Biomedical subjects

L Kilpatrick

Publications and source records attributed to L Kilpatrick.

At least 19 recordsLinked to original sources

PubMed2001

Recombinant human granulocyte colony-stimulating factor therapy for patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease type 1b.

The purpose of this study was to evaluate the efficacy and toxicity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy in patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease (GSD) type 1b. Thirteen patients with neutropenia and/or neutrophil dysfunction secondary to GSD type 1b were treated with rhG-CSF. The effects of therapy on neutrophil numbers and in vitro neutrophil function and on bone marrow cellularity and morphology were studied. The clinical status of the patients and the occurrence of adverse events associated with rhG-CSF use were monitored. Use of rhG-CSF therapy was associated with a significant increase in circulating neutrophil numbers (P <. 01) and an improvement in neutrophil function as assessed in vitro. In addition, rhG-CSF therapy produced a significant increase in marrow cellularity and an increase in myeloid:erythroid (M:E) ratio, indicating stimulation of granulopoeisis. No adverse effects on marrow function were noted; in particular, no myelodysplasia or marrow exhaustion was seen. Use of rhG-CSF therapy was associated with objective and subjective improvements in infection-related morbidity. The therapy was well tolerated, although all patients developed splenomegaly, and 5 patients developed mild hypersplenism that did not require any specific treatment. rhG-CSF therapy is efficacious in the management of neutropenia and neutrophil dysfunction associated with GSD type 1b. Patients on this therapy need to be monitored for hypersplenism. Continued follow-up will be necessary to confirm long-term safety; however, no significant short-term toxicity was noted.

Adolescent↗

PubMed2001

Sex-related difference in amygdala activity during emotionally influenced memory storage.

We tested the possibility suggested by previous imaging studies that amygdala participation in the storage of emotionally influenced memory is differentially lateralized in men and women. Male and female subjects received two PET scans for regional cerebral glucose-one while viewing a series of emotionally provocative (negative) films, and a second while viewing a series of matched, but emotionally more neutral, films. Consistent with suggestions from several previously published studies, enhanced activity of the right, but not the left, amygdala in men was related to enhanced memory for the emotional films. Conversely, enhanced activity of the left, but not the right, amygdala in women was related to enhanced memory for the emotional films. These results demonstrate a clear gender-related lateralization of amygdala involvement in emotionally influenced memory, and indicate that theories of the neurobiology of emotionally influenced memory must begin to account for the influence of gender.

Adult↗

PubMed1999

Decreased superoxide production, degranulation, tumor necrosis factor alpha secretion, and CD11b/CD18 receptor expression by adherent monocytes from preterm infants.

Preterm infants have an increased incidence of infection, which is principally due to deficiencies in neonatal host defense mechanisms. Monocyte adherence is important in localizing cells at sites of infection and is associated with enhanced antimicrobial functions. We isolated cord blood monocytes from preterm and full-term infants to study their adhesion and immune functions, including superoxide (O2-) generation, degranulation, and cytokine secretion and their adhesion receptors. O2- production and degranulation were significantly diminished, by 28 and 37%, respectively, in adherent monocytes from preterm infants compared to full-term infants (P < 0. 05); however, these differences were not seen in freshly isolated cells. We also observed a significant decrease of 35% in tumor necrosis factor alpha secretion by lipopolysaccharide-stimulated adherent monocytes from preterm infants compared to full-term infants (P < 0.05); however, this difference was not observed in interleukin-1beta or interleukin-6 production by the monocytes. The cell surface expression of the CD11b/CD18 adhesion receptor subunits was significantly decreased (by 60 and 52%, respectively) in monocytes from preterm infants compared to full-term infants (P < 0. 01). The cascade of the immune response to infection involves monocyte upregulation and adherence via CD11b/CD18 receptors followed by cell activation and the release of cytokines and bactericidal products. We speculate that monocyte adherence factors may be important in the modulation of immune responses in preterm infants.

Birth Weight↗

PubMed1997

Inhibition of human neutrophil beta2-integrin-dependent adherence by hyperbaric O2.

