Down-regulation of hypothalamic corticotropin-releasing hormone messenger ribonucleic acid (mRNA) precedes early-life experience-induced changes in hippocampal glucocorticoid receptor mRNA.

Early-life experiences, including maternal interaction, profoundly influence hormonal stress responses during adulthood. In rats, daily handling during a critical neonatal period leads to a significant and permanent modulation of key molecules that govern hormonal secretion in response to stress. Thus, hippocampal glucocorticoid receptor (GR) expression is increased, whereas hypothalamic CRH-messenger RNA (mRNA) levels and stress-induced glucocorticoid release are reduced in adult rats handled early in life. Recent studies have highlighted the role of augmented maternal sensory input to handled rats as a key determinant of these changes. However, the molecular mechanisms, and particularly the critical, early events leading from enhanced sensory experience to long-lasting modulation of GR and CRH gene expression, remain largely unresolved. To elucidate the critical primary genes governing this molecular cascade, we determined the sequence of changes in GR-mRNA levels and in hypothalamic and amygdala CRH-mRNA expression at three developmental ages, and the temporal relationship between each of these changes and the emergence of reduced hormonal stress-responses. Down-regulation of hypothalamic CRH-mRNA levels in daily-handled rats was evident already by postnatal day 9, and was sustained through postnatal days 23 and 45, i.e. beyond puberty. In contrast, handling-related up-regulation of hippocampal GR-mRNA expression emerged subsequent to the 23rd postnatal day, i.e. much later than changes in hypothalamic CRH expression. The hormonal stress response of handled rats was reduced starting before postnatal day 23. These findings indicate that early, rapid, and persistent changes of hypothalamic CRH gene expression may play a critical role in the mechanism(s) by which early-life experience influences the hormonal stress-response long-term.

Pulmonary function and bronchial hyperreactivity in long-term survivors of bronchopulmonary dysplasia.

Nine children with bronchopulmonary dysplasia were studied at a mean age of 8.4 years. Persistent respiratory symptoms were common. Pulmonary function tests demonstrated airway obstruction and abnormal blood gas levels in most. In six of eight children results of methacholine challenge tests were positive, indicating bronchial hyperreactivity. Abnormal chest radiographs persisted in eight children. The bronchial hyperreactivity is a likely consequence of airway damage in infancy and is the probable reason for episodic wheezing in the early years of life. Improvement in expiratory flow rates following bronchodilator inhalation suggests that such therapy may improve function in these children.

Leukotrienes (LTC4, LTD4) confer glass non-adherence on leukocytes of asthmatic individuals. Dependency on cyclooxygenase products and calcium ion.

It has been suggested that cysteinyl-containing leukotrienes (LT) are important mediators in bronchial asthma. Since leukotrienes have been shown to mediate the leukocyte adherence inhibition (LAI) phenomenon observed in cancer-bearing host we have devised a modified LAI assay which determines the acquisition of non-adherence properties of leukocytes following a challenge with pure synthetic LT. Our results demonstrate that peripheral blood leukocytes of asthmatic individuals acquire non-adherence properties when challenged with pure synthetic leukotriene C4 and D4, a property not shared by peripheral blood leukocytes of control healthy individuals. Furthermore, we demonstrate that LT activity as manifested by the LAI assay is dependent on cyclooxygenase products, since 2 X 10(-6) M Indomethacin abrogated the LT-induced LAI and is restored by the addition of 2 X 10(-6) M prostaglandin E2 which is also synergistic to LT activity. Our results further suggest the possibility that leukotriene activity is dependent on calcium ions since it was negated by known calcium antagonists. It is thus suggested that the LT-induced LAI may serve as a tool for the study of the interrelationship between the metabolic pathways of arachidonic acid and calcium ion homeostasis.

Cough capacity in patients with muscular dystrophy.

Cough capacity was evaluated in 22 patients with muscular dystrophy (MD) using subjective cough assessment, cough flow-volume curves, maximum expiratory pressures (MEP), forced vital capacity (FVC), and peak expiratory flow rates (PEFR). In ten of the 22 patients transients of peak flow were generated during cough flow-volume maneuvers, indicating dynamic compression of the airways, which is considered important in the physiology of an efficient cough. Patients who could not generate peak flow transients had significantly reduced PEFR, FVC, and MEP values. Measurement of MEP was the most sensitive predictor of flow transient production during coughing; all of the patients who exhibited transients had MEP values of above 60 cmH2O, whereas the highest value of MEP recorded in patients without transients was 45 cmH2O. Three of the 12 patients who were unable to generate flow transients were considered to have an adequate cough by subjective assessment. We concluded that the measurement of MEP is extremely useful for assessment of cough strength in patients with MD.

Superoxide production during refeeding in patients with anorexia nervosa.

The effect of undernutrition and refeeding on superoxide production by polymorphonuclear cells (PMN) was studied in 11 girls suffering from anorexia nervosa (AN) and 17 age-matched, normal, healthy, control subjects. Superoxide anion production by PMNs from undernourished AN patients was comparable to normal, while a significant decrease in this function was observed during the initial period of refeeding. After a more extended period of refeeding, superoxide production by PMNs from AN patients increased and gradually returned toward normal values. Superoxide production correlated with length of the refeeding period (RF), weight as a percentage of ideal weight for height (W/H%), and rate of weight gain (WG). These results imply that a variety of physiological parameters, including susceptibility to infection, may be altered by refeeding undernourished patients.

