Tau and 14-3-3 in glial cytoplasmic inclusions of multiple system atrophy

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the presence of glial cytoplasmic inclusions (GCIs), which are comprised of fibrils of the protein -synuclein (-syn). Increasing evidence indicate that the formation of these lesions leads to cellular dysfunction and degeneration. The events that result in the formation of GCIs remain poorly understood. It is possible that changes in the cytoplasmic milieu, perhaps the aberrant expression of -syn-interacting proteins, can promote the polymerization of -syn. The presence of the microtubule-binding protein, tau, in GCIs has been reported in some studies, but these findings have not been consistent, and these studies were performed prior to the availability of the more sensitive methods of detecting GCIs using anti--syn antibodies. Recently, 14-3-3 proteins, putative -syn-interacting partners, have been reported in Lewy bodies, which also are pathological inclusions comprised of -syn. In this study the presence of tau and 14-3-3 proteins in GCIs of 21 patients with MSA was investigated. For the majority of cases, tau and 14-3-3 proteins were detected only in a subset of GCIs. In some cases none of the GCIs contained 14-3-3 or tau. When present in GCIs, tau was in a hypophosphorylated state as demonstrated with phosphorylation-specific antibodies. -syn fibrillogenesis without 14-3-3 or tau appears to be sufficient for GCI formation, although it is possible that the accumulation of multi-functional proteins, like 14-3-3, in GCIs contribute to the disruption of cellular homeostasis.     

In vivo gene transfer to the rat retina using herpes simplex virus type 1 (HSV-1)-based amplicon vectors

The purpose of our study was to evaluate the transduction profiles of herpes simplex virus type 1 (HSV-1)-based amplicon vectors following subretinal injection in the rat. Two amplicon vectors were tested, pHy-CMVGFP and pHy-RPEGFP, both carrying the green fluorescent protein (GFP) under the control of the cytomegalovirus (CMV) ubiquitous promoter or the RPE65-specific promoter, respectively. For the two amplicon vectors, the GFP reporter gene was efficiently expressed in retinal pigment epithelial (RPE) cells but not in the adjacent photoreceptors. GFP expression was maximum as early as 2 days post-administration but decreased over time to become almost undetectable at 6 weeks postinjection. Super-transduction with a second amplicon vector, pHSVlac, reactivated expression of GFP in approximately 10% of the cells initially transduced at 2 days postinjection of pHy-CMVGFP or pHy-RPEGFP. Reactivation of transgene expression was transient, no GFP signal was detected 8 days after pHSVlac injection. In conclusion, HSV-1 amplicon vectors allow rapid and efficient, but transient, gene transfer in RPE cells following subretinal injection.     

Comparative genomics of Vibrio cholerae from Haiti, Asia, and Africa

Cholera was absent from the island of Hispaniola at least a century before an outbreak that began in Haiti in the fall of 2010. Pulsed-field gel electrophoresis (PFGE) analysis of clinical isolates from the Haiti outbreak and recent global travelers returning to the United States showed indistinguishable PFGE fingerprints. To better explore the genetic ancestry of the Haiti outbreak strain, we acquired 23 whole-genome Vibrio cholerae sequences: 9 isolates obtained in Haiti or the Dominican Republic, 12 PFGE pattern-matched isolates linked to Asia or Africa, and 2 nonmatched outliers from the Western Hemisphere. Phylogenies for whole-genome sequences and core genome single-nucleotide polymorphisms showed that the Haiti outbreak strain is genetically related to strains originating in India and Cameroon. However, because no identical genetic match was found among sequenced contemporary isolates, a definitive genetic origin for the outbreak in Haiti remains speculative.     

