190 results on '"Johnston RB Jr"'
Search Results
2. The inflammatory response to injury in children.
- Author
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Wood JH, Partrick DA, and Johnston RB Jr.
- Published
- 2010
- Full Text
- View/download PDF
3. Book and media reviews.
- Author
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Kritchevsky D, De Lorenzo RA, Gupta R, Labotka RJ, Johnston RB Jr., and Meyer HS
- Published
- 2006
4. The effect of using 'race of child' instead of 'race of mother' on the Black-White gap in infant mortality due to birth defects.
- Author
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Petrini J, Damus K, Roy S, Johnson K, and Johnston RB Jr.
- Abstract
Objective. For at least 20 years, birth defects have been the leading cause of infant mortality in the United States. Some studies have reported higher rates for black infants than white infants of mortality due to birth defects, while other studies have reported no black-white differences. The authors analyzed the effect on these rates of a change in the way the National Center for Health Statistics (NCHS) tabulates 'race' for newborns. Methods. The authors calculated infant mortality rates due to birth defects for 1980-1993 using two standard methods of assigning newborns to 'racial' categories: a 'race of child' algorithm and the 'race of mother' approach currently used by NCHS. Results. From 1980 through 1993, birth defect-specific infant mortality rates (BD-IMRs) were significantly higher for black infants than white infants 12 of the 14 years by 'race of mother' and only 5 of 14 years by 'race of child.' Calculation of BD-IMRs by 'race of mother' reduced the rate for white infants and increased the rate for black infants in each of the 14 years. The choice of method for assigning newborns to 'racial' categories had a progressively greater effect over time on the black-white gap in BD-IMRs. Conclusions. Calculations of trends in 'race'-specific BID-IMRs by may vary substantially by whether 'race of mother' or 'race of child' is used. Identifying the method of tabulation is imperative for appropriate comparisons and interpretations. [ABSTRACT FROM AUTHOR]
- Published
- 1998
5. Effect of phorbol myristate acetate on the oxidative metabolism of human polymorphonuclear leukocytes
- Author
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DeChatelet, LR, Shirley, PS, and Johnston, RB Jr
- Abstract
The addition of 0.1 mug/ml of phorbol myristate acetate (PMA) to a suspension of resting human neutrophils causes a marked stimulation of all aspects of cellular oxidative metabolism normally associated with phagocytosis. PMA induces a greatly increased rate of glucose oxidation via the hexose monophosphate shunt, increased production of superoxide anion and of hydrogen peroxide, increased cellular chemiluminescence, and increased iodination of protein material. The time course of hexose monophosphate shunt activation and of chemiluminescence are similar to those observed following phagocytosis of opsonized zymosan; the levels of activation achieved in all cases approximate those seen following phagocytosis. These phenomena are not simply reflections of altered cellular permeability, since PMA actually inhibits the uptake of radioactive 2-deoxyglucose and of uniformly labeled amino acids. The addition of PMA similarly inhibits the uptake of 14C-labeled bacteria, suggesting a competition between the effect of the chemical and the process of phagocytosis. These results suggest that PMA activates the cell in the same manner as does phagocytosis. This compound should provide a useful tool for elucidating the metabolic events underlying the phenomena of phagocytosis and bacterial killing by polymorphonuclear leukocytes.
- Published
- 1976
- Full Text
- View/download PDF
6. Stimulation of neutrophil oxidative metabolism by chemotactic peptides: influence of calcium ion concentration and cytochalasin B and comparison with stimulation by phorbol myristate acetate
- Author
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Lehmeyer, JE, Snyderman, R, and Johnston, RB Jr
- Published
- 1979
- Full Text
- View/download PDF
7. Fortifying food with folic acid... point of view commentary, 'Folic acid food supplementation: an idea whose time has not come,' Drs. Rosner and Grunwald.
- Author
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Johnston RB Jr., Schwarz RH, and Damus K
- Published
- 1997
- Full Text
- View/download PDF
8. The NAS perchlorate review: adverse effects?
- Author
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Johnston RB Jr., Corley R, Cowan L, and Utiger RD
- Published
- 2005
- Full Text
- View/download PDF
9. Disseminated histoplasmosis in a renal transplant patient.
- Author
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Johnston RB Jr, Thareja S, and Shenefelt PD
- Subjects
- Amphotericin B therapeutic use, Antifungal Agents therapeutic use, Bone Marrow microbiology, Dermatomycoses drug therapy, Dermatomycoses microbiology, Histoplasmosis drug therapy, Humans, Immunocompromised Host, Lung microbiology, Male, Middle Aged, Pyrimidines therapeutic use, Triazoles therapeutic use, Voriconazole, Dermatomycoses diagnosis, Histoplasmosis diagnosis, Kidney Transplantation adverse effects
- Abstract
Histoplasma capsulatum is a common endemic mycosis. Infection typically goes unnoticed by an individual, but in immunosuppressed patients, it may become disseminated. We report a case of disseminated histoplasmosis occurring 6 weeks after a kidney transplant. We discuss disseminated histoplasmosis and review its characteristic clinical, laboratory, and histologic manifestations, as well as current treatment modalities.
- Published
- 2013
10. A 16-year-old with white plaques on the palms. Aquagenic wrinkling of the palms (AWP).
- Author
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Halsey MA, Johnston RB Jr, and Shenefelt PD
- Subjects
- Adolescent, Hand Dermatoses diagnosis, Humans, Keratoderma, Palmoplantar diagnosis, Male, Hand Dermatoses pathology, Keratoderma, Palmoplantar pathology, Water adverse effects
- Published
- 2011
- Full Text
- View/download PDF
11. American Pediatric Society's 2008 John Howland award acceptance lecture: life goals for academic pediatrics.
- Author
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Johnston RB Jr
- Subjects
- Awards and Prizes, Congenital Abnormalities, Humans, Infections, Pediatrics education, Preventive Medicine, Societies, Medical, United States, Vaccination, Goals, Pediatrics trends
- Published
- 2008
- Full Text
- View/download PDF
12. Perianal abscesses.
- Author
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Johnston RB Jr and Barton LL
- Subjects
- Abscess diagnosis, Anti-Bacterial Agents therapeutic use, Anus Diseases diagnosis, Diagnosis, Differential, Drainage, Granulomatous Disease, Chronic diagnosis, Humans, Immunocompromised Host, Infant, Abscess therapy, Anus Diseases therapy
- Published
- 2008
- Full Text
- View/download PDF
13. Will increasing folic acid in fortified grain products further reduce neural tube defects without causing harm?: consideration of the evidence.
- Author
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Johnston RB Jr
- Subjects
- Dose-Response Relationship, Drug, Female, Humans, Neural Tube Defects physiopathology, Pregnancy, Risk Assessment, United States, United States Food and Drug Administration legislation & jurisprudence, Edible Grain, Flour, Folic Acid adverse effects, Food, Fortified adverse effects, Neural Tube Defects prevention & control, Nutrition Policy, Prenatal Nutritional Physiological Phenomena, Vitamin B Complex adverse effects
- Abstract
To reduce neural tube defects (NTDs), the U.S. Food and Drug Administration (FDA) mandated that by January 1998 all enriched grain products should contain 140 microg of folic acid (FA)/100 g of flour. Groups concerned with optimal prevention of NTDs had argued that the level should be 350 microg/100 g. However, when it appeared that the debate might delay implementation of any fortification, these groups petitioned the FDA to implement fortification at the originally proposed level of 140 microg/100 g, anticipating that the FDA might consider increasing the level at a later time. Mandated FA fortification (FAF) has now been in place in the United States for 9 y. The impact of this important public health intervention on NTD rates, the possible benefit to other disease conditions, and potential harms have been evaluated. As background for a possible request that the FDA consider increasing FAF, evidence bearing on the question of whether an increase can further reduce NTD births without causing harm is reviewed here. The published data indicate that it is appropriate that the FDA conduct or commission a balanced analysis of the evidence by scientists who will act on that evidence to decide this important question.
- Published
- 2008
- Full Text
- View/download PDF
14. Invasive Candida species disease in infants and children: occurrence, risk factors, management, and innate host defense mechanisms.
