RESUMO
INTRODUCTION/BACKGROUND: Early identification of suspected stroke patients who might be eligible for a reperfusion strategy is a daily challenge in the management of patient referrals. The aim of this study was to evaluate the performance of a remote medical assessment in identifying patients eligible for endovascular therapy (EVT) while not eligible for intravenous thrombolysis (IVT), compared with a decision based on bedside clinico-radiological data. METHODS: Patients admitted to the emergency department for acute neurological symptoms lasting for less than 24h were prospectively included. Assessment of the clinical severity and medical history was performed simultaneously by two vascular neurologists (VNs), one remotely using a mobile telemedicine solution (NOMADEEC), the other at the bedside. RACE score was calculated from the NIHSS score. At the end of the evaluation, both VNs quoted their treatment convictions (IVT/EVT). Final therapeutic decision following brain and vascular imaging was recorded and compared to remote and bedside predictions. The performances of three different conditions were evaluated: complete medical evaluation (NIHSS+medical history), NIHSS score alone, and RACE score alone. Remote and bedside performances were also compared. Diagnostic accuracy parameters (sensitivity, specificity, positive and negative predictive values) of each condition were estimated, along with their two-sided 95% binomial confidence intervals. RESULTS: Out of 215 enrolled patients, 186 had a complete evaluation, 91 (54.3%) were diagnosed with an ischemic stroke or transient ischemic attack and 46 (24.7%) had an intracranial occlusion. Considering the three conditions evaluated remotely, RACE score-based decision provided the best sensitivity 54.6% [95% CI 23.4; 83.2]/specificity 80.6% [73.9; 86.2] combination. However, the complete medical evaluation had the best specificity (88.6% [82.9; 92.9] compared to RACE scores alone (P=0.038). Remote and bedside performances did not differ (κ=0.68 [0.59; 0.77]). DISCUSSION/CONCLUSION: This real-life study performed in the setting of emergency demonstrates that remote medical evaluations including recording of extensive medical information and NIHSS examination to address patient's eligibility to revascularization treatment is swiftly feasible and is as effective as bedside prediction to EVT and/or IVT. Remote standardized medical evaluation might improve the decision of patients' primary orientation and avoid overcrowding of comprehensive stroke centres.
RESUMO
Background and aim: Post-COVID-19 condition (PCC) encompasses long-lasting symptoms in individuals with COVID-19 and is estimated to affect between 31-67% of patients, with women being more commonly affected. No definitive biomarkers have emerged in the acute stage that can help predict the onset of PCC, therefore we aimed at describing sex-disaggregated data of PCC patients from a local cohort and explore potential acute predictors of PCC and neurologic PCC. Methods: A local cohort of consecutive patients admitted with COVID-19 diagnosis between June 2020 and July 2021 were registered, and clinical and laboratory data were recorded. Only those <65 years, discharged alive and followed up at 6 and 12 months after admission were considered in these analyses. Multivariable logistic regression analysis was performed to explore variables associated with PCC (STATA v 18.0). Results: From 130 patients in the cohort, 104 were contacted: 30% were women, median age of 42 years. At 6 months, 71 (68%) reported PCC symptoms. Women exhibited a higher prevalence of any PCC symptom (87 vs. 60%, p = 0.007), lower ferritin (p = 0.001) and procalcitonin (p = 0.021) and higher TNF levels (p = 0.042) in the acute phase compared to men. Being women was independently associated to 7.60 (95% CI 1.27-45.18, p = 0.026) higher risk for PCC. Moreover, women had lower return to normal activities 6 and 12 months. Conclusion: Our findings highlight the lasting impact of COVID-19, particularly in young women, emphasising the need for tailored post-COVID care. The lower ferritin levels in women are an intriguing observation, warranting further research. The study argues for comprehensive strategies that address sex-specific challenges in recovery from COVID-19.