FLT3 mutations in childhood acute lymphoblastic leukemia

Activating mutations of the FLT3 receptor tyrosine kinase are common in acute myelogenous leukemia (AML) but are rare in adult acute lymphoblastic leukemia (ALL). We have recently shown that FLT3 is highly expressed and often mutated in ALLs with rearrangement of the mixed lineage leukemia (MLL) gene on chromosome 11q23. Because hyperdiploid ALL samples also show high-level expression of FLT3, we searched for the presence of FLT3 mutations in leukemic blasts from 71 patients with ALL. The data show that approximately 25% (6 of 25) of hyperdiploid ALL samples possess FLT3 mutations, whereas only 1 of 29 TEL/AML1-rearranged samples harbored mutations (P =.04, Fisher exact test). Three mutations are novel in-frame deletions within a 7-amino acid region of the receptor juxtamembrane domain. Finally, 3 samples from patients whose disease would relapse harbored FLT3 mutations. These data suggest that patients with hyperdiploid or relapsed ALL might be considered candidates for therapy with newly described small-molecule FLT3 inhibitors.     

Histopathologically confirmed ocular rhinosporidiosis in two Canadians

CASE REPORT: In India and Southeast Asia, rhinosporidiosis is a common infectious disease, but it has rarely been reported in western countries. Infrequently, isolated ocular rhinosporidial infections have been reported, but to our knowledge, there are no reported cases in Canada. Two cases of rhinosporidiosis have been recently diagnosed and managed at our university-based hospital. COMMENTS: Rhinosporidiosis presents with certain characteristic clinical features; however, the diagnosis is confirmed histopathologically. The presence of typical sporangia and spores in a fibrovascular stroma infiltrated by acute and chronic inflammatory cells including granulomas is diagnostic. Surgical excision is the treatment of choice, and recurrence is possible but rare.     

Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation

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Preliminary observations on the application of carcino-placental alkaline phosphatase to the investigation of patients with seminoma of the testes

Suitable tumour markers for monitoring the treatment of seminoma of the testis have not yet been established in clinical practice. Carcino-placental alkaline phosphatase (CPAP) has been suggested for this purpose but it is difficult to detect and specifically analyse this enzyme. We have devised an immunoenzymatic method of analysis in which cross-reactions with liver type and intestinal alkaline phosphatase are minimal and we have applied this test to seven patients with histologically proven seminoma. CPAP was raised in 4 patients prior to treatment and chorionic gonadotrophin in two of these. Alpha-fetoprotein was normal in all cases. We conclude that the use of CPAP in monitoring treatment of testicular seminoma is worthy of further attention.     

Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred

Previous genetic analysis of the familial Parkinson's disease Contursi kindred led to the identification of an Ala53Thr pathogenic mutation in the alpha-synuclein gene. We have re-examined one of the original brains from this kindred using new immunohistochemical reagents, thioflavin S staining and immunoelectron microscopy. Surprisingly, we uncovered a dense burden of alpha-synuclein neuritic pathology and rare Lewy bodies. Immunoelectron microscopy demonstrated fibrillar alpha-synuclein-immunoreactive aggregates. Unexpected tau neuritic and less frequent perikaryal inclusions were also observed. Some inclusions were comprised of both proteins with almost complete spatial disparity. We suggest that it is important to recognize that the neurodegenerative process caused by the Ala53Thr mutation in alpha-synuclein is not identical to that seen in typical idiopathic Parkinson's disease brains.     

Spontaneous corneal hydrops and perforation in keratoconus and pellucid marginal degeneration

PURPOSE: To report two cases of pellucid marginal degeneration and one case of keratoconus associated with spontaneous corneal hydrops leading either to perforation or imminent perforation, requiring urgent keratoplasty. METHOD: Retrospective interventional case series of three patients with noninflammatory peripheral corneal degenerations. A retrospective review was done of the clinical courses, surgical interventions, and pathologic specimens, development of spontaneous hydrops, perforation, need for surgical intervention, and final visual outcome. RESULTS: Two patients with pellucid marginal degeneration and one with keratoconus developed spontaneous hydrops followed by aqueous leakage through markedly thinned anterior stroma. In one case, the leak site was successfully sealed after three separate applications of tissue adhesive, although the remaining two cases required penetrating keratoplasty. CONCLUSIONS: These cases document the very unusual occurrence of corneal hydrops leading to spontaneous corneal perforation in patients with keratoconus and pellucid marginal degeneration.