Animal and clinical investigations have reported that exposure to hyperbaric O(2) improved the outcome of some reperfusion injuries. Animal studies have suggested that this may be due to an inhibition of leukocyte adherence to injured endothelium. This investigation tested the hypothesis that exposure to hyperbaric O(2) would inhibit beta2-integrin-dependent adherence of human neutrophils. Subjects were exposed to O(2) at partial pressures of up to 3 atmospheres absolute (ATA; 1 ATA = 0.1 MPa) for 45 min, and neutrophil binding to nylon columns and to fibrinogen-coated surfaces was measured. Exposure to O(2) at 2.8 or 3.0 ATA inhibited beta2-integrin-dependent neutrophil adherence but had no effect on the cell-surface expression of beta2-integrins, respiratory burst in response to phorbol ester, or non-beta2-integrin-dependent adherence to plastic plates coated with a fibronectin-like protein. beta2-Integrin adherence was restored by incubating blood with 8-bromoguanosine 3',5'-cyclic monophosphate (cGMP) and hyperbaric O(2) inhibited synthesis of cGMP by neutrophils stimulated with N-formyl-Met-Leu-Phe (FMLP). In studies of cell fractions, the activity of membrane guanylate cyclase was found to be increased by incubation with FMLP as well as by atrial natriuretic peptide (ANP) plus ATP. Hyperbaric O(2) had no effect on the basal activity of soluble or membrane-bound guanylate cyclase. However, hyperbaric O(2) inhibited the function of both the extracellular binding domain of membrane guanylate cyclase as well as intracellular catalytic activity. There are approximately 7,300 membrane guanylate cyclase molecules per cell, based on binding studies with ANP, with a dissociation constant of approximately 450 pM. Hyperbaric O(2) inhibits the function of human neutrophil beta2-integrins by a process linked to impaired synthesis of cGMP.

Adult↗

PubMed1996

Fibrous matrix of ventricular myocardium in tricuspid atresia compared with normal heart. A quantitative analysis.

BACKGROUND: The collagen matrix is a small component of the myocardium, but it provides a supportive framework. An increase in collagen in the pressure-overloaded ventricle is known to cause myocardial stiffness. However, little is known about the collagen matrix in the volume-overloaded ventricle, particularly in relation to congenital heart disease. METHODS AND RESULTS: We examined a total of 53 hearts with tricuspid atresia and 58 normal hearts matched for age. Using a microscopic-morphometric method, we analyzed the percentage per field area occupied by interstitial fibrous tissue in four sites in the ventricular mass for each specimen. A comparison of sampling sites showed no significant variations between normal and malformed hearts. Results from a homogeneity of regression co-efficients analysis suggested that the two groups shared the same basic relation of proportion of fibrosis with age. The use of ANCOVA, however, revealed a clear separation between the extents of fibrous tissue in the two groups of hearts. CONCLUSIONS: The myocardium of hearts with tricuspid atresia is consistently more fibrotic than normal heart and is probably an inherent part of the malformation. This difference could explain, at least in part, the clinical observation that the left ventricle is frequently abnormal, even at an early age.

Adolescent↗

PubMed1996

Production of T-helper cell subsets and cytokines by lymphocytes from patients with chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis (CMC) is a heterogeneous group of disorders characterized by recurrent and persistent superficial candidal infections. Cytokine-induced dysregulation of T-helper cell function has been described in other immune-deficient states but has not been studied in CMC patients. We studied T-helper cell subsets by flow cytometry and cytokine production by stimulated lymphocytes in six CMC patients, two healthy pediatric controls, and five healthy adult controls. Peripheral blood lymphocytes were stimulated in vitro with phytohemagglutinin or Candida albicans extract, and the production of interleukin-2R (IL-2R), IL-4, IL-10, and gamma interferon in the supernatants was measured by enzyme-linked immunosorbent assay. CMC patients had a decrease in the CD29+/CD29+ cell population compared with the numbers in controls (P < 0.02). The percentage of CD4+/CD45RA+ cells was greater in patients than in controls, but the difference was not significant. There was no difference in the production of IL-10 or gamma interferon by the patient lymphocytes. CMC patients produced more IL-4 than the controls (P < 0.001), whereas the controls tended to produce more IL-2R than the patients (P = 0.19). These findings support the concept that a decrease in CD4+/CD29+ T-helper inducer cells along with T-helper cell dysregulation may lead to defective memory responses to antigens in CMC patients and a decrease in cell-mediated immunity due to inhibition of TH1 cells by increased levels of IL-4.

Adult↗

PubMed1995

Resonance Raman spectroscopic characterization of the molybdopterin active site of DMSO reductase.

