Improvement of Emergency Department Chest Pain Evaluation Using Hs-cTnT and a Risk Stratification Pathway.

BACKGROUND: Chest pain is among the most common reasons for presentation to the emergency department (ED) worldwide. Additional studies on most cost-effective ways of differentiating serious vs. benign causes of chest pain are needed. OBJECTIVES: Our study aimed to evaluate the effectiveness of a novel risk stratification pathway utilizing 5th generation high-sensitivity cardiac troponin T assay (Hs-cTnT) and HEART score (History, Electrocardiogram, Age, Risk factors, Troponin) in assessing nontraumatic chest pain patients in reducing ED resource utilization. METHODS: A retrospective chart review was performed 6 months prior to and after the implementation of a novel risk stratification pathway that combined hs-cTnT with HEART score to guide evaluation of adult patients presenting with nontraumatic chest pain at a large academic quaternary care ED. Primary outcome was ED length of stay (LOS); secondary outcomes included cardiology consult rates, admission rates, number of ED boarders, and number of eloped patients. RESULTS: A total of 1707 patients and 1529 patients were included pre- and postimplementation, respectively. Median overall ED LOS decreased from 317 to 286 min, an absolute reduction of 31 min (95% confidence interval 22-41 min), after pathway implementation (p < 0.001). Furthermore, cardiology consult rate decreased from 26.9% to 16.0% (p < 0.0001), rate of admission decreased from 30.1% to 22.7% (p < 0.0001), and number of ED boarders as a proportion of all nontraumatic chest pain patients decreased from 25.13% preimplementation to 18.63% postimplementation (p < 0.0001). CONCLUSIONS: Implementation of our novel chest pain pathway improved numerous ED throughput metrics in the evaluation of nontraumatic chest pain patients.

Clinical presentation of rapidly progressive familial Danish dementia.

Familial Danish dementia (FDD) is a rare, autosomal dominant neurodegenerative disorder characterized by progressive hearing loss, cataracts, progressive ataxia, and dementia. While multiple pathophysiological studies exist in the literature, clinical case presentations are currently limited. We present a case of young-onset dementia in a 47-year-old patient with Danish heritage who was subsequently diagnosed FDD through genetic testing. Cognitive impairment was his initial symptom, followed by Parkinsonian symptoms, and mood disturbances. The patient experienced rapid decline over only 19 months. Increased awareness and understanding of familial forms of dementia (i.e., FDD) can contribute to an enhanced provision of care for patients with such conditions.

Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes.

BACKGROUND: Brain p38α mitogen-activated protein kinase (MAPK), a potential therapeutic target for cognitive dysfunction based on the neuroinflammation-synaptic dysfunction cycle of pathophysiology progression, offers an innovative pharmacological strategy via inhibiting the same activated target in both glia and neurons, thereby enhancing the possibility for efficacy. The highly selective, brain-penetrant p38αMAPK inhibitor MW150 attenuates cognitive dysfunction in two distinct Alzheimer's disease (AD)-relevant models and avoids the problems encountered with previous mixed-kinase inhibitor drug candidates. Therefore, it is essential that the glial effects of this CNS-active kinase inhibitor be addressed in order to anticipate future use in clinical investigations. METHODS: We explored the effects of MW150 on glial biology in the AD-relevant APP/PS1 knock-in (KI) mouse model where we previously showed efficacy in suppression of hippocampal-dependent associative and spatial memory deficits. MW150 (2.5 mg/kg/day) was administered daily to 11-12-month-old KI mice for 14 days, and levels of proinflammatory cytokines IL-1ß, TNFα, and IL-6 measured in homogenates of mouse cortex using ELISA. Glial markers IBA1, CD45, CD68, and GFAP were assessed by immunohistochemistry. Microglia and amyloid plaques were quantified by immunofluorescence staining followed by confocal imaging. Levels of soluble and insoluble of Aß40 and Aß42 were measured by ELISA. The studies of in vivo pharmacodynamic effects on markers of neuroinflammation were complemented by mechanistic studies in the murine microglia BV2 cell line, using live cell imaging techniques to monitor proliferation, migration, and phagocytosis activities. RESULTS: Intervention with MW150 in KI mice during the established therapeutic time window attenuated the increased levels of IL-1ß and TNFα but not IL-6. MW150 treatment also increased the IBA1+ microglia within a 15 µm radius of the amyloid plaques, without significantly affecting overall microglia or plaque volume. Levels of IBA1, CD45, CD68, GFAP, and Aß40 and Aß42 were not affected by MW150 treatment. MW150 did not significantly alter microglial migration, proliferation, or phagocytosis in BV2 cells. CONCLUSIONS: Our results demonstrate that MW150 at an efficacious dose can selectively modulate neuroinflammatory responses associated with pathology progression without pan-suppression of normal physiological functions of microglia.

