Howard M. Lederman

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (125)710.04 Total impact

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    ABSTRACT: Objective: To evaluate the potential link between systemic inflammation and impaired lung function in people with ataxia-telangiectasia (A-T), we hypothesized that serum levels of interleukin (IL)-6, a proinflammatory cytokine, would correlate inversely with lung function in subjects with A-T. Study design: Consecutive subjects with A-T were recruited from the Johns Hopkins Outpatient A-T Clinical Center. Serum levels of IL-6 and 8 were measured by enzyme-linked immunosorbent assay. Spirometry was performed in subjects ≥6 years of age on the same day that serum was obtained for measurements of cytokines. Results: Approximately 80% of subjects had elevated serum IL-6 levels (>1.0 pg/mL). No association was found between elevated IL-6 and age. Elevated IL-8 levels were found in 23.6% of subjects, and all subjects with elevated IL-8 levels had elevated IL-6 levels. Subjects with elevated IL-6 levels (mean: 6.14 ± 7.47 pg/mL) had significantly lower mean percent forced vital capacity (FVC%, 50.5% ± 17.8%) compared with subjects with normal serum IL-6 levels (FVC% of 66.2 ± 16.1, P = .018). Greater IL-6 levels were associated with lower FVC% even after adjustment for receiving gamma globulin therapy (P = .024) and supplemental nutrition (P = .055). Conclusions: An association was found between elevated serum IL-6 levels and lower lung function in subjects with A-T. In addition, subjects with both elevated IL-6 and IL-8 had the lowest mean lung function. These findings indicate that markers for systemic inflammation may be useful in identifying individuals with A-T at increased risk for lower lung function and may help in assessing response to therapy.
    No preview · Article · Feb 2016 · The Journal of pediatrics
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    Full-text · Dataset · Nov 2015
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    Full-text · Dataset · Nov 2015
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    Full-text · Dataset · Nov 2015
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    ABSTRACT: A spontaneously reverted iPSC line was identified from an A-T subject with heterozygous ATM truncation mutations. The reverted iPSC line expressed ATM protein and was capable of radiation-induced phosphorylation of CHK2 and H2A.X. Genome-wide SNP analysis confirmed a match to source T cells and also to a distinct, non-reverted iPSC line from the same subject. Rearranged T cell receptor sequences predict that the iPSC culture originated as several independently reprogrammed cells that resolved into a single major clone, suggesting that gene correction likely occurred early in the reprogramming process. Gene expression analysis comparing ATM−/− iPSC lines to unrelated ATM+/− cells identifies a large number of differences, but comparing only the isogenic pair of A-T iPSC lines reveals that the primary pathway affected by loss of ATM is a diminished expression of p53-related mRNAs. Gene reversion in culture, although likely a rare event, provided a novel, reverted cell line for studying ATM function.
    Full-text · Article · Nov 2015 · Stem Cell Reports
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    ABSTRACT: Background and objective: Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea's effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1-S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses. Methods: T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG). Results: Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use. Conclusions: Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced.
    Full-text · Article · Sep 2014 · Pediatrics
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    ABSTRACT: The present uncertainty of which live viral or bacterial vaccines can be given to immunodeficient patients and the growing neglect of societal adherence to routine immunizations has prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based on published literature and the collective experience of the committee members. These recommendations address the concern for immunodeficient patients acquiring infections from healthy subjects who have not been immunized or who are shedding live vaccine–derived viral or bacterial organisms. Such transmission of infectious agents can occur within the hospital, clinic, or home or at any public gathering. Collectively, we define this type of transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who might have an infection when exposed to subjects carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are receiving immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable subjects and their social needs to integrate into society, attend school, and benefit from peer education.
