Selective embolization with autologous fat to treat massive bleeding secondary to percutaneous renal biopsy.

Bleeding following a percutaneous renal biopsy is a complication that can be life-threatening. Embolization of the bleeding artery is a procedure that can limit the damage; however, embolization devices can be costly or not immediately available. This is why we present the case of a 25-year-old man with a history of multiple thromboses who underwent a renal biopsy due to suspected systemic lupus erythematosus. Five days after the procedure, he developed hypovolemic shock. A CT scan was performed due to suspected hemorrhage and showed active bleeding at the renal biopsy site. Since embolization devices were not immediately available, selective embolization of the bleeding artery was successfully performed using autologous fat. It is known that embolization with coils is the most frequently used interventional procedure to stop bleeding secondary to renal biopsies. However, embolization with autologous fat is a proven technique to stop bleeding in coronary perforations. In this case, we adapted this technique to treat an actively bleeding renal artery secondary to a renal biopsy. Based on this case, we consider that this technique may be an alternative when coil embolization is not available.

Adherence to optimal medical therapy and control of cardiovascular risk factors in patients after ST elevation myocardial infarction in Mexico.

Introduction: In developing countries, there is a notable scarcity of real-world data on adherence to optimal medical therapy (OMT) and its correlation with major cardiovascular adverse events (MACEs) after ST-elevation myocardial infarction (STEMI). Our study focuses on addressing this gap by evaluating adherence to OMT, examining its influence on the risk of MACEs after STEMI, and assessing subsequent cardiovascular risk factor control in Mexico. Methods: We conducted a prospective observational study of post-STEMI patients after hospital discharge. Adherence to treatment was assessed over a median of 683 days (interquartile range: 478-833) using the Simplified Medication Adherence Questionnaire (SMAQ). Patients were followed up for 4.5 years to monitor MACEs (cardiovascular death, cardiogenic shock, recurrent myocardial infarction, and heart failure). Results: We included 349 patients with a mean age of 58.08 years (±10.9), predominantly male (89.9%). Hypertension (42.4%), smoking (34.3%), type 2 diabetes mellitus (31.2%), obesity (22.92%), and dyslipidemia (21.4%) were highly prevalent. Adherence to OMT per SMAQ was 44.7%. The baseline clinical characteristics of adherent and non-adherent patients did not significantly differ. OMT prescription rates were as follows: acetylsalicylic acid, 91.1%; P2Y12 inhibitors, 76.5%; and high-intensity statins, 86.6%. While non-adherent patients had a numerically higher rate of MACEs (73 vs. 49 first events), there was no statistically significant difference (hazard ratio 1.30, 95% confidence interval 0.90-1.88). Discussion: In this real-world study of patients after STEMI, we observed low adherence to OMT, a low proportion of global cardiovascular risk factor control, and a numerically higher incidence of recurrent major adverse cardiovascular events in non-adherent patients. Strategies to improve adherence to OMT and risk factor control are needed.

Response predictors to cardiac resynchronization therapy in chronic heart failure: a 10-year-cardiovascular center experience.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been established as an effective therapy for heart failure with reduced ejection fraction. Randomized clinical trials have shown its impact on mortality and HF hospitalizations, as well as improvement of symptoms and quality of life. OBJECTIVES: Finding clinical, electrocardiographic, and echocardiographic variables that may predict the response to cardiac resynchronization therapy (CRT). METHODS: We performed a single-center, observational, analytic, and retrospective study that included 102 patients with heart failure (HF) diagnosis who underwent CRT according to guideline-directed therapy from January 2010 to April 2020 in a third-level center. CRT response was defined as an improvement of New York Heart Association functional class in at least 1 category associated with a recovery of ≥ 5% in the left ventricular ejection fraction (LVEF). RESULTS: Our study population was 102 patients of which 61 (59.8%) were men. The mean age at HF diagnosis was 54 ± 18.7 years. Ischemic heart disease was the etiology in 37 (36.3%) cases. Fifty-one (50%) patients were classified as responders. Responders had wider QRS, and lower LVEF and right ventricular fractional area change at baseline. After CRT, responders had a greater reduction of QRS duration, and improvement in LVEF, global longitudinal strain, and echocardiographic dyssynchrony parameters. Multivariate regression analysis showed that left bundle branch block (LBBB), left ventricular end-diastolic volume (LVEDV), tricuspid annular plane systolic excursion (TAPSE), and baseline difference of pre-ejection periods were predictors of a positive response to CRT in this population. CONCLUSIONS: LBBB, TAPSE, LVEDV, and pre-ejection time difference are independent variables that can predict adequate response to CRT.

