Total extrusion of the talus: A case report

Total extrusion of the talus without recovery of the bone is a very unusual injury. The authors present a case of a 25-year-old man who sustained an open total enucleation of the talus in a motorcycle accident. The talus was not recovered at the scene of the accident. An immediate tibiocalcaneal stabilization was performed by using an external fixator. In the postoperative period, a polymicrobic infection was observed and treated with parenteral antibiotics. Nine months after injury, the patient developed an infection of both the empty space and the distal third of the tibia. A wound debridement with tibial sequestrectomy and insertion of gentamicin-impregnated polymethylmethacrylate beads was performed. Three months later, after multiple negative bacteriologic examinations, a tibiocalcaneal arthrodesis with staples and autogenous bone graft was performed. Because of a pseudoarthrosis, the patient underwent a revision of the arthrodesis by retrograde tibiocalcaneal nailing, achieving clinical and radiographic success. The definitive treatment of total enucleation of the talus is still controversial because of its rarity and the high rate of complications, such as avascular necrosis, osteomyelitis, and ankle stiffness. In this case, without recovery of the talus, retrograde nailing afforded good stability by bypassing the bone defects.     

Cryptococcus neoformans capsule structure evolution in vitro and during murine infection

Cryptococcus neoformans capsule structure modifications after prolonged in vitro growth or in vivo passaging have been reported previously. However, nothing is known about the dynamics of these modifications or about their environmental specificities. In this study, capsule structure modifications after mouse passaging and prolonged in vitro culturing were analyzed by flow cytometry using the glucuronoxylomannan-specific monoclonal antibody E1. The capsule structures of strains recovered after 0, 1, 8, and 35 days were compared by using the level of E1-specific epitope expression and its cell-to-cell heterogeneity within a given cell population. In vitro, according to these parameters, the diversity of the strains was higher on day 35 than it was initially, suggesting the absence of selection during in vitro culturing. In contrast, the diversity of the strains recovered from the brain tended to decrease over time, suggesting that selection of more adapted strains had occurred. The strains recovered on day 35 from the spleen and the lungs had different phenotypes than the strains isolated from the brain of the same mouse on the same day, thus strongly suggesting that there is organ specificity for C. neoformans strain selection. Fingerprinting of the strains recovered in vitro and in vivo over time confirmed that genotypes evolved very differently in vitro and in vivo, depending on the environment. Overall, our results suggest that organ-specific selection can occur during cryptococcosis.     

A phase IB dose-finding trial of liposomal doxorubicin in combination with capecitabine in patients with pretreated metastatic breast cancer

Purpose

Anthracyclines and fluoropyrimidines are very active in breast cancer, while liposomal doxorubicin has low cardiotoxicity. We conducted a dose-finding study of the combination of liposomal doxorubicin and capecitabine in patients with pretreated metastatic breast cancer.

Patients and methods

Patients received liposomal doxorubicin 60 mg/m² on day 1 plus capecitabine 825 mg/m² bid (level 0) or 1,000 mg/m² bid (level 1) on days 1–14 of each 21-day cycle to establish the maximum tolerated dose (MTD) and cardiac safety.

Results

Nine patients were enrolled and a total of 52 courses were delivered (median 6 cycles per patient [range 4–7]). Grade 4 neutropenia occurred in 15% of cycles, with one episode of febrile neutropenia; most nonhematological toxicities were mild or moderate. No formal MTD was established, and the study was closed because two cardiac events were observed at dose level 1 and another at dose level 0 in patients pretreated with epirubicin ≥ 560 mg/m².

Conclusions

The recommended dose for phase II studies is liposomal doxorubicin 60 mg/m² on day 1 plus capecitabine 825 mg/m²/bid on days 1–14 of each 21-day cycle. Despite the lower cardiotoxicity of liposomal doxorubicin, the risk of cardiac damage persists in anthracycline-pretreated individuals and mandates close cardiac monitoring and careful evaluation of the overall cumulative dose.     

High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura

The major therapeutic goal for immune thrombocytopenic purpura (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. Eighty percent of patients with ITP possess anti–integrin αIIbβ3 IgG autoantibodies that cause platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in approximately 50% of patients to recover a normal platelet count after anti-CD20 rituximab-mediated B cell depletion and splenectomy suggests that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SCs) reside in other anatomical compartments. We analyzed more than 3,300 single IgG-SCs from spleen, bone marrow, and/or blood of 27 patients with ITP, revealing high interindividual variability in affinity for αIIbβ3, with variations over 3 logs. IgG-SC dissemination and range of affinities were, however, similar for each patient. Longitudinal analysis of autoreactive IgG-SCs upon treatment with the anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti–αIIbβ3 IgG-SCs in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.     

Temporal and Spatial Compartmentalization of Drug-Resistant Cytomegalovirus (CMV) in a Child with CMV Meningoencephalitis: Implications for Sampling in Molecular Diagnosis

We describe a case of antiviral-resistant cytomegalovirus meningoencephalitis occurring after hematopoietic stem cell transplantation. Antiviral-resistant cytomegalovirus was identified in blood 16 months earlier. However, wild-type cytomegalovirus was evidenced in blood when the meningoencephalitis was diagnosed. Treatment of meningoencephalitis should be adapted to all previously identified resistance mutations in any compartment.     

Pathophysiology of Parkinson's disease: Mitochondria,alpha-synuclein and much more…

Parkinson's disease (PD) is a complex, age-related, neurodegenerative disease whose pathogenesis remains incompletely understood. Here, we give an overview of the progress that has been made over the past four decades in our understanding of this disorder. We review the role of mitochondria, environmental toxicants, alpha-synuclein and neuroinflammation in the development of PD. We also discuss more recent data from genetics, which strongly support the endosomal-lysosomal pathways and mitophagy as being central to PD. Finally, we discuss the emerging role of the gut-brain axis as a modulator of PD progression. This article is intended to provide a comprehensive, general and practical review of PD pathogenesis for the general neurologist.