    No preview · Article · Apr 2014 · The Journal of allergy and clinical immunology
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    ABSTRACT: Background Pulmonary disease contributes to significant morbidity and mortality in people with ataxia telangiectasia (A-T). To determine the association between age and lung function in children and young adults with A-T and to identify factors associated with decreased lung function, pulmonary function tests were performed in 100 consecutive people with A-T. Methods Children and adults ranging from 6 to 29 years of age and with the diagnosis of A-T were recruited, and underwent pulmonary function tests. ResultsThe mean forced vital capacity % predicted (FVC %) in the population was 56.620.0. Males and females between 6 and 10 years of age had similar pulmonary function. Older females were found to have significantly lower FVCs % than both older males (P<0.02) and younger females (P<0.001). The use of supplemental gamma globulin was associated with significantly lower FVC %. A modest correlation was found between higher radiation-induced chromosomal breakage and lower FVC % in males. No significant change in FVC % was found in a subset of subjects (n=25) who underwent pulmonary function testing on two or more occasions over an average of 2 years. Conclusion In children and young adults with A-T, older females and people who required supplemental gamma globulin had significantly lower lung function by cross-sectional analysis. Stable lung function is possible over a 2-year period. Recognition of groups who are at higher risk for lower pulmonary function may help direct care and improve clinical outcomes in people with A-T. Pediatr Pulmonol. 2014; 49:84-990. (c) 2013 Wiley Periodicals, Inc.
    No preview · Article · Jan 2014 · Pediatric Pulmonology
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    D D M Lin · P B Barker · H M Lederman · T O Crawford
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    ABSTRACT: Ataxia-telangiectasia, an autosomal recessive disorder caused by defect of the ataxia-telangiectasia mutated gene, is characterized by progressive neurologic impairment with cerebellar atrophy, ocular and cutaneous telangiectasia, immunodeficiency, heightened sensitivity to ionizing radiation and susceptibility to developing lymphoreticular malignancy. Supratentorial brain abnormalities have been reported only rarely. In this study, brain MRI was performed in 10 adults with ataxia-telangiectasia having stable neurologic impairment. Intracerebral telangiectasia with multiple punctate hemosiderin deposits were identified in 60% of subjects. These lesions were apparently asymptomatic. They are similar in appearance to radiation-induced telangiectasia and to cryptogenic vascular malformations. Also noted, in the 2 oldest subjects, was extensive white matter T2 hyperintensity, and in 1 of these a space-occupying fluid collection consistent with transudative capillary leak and edema as evidenced by reduced levels of metabolites on MR spectroscopic imaging. Asymptomatic supratentorial vascular abnormalities appear to be common in adults with ataxia-telangiectasia.
    Full-text · Article · Jul 2013 · American Journal of Neuroradiology
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    ABSTRACT: Ataxia-telangiectasia is known for cerebellar degeneration, but clinical descriptions of abnormal tone, posture, and movements suggest involvement of the network between cerebellum and basal ganglia. We quantitatively assessed the nature of upper-limb movement disorders in ataxia-telangiectasia. We used a three-axis accelerometer to assess the natural history and severity of abnormal upper-limb movements in 80 ataxia-telangiectasia and 19 healthy subjects. Recordings were made during goal-directed movements of upper limb (kinetic task), while arms were outstretched (postural task), and at rest. Almost all ataxia-telangiectasia subjects (79/80) had abnormal involuntary movements, such as rhythmic oscillations (tremor), slow drifts (dystonia or athetosis), and isolated rapid movements (dystonic jerks or myoclonus). All patients with involuntary movements had both kinetic and postural tremor, while 48 (61%) also had resting tremor. The tremor was present in transient episodes lasting several seconds during two-minute recording sessions of all three conditions. Percent time during which episodic tremor was present was greater for postural and kinetic tasks compared to rest. Resting tremor had higher frequency but smaller amplitude than postural and kinetic tremor. Rapid non-rhythmic movements were minimal during rest, but were triggered during sustained arm postures and goal directed arm movements suggesting they are best considered a form of dystonic jerks or action myoclonus. Advancing age did not correlate with the severity of involuntary limb movements. Abnormal upper-limb movements in ataxia-telangiectasia feature classic cerebellar impairment, but also suggest involvement of the network between the cerebellum and basal ganglia.