- Author
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Maródi L and Johnston RB Jr
- Subjects
- Animals, Antifungal Agents therapeutic use, Candidiasis immunology, Candidiasis therapy, Catheterization, Central Venous, Child, Fungal Vaccines therapeutic use, Galectin 3 physiology, Humans, Incidence, Infant, Infant, Extremely Low Birth Weight, Infant, Newborn, Lectins, C-Type physiology, Mannose Receptor, Mannose-Binding Lectins physiology, Prevalence, Receptors, Cell Surface physiology, Receptors, Immunologic physiology, Risk Factors, Toll-Like Receptors physiology, Candidiasis epidemiology
- Abstract
Purpose of Review: Invasive infections by opportunistic Candida species significantly impact morbidity and mortality. This review provides an update of the incidence, risk factors, and management of invasive candidal disease in infants and children, focusing on very-low-birth-weight neonates, and highlights recent advances in understanding candidal virulence factors and innate anti-Candida species host defense mechanisms., Recent Findings: Invasive infections with Candida species are the most common cause of late-onset, blood culture-proven nosocomial sepsis in very-low-birth-weight neonates. Risk factors include colonization, long stay in neonatal intensive care units, and use of broad-spectrum antibiotics, central venous catheters, parenteral nutrition, and mechanical ventilation. These risks are compounded by increasing resistance of Candida species to standard antifungal agents. Recent data suggest that, in addition to the macrophage mannose receptor, beta-glucan receptors, Toll-like receptors, and galectin-3 play an important role in host recognition of Candida species., Summary: Reduction of proven risk factors, more aggressive eradication of colonizing fungi by anticandidal agents, and possibly Candida species vaccines may reduce Candida species-associated morbidity and mortality. Accumulating data of molecular mechanisms that underlie innate immune functions against Candida species may provide a basis to prevent and treat candidal infections more efficiently.
- Published
- 2007
- Full Text
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15. A history of pediatric immunology.
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Stiehm ER and Johnston RB Jr
- Subjects
- Allergy and Immunology organization & administration, Congresses as Topic, Education, Foundations, History, 18th Century, History, 19th Century, History, 20th Century, History, 21st Century, Humans, Immunologic Deficiency Syndromes drug therapy, Pediatrics organization & administration, Societies, Allergy and Immunology history, Pediatrics history
- Abstract
Immunology has played a prominent role in the history of medicine. Pediatric immunologists have focused on immune aberrations in pediatric disorders, particularly those involving host defense mechanisms. These efforts have paid rich dividends in terms of fundamental knowledge of the immune system and major therapeutic advances, including 1) i.v. immunoglobulin therapy, 2) hematopoietic stem cell transplantation, and 3) gene therapy. Pediatric immunology as an organized discipline emerged in the early 1950s, when pediatricians and their basic scientist colleagues began to focus on clinical and basic research related to immunodeficiency. Since then, key organizations and infrastructure have been developed to support this research and the clinical care of immunodeficient patients. We review here the evolution of contemporary pediatric immunology, particularly in North America, from its roots in 19th-century Europe to its current expression as one of the fundamental scientific and clinical disciplines of pediatrics.
- Published
- 2005
- Full Text
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16. Balancing benefits and harms in public health prevention programmes mandated by governments.
- Author
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Oakley GP Jr and Johnston RB Jr
- Subjects
- Choice Behavior, Congenital Abnormalities prevention & control, Edible Grain, Evidence-Based Medicine, Folic Acid administration & dosage, Food, Fortified, Government Programs organization & administration, Health Policy, Health Promotion legislation & jurisprudence, Humans, Preventive Health Services organization & administration, Safety, United Kingdom, Vaccines adverse effects, Health Promotion organization & administration, Public Health
- Published
- 2004
- Full Text
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17. Acute embolic occlusion of the distal aorta.
- Author
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Johnston RB Jr, Cohn EJ Jr, and Cotlar AM
- Subjects
- Acute Disease, Aged, Aged, 80 and over, Aorta, Abdominal, Female, Humans, Aortic Diseases therapy, Embolism therapy
- Abstract
Purpose: Acute occlusion of the abdominal aorta requires rapid diagnosis and intervention to prevent loss of life or limb. The overall mortality due to embolic occlusion is reported to be over 30%. The most common source of emboli is the heart, secondary to atrial fibrillation or myocardial infarction., Methods: A patient is herein presented who arrived at the emergency department 6 hours after onset of classic signs of acute arterial occlusion., Results: She had a saddle embolus of the distal abdominal aorta with extension of the clot into both iliac and femoral arteries., Conclusions: Heparin therapy and embolectomy successfully reestablished blood flow. The etiology, presentation and management of aortoiliac occlusion is discussed.
- Published
- 2003
- Full Text
- View/download PDF
18. Do vaccines cause harm? The need for open-minded analysis based on science and reason.
- Author
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Johnston RB Jr
- Subjects
- Child, Communication, Compensation and Redress, Decision Making, Health Promotion, Humans, Pediatrics methods, Attitude to Health, Evidence-Based Medicine, Vaccines adverse effects
- Abstract
Public concern about the safety of vaccines began when vaccination began, in the 18th century. Major resistance to vaccinations in the 1980s threatened to shut down vaccine manufacture and immunization programs. The US Congress responded with legislation in 1986-1987 that established a compensation program, communication strategies, and a process of objective, science-based analysis by the Institute of Medicine of whether childhood vaccines cause any of an array of possible adverse events. Since then, research, detection, communication, and education related to vaccine safety have improved but remain less than perfect. All of us who care about children, our own or in the abstract, will serve our children best if we remain vigilant and open-minded in considering issues of vaccine safety, and if we base our conclusions and actions on science, not emotion.
- Published
- 2003
19. Overview: new perspectives on the stubborn challenge of preterm birth.
- Author
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Johnston RB Jr, Williams MA, Hogue CJ, and Mattison DR
- Subjects
- Congresses as Topic, Female, Foundations, Humans, Infant, Low Birth Weight, Infant, Newborn, Infant, Premature, Nutritional Physiological Phenomena, Obstetric Labor, Premature etiology, Pregnancy, Prenatal Care, Program Evaluation, Research, Risk Factors, Obstetric Labor, Premature prevention & control
- Published
- 2001
- Full Text
- View/download PDF
20. Clinical aspects of chronic granulomatous disease.
- Author
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Johnston RB Jr
- Subjects
- Humans, Granulomatous Disease, Chronic physiopathology
- Abstract
Data from a registry of 368 patients with chronic granulomatous disease (CGD) documenta shift in the most common infecting organisms away from staphylococci and enteric bacteria to Aspergillus species, although staphylococci remain a threat. A. nidulans appears to have a particular virulence in CGD. Burkholderia cepacia sepsis/pneumonia was the second most lethal infection in patients in the registry. Seventy-six percent of registry patients had the X-linked recessive (XLR) form of CGD. Chorioretinitis may be more common than previously appreciated, and boys with the XLR disease should probably have routine full eye exams. A new variant of CGD has been described that is caused by an inhibitory mutation in Rac2, which regulates activity of the neutrophil respiratory burst and actin assembly. Interferon-gamma, antibacterial prophylaxis, and, probably, antifungal prophylaxis with itraconazole reduce the rate of infection, and bone marrow transplantation can cure the disease if a histocompatible donor is available. Gene therapy can cure CGD in knockout mouse models. Having even a small percentage of phagocytes that are nicotinamide adenine dinucleotide phospate oxidase-positive can reduce the risk of serious infection, and procedures now under study appear close to achieving that goal, if not a cure.
