Kaposi sarcoma in an HIV-negative Tunisian patient: A rare cause of metatarsalgia

AbstractBackgroundKaposi sarcoma (KS) is an angioproliferative neoplasm that is commonly associated with human herpes virus-8 (HHV-8) and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). KS with osseous involvement is a rare occurrence, and is far more common in acquired immunodeficiency syndrome (AIDS)-related KS.Case presentationWe present a 32-year-old Tunisian man, HIV negative, who presented with a 4-year history of atraumatic mechanical metatarsalgia that progressively worsened with a limping gait. Physical examination revealed marked symmetrical forefoot lymphedema and a painful restricted left knee joint movement. Physical examination showed purple-blue plaques and nodules on the feet and ankles. Serologic tests for HIV and syphilis were negative. Plain radiography of the feet revealed numerous small lytic lesions. There were also scattered lytic lesions in the metaphysis of the proximal tibia and fibula. Osteolysis was predominantly left. Magnetic resonance imaging of the feet showed abnormal bone marrow signal of metatarsals and phalanges. Skin lesion biopsy yielded the diagnosis of Kaposi sarcoma. The disease was managed with chemotherapy including vinblastine.ConclusionIn a patient presenting with metatarsalgia without a commonly detected cause, it is mandatory to search for other lesions that may point to a rare diagnosis as KS which is famous for involvement of the metatarsal bone

Spondylodiscite tuberculeuse : 12 ans d'expérience dans un centre hospitalier en Tunisie

Objectifs : Décrire les particularités épidémiologiques, cliniques et paracliniques des spondylodiscites tuberculeuses et déterminer les facteurs prédictifs d’une évolution défavorable. Patients et Méthode: Etude rétrospective sur une période de 12 ans. Le diagnostic a été porté sur des preuves bactériologiques, anatomopathologiques ou sur un faisceau d’arguments. Résultats : Il s’agissait de 49 patients (26F/23H), âgés en moyenne de 51,84 ans. Le délai moyen de diagnostic était de 6,65 mois. Un facteur prédisposant à l’infection a été relevé chez 38,7% des patients. L’étage lombaire était le plus touché (67,3%). L’imagerie par résonnance magnétique était pathologique dans tous les cas où elle a été effectuée. Le diagnostic de certitude a été porté dans 9 cas sur une preuve histologique. La ponction biopsie disco-vertébrale a permis de confirmer le diagnostic dans 6/36 cas. Tous les patients ont reçu un traitement anti-tuberculeux d’une durée moyenne de 13,59 mois associé à un geste interventionnel dans 8 cas. L’évolution était favorable dans 84,2% des cas. Nous avons identifiés quatre facteurs prédictifs d’une évolution défavorable: une hyperleucocytose initiale ≥11500 éléments/mm3 (p=0,031), la présence d’abcès ou de collection à l’imagerie (p=0,018); un tassement vertébral à l’IRM (p=0,018) et l’existence de déformation osseuse avant correction chirurgicale (p<0,001). Conclusion: La spondylodiscite tuberculeuse devrait être suspectée devant toute rachialgie inflammatoire. Une prise en charge précoce est la clé pour éviter les complications neurologiques et ostéo-articulaires

Retinal stem cells transplanted into models of late stages of retinitis pigmentosa preferentially adopt a glial or a retinal ganglion cell fate

