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2.
Genome Med ; 11(1): 46, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345272

RESUMO

BACKGROUND: A multi-disciplinary approach to promote engagement, inform decision-making and support clinicians and patients is increasingly advocated to realise the potential of genome-scale sequencing in the clinic for patient benefit. Here we describe the results of establishing a genomic medicine multi-disciplinary team (GM-MDT) for case selection, processing, interpretation and return of results. METHODS: We report a consecutive case series of 132 patients (involving 10 medical specialties with 43.2% cases having a neurological disorder) undergoing exome sequencing over a 10-month period following the establishment of the GM-MDT in a UK NHS tertiary referral hospital. The costs of running the MDT are also reported. RESULTS: In total 76 cases underwent exome sequencing following triage by the GM-MDT with a clinically reportable molecular diagnosis in 24 (31.6%). GM-MDT composition, operation and rationale for whether to proceed to sequencing are described, together with the health economics (cost per case for the GM-MDT was £399.61), the utility and informativeness of exome sequencing for molecular diagnosis in a range of traits, the impact of choice of sequencing strategy on molecular diagnostic rates and challenge of defining pathogenic variants. In 5 cases (6.6%), an alternative clinical diagnosis was indicated by sequencing results. Examples were also found where findings from initial genetic testing were reconsidered in the light of exome sequencing including TP63 and PRKAG2 (detection of a partial exon deletion and a mosaic missense pathogenic variant respectively); together with tissue-specific mosaicism involving a cytogenetic abnormality following a normal prenatal array comparative genomic hybridization. CONCLUSIONS: This consecutive case series describes the results and experience of a multidisciplinary team format that was found to promote engagement across specialties and facilitate return of results to the responsible clinicians.

3.
Eur J Neurosci ; 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31350860

RESUMO

The priming effect of rewards is a boost in the vigor of reward seeking resulting from the previous receipt of a reward. Extensive work has been carried out on the priming effect of electrical brain stimulation, but much less research exists on the priming effect of natural rewards, such as food. While both reinforcement and motivation are linked with dopamine transmission in the brain, the priming effect of rewards does not appear to be dopamine-dependent. In the present study, an operant method was developed to measure the priming effect of food and then applied to investigate whether it is affected by dopamine receptor antagonism. Long-Evans rats were administered saline or one of the three doses (0.01, 0.05, 0.075 mg/kg) of the dopamine D1 receptor family antagonist, SCH23390, or the dopamine D2 receptor family antagonist, eticlopride. Although dopamine receptor antagonism affected pursuit of food, it did not eliminate the priming effect. These data suggest that despite the involvement of dopamine transmission in reinforcement and motivation, the priming effect of food does not depend on dopamine transmission.

5.
Front Immunol ; 10: 1150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231365

RESUMO

Deficiency of complement factor I is a rare immunodeficiency that typically presents with increased susceptibility to encapsulated bacterial infections. However, non-infectious presentations including rheumatological, dermatological and neurological disease are increasingly recognized and require a high-index of suspicion to reach a timely diagnosis. Herein, we present two contrasting cases of complement factor I deficiency: one presenting in childhood with invasive pneumococcal disease, diagnosed using conventional immunoassays and genetics and the second presenting in adolescence with recurrent sterile neuroinflammation, diagnosed via a genomic approach. Our report and review of the literature highlight the wide spectrum of clinical presentations associated with CFI deficiency and the power of genomic medicine to inform rare disease diagnoses.

