[Management of orbital inflammatory disorders in internal medicine: New findings resulting from a retrospective study of 31 consecutive patients]. / Prise en charge des orbitopathies inflammatoires en médecine interne : nouvelles données issues de l'étude d'une série de 31 patients consécutifs.

PURPOSE: To describe a case series of patients investigated in internal medicine for orbital inflammation (OI) since the individualization of the clinical entity of the IgG4-related orbital disease (IgG4 ROD). PATIENTS AND METHODS: Thirty four patients were consecutively referred by a specialized center where orbital biopsy was performed when the lesion was surgically accessible. Fourteen patients were excluded in case of missing data or lymphoma, periocular xanthogranuloma or Graves' orbitopathy. Patients with systemic or auto-immune disease according to the international criteria, or presenting with idiopathic orbital inflammation syndrome (IOIS), were included. Knowing the histological similarities between IOIS and IgG4 ROD, immunohistochemical assessment of plasma cells for IgG4 positivity was performed for every patient with available biopsy. Clinical and biological characteristics, treatment and response to treatment of included patients are reported. RESULTS: Among 22 included patients, 10 presented with orbital manifestation of a systemic or autoimmune disease including 2 sarcoidosis (9%) and 8 (36%) cases of non specific OI which were reclassified in IgG4 ROD. Finally, IOIS of various clinicopathological presentation was diagnosed for 12 patients including 10 with histological documentation. Whereas relapse and resistance were not found to be related to IgG4 positivity (50% in both IOIS and IgG4 ROD groups), another treatment in addition to corticosteroids was more often necessary in IgG4 ROD patients (50%) than in IOIS patients (25%). CONCLUSION: After ruling out auto-immune orbital diseases, especially IgG4 ROD, IOIS should be discussed. Factors conditioning the corticosteroid response are yet to be determined.

[Sarcoidosis]. / Sarcoïdose.

Sarcoidosis is a systemic granulomatosis characterized by the formation of epithelioid and giant cell granulomas without caseous necrosis. To make the diagnosis, it is necessary to prove systemic granulomatosis involving at least two organs; but in practice, a combination of clinical, paraclinical and histologic findings is used. It affects predominantly women with a bimodal age distribution: 25-29years and 65-69years. The most commonly affected organs are the mediastinal lymphatic system, lungs, skin and eyes. Ophthalmological involvement is present in 20 to 50% of cases. The typical ocular presentation is that of granulomatous uveitis associated with venous retinal vasculitis and lesions of peripheral multifocal choroiditis. This ophthalmological presentation, although very evocative, is not always associated with systemic disease. The diagnosis of ocular sarcoidosis is then presumed in the absence of histological evidence. Algorithms combining ophthalmological and systemic signs have been proposed in cases of isolated uveitis. They make it possible to establish the diagnosis of ocular sarcoidosis with various levels of probability. The absence of significant granulomas on a systemic level during primary ocular involvement remains the main hypothesis to explain these diagnostic difficulties. Treatment is well described, as the uveitis of sarcoidosis is most often steroid responsive. In the case of corticosteroid-dependent uveitis, the first-line immunosuppressant remains methotrexate. The use of anti-tumor necrosis factor-alpha is an interesting alternative in patients whose ocular sarcoidosis is refractory to conventional immunosuppressants.

[Reliability and validity of a workbook for assessment of professional competencies of internal medicine residents]. / Évaluation multicentrique de la reproductibilité et de la validité d'un carnet d'évaluation des compétences professionnelles des internes de médecine interne.