    Full-text · Article · Jun 2013 · PLoS ONE
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    ABSTRACT: Ochroconis spp. are dematiaceous fungi and have recently become recognized as the cause of human disease. Infections due to members of this genus have primarily occurred in patients with impaired immunity following organ transplantation or chemotherapy for hematologic malignancies. There is no universally agreed upon therapy or duration of treatment, but amphotericin B and/or triazoles are typically employed. We present a case of Ochroconis gallopava infection in a patient with chronic granulomatous disease (CGD). The organism exhibited elevated minimal inhibitory concentrations against itraconazole (0.5 μg/ml) and voriconazole (2 μg/ml) in comparison with results from other studies reported in the literature. This case illustrates the complexities associated with antibiotic susceptibility testing, selection of appropriate drugs, and management in patients with Ochroconis infections. We also review the literature of human infections with Ochroconis to date, and discuss its microbiology to apprise both clinicians and laboratory personnel of this infrequently encountered but potentially aggressive pathogen.
    Preview · Article · May 2012 · Medical mycology: official publication of the International Society for Human and Animal Mycology
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    ABSTRACT: OBJECTIVES/AIM: To report our relatively large experience with perioperative care for patients with Ataxia-Telangiectasia (A-T) and to identify the nature and frequency of complications. Ataxia-Telangiectasia is a rare autosomal recessive genetic disorder resulting in progressive multisystem degeneration and characteristic findings including complex neurodegeneration, immunodeficiency, increased risk of malignancy, and lung disease. Anecdotal reports have suggested high perioperative morbidity in patients with A-T, but few data exist. The Ataxia-Telangiectasia Clinical Center database was cross-referenced with operative records between 1995 and 2009 to identify patients with perioperative A-T, and medical records were reviewed for preoperative history, management techniques, and complications. Twenty-one patients with A-T underwent 34 anesthetics during the study period. The median age was 12.5 years (range 6-33 years). Common comorbidities included neurologic (100%), pulmonary (68%), immunologic (50%), oncologic (47%), and gastroenterologic (35%) disorders. Supplemental oxygen was required on postanesthesia care unit discharge for 24% of patients with a maximal duration of 24 h. Although mild postoperative hypothermia was relatively common (44% of anesthetics), there were no major complications, no unplanned admissions, and no mortality in this series. Although limited by its retrospective nature, this is the first series describing perioperative risk for patients with A-T. Our results indicate that general anesthesia, airway manipulation, and perioperative mechanical ventilation may be tolerated with only minor postoperative anesthetic concerns. Perioperative providers should be aware of the complex multisystem medical concerns that may arise in these patients.
    No preview · Article · Nov 2011 · Pediatric Anesthesia
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    ABSTRACT: Immunomodulatory T cells are thought to influence development of allergy and asthma, but early life longitudinal data on their phenotype and function are lacking. As part of the Urban Environment and Childhood Asthma (URECA) study, we investigated the development of immunomodulatory T cell phenotype and function, and characterized their relation to allergic disease progression from birth through to 2 years of age. Immunomodulatory T cell phenotype and function in cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) at 1 and 2 years of age were characterized by analysing CD25(bright) and FoxP3(+) expression, proliferative responses and cytokine production. The relation of immunomodulatory T cell characteristics to allergic sensitization and disease at 1- and 2-years of age was investigated. The proportion of CD4(+)CD25(bright) and CD4(+)CD25(+)FoxP3(+)T cells (n = 114, 83, 82 at birth, 1- and 2-years respectively) increased significantly, whereas there were no significant changes in the suppressive function of CD25(+)T cells (n = 78, 71, 81 at birth, 1- and 2-years respectively). Birth immunomodulatory T cell characteristics were not related to subsequent allergic sensitization or disease. However, increases in the numbers of CD4(+)CD25(bright) cells and their ability to suppress lymphoproliferative responses at 1 year of age were associated with reduced allergic sensitization at 1 (P = 0.03) and 2 (P = 0.02) years of age. Production of the anti-inflammatory cytokine IL-10 by CD25(+)T cells appeared to mediate this protective suppressive function. In contrast, by 2 years of age, we observed the emergence of a positive association of CD4(+)CD25(+) FoxP3(+) T cell numbers with allergic sensitization (P = 0.05) and eczema (P = 0.02). These findings suggest that the relationship between immunomodulatory T cell subsets, allergic sensitization and eczema is developmentally regulated. In the first year of life, CD4(+)CD25(+) IL-10 producing T cells are associated with a reduced incidence of allergic sensitization. Once allergic sensitization or eczema is established, CD4(+)CD25(+)FoxP3(+)T-reg cells expand to potentially counteract the allergic inflammatory response. Understanding the relationship between development of immunoregulatory T cells and early onset atopy could lead to new preventive strategies for allergic diseases.