ANTECEDENTES: La terapia de resincronización cardíaca (TRC) se ha establecido como una terapia efectiva para la insuficiencia cardíaca con fracción de eyección reducida. Ensayos clínicos aleatorizados han demostrado su impacto en la mortalidad y hospitalizaciones por insuficiencia cardíaca, así como la mejora de los síntomas y la calidad de vida. OBJETIVOS: Determinar las variables clínicas, electrocardiográficas y ecocardiográficas que puedan predecir la respuesta a la terapia de resincronización cardíaca (TRC). MÉTODO: Estudio unicéntrico, observacional, analítico, retrospectivo, que incluyó 102 pacientes con diagnóstico de IC sometidos a TRC y terapia dirigida por guías, de enero de 2010 a abril de 2020, en un centro de tercer nivel. La respuesta a TRC fue definida como mejoría de la clase funcional de la New York Heart Association en al menos 1 categoría, asociado con una recuperación ≥ 5% en la fracción de expulsión del ventrículo izquierdo (FEVI). RESULTADOS: Incluimos a 102 pacientes, 61 (59.8%) fueron hombres. El promedio de edad al diagnóstico de IC fue 54 ± 18.7 años. La cardiopatía isquémica fue la etiología en 37 (36.3%) pacientes. 51 (50%) pacientes, fueron clasificados como respondedores. Los respondedores presentaron QRS amplio, menor FEVI y menor fracción de acortamiento del ventrículo derecho al inicio del estudio. Después de la TRC, los respondedores tuvieron una mayor reducción en la duración del QRS, mejoría en la FEVI, strain longitudinal global y parámetros de disincronía ecocardiográfica. El análisis de regresión multivariado mostró que el bloqueo de rama izquierdo (BRI), el volumen telediastólico del ventrículo izquierdo (VTDVI) la excursión sistólica del plano anular tricuspídeo (TAPSE) y la diferencia basal del período expulsivo fueron predictores de respuesta positiva a TRC. CONCLUSIONES: BRI, TAPSE, VTDVI y la diferencia basal de períodos preexpulsivos son variables independientes que predicen respuesta adecuada a TRC.

Response predictors to cardiac resynchronization therapy in chronic heart failure: a 10-year-cardiovascular center experience / Predictores de respuesta a la terapia de resincronización cardíaca en insuficiencia cardíaca crónica: 10 años de experiencia en un centro cardiovascular

Abstract Background: Cardiac resynchronization therapy (CRT) has been established as an effective therapy for heart failure with reduced ejection fraction. Randomized clinical trials have shown its impact on mortality and HF hospitalizations, as well as improvement of symptoms and quality of life. Objectives: Finding clinical, electrocardiographic, and echocardiographic variables that may predict the response to cardiac resynchronization therapy (CRT). Methods: We performed a single-center, observational, analytic, and retrospective study that included 102 patients with heart failure (HF) diagnosis who underwent CRT according to guideline-directed therapy from January 2010 to April 2020 in a third-level center. CRT response was defined as an improvement of New York Heart Association functional class in at least 1 category associated with a recovery of ≥ 5% in the left ventricular ejection fraction (LVEF). Results: Our study population was 102 patients of which 61 (59.8%) were men. The mean age at HF diagnosis was 54 ± 18.7 years. Ischemic heart disease was the etiology in 37 (36.3%) cases. Fifty-one (50%) patients were classified as responders. Responders had wider QRS, and lower LVEF and right ventricular fractional area change at baseline. After CRT, responders had a greater reduction of QRS duration, and improvement in LVEF, global longitudinal strain, and echocardiographic dyssynchrony parameters. Multivariate regression analysis showed that left bundle branch block (LBBB), left ventricular end-diastolic volume (LVEDV), tricuspid annular plane systolic excursion (TAPSE), and baseline difference of pre-ejection periods were predictors of a positive response to CRT in this population. Conclusions: LBBB, TAPSE, LVEDV, and pre-ejection time difference are independent variables that can predict adequate response to CRT.