- Published
- 2001
- Full Text
- View/download PDF
21. The phagocytosis-associated respiratory burst in human monocytes is associated with increased uptake of glutathione.
- Author
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Seres T, Knickelbein RG, Warshaw JB, and Johnston RB Jr
- Subjects
- Cysteine antagonists & inhibitors, Cysteine metabolism, Cystine metabolism, Humans, Hydrogen Peroxide metabolism, Kinetics, Lymphocytes immunology, Lymphocytes metabolism, Macrophage Activation, Monocytes immunology, Oxidative Stress immunology, Sodium physiology, Tetradecanoylphorbol Acetate pharmacology, Glutathione metabolism, Monocytes metabolism, Phagocytosis immunology, Respiratory Burst immunology
- Abstract
During the phagocytic respiratory burst, oxygen is converted to potent cytotoxic oxidants. Monocytes and macrophages are potentially long-lived, and we have hypothesized that protective mechanisms against oxidant stress are varied and fully expressed in these cells. We report here that the respiratory burst in monocytes is accompanied by an increase in the uptake of [35S]glutathione ([35S]GSH) after 20-30 min to levels up to 10-fold greater than those at baseline. By 30 min, 49% of the cell-associated radioactivity was in the cytosol, 41% was in membrane, and 10% was associated with the nuclear fraction. GSH uptake was inhibited by catalase, which removes hydrogen peroxide (H2O2), and micromolar H2O2 stimulated GSH uptake effectively in monocytes and also lymphocytes. Oxidation of GSH to glutathione disulfide with H2O2 and glutathione peroxidase prevented uptake. Acivicin, which inhibits GSH breakdown by gamma-glutamyl transpeptidase (GGT), had no effect on the enhanced uptake seen during the respiratory burst. Uptake of cysteine or cystine, possible products of GGT activity, stayed the same or decreased during the respiratory burst. These results suggest that a GGT-independent mechanism is responsible for the enhanced GSH uptake seen during the respiratory burst. We describe here a sodium-independent, methionine-inhibitable transport system with a Km (8.5 microM) for GSH approximating the plasma GSH concentration. These results suggest that monocytes have a specific GSH transporter that is triggered by the release of H2O2 during the respiratory burst and that induces the uptake of GSH into the cell. Such a mechanism has the potential to protect the phagocyte against oxidant damage.
- Published
- 2000
- Full Text
- View/download PDF
22. Chronic granulomatous disease. Report on a national registry of 368 patients.
- Author
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Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, Malech HL, Holland SM, Ochs H, Quie P, Buckley RH, Foster CB, Chanock SJ, and Dickler H
- Subjects
- Adolescent, Adult, Aged, Cause of Death, Child, Child, Preschool, Communicable Diseases epidemiology, Communicable Diseases etiology, Female, Follow-Up Studies, Granulomatous Disease, Chronic complications, Granulomatous Disease, Chronic genetics, Humans, Incidence, Infant, Male, Middle Aged, Prevalence, Racial Groups, Survival Analysis, United States epidemiology, Granulomatous Disease, Chronic epidemiology, Registries
- Abstract
A registry of United States residents with chronic granulomatous disease (CGD) was established in 1993 in order to estimate the minimum incidence of this uncommon primary immunodeficiency disease and characterize its epidemiologic and clinical features. To date, 368 patients have been registered; 259 have the X-linked recessive form of CGD, 81 have 1 of the autosomal recessive forms, and in 28 the mode of inheritance is unknown. The minimum estimate of birth rate is between 1/200,000 and 1/250,000 live births for the period 1980-1989. Pneumonia was the most prevalent infection (79% of patients; Aspergillus most prevalent cause), followed by suppurative adenitis (53% of patients; Staphylococcus most prevalent cause), subcutaneous abscess (42% of patients; Staphylococcus most prevalent cause), liver abscess (27% of patients; Staphylococcus most prevalent cause), osteomyelitis (25% of patients; Serratia most prevalent cause), and sepsis (18% of patients; Salmonella most prevalent cause). Fifteen percent of patients had gastric outlet obstruction, 10% urinary tract obstruction, and 17% colitis/enteritis. Ten percent of X-linked recessive kindreds and 3% of autosomal recessive kindreds had family members with lupus. Eighteen percent of patients either were deceased when registered or died after being registered. The most common causes of death were pneumonia and/or sepsis due to Aspergillus (23 patients) or Burkholderia cepacia (12 patients). Patients with the X-linked recessive form of the disease appear to have a more serious clinical phenotype than patients with the autosomal recessive forms of the disease, based on the fact that they are diagnosed significantly earlier (mean, 3.01 years of age versus 7.81 years of age, respectively), have a significantly higher prevalence of perirectal abscess (17% versus 7%), suppurative adenitis (59% versus 32%), bacteremia/fungemia (21% versus 10%), gastric obstruction (19% versus 5%), and urinary tract obstruction (11% versus 3%), and a higher mortality (21.2% versus 8.6%).
- Published
- 2000
- Full Text
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23. Function and cell biology of neutrophils and mononuclear phagocytes in the newborn infant.
- Author
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Johnston RB Jr
- Subjects
- Humans, Infant, Newborn blood, Infant, Newborn immunology, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear immunology, Macrophages cytology, Macrophages immunology, Neutrophils cytology, Neutrophils immunology, Infant, Newborn physiology, Leukocytes, Mononuclear physiology, Macrophages physiology, Neutrophils physiology
- Published
- 1998
- Full Text
- View/download PDF
24. Augmentation of human macrophage candidacidal capacity by recombinant human myeloperoxidase and granulocyte-macrophage colony-stimulating factor.
- Author
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Maródi L, Tournay C, Káposzta R, Johnston RB Jr, and Moguilevsky N
- Subjects
- Humans, Macrophage Activation, Macrophages immunology, Mannose Receptor, Monocytes drug effects, Monocytes immunology, Opsonin Proteins, Peroxidase genetics, Receptors, Cell Surface metabolism, Recombinant Proteins pharmacology, Candida albicans immunology, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Lectins, C-Type, Macrophages drug effects, Mannose-Binding Lectins, Peroxidase pharmacology, Phagocytosis immunology
- Abstract
Phagocyte myeloperoxidase (MPO) is believed to be particularly important in defense against candida infection. We reported earlier that monocytes, rich in MPO, killed Candida albicans at a significantly higher rate and extent than did monocyte-derived macrophages, known to lack MPO, and that C. albicans is less resistant to MPO-dependent oxidants than less pathogenic Candida species. We hypothesized, therefore, that the capacity of macrophages to kill C. albicans might be improved in the presence of MPO. In this study, we evaluated the ability of recombinant human MPO (rhMPO) to augment the killing of C. albicans by resident macrophages and macrophages activated by recombinant human granulocyte-macrophage colony-stimulating factor. Addition of rhMPO (concentration range, 0.8 to 6.4 U/ml) to suspensions of resident and activated macrophages and opsonized C. albicans resulted in concentration-dependent and significant increases in candida killing. This enhancement was particularly pronounced with activated macrophages, whether C. albicans was opsonized or unopsonized and ingested through the macrophage mannose receptor. rhMPO did not affect the killing of C. albicans by monocytes, nor did it affect phagocytosis of opsonized or unopsonized C. albicans. These results indicate that exogenous rhMPO can augment the candidacidal capacity of both resident and activated macrophages, with a more profound effect on activated cells. We suggest that rhMPO may be effective in the treatment of invasive candidiasis.
- Published
- 1998
- Full Text
- View/download PDF
25. Characterization of multiple cysteine and cystine transporters in rat alveolar type II cells.
- Author
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Knickelbein RG, Seres T, Lam G, Johnston RB Jr, and Warshaw JB
- Subjects
- Amino Acids pharmacology, Animals, Cell Membrane metabolism, Cells, Cultured, Glutathione pharmacology, Glutathione Disulfide pharmacology, Kinetics, Models, Biological, Pulmonary Alveoli cytology, Rats, Rats, Sprague-Dawley, Sodium metabolism, Carrier Proteins metabolism, Cysteine metabolism, Cystine metabolism, Pulmonary Alveoli metabolism
- Abstract
Cysteine availability is rate limiting for the synthesis of glutathione, an important antioxidant in the lung. We used rat alveolar epithelial type II cells to study the mechanism of cysteine and cystine uptake. Consistent with carrier-mediated transport, each uptake process was saturable with Michaelis-Menten kinetics and was inhibited at 4 degrees C and by micromolar levels of amino acids or analogs known to be substrates for a specific transporter. A unique system XAG was found that transports cysteine and cystine (as well as glutamate and aspartate, the only substrates previously described for system XAG). We also identified a second Na(+)-dependent cysteine transporter system, system ASC, and two Na(+)-independent transporter systems, system xc for cystine and system L for cysteine. In the presence of glutathione at levels measured in rat plasma and alveolar lining fluid, cystine was reduced to cysteine and was transported on systems ASC and XAG, doubling the transport rate. Cysteinylglycine, released from glutathione at the cell surface by gamma-glutamyl transpeptidase, also stimulated uptake after reduction of cystine. These findings suggest that, under physiological conditions, cysteine and cystine transport is influenced by the extracellular redox state.
