Jennifer Baccon

A patient with encephalitis associated with NMDA receptor antibodies

Background A 34-year-old woman presented with headache, feverish sensation and anxiety, rapidly followed by homicidal ideation, aggressive agitation, seizures, hypoventilation, hyperthermia and prominent autonomic instability requiring intubation and sedation. She developed episodes of hypotension and bradycardia with periods of asystole lasting up to 15 seconds. Upon weaning off sedation, her eyes opened but she was unresponsive to stimuli. There was muscle rigidity, frequent facial grimacing, rhythmic abdominal contractions, kicking motions of the legs, and intermittent dystonic postures of the right arm.Investigations Routine laboratory testing, toxicology screening, studies for autoimmune and infectious etiologies, brain MRI scan, lumbar puncture, electroencephalogram, whole-body CT scan, abdominal ultrasound, paraneoplastic and voltage-gated potassium channel antibody serologies, analysis of N-methyl-D-aspartate receptor antibodies.Diagnosis Paraneoplastic encephalitis associated with immature teratoma of the ovary and N-methyl-D-aspartate receptor antibodies.Management Intensive care, mechanical ventilation, antiepileptics, laparotomy and left salpingo-oophorectomy, corticosteroids, plasma exchange, intravenous immunoglobulin, cyclophosphamide, physical therapy, and chemotherapy.

The survival of motor neurons (SMN) protein interacts with the snoRNP proteins fibrillarin and GAR1.

BACKGROUND The survival of motor neurons (SMN) protein is the protein product of the spinal muscular atrophy (SMA) disease gene. SMN and its associated proteins Gemin2, Gemin3, and Gemin4 form a large complex that plays a role in snRNP assembly, pre-mRNA splicing, and transcription. The functions of SMN in these processes are mediated by a direct interaction of SMN with components of these machineries, such as Sm proteins and RNA helicase A. RESULTS We show that SMN binds directly to fibrillarin and GAR1. Fibrillarin and GAR1 are specific markers of the two classes of small nucleolar ribonucleoprotein particles (snoRNPs) that are involved in posttranscriptional processing and modification of ribosomal RNA. SMN interaction requires the arginine- and glycine-rich domains of both fibrillarin and GAR1 and is defective in SMN mutants found in some SMA patients. Coimmunoprecipitations demonstrate that the SMN complex associates with fibrillarin and with GAR1 in vivo. The inhibition of RNA polymerase I transcription causes a transient redistribution of SMN to the nucleolar periphery and loss of fibrillarin and GAR1 colocalization with SMN in gems. Furthermore, the expression of a dominant-negative mutant of SMN (SMNDeltaN27) causes snoRNPs to accumulate outside of the nucleolus in structures that also contain components of gems and coiled (Cajal) bodies. CONCLUSIONS These findings identify fibrillarin and GAR1 as novel interactors of SMN and suggest a function for the SMN complex in the assembly and metabolism of snoRNPs. We propose that the SMN complex performs functions necessary for the biogenesis and function of diverse ribonucleoprotein complexes.

Identification and Characterization of Gemin7, a Novel Component of the Survival of Motor Neuron Complex

The survival of motor neurons (SMN) protein is the product of the gene mutated or deleted in the neurodegenerative disease, spinal muscular atrophy. SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. Coimmunoprecipitation and immunolocalization experiments demonstrate that Gemin7 is a component of the SMN complex and colocalizes with SMN in the cytoplasm and in gems. Binding experiments show that Gemin7 interacts directly with SMN and Gemin6 and mediates the association of Gemin6 with the SMN complex. The amino acid sequence of Gemin7 does not contain any recognizable motifs with the exception of several arginine and glycine repeats that are necessary for its interaction with SMN. Moreover, Gemin7 interacts with several Sm proteins of spliceosomal small nuclear ribonucleoproteins, in particular, with SmE. With the identification of Gemin7, the inventory of the core components of the SMN complex appears essentially complete.