INTRODUCTION: Though several assessment tools for resident professional skills based on workplace direct observation have been validated, they remain scarcely used in France. The objective of this study was to evaluate the reliability and the validity of a workbook including several assessment forms for different components of the professional competency. METHODS: Three assessment forms have been tested over a period of 6 months in a multicentric study including 12 French internal medicine departments: the French version of the mini-CEX, an interpersonal skills assessment form (OD_CR) and the multisource feedback form (E_360). Reliability has been assess using the intra-class correlation coefficient (ICC) and the Cronbach alpha coefficient. Arguments for validity have been provided looking at the ability of the forms to detect an increase in the scores over time and according to the level of experience of the resident. RESULTS: Twenty-five residents have been included. The Cronbach alpha was of 0.90 (n=70) with the mini-CEX, 0.89 with the OD_CR (n=62) and 0.77 with the E_360 (n=86). ICC showed a wide variation according to the items of the mini-CEX and the OD-CR probably due to the poor number of observations performed by residents. The scores of most of the items of these two forms increased between M1 and M6. The scores of the E_360 were high: 7.3±0.8 to 8.3±2.4 (maximum 9) and did not vary according to the level of experience. CONCLUSION: This study suggest that it would be difficult to ensure a sufficient reliability for professional skills assessment using these tools given our available current human and material resources. However, these assessment forms could be added to the resident portfolio as supports for the debriefing in order to document their progression during their formation.

[Rhabdomyolysis in patients treated by corticosteroids for acute asthma in intensive care unit]. / La corticothérapie, une cause de rhabdomyolyse chez les asthmatiques en réanimation.

INTRODUCTION: Acute muscle involvement is an infrequent complication of corticosteroids, characterized by muscle weakness and a rhabdomyolysis, rapidly regressive after withdrawal of corticosteroids. CASE REPORT: We report the case of a woman admitted in intensive care unit for acute severe asthma, treated with high doses of methylprednisolone. Serum CPK level raised with a peak at 28,160 UI/L (n<250 UI/L) at day 15, suggesting acute rhabdomyolysis with renal failure. CPK rapidly normalized when corticosteroids were discontinued. Other causes of rhabdomyolysis were ruled out. CONCLUSION: This necrosing myopathy under high doses of corticosteroids has been described in patients with severe acute asthma. The mechanism of the muscle damage results from a combination of corticosteroids toxicity, respiratory acidosis and mechanic ventilation.

Sarcoidosis.

Sarcoidosis is a systemic granulomatosis characterized by the formation of epithelioid and giant cell granulomas without caseous necrosis. To make the diagnosis, it is necessary to prove systemic granulomatosis involving at least two organs; but in practice, a combination of clinical, paraclinical and histologic findings is used. It affects predominantly women with a bimodal age distribution: 25-29 years and 65-69 years. The most commonly affected organs are the mediastinal lymphatic system, lungs, skin and eyes. Ophthalmological involvement is present in 20 to 50% of cases. The typical ocular presentation is that of granulomatous uveitis associated with venous retinal vasculitis and lesions of peripheral multifocal choroiditis. This ophthalmological presentation, although very evocative, is not always associated with systemic disease. The diagnosis of ocular sarcoidosis is then presumed in the absence of histological evidence. Algorithms combining ophthalmological and systemic signs have been proposed in cases of isolated uveitis. They make it possible to establish the diagnosis of ocular sarcoidosis with various levels of probability. The absence of significant granulomas on a systemic level during primary ocular involvement remains the main hypothesis to explain these diagnostic difficulties. Treatment is well described, as the uveitis of sarcoidosis is most often steroid responsive. In the case of corticosteroid-dependent uveitis, the first-line immunosuppressant remains methotrexate. The use of anti-tumor necrosis factor alpha is an interesting alternative in patients whose ocular sarcoidosis is refractory to conventional immunosuppressants.

[Ocular tuberculosis]. / Tuberculose oculaire.