- Published
- 1997
- Full Text
- View/download PDF
26. American Pediatric Society Presidential Address 1997: the ever-whirling wheel of change.
- Author
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Johnston RB Jr
- Subjects
- History, 15th Century, History, 16th Century, History, 20th Century, History, Ancient, History, Medieval, Pediatrics trends, Societies, Medical trends, United States, History of Medicine, Pediatrics organization & administration, Societies, Medical organization & administration
- Published
- 1997
- Full Text
- View/download PDF
27. An overview of infant mortality and birth defects in the United States.
- Author
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Petrini J, Damus K, and Johnston RB Jr
- Subjects
- Black People, Congenital Abnormalities ethnology, Congenital Abnormalities prevention & control, Humans, Infant, Infant, Newborn, United States epidemiology, White People, Black or African American, Congenital Abnormalities mortality, Infant Mortality
- Published
- 1997
- Full Text
- View/download PDF
28. Folic acid: new dimensions of an old friendship.
- Author
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Johnston RB Jr
- Subjects
- Adolescent, Adult, Child, Female, Folic Acid metabolism, Food, Fortified, Humans, Infant, Infant, Newborn, Neural Tube Defects etiology, Neural Tube Defects physiopathology, Neural Tube Defects prevention & control, Pregnancy, Prenatal Care, Folic Acid therapeutic use, Folic Acid Deficiency complications, Folic Acid Deficiency physiopathology, Folic Acid Deficiency therapy, Pregnancy Complications physiopathology, Pregnancy Complications therapy
- Published
- 1997
29. Folic acid supplementation--when and how.
- Author
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Schwarz RH and Johnston RB Jr
- Subjects
- Female, Humans, Folic Acid therapeutic use, Food, Fortified, Prenatal Care
- Abstract
The periconceptional intake of 400 micrograms of folic acid can prevent 50-70% of neural tube defects. It is difficult to achieve this intake with diet alone, even with the recently approved levels for grain-food fortification. Therefore, a daily multivitamin with folic acid is recommended for all women of childbearing potential. Obstetrician-gynecologists should exercise every opportunity to educate their patients to this end. Although raised as a concern, the potential of masking the megaloblastic anemia of pernicious anemia is unlikely with these levels of supplementation, and considering the rarity of the disease in women of reproductive age.
- Published
- 1996
- Full Text
- View/download PDF
30. Diamide primes neutrophils for enhanced release of superoxide anion: relationship to S-thiolation of cellular proteins.
- Author
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Moriguchi T, Seres T, Ravichandran V, Sasada M, and Johnston RB Jr
- Subjects
- Calcium blood, Calcium pharmacology, Humans, Hydrogen Peroxide pharmacology, Intracellular Fluid metabolism, Lipopolysaccharides pharmacology, NADH, NADPH Oxidoreductases metabolism, NADPH Oxidases, Platelet Activating Factor pharmacology, Blood Proteins metabolism, Diamide pharmacology, Neutrophils drug effects, Neutrophils metabolism, Sulfhydryl Compounds blood, Superoxides metabolism
- Abstract
Stimulation of the respiratory burst in phagocytes induces the formation of mixed disulfides between sulfhydryl groups of proteins and low-molecular-weight thiols. We hypothesized that this process (S-thiolation) might be involved in turning off the respiratory burst. However, induction of S-thiolation by pretreatment of neutrophils with diamide, a direct thiol oxidizing agent, actually primed the cells for a two- to fivefold increase in total release and fourfold increase in rate of release of 02- on stimulation by f-Met-Leu-Phe. Generation of intracellular oxidants (hydroethidine fluorescence) was increased ninefold. Priming and S-thiolation were apparent at 1 min of incubation and peaked at 5-10 min. Diamide pretreatment also reduced the lag time between addition of phorbol diester and release of 02- by a mean of 23 s (41%). Dithioerythritol, a sulfhydryl-reducing agent, abolished both the S-thiolation and priming mediated by diamide. H202 also induced priming and S-thiolation; and these were eliminated by dithioerythritol. In contrast to the effect of endotoxin, diamide priming did not affect Ca2+ homeostasis of the neutrophils. Diamide did not significantly alter NADPH oxidase activity in a cell-free system. These findings suggest that sulfhydryl groups on one or more proteins play an important role in modulating the respiratory burst.
- Published
- 1996
- Full Text
- View/download PDF
31. Protein S-thiolation and dethiolation during the respiratory burst in human monocytes. A reversible post-translational modification with potential for buffering the effects of oxidant stress.
- Author
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Seres T, Ravichandran V, Moriguchi T, Rokutan K, Thomas JA, and Johnston RB Jr
- Subjects
- Glutathione metabolism, Humans, Hydrogen Peroxide blood, Hydrogen Peroxide pharmacology, Molecular Weight, Monocytes drug effects, Oxidation-Reduction, Protein Binding drug effects, Protein Processing, Post-Translational, Blood Proteins metabolism, Monocytes metabolism, Oxidants toxicity, Respiratory Burst drug effects, Sulfhydryl Compounds blood
- Abstract
Stimulation of the respiratory burst in mouse macrophages or human neutrophils results in the formation of disulfide bonds between low m.w. thiols and sulfhydryl groups on specific cytosolic proteins (S-thiolation). S-thiolation is reversible in certain chemical systems. The aim of the present study was to analyze the dynamic nature of this process in human monocytes under physiologic conditions. We report here that the extent of S-thiolation and the rate of respiratory burst stimulated by opsonized zymosan or phorbol diester increased for 10 to 20 min and then declined (dethiolation) in close association. Individual proteins underwent S-thiolation and dethiolation at different rates. H2O--appeared particularly effective in mediating S-thiolation, based on inhibition of S-thiolation by added catalase and accentuation by azide, which inhibits cellular catalase. S-thiolation did not occur in stimulated monocytes from patients with chronic granulomatous disease. The addition of H2O2 to monocytes or lymphocytes induced rapid S-thiolation (1 to 3 min); a subsequent dethiolation returned most of the proteins to baseline by 15 to 30 min. At 0 degrees C and after addition of 1,3-bis-(2-chloroethyl)-1-nitrosourea, there was effective S-thiolation on exposure to H2O2, but dethiolation was inhibited, suggesting a possible role for glutathione (GSH)/thioredoxin reductase systems in this process. GSH was determined to be the most abundant low m.w. thiol bound to S-thiolated proteins, but gamma-glutamylcysteine and cysteine were also bound. The time of maximal reduction in cytosolic GSH during the respiratory burst (10 min) coincided with the time at which protein-bound GSH was highest. S-thiolation-dethiolation represents a reversible post-translational modification that could protect cellular proteins from irreversible oxidative damage.