Resumen Antecedentes: La terapia de resincronización cardíaca (TRC) se ha establecido como una terapia efectiva para la insuficiencia cardíaca con fracción de eyección reducida. Ensayos clínicos aleatorizados han demostrado su impacto en la mortalidad y hospitalizaciones por insuficiencia cardíaca, así como la mejora de los síntomas y la calidad de vida. Objetivos: Determinar las variables clínicas, electrocardiográficas y ecocardiográficas que puedan predecir la respuesta a la terapia de resincronización cardíaca (TRC). Método: Estudio unicéntrico, observacional, analítico, retrospectivo, que incluyó 102 pacientes con diagnóstico de IC sometidos a TRC y terapia dirigida por guías, de enero de 2010 a abril de 2020, en un centro de tercer nivel. La respuesta a TRC fue definida como mejoría de la clase funcional de la New York Heart Association en al menos 1 categoría, asociado con una recuperación ≥ 5% en la fracción de expulsión del ventrículo izquierdo (FEVI). Resultados: Incluimos a 102 pacientes, 61 (59.8%) fueron hombres. El promedio de edad al diagnóstico de IC fue 54 ± 18.7 años. La cardiopatía isquémica fue la etiología en 37 (36.3%) pacientes. 51 (50%) pacientes, fueron clasificados como respondedores. Los respondedores presentaron QRS amplio, menor FEVI y menor fracción de acortamiento del ventrículo derecho al inicio del estudio. Después de la TRC, los respondedores tuvieron una mayor reducción en la duración del QRS, mejoría en la FEVI, strain longitudinal global y parámetros de disincronía ecocardiográfica. El análisis de regresión multivariado mostró que el bloqueo de rama izquierdo (BRI), el volumen telediastólico del ventrículo izquierdo (VTDVI) la excursión sistólica del plano anular tricuspídeo (TAPSE) y la diferencia basal del período expulsivo fueron predictores de respuesta positiva a TRC. Conclusiones: BRI, TAPSE, VTDVI y la diferencia basal de períodos preexpulsivos son variables independientes que predicen respuesta adecuada a TRC.

Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection.

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

Effect of the combination of bumetanide plus chlorthalidone on hypertension and volume overload in patients with chronic kidney disease stage 4-5 KDIGO without renal replacement therapy: a double-blind randomized HEBE-CKD trial.

BACKGROUND: The co-administration of loop diuretics with thiazide diuretics is a therapeutic strategy in patients with hypertension and volume overload. The aim of this study was to assess the efficacy and safety of treatment with bumetanide plus chlorthalidone in patients with chronic kidney disease (CKD) stage 4-5 KDIGO. METHODS: A double-blind randomized study was conducted. Patients were randomized into two groups: bumetanide plus chlorthalidone group (intervention) and the bumetanide plus placebo group (control) to evaluate differences in TBW, ECW and ECW/TBW between baseline and 30 Days of follow-up. Volume overload was defined as 'bioelectrical impedance analysis as fluid volume above the 90th percentile of a presumed healthy reference population. The study's registration number was NCT03923933. RESULTS: Thirty-two patients with a mean age of 57.2 ± 9.34 years and a median estimated glomerular filtration rate (eGFR) of 16.7 ml/min/1.73 m2 (2.2-29) were included. There was decreased volume overload in the liters of total body water (TBW) on Day 7 (intervention: -2.5 vs. control: -0.59, p = 0.003) and Day 30 (intervention: -5.3 vs. control: -0.07, p = 0.016); and in liters of extracellular water (ECW) on Day 7 (intervention: -1.58 vs. control: -0.43, p < 0.001) and Day 30 (intervention: -3.05 vs. control: -0.15, p < 0.000). There was also a decrease in systolic blood pressure on Day 7 (intervention: -18 vs. control: -7.5, p = 0.073) and Day 30 (intervention: -26.1 vs. control: -10, p = 0.028) and in diastolic blood pressure on Day 7 (intervention: -8.5 vs. control: -2.25, p = 0.059) and Day 30 (intervention: -13.5 vs. control: -3.4, p = 0.018). CONCLUSION: In CKD stage 4-5 KDIGO without renal replacement therapy, bumetanide in combination with chlorthalidone is more effective in treating volume overload and hypertension than bumetanide with placebo.

