Post-infectious Transverse Myelitis Secondary to Hand, Foot, and Mouth Disease in a Pregnant Daycare Worker.

Transverse myelitis (TM) is a rare inflammatory disorder of the spinal cord that infections, vaccines, and autoimmune processes can cause or may have no discernible cause. About half of the cases are caused by an infection, usually a viral respiratory infection, flu-like illness, or sometimes a gastrointestinal infection. Although coxsackieviruses and enteroviruses are known to cause TM, it is more commonly associated with respiratory symptoms or systemic signs than a rash. In this case, we present a pregnant daycare worker who had a case of longitudinally extensive TM after an episode of hand, foot, and mouth disease (HFMD), which only showed the typical rash without fever or systemic signs.

Hospital Readmission Rates in Patients With Neuromyelitis Optica Spectrum Disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an aggressive central nervous system astrocytopathy often resulting in rapid neurologic decline. Patients have recurrent flares that require immunomodulatory therapy for relapse prevention. These patients are usually hospitalized and may need rehospitalization after decline. Hospital readmission rates are important indicators that can be used to gauge health care quality and have direct implications on hospital compensation. This study aims to identify high-risk characteristics of patients with NMOSD that can be used to predict hospital readmissions. METHODS: The 2017 Nationwide Readmissions Database was searched for hospital admissions for NMOSD in the United States. All patients with hospital readmission within 30 days of discharge from the index hospitalization were included. RESULTS: The 30-day all-cause readmission rate for NMOSD was 11.9% (95% CI, 10.6%-13.3%). Patients aged 65 to 74 years had higher odds of readmission; those with private insurance had decreased odds. Sex did not affect readmission. Several comorbidities, such as respiratory failure, peripheral vascular disease, neurocognitive disorders, and neurologic blindness, were predictive of readmissions. Plasma exchange increased the odds of readmission, whereas intravenous immunoglobulin and immunomodulatory infusions, such as chemotherapies and monoclonal antibodies, did not affect readmission. CONCLUSIONS: The most common etiologies for 30-day read-mission were neurologic, infectious, and respiratory. Treatment targeted toward these etiologies may result in reduced overall readmission, thereby decreasing overall disease burden.

Cerebral Cavernous Malformation Associated With Left Middle Cerebral Artery (MCA) Aneurysm and Bilateral Internal Carotid Artery (ICA) Dissections.

Cerebral cavernous malformations (CCMs) are the second most common type of cerebral vascular lesions. They are often associated with other vascular lesions, typically developmental venous anomalies. CCMs are not known to be associated with cerebral aneurysms and there is a paucity of literature on this occurrence. We report the case of a patient who presented with a focal seizure from a symptomatic CCM with acute hemorrhage and was incidentally found to have a cerebral aneurysm and bilateral internal carotid artery (ICA) dissections secondary to fibromuscular dysplasia. The presence of a cerebral aneurysm has clinical implications as these patients will need closer monitoring.

Readmissions in patients with cerebral cavernous malformations: a national readmission database study.

BACKGROUND: Cerebral cavernous malformations (CCMs) are microvascular CNS lesions prone to hemorrhage leading to neurological sequela such as stroke and seizure. A subset of CCM patients have aggressive disease leading to multiple bleeding events, likely resulting multiple hospitalizations. Hospital admission rates are an important metric that has direct financial impact on hospitals and an indicator of overall disease burden. Furthermore, analysis of hospital readmissions can lead to early identification of high-risk patients and provides insight into the pathogenesis of CCM lesions. The purpose of this study is to identify high risk CCM patients with increased all cause readmission and comorbidities associated with increased readmissions. METHODS: All US hospital admissions due to CCMs were searched using the 2017 National Readmission Database (NRD). Patients with readmissions within 30 days of discharge from index hospitalization were identified and analyzed, relative to the remaining population. RESULTS: Among all patients hospitalized for CCM, 14.9% (13.7-16.2%) required all cause readmission within 30 days. Multivariate logistical regression analysis showed that substance abuse (P=0.003), diabetes (P=0.018), gastrointestinal bleed (P=0.002), renal failure (P=0.027), and coronary artery disease (P=0.010) were predictive of all cause readmissions, while age group 65-74 (P=0.042), private insurance (P<0.001), and treatment at a metropolitan teaching institution (P=0.039) were protective. Approximately half of all readmissions are caused by neurological (33.9%) and infectious (14.6%) etiologies. The 30-day lesion bleeding rate after index hospitalization is 0.8% (0.5-1.2%). CONCLUSIONS: All identified comorbidities associated with increased risks of readmission contribute to vascular stress, suggesting its role in lesion pathogenesis. This is the first and only study to analyze readmission metrics for CCMs in order to identify high risk patient factors to date.

mPR-Specific Actions Influence Maintenance of the Blood-Brain Barrier (BBB).

