[IgE reactivity of sera from patients with autoimmune diseases against a multi-epitope protein constructed from T epitopes of Ascaris lumbricoides allergens]. / Reactividad IgE de sueros en pacientes con enfermedades autoinmunes, frente a una proteína multi-epítopes construida a partir de epítopes T de alérgenos de Ascaris lumbricoides.

OBJECTIVE: To evaluate the IgE reactivity of sera in patients suffering from type 1 diabetes (T1D), lupus nephritis (LN) and juvenile idiopathic arthritis (JIA) against a molecule constructed from T epitopes of A. lumbricoides allergens. METHODS: We designed and expressed a synthetic multi-epítope protein named MP1 from A. lumbricoides and house dust mites allergens. By indirect ELISA, we evaluated IgE-reactivity to MP1 and to the whole-body extract of Ascaris lumbricoides in 45 sera from Colombian Caribbean patients with lupus nephritis (LN; n=25), type 1 diabetes (T1D; n=10) and Juvenil idiopathic arthritis (JIA; n=10). Individuals with poly autoimmunity were excluded. All patients were referred to the study by their specialist doctor. RESULTS: IgE to whole-body extract of A. lumbricoides showed the following median concentrations.484.2 ng/ml (IQR: 203.4) in JIA patients, 325.6 ng/ml (IQR: 179.3) in individuals with LN, and 424.7 ng/ml (IQR: 80.1) in the T1D group. On the other hand, IgE-reactivity to MP1 was 126.4 ng/ml (IQR: 90.9) in JIA patients, 130.7 ng/ml (IQR: 94.8) in an individual with LN, and 148.8 ng/ml (IQR: 102.1) in the T1D group. Although no statistical differences were observed between patient groups, the IgE to MP1 in all patients (n: 45) (IgE median: 134.2 ng/ml; IQR: 100) were significantly less compared to Ascaris extract (IgE median: 380.7 ng/ml; IQR: 175.8); (W: 0.732; p-value: 1.034x10-7). CONCLUSIONS: These preliminary results suggest that MP1 showed antigenic properties with low IgE- reactivity, compared to Ascaris lumbricoides extracted in individuals with autoimmune diseases. Further studies are needed to understand better the immune response induced by this molecule.

OBJETIVO: Evaluar la reactividad IgE de sueros en pacientes que padecen diabetes tipo 1 (DT1), nefritis lúpica (NL) y artritis idiopática juvenil (AIJ) frente a una molécula construida a partir de epítopes T de alérgenos de A. lumbricoides. MÉTODOS: Se diseñó y expresó una proteína multi-epítopes sintética (MP1), a partir de alérgenos de A. lumbricoides y ácaros del polvo doméstico. Mediante ELISA indirecto, se evaluaron las reactividades IgE anti-MP1 y al extracto de cuerpo entero de Ascaris lumbricoides, en sueros de pacientes con nefritis lúpica (NL; n=25), diabetes tipo 1 (T1D; n=10) y artritis idiopática juvenil (AIJ; n=10), procedentes del Caribe colombiano. Se excluyeron los individuos con poliautoinmunidad. Todos los pacientes fueron remitidos al estudio por su médico especialista. RESULTADOS: La IgE frente al extracto de cuerpo completo de A. lumbricoides mostró concentraciones de 484,2 ng/ml (RIQ: 203,4) en pacientes con AIJ; 325,6 ng/ml (RIQ: 179,3) en individuos con NL; y 424,7 ng/ml (RIQ: 80,1) en el grupo con DT1. Por otra parte, la reactividad de IgE anti-MP1 fue de 126,4 ng/ml (RIQ: 90,9) en los pacientes con AIJ; 130,7 ng/ml (RIQ: 94,8) en los individuos con NL; y 148,8 ng/ml (RIQ: 102,1) en el grupo con DT1. Aunque no se observaron diferencias estadísticas entre los grupos de pacientes, la reactividad IgE anti- MP1 en todos los pacientes (n: 45) (mediana de IgE: 134,2 ng/ml; RIQ: 100), fue significativamente inferior en comparación con el extracto de Ascaris (mediana de IgE: 380,7 ng/ml; RIQ: 175,8); (W: 0,732; p-valor: 1,034x10-7). CONCLUSIONES: Estos resultados preliminares sugieren que MP1 mostró propiedades antigénicas con baja reactividad IgE, en comparación con el extracto de Ascaris lumbricoides en individuos con enfermedades autoinmunes. Se necesitan más estudios para comprender mejor la respuesta inmunitaria inducida por esta molécula.

[Novel tropomyosin consensus B and T epitopes involved in cross-reactivity between 10 different species. An in silico study]. / Nuevos epítopes B y T, consenso de tropomiosina involucradas en reactividad cruzada entre diez especies diferentes. Un estudio in silico.

