Progressive disseminated histoplasmosis in the HIV population in Europe in the HAART era. Case report and literature review.

INTRODUCTION: In highly endemic areas, up to 20 % of human immunodeficiency virus (HIV)-infected persons will develop progressive disseminated histoplasmosis (PDH). Europe is not endemic to histoplasmosis, and the disease is mainly found in immigrants often co-infected with HIV. METHODS: We present a case of a patient with HIV and PDH highlighting the possible diagnostic difficulties that may arise in a non-endemic area and review the literature of histoplasmosis in the context of HIV infection with special focus on Europe. DISCUSSION: When cellular immunity wanes (usually at CD4 T-lymphocyte counts <150 cells/µL) histoplasma infection, acquired earlier, can reactivate and disseminate. PDH is an acquired immune deficiency syndrome(AIDS)-defining disease and a life-threatening infection, with a clinical spectrum ranging from an acute, fatal course with lung infiltrates and respiratory failure, shock, coagulopathy and multi-organ failure, to a more subacute disease with focal organ involvement, pancytopenia and hepatosplenomegaly. Mortality rates remain high for untreated patients, but early diagnosis, proper antifungal treatment and early initiation of antiretroviral therapy have improved the prognosis. CONCLUSION: European infectious diseases physicians, microbiologists and pathologists must be aware of histoplasmosis, particularly when facing HIV-infected immigrants from endemic areas. This is increasingly important due to migration and travel activities from these areas.

Minibeam radiation therapy at a conventional irradiator: Dose-calculation engine and first tumor-bearing animals irradiation.

PURPOSE: Minibeam radiation therapy (MBRT) is a novel therapeutic strategy, whose exploration was hindered due to its restriction to large synchrotrons. Our recent implementation of MBRT in a wide-spread small animal irradiator offers the possibility of performing systematic radiobiological studies. The aim of this research was to develop a set of dosimetric tools to reliably guide biological experiments in the irradiator. METHODS: A Monte Carlo (Geant4)-based dose calculation engine was developed. It was then benchmarked against a series of dosimetric measurements performed with gafchromic films. Two voxelized rat phantoms (ROBY, computer tomography) were used to evaluate the treatment plan of F98 tumor-bearing rats. The response of a group of 7 animals receiving a unilateral irradiation of 58 Gy was compared to a group of non-irradiated controls. RESULTS: The good agreement between calculations and the experimental data allowed the validation of the dose-calculation engine. The latter was first used to compare the dose distributions in computer tomography images of a rat's head and in a digital model of a rat's head (ROBY), obtaining a good general agreement. Finally, with respect to the in vivo experiment, the increase of mean survival time of the treated group with respect to the controls was modest but statistically significant. CONCLUSIONS: The developed dosimetric tools were used to reliably guide the first MBRT treatments of intracranial glioma-bearing rats outside synchrotrons. The significant tumor response obtained with respect to the non-irradiated controls, despite the heterogenous dose coverage of the target, might indicate the participation of non-targeted effects.

From phaeohyphomycosis to disseminated chromoblastomycosis: A retrospective study of infections caused by dematiaceous fungi.

OBJECTIVE: Infections caused by dematiaceous fungi are more common in tropical and subtropical areas. We aimed to describe the clinical, microbiological and therapeutic aspects of case patients diagnosed at a University Hospital located on an Indian Ocean island. PATIENTS AND METHODS: We performed an observational retrospective study of infections caused by dematiaceous fungi diagnosed at the University Hospital of Saint-Pierre, Reunion, from 2000 to 2015. Mycological identifications were performed at the National Reference Center for Invasive Mycosis and Antifungal Agents (Paris). RESULTS: The review of clinical and microbiological data of 11 patients identified revealed that five were infected by dematiaceous fungi. Two had cutaneous phaeohyphomycosis, two had cerebral phaeohyphomycosis and one had cutaneous chromoblastomycosis with brain and potentially medullary dissemination. Skin lesions and cerebral abscesses were quite varied. CONCLUSION: Infections caused by dematiaceous fungi are rare. Medullary and brain localizations are extremely rare, especially for chromoblastomycosis. Cutaneous manifestations of phaeohyphomycosis are varied; diagnosis is thus more difficult. It is therefore important, when confronted with a chronic tumor-like lesion in endemic areas, to perform a biopsy for pathology and fungal culture. While surgical excision is not always sufficient, medical treatment of these infections is not standardized, but relies on an azole, which can be associated with another antifungal agent.