RESUMO
Coprophagia by suckling rabbits, i.e. ingestion of feces from their mother, reduces mortality after weaning. We hypothesized that this beneficial effect of coprophagia is immune-mediated at the intestinal level. Therefore, this study investigated immune development after weaning by analyzing the ileal transcriptome at day 35 and 49 in rabbits with differential access to coprophagia in early life. Rabbit pups had access between day 1 and 15 to (i) no feces (NF) or (ii) feces from unrelated does (Foreign Feces, FF) or (iii) feces from unrelated does treated with antibiotics (FFab). 350 genes were differentially expressed between day 35 and day 49 in suckling rabbits with access to coprophagia. These genes coded for antimicrobial peptides, a mucin, cytokines and chemokines, pattern recognition receptors, proteins involved in immunoglobulin A secretion and in interferon signaling pathway. Strikingly, prevention of coprophagia or access to feces from antibiotic-treated does in early life blunted immune development between day 35 et 49 in the ileum of rabbits. Thus, coprophagia might be crucial for the maturation of intestinal immunity in rabbits and could explain why this behavior improves survival.
Assuntos
Coprofagia , Íleo , Animais , Coelhos , Desmame , Fezes , AntibacterianosRESUMO
OBJECTIVES: To investigate prevalence and clinical factors associated with diabetes among middle-aged women. METHODS: In this cross-sectional population-based study, clinical and laboratory examinations were collected from 298 women. Participants wore a digital pedometer for 7 days to assess habitual physical activity. Abdominal computed tomography scans were performed to measure total fat area and visceral fat area. RESULTS: Mean age was 57.1 years (SD, 5.4 y); 78.7% of women were postmenopausal. The prevalence of diabetes was 17.1%. Women with diabetes were older (P = 0.02); worked fewer hours per week in the past month (P = 0.04); had an earlier age at menarche (P = 0.03); were more frequently inactive (P = 0.01); had higher body mass index (P = 0.01), higher waist circumference (P < 0.01), higher visceral (P < 0.01), and higher total fat (P < 0.01) but not subcutaneous fat (P = 0.14); and had higher systolic blood pressure (BP) (P < 0.01). There was a prevalence of 19.5% of current smoking, 32.5% of alcohol use, and 16.1% of current hormone therapy use, prevalence similar among the groups of women. There was a higher prevalence of metabolic syndrome (P < 0.01) and statin use (P < 0.01) in women with diabetes. A higher prevalence ratio of diabetes was associated with physical inactivity (prevalence ratio, 2.137; 95% CI, 1.056-4.325; P < 0.03). The odds of having diabetes increased by 12% for each year of earlier menarche and by 1.4% for each millimeter of mercury increase in systolic BP. CONCLUSION: The prevalence of diabetes was 17.1%. Age, physical inactivity, early age at menarche, and systolic BP were independently associated with higher prevalence of diabetes in this unselected population of middle-aged women.
Assuntos
Diabetes Mellitus , Pessoa de Meia-Idade , Feminino , Humanos , Brasil/epidemiologia , Prevalência , Estudos Transversais , Diabetes Mellitus/epidemiologia , Fatores de Risco , Índice de Massa CorporalRESUMO
Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the "diagnostic odyssey" for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.
RESUMO
OBJECTIVE: Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence-based PCOS Guideline. DESIGN: Systematic review and meta-analysis of the literature. PATIENTS: Women with PCOS and treatment with insulin sensitisers. MEASUREMENTS: Hormonal and clinical outcomes, as well as side effects. RESULTS: Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]: -4.39, 95% confidence interval [CI]: -7.69 to -1.08 kg), body mass index (MD: -0.95, 95% CI: -1.41 to -0.49 kg/m2 ) and testosterone (MD: -0.10, 95% CI: -0.18 to -0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations. CONCLUSIONS: Metformin should remain the first-line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Metformina , Síndrome do Ovário Policístico , Tiazolidinedionas , Adulto , Humanos , Feminino , Rosiglitazona/uso terapêutico , Hipoglicemiantes/uso terapêutico , Pioglitazona/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Insulina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/uso terapêutico , Tiazolidinedionas/uso terapêuticoRESUMO
Inborn errors of immunity (IEI) or primary immune deficiencies (PIDD) are caused by variants in genes encoding for molecules that are relevant to the innate or adaptive immune response. To date, defects in more than 450 different genes have been identified as causes of IEI, causing a constellation of heterogeneous clinical manifestations ranging from increased susceptibility to infection, to autoimmunity or autoinflammation. IEI that are mainly characterized by autoinflammation are broadly classified according to the inflammatory pathway that they predominantly perturb. Among autoinflammatory IEI are those characterized by the transcriptional upregulation of type I interferon genes and are referred to as interferonopathies. Within the spectrum of interferonopathies, genetic defects that affect the proteasome have been described to cause autoinflammatory disease and represent a growing area of investigation. This review is focused on describing the clinical, genetic, and molecular aspects of IEI associated with mutations that affect the proteasome and how the study of these diseases has contributed to delineate therapeutic interventions.