- Published
- 1996
32. Hyperoxia enhances expression of gamma-glutamyl transpeptidase and increases protein S-glutathiolation in rat lung.
- Author
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Knickelbein RG, Ingbar DH, Seres T, Snow K, Johnston RB Jr, Fayemi O, Gumkowski F, Jamieson JD, and Warshaw JB
- Subjects
- Animals, Animals, Newborn, Blotting, Northern, Blotting, Western, Glucosephosphate Dehydrogenase metabolism, Immunohistochemistry, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, gamma-Glutamyltransferase genetics, Glutathione metabolism, Hyperoxia metabolism, Lung metabolism, Protein S metabolism, gamma-Glutamyltransferase metabolism
- Abstract
By participating in glutathione (GSH) synthesis, gamma-glutamyl transpeptidase (GGT) influences the GSH redox cycle, which is a major contributor in protecting against reactive oxygen metabolites. This study determined the effect of prolonged exposure of neonatal rats to > 98% oxygen on expression of GGT and on GSH metabolism. Lungs of neonatal rats chronically exposed to hyperoxia had increased expression of GGT mRNA, resulting in significantly higher GGT protein levels and enzyme activity than in lungs of animals raised in room air. Hyperoxia also upregulated glucose-6-phosphate dehydrogenase, but Na-K-ATPase activity was not changed. GGT mRNA, protein level, and enzyme activity returned to control levels after recovery in room air for 3 days. Levels of GSH, glutathione disulfide, and protein-bound GSH (S-glutathiolated protein) rose with hyperoxia and fell during recovery. S-glutathiolation is likely a mechanism for protection and a regulatory modification of protein sulfhydryl groups. Hyperoxia-induced upregulation of GGT and the concomitant increase in protein S-glutathiolation appear to be additional components fundamental in protecting the lung against oxidative injury.
- Published
- 1996
- Full Text
- View/download PDF
33. Candidacidal mechanisms in the human neonate. Impaired IFN-gamma activation of macrophages in newborn infants.
- Author
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Maródi L, Káposzta R, Campbell DE, Polin RA, Csongor J, and Johnston RB Jr
- Subjects
- Adult, Fetal Blood cytology, Humans, Monocytes immunology, Phagocytosis immunology, Receptors, Interferon immunology, Superoxides immunology, Interferon gamma Receptor, Candida albicans immunology, Infant, Newborn immunology, Interferon-gamma immunology, Macrophage Activation immunology
- Abstract
We studied the interaction between Candida albicans and mononuclear phagocytes derived from cord blood. In the presence of normal serum, the extent of phagocytosis and killing of candida by monocyte-derived macrophages was equivalent for newborns and adults. In the absence of serum both phagocytosis and killing by macrophages were reduced by half, but cord and adult cells were still equivalent. Mannosylated BSA and mannan inhibited ingestion of unopsonized candida by macrophages, suggesting a role for the mannose receptor. Exposure of cord and adult macrophages to IFN-gamma (10-500 U/ml) gave quantitatively different results in Candida killing, as well as in release of superoxide anion (O2-). Maximal increase in these functions with adult macrophages was achieved with 100 U/ml IFN-gamma. No enhancement with cord macrophages could be detected after treatment with 100 U/ml, and at 500 U/ml there was still significantly lower killing and O2- release compared with adult cells. Defective up-regulation of O2- release was also present in cord monocytes exposed to IFN-gamma on day 0. Studies of the surface expression of IFN-gamma receptors using a "nonblocking" mAb against the IFN-gamma receptor revealed a comparable number of receptors on cord and adult monocytes. When blocking Abs were used, however, there was a three times higher number of positive cells in cord monocytes. Specific binding of 125I-IFN-gamma to cord monocytes and macrophages was also higher compared with adult cells. These data suggest that neonatal macrophages have a normal capacity to ingest and kill both opsonized and unopsonized Candida but cannot be fully activated by IFN-gamma, a finding that could not be attributed to lower expression of IFN-gamma receptors on the neonatal cells.
- Published
- 1994
34. Chronic granulomatous disease: newly defined molecular abnormalities explain disease variability and normal phagocyte physiology.
- Author
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Forehand JR and Johnston RB Jr
- Subjects
- Child, Genetic Therapy, Granulomatous Disease, Chronic metabolism, Granulomatous Disease, Chronic therapy, Humans, Granulomatous Disease, Chronic genetics, Phagocytes physiology
- Abstract
Chronic granulomatous disease (CGD) typically presents as recurrent abscess formation beneath the skin and in the mononuclear phagocyte system. Common infecting organisms are staphylococci and enteric bacteria; Aspergillus organisms are a major threat. All CGD cases analyzed to date have revealed a defect in one of four proteins, each encoded on a separate gene. These four proteins are the major constituents of an enzyme complex that transfers electrons from NADPH to oxygen, creating microbicidal (yet tissue-toxic) oxidants. Recent research has defined the gene abnormalities in CGD and set the stage for gene therapy and pharmacologic modulation of host defense and inflammation.
- Published
- 1994
35. S-thiolation of glyceraldehyde-3-phosphate dehydrogenase induced by the phagocytosis-associated respiratory burst in blood monocytes.
- Author
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Ravichandran V, Seres T, Moriguchi T, Thomas JA, and Johnston RB Jr
- Subjects
- Ethylmaleimide pharmacology, Humans, Hydrogen Peroxide metabolism, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Sulfhydryl Compounds metabolism, Tetradecanoylphorbol Acetate pharmacology, Glyceraldehyde-3-Phosphate Dehydrogenases metabolism, Monocytes metabolism, Phagocytosis, Respiratory Burst
- Abstract
Chemical oxidants can induce the covalent binding of low molecular weight thiols to reactive sulfhydryls on proteins (S-thiolation). We found that stimulation of the respiratory burst of human blood monocytes resulted in S-thiolation of several proteins, most prominently one of 38 kDa. This purified protein was identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by enzyme activity, immunoblotting, and amino acid analysis. After stimulation of the respiratory burst, S-thiolation of GAPDH gradually increased, and cytosol GAPDH activity decreased; so that at 60 min, GAPDH activity was reduced by approximately 40%. Activity was restored by the addition of the sulfhydryl-reducing agent dithioerythritol. H2O2 appeared to be particularly important in mediating S-thiolation during the respiratory burst. Exposure of monocytes to H2O2 induced concentration-dependent S-thiolation of GAPDH and a concomitant decrease in enzyme activity. The addition of respiratory burst stimuli to lymphocytes, which lack a full respiratory burst, had no effect on GAPDH S-thiolation or activity; but H2O2 induced S-thiolation of lymphocyte GAPDH and inhibition of enzyme activity. Stimulation of monocytes from three patients with chronic granulomatous disease resulted in no respiratory burst, S-thiolation of GAPDH, or inactivation of GAPDH activity. The thiols covalently bound to purified S-thiolated GAPDH were removed by dithioerythritol and were identified as glutathione and cysteine; glutathione was predominant. These results indicate that during the respiratory burst in monocytes, low molecular weight thiols can bind to specific cytosolic proteins, including GAPDH. It is possible that S-thiolation of cytosolic proteins serves to modulate cellular metabolic events during phagocytosis.
- Published
- 1994
36. Adverse events associated with childhood vaccines other than pertussis and rubella. Summary of a report from the Institute of Medicine.
- Author
-
Stratton KR, Howe CJ, and Johnston RB Jr
- Subjects
- Child, Child, Preschool, Diphtheria Toxoid adverse effects, Diphtheria-Tetanus Vaccine, Drug Combinations, Haemophilus Vaccines adverse effects, Hepatitis B Vaccines adverse effects, Humans, Incidence, Infant, Measles Vaccine adverse effects, Measles-Mumps-Rubella Vaccine, Mumps Vaccine adverse effects, National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division, Poliovirus Vaccine, Inactivated adverse effects, Poliovirus Vaccine, Oral adverse effects, Risk Factors, Rubella Vaccine adverse effects, Tetanus Toxoid adverse effects, United States, Pharmacoepidemiology methods, Vaccination adverse effects, Vaccines adverse effects
- Abstract
In September 1993, the Institute of Medicine released a report entitled Adverse Events Associated With Childhood Vaccines: Evidence Bearing on Causality. The report examined putative serious adverse consequences associated with administration of diphtheria and tetanus toxoids; measles, mumps, and measles-mumps-rubella vaccines; oral polio vaccine and inactivated polio vaccine; hepatitis B vaccines; and Haemophilus influenzae type b (Hib) vaccines. The committee spent 18 months reviewing all available scientific and medical data, from individual case reports (published and unpublished) to controlled clinical trials. The committee found that the evidence favored the rejection of a causal relation between diphtheria and tetanus toxoids and encephalopathy, infantile spasms, and sudden infant death syndrome, and between conjugate Hib vaccines and susceptibility to Hib disease. The committee found that the evidence favored acceptance of a causal relation between diphtheria and tetanus toxoids and Guillain-Barré syndrome and brachial neuritis, between measles vaccine and anaphylaxis, between oral polio vaccine and Guillain-Barré syndrome, and between unconjugated Hib vaccine and susceptibility to Hib disease. The committee found that the evidence established causality between diphtheria and tetanus toxoids and anaphylaxis, between measles vaccine and death from measles vaccine-strain viral infection, between measles-mumps-rubella vaccine and thrombocytopenia and anaphylaxis, between oral polio vaccine and poliomyelitis and death from polio vaccine-strain viral infection, and between hepatitis B vaccine and anaphylaxis. For five vaccine-related adverse events, there was no evidence identified. For the remaining 33 vaccine-related adverse events, the evidence was inadequate to accept or reject a causal relation.