Brain glycogen serves as a critical glucosamine cache required for protein glycosylation.

Glycosylation defects are a hallmark of many nervous system diseases. However, the molecular and metabolic basis for this pathology is not fully understood. In this study, we found that N-linked protein glycosylation in the brain is metabolically channeled to glucosamine metabolism through glycogenolysis. We discovered that glucosamine is an abundant constituent of brain glycogen, which functions as a glucosamine reservoir for multiple glycoconjugates. We demonstrated the enzymatic incorporation of glucosamine into glycogen by glycogen synthase, and the release by glycogen phosphorylase by biochemical and structural methodologies, in primary astrocytes, and in vivo by isotopic tracing and mass spectrometry. Using two mouse models of glycogen storage diseases, we showed that disruption of brain glycogen metabolism causes global decreases in free pools of UDP-N-acetylglucosamine and N-linked protein glycosylation. These findings revealed fundamental biological roles of brain glycogen in protein glycosylation with direct relevance to multiple human diseases of the central nervous system.

Clear Cell Adenocarcinoma of the Urinary Bladder Is a Glycogen-Rich Tumor with Poorer Prognosis.

Clear cell adenocarcinoma (CCA) is a rare variant of urinary bladder carcinoma with a glycogen-rich phenotype and unknown prognosis. Using the National Cancer Institute's surveillance, epidemiology, and end results (SEER) program database, we documented recent trends in incidence, mortality, demographical characteristics, and survival on this rare subtype of urinary bladder cancer. The overall age-adjusted incidence and mortality of CCA was 0.087 (95% confidence interval (CI): 0.069-0.107) and 0.064 (95% CI: 0.049-0.081) respectively per million population. In comparison to non-CCAs, CCAs were more commonly associated with younger age (<60 years old, p = 0.005), female (p < 0.001), black ethnicity (p = 0.001), grade III (p < 0.001), and higher AJCC 6th staging (p < 0.001). In addition, CCA patients more frequently received complete cystectomy (p < 0.001) and beam radiation (p < 0.001) than non-CCA patients. Our study showed a poorer prognosis of CCAs compared to all other carcinomas of the urinary bladder (p < 0.001), accounted for by higher tumor staging of CCA cases. This study adds to the growing evidence that glycogen-rich cancers may have unique characteristics affecting tumor aggressiveness and patient prognosis. Additional mechanistic studies are needed to assess whether it's the excess glycogen that contributes to the higher stage at diagnosis.

Human papillomavirus insertions identify the PIM family of serine/threonine kinases as targetable driver genes in head and neck squamous cell carcinoma.

Human papillomavirus (HPV) insertions in cancer genomes have been linked to various forms of focal genomic instability and altered expression of neighboring genes. Here we tested the hypothesis that investigation of HPV insertions in a head and neck cancer squamous cell carcinoma (HNSCC) cell line would identify targetable driver genes contributing to oncogenesis of other HNSCC. In the cell line UPCI:SCC090 HPV16 integration amplified the PIM1 serine/threonine kinase gene ~16-fold, thereby increasing transcript and protein levels. We used genetic and pharmacological approaches to inhibit PIM kinases in this and other HNSCC cell lines. Knockdown of PIM1 transcripts by transfected short hairpin RNAs reduced UPCI:SCC090 viability. CRISPR/Cas9-mediated mutagenesis of PIM1 caused cell cycle arrest and apoptosis. Pharmacological inhibition of PIM family kinases decreased growth of UPCI:SCC090 and additional HNSCC cell lines in vitro and a xenograft UPCI:SCC090 model in vivo. Based on established interactions between intracellular signaling pathways and relatively high levels of gene expression in almost all HNSCC, we also evaluated combinations of PIM kinase and epidermal growth factor receptor (EGFR) inhibitors. Dual inhibition of these pathways resulted in supra-additive cell death. These data support clinical testing of PIM inhibitors alone or in combination in HNSCC.

Antibody-Mediated Enzyme Therapeutics and Applications in Glycogen Storage Diseases.