Assuntos
Autoimunidade , Complexo de Endopeptidases do Proteassoma , Humanos , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Autoimunidade/genética , Mutação/genética , SíndromeRESUMO
Gestation length (GL) is a moderately heritable trait in cattle with economic and management implications. This study aimed to characterize the gestation length of an Argentinian Holstein cattle population, understand contributing factors, and explore the GL effect on production performance. Further objectives were to estimate direct and maternal heritabilities for this trait and to identify genomic regions affecting it. Data consisted of GL records from 45,738 births corresponding to 17,004 Holstein cows and heifers. The effects of age and calving season over GL were analyzed using a Student's t-test for homoscedastic samples. The effects of the GL category (GL shorter than 1.5 SD, within ±1.5 SD, and longer than 1.5 SD from the mean) on production performance were studied by analysis of variance. A single-step genome-wide association study was performed using the BLUPF90 suite of programs with genotypes from 654 Holstein animals on 40,339 SNP. The results showed that the younger the age at calving, the shorter the GL. Moreover, gestations ending in warmer seasons were, in general, statistically shorter than those ending in colder seasons for both heifers and cows. Regarding the effect of GL on production performance, cows with gestation periods within ±1.5 SD from the population mean exhibited the highest 305-day cumulative milk, fat, and protein productions. Direct and maternal heritabilities for GL were 0.42 and 0.03, respectively. We detected a SNP suggestively associated with direct gestation length at 57.7 Mb on Bos taurus autosome 18, a locus included in a region described in the literature as associated with the trait. The information obtained on the environmental and genetic factors affecting GL in Argentinian Holstein cows contributes to characterizing the population in pursuit of improving the performance of national dairy cattle breeding systems.
Assuntos
Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Gravidez , Animais , Bovinos/genética , Feminino , Estudo de Associação Genômica Ampla/veterinária , Parto , Leite , Genótipo , Polimorfismo de Nucleotídeo Único , LactaçãoRESUMO
OBJECTIVE: Spironolactone (SPL) has been used to manage hyperandrogenic manifestations in women with polycystic ovary syndrome (PCOS), but data on the risk of hyperkalemia in this population are scarce. The aim of this study was to evaluate the incidence of hyperkalemia in women with PCOS using SPL in the long term. DESIGN: Single-centre retrospective study. PATIENTS: Inclusion and analysis of 98 treatment periods in 78 women with PCOS (20 of whom were duplicates, returning after treatment interruption for a mean of 38 months) who received SPL for a minimum of 12 months and had at least three measurements of potassium levels over time. MEASUREMENTS: Clinical and hormonal profiles before and during SPL treatment. RESULTS: Mean age was 29.1 (SD: 9.6) years, and body mass index was 32.2 (SD: 8.1) kg/m². Nine patients had diabetes, and 22 had prediabetes. SPL was used in combination with combined oral contraceptive pills in 55 participants and progestin-only pills/long-acting reversible contraception in 28; metformin was added in 35, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in 15. Median SPL dose was 100 (range: 50-150) mg. A total of 327 serum potassium measurements were obtained (84 pre-exposure and 243 postexposure). Four potassium measurements were above the reference range before exposure and 19 during exposure. All potassium measurements above the reference range during follow-up were classified as mild hyperkalemia (5.1-5.5 mEq/L). CONCLUSIONS: The present findings suggest that women with PCOS, without kidney or heart disease, using SPL combined with hormonal contraception for managing clinical hyperandrogenism have a low incidence of hyperkalemia and well-tolerated minor adverse effects.