OBJECTIVE: This study aimed to identify by in silico methods tropomyosin consensus B and T epitopes of shrimp species, house dust mites, insects, and nematodes associated with allergic diseases in tropical countries. METHODS: In silico analysis included tropomyosin from mites (Der p 10, Der f 10, Blo t 10), insects (Aed a 10, Per a 7, Bla g 7), shrimp (Lit v 1, Pen m 1, Pen a 1), and nematode (Asc l 3) all sequences were taken from the UniProt database. Linear IgE epitopes were predicted with AlgPred 2.0 and validated with BepiPred 3.0. MHC-II binding T cell epitopes were predicted using the IEDB server, which implements nine predictive methods (consensus method, combinatorial library, NN-align-2.3, NN- align-2.2, SMM-align, Sturniolo, NetMHCIIpan 3.1, and NetMHCIIpan 3.2) these predictions focused on 10 HLA-DR and 2 HLA-DQ alleles associated with allergic diseases. Subsequently, consensus B and T epitopes present in all species were identified. RESULTS: We identified 12 sequences that behaved as IgE-epitopes and B-cell epitopes, three of them: 160RKYDEVARKLAMVEA174, 192ELEEELRVVGNNLKSLEVSEEKAN215, 251KEVDRLEDELV261 were consensus in all species. Eleven peptides (T-epitopes) showed strong binding (percentile rank ≤ 2.0) to HLA-DRB1*0301, *0402, *0411, *0701, *1101, *1401, HLA-DQA1*03:01/DQB1*03:02, and HLA- DQA1*05:01/DQB1*02:01. Only two T-epitopes were consensus in all species: 167RKLAMVEADLERAEERAEt GEsKIVELEEELRV199, and 218EEeY KQQIKT LTaKLKEAEARAEFAERSV246. Subsequently, we identified 2 B and T epitope sequences and reached a consensus between species 167RKLAMVEA174 and 192ELEEELRV199. CONCLUSIONS: These data describe three sequences that may explain the IgE cross-reactivity between the analyzed species. In addition, the consensus B and T epitopes can be used for further in vitro investigations and may help to design multiple-epitope protein-based immunotherapy for tropomyosin-related allergic diseases.

OBJETIVO: Este estudio tuvo como objetivo identificar mediante métodos in silico epítopes B y T consenso de tropomiosina de especies de camarón, ácaros del polvo doméstico, insectos y nematodos asociados a enfermedades alérgicas en países tropicales. MÉTODOS: El análisis in silico incluyó tropomiosina de ácaros (Der p 10, Der f 10, Blo t 10), insectos (Aed a 10, Per a 7, Bla g 7), camarones (Lit v 1, Pen m 1, Pen a 1), y nematodo (Asc l 3). Todas las secuencias se tomaron de la base de datos UniProt. Los epítopes IgE lineales se predijeron con AlgPred 2.0 y se validaron con BepiPred 3.0. Los epítopes de células T de unión a MHC-II se predijeron utilizando el servidor IEDB, que implementa nueve métodos predictivos (método de consenso, biblioteca combinatoria, NN-align-2.3, NN-align-2.2, SMM-align, Sturniolo, NetMHCIIpan 3.1 y NetMHCIIpan 3.2). Estas predicciones se centraron en diez alelos HLA-DR y 2 HLA-DQ asociados con enfermedades alérgicas. Posteriormente, se identificaron epítopes consenso B y T presentes en todas las especies. RESULTADOS: Se identificaron 12 secuencias que se comportaron como epítopes de IgE y, también, como epítopes de células B. Tres de ellas: 160RKYDEVARKLAMVEA174, 192ELEEELRVVGNNLKSLEVSEEKAN213 y 251KEVDRLEDELV261, fueron consenso en todas las especies. Once péptidos mostraron una fuerte unión (rango percentil ≤ 2,0) a HLA-DRB1*0301, *0402, *0411, *0701, *1101, *1401 y a HLA HLA-DQA1*03:01/DQB1*03:02, o HLA-DQA1*05:01/DQB1*02:01. Solo se encontraron dos secuencias: 167RKLAMVEADLERAEERAEtGEsKIVELEEELRV199 con fuerte afinidad por HLA-DQA1*03:01/DQB1*03:02, y HLA-DQA1*05:01/DQB1*02:01. Se identificaron dos secuencias que son epítopos B y T, y son consenso entre especies: 167RKLAMVEA174 y 192ELEEELRV199. CONCLUSIONES: Estos datos describen tres secuencias que pueden explicar la reactividad cruzada de IgE entre las especies analizadas. Además, los epítopos B y T consenso se pueden usar para investigaciones in vitro adicionales, y pueden ayudar a diseñar inmunoterapia basada en proteínas de múltiepítopes para enfermedades alérgicas relacionadas con la tropomiosina.

Atypical Hemolytic Uremic Syndrome: A Nationwide Colombian Pediatric Series.