Gemin8 Is a Novel Component of the Survival Motor Neuron Complex and Functions in Small Nuclear Ribonucleoprotein Assembly

The survival motor neuron (SMN) protein is the product of the spinal muscular atrophy disease gene. SMN and Gemin2–7 proteins form a large macromolecular complex that localizes in the cytoplasm as well as in the nucleoplasm and in nuclear Gems. The SMN complex interacts with several additional proteins and likely functions in multiple cellular pathways. In the cytoplasm, a subset of SMN complexes containing unrip and Sm proteins mediates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). Here, by mass spectrometry analysis of SMN complexes purified from HeLa cells, we identified a novel protein that is evolutionarily conserved in metazoans, and we named it Gemin8. Co-immunoprecipitation and immunolocalization experiments demonstrated that Gemin8 is associated with the SMN complex and is localized in the cytoplasm and in the nucleus, where it is highly concentrated in Gems. Gemin8 interacts directly with the Gemin6-Gemin7 heterodimer and, together with unrip, these proteins form a heteromeric subunit of the SMN complex. Gemin8 is also associated with Sm proteins, and Gemin8-containing SMN complexes are competent to carry out snRNP assembly. Importantly, RNA interference experiments indicate that Gemin8 knock-down impairs snRNP assembly, and Gemin8 expression is down-regulated in cells with low levels of SMN. These results demonstrate that Gemin8 is a novel integral component of the SMN complex and extend the repertoire of cellular proteins involved in the pathway of snRNP biogenesis.

Unrip is a component of SMN complexes active in snRNP assembly

A macromolecular complex containing survival of motor neurons (SMN), the spinal muscular atrophy protein, and Gemin2–7 interacts with Sm proteins and snRNAs to carry out the assembly of these components into spliceosomal small nuclear ribonucleoproteins (snRNPs). Here we report the characterization of unr‐interacting protein (unrip), a GH‐WD protein of unknown function, as a component of the SMN complex that interacts directly with Gemin6 and Gemin7. Unrip also binds a subset of Sm proteins, and unrip‐containing SMN complexes are necessary and sufficient to mediate the assembly of spliceosomal snRNPs. These results demonstrate that unrip functions in the pathway of snRNP biogenesis and is a marker of cellular SMN complexes active in snRNP assembly.

Clinically silent somatotroph adenomas are common

Objective Somatotroph adenomas are typically recognized when they secrete GH excessively and cause acromegaly. Both ‘silent’ somatotroph adenomas (immunohistochemical evidence of GH excess without biochemical or clinical evidence) and ‘clinically silent’ somatotroph adenomas (immunohistochemical and biochemical evidence but no clinical evidence) have occasionally been reported. The relative frequency of each presentation is unknown. The goal of this study was, therefore, to determine the frequency of clinically silent somatotroph adenomas, a group that is potentially recognizable in vivo. Design We retrospectively identified 100 consecutive patients who had surgically excised and histologically confirmed pituitary adenomas. Methods Each pituitary adenoma was classified immunohistochemically by pituitary cell type. Somatotroph adenomas were further classified as ‘classic’ (obvious clinical features of acromegaly and elevated serum IGF1), ‘subtle’ (subtle clinical features of acromegaly and elevated IGF1), ‘clinically silent’ (no clinical features of acromegaly but elevated IGF1), and ‘silent’ (no clinical features of acromegaly and normal IGF1). Results Of the 100 consecutive pituitary adenomas, 29% were gonadotroph/glycoprotein, 24% somatotroph, 18% null cell, 15% corticotroph, 6% lactotroph, 2% thyrotroph, and 6% not classifiable. Of the 24 patients with somatotroph adenomas, classic accounted for 45.8%, subtle 16.7%, clinically silent 33.3%, and silent 4.2%. Conclusions Clinically silent somatotroph adenomas are more common than previously appreciated, representing one-third of all somatotroph adenomas. IGF1 should be measured in all patients with a sellar mass, because identification of a mass as a somatotroph adenoma expands the therapeutic options and provides a tumor marker to monitor treatment.

