Publications by authors named "Eli Silver"

9 Publications

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Irritable bowel syndrome is strongly associated with the primary and idiopathic mast cell disorders.

Neurogastroenterol Motil 2021 Sep 17:e14265. Epub 2021 Sep 17.

University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.

Background: Mounting evidence supports a mechanistic association between irritable bowel syndrome (IBS) symptoms and mast cell hyperactivity. Yet, association between IBS and mast cell disorders (MCDs) has not been studied. We examined this association using two large databases and verified with manual chart review.

Methods: The IBM Watson Health Explorys database (Somers, NY), an aggregate of electronic health record (EHR) data from over two dozen US healthcare systems, and Epic's SlicerDicer tool, a self-service tool containing de-identified data from the Epic EHR, were used to identify patients with IBS and MCDs. Patients with organic gastrointestinal disease or diseases associated with secondary mast cell hyperproliferation were excluded. Results were verified with manual chart review from two academic centers.

Key Results: Up to 4% of IBS patients had a comorbid MCD. IBS was strongly associated with all MCDs. The strongest association was between IBS and mast cell activation syndrome (OR 16.3; 95% CI 13.1-20.3). Odds ratios for IBS+urticaria, IBS+idiopathic urticaria, IBS+non-malignant mastocytosis, and IBS+mast cell malignancy ranged from 4.5 to 9.9. Patients from each of these overlap cohorts were predominantly female, and the overlap occurred with all IBS subtypes. Thorough endoscopic evaluation and comorbid mood disorders and migraines are more common in the overlap cohorts than in IBS alone.

Conclusions/inferences: In a large US database encompassing >53 million patients over >20 years, patients with IBS are at least 4 times more likely to have a MCD than the general population. Further study of mast cell involvement in the pathogenesis of IBS is warranted.
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September 2021

Atopy patch tests may identify patients at risk for systemic contact dermatitis.

Immun Inflamm Dis 2020 03 11;8(1):24-29. Epub 2019 Dec 11.

Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio.

Background: A subset of patients with positive patch tests demonstrates systemic contact dermatitis (SCD) upon ingestion or inhalation of the allergen. Concern has been raised about the use of patch tests for protein allergens (APTs) to detect SCD in atopic dermatitis (AD) patients.

Methods: We present atopy patch test (APT) data for 97 people. We reviewed APTs and tests for antigen-specific immunoglobulin E (IgE) to the same allergen in pediatric AD patients. We compared the frequency of APTs as a function of age in AD patients. To study the irritancy potential of APTs, we prospectively tested consenting non-AD dermatitis patients undergoing evaluation for allergic contact dermatitis and healthy controls to an APT panel.

Results: APT demonstrated fewer positive results than serum-specific IgE or skin prick tests to the same allergen. Positive APT to food was more common in children under 3 years, whereas positive APT to aeroallergens were more common in teens and adults. Only positive APTs to dust mite were significantly more common positive in subjects without AD.

Conclusion: Our aggregate findings suggest that most APTs, but not dust mite, behave like conventional patch tests to low-potency allergens. They are more likely to be positive in patients with chronically inflamed skin and to identify allergens that cause SCD. The higher prevalence of APT positivity to foods in young children is consistent with food allergy as a trigger of AD (also known as SCD) being more common in children than adults. Positive APTs define patients who may have SCD; negative APTs may guide elimination diets.
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March 2020

A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.

Nat Genet 2016 Jan 7;48(1):74-8. Epub 2015 Dec 7.

Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.

Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.
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January 2016

Lower levels of plasmacytoid dendritic cells in peripheral blood are associated with a diagnosis of asthma 6 yr after severe respiratory syncytial virus bronchiolitis.

Pediatr Allergy Immunol 2009 Aug 22;20(5):471-6. Epub 2008 Dec 22.

Washington University School of Medicine, St Louis, MO 63110-1093, USA.