PURPOSE: To characterize the potential of newborn retinal stem cells (RSCs) isolated from the radial glia population to integrate the retina, this study was conducted to investigate the fate of in vitro expanded RSCs transplanted into retinas devoid of photoreceptors (adult rd1 and old VPP mice and rhodopsin-mutated transgenic mice) or partially degenerated retina (adult VPP mice) retinas. METHODS: Populations of RSCs and progenitor cells were isolated either from DBA2J newborn mice and labeled with the red lipophilic fluorescent dye (PKH26) or from GFP (green fluorescent protein) transgenic mice. After expansion in EGF+FGF2 (epidermal growth factor+fibroblast growth factor), cells were transplanted intravitreally or subretinally into the eyes of adult wild-type, transgenic mice undergoing slow (VPP strain) or rapid (rd1 strain) retinal degeneration. RESULTS: Only limited migration and differentiation of the cells were observed in normal mice injected subretinally or in VPP and rd1 mice injected intravitreally. After subretinal injection in old VPP mice, transplanted cells massively migrated into the ganglion cell layer and, at 1 and 4 weeks after injection, harbored neuronal and glial markers expressed locally, such as beta-tubulin-III, NeuN, Brn3b, or glial fibrillary acidic protein (GFAP), with a marked preference for the glial phenotype. In adult VPP retinas, the grafted cells behaved similarly. Few grafted cells stayed in the degenerating outer nuclear layer (ONL). These cells were, in rare cases, positive for rhodopsin or recoverin, markers specific for photoreceptors and some bipolar cells. CONCLUSIONS: These results show that the grafted cells preferentially integrate into the GCL and IPL and express ganglion cell or glial markers, thus exhibiting migratory and differentiation preferences when injected subretinally. It also appears that the retina, whether partially degenerated or already degenerated, does not provide signals to induce massive differentiation of RSCs into photoreceptors. This observation suggests that a predifferentiation of RSCs into photoreceptors before transplantation may be necessary to obtain graft integration in the ONL

Anti-Inflammatory Effect of Dexamethasone Controlled Released From Anterior Suprachoroidal Polyurethane Implants on Endotoxin-Induced Uveitis in Rats.

Targeted drug delivery to the ocular tissues remains a challenge. Biodegradable intraocular implants allow prolonged controlled release of drugs directly into the eye. In this study, we evaluated an anterior suprachoroidal polyurethane implant containing dexamethasone polyurethane dispersions (DX-PUD) as a drug delivery system in the rat model of endotoxin-induced uveitis (EIU). In vitro drug release was studied using PUD implants containing 8%, 20%, and 30% (wt/wt) DX. Cytotoxicity of the degradation products of DX-PUD was assessed on human ARPE-19 cells using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) test. Short-term ocular biocompatibility of suprachoroidal DX-PUD implants was evaluated in normal rat eyes. Endotoxin-induced uveitis was then induced in rat eyes preimplanted with DX-PUD. Clinical examination was performed at 24 hours; eyes were used to assess inflammatory cell infiltration and macrophage/microglial activation. Cytokine and chemokine expression in the iris/ciliary body and in the retina was investigated using quantitative PCR. Feasibility of anterior suprachoroidal PUD implantation was also tested using postmortem human eyes. A burst release was followed by a sustained controlled release of DX from PUD implants. By-products of the DX-PUD were not toxic to human ARPE-19 cells or to rat ocular tissues. Dexamethasone-PUD implants prevented EIU in rat eyes, reducing inflammatory cell infiltration and inhibiting macrophage/microglial activation. Dexamethasone-PUD downregulated proinflammatory cytokines/chemokines (IL-1β, IL-6, cytokine-induced neutrophil chemoattractant [CINC]) and inducible nitric oxide synthase (iNOS) and upregulated IL-10 anti-inflammatory cytokine. Polyurethane dispersion was successfully implanted into postmortem human eyes. Dexamethasone-PUD implanted in the anterior suprachoroidal space may be of interest in the treatment of intraocular inflammation

ADP Ribosylation Factors 1 and 4 and Group VIA Phospholipase A2 Regulate Morphology and Intraorganellar Traffic in the Endoplasmic Reticulum–Golgi Intermediate Compartment

In search of morphological determinants for the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), we found that a concerted action of Arf1, Arf4, and PLA2G6-A controls the architecture of the ERGIC by regulating tubular carriers. This is predicted to impact the rate of transport and destination of cargos in the ERGIC

Retinal Degeneration Progression Changes Lentiviral Vector Cell Targeting in the Retina