Colonization with Helicobacter is concomitant with modified gut microbiota and drastic failure of the immune control of Mycobacterium tuberculosis.

Epidemiological and experimental observations suggest that chronic microbial colonization can impact the immune control of other unrelated pathogens contracted in a concomitant or sequential manner. Possible interactions between Mycobacterium tuberculosis infection and persistence of other bacteria have scarcely been investigated. Here we demonstrated that natural colonization of the digestive tract with Helicobacter hepaticus in mice is concomitant with modification of the gut microbiota, subclinical inflammation, and drastic impairment of immune control of the growth of subsequently administered M. tuberculosis, which results in severe lung tissue injury. Our results provided insights upon the fact that this prior H. hepaticus colonization leads to failures in the mechanisms that could prevent the otherwise balanced cross-talk between M. tuberculosis and the immune system. Such disequilibrium ultimately leads to the inhibition of control of mycobacterial growth, outbreak of inflammation, and lung pathology. Among the dysregulated immune signatures, we noticed a correlation between the detrimental lung injury and the accumulation of activated T-lymphocytes. Our findings suggest that the impact of prior Helicobacter spp. colonization and subsequent M. tuberculosis parasitism might be greater than previously thought, which is a key point given that both species are among the most frequent invasive bacteria in human populations.

Transfer of Minibeam Radiation Therapy into a cost-effective equipment for radiobiological studies: a proof of concept.

Minibeam radiation therapy (MBRT) is an innovative synchrotron radiotherapy technique able to shift the normal tissue complication probability curves to significantly higher doses. However, its exploration was hindered due to the limited and expensive beamtime at synchrotrons. The aim of this work was to develop a cost-effective equipment to perform systematic radiobiological studies in view of MBRT. Tumor control for various tumor entities will be addressable as well as studies to unravel the distinct biological mechanisms involved in normal and tumor tissues responses when applying MBRT. With that aim, a series of modifications of a small animal irradiator were performed to make it suitable for MBRT experiments. In addition, the brains of two groups of rats were irradiated. Half of the animals received a standard irradiation, the other half, MBRT. The animals were followed-up for 6.5 months. Substantial brain damage was observed in the group receiving standard RT, in contrast to the MBRT group, where no significant lesions were observed. This work proves the feasibility of the transfer of MBRT outside synchrotron sources towards a small animal irradiator.

Lymphocytic insulitis in a juvenile dog with diabetes mellitus.

Autoimmune diabetes has never been described in a juvenile dog, whereas serological evidence has established its development in adult dogs. Diabetes mellitus was diagnosed in a 3-mo-old Donge de Bordeaux dog suffering from persistent hyperglycemia and concurrent insulinopenia. Histological analysis of the pancreas revealed inflammatory lesions in 40% of the islets of Langerhans, with infiltration predominantly by T lymphocytes (more than 90%), either at the edge (peri-insulitis: 10%) or in the islets (insulitis: 30%). The remaining 60% of the islets showed a marked atrophy due to massive beta cell loss with no loss of alpha cells. This pattern is quite similar to that observed in humans in which a characteristic insulitis containing high numbers of T lymphocytes is found in 20% of the islets at diabetes diagnosis. By contrast, in rodent models, nearly 70% of the islets of Langerhans show inflammation at diagnosis and macrophages and dendritic cells predominate in the inflammatory lesions. This is the first report of lymphocytic insulitis in a juvenile dog exhibiting diabetes mellitus. Our observations suggest an autoimmune origin for the disease in this dog that is similar to human type 1 diabetes mellitus, for which there is no accurate spontaneous large animal model.