Objectives. Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated kidney disease with genetic predisposition and represents up to 10% of pediatric hemolytic uremic syndrome (HUS) cases. Few studies have evaluated aHUS in Latin American population. We studied a Colombian pediatric cohort to delineate disease presentation and outcomes. Methods. A multicenter cohort of 27 Colombian children with aHUS were included. Patients were grouped by age at onset. Clinical features were compared using analysis of variance (ANOVA) and Fisher exact tests. Renal biopsy was performed on 6 patients who were suspected of having other renal diseases before aHUS diagnosis. Results. Most patients were male (70%). The onset of aHUS occurred frequently before age 4 years (60%) and followed gastroenteritis as the main triggering event (52%). Age groups showed comparable clinical presentation, disease severity, treatment, and outcomes. Pulmonary involvement (67%) was the main extrarenal manifestation, particularly in the 1 to 7 age group (P = .01). Renal biopsies were as follows: 3 had membranoproliferative glomerulonephritis (MPGN) type I, one MPGN type III, one C3-glomerulonephritis, and one rapidly progressive GN. Genetic screening was available in 6 patients and identified 2xCFHR5, 2xMCP, 1xADAMTS13/THBD, and 1xDGKE mutations. A total of 15 relapses were seen, of which 8 (72%) occurred in the 1 to 7 age group. The renal outcome was not significantly different regardless of age group. Conclusion. In our cohort, we observed a relatively high frequency of extrarenal involvement at first presentation represented by pulmonary manifestations. The renal prognosis at initial presentation was worse than in previous reports.

Pregnancy-Associated Atypical Hemolytic Uremic Syndrome: A Case Report with MCP Gene Mutation and Successful Eculizumab Treatment.

Pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) is a rare condition characterized by microangiopathic hemolytic anemia and kidney injury from thrombotic microangiopathy. P-aHUS occurs in approximately 1 in 25,000 pregnancies and is strongly related to complement dysregulation and pregnancy-related disorders, such as preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome, resulting in adverse perinatal and fetal outcomes. Complement dysregulation in P-aHUS is commonly attributed to genetic mutations or autoantibodies affecting complement factors, including CFH , CFI , and MCP. We present a case of a 25-year-old primigravida who experienced severe preeclampsia and HELLP syndrome followed by the development of complicated P-aHUS during the early postpartum period. The patient exhibited severe clinical manifestations, including hypertensive emergency, central nervous system involvement, renal impairment, and microangiopathic hemolytic anemia. Timely initiation of eculizumab therapy resulted in successful disease remission. Further genetic analysis revealed a likely rare pathogenic MCP gene variant.

Neutrophil Granulopoiesis Optimized Through Ex Vivo Expansion of Hematopoietic Progenitors in Engineered 3D Gelatin Methacrylate Hydrogels.

Neutrophils are the first line of defense of the innate immune system. In response to methicillin-resistant Staphylococcus aureus infection in the skin, hematopoietic stem, and progenitor cells (HSPCs) traffic to wounds and undergo extramedullary granulopoiesis, producing neutrophils necessary to resolve the infection. This prompted the engineering of a gelatin methacrylate (GelMA) hydrogel that encapsulates HSPCs within a matrix amenable to subcutaneous delivery. The authors study the influence of hydrogel mechanical properties to produce an artificial niche for granulocyte-monocyte progenitors (GMPs) to efficiently expand into functional neutrophils that can populate infected tissue. Lin-cKIT+ HSPCs, harvested from fluorescent neutrophil reporter mice, are encapsulated in GelMA hydrogels of varying polymer concentration and UV-crosslinked to produce HSPC-laden gels of specific stiffness and mesh sizes. Softer 5% GelMA gels yield the most viable progenitors and effective cell-matrix interactions. Compared to suspension culture, 5% GelMA results in a twofold expansion of mature neutrophils that retain antimicrobial functions including degranulation, phagocytosis, and ROS production. When implanted dermally in C57BL/6J mice, luciferase-expressing neutrophils expanded in GelMA hydrogels are visualized at the site of implantation for over 5 days. They demonstrate the potential of GelMA hydrogels for delivering HSPCs directly to the site of skin infection to promote local granulopoiesis.

Ambulatory blood pressure monitoring in pediatric patients with sickle cell anemia.

INTRODUCTION: Sickle cell anemia (SCA) is a hemoglobinopathy presenting severe endothelial damage associated with increased prevalence of hypertension (HTN). Few studies have used ambulatory blood pressure monitoring (ABPM) in pediatric patients with SCA. The aim of this study was to characterize the ABPM profile in children with SCA. METHODS: A retrospective cross-sectional study was conducted on all subjects <18 years of age with SCA who presented at a medical reference center in the city of Cartagena, Colombia. Anthropometric, clinical laboratory, treatment, and ABPM parameters, including ambulatory arterial stiffness index (AASI) were registered. RESULTS: The study included 79 patients, of these, 23 (29%) children had normal BP, 49 (62%) had abnormal BP and 7 (9%) had HTN. Mean age was 10.5 ±â€…3.6 years and 44 (56%) cases were male. Forty-eight (60%) patients had pre-HTN. Masked HTN was present in 6 (8%) patients. One (1%) had ambulatory HTN, and another one (1%) had white coat HTN. The HTA group exhibited significantly higher systolic BP and diastolic BP compared to the other groups in 24-hour BP readings, daytime BP, and night-time BP ABPM parameters ( P  < 0.05), except for daytime DBP ( P  = 0.08). Mean AASI was 0.4 ±â€…0.2. The HTN group had the highest AASI value compared to the other groups ( P = 0.006). CONCLUSION: Significant alterations in ABPM parameters are frequently observed in pediatric patients with SCA. The incorporation of ABPM, along with the assessment of AASI, is recommended for a comprehensive evaluation of cardiovascular and renal risk in SCA patients.