Pulmonary Congestion Assessed by Lung Ultrasound and Cardiovascular Outcomes in Patients With ST-Elevation Myocardial Infarction.

Background: Lung ultrasound (LUS) shows a higher sensitivity when compared with physical examination for the detection of pulmonary congestion. The objective of our study was to evaluate the association of pulmonary congestion assessed by LUS after reperfusion therapy with cardiovascular outcomes in patients with ST-segment Elevation acute Myocardial Infarction (STEMI) who received reperfusion therapy. Methods: A prospective observational study including patients with STEMI from the PHASE-Mx study. LUS was performed in four thoracic sites (two sites in each hemithorax). We categorized participants according to the presence of pulmonary congestion. The primary endpoint of the study was the composite of death for any cause, new episode or worsening of heart failure, recurrent myocardial infarction and cardiogenic shock at 30 days of follow-up. Results: A total of 226 patients were included, of whom 49 (21.6%) patients were classified within the "LUS-congestion" group and 177 (78.3%) within the "non-LUS-congestion" group. Compared with patients in the "non-LUS-congestion" group, patients in the "LUS-congestion" group were older and had higher levels of blood urea nitrogen and NT-proBNP. Pulmonary congestion assessed by LUS was significantly associated with a higher risk of the primary composite endpoint (HR: 3.8, 95% CI 1.91-7.53, p = 0.001). Differences in the primary endpoint were mainly driven by an increased risk of heart failure (HR 3.91; 95%CI 1.62-9.41, p = 0.002) and cardiogenic shock (HR 3.37; 95%CI 1.30-8.74, p = 0.012). Conclusion: The presence of pulmonary congestion assessed by LUS is associated with increased adverse cardiovascular events, particularly heart failure and cardiogenic shock. The application of LUS should be integrated as part of the initial risk stratification in patients with STEMI as it conveys important prognostic information.

Large-scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma.

BACKGROUND: Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens. METHODS: We performed provocation studies wherein six separate cohorts of persons (total n = 217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC). RESULTS: Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a non-endemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury/repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE. CONCLUSIONS: Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (ie, ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient or adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.

Case report: Polyarteritis nodosa as a substrate for a massive myocardial infarction.

This report describes a rare case of a global myocardial infarction caused by severe vasospasm of the coronary arteries secondary to the administration of pyridostigmine in a patient with polyarteritis nodosa (PAN). Details about the clinical presentation, the typical electrocardiographic pattern of multivessel disease, the differential diagnoses suspected in the multi-imaging approach, and the treatment of cardiogenic shock are described. The definitive diagnosis of infarction and the histopathological findings compatible with polyarteritis nodosa were made by autopsy.

Immunologic resilience and COVID-19 survival advantage.

BACKGROUND: The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). OBJECTIVE: We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality. METHODS: IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes. RESULTS: IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. CONCLUSIONS: Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.

Systemic thrombolysis in a patient with massive acute valvular thrombosis.

Prosthetic valve thrombosis (PVT) is considered an exceptionally rare condition, often associated with pro-thrombotic factors or suboptimal anticoagulant therapy. Guidelines recommend emergent surgery for patients with left heart valve prosthetic thrombosis who present in cardiogenic shock, and systemic thrombolysis is reserved in scenarios where surgery is not immediately available. However, several factors may affect surgical prognosis and are overlooked by current recommendations. We describe the case of a 34-year-old female who presented in the emergency department with cardiogenic shock and acute pulmonary edema due to acute valve thrombosis.

