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OBJECTIVE: This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti-neutrophil extracellular trap (anti-NET) antibodies in a multinational cohort of antiphospholipid (aPL) antibody-positive patients who did not have lupus. METHODS: Anti-NET IgG/IgM levels were measured in serum samples from 389 aPL-positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n = 214), we profiled autoantibodies using an autoantigen microarray platform. RESULTS: We found elevated levels of anti-NET IgG and/or IgM in 45% of the aPL-positive patients. High anti-NET antibody levels are associated with more circulating myeloperoxidase (MPO)-DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti-NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti-NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti-NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti-NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO-DNA complexes, and nucleosomes. Anti-NET IgM positivity was associated with autoantibodies targeting single-stranded DNA, double-stranded DNA, and proliferating cell nuclear antigen. CONCLUSION: These data reveal high levels of anti-NET antibodies in 45% of aPL-positive patients, where they potentially activate the complement cascade. While anti-NET IgM may especially recognize DNA in NETs, anti-NET IgG species appear to be more likely to target NET-associated protein antigens.
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Síndrome Antifosfolípido , Trampas Extracelulares , Humanos , Anticuerpos Antifosfolípidos , Autoanticuerpos , Inmunoglobulina G , Inmunoglobulina MRESUMEN
PURPOSE OF REVIEW: Antiphospholipid syndrome (APS) is an acquired thrombo-inflammatory disease that has morbid and sometimes devastating effects on patients and their families. This review will discuss the most recent international societal treatment guidelines and propose practical management algorithms for various APS sub-types. RECENT FINDINGS: APS represents a disease spectrum. Although thrombosis and pregnancy morbidities are traditional hallmarks of APS, a variety of extra-criteria clinical phenotypes can often be seen, which makes clinical management more challenging. Primary APS thrombosis prophylaxis should take a risk-stratified approach. Although vitamin K antagonists (VKAs) or heparin/low molecular weight heparin (LMWH) remain the preferred treatment for secondary APS thrombosis prophylaxis, some international society guidelines support the use of direct oral anticoagulants (DOACs) in certain circumstances. Careful monitoring and individualized obstetric care with the use of aspirin and heparin/LMWH will improve pregnancy outcomes among pregnant individuals with APS. Treatment of microvascular and catastrophic APS remains challenging. While the addition of various immunosuppressive agents is often utilized, further systemic evaluations of their use are warranted before definitive recommendations can be made. Several new therapeutic strategies are on the horizon that might enable more personalized and targeted APS management in the near future. SUMMARY: Although the knowledge of APS pathogenesis has grown in recent years, the management principles and strategies are largely unchanged. There is an unmet need for evaluating pharmacological agents, beyond anticoagulants, that target diverse thromboinflammatory pathways.
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Síndrome Antifosfolípido , Trombosis , Embarazo , Femenino , Humanos , Síndrome Antifosfolípido/complicaciones , Síndrome Antifosfolípido/tratamiento farmacológico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Anticoagulantes/uso terapéutico , Aspirina/uso terapéutico , Trombosis/tratamiento farmacológicoRESUMEN
PURPOSE OF REVIEW: Antiphospholipid syndrome (APS) is an acquired thrombo-inflammatory disease associated with diverse clinical manifestations in the setting of persistently circulating antiphospholipid antibodies (aPL). This review summarizes recent developments in our understanding of the pathogenesis of APS and its various clinical manifestations with a focus on the activation of endothelial cells, complement, and neutrophils. RECENT FINDINGS: Elucidating the pathophysiology that leads to the diverse array of clinical manifestations of APS is an area of active exploration. Here, we highlight recent studies that have explored various impacts of endothelial activation and injury in APS, including the promotion of circulating endothelial cells and extracellular vesicles; the association between complement activity and different APS phenotypes, including pregnancy loss; and the relationship between neutrophil extracellular traps (NETs) and high-risk aPL profiles in thrombotic APS. We also call attention to recent work that proposes approaches to mitigating these pathologic changes as potential treatment strategies for APS. Lastly, we highlight promising future directions in APS research, such as multiomics approaches to molecularly stratifying APS patients. SUMMARY: The identification of novel aspects of pathogenesis and more nuanced approaches to phenotyping patients will hopefully pave the way for developing safer and more effective patient-specific therapeutic strategies for APS.