Simulating A Subcondylar Mandibular Fracture With Intraoral Open Reduction and Internal Fixation: A Novel Education Tool for Residents.

Study Design: Face and content validation of a surgical simulation model. Objective: Open reduction and internal fixation in displaced subcondylar mandibular fractures is standard care. This requires an extraoral (eg: retromandibular, transparotideal) or intraoral approach. An intraoral approach requires further training since specialized instrumentation such as the 90° screwdriver system and endoscopes might be needed. Currently, no simulation models are available for training residents in intraoral reduction and fixation of subcondylar mandibular fractures. Therefore, we present a validated simulation model for intraoral treatment of subcondylar mandibular fractures. Methods: Based on a computer tomography data set, we designed and printed a 3D model of a mandible with a unilateral subcondylar fracture. To simulate intraoral work depth, it was positioned inside a dental phantom. We tested the model by a group of experts (n = 8), simulating intraoral reduction and fixation of a unilateral subcondylar fracture, using a 90° screwdriver system, a 1.0 subcondylar plate (lambda), and 5-6 mm screws.We assessed Face and Content validity by survey. Results: We provided an open-source printable fracture model. Printing costs were approximately US $10. Experts "Agreed" the model resembling the real scenario and its use for training intraoral reduction and fixation of subcondylar mandibular fractures. Conclusions: We developed a low cost, reproducible, open-source simulator for subcondylar mandibular fractures. Face and Content validity was achieved through evaluation by a group of experts.

Autophagy impairment and lifespan reduction caused by Atg1 RNAi or Atg18 RNAi expression in adult fruit flies (Drosophila melanogaster).

Autophagy, an autophagosome and lysosome-based eukaryotic cellular degradation system, has previously been implicated in lifespan regulation in different animal models. In this report, we show that expression of the RNAi transgenes targeting the transcripts of the key autophagy genes Atg1 or Atg18 in adult fly muscle or glia does not affect the overall levels of autophagosomes in those tissues and does not change the lifespan of the tested flies but the lifespan reduction phenotype has become apparent when Atg1 RNAi or Atg18 RNAi is expressed ubiquitously in adult flies or after autophagy is eradicated through the knockdown of Atg1 or Atg18 in adult fly adipocytes. Lifespan reduction was also observed when Atg1 or Atg18 was knocked down in adult fly enteroblasts and midgut stem cells. Overexpression of wild-type Atg1 in adult fly muscle or adipocytes reduces the lifespan and causes accumulation of high levels of ubiquitinated protein aggregates in muscles. Our research data have highlighted the important functions of the key autophagy genes in adult fly adipocytes, enteroblasts, and midgut stem cells and their undetermined roles in adult fly muscle and glia for lifespan regulation.

Association of Fokl polymorphism of the VDR gene with systemic lupus erythematosus in an adolescent population of the Colombian Caribbean

Introduction: Vitamin D and vitamin D receptor (VDR) polymorphisms are associated with autoimmune diseases including systemic lupus erythematosus (SLE). The aim of this study is to assess the genetic association between VDR polymorphisms: TaqI, ApaI, Bsml and FokI and SLE with serum levels of Vitamin D in the Colombian Caribbean population. Method: Case and control study. One hundred and thirty-three patients with SLE and 100 healthy individuals were included. VDR polymorphism were genotyped by RT-PCR and Taqman® probes. Allelic, genotypic and haplotype associations were estimated. Serum vitamin D concentrations were quantified by Elisa. Values of 30 to 100ng/ml were established as a normal reference range. P values <.05 were considered statistically significant. Results: A high prevalence of SLE was observed in women (94%) and was associated with a higher risk of SLE [OR: 10.8; 95% CI: 4.7-24.6] (p<.05). Moreover, higher risk of SLE was observed in individuals with FokI VDR [rs2228570] [OR: 1.58; 95% CI: 1.05-2.36] in allelic models. The ACCA Haplotype of TaqI/ApaI/Bsml/FokI polymorphisms was associated with higher risk of SLE [OR = 2.28, 95% CI = 1.12-4.66, psim <.01]. Vitamin D deficiency was evidenced in 11.3% of the patients. Conclusion: In this study, the VDR rs2228570 polymorphism and ACCA haplotype were associated with higher SLE risk in an adolescent population.

