microglial and astrocytic reaction in the ipsilateral gracile nucleus, the GABA transporter GAT-1 is upregulated with no change in GAT-3 or glutamate transporters. Furthermore, [(3)H] GABA reuptake on crude synaptosome preparation shows that transporter activity is functionally increased ipsilaterally in SNI rats. This GAT-1 upregulation appears evenly distributed in the gracile nucleus and colocalizes with astrocytic activation. Neither glial activation nor GAT-1 modulation was detected in the cuneate nucleus. Together, the present results point to GABA transport in the gracile nucleus as a putative therapeutic target against abnormal sensory perceptions related to neuropathic pain.

Intrathecal drug delivery systems for cancer pain

Introduction: A substantial number of patients with cancer suffer considerable pain at some point during their disease, and approximately 25% of cancer patients die in pain. In cases of uncontrolled pain or intolerable side effects, intrathecal drug delivery system (IDDS) is a recognised management option. Indeed, IDDS offer rapid and effective pain relief with less drug side effects compared to oral or parenteral administration. The aim of this study is to retrospectively review our series of cancer patients treated with IDDS. Method: Data was extracted from the institutional neuromodulation registry. Patients with cancer pain treated with IDDS from 01.01.1997 to 30.12.2009 were analysed for subjective improvement, changes in pain intensity (VAS) and survival time after implantation. Measurements were available for a decreasing number of patients as time since baseline increased. Results: During the studied period, 78 patients were implanted with IDDS for cancer pain. The mean survival time was 11.1 months (median: 3.8 months) and 14 patients (18%) were still alive at the end of the studied period. Subjective improvement was graded between 55 and 83% during the first year. Mean VAS during the first year remained lower than VAS at baseline. Discussion: IDDS has been shown to be cost-effective in several studies. Although initial costs of implantation are high, the cost benefits favour analgesia with implanted intrathecal pumps over epidural external systems after 3 to 6 months in cancer patients. Improved survival has been associated with IDDS and in this series both the mean and median survival times were above the cut-off value of three months. The mean subjective improvement was above 50% during the whole first year, suggesting a good efficacy of the treatment, a finding that is consistent with the results from other groups. Changes in pain intensity are difficult to interpret in the context of rapidly progressive disease such as in terminal cancer. However, mean VAS from 1 thru12 months were lower than baseline, suggesting improved pain control with IDDS, or at least a stabilisation of the pain symptoms. Conclusion: Our retrospective series suggests IDDS is effective in intractable cancer pain and we believe it should be considered even in terminally ill patients with limited life expectancies.