Sustained Hemostasis With the Padlock™ Over-the-scope Clip for Gastric Fundus Dieulafoy's Lesion in the Setting of Anticoagulation Following Hemorrhagic Shock From Two Dieulafoy's Lesions.

Dieulafoy's lesions (DLs) are a rare and difficult-to-identify cause of acute gastrointestinal bleeding that can lead to hemorrhagic shock. We present a case of a 23-year-old previously healthy male presenting with melenic stools and hemorrhagic shock. Computed tomography of abdomen and pelvis with oral and intravenous contrast showed a possible source of hemorrhage as a hyperdense intraluminal material within the stomach. Initial urgent esophagogastroduodenoscopy showed a large, nonbleeding distal esophageal DL, which was treated successfully with 10 mL of 1:10,000 epinephrine and bipolar cauterization with 10 Fr Gold Probe™. Hemorrhage recurred 2 d later, prompting another esophagogastroduodenoscopy, which found another DL within the gastric fundus. Treatment with epinephrine, Gold Probe™, and through-the-scope Hemoclips was unsuccessful because of difficult visualization and positioning. A subsequent attempt was made using the over-the-scope clip (OTSC) Padlock™ Clip Defect Closure System with successful hemostasis and stabilization of the patient. His hospital course was complicated by left lower lobe segmental pulmonary embolism without right heart strain for which he was discharged on 3 months of anticoagulation with apixaban. On follow-up, there was no recurrence of gastrointestinal bleeding (GIB) despite 3 months of anticoagulation. He did not complete the Basic Underwater Demolition/SEAL (BUD/S) Training. This case report demonstrates the evaluation and management of a patient with hemorrhagic shock from two DLs and sustained hemostasis with the Padlock™ OTSC in the setting of apixaban anticoagulation.

Treatment with an antigen-specific dual microparticle system reverses advanced multiple sclerosis in mice.

Antigen-specific therapies hold promise for treating autoimmune diseases such as multiple sclerosis while avoiding the deleterious side effects of systemic immune suppression due to delivering the disease-specific antigen as part of the treatment. In this study, an antigen-specific dual-sized microparticle (dMP) treatment reversed hind limb paralysis when administered in mice with advanced experimental autoimmune encephalomyelitis (EAE). Treatment reduced central nervous system (CNS) immune cell infiltration, demyelination, and inflammatory cytokine levels. Mechanistic insights using single-cell RNA sequencing showed that treatment impacted the MHC II antigen presentation pathway in dendritic cells, macrophages, B cells, and microglia, not only in the draining lymph nodes but also strikingly in the spinal cord. CD74 and cathepsin S were among the common genes down-regulated in most antigen presenting cell (APC) clusters, with B cells also having numerous MHC II genes reduced. Efficacy of the treatment diminished when B cells were absent, suggesting their impact in this therapy, in concert with other immune populations. Activation and inflammation were reduced in both APCs and T cells. This promising antigen-specific therapeutic approach advantageously engaged essential components of both innate and adaptive autoimmune responses and capably reversed paralysis in advanced EAE without the use of a broad immunosuppressant.

Multimodality Imaging Assessment of Anomalous Aortic Origin of the Left Main Coronary Artery Presenting With Syncope and Non-ST Elevation Myocardial Infarction.

Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital abnormality associated with myocardial ischemia and sudden cardiac death. We present a case of a 20 year old previously healthy male presenting with exertional syncope and non-ST elevation myocardial infarction. Coronary computed tomography angiography showed an anomalous left main coronary artery arising from the right coronary cusp with a slit-like appearance, acute angle origin, intramural course, and a subsequent inter-arterial course between the main pulmonary artery and the proximal aorta. Cardiac magnetic resonance imaging demonstrated myocardial infarction in the distribution of the left main coronary artery. The patient underwent successful surgical correction with unroofing of the left main coronary artery. He has had no syncopal episodes or recurrence of chest pain and returned to full duty status in the United States Marine Corps. This case report demonstrates the evaluation and management of a patient with AAOCA.

Nano and Microparticle Emerging Strategies for Treatment of Autoimmune Diseases: Multiple Sclerosis and Type 1 Diabetes.