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases.

BACKGROUND: Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. OBJECTIVE: We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. METHODS: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. RESULTS: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8+ T cells, whereas airway inflammation associated with both CD8+ T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8+ T cells, lower CD4+ mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. CONCLUSIONS: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.

Adult Nesidioblastosis in Chronic Kidney Disease.

CONTEXT: Nesidioblastosis is a rare cause of hyperinsulinemic hypoglycemia in adults. The diagnosis is further complicated in patients with kidney failure, since impaired renal function can cause hypoglycemia by itself and diagnostic criteria for this clinical scenario have not been developed yet. CASE DESCRIPTION: We present the case report of a 36-year-old patient with end stage chronic kidney disease who presented to the emergency department because of hypoglycemia. However, the patient's hypoglycemia did not respond well to medical treatment; the diagnosis of hyperinsulinemic hypoglycemia was made due to the presence of inappropriately high levels of insulin, proinsulin, and C-peptide during an episode of hypoglycemia. Imaging studies were performed without any conclusive findings; so selective intra-arterial pancreatic stimulation with hepatic venous sampling (SACTS) was done. Based on the results of this study the patient was referred for subtotal pancreatectomy. Classic criteria for the diagnosis of insulinoma with SACTS required a 2-fold increase in insulin levels but newer criteria suggest thresholds that are useful in the differential diagnosis of insulinoma and nesidioblastosis. In our patient, the former criteria were positive; however, the new criteria were not compatible with insulinoma but with nesidioblastosis, which was the final histopathological diagnosis. CONCLUSION: This seems to be the first case report of a patient with end stage chronic kidney disease and nesidioblastosis, as well as the first case of hyperinsulinemic hypoglycemia in the context of kidney failure diagnosed by SACTS. We consider this method to be very useful in patients with renal impairment because peripancreatic insulin levels do not depend on the renal function.

Sticky Platelet Syndrome: An Unrecognized Cause of Acute Thrombosis and Graft Loss.

INTRODUCTION: Sticky platelet syndrome (SPS) is a prothrombotic disease that is not well recognized and difficult to diagnose. CASE REPORT: We present a case of a 49-year-old diabetic woman on ambulatory peritoneal dialysis therapy who underwent a kidney transplant from living-related donor. The donor was her sister with whom she shared one haplotype and absence of donor specific antibodies. The posttransplant evolution was torpid, developing progressive deterioration, which made us suspect a failure in the graft. Doppler ultrasound reported renal vein thrombosis and hypoperfusion of the renal artery. Without clinical improvement, she required a reintervention that ended in graftectomy, in which the histopathological report showed negative C4d with medullary and cortical infarction. Hematological studies were negative for antibodies against phospholipids, with correct levels of proteins C and S and antithrombin. Platelet aggregometry studies were carried out, which were compatible with SPS. CONCLUSIONS: Recognition of SPS in pretransplant studies is difficult if there is no history of previous thrombotic events. However, we must consider this entity in cases of acute thrombosis and loss of the graft of uncertain origin.

Preservation of epithelial cell barrier function and muted inflammation in resistance to allergic rhinoconjunctivitis from house dust mite challenge.

BACKGROUND: An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen. OBJECTIVE: The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis. METHODS: Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M-) participants completed 3-hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing-derived expression profiles of nasal cells, before and after HDM exposure. RESULTS: On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M- participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4+ and CD8+ T-cell activation levels initially decreased in M- participants versus increased in M+ participants. Second, in M- compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively. CONCLUSION: An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.

Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor.