The use of antibodies as targeting molecules or cell-penetrating tools has emerged at the forefront of pharmaceutical research. Antibody-directed therapies in the form of antibody-drug conjugates, immune modulators, and antibody-directed enzyme prodrugs have been most extensively utilized as hematological, rheumatological, and oncological therapies, but recent developments are identifying additional applications of antibody-mediated delivery systems. A novel application of this technology is for the treatment of glycogen storage disorders (GSDs) via an antibody-enzyme fusion (AEF) platform to penetrate cells and deliver an enzyme to the cytoplasm, nucleus, and/or other organelles. Exciting developments are currently underway for AEFs in the treatment of the GSDs Pompe disease and Lafora disease (LD). Antibody-based therapies are quickly becoming an integral part of modern disease therapeutics.

Randomized Evaluation of Videoconference Meetings for Medical Students' Mid-clerkship Feedback Sessions.

INTRODUCTION: Videoconferencing has been employed in numerous medical education settings ranging from remote supervision of medical trainees to conducting residency interviews. However, no studies have yet documented the utility of and student response to videoconference meetings for mid-clerkship feedback (MCF) sessions required by the Liaison Committee on Medical Education (LCME). METHODS: From March 2017 to June 2018, third-year medical students rotating through the mandatory, four-week emergency medicine (EM) clerkship at a single medical school were randomly assigned either to a web-based videoconference meeting via Google Hangouts, or to a traditional in-person meeting for their MCF session. To compare students' MCF experiences we sent out an electronic survey afterward to assess the following using a 0-100 sliding scale: overall satisfaction with the meeting; the effectiveness of communication; the helpfulness of the meeting; their stress levels, and the convenience of their meeting location. The survey also collected data on these demographic variables: the name of the faculty member with whom the student met; student gender, age, and interest in EM; location prior to meeting; meeting-method preference; and number of EM shifts completed. RESULTS: During the study period, 133 third-year medical students responded to the survey. When comparing survey responses between individuals who met online and in person, we did not detect a difference in demographics with the exception of preferred meeting method (p=0.0225). We found no significant differences in the overall experience, helpfulness of the meeting, or stress levels of the meeting between those who met via videoconference vs. in-person (p=0.9909; p=0.8420; p=0.2352, respectively). However, individuals who met in-person with a faculty member rated effectiveness of communication higher than those who met via videoconference (p=0.0002), while those who met online rated convenience higher than those who met in-person (p<0.0001). Both effects remained significant after controlling for preferred meeting method (p<0.0001 and p=0.0003, respectively) and among EM-bound students (p=.0423 and p<0.0110, respectively). CONCLUSION: Our results suggest that LCME-required MCF sessions can be successfully conducted via web-based programs such as Google Hangouts without jeopardizing overall meeting experience. While the convenience of the meetings was improved, it is also important for clerkship directors to note the perceived deficit in the effectiveness of communication with videoconferencing.

Nuclear Glycogenolysis Modulates Histone Acetylation in Human Non-Small Cell Lung Cancers.

Nuclear glycogen was first documented in the early 1940s, but its role in cellular physiology remained elusive. In this study, we utilized pure nuclei preparations and stable isotope tracers to define the origin and metabolic fate of nuclear glycogen. Herein, we describe a key function for nuclear glycogen in epigenetic regulation through compartmentalized pyruvate production and histone acetylation. This pathway is altered in human non-small cell lung cancers, as surgical specimens accumulate glycogen in the nucleus. We demonstrate that the decreased abundance of malin, an E3 ubiquitin ligase, impaired nuclear glycogenolysis by preventing the nuclear translocation of glycogen phosphorylase and causing nuclear glycogen accumulation. Re-introduction of malin in lung cancer cells restored nuclear glycogenolysis, increased histone acetylation, and decreased growth of cancer cells transplanted into mice. This study uncovers a previously unknown role for glycogen metabolism in the nucleus and elucidates another mechanism by which cellular metabolites control epigenetic regulation.

Clinical Features, Survival and Prognostic Factors of Glycogen-Rich Clear Cell Carcinoma (GRCC) of the Breast in the U.S. Population.

The World Health Organization (WHO) defines glycogen-rich clear cell carcinoma (GRCC) of the breast as a carcinoma with glycogen accumulation in more than 90% of its tumor cells. Due to the rarity of this disease, its reported survival and clinical associations have been inconsistent due to reliance on case reports and limited case series. As a result, the prognostic implication of this cancer subtype remains unclear. Using the U.S. Surveillance, Epidemiology, and End Results (SEER) program database, we compared the incidence, demographics and prognostic factors of 155 cases of GRCC of the breast to 1,251,584 cases of other (non-GRCC) breast carcinomas. We demonstrate that GRCC is more likely to be identified as high grade, advanced stage, and more likely to have triple negative receptor status. GRCC cases display a poorer prognosis than non-GRCC carcinomas of the breast irrespective of age, AJCC staging, tumor grade, joint hormone receptor/human epidermal growth factor receptor 2 (HER2) status, and treatment. Similar to non-GRCC carcinomas, older age and higher American Joint Committee on Cancer (AJCC)/TNM staging were associated with poorer prognosis for GRCC, while treatment with surgery and radiation were associated with improved survival. Radiation, specifically in the setting of breast-conserving surgery, further improved survival compared to surgery alone. Our study highlights the poorer prognosis associated with glycogen accumulation in breast cancers and hence stresses the importance of identifying this more aggressive tumor type.

Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion.

Lafora disease (LD) is a fatal childhood epilepsy caused by recessive mutations in either the EPM2A or EPM2B gene. A hallmark of LD is the intracellular accumulation of insoluble polysaccharide deposits known as Lafora bodies (LBs) in the brain and other tissues. In LD mouse models, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Therefore, LBs have become a therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic α-amylase degrades LBs. We fused this amylase to a cell-penetrating antibody fragment, and this antibody-enzyme fusion (VAL-0417) degrades LBs in vitro and dramatically reduces LB loads in vivo in Epm2a-/- mice. Using metabolomics and multivariate analysis, we demonstrate that VAL-0417 treatment of Epm2a-/- mice reverses the metabolic phenotype to a wild-type profile. VAL-0417 is a promising drug for the treatment of LD and a putative precision therapy platform for intractable epilepsy.

Metabolic Alterations in Cancer Cells and the Emerging Role of Oncometabolites as Drivers of Neoplastic Change.

The mitochondrion is an important organelle and provides energy for a plethora of intracellular reactions. Metabolic dysregulation has dire consequences for the cell, and alteration in metabolism has been identified in multiple disease states-cancer being one. Otto Warburg demonstrated that cancer cells, in the presence of oxygen, undergo glycolysis by reprogramming their metabolism-termed "aerobic glycolysis". Alterations in metabolism enable cancer cells to gain a growth advantage by obtaining precursors for macromolecule biosynthesis, such as nucleic acids and lipids. To date, several molecules, termed "oncometabolites", have been identified to be elevated in cancer cells and arise from mutations in nuclear encoded mitochondrial enzymes. Furthermore, there is evidence that oncometabolites can affect mitochondrial dynamics. It is believed that oncometabolites can assist in reprogramming enzymatic pathways and providing cancer cells with selective advantages. In this review, we will touch upon the effects of normal and aberrant mitochondrial metabolism in normal and cancer cells, the advantages of metabolic reprogramming, effects of oncometabolites on metabolism and mitochondrial dynamics and therapies aimed at targeting oncometabolites and metabolic aberrations.

Mitochondrial Metabolism in Major Neurological Diseases.

Mitochondria are bilayer sub-cellular organelles that are an integral part of normal cellular physiology. They are responsible for producing the majority of a cell's ATP, thus supplying energy for a variety of key cellular processes, especially in the brain. Although energy production is a key aspect of mitochondrial metabolism, its role extends far beyond energy production to cell signaling and epigenetic regulation⁻functions that contribute to cellular proliferation, differentiation, apoptosis, migration, and autophagy. Recent research on neurological disorders suggest a major metabolic component in disease pathophysiology, and mitochondria have been shown to be in the center of metabolic dysregulation and possibly disease manifestation. This review will discuss the basic functions of mitochondria and how alterations in mitochondrial activity lead to neurological disease progression.

Long-term daily temozolomide with dose-dependent efficacy in MGMT promotor methylation negative recurrent high-grade astrocytoma.

Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown. We document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day. Prior to the daily TMZ, the patient underwent three surgical resections, radiation therapy with concurrent TMZ according to the EORTC-NCIC protocol, and subsequently bevacizumab in combination with use of the Optune device. Long-term survival of patients with recurrent malignant gliomas is uncommon, and currently no standard treatment strategies exist for these patients. We present this case to demonstrate the tolerability and dose dependency of prolonged daily TMZ dosing as a therapeutic option for recurrent anaplastic astrocytomas.

Chronic Neuropsychological Sequelae in a Patient with Nontumorous Anti-NMDA-Receptor Encephalitis.

Anti-N-methyl-D-aspartate receptor encephalitis is a neurological, autoimmune disorder tightly conceptualized only as recently as the mid-2000s. It presents itself in a combination of psychiatric, neurological, and autonomic features. We observe a unique case with probable earlier episode (prior to the mid-2000s conceptualization of the disease) and a later relapse, accompanying a comprehensive neuropsychological profile tracked after the relapse and subsequent improvement. Neurocognitive findings revealed residual frontal deficits with mood changes even in the state after plasmapheresis. This case is the first to describe posttreatment cognition in anti-NMDAR encephalitis after probable serial autoimmune episodes.