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Síndrome Antifosfolípido , Embarazo , Femenino , Humanos , Células Endoteliales , Anticuerpos Antifosfolípidos , Proteínas del Sistema Complemento , Inflamación/complicacionesRESUMEN
OBJECTIVE: This study assessed patient-reported outcomes (PROs) in individuals with persistently positive antiphospholipid antibodies (aPL) to better understand how living with aPL may affect their quality of life. METHODS: Patients completed Patient-Reported Outcomes Measurement Information System Physical Function (PF) and Cognitive Function (CF) Short Forms as well as the pain intensity (PI) rating (scale of 1-10). Patients were characterized for demographics, clinical manifestations of antiphospholipid syndrome (APS), cardiovascular risk factors, laboratory test results, and medication usage. Multivariate modeling was done via linear regression. RESULTS: Of 139 patients, 89 had primary APS, 21 had secondary APS, and 29 had persistent aPL without meeting clinical criteria for APS. The average T scores (±SD) for PF and CF were 45.4 ± 9.2 and 48.6 ± 11.6, respectively; the average for PI was 3.0 ± 2.6. Approximately half of the patients (47%) endorsed at least mild impairment in PF (T score < 45). Mean PF, CF, and PI did not differ between diagnostic groups. Individuals who endorsed more impairment on one measure also tended to endorse more impairment on another (Pearson r = 0.43-0.59). In the multivariate models, age, smoking, pain medications, and serotonergic medications were associated with impairment in at least one PRO domain. The Damage Index for APS was significantly correlated with both PF and CF. CONCLUSION: Individuals living with APS endorsed more impairment in PF (and potentially CF) than expected for the general population. The relationship between certain medications and PROs warrants further study, as does the longitudinal trajectory of these and other PROs.
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Henoch-Schonlein purpura (HSP) is a multi-system autoimmune disease that is relatively common in pediatric patients. HSP usually manifests as palpable purpura, arthralgia, abdominal pain, and acute kidney injury. Here, we present a case of an adult male with hematemesis as the initial presenting symptom of HSP. A previously healthy, 18-year-old Caucasian male presented with a one-day history of hematemesis associated with abdominal pain and non-bloody diarrhea. He also reported bilateral knee and ankle arthralgias with a painless skin rash on both lower extremities. Physical exam was positive for palpable, purpuric, non-blanchable skin rash involving bilateral lower extremities. Notable labs on admission included a white cell count of 10.8 x 109/L and C-reactive protein of 4.8 mg/L. Upper endoscopy showed non-bleeding erosive gastropathy and duodenal erosions. Skin biopsy of the left leg showed immunoglobulin A (IgA) deposition within the walls of the superficial dermal vessels. The patient was started on intravenous methylprednisolone 500 mg daily followed by a steroid taper. Due to incomplete clinical response to steroids, mycophenolate mofetil 1000 mg twice daily was added and maintained for three months. His symptoms improved significantly, and he no longer complained of abdominal pain or diarrhea. Gastrointestinal manifestations are common in HSP patients. However, the diagnosis will be challenging when these symptoms precede other classical manifestations of HSP. History and physical exam are key components in accurately diagnosing HSP; nevertheless, skin biopsy remains the gold standard to confirm the diagnosis.