A visual latent semantic approach for automatic analysis and interpretation of anaplastic medulloblastoma virtual slides

A method for automatic analysis and interpretation of histopathology images is presented. The method uses a representation of the image data set based on bag of features histograms built from visual dictionary of Haar-based patches and a novel visual latent semantic strategy for characterizing the visual content of a set of images. One important contribution of the method is the provision of an interpretability layer, which is able to explain a particular classification by visually mapping the most important visual patterns associated with such classification. The method was evaluated on a challenging problem involving automated discrimination of medulloblastoma tumors based on image derived attributes from whole slide images as anaplastic or non-anaplastic. The data set comprised 10 labeled histopathological patient studies, 5 for anaplastic and 5 for non-anaplastic, where 750 square images cropped randomly from cancerous region from whole slide per study. The experimental results show that the new method is competitive in terms of classification accuracy achieving 0.87 in average.

An integrated texton and bag of words classifier for identifying anaplastic medulloblastomas

In this paper we present a combined Bag of Words and texton based classifier for differentiating anaplastic and non-anaplastic medulloblastoma on digitized histopathology. The hypothesis behind this work is that histological image signatures may reflect different levels of aggressiveness of the disease and that texture based approaches can help discriminate between more aggressive and less aggressive phenotypes of medulloblastoma. The bag of words approach attempts to model the occurrence of differently expressed image features. In this work we choose to model the image features via textons which can quantitatively capture and model texture appearance in the images. The texton-based features, obtained via two methods, the Haar Wavelet responses and MR8 filter bank, provide spatial orientation and rotation invariant attributes. Applying these features to the bag of words framework yields textural representations that can be used in conjunction with a classifier (κ-nearest neighbor) or a content based image retrieval system. Over multiple runs of randomized cross validation, a κ-NN classifier in conjunction with Haar wavelets and the texton, bag of words approach yielded a mean classification accuracy of 80, an area under the precision recall curve of 87 and an area under the ROC curve of 83 in distinguishing between anaplastic and non-anaplastic medulloblastomas on a cohort of 36 patient studies.

Pathology residency training: time for a new paradigm

The exponential growth of the field of pathology over the past several decades has created challenges for residency training programs. These challenges include the ability to train competent pathologists in 4 years, an increased demand for fellowship training, and the structuring and completion of maintenance of certification. The authors feel that pathology residency training has reached a critical point and that a new paradigm for training is required.

The innate immune adaptor MyD88 is dispensable for spontaneous autoimmune demyelination in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease that is mediated by myelin-reactive T cells resulting in CNS demyelination, however the mechanisms that control their activation are unclear. Mice that are transgenic for a myelin proteolipid protein (PLP)-specific TCR spontaneously develop experimental autoimmune encephalomyelitis (EAE), the animal model of MS. They mimic the spontaneous onset of MS and thus offer the unique opportunity to investigate the mechanisms that may contribute to the development of spontaneous CNS autoimmunity. MyD88 is an adaptor protein that mediates signal transduction by TLRs, IL-1R and IL-18R, resulting in the activation of innate immune cells, including DCs. We investigated the requirement of MyD88 in the pathogenesis of spontaneous EAE in PLP TCR transgenic SJL mice. We show that genetic loss of MyD88 does not intrinsically preclude development of spontaneous EAE and autoimmune demyelination in these mice. EAE was associated with functionally mature peripheral DCs that promoted superior PLP-specific Th1 and Th17 responses compared to those from disease-free mice. Together, our data suggest that MyD88-independent innate immune signaling critically contributes to priming of myelin-reactive T cells and development of spontaneous EAE in MyD88-deficient PLP TCR transgenic mice.