Richard B. Johnston

Chronic granulomatous disease. Report on a national registry of 368 patients.

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%).

Characterization of multiple cysteine and cystine transporters in rat alveolar type II cells

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°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 γ-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.

The Phagocytosis-Associated Respiratory Burst in Human Monocytes Is Associated with Increased Uptake of Glutathione

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 γ-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 μM) 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.

Will increasing folic acid in fortified grain products further reduce neural tube defects without causing harm?: consideration of the evidence.

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 μg of folic acid (FA)/100 g of flour. Groups concerned with optimal prevention of NTDs had argued that the level should be 350 μg/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 μg/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.

Increased susceptibility to severe pyogenic infections in patients with an inherited deficiency of the second component of complement

identify what size hernia present at age 5 years or any age is most likely to close. Moreover, the number of children at each age is too small to predict closure rates on a year-by-year basis (Table II). However, the study casts doubt on the teaching that umbilical hernias present at school age are unlikely to close without surgery. Available literature suggests that morbidity in childhood from this condition is minimal. Based on the information now at hand, we see no reason to repair umbilical hernias until near puberty unless there is an episode of incarceration or the hernia is a cause of psychologic disturbance for the child.

American Pediatric Society's 2008 John Howland Award Acceptance Lecture: Life Goals for Academic Pediatrics

American Pediatric Societys 2008 John Howland Award Acceptance Lecture: Life Goals for Academic Pediatrics

Demonstration of Multiple Transporters for Cyst(e)ine Uptake in Type II Pneumocytes. ▴ 2311

Demonstration of Multiple Transporters for Cyst(e)ine Uptake in Type II Pneumocytes. ▴ 2311

Host Defense against Infection in the Newborn

Prof. Richard B. Johnston, Jr., MD, March of Dimes Birth Defects Foundation, National Office, 1275 Mamaronock Avenue, White Plains, N.Y. (USA) It has long been recognized that newborn infants exhibit a predispostion to infection by a variety of microorganisms. Infection remains one of the major threats to the neonate even today. In some cases, infection might be explained by massive exposure to the infecting organism in utero or during the birth process, e.g., syphilis, group B streptococcus, and herpes simplex virus. In general, however, it appears likely that newborn infants carry an undue susceptibility to infection because they cannot mount normal host defense. A large number of studies have been conducted in an attempt to discover specific abnormalities. Many of these have detected subnormal function of various aspects of the newborn’s inflammatory response, yet no single defect can explain why newborns sustain serious infection so commonly. The barrier function of skin and mucous membranes is clearly important in the neonatal period, but the function of antimicrobial peptides such as magainins and defensins has not been described in the human newborn. The maternal dowry of antibodies in the IgG class reflects the mother’s experience with infection except in preterm babies, especially those born at less than about 32-34 weeks of gestation, who start at antibody deficit. The active antibody response by the baby to new polysaccharide antigens is blunted, and the baby lacks memory lymphocytes that expedite a rapid response to familiar microbial products. This problem undoubtedly plays a role in the predisposition of the newborn to bacterial infections, but to date prophylactic infusion of immunoglobulin had not been shown conclusively to reduce the threat of infection. Complement, to other key system involved in opsonization, is clearly deficient in newborns, and the deficiency is more pronounced in pre-term babies. The alternative pathway, which allows complement activation in the absence of specific antibody, is relatively more defective than the classical pathway. Thus, the effect of antibody deficiency is compounded by defective function of the complement system. Newborns generally begin life with normal or increased numbers of circulating phagocytes (neutrophils and monocytes), as well as lymphocytes. However, the reserve supply of