6.
J Digit Imaging ; 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073815

RESUMO

Annotating lesion locations by radiologists' manual marking is a key step to provide reference standard for the training and testing of a computer-aided detection system by supervised machine learning. Inter-reader variability is not uncommon in readings even by expert radiologists. This study evaluated the variability of the radiologist-identified pulmonary emboli (PEs) to demonstrate the importance of improving the reliability of the reference standard by a multi-step process for performance evaluation. In an initial reading of 40 CTPA PE cases, two experienced thoracic radiologists independently marked the PE locations. For markings from the two radiologists that did not agree, each radiologist re-read the cases independently to assess the discordant markings. Finally, for markings that still disagreed after the second reading, the two radiologists read together to reach a consensus. The variability of radiologists was evaluated by analyzing the agreement between two radiologists. For the 40 cases, 475 and 514 PEs were identified by radiologists R1 and R2 in the initial independent readings, respectively. For a total of 545 marks by the two radiologists, 81.5% (444/545) of the marks agreed but 101 marks in 36 cases differed. After consensus, 65 (64.4%) and 36 (35.6%) of the 101 marks were determined to be true PEs and false positives (FPs), respectively. Of these, 48 and 17 were false negatives (FNs) and 14 and 22 were FPs by R1 and R2, respectively. Our study demonstrated that there is substantial variability in reference standards provided by radiologists, which impacts the performance assessment of a lesion detection system. Combination of multiple radiologists' readings and consensus is needed to improve the reliability of a reference standard.

7.
Circ Arrhythm Electrophysiol ; 12(5): e007023, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31006314

RESUMO

BACKGROUND: Postinfarction ventricular tachycardia (VT) generally involves myocardial fibers surrounded by scar. Calcification of scar tissue has been described, but the relationship between calcifications within endocardial scar and VTs is unclear. The purpose of this study was to assess the prevalence of myocardial calcifications as detected by cardiac computed tomography (CT) and the benefit for mapping and ablation focusing on nontolerated VTs. METHODS: Fifty-six consecutive postinfarction patients had a cardiac CT performed before a VT ablation procedure. Another 56 consecutive patients with prior infarction without VT who had cardiac CTs served as a control group. RESULTS: Myocardial calcifications were identified in 39 of 56 patients (70%) in the postinfarction group with VT, compared with 6 of 56 patients (11%) in the control group without VT. Calcifications were associated with VT when compared with a control group. A calcification volume of 0.538 cm3 distinguished patients with calcification-associated VT from patients without calcification-associated VTs (area under the curve, 0.87; sensitivity, 0.87; specificity, 0.88). Myocardial calcifications corresponded to areas of electrical nonexcitability and formed a border for reentry circuits for 49 VTs (33% of all VTs for which target sites were identified) in 24 of 39 patients (62%) with myocardial calcifications. A nonconfluent calcification pattern was associated with VT target sites independent of calcification volume ( P=0.01). CONCLUSIONS: Myocardial calcifications detected by cardiac CT in patients with prior infarction are associated with VT. The calcifications correspond to areas of unexcitability and represent a fixed boundary of reentry circuits that can be visualized by CT. Calcifications correspond to effective ablation sites in >1/3 of patients with postinfarction VT.

8.
Nat Commun ; 10(1): 1869, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015479

RESUMO

Whole-genome sequencing (WGS) is becoming widely used in clinical medicine in diagnostic contexts and to inform treatment choice. Here we evaluate the potential of the Oxford Nanopore Technologies (ONT) MinION long-read sequencer for routine WGS by sequencing the reference sample NA12878 and the genome of an individual with ataxia-pancytopenia syndrome and severe immune dysregulation. We develop and apply a novel reference panel-free analytical method to infer and then exploit phase information which improves single-nucleotide variant (SNV) calling performance from otherwise modest levels. In the clinical sample, we identify and directly phase two non-synonymous de novo variants in SAMD9L, (OMIM #159550) inferring that they lie on the same paternal haplotype. Whilst consensus SNV-calling error rates from ONT data remain substantially higher than those from short-read methods, we demonstrate the substantial benefits of analytical innovation. Ongoing improvements to base-calling and SNV-calling methodology must continue for nanopore sequencing to establish itself as a primary method for clinical WGS.