    Full-text · Article · Nov 2011 · Clinical & Experimental Allergy
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    ABSTRACT: Cerebrospinal fluid (CSF) has been used for biomarker discovery of neurodegenerative diseases in humans since biological changes in the brain can be seen in this biofluid. Inactivation of A-T-mutated protein (ATM), a multifunctional protein kinase, is responsible for A-T, yet biochemical studies have not succeeded in conclusively identifying the molecular mechanism(s) underlying the neurodegeneration seen in A-T patients or the proteins that can be used as biomarkers for neurologic assessment of A-T or as potential therapeutic targets. In this study, we applied a high-throughput LC/MS-based label-free protein quantification technology to quantitatively characterize the proteins in CSF samples in order to identify differentially expressed proteins that can serve as potential biomarker candidates for A-T. Among 204 identified CSF proteins with high peptide-identification confidence, thirteen showed significant protein expression changes. Bioinformatic analysis revealed that these 13 proteins are either involved in neurodegenerative disorders or cancer. Future molecular and functional characterization of these proteins would provide more insights into the potential therapeutic targets for the treatment of A-T and the biomarkers that can be used to monitor or predict A-T disease progression. Clinical validation studies are required before any of these proteins can be developed into clinically useful biomarkers.
    Full-text · Article · Jun 2011
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    ABSTRACT: Ataxia Telangiectasia (A-T) is a rare monogenetic neurodegenerative disease with pulmonary, nutritional, and dysphagic complications. Gastrostomy tube (GT) feedings are commonly recommended to manage these co-morbidities. In general, outcomes of GT placement in patients with progressive diseases that develop during childhood are not well characterized. The primary purposes of this study were to determine whether GT placement in patients with A-T would be tolerated and associated with caregiver satisfaction. We completed a retrospective review of 175 patients who visited the A-T Children's Center at Johns Hopkins Hospital from 2001 through 2008, and identified 28 patients with A-T (19 males, 9 females) who underwent GT placement for non-palliative reasons. Information was obtained from medical records, interviews with primary health care providers, and 24 (83%) caregivers of patients with GT's who responded to survey requests. Twenty-five (89%) patients tolerated GT placement and were a median of 5.0 (0.4-12.6) years post GT placement at the time of this investigation. Three (11%) patients died within one month of GT placement. In comparison to patients who tolerated GT placement, patients with early mortality were older when GT's were placed (median 24.9 vs. 12.3 years, p = 0.006) and had developed a combination of dysphagia, nutritional, and respiratory problems. Caregivers of patients tolerating GT placement reported significant improvements in mealtime satisfaction and participation in daily activities. GT placement can be well tolerated and associated with easier mealtimes in patients with A-T when feeding tubes are placed at young ages. Patients with childhood onset of disorders with predictable progression of the disease process and impaired swallowing may benefit from early versus late placement of feeding tubes.
    Full-text · Article · May 2011 · Orphanet Journal of Rare Diseases
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    ABSTRACT: Caregiver Survey.
    Preview · Dataset · May 2011
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    ABSTRACT: To describe the presentation, clinical course, and outcomes of critically ill patients with ataxia-telangiectasia. Retrospective case series. Adult and pediatric intensive care units at an urban tertiary academic center. Seven consecutive patients with confirmed diagnosis of ataxia-telangiectasia had nine intensive care admissions between January 1995 and December 2009. None. Mean age at time of admission 15.9 yrs (median, 13.9 yrs; range, 7.3-33.9 yrs). Mean duration of intensive care unit stay was 17 days (median, 9 days; range, 2-39 days). The most common admitting diagnosis was respiratory distress (six of seven patients). There was no difference in ventilator settings or duration of intensive care unit stay between survivors and nonsurvivors (p > .05). Forty-three percent (three of seven patients) survived to intensive care unit discharge with a 3-yr survival that was 14% (one of seven patients). Critically ill patients with ataxia-telangiectasia have complex, multisystem diseases. In this case series, the most common intensive care unit admission diagnosis was respiratory failure. Suspected or confirmed bacterial infections were prevalent. Neuropathologic autopsy findings were similar to those previously reported. Special considerations for the critical care of patients with ataxia-telangiectasia are discussed.