T-cell expression levels of CC chemokine receptor 5 (CCR5) are a critical determinant of HIV/AIDS susceptibility, and manifest wide variations (i) between T-cell subsets and among individuals and (ii) in T-cell activation-induced increases in expression levels. We demonstrate that a unifying mechanism for this variation is differences in constitutive and T-cell activation-induced DNA methylation status of CCR5 cis-regulatory regions (cis-regions). Commencing at an evolutionarily conserved CpG (CpG -41), CCR5 cis-regions manifest lower vs. higher methylation in T cells with higher vs. lower CCR5 levels (memory vs. naïve T cells) and in memory T cells with higher vs. lower CCR5 levels. HIV-related and in vitro induced T-cell activation is associated with demethylation of these cis-regions. CCR5 haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status of CCR5 intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protective CCR5-HHA haplotype bears a polymorphism at CpG -41 that is (i) specific to southern Africa, (ii) abrogates binding of the transcription factor CREB1 to this cis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking the CCR5-Δ32 mutation but with hypermethylated cis-regions have CCR5 levels similar to genotypes heterozygous for CCR5-Δ32. In HIV-infected individuals, CCR5 cis-regions remain demethylated, despite restoration of CD4+ counts (≥800 cells per mm(3)) with antiretroviral therapy. Thus, methylation content of CCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes.

Cockroach sensitization mitigates allergic rhinoconjunctivitis symptom severity in patients allergic to house dust mites and pollen.

BACKGROUND: Modifiers of symptom severity in patients with allergic rhinoconjunctivitis (AR) are imprecisely characterized. The hygiene hypothesis implicates childhood microbial exposure as a protective factor. Cockroach sensitization (C+) might be a proxy for microbial exposure. OBJECTIVE: We sought to determine whether C+ assayed by means of skin prick tests influenced AR symptom severity in controlled and natural settings. METHODS: Total symptom scores (TSSs) were recorded by 21 participants with house dust mite allergy (M+) in the natural setting and during repeated exposures of 3 hours per day to house dust mite allergen in an allergen challenge chamber (ACC). In M+ participants the peripheral blood and nasal cells were assayed for T-cell activation and transcriptomic profiles (by using RNA sequencing), respectively. Participants allergic to mountain cedar (n = 21), oak (n = 34), and ragweed (n = 23) recorded TSSs during separate out-of-season exposures to these pollens (any pollen sensitization [P+]) in the ACC; a subset recorded TSSs in the pollination seasons. RESULTS: The hierarchy of TSSs (highest to lowest) among M+ participants tracked the following skin prick test sensitization statuses: M+P+C- > M+P+C+ > M+P-C- > M+P-C+. In nasal cells and peripheral blood the immune/inflammatory responses were rapidly resolved in M+P+C+ compared with M+P+C- participants. Among those allergic to pollen, C+ was associated with a lower TSS during pollen challenges and the pollination season. After aggregated analysis of all 4 ACC studies, C+ status was associated with a 2.8-fold greater likelihood of a lower TSS compared with C- status (odds ratio, 2.78; 95% CI, 1.18-6.67; P = .02). CONCLUSIONS: C+ status is associated with mitigation of AR symptom severity in adults with AR.

Nox2 mediates skeletal muscle insulin resistance induced by a high fat diet.

Inflammation and oxidative stress through the production of reactive oxygen species (ROS) are consistently associated with metabolic syndrome/type 2 diabetes. Although the role of Nox2, a major ROS-generating enzyme, is well described in host defense and inflammation, little is known about its potential role in insulin resistance in skeletal muscle. Insulin resistance induced by a high fat diet was mitigated in Nox2-null mice compared with wild-type mice after 3 or 9 months on the diet. High fat feeding increased Nox2 expression, superoxide production, and impaired insulin signaling in skeletal muscle tissue of wild-type mice but not in Nox2-null mice. Exposure of C2C12 cultured myotubes to either high glucose concentration, palmitate, or H2O2 decreases insulin-induced Akt phosphorylation and glucose uptake. Pretreatment with catalase abrogated these effects, indicating a key role for H2O2 in mediating insulin resistance. Down-regulation of Nox2 in C2C12 cells by shRNA prevented insulin resistance induced by high glucose or palmitate but not H2O2. These data indicate that increased production of ROS in insulin resistance induced by high glucose in skeletal muscle cells is a consequence of Nox2 activation. This is the first report to show that Nox2 is a key mediator of insulin resistance in skeletal muscle.