Assuntos
Testes Genéticos/métodos , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Nanoporos , Sequenciamento Completo do Genoma/métodos , Adulto , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Feminino , Genoma Humano/genética , Genômica/instrumentação , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Humanos , Lactente , Masculino , Nanotecnologia , Pancitopenia/diagnóstico , Pancitopenia/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Supressoras de Tumor/genética , Sequenciamento Completo do Genoma/instrumentação
10.
Methods ; 159-160: 90-95, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30707952

RESUMO

During transcription along nucleosomal DNA, RNA polymerase II (Pol II) pauses at multiple positions and induces formation of multiple intermediates that aid in maintaining proper chromatin structure. To describe the kinetics of this multiple-step reaction, we utilized a computational model-based approach and KinTek Explorer software to analyze the time courses. Here we describe the stepwise protocol for analysis of the kinetics of transcription through a nucleosome that provides the rate constants for each step of this complex process. We also present an example where this time-resolved approach was applied to study the mechanism of histone chaperone FACT action during Pol II transcription through a single nucleosome by comparing the rate constants derived in the presence or in the absence of FACT.

11.
Front Immunol ; 10: 33, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30800120

RESUMO

Antibody deficiency or hypogammaglobulinemia can have primary or secondary etiologies. Primary antibody deficiency (PAD) is the result of intrinsic genetic defects, whereas secondary antibody deficiency may arise as a consequence of underlying conditions or medication use. On a global level, malnutrition, HIV, and malaria are major causes of secondary immunodeficiency. In this review we consider secondary antibody deficiency, for which common causes include hematological malignancies, such as chronic lymphocytic leukemia or multiple myeloma, and their treatment, protein-losing states, and side effects of a number of immunosuppressive agents and procedures involved in solid organ transplantation. Secondary antibody deficiency is not only much more common than PAD, but is also being increasingly recognized with the wider and more prolonged use of a growing list of agents targeting B cells. SAD may thus present to a broad range of specialties and is associated with an increased risk of infection. Early diagnosis and intervention is key to avoiding morbidity and mortality. Optimizing treatment requires careful clinical and laboratory assessment and may involve close monitoring of risk parameters, vaccination, antibiotic strategies, and in some patients, immunoglobulin replacement therapy (IgRT). This review discusses the rapidly evolving list of underlying causes of secondary antibody deficiency, specifically focusing on therapies targeting B cells, alongside recent advances in screening, biomarkers of risk for the development of secondary antibody deficiency, diagnosis, monitoring, and management.

12.
J Clin Immunol ; 39(1): 45-54, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30547383

RESUMO

Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.

13.
Front Immunol ; 9: 2545, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532750

RESUMO

Common variable immune deficiency disorder (CVID) is the most clinically relevant cause of antibody failure. It is a highly heterogeneous disease with different underlying etiologies. CVID has been associated with a quantitative B cell defect, however, little is known about the quality of B cells present. Here, we studied the naïve and antigen selected B-cell receptor (BCR) repertoire in 33 CVID patients using next generation sequencing, to investigate B cells quality. Analysis for each individual patient revealed whether they have a defect in immune repertoire formation [V(D)J recombination] or specification (somatic hypermutation, subclass distribution, or selection). The naïve BCR repertoire was normal in most of the patients, although alterations in repertoire diversity and the junctions were found in a limited number of patients indicating possible defects in early B-cell development or V(D)J recombination in these patients. In contrast, major differences were found in the antigen selected BCR repertoire. Here, most patients (15/17) showed a reduced frequency of somatic hypermutation (SHM), changes in subclass distribution and/or minor alterations in antigen selection. Together these data show that in our CVID cohort only a small number of patients have a defect in formation of the naïve BCR repertoire, whereas the clear majority of patients have disturbances in their antigen selected repertoire, suggesting a defect in repertoire specification in the germinal centers of these patients. This highlights that CVID patients not only have a quantitative B cell defect, but that also the quality of, especially post germinal center B cells, is impaired.


Assuntos
Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Centro Germinativo/imunologia , Receptores de Antígenos de Linfócitos B/genética , Adolescente , Adulto , Idoso , Diferenciação Celular , Criança , Seleção Clonal Mediada por Antígeno , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Hipermutação Somática de Imunoglobulina/genética , Adulto Jovem
14.
Nat Commun ; 9(1): 5366, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30560918