Resonance Raman spectra are compared for Rhodobacter sphaeroides dimethyl sulfoxide reductase, an enzyme containing a molybdopterin cofactor, and two model compounds, I and II, which have pterin and quinoxaline, respectively, attached to a Cp2Mo[IV]-dithiolene chelate [Cp = cyclopentadienyl]. The effect of 34S incorporation was also determined. Several bands in the 200-500 cm-1 region show remarkably similar patterns of frequencies and isotope shifts between protein and models: a band at 351 cm-1 shifts 6-8 cm-1, and bands at lower and higher frequencies show smaller shifts upon 34S substitution. A normal coordinate analysis on II indicates the 351 cm-1 mode to be the symmetric Mo-S[dithiolene] stretch and the remaining low-frequency modes to contain contributions from deformations of the quinoxaline ring as well as from Mo-S stretching. The similarity in the low-frequency spectra between the model compounds and the enzyme strongly supports a dithiolene chelate as the mode of Mo-pterin interaction in the cofactor. Resonance enhancement of both high- and low-frequency quinoxaline or pterin modes is observed for both model compounds, implicating the heterocyclic rings as part of the electronic system involved in the Mo-dithiolene charge transfer transitions. RR spectra of 6-methylpterin and biopterin are reported and used to identify the pterin and quinoxaline high-frequency bands in the model compound spectra. The dithiolene C = C stretch is tentatively assigned to bands at 1506 cm-1 in I and 1515 cm-1 in II.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗

PubMed1995

Cytokine elevations in infants with bacterial and aseptic meningitis.

We sought to determine whether the detection of cytokines, produced during the inflammatory response, would aid in the diagnosis of meningitis in young infants. We measured cerebrospinal fluid (CSF) and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) in 62 infants less than 6 months of age whose condition was evaluated for meningitis. Twenty infants had culture-proved meningitis, 22 had aseptic meningitis, and 20 control infants had no evidence of meningitis. The CSF IL-6 levels were elevated in all 20 infants with bacterial meningitis and in 9 of 22 infants with aseptic meningitis but were undetectable in all control subjects. Furthermore, CSF IL-6 levels were 10 times greater in infants with bacterial versus aseptic meningitis (p < 0.001). Levels of TNF in CSF were detected in 12 of 20 infants with bacterial meningitis and were undetectable in infants with aseptic meningitis and in control infants (p < 0.02). Plasma IL-6 and TNF levels were unreliable for the detection of meningitis in this patient population. We conclude that the presence of IL-6 in the CSF reliably identifies infants with meningitis and that the presence of CSF TNF is a highly specific indicator of bacterial meningeal inflammation.

Humans↗

PubMed1995

The architecture of the atrioventricular conduction axis in dog compared to man: its significance to ablation of the atrioventricular nodal approaches.

UNLABELLED: AV Node in Dog and Man. INTRODUCTION: Advances in treating patients with dual atrioventricular nodal pathways have called for a better understanding of the morphology of the approaches to the atrioventricular node. In this respect, it has recently been suggested that, in dog, anatomically discrete muscle bundles originating from the sinus node represent the substrate of the dual pathways recognized electrophysiologically in patients with atrioventricular nodal reentrant tachycardia. This concept is at odds with most anatomic studies of the human specialized atrioventricular junctional area. In this study, therefore, we studied histologically the junctional area in dog hearts, comparing them with our own findings in human heart and the descriptions of the earliest investigators. METHODS AND RESULTS: Five dog and six human hearts were prepared for histology and sectioned serially in different planes. Reconstructions were then made from each of three dog and two human hearts sectioned in orthogonal planes. Gross differences in the anatomy of the atrioventricular junctional area and in the structure of the conduction system were obvious between dog and human hearts. The penetrating portion of the conduction axis was longer in the dog, being much more extensively embedded in the central fibrous body. The atrioventricular node, in both dog and man, was composed of a zone of transitional cells overlying a compact region. The zone of transitional cells in the dog was more extensive posteriorly than anteriorly. No bundles insulated anatomically by fibrous tissue were found either in the internodal atrial myocardium or in the approaches to the atrioventricular node. Our findings in both dog and man are comparable with the initial descriptions of the atrioventricular junctional area. CONCLUSION: Although the disposition of the conduction system in dog and man is basically similar, there are important differences which relate to the gross anatomy. The anatomic substrate for functional duality of the inputs to the atrioventricular node remains unclear, since our study confirms that the concept of insulated atrionodal tract has no morphologic basis.

Animals↗

PubMed1995

Amrinone prevents muscle protein wasting during chronic sepsis.