Assuntos
Hiperpotassemia , Síndrome do Ovário Policístico , Potássio , Espironolactona , Adulto , Feminino , Humanos , Hirsutismo , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/complicações , Hiperpotassemia/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Potássio/sangue , Estudos Retrospectivos , Espironolactona/efeitos adversosRESUMO
These are the recommendations of French glaucoma and retina experts on the management of ocular hypertension (OHT) observed in 1/3 of cases after intravitreal steroid implant injections. They are an update to the recommendations first published in 2017. There are two implants on the French market: the dexamethasone (DEXi) and fluocinolone acetonide (FAci) implants. It is important to know the pressure status before injecting a patient with a steroid implant. Monitoring of the IOP adapted to the specific drug is necessary throughout follow-up and reinjections. Real-life studies have made it possible to optimize the management algorithm by significantly increasing the safety of use of these implants. A corticosteroid test with DEXi is necessary before switching to FAci to optimize the pressure tolerance of the latter. In addition to topical glaucoma medications, SLT laser can be considered in the therapeutic arsenal for the management of steroid-induced OHT and future injections.
Assuntos
Glaucoma , Hipertensão Ocular , Oftalmologia , Humanos , Pressão Intraocular , Procedimentos Cirúrgicos Oftalmológicos , Glaucoma/tratamento farmacológico , Tonometria Ocular , Hipertensão Ocular/tratamento farmacológicoRESUMO
These guidelines are a consensus of French glaucoma and retina experts on the management of ocular hypertension (OHT) observed in a third of the cases after corticosteroid implant intravitreal injections. They update the first guidelines published in 2017. Two implants are marketed in France: the dexamethasone implant (DEXi) and the fluocinolone acetonide implant (FAci). It is essential to assess the pressure status before injecting a patient with a corticosteroid implant. A molecule-specific monitoring of the intraocular pressure is needed throughout the follow-up and at the time of reinjections. Real-life studies have allowed optimizing the management algorithm by significantly increasing the safety of these implants. Corticosteroid testing with DEXi should be performed before switching to FAci to optimize pressure tolerance of FAci. Beyond topical hypotensive treatments, selective laser trabeculoplasty may be considered in the therapeutic arsenal for the management of steroid-induced OHT and subsequent injections.
Assuntos
Glaucoma , Hipertensão Ocular , Oftalmologia , Humanos , Dexametasona , Hipertensão Ocular/induzido quimicamente , Glaucoma/tratamento farmacológico , Glucocorticoides/uso terapêutico , Pressão Intraocular , Corticosteroides/efeitos adversos , Injeções Intravítreas , Esteroides/uso terapêutico , Retina , Implantes de Medicamento/efeitos adversosRESUMO
STUDY QUESTION: Can chromosomal abnormalities beyond copy-number aneuploidies (i.e. ploidy level and microdeletions (MDs)) be detected using a preimplantation genetic testing (PGT) platform? SUMMARY ANSWER: The proposed integrated approach accurately assesses ploidy level and the most common pathogenic microdeletions causative of genomic disorders, expanding the clinical utility of PGT. WHAT IS KNOWN ALREADY: Standard methodologies employed in preimplantation genetic testing for aneuploidy (PGT-A) identify chromosomal aneuploidies but cannot determine ploidy level nor the presence of recurrent pathogenic MDs responsible for genomic disorders. Transferring embryos carrying these abnormalities can result in miscarriage, molar pregnancy, and intellectual disabilities and developmental delay in offspring. The development of a testing strategy that integrates their assessment can resolve current limitations and add valuable information regarding the genetic constitution of embryos, which is not evaluated in PGT providing new level of clinical utility and valuable knowledge for further understanding of the genomic causes of implantation failure and early pregnancy loss. To the best of our knowledge, MDs have never been studied in preimplantation human embryos up to date. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort analysis including blastocyst biopsies collected between February 2018 and November 2021 at multiple collaborating IVF clinics from prospective parents of European ancestry below the age of 45, using autologous gametes and undergoing ICSI for all oocytes. Ploidy level determination was validated using 164 embryonic samples of known ploidy status (147 diploids, 9 triploids, and 8 haploids). Detection of nine common MD syndromes (-4p=Wolf-Hirschhorn, -8q=Langer-Giedion, -1p=1p36 deletion, -22q=DiGeorge, -5p=Cri-du-Chat, -15q=Prader-Willi/Angelman, -11q=Jacobsen, -17p=Smith-Magenis) was developed and tested using 28 positive controls and 97 negative controls. Later, the methodology was blindly applied in the analysis of: (i) 100 two pronuclei (2PN)-derived blastocysts that were previously defined as uniformly euploid by standard PGT-A; (ii) 99 euploid embryos whose transfer resulted in pregnancy loss. PARTICIPANTS/MATERIALS, SETTING, METHODS: The methodology is based on targeted next-generation sequencing of selected polymorphisms across the genome and enriched within critical regions of included MD syndromes. Sequencing data (i.e. allelic frequencies) were analyzed by a probabilistic model which estimated the likelihood of ploidy level and MD presence, accounting for both sequencing noise and population genetics patterns (i.e. linkage disequilibrium, LD, correlations) observed in 2504 whole-genome sequencing data from the 1000 Genome Project database. Analysis of phased parental haplotypes obtained by single-nucleotide polymorphism (SNP)-array genotyping was performed to confirm the presence of MD. MAIN RESULTS AND THE ROLE OF CHANCE: In the analytical validation phase, this strategy showed extremely high accuracy both in ploidy classification (100%, CI: 98.1-100%) and in the identification of six out of eight MDs (99.2%, CI: 98.5-99.8%). To improve MD detection based on loss of heterozygosity (LOH), common haploblocks were analyzed based on haplotype frequency and LOH occurrence in a reference population, thus developing two further mathematical models. As a result, chr1p36 and chr4p16.3 regions were excluded from MD identification due to their poor reliability, whilst a clinical workflow which incorporated parental DNA information was developed to enhance the identification of MDs. During the clinical application phase, one case of triploidy was detected among 2PN-derived blastocysts (i) and one pathogenic MD (-22q11.21) was retrospectively identified among the biopsy specimens of transferred embryos that resulted in miscarriage (ii). For the latter case, family-based analysis revealed the same MD in different sibling embryos (n = 2/5) from non-carrier parents, suggesting the presence of germline mosaicism in the female partner. When embryos are selected for transfer based on their genetic constitution, this strategy can identify embryos with ploidy abnormalities and/or MDs beyond aneuploidies, with an estimated incidence of 1.5% (n = 3/202, 95% CI: 0.5-4.5%) among euploid embryos. LIMITATIONS, REASONS FOR CAUTION: Epidemiological studies will be required to accurately assess the incidence of ploidy alterations and MDs in preimplantation embryos and particularly in euploid miscarriages. Despite the high accuracy of the assay developed, the use of parental DNA to support diagnostic calling can further increase the precision of the assay. WIDER IMPLICATIONS OF THE FINDINGS: This novel assay significantly expands the clinical utility of PGT-A by integrating the most common pathogenic MDs (both de novo and inherited ones) responsible for genomic disorders, which are usually evaluated at a later stage through invasive prenatal testing. From a basic research standpoint, this approach will help to elucidate fundamental biological and clinical questions related to the genetics of implantation failure and pregnancy loss of otherwise euploid embryos. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. S.C., M.F., F.C., P.Z., I.P., L.G., C.P., M.P., D.B., J.J.-A., D.B.-J., J.M.-V., and C.R. are employees of Igenomix and C.S. is the head of the scientific board of Igenomix. A.C. and L.P. are employees of JUNO GENETICS. Igenomix and JUNO GENETICS are companies providing reproductive genetic services. TRIAL REGISTRATION NUMBER: N/A.