Cerebral cavernous malformations (CCMs) are characterized by abnormally dilated intracranial microvascular sinusoids that result in increased susceptibility to hemorrhagic stroke. It has been demonstrated that three CCM proteins (CCM1, CCM2, and CCM3) form the CCM signaling complex (CSC) to mediate angiogenic signaling. Disruption of the CSC will result in hemorrhagic CCMs, a consequence of compromised blood-brain barrier (BBB) integrity. Due to their characteristically incomplete penetrance, the majority of CCM mutation carriers (presumed CCM patients) are largely asymptomatic, but when symptoms occur, the disease has typically reached a clinical stage of focal hemorrhage with irreversible brain damage. We recently reported that the CSC couples both classic (nuclear; nPRs) and nonclassic (membrane; mPRs) progesterone (PRG)-receptors-mediated signaling within the CSC-mPRs-PRG (CmP) signaling network in nPR(-) breast cancer cells. In this report, we demonstrate that depletion of any of the three CCM genes or treatment with mPR-specific PRG actions (PRG/mifepristone) results in the disruption of the CmP signaling network, leading to increased permeability in the nPR(-) endothelial cells (ECs) monolayer in vitro. Finally, utilizing our in vivo hemizygous Ccm mutant mice models, we demonstrate that depletion of any of the three CCM genes, in combination with mPR-specific PRG actions, is also capable of leading to defective homeostasis of PRG in vivo and subsequent BBB disruption, allowing us to identify a specific panel of etiological blood biomarkers associated with BBB disruption. To our knowledge, this is the first report detailing the etiology to predict the occurrence of a disrupted BBB, an indication of early hemorrhagic events.

Readmission Rates in Patients With Multiple Sclerosis: A Nationwide Cohort Study.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory central nervous system demyelinating disorder resulting in neurologic decline. Patients predominantly have a relapsing and remitting disease course requiring multiple hospitalizations and, occasionally, rehospitalizations. Hospitalization readmission rates are important metrics that have direct financial implications for hospitals and serve as an indicator of disease burden on patients and society. We sought to analyze hospital readmissions of patients with MS and identify the subsequent predictive characteristics/comorbidities for readmission. METHODS: All hospital admissions due to MS were queried using the 2017 Nationwide Readmissions Database. All patients with nonelective rehospitalization within 30 days of discharge were examined. RESULTS: The 30-day readmission rate for MS is 10.6% (range, 10.4%-10.8%). Female sex has a protective role in readmission rates, and age has no effect. Comorbidities, including heart failure, acute kidney injury, chronic obstructive pulmonary disease, chronic kidney disease, respiratory failure, substance abuse, diabetes, hypertension, peripheral artery disease, liver failure, anemia, coagulation disorders, cancer, depression, and infections, are predictive of readmissions, whereas sleep apnea is protective. No effect is seen with neurologic blindness, plasma exchange, or intravenous immunoglobulin treatment. CONCLUSIONS: Several medical comorbidities are predictive of hospital readmission of patients with MS. Most rehospitalizations are due to infectious and neurologic etiologies; thus, targeted interventions may lead to lower readmission rates.

CCM signaling complex (CSC) couples both classic and non-classic Progesterone receptor signaling.

BACKGROUND: Breast cancer, the most diagnosed cancer, remains the second leading cause of cancer death in the United States, and excessive Progesterone (PRG) or Mifepristone (MIF) exposure may be at an increased risk for developing breast cancer. PRG exerts its cellular responses through signaling cascades involving classic, non-classic, or combined responses by binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs). Currently, the intricate balance and switch mechanisms between these two signaling cascades remain elusive. Three genes, CCM1-3, form the CCM signaling complex (CSC) which mediates multiple signaling cascades. METHODS: Utilizing molecular, cellular, Omics, and systems biology approaches, we analyzed the relationship among the CSC, PRG, and nPRs/mPRs during breast cancer tumorigenesis. RESULTS: We discovered that the CSC plays an essential role in coupling both classic and non-classic PRG signaling pathways by mediating crosstalk between them, forming the CmPn (CSC-mPRs-PRG-nPRs) signaling network. We found that mPR-specific PRG actions (PRG + MIF) play an essential role in this CmPn network during breast cancer tumorigenesis. Additionally, we have identified 4 categories of candidate biomarkers (9 intrinsic, 2 PRG-inducible, 1 PRG-repressive, 1 mPR-specific PRG-repressive, and 2 mPR-responsive) for Luminal-A breast cancers during tumorigenesis and have confirmed the prognostic application of RPL13 and RPL38 as intrinsic biomarkers using a dual validation method. CONCLUSIONS: We have discovered that the CSC plays an essential role in the CmPn signaling network for Luminal-A breast cancers with identification of two intrinsic biomarkers. Video Abstract.