The time course for the effects of sepsis on rates of protein synthesis, RNA contents, and translational efficiencies was measured in mixed muscles of rat hindlimb perfused in vitro 3, 5, and 10 days after induction of sepsis. Furthermore, the effect of daily injections of amrinone (5 mg.kg-1.day-1) on muscle protein synthesis was investigated. On day 3 of sepsis, decreased rates of protein synthesis in muscle from untreated septic animals or septic rats treated with amrinone resulted from a reduced food intake. When food intake became normalized to control after 5 days, rates of protein synthesis in untreated septic rats remained depressed. Treatment of septic animals with amrinone for 5 days prevented the sepsis-induced inhibition of protein synthesis by abolishing the inhibition of peptide-chain initiation and restoring translational efficiency to control values. In contrast, amrinone treatment of control rats for 5 days did not cause an accretion of muscle protein or augment protein synthesis. Ten days after induction of sepsis, there were no differences in rates of protein synthesis, RNA content, or translational efficiency in septic animals compared with control or amrinone-treated septic rats. Thus, amrinone prevented the sepsis-induced abnormalities in skeletal muscle protein synthesis.

Abscess↗

PubMed1994

Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis.

We hypothesized that plasma levels of cytokines such as interleukin-6 and tumor necrosis factor (TNF) are elevated in critically ill infants with sepsis and necrotizing enterocolitis (NEC) and that the magnitude of their elevation is correlated with mortality rate. We measured plasma levels of interleukin-6 and TNF in 62 newborn infants with suspected sepsis or NEC. Eighteen infants had bacterial sepsis, 9 had bacterial sepsis plus NEC, and 15 had NEC but negative culture results. Twenty comparably ill infants with negative results on culture of systemic specimens served as study control subjects. Interleukin-6 levels were five- to tenfold higher in infants with bacterial sepsis plus NEC at the onset of disease than in infants with bacterial sepsis alone, in infants with NEC but negative culture results, and in control infants (p < 0.01). These differences persisted throughout the 48-hour study period. Interleukin-6 levels were also significantly higher in nonsurvivors than in survivors (p < 0.001). In contrast, plasma TNF values were not consistently increased in any of the groups. We conclude that plasma interleukin-6 is a more reliable indicator of bacterial sepsis and NEC than plasma TNF and may identify infants who might benefit from immunotherapeutic strategies.

Analysis of Variance↗

PubMed1994

Plasma cytokine determinations in emergency department patients as a predictor of bacteremia and infectious disease severity.

OBJECTIVE: To determine the predictive value of plasma interleukin (IL)-6 and tumor necrosis factor-alpha (TNF) measurements in assessing bacteremia and subsequent morbidity and mortality rates in emergency department patients. DESIGN: Prospective case series. SETTING: Emergency department and inpatient services of a large urban university hospital. PATIENTS: A total of 100 patients admitted through the emergency department with signs of infection and the presumptive diagnosis of bacteremia. INTERVENTIONS: Blood samples were collected for cytokine determinations. MEASUREMENTS AND MAIN RESULTS: IL-6 and TNF concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in plasma samples obtained on patient admission to the emergency department. Patient's hospital course and culture results were documented by chart review. Severity of patient illness was estimated serially using the Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system at entry into the study, and then again at 24 and 48 hrs. A quantified, subjective assessment of the severity of patient illness was recorded by the admitting physician in the emergency department. Multivariate logistic regression analysis using the variables of plasma IL-6 concentrations, TNF concentrations, APACHE II score at entry, physician assessment of illness severity, and patient age indicated that of these variables, only plasma IL-6 concentrations predicted bacteremia (p = .006) and death from infection (p = .009). A plasma IL-6 concentration > or = 2.0 ng/mL detected bacteremia with a positive predictive value of 72.7%, a sensitivity of 42.1%, and a specificity of 96.7%. Plasma TNF concentrations predicted mortality from all causes (p = .009) as did physician assessment of illness severity (p = .001). Increased APACHE II scores predicted the use of vasopressor medications (p = .002), length of hospital stay (p = .001), and subsequent increased APACHE II scores (p = .001) but did not predict bacteremia, death from infection, or death from all causes. Greater patient age predicted admission to the intensive care unit (p = .016). CONCLUSIONS: Measurement of plasma IL-6 concentrations in a population of emergency department patients with apparent bacterial infections predicted bacteremia and death from infection. The characteristics of the test indicated a potential use in selecting patients for the administration of novel therapies for sepsis.

Adolescent↗

PubMed1994

Cytokines inhibit fatty acid oxidation in isolated rat hepatocytes: synergy among TNF, IL-6, and IL-1.