Despite extensive investigations, including the use of Interferon-gamma release assays (IGRA), the diagnosis of intraocular tuberculosis (TB) remains challenging. Ocular evidence of Mycobacterium tuberculosis in low endemic countries for TB is extremely rare, leading mostly to a TB-related ocular inflammation presumptive diagnosis. This present work aims: to highlights the main clinical patterns suggestive of ocular TB; and the latest recommended guidelines for diagnosing ocular TB to clarify interferon-gamma release assay (IGRA) contribution and accuracy to the management of intraocular TB and its diagnosis, in addition to other available diagnostic tools, such as tuberculin skin test, bacteriologic and histologic analysis from intra/extra ocular sample and radiographic investigations; to define the accuracy of these diagnostic tools according to the endemic TB prevalence; and finally to identify therapeutic strategies adapted to the main clinical presentations of ocular TB. Our review of the literature shows that management of suspected ocular TB differs significantly based on whether patients are from high or low TB prevalence countries since accuracy of chest X-ray, tuberculin skin test and IGRA is significantly different. Taking into account these discrepancies, distinct guidelines should be determined for managing patients with suspected ocular TB, taking into consideration home prevalence of TB-patients.

[Therapeutic strategy for the treatment of non-infectious uveitis proposed by an expert panel]. / Avis d'experts pour le traitement des uvéites non infectieuses.

Conventional immunosuppressive drugs, anti-TNF alpha and other biotherapies used in clinical practice are capable of controlling non-infectious anterior uveitis, posterior uveitis and panuveitis. The present work has been led by a multidisciplinary panel of experts, internists, rheumatologists and ophthalmologists and is based on a review of the literature. In case of corticodependency or sight-threatening disease, conventional immunosuppressive drugs (methotrexate, azathioprine and mycophenolate mofetil) and/or anti-TNF alpha (adalimumab, infliximab) are used to achieve and maintain remission. Interferon is an efficient immunomodulatory treatment, as a second-line therapy, for some therapeutic indications (refractory macular edema, Behçet's vascularitis). Other biologics, especially tocilizumab, are showing promising results. Local treatments (corticosteroids, sirolimus etc.) are adjuvant therapies in case of unilateral inflammatory relapse. Therapeutic response must be evaluated precisely by clinical examination and repeated complementary investigations (laser flare photometry, multimodal imaging, perimetry, electroretinography measures).

[Scleritis and systemic diseases: What should know the internist?] / Sclérites et maladies systémiques : que doit savoir l'interniste ?

Scleritis is an inflammatory disease of the sclera; outer tunic of the eye on which the oculomotor muscles are inserted. It can be associated with a systemic disease up to one time out of 3. These associated diseases are mainly rheumatoid arthritis, vasculitis, including granulomatosis with polyangiitis in the first line and spondyloarthropathies. Before mentioning such an etiology, it is necessary to eliminate an infectious cause, mainly herpetic, which is regularly underestimated. The classification of scleritis is clinical. We distinguish between anterior scleritis and posterior scleritis. Anterior scleritis is diffuse or nodular, usually of good prognosis. Anterior necrotizing scleritis with inflammation is often associated with an autoimmune disease, necrotizing scleritis without inflammation usually reflects advanced rheumatoid arthritis. The treatment of these conditions requires close collaboration between internists and ophthalmologists to decide on the use of corticosteroid therapy with or without immunosuppressors or biotherapies.

[Management of orbital inflammation in internal medicine. Proposal for a diagnostic work-up]. / Orbitopathies inflammatoires. Que doit savoir l'interniste ?

Inflammatory orbitopathies relate to an inflammatory state originating within the orbit and its adnexes, except the inner ocular globe. Orbital inflammation (OI) may be either localized manifestation of a proven or like autoimmune disease, or local response from immune system against infectious, structural or tumoral antigens. We review the clinical manifestations of OI, which provide helpful clues to the diagnosis and describe the inflammatory, infectious and neoplastic conditions classically associated with OI. Autoimmune diseases are probably the most common causes of OI associated with a bilateral dacryoadenitis (e.g., sarcoidosis, granulomatosis with polyangiitis, IgG4-related disease). We focused on a major part of the IgG4-RD spectrum, the IgG4-related orbital disease which has been recently described and the idiopathic orbital inflammation syndrome that one should consider in patients 40 years of age or older with non specific inflammation OI on biopsy but without underlying local or systemic disease. An algorithm for the diagnostic approach of OI was proposed. If systemic explorations fail to diagnose an underlying disease, histopathologic control is required for distinguishing non-specific OI from other differential diagnosis, especially lymphoma. In the cases of pure myositic locations and posteriorly located tumours where biopsy could damage to the optic nerve, analysis of orbital lesions in T2W IRM sequence may be helpful to distinguish idiopathic OI (IOI) from lymphoma. When the diagnostic work-up fails, a corticosteroid trial could be used, but its beneficial effect has to be cautiously interpretated before definitively diagnosing IOI. Finally, treatments used in main infllammatory orbitopathies were also reviewed.