RESUMO

Retinoic acid inducible gene-I (RIG-I) ensures immune surveillance of viral RNAs bearing a 5'-triphosphate (5'ppp) moiety. Mutations in RIG-I (C268F and E373A) lead to impaired ATPase activity, thereby driving hyperactive signaling associated with autoimmune diseases. Here we report, using hydrogen/deuterium exchange, mechanistic models for dysregulated RIG-I proofreading that ultimately result in the improper recognition of cellular RNAs bearing 7-methylguanosine and N1-2'-O-methylation (Cap1) on the 5' end. Cap1-RNA compromises its ability to stabilize RIG-I helicase and blunts caspase activation and recruitment domains (CARD) partial opening by threefold. RIG-I H830A mutation restores Cap1-helicase engagement as well as CARDs partial opening event to a level comparable to that of 5'ppp. However, E373A RIG-I locks the receptor in an ATP-bound state, resulting in enhanced Cap1-helicase engagement and a sequential CARDs stimulation. C268F mutation renders a more tethered ring architecture and results in constitutive CARDs signaling in an ATP-independent manner.


Assuntos
Autoimunidade/genética , Proteína DEAD-box 58/genética , Imunidade Inata/genética , Capuzes de RNA/imunologia , RNA de Cadeia Dupla/imunologia , Adenosina Trifosfatases/metabolismo , Domínio de Ativação e Recrutamento de Caspases/imunologia , Proteína DEAD-box 58/química , Proteína DEAD-box 58/imunologia , Proteína DEAD-box 58/metabolismo , Medição da Troca de Deutério/métodos , Mutação com Ganho de Função , Guanosina/análogos & derivados , Guanosina/química , Guanosina/imunologia , Guanosina/metabolismo , Helicase IFIH1 Induzida por Interferon/imunologia , Helicase IFIH1 Induzida por Interferon/metabolismo , Espectrometria de Massas/métodos , Metilação , Modelos Moleculares , Mutagênese Sítio-Dirigida , Ligação Proteica/genética , Ligação Proteica/imunologia , Capuzes de RNA/química , Capuzes de RNA/metabolismo , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/metabolismo , RNA Viral/imunologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia
15.
Elife ; 72018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30526856

RESUMO

Bacterial and eukaryotic nuclear RNA polymerases (RNAPs) cap RNA with the oxidized and reduced forms of the metabolic effector nicotinamide adenine dinucleotide, NAD+ and NADH, using NAD+ and NADH as non-canonical initiating nucleotides for transcription initiation. Here, we show that mitochondrial RNAPs (mtRNAPs) cap RNA with NAD+ and NADH, and do so more efficiently than nuclear RNAPs. Direct quantitation of NAD+- and NADH-capped RNA demonstrates remarkably high levels of capping in vivo: up to ~60% NAD+ and NADH capping of yeast mitochondrial transcripts, and up to ~15% NAD+ capping of human mitochondrial transcripts. The capping efficiency is determined by promoter sequence at, and upstream of, the transcription start site and, in yeast and human cells, by intracellular NAD+ and NADH levels. Our findings indicate mtRNAPs serve as both sensors and actuators in coupling cellular metabolism to mitochondrial transcriptional outputs, sensing NAD+ and NADH levels and adjusting transcriptional outputs accordingly.


Assuntos
RNA Polimerases Dirigidas por DNA/genética , Capuzes de RNA/genética , RNA Mitocondrial/genética , Transcrição Genética , Citoplasma/genética , Citoplasma/metabolismo , Humanos , Mitocôndrias/genética , NAD/genética , Oxirredução , Regiões Promotoras Genéticas , Saccharomyces cerevisiae/genética , Sítio de Iniciação de Transcrição
16.
Mol Cell ; 72(2): 355-368.e4, 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30270105

RESUMO

RIG-I has a remarkable ability to specifically select viral 5'ppp dsRNAs for activation from a pool of cytosolic self-RNAs. The ATPase activity of RIG-I plays a role in RNA discrimination and activation, but the underlying mechanism was unclear. Using transient-state kinetics, we elucidated the ATPase-driven "kinetic proofreading" mechanism of RIG-I activation and RNA discrimination, akin to DNA polymerases, ribosomes, and T cell receptors. Even in the autoinhibited state of RIG-I, the C-terminal domain kinetically discriminates against self-RNAs by fast off rates. ATP binding facilitates dsRNA engagement but, interestingly, makes RIG-I promiscuous, explaining the constitutive signaling by Singleton-Merten syndrome-linked mutants that bind ATP without hydrolysis. ATP hydrolysis dissociates self-RNAs faster than 5'ppp dsRNA but, more importantly, drives RIG-I oligomerization through translocation, which we show to be regulated by helicase motif IVa. RIG-I translocates directionally from the dsRNA end into the stem region, and the 5'ppp end "throttles" translocation to provide a mechanism for threading and building a signaling-active oligomeric complex.