We have developed an in vitro rat hepatocyte model in which cytokines inhibit fatty acid oxidation. Cytokine administration resulted in decreased fatty acid oxidation, ketone body production and acetyl CoA/CoA ratios. The inhibitory effects of TNF on fatty acid oxidation were enhanced by either IL-1 or IL-6. TNF (20 U/ml) + IL-6 (30 ng/ml) produced maximal inhibition, whereas IL-1 enhanced inhibition at submaximal TNF concentrations. The key to our model is that substrate input into the tricarboxylic acid cycle in the form of either alanine or pyruvate was required for cytokine mediated inhibition of fatty acid oxidation. Alanine or pyruvate may serve as a source for increased production of malonyl CoA, a potent inhibitor of fatty acid oxidation. We hypothesize that cytokines cause an inappropriate switch from fatty acid oxidation to fatty acid synthesis which has serious consequences for energy levels in the liver and can lead to end organ failure.

Acetyl Coenzyme A↗

PubMed1994

Characterization of the iron-sulfur clusters in ferredoxin from acetate-grown Methanosarcina thermophila.

Ferredoxin from Methanosarcina thermophila is an electron acceptor for the CO dehydrogenase complex which decarbonylates acetyl-coenzyme A and oxidizes the carbonyl group to carbon dioxide in the pathway for conversion of the methyl group of acetate to methane (K. C. Terlesky and J. G. Ferry, J. Biol. Chem. 263:4080-4082, 1988). Resonance Raman spectroscopy and electron paramagnetic resonance spectroelectrochemistry indicated that the ferredoxin contained two [4Fe-4S] clusters per monomer of 6,790 Da, each with a midpoint potential of -407 mV. A [3Fe-4S] species, with a midpoint potential of +103 mV, was also detected in the protein at high redox potentials. Quantitation of the [3Fe-4S] and [4Fe-4S] centers revealed 0.4 and 2.1 spins per monomer, respectively. The iron-sulfur clusters were unstable in the presence of air, and the rate of cluster loss increased with increasing temperature. A ferredoxin preparation, with a low spin quantitation of [4Fe-4S] centers, was treated with Fe2+ and S2-, which resulted in an increase in [4Fe-4S] and a decrease in [3Fe-4S] clusters. The results of these studies suggest the [3Fe-4S] species may be an artifact formed from degradation of [4Fe-4S] clusters.

Acetates↗

PubMed1994

In vitro and in vivo effects of granulocyte colony-stimulating factor on neutrophils in glycogen storage disease type 1B: granulocyte colony-stimulating factor therapy corrects the neutropenia and the defects in respiratory burst activity and Ca2+ mobilization.

Children with glycogen storage disease (GSD) type 1b are susceptible to recurrent bacterial infections and have chronic neutropenia accompanied by phagocytic cell dysfunction including decreased superoxide anion (O2-) generation, calcium (Ca2+) mobilization, and chemotactic activity. Granulocyte colony-stimulating factor (G-CSF), a cytokine that corrects neutropenia in other diseases, in vitro enhances f-Met-Leu-Phe-triggered neutrophil O2- generation. Short-term pretreatment (15 min) of GSD 1b neutrophils with G-CSF increased the rate of O2- production (p < 0.01); however, this rate was still significantly below the rate of O2- production in control neutrophils. Recombinant human G-CSF (5 micrograms/kg/d) was administered s.c. to a GSD 1b patient. Before treatment, absolute neutrophil counts were < 500/mm3. Two d after G-CSF administration, the absolute neutrophil counts increased to 1333 and remained in the normal range during a 12-mo follow-up period. In vivo, G-CSF therapy increased f-Met-Leu-Phe-stimulated O2- production to 52% of control after 1 mo, and by mo 4, O2- production reached control levels. Our previous studies (J Clin Invest 56:196-202, 1990) demonstrated that decreased O2- production in neutrophils was associated with impaired Ca2+ mobilization. In vivo administration of G-CSF increased f-Met-Leu-Phe-triggered Ca2+ mobilization by neutrophils to 43% of control by mo 1 of G-CSF therapy and to 93% of control by mo 4, thus paralleling the improvements in O2- generation. In contrast, G-CSF therapy had no effect on the defective neutrophil chemotaxis. In summary, G-CSF therapy produced a rapid increase in circulating neutrophils and a gradual correction of O2- production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

Impairment of calcium mobilization in phagocytic cells in glycogen storage disease type 1b.