CmP signaling network unveils novel biomarkers for triple negative breast cancer in African American women.

Breast cancer is the most diagnosed cancer worldwide and remains the second leading cause of cancer death. While breast cancer mortality has steadily declined over the past decades through medical advances, an alarming disparity in breast cancer mortality has emerged between African American women (AAW) and Caucasian American women (CAW). New evidence suggests more aggressive behavior of triple-negative breast cancer (TNBC) in AAW may contribute to racial differences in tumor biology and mortality. Progesterone (PRG) can exert its cellular effects through either its classic, non-classic, or combined responses through binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs), warranting both pathways equally important in PRG-mediated signaling. In our previous report, we demonstrated that the CCM signaling complex (CSC) consisting of CCM1, CCM2, and CCM3 can couple both nPRs and mPRs signaling cascades to form a CSC-mPRs-PRG-nPRs (CmPn) signaling network in nPR positive(+) breast cancer cells. In this report, we furthered our research by establishing the CSC-mPRs-PRG (CmP) signaling network in nPR(-) breast cancer cells, demonstrating that a common core mechanism exists, regardless of nPR(+⁣/⁣-) status. This is the first report stating that inducible expression patterns exist between CCMs and major mPRs in TNBC cells. Furthermore, we firstly show mPRs in TNBC cells are localized in the nucleus and participate in nucleocytoplasmic shuttling in a coordinately synchronized fashion with CCMs under steroid actions, following the same cellular distribution as other well-defined steroid hormone receptors. Finally, for the first time, we deconvoluted the CmP signalosome by using systems biology and TNBC clinical data, which helped us understand key factors within the CmP network and identify 6 specific biomarkers with potential clinical applications associated with AAW-TNBC tumorigenesis. These novel biomarkers could have immediate clinical implications to dramatically improve health disparities among AAW-TNBCs.

In-silico analysis of nonsynonymous genomic variants within CCM2 gene reaffirm the existence of dual cores within typical PTB domain.

PURPOSE: The objective of this study is to validate the existence of dual cores within the typical phosphotyrosine binding (PTB) domain and to identify potentially damaging and pathogenic nonsynonymous coding single nuclear polymorphisms (nsSNPs) in the canonical PTB domain of the CCM2 gene that causes cerebral cavernous malformations (CCMs). METHODS: The nsSNPs within the coding sequence for PTB domain of human CCM2 gene, retrieved from exclusive database searches, were analyzed for their functional and structural impact using a series of bioinformatic tools. The effects of mutations on the tertiary structure of the PTB domain in human CCM2 protein were predicted to examine the effect of nsSNPs on the tertiary structure of PTB Cores. RESULTS: Our mutation analysis, through alignment of protein structures between wildtype CCM2 and mutant, predicted that the structural impacts of pathogenic nsSNPs is biophysically limited to only the spatially adjacent substituted amino acid site with minimal structural influence on the adjacent core of the PTB domain, suggesting both cores are independently functional and essential for proper CCM2 PTB function. CONCLUSION: Utilizing a combination of protein conservation and structure-based analysis, we analyzed the structural effects of inherited pathogenic mutations within the CCM2 PTB domain. Our results predicted that the pathogenic amino acid substitutions lead to only subtle changes locally, confined to the surrounding tertiary structure of the PTB core within which it resides, while no structural disturbance to the neighboring PTB core was observed, reaffirming the presence of independently functional dual cores in the CCM2 typical PTB domain.

Thrombocytopenia Due to Direct Oral Anticoagulation and Low-Molecular-Weight Heparin.