17.
Mayo Clin Proc Innov Qual Outcomes ; 2(1): 49-59, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30225432

RESUMO

Objective: We describe our experience with routinely capturing and analyzing Mediterranean diet data via structured clinical documentation support tools built into the electronic medical record and describe adherence to the Mediterranean diet in patients at risk for either stroke or dementia in a US neurology clinical practice. Patients and Methods: The Mediterranean diet is associated with a reduced risk of stroke and dementia. The Department of Neurology at NorthShore University HealthSystem routinely evaluates patients at initial and annual outpatient visits using structured clinical documentation support (SCDS) tools built into the electronic medical record (EMR). For patient evaluations in our Vascular Neurology and Brain Health subspecialty clinics, SCDS tools in the EMR include the validated 14-item questionnaire for Mediterranean diet adherence (PREvención con DIeta MEDiterránea [PREDIMED]) that autoscores, auto-interprets, writes to the progress note, and electronically captures data. Our study population includes patients seen at these clinics from July 1, 2015, through November 29, 2017. Results: At their initial office visit, 25.5% (95/373) of Brain Health patients scored 10 or more points ("strongly adherent") on the PREDIMED (median, 8; range, 0-14) whereas 6.7% (55/829) of Vascular Neurology patients achieved a score of 10 or more points (median, 6; range, 0-12). By contrast, 34.7% (2586/7447) of individuals in the original PREDIMED cohort were strongly adherent to the Mediterranean diet. Conclusion: PREDIMED scores can be electronically captured to tailor nutrition interventions by assessing baseline adherence at the time of their initial neurology clinic visit. Patients in our Midwestern US clinics were weakly adherent to the Mediterranean diet. This suggests a major opportunity for nutrition intervention and education in US neurology clinical practices, toward preserving and improving brain health.

18.
Artigo em Inglês | MEDLINE | ID: mdl-30170123

RESUMO

BACKGROUND: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. OBJECTIVES: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. METHODS: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

19.
Front Immunol ; 9: 1656, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30072997

RESUMO

Background: A significant amount of common variable immunodeficiency (CVID) patients manifest with autoimmunity. Particularly, autoimmune thrombocytopenia (AITP) is commonly seen. Intravenous immunoglobulins (IVIG) are an established treatment option for both, CVID and AITP. Nonetheless, due to fewer systemic side effects, immunoglobulins are increasingly applied subcutaneously (SCIG). Objective: To compare the efficacy and safety of IVIG and SCIG treatment in patients with both CVID and clinical relevant thrombocytopenia in the prevention of AITP bouts. Methods: Patients with both CVID and AITP were enrolled at the Centre for Chronic Immunodeficiency in Freiburg, Germany and at the Royal Free Hospital, London, UK. Clinical and laboratory features of patients were collected and analyzed. Results: This retrospective study recruited 61 adult patients between 19 and 71 years of age who had a diagnosis of CVID and at least one bout of thrombocytopenia defined as a platelet count of <50,000/µl if bleeding episodes occurred, or a platelet count of <20,000/µl without bleeding. Thirty patients received immunoglobulin through IVIG, and 31 patients were on SCIG replacement. One patient of the IVIG-group was excluded, because of a diffuse large B-cell lymphoma. We did not find a higher occurrence of thrombocytopenic events in CVID patients who received SCIG, compared to CVID patients who had IVIG, but we identified a low IgG through level as a risk factor for AITP bouts. Conclusion: SCIG is at least as safe as IVIG for patients with CVID and concomitant AITP. However, an IgG through level under 7 g/l is a key factor for the development of AITP.

20.
Blood ; 132(3): 341, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30026303
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