BACKGROUND Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.)
/-groups, in which the /-subgroup is a direct product of Archimedian o-groups, is embeddable in an /-group. The first result implies an alternate proof-similar in technique to the proof of the classic analogue for groupsof the result of Holland's [5, Theorem 5, p. 405], that any /-group can be embedded in a divisible /-group. Finally, as a corollary to the proof of the first result, we get that an /-group can be embedded in an /-group of the same cardinality in which any two positive elements are conjugate. Notation. All groups are written multiplicatively, and all maps are written on
The contribution of genetic variation to urinary tract infection (UTI) risk in children with vesicoureteral reflux is largely unknown. The innate immune system, which includes antimicrobial peptides, such as the α-defensins, encoded by DEFA1A3, is important in preventing UTIs but has not been investigated in the vesicoureteral reflux population. We used quantitative real-time PCR to determine DEFA1A3 DNA copy numbers in 298 individuals with confirmed UTIs and vesicoureteral reflux from the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Study and 295 controls, and we correlated copy numbers with outcomes. Outcomes studied included reflux grade, UTIs during the study on placebo or antibiotics, bowel and bladder dysfunction, and renal scarring. Overall, 29% of patients and 16% of controls had less than or equal to five copies of DEFA1A3 (odds ratio, 2.09; 95% confidence interval, 1.40 to 3.11; P<0.001). For each additional copy of DEFA1A3, the odds of recurrent UTI in patients receiving antibiotic prophylaxis decreased by 47% when adjusting for vesicoureteral reflux grade and bowel and bladder dysfunction. In patients receiving placebo, DEFA1A3 copy number did not associate with risk of recurrent UTI. Notably, we found that DEFA1A3 is expressed in renal epithelium and not restricted to myeloid-derived cells, such as neutrophils. In conclusion, low DEFA1A3 copy number associated with recurrent UTIs in subjects in the RIVUR Study randomized to prophylactic antibiotics, providing evidence that copy number polymorphisms in an antimicrobial peptide associate with UTI risk.
The urinary tract is usually culture negative despite its close proximity to microbial flora. The precise mechanism by which the kidneys and urinary tract defends against infection is not well understood. The initial kidney cells to encounter ascending pathogens are the collecting tubule cells that consist of principal cells (PCs) that express aquaporin 2 (AQP2) and intercalated cells (ICs) that express vacuolar H-ATPase (V-ATPase, B1 subunit). We have previously shown that ICs are involved with the human renal innate immune defense. Here we generated two reporter mice, VATPase B1-cretdT mice to fluorescently label ICs and AQP2-cretdT mice to fluorescently label PCs, and then performed flow sorting to enrich PCs and ICs for analysis. Isolated ICs and PCs along with proximal tubular cells were used to measure antimicrobial peptide (AMP) mRNA expression. ICs and PCs were significantly enriched for AMPs. Isolated ICs responded to uropathogenic Escherichia coli (UPEC) challenge in vitro and had higher RNase4 gene expression than control while both ICs and PCs responded to UPEC challenge in vivo by upregulating Defb1 mRNA expression. To our knowledge, this is the first report of isolating murine collecting tubule cells and performing targeted analysis for multiple classes of AMPs.
The renal collecting duct consists of intercalated cells (ICs) and principal cells (PCs). We have previously demonstrated that collecting ducts have a role in the innate immune defense of the kidney. Transcriptomics is an important tool used to enhance systems-level understanding of cell biology. However, transcriptomics performed on whole kidneys provides limited insight of collecting duct cell gene expression, because these cells comprise a small fraction of total kidney cells. Recently we generated reporter mouse models to enrich collecting duct specific PC and ICs and reported targeted gene expression of anti-microbial peptide genes. Here we report transcriptomics on enriched ICs and PCs and performed a pilot study sequencing four single ICs. We identified 3,645 genes with increased relative expression in ICs compared to non-ICs. In comparison to non-PCs, 2,088 genes had higher relative expression in PCs. IC associated genes included the innate interleukin 1 receptor, type 1 and the antimicrobial peptide(AMP) adrenomedullin. The top predicted canonical pathway for enriched ICs was lipopolysaccharide/Interleukin 1 mediated inhibition of Retinoid X Receptor alpha function and decreased Retinoid X Receptor expression was confirmed to occur 1-hour post experimental murine UTI in ICs but not in non-ICs.
IntroductionVesicoureteral reflux is a common disorder in children but can result in kidney scarring following acute pyelonephritis. The gold standard diagnostic to detect renal scars in children is 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy. DMSA has a number of limitations including radiation exposure, need for sedation, and radiotracer supply shortages. Contrast-enhanced ultrasound (CEUS) is a technique whereby biocompatible microspheres of inert gas are administered i.v. that reflect ultrasonography sound waves and do not involve radiation. Because the contrast agent is rapidly cleared, contrast images must be obtained within minutes of administration. CEUS has been used in a variety of organ systems, but its use in pediatric kidney diseases is limited.MethodsIn this study, we performed CEUS in 7 children with documented renal scars by radiographic imaging consistent with reflux nephropathy.ResultsIn all subjects, CEUS detected all previously known radiologic abnormalities as well as detecting new areas of hypoenhancing renal parenchyma. None of the patients experienced any serious adverse events.DiscussionThis study represents the first report of using CEUS to characterize renal scars in children with reflux nephropathy. We conclude that CEUS is a highly sensitive, rapid, and cost-effective diagnostic imaging modality for detecting and monitoring renal scars in children with vesicoureteral reflux.
Abstract. The theory of abelian totally ordered groups has a model completion. We show that the theory of abelian lattice-ordered groups has no model companion. Indeed, the Archimedean property can be captured by a first order V3V sentence for existentially complete abelian lattice-ordered groups, and distinguishes between finitely generic abelian lattice-ordered groups and infinitely generic ones. We then construct (by sheaf techniques) the model companions of certain classes of discrete abelian lattice-ordered groups.The class of abelian groups has a model companion [7]. The slightly larger class of nilpotent class 2 groups, however, is already very misbehaved; there is no model companion and, indeed, the finitely generic and infinitely generic theories share no models in common ([17] and [18] When total order is replaced by lattice-order, the conclusion changes radically. Our main theorem is:(1) The theory of abelian lattice-ordered groups has no model companion. Moreover, (2) the Archimedean property is equivalent to a V3V sentence for existentially complete abelian lattice-ordered groups, and (3) finitely generic abelian lattice-ordered groups satisfy the sentence (i.e., are Archimedean) but infinitely generic ones do not (i.e., are not Archimedean).Of course, the Archimedean property is not expressible by a first order sentence in general; it is only when we restrict to existentially complete abelian latticeordered groups that we can capture it by a first order sentence. This expressibility phenomenon is frequently used to distinguish between finitely generic structures
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.