Direct oral anticoagulants (DOACs) are becoming increasingly prevalent in the general population for anticoagulation. However, rare adverse effects from these medications are still being discovered. Thrombocytopenia has previously been reported with these medications, but its clinical significance is still unknown. We present a patient who developed thrombocytopenia from apixaban and who subsequently developed a severe presentation of heparin-induced thrombocytopenia (HIT) from enoxaparin. This raises the possibility that thrombocytopenia from oral anticoagulants increases the likelihood of the development of heparin-induced thrombocytopenia.

Resurgence of phosphotyrosine binding domains: Structural and functional properties essential for understanding disease pathogenesis.

BACKGROUND: Phosphotyrosine Binding (PTB) Domains, usually found on scaffold proteins, are pervasive in many cellular signaling pathways. These domains are the second-largest family of phosphotyrosine recognition domains and since their initial discovery, dozens of PTB domains have been structurally determined. SCOPE OF REVIEW: Due to its signature sequence flexibility, PTB domains can bind to a large variety of ligands including phospholipids. PTB peptide binding is divided into classical binding (canonical NPXY motifs) and non-classical binding (all other motifs). The first atypical PTB domain was discovered in cerebral cavernous malformation 2 (CCM2) protein, while only one third in size of the typical PTB domain, it remains functionally equivalent. MAJOR CONCLUSIONS: PTB domains are involved in numerous signaling processes including embryogenesis, neurogenesis, and angiogenesis, while dysfunction is linked to major disorders including diabetes, hypercholesterolemia, Alzheimer's disease, and strokes. PTB domains may also be essential in infectious processes, currently responsible for the global pandemic in which viral cellular entry is suspected to be mediated through PTB and NPXY interactions. GENERAL SIGNIFICANCE: We summarize the structural and functional updates in the PTB domain over the last 20 years in hopes of resurging interest and further analyzing the importance of this versatile domain.

Redefining PTB domain into independently functional dual cores.

Current understanding of phosphotyrosine binding (PTB) domain is limited. Recently, we revealed a novel atypical phosphotyrosine binding (aPTB) domain in CCM2, making it a dual PTB domain-containing protein. Since aPTB domain is only 1/3 of the size of typical PTB domain, we explored the possibility to decrease the size of PTB domain and demonstrate that the typical PTB domain can be divided into two similarly structural and functional cores that can independently bind to NPXY motif. Further, we reduced each PTB core into a minimum core motif (mCore) which is the functional unit of PTB domains and structurally similar to the novel aPTB domain. Based on structural data, we developed several cis- and trans-inhibitors for NPXY binding scheme, with potential applications for therapeutic strategies in human health conditions.

Alternatively spliced isoforms reveal a novel type of PTB domain in CCM2 protein.

Cerebral cavernous malformations (CCMs) is a microvascular disorder in the central nervous system. Despite tremendous efforts, the causal genetic mutation in some CCM patients has not be identified, raising the possibility of an unknown CCM locus. The CCM2/MGC4607 gene has been identified as one of three known genes causing CCMs. In this report, we defined a total of 29 novel exons and 4 novel promoters in CCM2 genomic structure and subsequently identified a total of 50 new alternative spliced isoforms of CCM2 which eventually generated 22 novel protein isoforms. Genetic analysis of CCM2 isoforms revealed that the CCM2 isoforms can be classified into two groups based on their alternative promoters and alternative start codon exons. Our data demonstrated that CCM2 isoforms not only are specific in their subcellular compartmentation but also have distinct cellular expression patterns among various tissues and cells, indicating the pleiotropic cellular roles of CCM2 through their multiple isoforms. In fact, the complexity of the CCM2 genomic structure was reflected by the multiple layers of regulation of CCM2 expression patterns. At the transcriptional level, it is accomplished by alternative promoters, alternative splicing, and multiple transcriptional start sites and termination sites; while at the translational level, it is carried out with various cellular functions with a distinguishable CCM2 protein group pattern, specified abundance and composition of selective isoforms in a cell and tissue specific fashion. Through experimentation, we discovered a unique phosphotyrosine binding (PTB) domain, namely atypical phosphotyrosine binding (aPTB) domain. Some long CCM2 isoform proteins contain both classes of PTB domains, making them a dual PTB domain-containing protein. Both CCM1 and CCM3 can bind competitively to this aPTB domain, indicating CCM2 as the cornerstone for CCM signaling complex (CSC).

Asymmetric Bisvinylogous Aldolation of Aldehydes via 2-Oxonia-Cope Rearrangement Enabling Total Stereochemical Control.