Increased neutrophil chemiluminescence production in patients with cystic fibrosis.

Increased free radical production has been suggested as a possible mechanism involved in lung deterioration of patients with cystic fibrosis (CF). Vitamins A and E are known to be involved in the defense mechanism preventing damage caused by free radicals. Both vitamins are fat-soluble and are therefore malabsorbed in patients with CF. We hypothesized that low concentrations of vitamins A and E may be involved in the increased free radical production of these patients. Neutrophils' chemiluminescence and superoxide and hydrogen peroxide production were examined in 11 patients with CF aged 4 to 14 years, and 10 age-matched healthy controls. All our patients were on prolonged supplementation with vitamins A and E, but the control group was not supplemented. Serum vitamins A and E levels and neutrophil vitamin E concentrations were examined concomitantly. Chemiluminescence production was increased 10 minutes after neutrophil stimulation by phorbol myristate acetate (PMA) as compared with that in normals (20,400 +/- 9,463 v 11,990 +/- 3,778 cpm, P < .03). No difference was found in superoxide or hydrogen peroxide production between CF patients and controls. Serum vitamin A levels were significantly higher in CF patients compared with healthy controls (0.641 +/- 0.049 v 0.398 +/- 0.038 mg/L, P < .04) and so were vitamin E levels (13.94 +/- 2.25 v 5.64 +/- 1.15 mg/L, P < .05). Neutrophil vitamin E concentrations were higher in CF patients compared with healthy controls (70.8 +/- 26.0 v 23.6 +/- 9.0 micrograms/10(6) cells). We conclude that neutrophils from CF patients exhibit increased chemiluminescence activity not related to increased free radical production or fat-soluble vitamin deficiency.

Role of neutrophil elastase in allergen-induced lysozyme secretion in the dog trachea.

To test our hypothesis that neutrophil elastase plays a role in airway hypersecretion associated with the allergic late-phase response, using an isolated tracheal segment system in vivo and measuring lysozyme activity in the perfusate of the lumen as a marker of submucosal gland secretion over 8 h, we studied the response of five allergic dogs to ragweed. The dogs were exposed on separate occasions to specific allergen, to allergen vehicle, and to allergen in the presence of a selective neutrophil elastase inhibitor, ICI 200,355. Allergen exposure caused a marked increase in lysozyme secretion that was significantly increased at 4, 6, and 8 h compared with controls and ICI 200,355-treated dogs. Neutrophil elastase appeared in the perfusate after allergen exposure and was positively correlated with lysozyme secretion at 8 h. These findings suggest that neutrophil elastase plays an important role as a secretagogue in the allergic late-phase response.

Differential regulation of glucocorticoid receptor messenger RNA (GR-mRNA) by maternal deprivation in immature rat hypothalamus and limbic regions.

Maternal deprivation (MDep) of neonatal rats significantly influences the hypothalamic-pituitary-adrenal (HPA) axis. This study hypothesized that GR-mRNA modulation constituted an early, critical mechanism for the acute effects of MDep on neuroendocrine stress-responses. GR-mRNA hybridization signal in hippocampal CA1, hypothalamic paraventricular nucleus (PVN) and frontal cortex was significantly reduced immediately following 24 h MDep. In amygdala, cingulate cortex, PVN and CA1, apparent gender-dependent MDep effects on GR-mRNA expression were observed, without significant differences in absolute levels. Thus, rapid, region-specific MDep effects on GR-mRNA expression in HPA-regulating areas are shown, consistent with involvement of GR-expression in mechanisms of MDep influence on HPA tone.

Normal values of maximal inspiratory and expiratory pressures with a portable apparatus in children, adolescents, and young adults.

Maximal inspiratory and expiratory mouth pressures (Plmax and PEmax) were measured over a wide age range using a cylindrical mouthpiece and a multiple trial procedure. Two hundred forty-three students and 30 adults were studied. In addition, a comparison of a cylindrical and a scuba-type mouthpiece was made in 16 subjects. Fifty percent of the subjects required five or more trials to achieve their maximal mouth pressures. Higher PEmax values were obtained using a cylindrical mouthpiece than with a scuba-type mouthpiece in 15 of the 16 subjects tested. Plmax was not affected by mouthpiece type. Males had higher Plmax and PEmax values than females except in the 8-10 years age group. Maximal mouth pressures correlated with age in boys only. Technical considerations, such as the number of trials and the type of mouthpiece used, are important determinants of maximal mouth pressure values.

Allergen-induced leukotriene production by nasal mucosa and peripheral blood leukocytes.