- Published
- 1994
37. S-thiolation of individual human neutrophil proteins including actin by stimulation of the respiratory burst: evidence against a role for glutathione disulfide.
- Author
-
Chai YC, Ashraf SS, Rokutan K, Johnston RB Jr, and Thomas JA
- Subjects
- Glutathione analysis, Glutathione Disulfide, Humans, Neutrophils drug effects, Proteins metabolism, Sulfur Radioisotopes, Tetradecanoylphorbol Acetate pharmacology, Actins metabolism, Disulfides metabolism, Glutathione analogs & derivatives, Neutrophils metabolism, Respiratory Burst, Sulfhydryl Compounds metabolism
- Abstract
Protein S-thiolation, a reversible modification of protein sulfhydryls resulting in formation of mixed-disulfides, was studied in human neutrophils stimulated with phorbol diester to produce superoxide anion. Rapid S-thiolation of several proteins was examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Glutathione was identified as the primary protein-bound thio by HPLC chromatography, contributing considerably more than 85% of the total. Minor amounts of homocysteine and/or cysteine were also detected as protein-bound thiols. During the first 30 min after stimulation, 10% of the cellular glutathione became protein bound (2 nmol/mg of protein). There was no increase in glutathione disulfide suggesting that S-thiolation of the proteins did not occur by thiol/disulfide exchange. Approximately 10 mol% of one heavily modified band (29 kDa) was S-thiolated after 30 min. A second major band of 42 kDa was identified as actin. It contained 1/10th of the total protein-bound glutathione and approximately 5 mol% was S-thiolated after 30 min. These experiments identify a subset of S-thiolated neutrophil proteins, including actin, whose modification is related to the phorbol diester stimulation of superoxide anion production in human neutrophils. Ten percent of the total glutathione pool became protein-bound without an appreciable change in non-bound concentration of glutathione or glutathione disulfide. These results suggest that glutathione was synthesized during initial phases of the respiratory burst, compensating for the amount of glutathione that became protein-bound. Since there was no significant increase in glutathione disulfide, it was probably not important in the observed protein S-thiolation.
- Published
- 1994
- Full Text
- View/download PDF
38. Oxidative stress induces S-thiolation of specific proteins in cultured gastric mucosal cells.
- Author
-
Rokutan K, Johnston RB Jr, and Kawai K
- Subjects
- Actin Cytoskeleton ultrastructure, Actins metabolism, Animals, Cells, Cultured, Cystine pharmacokinetics, Gastric Mucosa cytology, Gastric Mucosa ultrastructure, Glutathione metabolism, Guinea Pigs, Intracellular Membranes metabolism, Male, Microscopy, Fluorescence, Diamide pharmacology, Gastric Mucosa metabolism, Hydrogen Peroxide pharmacology, Proteins metabolism, Sulfhydryl Compounds metabolism
- Abstract
Oxidative stress induces the formation of protein-mixed disulfides with low-molecular-weight thiols, especially glutathione. We analyzed this process, termed S-thiolation, in cultured gastric mucosal cells from guinea pigs by gel electrophoresis and autoradiography after radiolabeling of the intracellular glutathione pool with 35S. Hydrogen peroxide (H2O2) or diamide initiated rapid and reversible S-thiolation of specific proteins with molecular masses of 42, 30, 29, 28, and 22 kDa. Diamide caused particularly prominent S-thiolation of the 42 kDa protein. This protein was identified as actin by immunoblot analysis and actin-myosin precipitation. Fluorescence microscopy revealed that diamide caused a disappearance of normal stress fibers and a concomitant increase in actin polymerization in association with contraction of the cells. These morphological changes were completely reversible within minutes. With cells depleted of glutathione by incubation with DL-buthionine-[S,R]-sulfoximine, diamide caused severe contraction and rounding, and the cells detached from the culture plates. S-thiolation of actin could help protect gastric mucosal cells against irreversible organization of microfilaments by preserving microfilament dynamics under oxidative stress.
- Published
- 1994
- Full Text
- View/download PDF
39. Phospholipase A2 activity in human neutrophils. Stimulation by lipopolysaccharide and possible involvement in priming for an enhanced respiratory burst.
- Author
-
Forehand JR, Johnston RB Jr, and Bomalaski JS
- Subjects
- Fatty Acids metabolism, Humans, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Neutrophils drug effects, Neutrophils metabolism, Phospholipases A2, Superoxides metabolism, Lipopolysaccharides pharmacology, Neutrophils enzymology, Phospholipases A metabolism, Respiratory Burst
- Abstract
Exposure to LPS, platelet-activating factor, certain cytokines, and other agents can prime human neutrophils for an increased release of superoxide anion (O2-) in response to stimuli. Previous work with LPS has suggested that priming may involve alterations in signal transduction pathways related to the release of O2-. Products derived from the enzymatic activity of phospholipase A2 (PLA2) on membrane phospholipids reportedly activate certain of these signaling events. Thus, PLA2 could play a regulatory role in the release of O2- by neutrophils. We examined this possibility by studying the effect of LPS on neutrophil PLA2 activity. Exposure to LPS triggered a fivefold increase in activity of an endogenous PLA2; control cells incubated under identical conditions without LPS showed no increase. Neutrophil-associated PLA2 activity increased 5 to 10 min after the addition of LPS to the cells and preceded the emergence of the primed state. Quinacrine and p-bromophenacylbromide, inhibitors of PLA2, blocked LPS priming but not the baseline O2- release from unprimed cells. The LPS-provoked increase in PLA2 activity resulted in release of oleic acid (38 +/- 4% above baseline) but not arachidonic, linoleic, or palmitic acid. In contrast, ionomycin resulted in significant release of all four fatty acids. The addition of exogenous PLA2 to neutrophils primed them. Priming was rapid and was 80 +/- 5% complete within 3 min. Thus, LPS and perhaps other agents may mediate their effects on O2- release at least in part by triggering PLA2 activity. PLA2 activation may play a role in regulating production and release of O2- by the human neutrophil.
- Published
- 1993
40. Acute encephalopathy and chronic neurological damage after pertussis vaccine.
- Author
-
Cowan LD, Griffin MR, Howson CP, Katz M, Johnston RB Jr, Shaywitz BA, and Fineberg HV
- Subjects
- Acute Disease, Brain Diseases epidemiology, Case-Control Studies, Child, Child, Preschool, Chronic Disease, Encephalomyelitis, Acute Disseminated epidemiology, Humans, Infant, Infant, Newborn, Nervous System Diseases epidemiology, Brain Diseases chemically induced, Encephalomyelitis, Acute Disseminated etiology, Nervous System Diseases chemically induced, Pertussis Vaccine adverse effects
- Abstract
In August 1991, the Institute of Medicine released a report entitled Adverse Effects of Pertussis and Rubella Vaccines, which examined, among others, the relation between immunization with whole-cell diphtheria-tetanus-pertussis (DTP) vaccine and both acute encephalopathy and chronic neurological damage. The committee reviewed information from a wide range of both professional and lay sources and found that the evidence is consistent with a possible causal relation between DTP vaccine and acute encephalopathy, although it is insufficient to establish causality. The range of excess risk of acute encephalopathy following DTP immunization is consistent with that estimated from the National Childhood Encephalopathy Study: 0.0 to 10.5 cases per million immunizations. The committee concluded that the evidence is insufficient to indicate either the presence or absence of a causal relationship between DTP vaccine and permanent neurological damage. The evaluative methods used by the committee are briefly described and the evidence underlying its conclusions presented.