Una revisión de los avances en la terapéutica de la enfermedad de Alzheimer: estrategia frente a la proteína Beta-amiloide / Review of the advances in treatment for Alzheimer disease: Strategies for combating Beta-amyloid protein

Introducción: La enfermedad de Alzheimer (EA) es el principal trastorno neurodegenerativo que provoca una discapacidad intelectual total en los pacientes que la presentan. La elevada prevalencia a nivel mundial, así como la elevada carga socioeconómica que conlleva la EA para la sociedad en general, hace que sea considerada un importante problema de salud pública en este siglo xxi. En este trabajo se revisan los tratamientos actuales y en fase de desarrollo que actúan principalmente sobre la proteína Beta-amiloide. Discusión: La hipótesis amiloidogénica propone que el péptido β-amiloide tiene un papel clave en esta enfermedad. Se han desarrollado varias estrategias farmacológicas diferentes con el objetivo de inhibir la formación de los péptidos β-amiloides, como son los inhibidores de Beta-secretasa y γ-secretasa. Además, se han desarrollado los tratamientos antiamiloide, que incluyen inmunoterapias pasivas y activas enfocadas a inhibir la agregación del péptido Beta-amiloide. Conclusiones: Los avances en la identificación de las bases moleculares de la EA pueden servir como modelo para comprender las causas de esta enfermedad neurodegenerativa. Sin embargo, los ensayos clínicos más recientes en 2 ensayos de fase iii con solanezumab, un anticuerpo monoclonal humanizado que promueve el aclaramiento del Beta-amiloide en el cerebro, indican que este anticuerpo no muestra eficacia en pacientes con EA leve, sugiriendo que hay que replantearse esta hipótesis amiloidogénica de la EA (AU)

Introduction: Alzheimer disease (AD) is a major neurodegenerative disorder which eventually results in total intellectual disability. The high global prevalence and the socioeconomic burden associated with the disease pose major challenges for public health in the 21st century. In this review we focus on both existing treatments and the therapies being developed, which principally target the Beta-amyloid protein. Discussion: The amyloidogenic hypothesis proposes that Beta-amyloid plays a key role in AD. Several pharmacological approaches aim to reduce the formation of Beta-amyloid peptides by inhibiting the Beta-secretase and γ-secretase enzymes. In addition, both passive and active immunotherapies have been developed for the purpose of inhibiting β-amyloid peptide aggregation. Conclusions: Progress in identifying the molecular basis of AD may provide better models for understanding the causes of this neurodegenerative disease. The lack of efficacy of solanezumab (a humanised monoclonal antibody that promotes Beta-amyloid clearance in the brain), demonstrated by 2 recent Phase III clinical trials in patients with mild AD, suggests that the amyloidogenic hypothesis needs to be revised (AU)

Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors.

Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines' effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high-anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions.

Review of the advances in treatment for Alzheimer disease: Strategies for combating ß-amyloid protein. / Una revisión de los avances en la terapéutica de la enfermedad de Alzheimer: estrategia frente a la proteína ß-amiloide.