Plasmacytoid dendritic cells (pDC) play a crucial role in antiviral immunity and promoting Th1 polarization, possibly protecting against development of allergic disease. Examination of the relationship between peripheral blood plasmacytoid DC levels and manifestations of asthma and atopy early in life. We have isolated peripheral blood mononuclear cells (PBMC) from 73 children (mean age +/- SD: 6.6 +/- 0.5 yr old) participating in the RSV Bronchiolitis in Early Life (RBEL) study. Flow cytometry was performed on PBMC detecting DC surface-markers: Blood Dendritic Cell Antigens (BDCA) 1, 3, and 2 which identify myeloid type 1, type 2, and plasmacytoid cells, respectively. Total serum IgE, peripheral eosinophil count, and allergy skin tests were documented. About 45% (n = 33) of study participants had physician-diagnosed asthma by 6 yr of age. These children had significantly lower quantities (mean +/- SD) of plasmacytoid DC than their non-asthmatic counterparts (1020 +/- 921 vs. 1952 +/- 1170 cells per 10(6) PBMC, p = 0.003). We found significantly lower numbers of myeloid dendritic cells in children with asthma (3836 +/- 2472 cells per 10(6) PBMC) compared with those without asthma (4768 +/- 2224 cells per 10(6) PBMC, p = 0.02); however, this divergence was not significant after adjusting for covariates of age, gender, race, skin test reactivity, smoke exposure, and daycare attendance. We did not identify any direct association between DC levels and markers of atopy: skin test reactivity, peripheral eosinophilia, and IgE level. Children who are diagnosed with asthma after severe RSV bronchiolitis appear to have a relative deficiency of plasmacytoid DC in peripheral blood.
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August 2009

A cerebriform mass on the right buttock.

Dermatol Surg 2003 Jul;29(7):780-1

Department of Dermatology, University of California, Davis School of Medicine Alameda County Medical Center, Oakland, California 95817, USA.

Background: Nevus lipomatosus cutaneous superficialis of Hoffmann-Zurhelle (NLCS) is a rare disorder that is characterized by tumors of mature fat cells situated within the dermis.

Objective: To illustrate by a case report the clinical presentation and management of this rare condition.

Methods: Wide excision of the right thigh and buttock mass was performed, and pathological material was submitted. The defect was repaired with a split-thickness skin graft.

Results: The largest measured nevus lipomatosus, congenital type (20 x 30 cm), was removed from this patient.

Conclusion: Physicians should be aware of this rare tumor, which can become extremely large if untreated.
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July 2003

High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms.

Am J Clin Nutr 2002 Apr;75(4):616-58

Department of Molecular and Cellular Biology, University of California, Berkeley, USA.

As many as one-third of mutations in a gene result in the corresponding enzyme having an increased Michaelis constant, or K(m), (decreased binding affinity) for a coenzyme, resulting in a lower rate of reaction. About 50 human genetic dis-eases due to defective enzymes can be remedied or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme, which at least partially restores enzymatic activity. Several single-nucleotide polymorphisms, in which the variant amino acid reduces coenzyme binding and thus enzymatic activity, are likely to be remediable by raising cellular concentrations of the cofactor through high-dose vitamin therapy. Some examples include the alanine-to-valine substitution at codon 222 (Ala222-->Val) [DNA: C-to-T substitution at nucleo-tide 677 (677C-->T)] in methylenetetrahydrofolate reductase (NADPH) and the cofactor FAD (in relation to cardiovascular disease, migraines, and rages), the Pro187-->Ser (DNA: 609C-->T) mutation in NAD(P):quinone oxidoreductase 1 [NAD(P)H dehy-drogenase (quinone)] and FAD (in relation to cancer), the Ala44-->Gly (DNA: 131C-->G) mutation in glucose-6-phosphate 1-dehydrogenase and NADP (in relation to favism and hemolytic anemia), and the Glu487-->Lys mutation (present in one-half of Asians) in aldehyde dehydrogenase (NAD + ) and NAD (in relation to alcohol intolerance, Alzheimer disease, and cancer).
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April 2002