- Published
- 1993
- Full Text
- View/download PDF
41. The complement system in host defense and inflammation: the cutting edges of a double edged sword.
- Author
-
Johnston RB Jr
- Subjects
- Complement Activation, Complement System Proteins deficiency, Humans, Receptors, Complement, Complement System Proteins physiology, Inflammation immunology
- Published
- 1993
- Full Text
- View/download PDF
42. Crohn's disease monocytes are primed for accentuated release of toxic oxygen metabolites.
- Author
-
Baldassano RN, Schreiber S, Johnston RB Jr, Fu RD, Muraki T, and MacDermott RP
- Subjects
- Adolescent, Adult, Calcium metabolism, Cells, Cultured, Child, Crohn Disease etiology, Endotoxins blood, Endotoxins toxicity, Humans, Polymyxin B pharmacology, Superoxides metabolism, Crohn Disease immunology, Monocytes metabolism, Respiratory Burst
- Abstract
Background: Inflammatory bowel disease occurs in regions of the intestine characterized by a bowel content high in bacteria. Intestinal bacteria synthesize cell wall products such as lipopolysaccharide; when normal monocytes or macrophages come in contact with these products, they can be primed to release a number of inflammatory mediators. Mediators such as toxic oxygen metabolites released as part of the respiratory burst may contribute to inflammatory tissue damage. The aim of this study was to determine if monocytes from patients with Crohn's disease are primed by lipopolysaccharide for a greater respiratory burst., Methods: The generation of superoxide anion was measured by superoxide dismutase inhibitable reduction of ferricytochrome c., Results: Freshly isolated monocytes from active untreated Crohn's disease patients (n = 8) showed enhanced stimulated release of superoxide anion when compared with normal monocytes (n = 15; 3.80 +/- 0.12 vs. 1.02 +/- 0.06 nmol/5 min; P < 0.001). We tested the hypothesis that the monocyte priming factor in Crohn's disease serum may be lipopolysaccharide by showing that Crohn's disease serum lost its ability to prime normal monocytes after lipopolysaccharide was removed (0.25 +/- 0.25 nmol/5 min, P < 0.001)., Conclusions: These studies indicate that bacterial cell wall products may be important proinflammatory molecules involved in the initiation and/or perpetuation of Crohn's disease.
- Published
- 1993
- Full Text
- View/download PDF
43. Enhancement of macrophage candidacidal activity by interferon-gamma. Increased phagocytosis, killing, and calcium signal mediated by a decreased number of mannose receptors.
- Author
-
Maródi L, Schreiber S, Anderson DC, MacDermott RP, Korchak HM, and Johnston RB Jr
- Subjects
- Calcium metabolism, Dose-Response Relationship, Drug, Humans, Macrophages drug effects, Mannose Receptor, Phagocytosis, Superoxides metabolism, Candida albicans, Interferon-gamma pharmacology, Lectins, C-Type, Macrophages immunology, Mannose-Binding Lectins, Receptors, Cell Surface, Receptors, Immunologic metabolism
- Abstract
In contrast to its macrophage-activating capacity, IFN-gamma downregulates expression of the macrophage mannose receptor (MMR), which mediates uptake of Candida and other microorganisms. We found that IFN-gamma induced a concentration-dependent increase in the capacity of human monocyte-derived macrophages to ingest and kill both opsonized and unopsonized Candida albicans and to release superoxide anion upon stimulation with Candida. Mannan or mannosylated albumin inhibited this activated uptake of unopsonized Candida, but glucan did not. Addition of mAb to complement receptor (CR) 3 did not inhibit ingestion; macrophages that lacked CR3 (leukocyte adhesion defect) showed normal upregulation of ingestion by IFN-gamma. The increased candidacidal activity of IFN-gamma-activated macrophages was associated with reduced expression of MMR by a mean of 79% and decreased pinocytic uptake of 125I-mannosylated BSA by 73%; K(uptake) of pinocytosis was not changed. Exposure of resident macrophages to unopsonized Candida did not elicit a transient increase in intracellular free Ca2+ ([Ca2+]i); macrophages activated by IFN-gamma expressed a brisk increase in [Ca2+]i on exposure to Candida. These data suggest that macrophage activation by IFN-gamma can enhance resistance to C. albicans infection in spite of downregulation of the MMR, perhaps through enhanced coupling of the MMR to microbicidal functions.
- Published
- 1993
- Full Text
- View/download PDF
44. Academic pediatrics and the health of medically underserved children in America.
- Author
-
Johnston RB Jr
- Subjects
- Child, Child Health Services economics, Humans, Internship and Residency, Pediatrics economics, Pediatrics education, Social Responsibility, United States, Academic Medical Centers, Child Health Services organization & administration, Medically Underserved Area, Pediatrics organization & administration, Poverty
- Published
- 1993
- Full Text
- View/download PDF
45. Enhancement of macrophage candidacidal activity by interferon-gamma.
- Author
-
Maródi L and Johnston RB Jr
- Subjects
- Adult, Cytotoxicity, Immunologic, Glucans pharmacology, Humans, In Vitro Techniques, Macrophage Activation drug effects, Macrophages drug effects, Macrophages metabolism, Mannans pharmacology, Monocytes immunology, Phagocytosis drug effects, Recombinant Proteins, Superoxides metabolism, Candida albicans immunology, Interferon-gamma pharmacology, Macrophages immunology
- Abstract
In previous studies, we have reported that opsonized candida species are ingested by monocytes and monocyte-derived macrophages (MDM), but uptake of unopsonized candida is mediated only by MDM, primarily through the mannose receptor (MR). This study examines the effects of recombinant IFN-gamma on the uptake and killing of unopsonized C. albicans by MDM. We report here that MDM treated with IFN-gamma developed an increase in their capacity to ingest and kill unopsonized C. albicans and to release O2- upon stimulation with candida. Mannan (0.1 to 5 mg/ml) inhibited uptake of candida in a dose-dependent manner, but glucan (5 mg/ml) did not. These data suggest that mannose receptors may be involved in the increased phagocytosis and killing of unopsonized candida by human macrophages treated with IFN-gamma.
- Published
- 1993
46. Chronic arthritis after rubella vaccination.
- Author
-
Howson CP, Katz M, Johnston RB Jr, and Fineberg HV
- Subjects
- Adult, Causality, Double-Blind Method, Epidemiologic Methods, Female, Humans, National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division, Prospective Studies, Retrospective Studies, United States, Arthritis etiology, Rubella Vaccine adverse effects
- Abstract
In August 1991 the Institute of Medicine released a report entitled "Adverse Effects of Pertussis and Rubella Vaccines" that examined, among other relations, the relation between immunization with the RA 27/3 rubella vaccine strain and chronic arthritis. The committee spent 20 months reviewing a wide range of information sources including case series and individual case reports published in peer-reviewed journals and reported by vaccine manufacturers; unpublished case reports from physicians, parents, and other concerned persons; epidemiological studies; and laboratory studies. There were no animal studies available. The committee found that the evidence is consistent with a causal relation between the RA 27/3 rubella vaccine strain and chronic arthritis in adult women, although the evidence is limited in scope. Proving that rubella vaccination can cause chronic arthritis will require a better understanding of pathogenetic mechanisms and additional well-designed studies. We briefly describe the committee's evaluative methods and present the evidence underlying its conclusion.