MW151 Inhibited IL-1ß Levels after Traumatic Brain Injury with No Effect on Microglia Physiological Responses.

A prevailing neuroinflammation hypothesis is that increased production of proinflammatory cytokines contributes to progressive neuropathology, secondary to the primary damage caused by a traumatic brain injury (TBI). In support of the hypothesis, post-injury interventions that inhibit the proinflammatory cytokine surge can attenuate the progressive pathology. However, other post-injury neuroinflammatory responses are key to endogenous recovery responses. Therefore, it is critical that pharmacological attenuation of detrimental or dysregulated neuroinflammatory processes avoid pan-suppression of inflammation. MW151 is a CNS-penetrant, small molecule experimental therapeutic that restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis without immunosuppression. Post-injury administration of MW151 in a closed head injury model of mild TBI suppressed acute cytokine up-regulation and downstream cognitive impairment. Here, we report results from a diffuse brain injury model in mice using midline fluid percussion. Low dose (0.5-5.0 mg/kg) administration of MW151 suppresses interleukin-1 beta (IL-1ß) levels in the cortex while sparing reactive microglia and astrocyte responses. To probe molecular mechanisms, we used live cell imaging of the BV-2 microglia cell line to demonstrate that MW151 does not affect proliferation, migration, or phagocytosis of the cells. Our results provide insight into the roles of glial responses to brain injury and indicate the feasibility of using appropriate dosing for selective therapeutic modulation of injurious IL-1ß increases while sparing other glial responses to injury.

Traditional Chinese medicine compound ShengJinRunZaoYangXue granules for treatment of primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Traditional Chinese medical treatment of primary Sjögren's syndrome has advantages over Western medicine in terms of fewer side effects and improved patient conditions. This study was a multicenter, randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of ShengJinRunZaoYangXue granules for the treatment of primary Sjögren's syndrome, including the symptoms of dry mouth and dry eye. METHODS: We undertook a 6-week, double-blind, randomized trial involving 240 patients with primary Sjögren's syndrome at five centers in East China. A computer-generated randomization schedule assigned patients at a 2:1 ratio to receive either ShengJinRunZaoYangXue granules or placebo once daily. Patients and investigators were blinded to treatment allocation. The primary endpoints were the salivary flow rate, Schirmer test results, and sugar test results. Intention-to-treat and per-protocol analyses were performed. RESULTS: All 240 patients were randomly allocated to either the treatment group (n = 160, ShengJinRunZaoYangXue granules) or placebo group (n = 80) and were included in the intention-to-treat analysis. After program violation and loss to follow-up, a total of 199 patients were included in the per-protocol analysis. At six week, intention-to-treat and per-protocol analyses of the left-eye Schirmer I test results showed an improved difference of 1.36 mm/5 min (95% CI: 0.03 to 2.69 mm/5 min) and 1.35 mm/5 min (95% CI: 0.04 to 2.73 mm/5 min), respectively, and those of the right-eye Schirmer I test results showed an improved difference of 1.12 mm/5 min (95% CI: 0.02 to 2.22 mm/5 min) and 1.12 mm/5 min (95% CI: -0.02 to 2.27 mm/5 min), respectively. There was no significant difference between the two groups before treatment. After treatment, the between-group and within-group before-and-after paired comparison results were statistically significant (P < 0.05). Intention-to-treat and per-protocol analyses showed an improved salivary flow rate by 0.04 ml/15 min (95% CI: -0.49 to 0.58 ml/15 min) and 0.04 ml/15 min (95% CI: -0.52 to 0.60 ml/15 min), respectively, but the differences were not significant. Intention-to-treat and per-protocol analyses showed that the sugar test results were improved by 1.77 minutes (95% CI: 0.11 to 3.44 minutes) and 1.84 minutes (95% CI: 0.12 to 3.55 minutes), respectively, but the differences were not significant. For the secondary endpoint, intention-to-treat and per-protocol analyses showed significant improvement in the integrated evaluation of treated patients with dry eye and dry mouth after six weeks of treatment. The incidence of adverse events was 15.6% in the treatment group and 10.0% in the placebo group. Most (94%) adverse events were mild to moderate in the two groups, and only two cases of serious adverse events occurred in the treatment group; both were caused by autoimmune liver disease. CONCLUSIONS: Six-week treatment with ShengJinRun ZaoYangXue granules for primary Sjögren's syndrome in this large-scale study improved the symptoms of dry mouth, dry eyes, and low tear flow rate with minimal adverse events.