Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy.

Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired.

Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder of the nervous system characterized by axonopathy in spinal cords and/or cerebral demyelination, adrenal insufficiency and accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues. The disease is caused by malfunction of the ABCD1 gene, which encodes a peroxisomal transporter of VLCFAs or VLCFA-CoA. In the mouse, Abcd1 loss causes late onset axonal degeneration in the spinal cord, associated with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. We have formerly shown that an excess of the VLCFA C26:0 induces oxidative damage, which underlies the axonal degeneration exhibited by the Abcd1(-) mice. In the present study, we sought to investigate the noxious effects of C26:0 on mitochondria function. Our data indicate that in X-ALD patients' fibroblasts, excess of C26:0 generates mtDNA oxidation and specifically impairs oxidative phosphorylation (OXPHOS) triggering mitochondrial ROS production from electron transport chain complexes. This correlates with impaired complex V phosphorylative activity, as visualized by high-resolution respirometry on spinal cord slices of Abcd1(-) mice. Further, we identified a marked oxidation of key OXPHOS system subunits in Abcd1(-) mouse spinal cords at presymptomatic stages. Altogether, our results illustrate some of the mechanistic intricacies by which the excess of a fatty acid targeted to peroxisomes activates a deleterious process of oxidative damage to mitochondria, leading to a multifaceted dysfunction of this organelle. These findings may be of relevance for patient management while unveiling novel therapeutic targets for X-ALD.

[Morel-Lavallee syndrome of the lower leg]. / Syndrome de Morel-Lavallée du membre inférieur.

BACKGROUND: Morel-Lavallée syndrome, which appears after tangential trauma of highly vascularised tissues, is characterized by closed internal degloving injuries resulting in subcutaneous fluid collection. It can cause many complications. A 42-year-old man presented with open wounds after a violent right lower extremity trauma; the wounds were sutured. One month after the trauma, the patient complained of painful edema of the lower limb and fluid discharge from the previously sutured wounds. Local examination showed fluctuating fluid collection. Serum inflammatory markers were within the normal range. Ultrasound investigation of the right lower limb confirmed an extended fluid collection from the lower third of the thigh to the upper third of the leg, and CT scan delineated a surrounding capsule. The clinical and radiological data supported a diagnosis of post-traumatic Morel-Lavallée syndrome. Local surgical debridement and drainage associated with systemic antibiotic therapy (the fluid was found to be infected with oxacillin-resistant Staphylococcus epidermidis) resulted in rapid improvement. DISCUSSION: Morel-Lavallée syndrome commonly appear after tangential trauma of highly vascularised tissues. The skin and the subcutaneous fat tissue are abruptly torn from the underlying muscle fascia, shearing the lymphatic vessels, rendering lymphostasis impossible. The local inflammatory reaction can cause the formation of a fibrous capsule resulting in a fluid collection. The clinical signs are not specific. When examining a soft-tissue collection or slow-healing wounds, the dermatologist should always rule out previous soft-tissue trauma; simple imaging studies will confirm the diagnosis if Morel-Lavallée injuries are suspected. CONCLUSION: All dermatologists consulted by young patients without vascular disease for an unusual swelling and/or for slow-healing wounds should be mindful of this syndrome.

[Mucocutaneous leishmaniasis due to Leishmania guyanensis: a case report in an HIV-infected patient]. / Leishmaniose cutanéo-muqueuse à Leishmania guyanensis: une observation chez un patient infecté par le VIH.

In French Guiana cutaneous leishmaniasis occurs mainly in the localized form with L. guyanensis accounting for more than 90% of cases. Mucocutaneous leishmaniasis is uncommon (less than 2% of cases) with L. braziliensis accounting for all previously reported cases. The purpose of this report is to describe a case of mucocutaneous leishmaniasis due to L. guyanensis that led to diagnosis of HIV infection in a patient living in French Guiana.

MR imaging, proton MR spectroscopy, ultrasonographic, histologic findings in patients with chronic lymphedema.

Lymphedema is a progressive disease with multiple alterations occurring in the dermis. We undertook this study using high-frequency ultrasonography (US), magnetic resonance imaging, proton MR spectroscopy and histology to examine structural changes occurring in the subcutaneous tissue and precisely describe the nature of intralobular changes in chronic lymphedema. Four cutaneous and subcutaneous tissue biopsies from patients with chronic lymphedema during lymphonodal transplantation were studied. We performed US with a 13.5 MHz transducer, TSE T1 and TSE T2 magnetic resonance images with and without fat-suppression, MR Chemical Shift Imaging Spectroscopy and histological evaluation on these biopsies. We found that normal subcutaneous septa are seen as hyperechogenic lines in US and hyposignal lines in MRI and that hyperechogenic subcutis in US can be due to interlobular and intralobular water accumulation and/or to interlobular and intralobular fibrosis. Our study also confirms the usefulness of MR spectroscopy to assess water or fat content of soft tissue. Thus, multiple imaging modalities may be necessary to precisely delineate the nature of tissue alterations in chronic lymphedema.