INTRODUCTION: Alzheimer disease (AD) is a major neurodegenerative disorder which eventually results in total intellectual disability. The high global prevalence and the socioeconomic burden associated with the disease pose major challenges for public health in the 21st century. In this review we focus on both existing treatments and the therapies being developed, which principally target the ß-amyloid protein. DISCUSSION: The amyloidogenic hypothesis proposes that ß-amyloid plays a key role in AD. Several pharmacological approaches aim to reduce the formation of ß-amyloid peptides by inhibiting the ß-secretase and γ-secretase enzymes. In addition, both passive and active immunotherapies have been developed for the purpose of inhibiting ß-amyloid peptide aggregation. CONCLUSIONS: Progress in identifying the molecular basis of AD may provide better models for understanding the causes of this neurodegenerative disease. The lack of efficacy of solanezumab (a humanised monoclonal antibody that promotes ß-amyloid clearance in the brain), demonstrated by 2 recent Phase III clinical trials in patients with mild AD, suggests that the amyloidogenic hypothesis needs to be revised.

Voltage-dependent anion channel 2 is involved in in vitro capacitation of boar sperm.

Ion channels play an important role during sperm capacitation allowing the transport through plasma and mitochondrial membranes of specific molecules that are essential for the achievement of this physiologic status. Given that voltage-dependent anion channel 2 (VDAC2) is present in boar spermatozoa and is known to be involved in calcium transport in somatic cells, this study aimed at determining whether it is implicated in sperm capacitation and the acrosome reaction. With this purpose, boar spermatozoa were capacitated in vitro for 4 hr, and acrosome reaction was induced with progesterone for a further hour, with or without the presence of two VDAC2-inhibitors (erastin and olesoxime) at two different concentrations (10 and 100 µM). At different time points (0, 120, 240, 270 and 300 min), an aliquot was taken and sperm motility, membrane integrity and lipid disorder were evaluated using computer-assisted sperm analysis and flow cytometry. The addition of the two inhibitors resulted in opposite effects. While erastin 100 µM reduced the percentage of non-capacitated spermatozoa, the presence of olesoxime at the same concentration prevented the increase in membrane lipid disorder, which is a feature of sperm capacitation. Such prevention was concomitant with a maintaining effect on sperm membrane integrity evaluated through SYBR14/PI. Our results suggest that VDAC2 is involved in the regulation of sperm capacitation, despite the fact that the mechanisms through which erastin and olesoxime act are different.

[Management of uveomeningitis in internal medicine: Proposal for a diagnostic work-up]. / Prise en charge diagnostique des uvéoméningites en médecine interne.

Uveomeningitis relates to an inflammatory state extending from iris and ciliary bodies to the choroid behind the eye. Because of a close contact between eye and brain, and barrier disruption, the inflammation can spread into the central nervous system (CNS). We review the clinical manifestations of uveitis, which are known to provide helpful clues to the diagnosis and describe the infectious, inflammatory, and neoplastic conditions classically associated with the uveomeningitis. Inflammatory or auto-immune diseases are probably the most common clinically recognized causes of uveomeningitis associated with a significant pleiocytosis. These entities often cause inflammation of various tissues in the body, including ocular structures and the meninges (i.e., sarcoidosis, Behçet's disease, and Vogt-Koyanagi-Harada syndrome). The association of an infectious uveitis with an acute or a chronic meningo-encephalitis is unusual but occasionally the eye examination may suggest an infectious etiology or even a specific organism responsible for an uveomeningitis. One should consider the diagnosis of primary ocular-CNS lymphoma in patients of 40 years of age or older with bilateral uveitis, especially with prominent vitritis, showing poor response to corticosteroid therapy. Finally, an algorithm for the diagnostic approach of uveomeningitis is proposed.

Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits.