In normal mice, the lentiviral vector (LV) is very efficient to target the RPE cells, but transduces retinal neurons well only during development. In the present study, the tropism of LV has been investigated in the degenerating retina of mice, knowing that the retina structure changes during degeneration. We postulated that the viral transduction would be increased by the alteration of the outer limiting membrane (OLM). Two different LV pseudotypes were tested using the VSVG and the Mokola envelopes, as well as two animal models of retinal degeneration: light-damaged Balb-C and Rhodopsin knockout (Rho-/-) mice. After light damage, the OLM is altered and no significant increase of the number of transduced photoreceptors can be obtained with a LV-VSVG-Rhop-GFP vector. In the Rho-/- mice, an alteration of the OLM was also observed, but the possibility of transducing photoreceptors was decreased, probably by ongoing gliosis. The use of a ubiquitous promoter allows better photoreceptor transduction, suggesting that photoreceptor-specific promoter activity changes during late stages of photoreceptor degeneration. However, the number of targeted photoreceptors remains low. In contrast, LV pseudotyped with the Mokola envelope allows a wide dispersion of the vector into the retina (corresponding to the injection bleb) with preferential targeting of Müller cells, a situation which does not occur in the wild-type retina. Mokola-pseudotyped lentiviral vectors may serve to engineer these glial cells to deliver secreted therapeutic factors to a diseased area of the retina

γCOP Is Required for Apical Protein Secretion and Epithelial Morphogenesis in Drosophila melanogaster

Background: There is increasing evidence that tissue-specific modifications of basic cellular functions play an important role in development and disease. To identify the functions of COPI coatomer-mediated membrane trafficking in Drosophila development, we were aiming to create loss-of-function mutations in the γCOP gene, which encodes a subunit of the COPI coatomer complex. Principal Findings: We found that γCOP is essential for the viability of the Drosophila embryo. In the absence of zygotic γCOP activity, embryos die late in embryogenesis and display pronounced defects in morphogenesis of the embryonic epidermis and of tracheal tubes. The coordinated cell rearrangements and cell shape changes during tracheal tube morphogenesis critically depend on apical secretion of certain proteins. Investigation of tracheal morphogenesis in γCOP loss-of-function mutants revealed that several key proteins required for tracheal morphogenesis are not properly secreted into the apical lumen. As a consequence, γCOP mutants show defects in cell rearrangements during branch elongation, in tube dilation, as well as in tube fusion. We present genetic evidence that a specific subset of the tracheal defects in γCOP mutants is due to the reduced secretion of the Zona Pellucida protein Piopio. Thus, we identified a critical target protein of COPI-dependent secretion in epithelial tube morphogenesis. Conclusions/Significance: These studies highlight the role of COPI coatomer-mediated vesicle trafficking in both general and tissue-specific secretion in a multicellular organism. Although COPI coatomer is generally required for protein secretion, we show that the phenotypic effect of γCOP mutations is surprisingly specific. Importantly, we attribute a distinct aspect of the γCOP phenotype to the effect on a specific key target protein

Assembly, organization, and function of the COPII coat

A full mechanistic understanding of how secretory cargo proteins are exported from the endoplasmic reticulum for passage through the early secretory pathway is essential for us to comprehend how cells are organized, maintain compartment identity, as well as how they selectively secrete proteins and other macromolecules to the extracellular space. This process depends on the function of a multi-subunit complex, the COPII coat. Here we describe progress towards a full mechanistic understanding of COPII coat function, including the latest findings in this area. Much of our understanding of how COPII functions and is regulated comes from studies of yeast genetics, biochemical reconstitution and single cell microscopy. New developments arising from clinical cases and model organism biology and genetics enable us to gain far greater insight in to the role of membrane traffic in the context of a whole organism as well as during embryogenesis and development. A significant outcome of such a full understanding is to reveal how the machinery and processes of membrane trafficking through the early secretory pathway fail in disease states

Quasi-static cyclic loadings induced inelastic deformation in a Zr-based bulk metallic glass under nanoindentation

Cyclic nanoindentation tests were carried outon Zr50Cu40Al10 bulk metallic glass (BMG). From thedesigned quasi-static and incremental cyclic experiments atloading rates ranging from 250 to 2500 lN/s and atambient temperature, we observed significant difference ininelastic deformation as a function of solicitation modes.Under incremental cyclic loadings, the hardness of theBMG increased each time when the sample was reloadedimmediately after unloading and then gradually reducedbefore the next unloading. In contrast, we found that quasistaticcyclic loadings induced a mechanical softeningwhich appears to be dependent on the number of cycles andthe loading rates. The inelastic deformation was studied byanalysing the remnant indent morphology using atomicforce microscopy. A free-volume mechanism was proposedfor interpreting these observations quantitatively