Pediatric Blastic Plasmacytoid Dendritic Cell Neoplasm: A Case Report.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive neoplastic process of precursor plasmacytoid dendritic cells. The diagnostic evaluation of this heterogenous entity is challenging, requiring a comprehensive approach of incorporating clinical, morphologic, immunohistochemical, and molecular/cytogenetic evaluations. Optimal management of BPDCN remains controversial, and clinical outcomes continues to be poor.

Dysuria and Vaginal Pain, Unusual Manifestations of B-acute Lymphoblastic Lymphoma.

Urinary symptoms are one of the most common reasons for emergency visits in females of pediatric age group and can be associated with various conditions like infections (most common), sexual trauma and rarely neoplastic processes. Here, we report a case of a 7-year-old female who presented in the emergency multiple times with the complaints of urinary symptoms and vaginal pain and was empirically treated with antibiotics and antifungals without symptomatic improvement. Her blood tests, physical examination during this time remained unrevealing.

Does concomitant tricuspid valve intervention at the time of left ventricular assist device placement for patients with significant tricuspid regurgitation lead to improved outcomes compared to isolated left ventricular assist device placement?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'In patients with advanced heart failure (HF) and moderate to severe functional tricuspid regurgitation (TR) undergoing left ventricular assist device (LVAD) placement is concomitant tricuspid valve intervention (TVI) superior for the clinical outcomes of survival, right ventricular failure, rehospitalizations for HF, functional status, and quality of life?' Altogether, 56 papers were found using the reported search, of which 12 papers represented the best evidence to answer the clinical question. The authors, journal, date, country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated.

AAV- partially corrects motor deficits and ALS/FTLD-related pathology in mice.

Loss of function of progranulin (PGRN), encoded by the () gene, is implicated in several neurodegenerative diseases. Several therapeutics to boost PGRN levels are currently in clinical trials. However, it is difficult to test the efficacy of PGRN-enhancing drugs in mouse models due to the mild phenotypes of mice.

Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia.

Background: Heterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN.

Tricuspid regurgitation in the setting of LVAD support.

Tricuspid valve regurgitation (TR) is a common complication of end-stage heart failure. Increased pulmonary venous pressures caused by left ventricular (LV) dysfunction can result in a progressive dilation of the right ventricle and tricuspid valve annulus, resulting in functional TR. Here, we review what is known about TR in the setting of severe LV dysfunction necessitating long-term mechanical support with left ventricular assist devices (LVADs), including the occurrence of significant TR, its pathophysiology, and natural history.

Hidden treasures: Incidental findings in two cases of chronic subdural hematoma.

Background: Extramedullary hematopoiesis (EMH) and plasmacytomas occurring within the cranium are rare entities.

Case Description: We review two cases in which patients presented with subdural hematoma and underwent evacuation. On routine histopathologic examination of their membranes, both patients were subsequently found to have focal EMH, as well as a clonal plasma cell proliferation in one case.

Peptidyl arginine deiminase expression and macrophage polarization following stimulation with citrullinated and malondialdehyde-acetaldehyde modified fibrinogen.

Objective: Post-translational modifications of extracellular matrix proteins such as fibrinogen may lead to tolerance loss and have been implicated in rheumatoid arthritis (RA) pathogenesis. The purpose of this study was to determine whether fibrinogen (FIB) modified with citrulline (CIT), malondialdehyde-acetaldehyde (MAA) or both leads to altered macrophage polarization, peptidyl arginine deiminase (PAD) expression, or production of citrullinated proteins.

Methods: PMA-treated U-937 cells (M0 cells) were stimulated with MAA, CIT or MAA-CIT modified FIB.

Increased susceptibility to organic dust exposure-induced inflammatory lung disease with enhanced rheumatoid arthritis-associated autoantigen expression in HLA-DR4 transgenic mice.

Immunogenetic as well as environmental and occupational exposures have been linked to the development of rheumatoid arthritis (RA), RA-associated lung disease, and other primary lung disorders. Importantly, various inhalants can trigger post-translational protein modifications, resulting in lung autoantigen expression capable of stimulating pro-inflammatory and/or pro-fibrotic immune responses. To further elucidate gene-environment interactions contributing to pathologic lung inflammation, we exploited an established model of organic dust extract (ODE) exposure with and without collagen-induced arthritis (CIA) in C57BL/6 wild type (WT) versus HLA-DR4 transgenic mice.

Cholangiocarcinoma obscured by a large paraesophageal hernia causing traction compression of the common hepatic duct ultimately diagnosed with percutaneous cholangioscopy.

Video 1Case presentation including cross-sectional imaging, percutaneous cholangiogram, percutaneous cholangioscopy, and histopathology of cholangioscopy-directed biopsies.

Identification of Immunoglobulin G Autoantibody Against Malondialdehyde-Acetaldehyde Adducts as a Novel Serological Biomarker for Ulcerative Colitis.

Introduction: Inflammatory bowel disease (IBD) is associated with immune responses with oxidative stress wherein high levels of malondialdehyde result in the formation of a highly stable and immunogenic malondialdehyde-acetaldehyde adduct (MAA). Thus, this study evaluated the status of MAA and anti-MAA antibody isotypes in IBD and their potential as novel serological biomarkers for differentiating ulcerative colitis (UC) from Crohn's disease (CD).

Methods: Levels of MAA and anti-MAA antibodies were examined in patients with IBD (171), non-IBD gastrointestinal diseases (77), and controls (83) from 2 independent cohorts using immunohistochemistry and enzyme-linked immunosorbent assay.

Educational Case: Myeloid Sarcoma: A Subtype of Acute Myeloid Leukemia.

http://journals.sagepub.com/doi/10.