(±)3,4-Methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. This study was designed to evaluate whether MDMA exposure affects their recognition memory and hippocampal expression of plasticity markers. Mice were administered with increasing doses of MDMA once per week for 8 weeks (three times in 1 day, every 3 h) and killed 2 weeks (2w) or 3 months (3m) later. The treatment did not modify hippocampal tryptophan hydroxylase 2, a serotonergic indicator, but induced an initial reduction in dopaminergic markers in substantia nigra, which remained stable for at least 3 months. In parallel, MDMA produced a decrease in dopamine (DA) levels in the striatum at 2w, which were restored 3 months later, suggesting dopaminergic terminal regeneration (sprouting phenomenon). Moreover, recognition memory was assessed using the object recognition test. Young (2w) and mature (3m) adult mice exhibited impaired memory after 24-h but not after just 1-h retention interval. Two weeks after the treatment, animals showed constant levels of CREB but an increase in its phosphorylated form and in c-Fos expression. Brain-derived neurotrophic factor (BDNF) and especially Arc overexpression was sustained and long-lasting. We cannot rule out the absence of MDMA injury in the hippocampus being due to the generation of BDNF. The levels of NMDAR2B, PSD-95, and synaptophysin were unaffected. In conclusion, the young mice exposed to MDMA showed increased expression of early key markers of plasticity, which sometimes remained for 3 months, and suggests hippocampal maladaptive plasticity that could explain memory deficits evidenced here.

Adipokine pathways are altered in hippocampus of an experimental mouse model of Alzheimer's disease.

A growing body of evidence suggests that ß-amyloid peptides (Aß) are unlikely to be the only factor involved in Alzheimer's disease (AD) aetiology. In fact, a strong correlation has been established between AD patients and patients with type 2 diabetes and/or cholesterol metabolism alterations. In addition, a link between adipose tissue metabolism, leptin signalling in particular, and AD has also been demonstrated. In the present study we analyzed the expression of molecules related to metabolism, with the main focus on leptin and prolactin signalling pathways in an APPswe/PS1dE9 (APP/PS1) transgenic mice model, at 3 and 6 months of age, compared to wild-type controls. We have chosen to study 3 months-old APP/PS1 animals at an age when neither the cognitive deficits nor significant Aß plaques in the brain are present, and to compare them to the 6 months-old mice, which exhibit elevated levels of Aß in the hippocampus and memory loss. A significant reduction in both mRNA and protein levels of the prolactin receptor (PRL-R) was detected in the hippocampi of 3 months old APP/PS1 mice, with a decrease in the levels of the leptin receptor (OB-R) first becoming evident at 6 months of age. We proceeded to study the expression of the intracellular signalling molecules downstream of these receptors, including stat (1-5), sos1, kras and socs (1-3). Our data suggest a downregulation in some of these molecules such as stat-5b and socs (1-3), in 3 months-old APP/PS1 brains. Likewise, at the same age, we detected a significant reduction in mRNA levels of lrp1 and cyp46a1, both of which are involved in cholesterol homeostasis. Taken together, these results demonstrate a significative impairment in adipokine receptors signalling and cholesterol regulation pathways in the hippocampus of APP/PS1 mice at an early age, prior to the Aß plaque formation.

[Orbital inflammation]. / Inflammation orbitaire.

Orbital inflammation is a generic term encompassing inflammatory pathologies affecting all structures within the orbit : anterior (involvement up to the posterior aspect of the globe), diffuse (involvement of intra- and/or extraconal fat), apical (involvement of the posterior orbit), myositis (involvement of only the extraocular muscles), dacryoadenitis (involvement of the lacrimal gland). We distinguish between specific inflammation and non-specific inflammation, commonly referred to as idiopathic inflammation. Specific orbital inflammation corresponds to a secondary localization of a "generalized" disease (systemic or auto-immune). Idiopathic orbital inflammation corresponds to uniquely orbital inflammation without generalized disease, and thus an unknown etiology. At the top of the differential diagnosis for specific or idiopathic orbital inflammation are malignant tumors, represented most commonly in the adult by lympho-proliferative syndromes and metastases. Treatment of specific orbital inflammation begins with treatment of the underlying disease. For idiopathic orbital inflammation, treatment (most often corticosteroids) is indicated above all in cases of visual loss due to optic neuropathy, in the presence of pain or oculomotor palsy.