Introducción: La vitamina D y los polimorfismos en el receptor de vitamina D (VDR) se asocian con enfermedades autoinmunes, incluido el lupus eritematoso sistémico (LES). El objetivo de este estudio es analizar la asociación genética entre los polimorfismos de VDR (Taql, Apal, Bsml y Fokl) y la susceptibilidad al LES, así como su relación con los niveles séricos de vitamina D en población del Caribe colombiano. Metodología: Estudio de casos y controles. Se incluyeron 133 pacientes adultos con diagnóstico de LES y 100 individuos sanos. Los polimorfismos VDR fueron genotipados por RT-PCR y sondas Taqman®. Se estimaron asociaciones alélicas, genotípicas y haplotípicas. Las concentraciones séricas de vitamina D fueron cuantificadas por Elisa. Se establecieron valores de 30 a 100ng/ml como rango normal de referencia. Valores p<0,05 fueron considerados estadísticamente significativos. Resultados: Se observó una alta prevalencia de LES en pacientes femeninas (94%) y se asoció a mayor riesgo de LES (OR: 10,8; IC95%: 4,7-24,6; p < 0,05). Se evidenció mayor riesgo de LES en individuos con polimorfismo Fokl del gen VDR [rs2228570] (OR: 1,58; IC95%: 1,05-2,36) en modelos alélicos. El haplotipo ACCA de los polimorfismos Taql, Apal, Bsml y Fokl se asoció a mayor riesgo de LES (OR: 2,28, IC95%: 1,12-4,66; psim<0,01). Se evidenció deficiencia de vitamina D en el 11,3% de los pacientes. Conclusión: En este estudio, el polimorfismo VDR rs2228570 y el haplotipo ACCA se asociaron a mayor riesgo de LES en población adolescente.

A Designed Host Defense Peptide for the Topical Treatment of MRSA-Infected Diabetic Wounds.

Diabetes mellitus is a chronic disease characterized by metabolic dysregulation which is frequently associated with diabetic foot ulcers that result from a severely compromised innate immune system. The high levels of blood glucose characteristic of diabetes cause an increase in circulating inflammatory mediators, which accelerate cellular senescence and dampen antimicrobial activity within dermal tissue. In diabetic wounds, bacteria and fungi proliferate in a protective biofilm forming a structure that a compromised host defense system cannot easily penetrate, often resulting in chronic infections that require antimicrobial intervention to promote the healing process. The designed host defense peptide (dHDP) RP557 is a synthesized peptide whose sequence has been derived from naturally occurring antimicrobial peptides (AMPs) that provide the first line of defense against invading pathogens. AMPs possess an amphipathic α-helix or ß-sheet structure and a net positive charge that enables them to incorporate into pathogen membranes and perturb the barrier function of Gram-positive and Gram-negative bacteria along with fungi. The capacity of skin to resist infections is largely dependent upon the activity of endogenous AMPs that provided the basis for the design and testing of RP557 for the resolution of wound infections. In the current study, the topical application of RP557 stopped bacterial growth in the biofilm of methicillin-resistant Staphylococcus aureus (MRSA) USA300 infected wounds on the flanks of clinically relevant diabetic TALLYHO mice. Topical application of RP557 reduced bacterial load and accelerated wound closure, while wound size in control diabetic mice continued to expand. These studies demonstrate that RP557 reduces or eliminates an infection in its biofilm and restores wound-healing capacity.

Significant association between TaqI and FokI VDR gene polymorphisms and chronic spontaneous urticaria in a Colombian Caribbean population.

INTRODUCTION: Chronic spontaneous urticaria (CSU) is an inflammatory skin disease related to poor quality of life. Previous studies have found that vitamin D deficiency and vitamin D receptor (VDR) TaqI, BsmI, FokI, and ApaI gene single-nucleotide polymorphisms (SNPs) influence immune response and susceptibility to skin disorders. AIM: To explore the role of VDR SNPs, and the association of vitamin D serum levels in a sample of Colombian Caribbean CSU patients. Methods: It is a case-control study. A group of CSU patients (n = 100) was compared with healthy individuals as a control group (n = 100). VDR polymorphisms were genotyped by quantitative polymerase chain reaction and Taqman® probes. Allelic, genotypic, and haplotype associations were estimated. Serum vitamin D levels were measured using enzyme-linked-immunosorbent serologic assay. RESULTS: Compared to the control group, the presence of G allele in TaqI and A allele in FokI SNPs of VDR gene was found to be a risk factor for CSU (odds ratio (OR) estimated using logistic regression adjusted by gender: 2.08 and 1.61, respectively, all P values < 0.05). The individuals who carry GCCA haplotype showed decrease in vitamin D levels (11.34 ng/mL; P = 0.002) with the G allele of TaqI and A allele of FokI gene SNPs. CONCLUSION: We reported for the first time the association of TaqI [rs731236] and FokI [rs2228570] VDR gene SNPs showing as a risk factor for CSU in a sample of multiethnic patients from the Colombian Caribbean population.

