Cerebral venous sinus thrombosis due to oral contraceptive use: Postmortem 3T-MRI and autopsy findings

AbstractCerebral venous sinus thrombosis (CVST) is an uncommon form of stroke, and mortality of the acute phase is high. We report the clinical, postmortem 3T-MRI, and autopsy features of a patient, 20-year-old Japanese woman, with CVST who died shortly after starting to use low-dose estrogen combined hormonal contraceptives (CHCs). A postmortem 3T-MRI study with our originally developed system revealed abnormal intensities suggestive of thrombi extending throughout the straight sinus and left sigmoid sinus. At autopsy, in accordance with the images, we performed careful preparations of the sinuses. Histological examination revealed an organizing white thrombus occupying the lumen of the left sigmoid sinus, and an acute, red thrombus in the lumen of the left transverse, straight, and tentorial sinuses, and vein of Galen, indicating that the thrombus had developed first in the left sigmoid sinus, then extended retrogradely to the more proximal portion of the sinus system, reaching the vein of Galen. The features of the present CVST patient appear to be informative, when encountering CHC users with neurological symptoms, even in those who begun to use low-dose estrogen CHCs only recently

Alteration of <em>POLDIP3</em> Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS

<div><p>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (<em>POLDIP3</em>) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type <em>POLDIP3</em> (variant-1) decreased and <em>POLDIP3</em> lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of <em>POLDIP3</em> exon 3. Moreover, we found an increment of <em>POLDIP3</em> variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.</p> </div

Additional file 2: of Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: Evidence for clinico-pathologic subtypes

Contains supplementary methods regarding ISH and biochemical studies, and legends to Supplementary Figure 1. (DOC 36 kb

Reduction of TDP-43 expression makes cells smaller.

<p>(<b>A</b>) A flow cytometer was used to obtain forward scatter (FSC) histograms of SH-SY5Y cells transfected with siRNA targeting POLDIP3 (blue) or TDP-43 (red) or non-targeting control (black). The FSC histogram is one representative transfection from which 10,000 cells were counted. (<b>B</b>) Data represent the mean with standard error of forward scatter of the siRNA-transfected cells from three independent experiments. Note that down-regulation of TDP-43 leads to a reduction in cell size as well as POLDIP3 depression. Asterisk indicates significant difference (*<i>P</i><0.01, Tukey multiple comparison test). (<b>C and D</b>) Cell lysates from the SHSY5Y cells stably expressed GFP-tagged POLDIP3 variants were subjected to immunoblotting for POLDIP3 (<b>C</b>) or TDP-43 (<b>D</b>). Anti-actin immunoblotting served as a loading control. (<b>E</b>) Recovery rate of the cell size in the TDP-43-depleted SH-SY5Y with or without expression of GFP-tagged POLDIP3 variant. Data represent the mean with standard error from three independent experiments. Note that the cell size recovery rate is significantly increased in the cells expressing POLDIP3 variant-1 compared to in the cells expressing variant-2. Asterisk indicates significant difference (*<i>P</i><0.01, Student <i>t</i> test).</p