Microcystic meningioma in a dolphin (Delphinus delphis): immunohistochemical and ultrastructural study.

A wild common dolphin was found stranded on the French Atlantic coast. At necropsy, an intracranial grey- to tan-coloured mass (7 x 5 x 4 cm) was found at the right cerebellopontine angle, compressing the right cerebellar hemisphere, the brainstem and the occipital lobe of the right cerebral hemisphere. Microscopically, the tumour was composed of small lobules of polygonal to elongated neoplastic cells with multifocal areas of stellate and vacuolated cells. Neoplastic cells strongly expressed vimentin, S-100 protein and neuron-specific enolase. They were rarely positive for cytokeratin. Ultrastructurally, the neoplastic cells displayed all the diagnostic features of meningiomas and in some areas showed long cytoplasmic processes delimiting extracellular spaces. The immunohistochemical and ultrastructural features were consistent with the histopathological diagnosis of a microcystic meningioma. This is the first report of a meningioma in dolphins or in any other cetacean species.

Necrotizing Meningoencephalitis in a Captive Black and White Ruffed Lemur (Varecia variegata variegata) Caused by Acanthamoeba T4 Genotype.

A mature male, black and white ruffed lemur (Varecia variegata variegata) died in a zoological garden after a 4-day history of lethargy and non-responsive convulsions. Necropsy and histopathological examinations revealed acute necrotizing and haemorrhagic meningoencephalitis with intralesional amoebas confirmed by immunohistochemistry. Acanthamoeba T4 genotype was identified as the causative agent of the brain lesion, based on amplification and sequencing of 18S ribosomal RNA genes. The presence of free-living amoebas in water and mud from the lemur's environment was investigated by morphological and molecular analyses. The two predominant genera, representing 80% of isolated amoebas, were Naegleria spp. and Acanthamoeba spp. All Acanthamoeba isolates belonged to the T4 genotype. To the author's knowledge, this is the first report of a meningoencephalitis due to Acanthamoeba T4 genotype in Lemuridae with concurrent analysis of pathological tissues and environment.

Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy.

Sepsis, or systemic inflammatory response syndrome, is the major cause of critical illness resulting in admission to intensive care units. Sepsis is caused by severe infection and is associated with mortality in 60% of cases. Morbidity due to sepsis is complicated by neuromyopathy, and patients face long-term disability due to muscle weakness, energetic dysfunction, proteolysis and muscle wasting. These processes are triggered by pro-inflammatory cytokines and metabolic imbalances and are aggravated by malnutrition and drugs. Skeletal muscle regeneration depends on stem (satellite) cells. Herein we show that mitochondrial and metabolic alterations underlie the sepsis-induced long-term impairment of satellite cells and lead to inefficient muscle regeneration. Engrafting mesenchymal stem cells improves the septic status by decreasing cytokine levels, restoring mitochondrial and metabolic function in satellite cells, and improving muscle strength. These findings indicate that sepsis affects quiescent muscle stem cells and that mesenchymal stem cells might act as a preventive therapeutic approach for sepsis-related morbidity.

Genetic variability and integration of Merkel cell polyomavirus in Merkel cell carcinoma.

Merkel cell polyomavirus (MCPyV) is associated to Merkel cell carcinoma (MCC). We studied 113 MCC tumoral skin lesions originating from 97 patients. MCPyV detection was higher in fresh-frozen (FF) biopsies (94%) than in formalin-fixed paraffin-embedded biopsies (39-47%). Mean viral load in FF tumor was of 7.5 copies per cell with a very wide range (0.01-95.4). Nineteen complete sequences of LTAg were obtained, mainly from FF biopsies when the viral load was high. Seventeen showed stop codons, all localized downstream of the pRb protein binding domain. Sequence comparison and phylogenetic analysis showed that all sequences clustered in the large C clade of MCPyV strains. MCPyV integration was demonstrated in 19 out of 27 FF MCC DNA biopsies without evidence of specific host cellular genome integration site. In 13/19 cases, the viral junction was located within the second exon of the LTAg, after the pRB binding domain.