Timing of propulsion-related biomechanical variables is impaired in individuals with post-stroke hemiparesis.

BACKGROUND: In individuals with post-stroke hemiparesis, reduced paretic leg propulsion, measured through anterior ground reaction forces (AGRF), is a common and functionally-relevant gait impairment. Deficits in other biomechanical variables such as plantarflexor moment, ankle power, and ankle excursion contribute to reduced propulsion. While reduction in the magnitude of propulsion post-stroke is well studied, here, our objective was to compare the timing of propulsion-related biomechanical variables. RESEARCH QUESTION: Are there differences in the timing of propulsion and propulsion-related biomechanical variables between able-bodied individuals, the paretic leg, and non-paretic leg of post-stroke individuals? METHODS: Nine able-bodied and 13 post-stroke individuals completed a gait analysis session comprising treadmill walking trials at each participant's self-selected speed. Two planned independent sample t-tests were conducted to detect differences in the timing of dependent variables between the paretic versus non-paretic leg post-stroke and paretic leg versus the dominant leg of able-bodied individuals. RESULTS: Post-stroke individuals demonstrated significantly earlier timing of peak AGRF of their paretic leg versus their non-paretic leg and able-bodied individuals. Post-stroke participants displayed earlier timing of peak power of their paretic leg versus their non-paretic leg and able-bodied individuals, and earlier timing of peak ankle moment of the paretic leg versus able-bodied. No significant differences were detected in the timing of peak ankle angle. SIGNIFICANCE: The earlier onset of peak AGRF, peak ankle power, and peak ankle moment may be an important, under-studied biomechanical factor underlying stroke gait impairments, and a potential therapeutic target for stroke gait retraining. Future investigations can explore the use of interventions such as gait biofeedback to normalize the timing of these peaks, thereby improving propulsion and walking function post-stroke.

Glomerular Diseases in the Colombian Caribbean: Data from the Colombian Nephropathy Registry (NEFRORED®).

Our study aimed to describe the glomerular diseases, both primary glomerular disease (PGD) and secondary glomerular disease (SGD) in the Colombian Caribbean based on the first regional Colombian Nephropathy Registry (NEFRORED®). A descriptive and retrospective study of adult patients with glomerular diseases from the Colombian Caribbean region was made. All diagnoses by renal biopsy with light microscopy and immunofluorescence obtained between January 2008 and June 2018 were recorded. Eight hundred and seventy-one renal biopsies were obtained. The main clinical indication for biopsy was nephritic syndrome (36%). SGD was more frequent than PGD (55% vs. 45%). Within SGD group, lupus nephritis (LN) was the most frequent etiology (83%). Within PGD group, membranous nephropathy (33%) and focal segmental glomerulosclerosis (FSGS) (19%) were the most common glomerular diseases. At a 24-month follow-up, the patients with FSGS and paraproteinemia-mediated glomerular disease had the worst renal survival prognosis. This is the first Colombian Nephropathy Registry in a Caribbean population, demonstrating a high predominance of SGD due to LN.

Atypical hemolytic uremic syndrome in the Colombian Caribbean: its particular characteristics.

INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a rare and genetically mediated systemic disease most often caused by uncontrolled and chronic complement activation that leads to systemic thrombotic microangiopathy, renal and extra-renal damage. MATERIALS AND METHODS: This is descriptive, retrospective and multicenter study, which reports demographic, clinical, laboratory, and genetic characteristics, as well as their treatment response and outcome of 20 aHUS patients diagnosed between 2014 and 2018. RESULTS: Most patients were female adults (75%) and 30% were associated to pregnancy/postpartum, 15% to autoimmune disease, and 65% to infections. Gastrointestinal involvement (75%) was the most frequent extra-renal organ damage. Antenatal mortality and mortality rate were 5% and 10%, respectively. 25% of the patients progressed to end-stage renal disease. In 4/8 of patients treated within 1 week of presentation, eculizumab treatment restored multi-organ function after 4 weeks of treatment. CFH (37%) and CFI (25%) mutations were the most frequent. CONCLUSION: This is the first series of aHUS cases of Colombian Caribbean region which reports the clinical and epidemiological characteristics of this condition in this region.

Comodulation of h- and Na+/K+ Pump Currents Expands the Range of Functional Bursting in a Central Pattern Generator by Navigating between Dysfunctional Regimes.