Highly stereoselective 2-oxonia-Cope rearrangement reactions between newly designed bisvinylogous aldolation synthons and aldehydes, which can provide ε-hydroxy-α,ß,γ,δ-unsaturated esters with excellent enantioselectivities, as well as with unprecedented E- and Z-selectivities without regioselectivity issues, are described.

Rationally Designed Chiral Synthons Enabling Asymmetric Z- and E-Selective Vinylogous Aldol Reactions of Aldehydes.

In a conceptually different approach, highly stereoselective 2-oxonia-Cope rearrangement reactions between rationally designed nonracemic vinylogous aldolation synthons and aldehydes are described to provide δ-hydroxy-α,ß-unsaturated esters with excellent enantioselectivities and, for the first time, unprecedented Z- and E-selectivities without the regioselectivity issue.

Highly Stereoselective 2-Oxonia-Cope Rearrangement: A Platform Enabling At-Will Control of Regio-, Enantio-, and Diastereoselectivity in the Vinylogous Aldol Reactions of Aldehydes.

A distinctly different approach for the vinylogous aldolation of aldehydes is described, which exploits 2-oxonia-Cope rearrangement reactions between two readily available partners, a set of rationally designed chiral homoallylic alcohol synthons and aldehydes, under simple conditions. In these processes, chirality transfer from the former to the latter is nearly perfect, giving rise to excellent enantio- and diastereoselectivity without the regioselectivity issue associated with traditional vinylogous aldol reactions.

Recent advances in cerebral cavernous malformation research.

Cerebral cavernous malformations (CCM) are manifested by microvascular lesions characterized by leaky endothelial cells with minimal intervening parenchyma predominantly in the central nervous system predisposed to hemorrhagic stroke, resulting in focal neurological defects. Till date, three proteins are implicated in this condition: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). These multi-domain proteins form a protein complex via CCM2 that function as a docking site for the CCM signaling complex, which modulates many signaling pathways. Defects in the formation of this signaling complex have been shown to affect a wide range of cellular processes including cell-cell contact stability, vascular angiogenesis, oxidative damage protection and multiple biogenic events. In this review we provide an update on recent advances in structure and function of these CCM proteins, especially focusing on the signaling cascades involved in CCM pathogenesis and the resultant CCM cellular phenotypes in the past decade.

Novel functions of CCM1 delimit the relationship of PTB/PH domains.

BACKGROUND: Three NPXY motifs and one FERM domain in CCM1 makes it a versatile scaffold protein for tethering the signaling components together within the CCM signaling complex (CSC). The cellular role of CCM1 protein remains inadequately expounded. Both phosphotyrosine binding (PTB) and pleckstrin homology (PH) domains were recognized as structurally related but functionally distinct domains. METHODS: By utilizing molecular cloning, protein binding assays and RT-qPCR to identify novel cellular partners of CCM1 and its cellular expression patterns; by screening candidate PTB/PH proteins and subsequently structurally simulation in combining with current X-ray crystallography and NMR data to defined the essential structure of PTB/PH domain for NPXY-binding and the relationship among PTB, PH and FERM domain(s). RESULTS: We identified a group of 28 novel cellular partners of CCM1, all of which contain either PTB or PH domain(s), and developed a novel classification system for these PTB/PH proteins based on their relationship with different NPXY motifs of CCM1. Our results demonstrated that CCM1 has a wide spectrum of binding to different PTB/PH proteins and perpetuates their specificity to interact with certain PTB/PH domains through selective combination of three NPXY motifs. We also demonstrated that CCM1 can be assembled into oligomers through intermolecular interaction between its F3 lobe in FERM domain and one of the three NPXY motifs. Despite being embedded in FERM domain as F3 lobe, F3 module acts as a fully functional PH domain to interact with NPXY motif. The most salient feature of the study was that both PTB and PH domains are structurally and functionally comparable, suggesting that PTB domain is likely evolved from PH domain with polymorphic structural additions at its N-terminus. CONCLUSIONS: A new ß1A-strand of the PTB domain was discovered and new minimum structural requirement of PTB/PH domain for NPXY motif-binding was determined. Based on our data, a novel theory of structure, function and relationship of PTB, PH and FERM domains has been proposed, which extends the importance of the NPXY-PTB/PH interaction on the CSC signaling and/or other cell receptors with great potential pointing to new therapeutic strategies. GENERAL SIGNIFICANCE: The study provides new insight into the structural characteristics of PTB/PH domains, essential structural elements of PTB/PH domain required for NPXY motif-binding, and function and relationship among PTB, PH and FERM domains.