- Published
- 1992
- Full Text
- View/download PDF
47. Impairment of macrophage activation and granuloma formation by protein deprivation in mice.
- Author
-
Reynolds JV, Redmond HP, Ueno N, Steigman C, Ziegler MM, Daly JM, and Johnston RB Jr
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Granuloma immunology, Histocompatibility Antigens Class II analysis, Histocompatibility Antigens Class II biosynthesis, Interleukin-1 analysis, Interleukin-1 metabolism, Lipopolysaccharides, Male, Mice, Superoxides analysis, Macrophage Activation immunology, Macrophages immunology, Protein Deficiency immunology
- Abstract
Protein-calorie malnutrition predisposes to infection by intracellular pathogens, but the basis for this predisposition is unclear. We studied the effect of protein deprivation on mouse peritoneal macrophage function and on granuloma formation during infection by bacille Calmette-Gueŕin (BCG). Injection of lipopolysaccharide (LPS) to induce inflammation elicited fewer peritoneal cells from mice fed a 2.5% protein diet than from mice fed an isocaloric chow in which protein calories constituted 24% of the total. LPS-elicited macrophages from protein-deprived mice demonstrated a reduction in spreading, total cell protein, cell lactate dehydrogenase, and release of superoxide anion (O2-) in response to stimulation. Priming in vitro by interferon (IFN)-gamma for enhanced release of O2- was also significantly impaired in protein-deprived mice. This defect was reversible by repletion with 24% protein diet for 10 days. Impairment of macrophage function in protein-deprived mice was further evidenced by an impaired capacity to express Ia antigen in response to IFN-gamma and by reduced production of IL-1 activity in response to LPS. Infection by BCG in protein-deprived mice was characterized by impaired granuloma development in liver, lungs, and spleen. Thus, in this model, protein deprivation significantly impaired macrophage activation, as assessed by morphologic, metabolic, and functional criteria. This impairment might compromise immune effector mechanisms dependent on macrophage activation, including rejection of intracellular pathogens.
- Published
- 1992
- Full Text
- View/download PDF
48. Phagocytosis and stimulation of the respiratory burst by phorbol diester initiate S-thiolation of specific proteins in macrophages.
- Author
-
Rokutan K, Thomas JA, and Johnston RB Jr
- Subjects
- Animals, Lipopolysaccharides pharmacology, Mice, Molecular Weight, Oxidation-Reduction, Proteins chemistry, Sulfhydryl Compounds metabolism, Superoxides metabolism, Tetradecanoylphorbol Acetate pharmacology, Disulfides metabolism, Glutathione metabolism, Macrophages physiology, Phagocytosis, Proteins metabolism
- Abstract
Addition of chemical oxidants to cells in culture has been shown to induce binding of low-molecular-weight thiols to reactive sulfhydryls on proteins in a process termed S-thiolation. We found that stimulation of the respiratory burst in mouse macrophages, with release of O2-, resulted in S-thiolation of several proteins, most prominently three with molecular weights of 74, 33, and 22 kDa. One protein (28 kDa) was S-thiolated without addition of an exogenous stimulus. Exposure of cells to concentrations of hydrogen peroxide like those released in the respiratory burst induced S-thiolation of these same proteins. S-thiolation and release of O2- began at approximately the same time. Stimulation of LPS-elicited macrophages induced prominent S-thiolation of three different proteins (38, 30, and 21 kDa). Under the conditions of these experiments, there was no detectable increase in glutathione disulfide and a negligible decrease in glutathione, which suggests that S-thiolation can occur without significant perturbation of the glutathione peroxidase/reductase cycle. S-thiolation of proteins could help protect the macrophage against the autoxidative damage associated with the respiratory burst. Modification of specific proteins by S-thiolation might serve to modulate cellular metabolic events.
- Published
- 1991
49. Protein kinase C isotypes and signaling in neutrophils. Differential substrate specificities of a translocatable calcium- and phospholipid-dependent beta-protein kinase C and a phospholipid-dependent protein kinase which is inhibited by long chain fatty acyl coenzyme A.
- Author
-
Majumdar S, Rossi MW, Fujiki T, Phillips WA, Disa S, Queen CF, Johnston RB Jr, Rosen OM, Corkey BE, and Korchak HM
- Subjects
- Acyl Coenzyme A pharmacology, Amino Acid Sequence, Antibodies, Monoclonal immunology, Calcium physiology, Cell Compartmentation, Coenzyme A metabolism, Diglycerides physiology, Fatty Acids, Nonesterified pharmacology, Humans, In Vitro Techniques, Molecular Sequence Data, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Peptides chemistry, Phosphatidylserines physiology, Phosphoproteins metabolism, Phosphorylation, Protein Kinase C classification, Protein Kinase C immunology, Protein Kinase C isolation & purification, Signal Transduction, Tetradecanoylphorbol Acetate pharmacology, Neutrophils enzymology, Protein Kinase C physiology
- Abstract
Neutrophils possess a classical Ca2+, phosphatidyl serine (PS) and diglyceride (DG)-dependent protein kinase C (beta-PKC) which was translocatable from cytosol to membrane in response to elevated Ca2+ in the physiologic range or to pretreatment with phorbol myristate acetate (PMA). The translocatable beta-PKC was purified from neutrophil membranes prepared in the presence of Ca2+, eluted with EGTA and subjected to hydroxyapatite chromatography. An 80-kDa protein possessing Ca/DG/PS-dependent histone phosphorylating activity was recognized by a monoclonal antibody to beta-PKC but not to alpha-PKC or gamma-PKC. A cytosolic kinase activity remaining after Ca(2+)-induced translocation of beta-PKC was dependent on PS and DG but did not require Ca2+. This novel Ca(2+)-independent, PS/DG-dependent kinase, termed nPKC, eluted from hydroxyapatite between alpha-PKC and beta-PKC, ran as a 76-kDa band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and was reactive to a polyclonal consensus antibody but not to monoclonal antibodies to alpha-PKC, beta-PKC, or gamma-PKC. Long chain fatty acyl-CoA, but not the corresponding free fatty acids, inhibited nPKC in the 1-10 microM range. The chemotactic peptide fMet-Leu-Phe triggered prompt but transient increases in neutrophil long chain fatty acid acyl-CoA, suggesting that nPKC is regulated by fatty acyl-CoA as well as DG during neutrophil activation. Purified beta-PKC phosphorylated a number of cytosolic proteins in a Ca(2+)-dependent manner, including a major 47-kDa cytosolic protein, which may be implicated in superoxide anion generation. In contrast, nPKC did not phosphorylate the 47-kDa protein, but phosphorylated numerous cytosolic proteins in a Ca(2+)-independent manner, including a 66-kDa protein which was not phosphorylated by beta-PKC. Differences in location, substrate specificity, and cofactor dependence between nPKC and beta-PKC suggest these kinases may play selective roles in the activation sequence of the neutrophil.
- Published
- 1991
50. Pathogenesis of pneumococcal pneumonia.
- Author
-
Johnston RB Jr
- Subjects
- Child, Child, Preschool, Humans, Infant, Lung pathology, Pneumonia, Pneumococcal complications, Pneumonia, Pneumococcal etiology, Pneumonia, Pneumococcal immunology, Pneumonia, Pneumococcal pathology, Developing Countries, Pneumonia, Pneumococcal microbiology, Streptococcus pneumoniae physiology
- Abstract
Pneumococcal pneumonia poses a serious threat to children in developing countries and remains an important disease in the industrialized world. Capsular polysaccharide is the only bacterial factor proven to contribute to pathogenesis. However, the mechanisms responsible for the hypoxemia, toxemia, crisis, and death associated with this common infection are poorly understood. Toxins secreted by the bacteria, byproducts of bacterial breakdown (e.g., pneumolysin or teichoic acid), or constituents of the intense inflammatory response in the lung might play a role in these phenomena. Malnourished children presumably carry less metabolic reserve with which they can resist the exceptional stresses of pneumococcal disease, and underlying parasitic infestation or other chronic infections, through release of potent mediators such as tumor necrosis factor or platelet-activating factor, might prime the mechanisms of host defense for a more fulminant and systemic response to infection. Vaccines that can protect infants are badly needed, and a better understanding must be gained of the mechanisms by which this pathogen continues to cause such devastating disease in the world's children and elderly.
- Published
- 1991
- Full Text
- View/download PDF
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