Autoimmune diseases affect 10% of the world's population, and 1 in 200 people worldwide suffer from either multiple sclerosis (MS) or type 1 diabetes (T1D). While the targeted organ systems are different, MS and T1D share similarities in terms of autoreactive immune cells playing a critical role in pathogenesis. Both diseases can be managed only symptomatically without curative remission, and treatment options are limited and non-specific. Most current therapies cause some degree of systemic immune suppression, leaving the patients susceptible to opportunistic infections and other complications. Thus, there is considerable interest in the development of immunotherapies not associated with generalized immune suppression for these diseases. This review presents current and preclinical strategies for MS and T1D treatment, emphasizing those aimed to modulate the immune response, including the most recent strategies for tolerance induction. A central focus is on the emerging approaches using nano- and microparticle platforms, their evolution as immunotherapeutic carriers, including those incorporating specific antigens to induce tolerance and reduce unwanted generalized immune suppression.

A case report of recurrent acute pancreatitis associated with life threatening atypical hemolytic uremic syndrome.

INTRODUCTION: Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy defined by the sudden onset of hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). HUS is categorized as either typical, caused by Shiga toxin-producing Escherichia coli infection, or atypical HUS (aHUS), usually complement mediated or secondary to systemic disease. We describe a rare case of aHUS in an adult male patient with recurrent acute pancreatitis. PATIENT CLINICAL FINDINGS: A 32-year-old Caucasian male presented to our institution for his third episode of alcohol-induced pancreatitis. He presented with abdominal pain, elevated lipase and pancreatic inflammation on computed tomography consistent with acute pancreatitis. While admitted, he developed sudden onset severe thrombocytopenia, AKI and hemolytic anemia. DIAGNOSIS, THERAPEUTIC INTERVENTIONS, OUTCOMES: Peripheral blood smear, haptoglobin and hemoglobin level confirmed microangiopathic hemolytic anemia. Worsening anemia, thrombocytopenia and AKI were consistent with the diagnosis of aHUS. The patient's pancreatitis resolved with supportive measures, but resolution of significant thrombocytopenia and AKI was not achieved until administration of eculizumab, a complement inhibiting therapy. Eculizumab therapy provided dramatic improvement in this patient, with platelet count increasing from a low of 11,000 to >100,000 within 48 hours of therapy. Creatinine and hemoglobin levels returned to baseline within 3 weeks. CONCLUSION: Recurrent pancreatitis is suggested as the etiology of atypical HUS in this patient and this condition should be recognized and treated in a timely manner for optimal clinical outcomes.

Bcl11b prevents fatal autoimmunity by promoting Treg cell program and constraining innate lineages in Treg cells.

Regulatory T (Treg) cells are essential for peripheral tolerance and rely on the transcription factor (TF) Foxp3 for their generation and function. Several other TFs are critical for the Treg cell program. We found that mice deficient in Bcl11b TF solely in Treg cells developed fatal autoimmunity, and Bcl11b-deficient Treg cells had severely altered function. Bcl11b KO Treg cells showed decreased functional marker levels in homeostatic conditions, inflammation, and tumors. Bcl11b controlled expression of essential Treg program genes at steady state and in inflammation. Bcl11b bound to genomic regulatory regions of Treg program genes in both human and mouse Treg cells, overlapping with Foxp3 binding; these genes showed altered chromatin accessibility in the absence of Bcl11b. Additionally, Bcl11b restrained myeloid and NK cell programs in Treg cells. Our study provides new mechanistic insights on the Treg cell program and identity control, with major implications for therapies in autoimmunity and cancer.

Acute Seroconversion of Eastern Equine Encephalitis Coinfection With California Serogroup Encephalitis Virus.

Eastern equine encephalitis (EEE) is a severe arboviral neuroinvasive disease with high mortality and neurological sequelae. Treatment for EEE is primarily supportive. Intravenous immunoglobulin (IVIg) and high-dose steroids have been used as empirical therapy for EEE with some case reports of benefit. We report a case of a patient who presented with encephalopathy with initial cerebrospinal spinal fluid (CSF) serology analysis showing California serogroup encephalitis virus IgG positivity. However, the rapid clinical deterioration of the patient into a comatose state prompted a second CSF serology analysis that showed seroconversion of high titer Eastern Equine Encephalitis virus IgM and positive titer of California serogroup encephalitis virus IgG. The patient completed a 5-day course of empiric IVIg without concurrent corticosteroid therapy but did not show significant clinical improvement.

Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation.