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BACKGROUND: There are no prospective studies comparing hospitalization and post-hospitalization outcomes between teaching internal medicine services and non-teaching hospitalists, and no prospective studies comparing these outcomes between locum and employed hospitalists. OBJECTIVE: To compare the length of stay, hospital costs readmission rate, and mortality rate in patients treated by teaching internal medicine services vs. hospitalists and among patients treated by locum vs. employed hospitalists. DESIGN: Prospective cohort study. Propensity score was used to obtain weighted estimates. SETTING: Referral center. PATIENTS: All patients 18 years and older admitted to internal medicine services. INTERVENTION: Treatment by teaching internal medicine services vs. hospitalists. Treatment by locum hospitalists vs. employed hospitalists. MAIN MEASURES: Primary outcome was adjusted length of stay and secondary outcomes included hospital cost, inpatient mortality, 30-day all-cause readmission, and 30-day mortality. KEY RESULTS: A total of 1273 patients were admitted in the study period. The mean patient age was 61 ± 19 years, and the sample was 52% females. Teaching internal medicine physicians admitted 526 patients and non-teaching hospitalists admitted 747 patients. Being seen exclusively by teaching internal medicine physicians comports with a shorter adjusted hospital stay by 0.6 days (95% CI - 1.07 to - 0.22, P = .003) compared to non-teaching hospitalists. Adjusted length of stay was 1 day shorter in patients seen exclusively by locums compared to patients seen exclusively by employed services (95% CI - 1.6 to - 0.43, P < .001) with an adjusted average hospital cost saving of 1339 dollars (95% CI - 2037 to - 642, P < .001). There was no statistically significant difference in other outcomes. CONCLUSIONS: Teaching internal medicine services care was associated with a shorter stay but not with increased costs, readmission, or mortality compared to non-teaching services. In contrary to the "expected," patients treated by locums had shorter stays and decreased hospital costs but no increase in readmissions or mortality.
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Médicos Hospitalarios , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Costos de Hospital , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Readmisión del Paciente , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that affects multiple systems throughout the body. Although there are multiple documented vasculopathies that can be seen in NF1, there are very few documented cases of coronary artery aneurysms with complete thrombosis of the ectatic vessel resulting in myocardial infarction. This case report describes a 28-year-old male with a past medical history of NF1 who presented with an anterolateral ST-segment elevation myocardial infarction. He underwent urgent cardiac catheterization, which was significant for severe thrombotic occlusion of the mid-left anterior descending artery (LAD) with thrombolysis in myocardial infarction (TIMI) flow 0. The LAD was noted to be severely ectatic. Percutaneous coronary intervention (PCI) with thrombectomy was attempted and was unsuccessful, with TIMI flow 0 after the intervention attempt. An echocardiogram was performed, which showed left ventricular ejection fraction (LVEF) of 30%-35%. This case report is presented to familiarize physicians with the rare vasculopathies that can occur in patients with NF1. Occlusive or aneurysmal disease can occur almost anywhere in the body in patients with NF1 due to the proliferation of fusiform endothelial cells in the blood vessels.
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BACKGROUND: Primary keratinocytes derived from epidermis, oral mucosa, and urothelium are used in construction of cell based wound healing devices and in regenerative medicine. This study presents in vitro technology that rapidly expands keratinocytes in culture by growing monolayers under large volumes of serum-free, essential fatty acid free, low calcium medium that is replaced every 24 hrs. METHODS: Primary cell cultures were produced from epidermal skin, oral mucosa and ureter by trypsinization of tissue. Cells were grown using Epilife medium with growth factors under high medium volumes. Once densely confluent, the keratinocyte monolayer produced cells in suspension in the overlying medium that can be harvested every 24 hrs. over a 7-10 day period. The cell suspension (approximately 8 X 105 cells/ml) is poured into a new flask to form another confluent monolayer over 2-4 days. This new culture, in turn produced additional cell suspensions that when serially passed expand the cell strain over 2-3 months, without the use of enzymes to split the cultures. The cell suspension, called epithelial Pop Up Keratinocytes (ePUKs) were analyzed for culture expansion, cell size and glucose utilization, attachment to carrier beads, micro-spheroid formation, induction of keratinocyte differentiation, and characterized by immunohistochemistry. RESULTS: The ePUKs expanded greatly in culture, attached to carrier beads, did not form micro-spheroids, used approximately 50% of medium glucose over 24 hrs., contained a greater portion of smaller diameter cells (8-10 microns), reverted to classical appearing cultures when returned to routine feeding schedules (48 hrs. and 15 ml/T-75 flask) and can be differentiated by either adding 1.2 mM medium calcium, or essential fatty acids. The ePUK cells are identified as cycling (Ki67 expressing) basal cells (p63, K14 expressing). CONCLUSIONS: Using this primary culture technique, large quantities of epithelial cells can be generated without the use of the enzyme trypsin to split the cultures. The cells are small in diameter and have basal cell progenitor/"stem" (P/SC) cell characteristics induced by daily feeding with larger than normal medium volumes. The ePUK epithelial cells have the potential to be used in regenerative medicine and for basic studies of epithelia P/SC phenotype.