Patients with glycogen storage disease (GSD) type 1b, in contrast to patients with GSD 1a, are susceptible to recurrent bacterial infections suggesting defective phagocytic function. We have demonstrated a selective defect in respiratory burst activity but not in degranulation by phagocytic cells in GSD 1b but not in GSD 1a. The respiratory burst abnormality in phagocytic cells from GSD 1b patients was associated with impaired calcium mobilization, whereas these processes were normal in GSD 1a patients. Therefore, the alteration in calcium mobilization was an indication of a signalling defect in phagocytic cells from GSD 1b. However, calcium mobilization was normal in lymphocytes, indicating that defective calcium mobilization was not a global finding in circulating leukocytes, but was specific to phagocytic cells. Calcium mobilization in response to ionomycin was reduced suggesting decreased calcium stores in GSD 1b neutrophils. Therefore, altered phagocytic cell function in GSD 1b patients appears to be associated with diminished calcium mobilization and defective calcium stores. This defective calcium signalling was associated with a selective defect in respiratory burst activity but not degranulation.

Calcium↗

PubMed1993

Recombinant human GM-CSF treatment of neutropenia in glycogen storage disease-1b.

PURPOSE: Recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) was administered to two patients with glycogen storage disease, type 1b (GSD-1b), with chronic neutropenia, neutrophil dysfunction, and recurrent infections in an effort to increase neutrophil counts and increase resistance to infections. PATIENTS AND METHODS: The patients' baseline absolute neutrophil counts (ANC) ranged from 56 to 480 cells/mm3 despite increased granulocyte precursors in the bone marrow. GM-CSF was given s.c. at starting doses of 500 micrograms/m2/day divided into two doses. RESULTS: After 48 h, ANC rose to 2,025 cells/mm3 and 3,132 cells/mm3, respectively. Absolute eosinophil counts also rose to 1,048 cells/mm3 (24%) and 4,820 cells/mm3 (33%) on days 10 and 9 in the two patients. Although an initial 10-day course of GM-CSF was tolerated in one patient without significant reactions, subsequent s.c. injections of GM-CSF were complicated by increasingly painful local reactions that necessitated discontinuation after 7 to 8 days. Intravenous infusion was associated with a febrile systemic reaction. Despite lack of improvement in neutrophil superoxide anion generation measured in one, both patients demonstrated unusually rapid healing of cutaneous infections on GM-CSF. CONCLUSION: Our experience suggests that GM-CSF may be useful for short-term treatment of serious infections in GSD-1b. However, alternate dosage schedules or different preparations of GM-CSF to diminish local reactions would be required for long-term maintenance therapy. Granulocyte colony stimulating factor (G-CSF) has also been shown to increase neutrophils in this disease and has not been associated with allergic reactions.

Adolescent↗

PubMed1993

Interferon-gamma corrects the respiratory burst defect in vitro in monocyte-derived macrophages from glycogen storage disease type 1b patients.

Glycogen storage disease (GSD) type 1b is accompanied by decreased respiratory burst activity in peripheral blood phagocytic cells (i.e. monocytes and neutrophils). To elucidate whether this depressed respiratory burst was due to an intrinsic defect of phagocytic cells or due in part to in vivo host factors, we examined superoxide anion (O2-) production in monocytes from five GSD 1b patients cultured 9 d in vitro to allow for differentiation into macrophages (MDM). O2- production in MDM was measured in response to concanavalin A, fMet-Leu-Phe, and phorbol myristate acetate (PMA) stimulation. GSD 1b MDM had significantly depressed O2- generation with fMet-Leu-Phe and concanavalin A stimulation; however, unlike peripheral blood monocytes, GSD 1b MDM responded to PMA stimulation with O2- production comparable to healthy control donors. The cytokine interferon-gamma (IFN-gamma) has been shown to enhance O2- production in MDM. When GSD 1b MDM were cultured in the presence of IFN-gamma (1 x 10(5) U/L), O2- production in response to fMet-Leu-Phe, concanavalin A, and PMA was enhanced to rates similar to those of control MDM cultured in the presence of IFN-gamma. Thus, the respiratory burst defect observed in circulating phagocytic cells is also present in vitro in cultured GSD 1b MDM. However, in contrast to circulating phagocytic cells, depressed O2- production in GSD 1b MDM is selective to receptor-mediated activation, but not to PMA stimulation. This defect is correctable after short-term treatment with IFN-gamma, suggesting a role for IFN-gamma in treating the phagocytic defect in this disease.

Adolescent↗