Polyubiquitination promotes proteasomal degradation, or signaling and localization, of targeted proteins. Here we show that the E3 ubiquitin ligase Hectd3 is necessary for pathogenic Th17 cell generation in experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. Hectd3-deficient mice have lower EAE severity, reduced Th17 program and inefficient Th17 cell differentiation. However, Stat3, but not RORγt, has decreased polyubiquitination, as well as diminished tyrosine-705 activating phosphorylation. Additionally, non-degradative polyubiquitination of Malt1, critical for NF-κB activation and Th17 cell function, is reduced. Mechanistically, Hectd3 promotes K27-linked and K29-linked polyubiquitin chains on Malt1, and K27-linked polyubiquitin chains on Stat3. Moreover, Stat3 K180 and Malt1 K648 are targeted by Hectd3 for non-degradative polyubiquitination to mediate robust generation of RORγt+IL-17Ahi effector CD4+ T cells. Thus, our studies delineate a mechanism connecting signaling related polyubiquitination of Malt1 and Stat3, leading to NF-kB activation and RORγt expression, to pathogenic Th17 cell function in EAE.

Publisher Correction: Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma.

In the originally published version of this Article, the affiliation details for Dorina Avram incorrectly included "Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, 2015 SW 16th Ave, Gainesville, FL, 32608, USA", instead of "UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA". This has now been corrected in both the PDF and HTML versions of the Article.

Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma.

During helminth infection and allergic asthma, naive CD4+ T-cells differentiate into cytokine-producing Type-2 helper (Th2) cells that resolve the infection or induce asthma-associated pathology. Mechanisms regulating the Th2 differentiation in vivo remain poorly understood. Here we report that mice lacking Bcl11b in mature T-cells have a diminished capacity to mount Th2 responses during helminth infection and allergic asthma, showing reduced Th2 cytokines and Gata3, and elevated Runx3. We provide evidence that Bcl11b is required to maintain chromatin accessibility at Th2-cytokine promoters and locus-control regions, and binds the Il4 HS IV silencer, reducing its accessibility. Bcl11b also binds Gata3-intronic and downstream-noncoding sites, sustaining the Gata3 expression. In addition, Bcl11b binds and deactivates upstream enhancers at Runx3 locus, restricting the Runx3 expression and its availability to act at the Il4 HS IV silencer. Thus, our results establish novel roles for Bcl11b in the regulatory loop that licenses Th2 program in vivo.

Paraneoplastic Lambert-Eaton Myasthenic Syndrome With Limbic Encephalitis: Clinical Correlation With the Coexistence of Anti-VGCC and Anti-GABAB Receptor Antibodies.

OBJECTIVE: To characterize Lambert-Eaton myasthenic syndrome and limbic encephalitis with coexistent voltage-gated calcium channel (VGCC) antibody and γ-aminobutyric acid (GABA) B receptor antibody. METHODS: Case study. RESULTS: A 57-year-old man presented with 6 months of weakness, unsteadiness, and vision difficulties. Examination revealed proximal weakness and diminished reflexes. Electrodiagnostic study revealed low-amplitude motor potentials and facilitation on high-frequency stimulation. Laboratory evaluation identified P/Q-type VGCC antibody. Positron emission tomography identified a mediastinal lesion, confirmed as small-cell lung carcinoma. The patient developed confusion and seizures. Cerebrospinal fluid analysis identified antibodies to GABAB receptor. CONCLUSIONS: This case describes a patient with Lambert-Eaton myasthenic syndrome, limbic encephalitis, and autoantibodies to VGCC and GABAB receptor. Atypical presentation of paraneoplastic neurological syndromes could indicate the presence of a second antibody that may have significant impact on therapy.

An antigen-specific semi-therapeutic treatment with local delivery of tolerogenic factors through a dual-sized microparticle system blocks experimental autoimmune encephalomyelitis.

Antigen-specific treatments are highly desirable for autoimmune diseases in contrast to treatments which induce systemic immunosuppression. A novel antigen-specific therapy has been developed which, when administered semi-therapeutically, is highly efficacious in the treatment of the mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). The treatment uses dual-sized, polymeric microparticles (dMPs) loaded with specific antigen and tolerizing factors for intra- and extra-cellular delivery, designed to recruit and modulate dendritic cells toward a tolerogenic phenotype without systemic release. This approach demonstrated robust efficacy and provided complete protection against disease. Therapeutic efficacy required encapsulation of the factors in controlled-release microparticles and was antigen-specific. Disease blocking was associated with a reduction of infiltrating CD4+ T cells, inflammatory cytokine-producing pathogenic CD4+ T cells, and activated macrophages and microglia in the central nervous system. Furthermore, CD4+ T cells isolated from dMP-treated mice were anergic in response to disease-specific, antigen-loaded splenocytes. Additionally, the frequency of CD86hiMHCIIhi dendritic cells in draining lymph nodes of EAE mice treated with Ag-specific dMPs was reduced. Our findings highlight the efficacy of microparticle-based drug delivery platform to mediate antigen-specific tolerance, and suggest that such a multi-factor combinatorial approach can act to block autoimmunity.