    No preview · Article · Apr 2011 · Pediatric Critical Care Medicine
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    ABSTRACT: Given the complex immune function of the gastrointestinal (GI) tract, it is not surprising that many children with primary immunodeficiencies present with GI tract manifestations. Although many immunodeficiency disorders present with overt evidence of immune dysregulation, a few can present in older children with more subtle signs and symptoms. Such children may present first to a gastroenterologist with common symptoms, including malabsorption, diarrhea, hepatomegaly, or inflammatory bowel disease, which may actually be a manifestation of their underlying immune disorder. A thorough clinical history in combination with a careful review of histology from biopsies may reveal clues that one is dealing with a disease entity outside the norm and may prompt additional laboratory studies beyond the usual set of screening laboratory tests. Once the true underlying diagnosis is revealed, more appropriate therapy can be initiated. Additionally, more appropriate anticipatory guidance regarding the expected disease course, response to medications, and any additional risks that therapy may entail can be provided to the family.
    No preview · Article · Nov 2010 · Journal of pediatric gastroenterology and nutrition
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    ABSTRACT: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ATM gene, resulting in faulty repair of breakages in double-stranded DNA. The clinical phenotype is complex and is characterized by neurologic abnormalities, immunodeficiencies, susceptibility to malignancies, recurrent sinopulmonary infections, and cutaneous abnormalities. Lung disease is common in patients with A-T and often progresses with age and neurological decline. Diseases of the respiratory system cause significant morbidity and are a frequent cause of death in the A-T population. Lung disease in this population is thought to exhibit features of one or more of the following phenotypes: recurrent sinopulmonary infections with bronchiectasis, interstitial lung disease, and lung disease associated with neurological abnormalities. Here, we review available evidence and present expert opinion on the diagnosis, evaluation, and management of lung disease in A-T, as discussed in a recent multidisciplinary workshop. Although more data are emerging on this unique population, many recommendations are made based on similarities to other more well-studied diseases. Gaps in current knowledge and areas for future research in the field of pulmonary disease in A-T are also outlined. Pediatr. Pulmonol. 2010; 45:847–859. © 2010 Wiley-Liss, Inc.
    No preview · Article · Sep 2010 · Pediatric Pulmonology
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    ABSTRACT: Serum interleukin (IL)-8 levels were measured in 50 patients with ataxia telangiectasia (A-T) and 22 without A-T. In a cross-sectional study, the geometric mean of IL-8 level was significantly higher in the patients with A-T (P <.0001). Elevated serum IL-8 levels in patients with A-T suggest that systemic inflammation may contribute to the disease phenotype.
    No preview · Article · Feb 2010 · The Journal of pediatrics

Publication Stats

4k Citations
710.04 Total Impact Points

Institutions

  • 1983-2015
    • Johns Hopkins University
      • • Department of Pediatrics
      • • Department of Medicine
      • • Department of Neurology
      • • Department of Otolaryngology - Head and Neck Surgery
      • • Department of Biophysics
      Baltimore, Maryland, United States
    • SickKids
      • Division of Rheumatology
      Toronto, Ontario, Canada
  • 1989-2011
    • Johns Hopkins Medicine
      • Department of Pediatrics
      Baltimore, Maryland, United States
  • 2001
    • Dartmouth–Hitchcock Medical Center
      LEB, New Hampshire, United States
    • Mount Sinai Medical Center
      New York, New York, United States
  • 1997
    • Duke University Medical Center
      Durham, North Carolina, United States
  • 1995
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States