Assuntos
Aborto Espontâneo , Diagnóstico Pré-Implantação , Gravidez , Feminino , Humanos , Diagnóstico Pré-Implantação/métodos , Estudos Retrospectivos , Reprodutibilidade dos Testes , Aborto Espontâneo/patologia , Estudos Prospectivos , Testes Genéticos/métodos , Blastocisto/patologia , AneuploidiaRESUMO
INTRODUCTION: The cognitive effects of cross-sex hormone therapy (CSHT) are not well understood. In cisgender individuals, sex hormone therapy can impact neurotransmitter levels and structural anatomy. Similarly, in gender-diverse persons, CSHT has been associated with neural adaptations, such as growth in brain structures resembling those observed in cisgender individuals of the same sex. Hormone-related changes in learning and memory, as seen in menopause, are associated with physiological hypogonadism or a decline in hormones, such as estradiol. The present study examined the effect of estradiol administration in humans on glutamate concentration in brain regions involved in semantic and working memory (i.e., the dorsolateral prefrontal cortex [DLPFC], the posterior hippocampus, and the pregenual anterior cingulate cortex) and its relationship with memory. METHODS: Eighteen trans women (male biological sex assigned at birth) ceased CSHT for 30 days for a washout phase (t1) upon study enrollment to reach a hypogonadal state. Working and semantic memory, cognition, hormonal assays, and brain imaging were assessed. Participants resumed CSHT for 60 days for a replacement phase (t2), after which the same evaluations from t1 were repeated. RESULTS: Estradiol increased among trans women after 60 days of resumed CSHT with significant improvements in semantic memory compared to the hypogonadal phase. Working memory recall was significantly and positively correlated to glutamate in the DLPFC during the reinstatement phase, although the relationship was not moderated by levels of estradiol. DISCUSSION: These results may have clinical implications for the therapeutic effects of estradiol replacement, serving as a protective factor against cognitive decline and impairment for trans women post-gonadectomy.
Assuntos
Estradiol , Memória de Curto Prazo , Recém-Nascido , Humanos , Masculino , Feminino , Estradiol/farmacologia , Memória de Curto Prazo/fisiologia , Hormônios Esteroides Gonadais/farmacologia , Encéfalo , Plasticidade NeuronalRESUMO
Human NK cell deficiency (NKD) is a primary immunodeficiency in which the main clinically relevant immunological defect involves missing or dysfunctional NK cells. Here, we describe a familial NKD case in which 2 siblings had a substantive NKD and neutropenia in the absence of other immune system abnormalities. Exome sequencing identified compound heterozygous variants in Go-Ichi-Ni-San (GINS) complex subunit 4 (GINS4, also known as SLD5), an essential component of the human replicative helicase, which we demonstrate to have a damaging impact upon the expression and assembly of the GINS complex. Cells derived from affected individuals and a GINS4-knockdown cell line demonstrate delayed cell cycle progression, without signs of improper DNA synthesis or increased replication stress. By modeling partial GINS4 depletion in differentiating NK cells in vitro, we demonstrate the causal relationship between the genotype and the NK cell phenotype, as well as a cell-intrinsic defect in NK cell development. Thus, biallelic partial loss-of-function mutations in GINS4 define a potentially novel disease-causing gene underlying NKD with neutropenia. Together with the previously described mutations in other helicase genes causing NKD, and with the mild defects observed in other human cells, these variants underscore the importance of this pathway in NK cell biology.