Striatal Kir2 K+ channel inhibition mediates the antidyskinetic effects of amantadine.

Levodopa-induced dyskinesia (LID) poses a significant health care challenge for Parkinson's disease (PD) patients. Amantadine is currently the only drug proven to alleviate LID. Although its efficacy in treating LID is widely assumed to be mediated by blockade of N-methyl-D-aspartate (NMDA) glutamate receptors, our experiments demonstrate that at therapeutically relevant concentrations, amantadine preferentially blocks inward-rectifying K+ channel type 2 (Kir2) channels in striatal spiny projection neurons (SPNs) - not NMDA receptors.

Activity of diphenyl ether benzyl amines against Human African Trypanosomiasis.

Insect-borne parasite Trypanosoma brucei plagues humans and other animals, eliciting the disease Human African trypanosomiasis, also known as African sleeping sickness. This disease poses the biggest threat to the people in Sub-Saharan Africa. Given the high toxicity and difficulties with administration of currently available drugs, a novel treatment is needed.

Limited Number of Cases May Yield Generalizable Models, a Proof of Concept in Deep Learning for Colon Histology.

Background: Little is known about the effect of a minimum number of slides required in generating image datasets used to build generalizable machine-learning (ML) models. In addition, the assumption within deep learning is that the increased number of training images will always enhance accuracy and that the initial validation accuracy of the models correlates well with their generalizability. In this pilot study, we have been able to test the above assumptions to gain a better understanding of such platforms, especially when data resources are limited.

Ovarian teratoma associated Anti-N-methyl-D-aspartate receptor encephalitis: a difficult diagnosis with a favorable prognosis.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a recently described auto-immune and paraneoplastic encephalitis with prominent neuropsychiatric manifestations affecting young adults with ovarian teratoma. The availability of a novel assay to measure these antibodies might suggest an etiology for this potentially life-threatening disease, which if early recognized can be treated promptly with surgery with chances of a good clinical outcome. Reported prognostic indicators for a good outcome depend on the presence of a tumor, prompt treatment and no admission to an intensive care unit.

Virtual finger boosts three-dimensional imaging and microsurgery as well as terabyte volume image visualization and analysis.

Three-dimensional (3D) bioimaging, visualization and data analysis are in strong need of powerful 3D exploration techniques. We develop virtual finger (VF) to generate 3D curves, points and regions-of-interest in the 3D space of a volumetric image with a single finger operation, such as a computer mouse stroke, or click or zoom from the 2D-projection plane of an image as visualized with a computer. VF provides efficient methods for acquisition, visualization and analysis of 3D images for roundworm, fruitfly, dragonfly, mouse, rat and human.

Developmentally altered inhibition in Ts65Dn, a mouse model of Down syndrome.

We studied the development of GABA-mediated synaptic inhibition in the CA1 region of the hippocampus in Ts65Dn mice, a model system for Down syndrome (DS). While there was no significant difference in the amplitude of stimulus-evoked monosynaptic inhibitory postsynaptic potentials (IPSPs) between acute hippocampal slices from Ts65Dn mice and diploid (2N) wild-type littermates at the end of the first and third postnatal weeks, the Ts65Dn animals showed significantly larger inhibitory responses when compared to age-matched controls at the end of the second postnatal week. This transient change in evoked inhibition was strikingly layer specific, observed only when stimulating in the strata radiatum and pyramidale but not in the stratum oriens.

Heterogeneous reallocation of presynaptic efficacy in recurrent excitatory circuits adapting to inactivity.

Recurrent excitatory circuits face extreme challenges in balancing efficacy and stability. We recorded from CA3 pyramidal neuron pairs in rat hippocampal slice cultures to characterize synaptic and circuit-level changes in recurrent synapses resulting from long-term inactivity. Chronic tetrodotoxin treatment greatly reduced the percentage of connected CA3-CA3 neurons, but enhanced the strength of the remaining connections; presynaptic release probability sharply increased, whereas quantal size was unaltered.

Inhibitory role for GABA in autoimmune inflammation.

GABA, the principal inhibitory neurotransmitter in the adult brain, has a parallel inhibitory role in the immune system. We demonstrate that immune cells synthesize GABA and have the machinery for GABA catabolism. Antigen-presenting cells (APCs) express functional GABA receptors and respond electrophysiologically to GABA.

A stepwise mechanism for acetylcholine receptor channel gating.

Muscle contraction is triggered by the opening of acetylcholine receptors at the vertebrate nerve-muscle synapse. The M2 helix of this allosteric membrane protein lines the channel, and contains a 'gate' that regulates the flow of ions through the pore. We used single-molecule kinetic analysis to probe the transition state of the gating conformational change and estimate the relative timing of M2 motions in the alpha-subunit of the murine acetylcholine receptor.

Plasticity of acetylcholine receptor gating motions via rate-energy relationships.

Like other protein conformational changes, ion channel gating requires the protein to achieve a high-energy transition-state structure. It is not known whether ion channel gating takes place on a broad energy landscape on which many alternative transition state structures are accessible, or on a narrow energy landscape where only a few transition-state structures are possible. To address this question, we measured how rate-equilibrium free energy relationships (REFERs) for di-liganded and unliganded acetylcholine receptor gating vary as a function of the gating equilibrium constant.

Structural dynamics of the M4 transmembrane segment during acetylcholine receptor gating.

The transition state structures that link the stable end states of allosteric proteins are largely unresolved. We used single-molecule kinetic analysis to probe the dynamics of the M4 transmembrane segments during the closed<==>open isomerization of the neuromuscular acetylcholine receptor ion channel (AChR). We measured the slopes (phi) of the free energy relationships for 87 mutants, which reveal the open- versus closed-like characters of the mutated residues at the transition state and hence the sequence and organization of gating molecular motions.