Studies on levamisole--induced agranulocytosis

Widespread clinical trials of leavo-tetramisole (levamisole) as an immunopotentiating agent in rheumatoid arthritis, metastatic carcinoma, and immunodeficiency states have been complicated by agranulocytosis (AGC) in 2.5%-13% of patients. Other than a relationship with prolonged high dosage, very little is known regarding the pathogenesis of levamisole-induced AGC. Whereas leukoagglutination was negative, fluorochromatic microgranulocytotoxicity (GCY) tests were positive with serum from 10 of 10 acutely neutropenic patients. The antibody was IgM, reacted with 100% of unrelated granulocytes, but not with T or B lymphocytes. Some sera also reacted with monocytes and the myeloid cell line, K-562. Tests for antigen-antibody complexes or cold autoantibodies were negative. Although clinical evidence strongly suggests a haptene (drug) mechanism, in vitro mixing experiments were also negative. An alternative choice parallels the model of aldomet- induced Coombs'-positive hemolytic anemia. Finally, GCY first became positive 2-3 mo prior to the onset of AGC on two patients, suggesting the possibility of identifying those at risk well before the onset of neutropenia.     

Role of metallothionein in nitric oxide signaling as revealed by a green fluorescent fusion protein

Although the function of metallothionein (MT), a 6- to 7-kDa cysteine-rich metal binding protein, remains unclear, it has been suggested from in vitro studies that MT is an important component of intracellular redox signaling, including being a target for nitric oxide (NO). To directly study the interaction between MT and NO in live cells, we generated a fusion protein consisting of MT sandwiched between two mutant green fluorescent proteins (GFPs). In vitro studies with this chimera (FRET-MT) demonstrate that fluorescent resonance energy transfer (FRET) can be used to follow conformational changes indicative of metal release from MT. Imaging experiments with live endothelial cells show that agents that increase cytoplasmic Ca(2+) act via endogenously generated NO to rapidly and persistently release metal from MT. A role for this interaction in intact tissue is supported by the finding that the myogenic reflex of mesenteric arteries is absent in MT knockout mice (MT(-/-)) unless endogenous NO synthesis is blocked. These results are the first application of intramolecular green fluorescent protein (GFP)-based FRET in a native protein and demonstrate the utility of FRET-MT as an intracellular surrogate indicator of NO production. In addition, an important role of metal thiolate clusters of MT in NO signaling in vascular tissue is revealed.     

Abnormal surfactant composition and activity in severe bronchiolitis

A prospective study of infants under 1 y of age, ventilated for severe viral bronchiolitis, was carried out in four paediatric intensive care units in order to study surfactant activity and composition in this condition. Lung lavage fluid from 24 infants with bronchiolitis, 19 with bronchiolitis and sepsis or cardiac failure and 12 controls were analysed by the “click test” for surfactant activity and for phospholipids. Surfactant activity was present in all controls, but in only 2 of the 24 infants with bronchiolitis alone. The presence of phosphatidylglycerol correlated perfectly with the click test, suggesting that reduced activity is due to changes in surfactant lipid composition. In those with bronchiolitis plus coexisting disease, surfactant activity and phosphatidylglycerol were absent in only half. Surfactant activity and phosphatidylglycerol re-appeared by extubation. Severe viral bronchiolitis is associated with an absence of surfactant activity and PG, which resolves by clinical recovery. Infants with coexisting conditions are not always surfactant deficient. Surfactant administration is likely to be beneficial, but requires a selective approach.     

Changing mortality and causes of death in infants 23–27 weeks' gestational age

OBJECTIVE: To contrast the mortality rates and changes in the causes of death of very preterm infants (23-27 weeks), before and after the introduction of exogenous surfactant in 1991, and to identify any preventable causes of death remaining in the 1990s. METHODOLOGY: This was a cohort study on consecutive preterm infants of 23-27 weeks' gestational age born in the Royal Women's Hospital, Melbourne, a level III perinatal centre. The infants were livebirths free of lethal anomalies from two distinct eras, 1983-90, and 1992-96, inclusive. The main outcome measures were mortality during the primary hospitalization and the causes of death before and after the introduction of exogenous surfactant in 1991. RESULTS: In 1983-90, 261 of 508 livebirths (51.4%) of 23-27 weeks' gestational age died, a significantly higher proportion than the 109 of 384 (28.4%) livebirths who died in the period 1992-96. The mortality rate fell significantly with increasing gestational age and was lower at each week of gestational age in 1992-96. More infants who died in 1992-96 were treated intensively in the neonatal intensive care unit (NICU). Of the group of infants who died or who were treated intensively in NICU, respiratory causes of death predominated. However, the causes of death changed over time. In 1992-96 proportionally fewer infants died from respiratory causes (1983-90, 82.5%; 1992-96, 60.0%; odds ratio (OR) 0.31, 95%; confidence interval (CI) 0.16-0.57), but more from septic causes (1983-90, 14.3%; 1992-96, 43.8%; OR 4.9, 95%; CI 2.6-9.2). CONCLUSIONS: As the mortality rate has fallen over time, respiratory causes of death have diminished, but septic causes of death have increased. Further advances in the use of exogenous surfactant and respiratory support may reduce respiratory deaths. Effective strategies to reduce nosocomial infections are urgently required.     

Knowledge and attitudes toward breast-feeding: Differences among dietitians, nurses, and physicians working with WIC clients

We assessed the knowledge of and attitude toward breast-feeding of dietitians, nurses, and physicians who work with individuals in the Alabama Special Supplemental Food Program for Women, Infants, and Children. On a scale of 0 to 100, dietitians expressed stronger interest in lactation (78.6) and exhibited greater knowledge (79.6) of the questions asked than nurses (74.5 and 73.0, respectively). Attitude and knowledge scores of physicians (70.2 and 75.5, respectively) were not statistically different from those of dietitians or nurses. Respondents disagreed greatly about the relationship of breast-feeding to weight loss and the appropriateness of oral contraceptive during breast-feeding 6 weeks postpartum. Professionals were more knowledgeable about benefits to infants than about maternal concerns. Results of this study suggest that professional breast-feeding education programs should address maternal concerns such as weight loss, contraception, and mastitis as well as benefits to the infant.     

Coexistence of Incontinentia Pigmenti and Neonatal Herpes Simplex Virus Infection

Abstract: We present a female infant with classic clinical and histologic features of stage I incontinentia pigmenti with coexistent neonatal herpes simplex virus infection. The diagnosis of a heritable cutaneous condition does not exclude the possibility of a coexistent infection and, given the similar clinical presentation of neonatal vesicular eruptions, accurate diagnoses may require skin biopsy and culture.