Central pattern generators (CPGs), specialized oscillatory neuronal networks controlling rhythmic motor behaviors such as breathing and locomotion, must adjust their patterns of activity to a variable environment and changing behavioral goals. Neuromodulation adjusts these patterns by orchestrating changes in multiple ionic currents. In the medicinal leech, the endogenous neuromodulator myomodulin speeds up the heartbeat CPG by reducing the electrogenic Na+/K+ pump current and increasing h-current in pairs of mutually inhibitory leech heart interneurons (HNs), which form half-center oscillators (HN HCOs). Here we investigate whether the comodulation of two currents could have advantages over a single current in the control of functional bursting patterns of a CPG. We use a conductance-based biophysical model of an HN HCO to explain the experimental effects of myomodulin. We demonstrate that, in the model, comodulation of the Na+/K+ pump current and h-current expands the range of functional bursting activity by avoiding transitions into nonfunctional regimes, such as asymmetric bursting and plateau-containing seizure-like activity. We validate the model by finding parameters that reproduce temporal bursting characteristics matching experimental recordings from HN HCOs under control, three different myomodulin concentrations, and Cs+ treated conditions. The matching cases are located along the border of an asymmetric regime away from the border with more dangerous seizure-like activity. We found a simple comodulation mechanism with an inverse relation between the pump and h-currents makes a good fit of the matching cases and comprises a general mechanism for the robust and flexible control of oscillatory neuronal networks.SIGNIFICANCE STATEMENT Rhythm-generating neuronal circuits adjust their oscillatory patterns to accommodate a changing environment through neuromodulation. In different species, chemical messengers participating in such processes may target two or more membrane currents. In medicinal leeches, the neuromodulator myomodulin speeds up the heartbeat central pattern generator by reducing Na+/K+ pump current and increasing h-current. In a computational model, we show that this comodulation expands the range of central pattern generator's functional activity by navigating the circuit between dysfunctional regimes resulting in a much wider range of cycle period. This control would not be attainable by modulating only one current, emphasizing the synergy of combined effects. Given the prevalence of h-current and Na+/K+ pump current in neurons, similar comodulation mechanisms may exist across species.

Randomized clinical trial to evaluate safety and efficacy of convalescent plasma use among hospitalized patients with COVID-19 (PERUCONPLASMA): a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: The general objective of this study is to test the hypothesis that administration of convalescent plasma from donors with previous diagnosis of severe COVID-19 pneumonia is safe and associated with a decrease in all-cause in-hospital mortality among hospitalized patients with COVID-19 at 30 days in comparison with standard treatment alone. The secondary objectives are as follows: (1) to assess the efficacy of convalescent plasma to reduce the length of hospitalization, (2) to assess the efficacy of convalescent plasma to reduce the length of ICU stay, and (3) to assess the efficacy of convalescent plasma on reducing the requirement of invasive mechanical ventilation or ICU stay. TRIAL DESIGN: PERUCONPLASMA is a IIb phase open label, randomized, superiority clinical trial with 1:1 allocation taking place in real life routine clinical practice at public hospitals in Lima, Peru. Participants will be randomized to receive convalescent plasma along with local standard treatment or local standard treatment alone. After allocation, all participants will be followed for a total of 30 days or until hospital discharge, whichever occurs first. PARTICIPANTS: The population for the study are patients with severe disease with a confirmed laboratory test for SARS-CoV-2 infection hospitalized in 3 tertiary-care hospitals in Lima, Peru. Subjects are eligible for the trial if they meet all of the following inclusion criteria: 1. Age 18 or older 2. Hospitalization due to COVID-19 with laboratory confirmation (either with serologic, molecular, or antigen test along with a compatible clinical presentation) 3. Severe or critical COVID-19 disease Severe illness was defined by 2 or more of the following: Respiratory rate of 22 or more Hypoxemia with oxygen saturation equal or less than 93% Abnormal blood gas analysis (PaO2 < 60 mmHg, PaCO2 > 50 mmHg, or Pa/FiO2 < 300) Critical disease was defined by either: Mechanical ventilation requirement less than 72 h. Shock. 4. Capacity to provide informed consent (patient or patient's direct relative) 5. Availability of convalescent plasma units compatible with ABO blood type of the subject. EXCLUSION CRITERIA: Subjects are not eligible for the trial if they meet any of the following criteria: 1. Contraindication for transfusion (e.g., prior anaphylaxis, congestive heart failure) 2. Hemodynamic instability (PA < 60 mmHg refractory to vasopressors) 3. Uncontrolled concomitant infections\ 4. Stupor or coma 5. Platelets < 50,000/µL or disseminated intravascular coagulation 6. Serum creatinine > 3.5 mg/dL or dialysis requirement 7. Total bilirubin > 6 mg/dL or jaundice of unknown etiology 8. Myocardial infarction or acute coronary syndrome 9. Active or recent (< 7 days) intracranial hemorrhage 10. Pregnancy Donors: The donors have to meet the following criteria: male between 30 and 60 years with a previous diagnosis of severe COVID-19-associated pneumonia within the last 3 months, with resolution of symptoms of at least 28 days. The rationale for including donors with severe disease is to maximize the probability of collecting convalescent plasma units with high titer of neutralizing antibodies, as the technology to measure this specific type of antibodies is not routinely available in Peru. Aliquots of plasma will be stored for future quantification of neutralizing antibodies. INTERVENTION AND COMPARATOR: Convalescent plasma from donors with previous severe COVID-19 is the investigational medical product. The experimental group will receive 1 to 2 units of 200 to 250 ml of convalescent plasma along with local standard treatment. The control group will receive local standard treatment alone. The participants randomized to plasma will have evaluations at 6 h and 24 h to specifically evaluate possible post transfusion events. All the participants will be evaluated at day 3, day 7, and day 30 after enrolment. MAIN OUTCOMES: Safety outcome: Incidence of serious adverse reactions related to convalescent plasma transfusion within 24 h after convalescent plasma administration. Efficacy outcomes: Mortality from any cause during hospitalization at 30 days post randomization. Length of hospitalization at 30 days post randomization or until hospital discharge. Duration of mechanical ventilation at 30 days post randomization or until hospital discharge. Length of hospitalization in an intensive care unit at 30 days post randomization or until hospital discharge. Exploratory: Oxygen requirement evolution at days 3 and 7. Score Sequential Organ Failure Assessment (SOFA) evolution at days 3 and 7. Dynamics of inflammatory marker (lymphocyte, C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH)) evolution at days 3 and 7. Proportion of patients progressing to multi-organ failure at 30 days post randomization or until hospital discharge. Proportion of transfusion related adverse reactions at 30 days post randomization or until hospital discharge. RANDOMIZATION: Randomization will be carried out within the electronic case report form (eCRF) in 1:1 ratio (receive plasma/control) in a randomization process established by blocks of size 2, 4, and 6. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomization process. Randomization blocks will be performed with "ralloc", Stata's randomization process v.16.0. Randomization through the eCRF will be available 24 h every day. BLINDING (MASKING): Both the participants and study staff will be aware of the allocated intervention. Blinded statistical analysis will be performed. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The sample size was calculated using the Fleiss formula with continuity correction to detect a mortality reduction from 50 to 20% between the two treatment arms with a confidence level of 95% and a power of 80%. Based on this information, a total of 45 patients per arm would be needed. After adjustment for a drop-out rate of 10% after enrolment, a total of 50 patients per arm (100 patients in total) will be enrolled. TRIAL STATUS: Current protocol version: 5.0 dated January 04, 2021. Recruitment started on September 21, 2020, and is expected to finish by the end of March 2021. TRIAL REGISTRATION: Peruvian Register of Clinical Trials (REPEC) ID: PER-016-20, registered on June 27, 2020. Clinicaltrials.gov ID: NCT04497324 , registered on August 4, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Contributions of h- and Na+/K+ Pump Currents to the Generation of Episodic and Continuous Rhythmic Activities.

