Antibiotics: mechanisms of action.

Medical practice rests on the foundation of science. Clinicians are constantly making practical decisions and dealing with immediate situations that demand solutions. Time should be taken to focus on those scientific principles that underlie our diagnostic and therapeutic maneuvers. This section of Pediatrics in Review presents selected topics that are relevant to practice from the areas of physiology, pharmacology, biochemistry, and other disciplines; clarification of these will augment the pediatrician's understanding of clinical procedures.

Hypoxia-induced sympathetic inhibition of the fetal plasma insulin response to hyperglycemia.

Large-for-delivery date babies, considered characteristic of diabetic pregnancy, are believed to result from fetal hyperinsulinemia. Paradoxically, infant birth weights tend to be low-for-delivery date in mothers with more severe diabetes. We tested the hypothesis that hypoxemia in such fetuses leads to sympathoadrenal stimulation and inhibition of insulin secretion; and, thus, produces a net reduction in the growth-promoting effects. Fetal sheep were prepared with chronic peripheral and adrenal cannulas. Fetal blood gases, lactate, norepinephrine, and epinephrine secretion rates; and plasma norepinephrine, glucose, and immunoreactive insulin concentrations were determined at 30-min intervals during a 2-h baseline period and a 4-h period of hyperglycemia divided into 2-h segments of hypoxemia (with and without alpha-blockade) and hyperoxia. Hypoxemia-hyperoxia sequences were varied randomly. Well-oxygenated fetuses responded to a threefold increase in glucose with a sixfold increase in plasma immunoreactive insulin. With hypoxemia, norepinephrine and epinephrine secretion were elevated and the insulin response was blocked. With hypoxemia and phentolamine blockade, the insulin response was enhanced with a 10-fold increase above baseline. In severe maternal diabetes with vascular disease or with poor control and very high glucose levels, the fetus is likely to be relatively hypoxemic. Our experiments suggest that in this situation, the fetal insulin response to hyperglycemia will be attenuated; this effect is mediated, at least partly, through sympathoadrenal stimulation.

Adrenal corticosteroid secretion in fetal sheep: pulsatile pattern at rest.

This study was undertaken to define the resting pattern of fetal pituitary-adrenocortical function. Experiments were performed at 127-145 days gestation in fetal sheep with chronic peripheral and adrenal cannulas inserted under halothane anesthesia. With the fetus in a baseline state, over 6 h, at 30-min intervals, maternal and fetal peripheral samples were collected for blood gases and cortisol (F), corticosterone (B), and adrenocorticotropic hormone (ACTH) concentrations, and three successive, 2-min adrenal samples were collected for determination of F and B secretion rates. We observed high-frequency, episodic bursts of F secretion. A lower frequency oscillation of F secretion, with a period of approximately 90 min, was defined by cosinor analysis. The mean amplitude of the oscillation increased from 45 to 507 ng/min with advancing gestation. The pattern of B secretion was similar to that for F but was quantitatively lower. An oscillatory period of approximately 90 min for plasma F was present in a majority of experiments. Pulsatile rhythms for ACTH were defined in 10 of 14 experiments, with periods ranging from 1.64 h in the least mature group to 2.37 h in the oldest fetus. Mean data revealed exponential increases in both F secretion and plasma ACTH from 129 to 145 days gestation.

Adrenal secretion of glucocorticoids during hypoxemia in fetal sheep.