[Chikungunya: a case of painful rash and fever in a patient returning from the Indian Ocean]. / Chikungunya: un syndrome algo-éruptif fébrile au retour de l'Océan Indien.

A 40-year-old woman presented with invalidating polyarthritis associated with high fever and diffuse macular exanthema after returning from a two-week visit to Reunion Island. In this paper, we discuss the different diagnoses to be considered in a case of fever with pain and rash and we examine the epidemiology, clinical features, diagnostic methods and management of Chikungunya virus.

Characterization of a mammalian smooth muscle cell line that has retained transcriptional and posttranscriptional potencies.

Unlike skeletal and cardiac muscle cells that differentiate irreversibly, smooth muscle cells (SMCs) retain a high degree of plasticity. During the so-called phenotypic modulation, SMCs can undergo transition between a contractile phenotype and a highly proliferative synthetic phenotype, as apparent from the extinction of numerous smooth muscle (SM) markers when they are passaged in culture. It would be very useful to have an SMC line that can be indefinitely propagated for the cellular and molecular analysis of the mechanisms that underlie the control of SM differentiation. This report describes an immortalized rabbit aorta SMC-derived cell line (U8A4) that has conserved differentiated properties through multiple subcultures. U8A4 cells can grow in the absence of serum and express the SMC markers studied, including SM alpha-actin, SM calponin, SM22alpha, SM alpha-tropomyosin (alpha-TM), SM myosin heavy chain (SM-MHC), and myocardin. U8A4 cells can activate SMC-restricted promoters like those of SM22alpha, SM calponin, and SM-MHC genes as efficiently as described previously for rat SMC lines (PAC1, A7r5, and A10). These cells can also process exogenous alpha-TM transcripts according to an SM-specific pattern. These results demonstrate that the U8A4 cell line constitutes a good alternative model to existing SMC lines that could facilitate the study of the transcriptional and posttranscriptional regulatory mechanisms underlying SMC differentiation.

Fibrate induction of the adrenoleukodystrophy-related gene (ABCD2): promoter analysis and role of the peroxisome proliferator-activated receptor PPARalpha.

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease due to a defect in the ABCD1 (ALD) gene. ABCD1, and the two close homologues ABCD2 (ALDR) and ABCD3 (PMP70), are genes encoding ATP-binding cassette half-transporters of the peroxisomal membrane. As overexpression of the ABCD2 or ABCD3 gene can reverse the biochemical phenotype of X-ALD (reduced beta-oxidation of very-long-chain fatty acids), pharmacological induction of these partially redundant genes may represent a therapeutic approach to X-ALD. We previously reported that the ABCD2 and ABCD3 genes could be strongly induced by fibrates, which are hypolipidaemic drugs and peroxisome-proliferators in rodents. We provide evidence that the induction is dependent on peroxisome proliferator-activated receptor (PPARalpha) as both genes were not induced in fenofibrate-treated PPARalpha -/- knock-out mice. To further characterize the PPARalpha pathway, we cloned and analysed the promoter of the ABCD2 gene, the closest homologue of the ABCD1 gene. The proximal region (2 kb) of the rat promoter displayed a high conservation with the human and mouse cognate sequences suggesting an important role of the region in regulation of the ABCD2 gene. Classically, fibrate-induction involves interaction of PPARalpha with a response element (PPRE) characterized by a direct repeat of the AGGTCA-like motif. Putative PPRE motifs of the rat ABCD2 promoter were studied in the isolated form or in their promoter context by gel-shift assay and transfection of COS-7 cells. We failed to characterize a functional PPRE, suggesting a different mechanism for the PPARalpha-dependent regulation of the ABCD2 gene.

In vitro release of gentamicin from beads, an original galenic form, and in vivo efficacy in abdomino-perineal surgery.

The kinetics of the in vitro release of gentamicin by beads, an original galenic form (Gentabilles, Laboratoires Unicet-Unilabo France) was studied for 85 d during which time considerable quantities of antibiotic were released. A very large quantity was released on the 1st d (415 micrograms every 24 h per bead) and overall-there was a considerable time-effect, since on the 85th d, an average of 10 micrograms per 24 h per bead was still being released. The assessment of criteria of bacteriological effectiveness in the use in the in vivo treatment of abdomino-perineal excisions has shown that the MIC of gentamicin determined in relation to isolated organism is much lower than the tissue concentrations. The very low serum concentrations eliminate the possibility of an eventual cochleovestibulary toxicity or renal toxicity. The clinical results, the absence of infectious complications, the shortening of healing time and of duration of hospitalization are in favour of the extended use of this antibiotic prophylaxis in colo-rectal surgery.

Rubidium-87/strontium-87 age of juvinas basaltic achondrite and early igneous activity in the solar system.

A (4.60+/-0.07)x10(9) year internal isochron has been drawn for the achondrite Juvinas by the rubidium-87/strontium-87 method. Earlier petrographic investigation of achondrites supplemented by a new ion microprobe study of Juvinas strongly suggest an igneous origin for this class of meteorites. The results thus indicate that igneous activity may have rapidly followed the formation of the achondrites' parent body 4.6x10(9) years ago.