Developing spinal motor networks produce a diverse array of outputs, including episodic and continuous patterns of rhythmic activity. Variation in excitability state and neuromodulatory tone can facilitate transitions between episodic and continuous rhythms; however, the intrinsic mechanisms that govern these rhythms and their transitions are poorly understood. Here, we tested the capacity of a single central pattern generator (CPG) circuit with tunable properties to generate multiple outputs. To address this, we deployed a computational model composed of an inhibitory half-center oscillator (HCO). Following predictions of our computational model, we tested the contributions of key properties to the generation of an episodic rhythm produced by isolated spinal cords of the newborn mouse. The model recapitulates the diverse state-dependent rhythms evoked by dopamine. In the model, episodic bursting depended predominantly on the endogenous oscillatory properties of neurons, with Na+/K+ ATPase pump (I Pump) and hyperpolarization-activated currents (I h ) playing key roles. Modulation of either I Pump or I h produced transitions between episodic and continuous rhythms and silence. As maximal activity of I Pump decreased, the interepisode interval and period increased along with a reduction in episode duration. Decreasing maximal conductance of I h decreased episode duration and increased interepisode interval. Pharmacological manipulations of I h with ivabradine, and I Pump with ouabain or monensin in isolated spinal cords produced findings consistent with the model. Our modeling and experimental results highlight key roles of I h and I Pump in producing episodic rhythms and provide insight into mechanisms that permit a single CPG to produce multiple patterns of rhythmicity.

Osteonecrosis de los maxilares asociada a medicamentos: revisión de la literatura y propuesta para la prevención y manejo / Osteonecrosis of the jaws

Medication-related osteonecrosis of the jaw is a disease where there is necrotic bone exposed or that can be explored by means of a fistula in the maxillofacial region. It has been associated with the use Biphosphonates and denosumab for osteoporosis. Although its etiology is unclear, it may be related to a decrease in bone turnover produced by these drugs, rendering the bone more prone to generate cell necrosis during invasive dental procedures, especially in the posterior region of the jaw. There is no consensus about the prevention and treatment of this condition. The aim of this paper is to present a review of the literature with the main characteristics of osteonecrosis of the jaws associated with drugs, together with a proposal for prevention and treatment for these patients.