This work was undertaken to investigate the fetal adrenal corticoid secretory response to hypoxic stress in late gestation. Experiments were performed in two groups of fetal sheep of different gestational ages, group I, 129-132 (mean, 130) days and group II, 135-139 (mean, 136) days. Fetuses were prepared with chronic adrenal cannulas as well as peripheral arterial and venous catheters. With the fetus at rest and after 7, 9, 11 and, in some instances, 30 and 60 min of hypoxia (maternal FIO2 10%), precisely timed (2 min) samples of adrenal effluent were collected for determination of cortisol (F) and corticosterone (B) secretion rates. Peripheral samples were obtained intermittently for blood gas and lactate determinations. Resting corticoid secretory rates were highly variable, suggesting an episodic secretory pattern. Corticoid secretory responses to hypoxemia were significantly elevated at 7-11 min, peaked at 30 min, and remained stable at 60 min. Specifically, in group I, F secretion increased from a baseline value of 37 +/- 19 ng/min to a peak hypoxemic response of 376 +/- 80 ng/min; B secretion increased from 6 +/- 4 to 170 +/- 32 ng/min. In group II, F secretion increased from 99 +/- 20 to 653 +/- 107 ng/min; B secretion increased from 12 +/- 5 to 200 +/- 28 ng/min. When related to adrenal gland weight, there was no difference between F secretory responses in groups I and II, whereas relative B secretory responses were lower in group II than in group I at 9 and 11 min of hypoxemia. We conclude that the 129-139 day sheep fetal adrenal cortex is highly sensitive to hypoxic stress with the effect presumably mediated by elevated levels of endogenous ACTH. The B stress response decreases as gestational age advances from the 129-132 day range to 135-139 days.

Persistent human immunodeficiency virus type 1 antigenemia in children correlates with disease progression.

In a longitudinal study, human immunodeficiency virus type 1 (HIV-1) antigen (HIV-Ag) was measured in serum specimens from 54 children with HIV-1 infection followed for a median duration of 17 months. The persistent detection of free HIV-Ag in a group of 25 children was associated with clinical deterioration in 22 (88%) and a mortality of 52%, whereas the persistent nondetection of free HIV-Ag in a group of 18 children was associated with clinical deterioration in five (28%) and a mortality of 11% during the period of observation. Nine children had transient HIV-1 antigenemia and two children converted from HIV-Ag negative to positive during the study. Free HIV-Ag levels varied inversely with antibody reactivity to viral core proteins p24 and p17 determined by Western immunoblot, suggesting either the formation of immune complexes or a balance between viral expression and the host immune response. Five mother-infant pairs were studied for HIV-Ag expression in the perinatal period. In three of these pairs, both mother and infant were HIV-Ag negative, in one pair the mother had high levels of HIV-Ag and the infant was HIV-Ag negative. In the remaining mother-infant pair, the neonate became HIV-Ag positive but the mother was HIV-Ag negative prepartum and postpartum. These data suggest that HIV-Ag probably does not cross the placenta and that the detection of free HIV-Ag in the offspring of a HIV-1 infected mother most likely indicates viral infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Cutaneous manifestations of the acquired immunodeficiency syndrome in children.

The acquired immunodeficiency syndrome (AIDS) in children is now known to be a clinical entity separate and distinct from AIDS in adults. In this article we present a review of the recent literature describing the history, definitions, epidemiology, differential diagnosis, and immunologic and clinical features of pediatric AIDS. Special emphasis is placed on the cutaneous manifestations of human immunodeficiency virus infection in children, which, to date, have not been the subject of a comprehensive review.

Expression of human immunodeficiency virus in cerebrospinal fluid of children with progressive encephalopathy.

The retrovirus that causes acquired immune deficiency syndrome (AIDS) is now designated the human immunodeficiency virus (HIV). The cerebrospinal fluid (CSF) of 27 children with HIV infection was assayed for intra-blood-brain barrier (IBBB) synthesis of HIV-specific antibodies and for the presence of HIV antigen. In this cohort, 11 children had a progressive encephalopathy (PE), 9 had a static encephalopathy (SE), and 7 had normal neurological findings (N). IBBB synthesis of HIV-specific antibodies was identified (using matched serum and CSF specimens) in 7 of 11 children with PE, 4 of 9 children with SE, and 2 of 7 children with N. HIV antigen was found (using a highly sensitive solid-phase enzyme immunoassay) in the CSF of 8 of 11 children with PE, none of the children with SE, and none of the 7 children with N. On the basis of these data, we conclude that: IBBB synthesis of HIV antibodies indicates invasion of the central nervous system but may reflect prior or current infection; and HIV antigen in CSF indicates viral expression and correlates with the occurrence of PE. These findings strongly implicate HIV as the causative agent of PE in these children. The assay for HIV antigen in the CSF may be of value in determining the prognosis of children with HIV infection and for evaluating the efficacy of therapeutic agents against this retrovirus.