Assuntos
Neutropenia , Humanos , Neutropenia/genética , Replicação do DNA , Células Matadoras Naturais , Mutação , Divisão Celular , Proteínas Cromossômicas não Histona/genéticaRESUMO
BACKGROUND: Multisystemic inflammatory syndrome in children (MIS-C) is a life-threatening disease that occurs 2-5 weeks after severe acute respiratory syndrome coronavirus 2 exposure and is characterized by severe multisystemic inflammation. Early recognition of MIS-C is key to prognosis; therefore, establishing clinical and laboratory biomarkers that predict complications is urgently needed. OBJECTIVE: We characterized the immune response and clinical features of patients with acute MIS-C and determined biomarkers of disease in a cohort of 42 Latin American patients. METHODS: Immune characterization was performed using flow cytometry from peripheral mononuclear cells and severe acute respiratory syndrome coronavirus 2-specific humoral and cellular response was performed using flow cytometry, enzyme-linked immunospot, enzyme-linked immunosorbent assay, and neutralizing antibody assays. RESULTS: MIS-C is characterized by robust T-cell activation and cytokine storm. We uncovered that while C-X-C motif chemokine ligand (CXCL) 9, IL-10, CXCL8, CXCL10, IL-6, and IL-18 are significantly elevated in patients with shock, while CCL5 was increased in milder disease. Monocyte dysregulation was specifically associated with KD-like MIS-C. Interestingly, MIS-C patients show a natural killer cell degranulation defect that is persistent after 6 months of disease presentation, suggesting it could underlie disease susceptibility. Most MIS-C had gastrointestinal involvement, and higher levels of neopterin were identified in their stools, potentially representing a biomarker of intestinal inflammation in MIS-C. Severe acute respiratory syndrome coronavirus 2-specific cellular response and neutralizing antibodies were identifiable in convalescent MIS-C patients, suggesting sustained immunity. CONCLUSION: Clinical characterization and comprehensive immunophenotyping of Chilean MIS-C cohort provide valuable insights in understanding immune dysregulation in MIS-C and identify relevant biomarkers of disease that could be used to predict severity and organ involvement.
Assuntos
COVID-19 , Criança , Humanos , Imunofenotipagem , América Latina , SARS-CoV-2 , Síndrome da Liberação de Citocina , Anticorpos Neutralizantes , BiomarcadoresRESUMO
OBJECTIVE: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of "points to consider" to improve diagnosis, treatment, and long-term monitoring of patients with these rare diseases. METHODS: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, "points to consider" to guide patient management were developed. RESULTS: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment, and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI, and AGS. CONCLUSION: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Malformações do Sistema Nervoso , Reumatologia , Dermatopatias , Doenças Autoimunes do Sistema Nervoso/genética , Eritema Nodoso , Dedos/anormalidades , Humanos , Qualidade de VidaRESUMO
Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αß) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor-induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum-associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.
Assuntos
Imunidade Inata/imunologia , Interleucinas/imunologia , eIF-2 Quinase/imunologia , Animais , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , eIF-2 Quinase/deficiênciaRESUMO
BACKGROUND AND PURPOSE: Early glycemic variability (GV) in diabetic patients is a poor prognosis factor following cardiovascular events. However, its influence on the course of acute ischemic stroke (AIS) with large vessel occlusion remains unclear. We investigated the relationship between high GV during acute stroke and three-month functional outcome among patients treated with combined intravenous thrombolysis and endovascular therapy for large vessel occlusion. METHODS: A single-center retrospective analysis of AIS patients with proximal intracranial occlusion who underwent thrombolysis and mechanical thrombectomy between January 2015 and May 2017. Early GV was assessed using standard deviation (SD) of blood glucose levels for the first 24hours. The main outcome was functional status at three months as defined by the modified Rankin scale (mRS). Secondary outcomes were change in NIHSS score from baseline to 24hours and occurrence of severe hemorrhagic transformation. Multivariate logistic regression analyses including GV, admission glycemia and mean glycemia were performed. RESULTS: Among the 93 patients evaluated, 26 had early high GV (≥20.9mg/dl). High GV was associated with poor functional outcome (OR=8.00; 95%CI [1.34-47.89]; P=0.02) unlike admission glycemia and mean glycemia (OR=2.92; 95%CI [0.51-16.60]; P=0.23 and OR=0.36; 95%CI [0.05-2.6]; p=0.31, respectively). High GV was not associated with NIHSS at 24hours or hemorrhagic transformation. CONCLUSION: Acute high GV contributes to poorer functional outcome following AIS related to large vessel occlusion and should be considered as a new target in acute stroke management.
Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/complicações , Isquemia Encefálica/terapia , Humanos , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/terapia , Trombectomia/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVE: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of 'points to consider' to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases. METHODS: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, 'points to consider' to guide patient management were developed. RESULTS: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS. CONCLUSION: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.