Transcription Factor Bcl11b Controls Effector and Memory CD8 T cell Fate Decision and Function during Poxvirus Infection.

CD8+ T cells play an important role in host resistance to many viral infections, but the underlying transcriptional mechanisms governing their differentiation and functionality remain poorly defined. By using a highly virulent systemic and respiratory poxvirus infection in mice, we show that the transcription factor Bcl11b provides a dual trigger that sustains the clonal expansion of virus-specific effector CD8+ T cells, while simultaneously suppressing the expression of surface markers associated with short-lived effector cell (SLEC) differentiation. Additionally, we demonstrate that Bcl11b supports the acquisition of memory precursor effector cell (MPEC) phenotype and, thus, its absence causes near complete loss of lymphoid and lung-resident memory cells. Interestingly, despite having normal levels of T-bet and Eomesodermin, Bcl11b-deficient CD8+ T cells failed to execute effector differentiation needed for anti-viral cytokine production and degranulation, suggesting a non-redundant role of Bcl11b in regulation of this program. Thus, Bcl11b is a critical player in fate decision of SLECs and MPECs, as well as effector function and memory formation.

Downregulation of a novel human gene, ROGDI, increases radiosensitivity in cervical cancer cells.

ROGDI is a protein that contains a leucine zipper domain and may be involved in cell proliferation. In addition, ROGDI is associated with genome stability by regulating the activity of a DNA damage marker, γ-H2AX. The role of ROGDI in tumor radiosensitization has not been investigated. Previous studies have indicated that radiosensitivity is associated with DNA repair and the cell cycle. In general, the G2/M DNA damage checkpoint is more sensitive to radiation, whereas the G1/S phase transition is more resistant to radiation. Inhibition of cyclin-dependent kinases (CDKs) can lead to a halt of cell cycle progression and a stay at different phases or checkpoints. Our data show that the downregulation of ROGDI led to a decreased expression of CDK 1, 2, cyclin A, B and resulted in a G2/M phase transition block. In addition, the downregulation of ROGDI increased cell accumulation at the G2 phase as detected using flow cytometry and decreased cell survival as revealed by clonogenic assay in HeLa and C33A cells following irradiation. These findings suggest that the downregulation of ROGDI can mediate radiosensitivity by blocking cells at G2/M, the most radiosensitive phase of the cell cycle, as well as exerting deleterious effects in the form of DNA damage, as shown by increased γ-H2AX activation.

Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival.

Invariant natural killer T (iNKT) cells are innate-like T cells that recognize glycolipid antigens and play critical roles in regulation of immune responses. Based on expression of the transcription factors (TFs) Tbet, Plzf, and Rorγt, iNKT cells have been classified in effector subsets that emerge in the thymus, namely, iNKT1, iNKT2, and iNKT17. Deficiency in the TF Bcl11b in double-positive (DP) thymocytes has been shown to cause absence of iNKT cells in the thymus and periphery due to defective self glycolipid processing and presentation by DP thymocytes and undefined intrinsic alterations in iNKT precursors. We used a model of cre-mediated postselection deletion of Bcl11b in iNKT cells to determine its intrinsic role in these cells. We found that Bcl11b is expressed equivalently in all three effector iNKT subsets, and its removal caused a reduction in the numbers of iNKT1 and iNKT2 cells, but not in the numbers of iNKT17 cells. Additionally, we show that Bcl11b sustains subset-specific cytokine production by iNKT1 and iNKT2 cells and restricts expression of iNKT17 genes in iNKT1 and iNKT2 subsets, overall restraining the iNKT17 program in iNKT cells. The total numbers of iNKT cells were reduced in the absence of Bcl11b both in the thymus and periphery, associated with the decrease in iNKT1 and iNKT2 cell numbers and decrease in survival, related to changes in survival/apoptosis genes. Thus, these results extend our understanding of the role of Bcl11b in iNKT cells beyond their selection and demonstrate that Bcl11b is a key regulator of iNKT effector subsets, their function, identity, and survival.