The relationship between release of leukotriene C4 (LTC4) from nasal mucosa in vivo and from peripheral blood leukocytes (PBLs) in vitro was examined in 18 patients with untreated rhinitis allergic to the house dust mite, Dermatophagoides pteronyssinus, and in 20 nonallergic control subjects following challenge with the specific allergen. Allergic patients were subjected to intranasal and PBL challenge with D pteronyssinus and a nonrelevant allergen, Artemisia vulgaris. In all allergic patients, intranasal challenge by D pteronyssinus, but not by A vulgaris, resulted in a release of substances from the nasal mucosa that reacted in a radioimmunoassay with antiserum to LTC4. Dermatophagoides pteronyssinus challenge in vitro of PBLs from the same patients, but not A vulgaris challenge, induced release of the same immunoreactive material into the supernatant. By comparison, the nonallergic subjects challenged with D pteronyssinus showed significantly lower LTC4 levels in their nasal secretions and PBL supernatants. The results show that, following specific allergen challenge, the release of LTC4 by the allergic nasal mucosa is similar in extent and nature to that of PBLs, indicating that these procedures can be used as tools to measure the efficacy of topically and systemically administered antiallergic drugs.

Once-daily intramuscular ceftriaxone in the outpatient treatment of severe community-acquired pneumonia in children.

Ceftriaxone, a broad spectrum third-generation cephalosporin with a half-life of six to eight hours, was evaluated prospectively in 147 children with severe community-acquired bacterial pneumonia during the period 11/15/88-5/15/89. Thirty-nine of the children had been unsuccessfully treated with vanous oral antibiotics prior to admission [corrected]. All the patients were initially hospitalized and started on once a day intramuscular ceftriaxone. Mean duration of ceftriaxone therapy was five days. Pathogens were recovered from blood cultures of 17 (11.6%) patients and included S. pneumoniae (13 patients), H. influenzae (three, all resistant to ampicillin) and S. viridans (1) [corrected]. All isolates were sensitive to ceftriaxone. An additional patient had L. pneumophila diagnosed by serology. Cure was achieved in 142 (96.6%) patients; improvement was usually observed within 24-48 hours. After 48 hours, 121 (82.2%) children could be discharged and continued the therapy on ambulatory basis. Based on previous experience we estimated that 383 hospitalization days were saved. No serious side effects were observed. Five patients were considered therapeutic failures; two of them developed empyema and one of them required repeated drainage procedures. A third patient experienced a relapse of pneumonia shortly after completion of therapy. The other two remained febrile for more than seven days; their subsequent improvement was unrelated to the antibiotic therapy, suggesting a viral or mycoplasmal syndrome. Our data suggest that once daily intramuscular ceftriaxone can be successfully used for the outpatient treatment of most community-acquired severe bacterial pneumonias in children. In our opinion it represents the treatment of choice for patients who failed treatment with other antimicrobials and are clinically stable enough not to require hospitalization.

Cellular immunity and suppressor T cell function in asthmatic children on prolonged theophylline therapy.

Measurements of cellular immunity including the percentage of T-cell mitogenic response of lymphocytes to phytohemagglutinin (PHA) and concanavalin A (Con A), as well as Con A-induced suppressor function, were determined in 20 asthmatic children (mean age 12.4 +/- 0.6 years) before and after 6 months of theophylline therapy. Only 9 of the 20 children patients that commenced the study completed the entire 6 months of therapy. A group of 37 healthy children (mean age 12.6 +/- 0.3 years) served as control. During the 6-month period of therapy, theophylline levels were maintained between 10 and 20 micrograms%. No significant difference in any of the parameters examined were found between the initial 20 asthmatic patients and the control group. Furthermore, in the 9 patients that were evaluated before and after 6 months of theophylline therapy no significant change in lymphocyte function including suppressor function was detected. We conclude that the beneficial effect of long-term theophylline therapy in asthmatic children is probably not related to an immuno-modulatory effect.

Postgraduate course presentation. Infantile bronchial asthma.

There is no evidence that any type of therapy, including hyposensitization therapy, will directly influence prognosis. The long-term prognosis of childhood asthma is less optimistic than previously believed. Approximately 30% of the patients who become symptom-free in adolescence relapse and become symptomatic in early adulthood. Blair's recent 20-yr follow-up report on 267 childhood asthmatics revealed that only 50% had become almost or completely symptom-free. Moreover, there is evidence that 60% of those who become symptom-free still demonstrate bronchial hyperreactivity and are liable to wheeze again if challenged with an appropriate stimuli. Therefore, the dictum that most children "outgrow" their asthma is incorrect and a more likely explanation is that most childhood asthmatics "outgrow" their pediatricians.

Short-chain fatty acid absorption in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) often exhibit malabsorption despite the use of supplemental pancreatic enzymes. Unabsorbed carbohydrates and amino acids can serve as substrates for large intestine anaerobic fermentation, thus increasing excretion of short-chain fatty acids (SCFA) in the feces. Nine patients with CF on regular pancreatic enzyme supplementations in the age range of 5-11 years and one older patient were studied. Three-day stool samples were collected, as were 72-h food records. Stools were analyzed for gross energy, total nitrogen, fat content, and SCFA concentration. A significant difference was found between CF and normal controls in total caloric excretion due to fat malabsorption. No significant difference was found between CF and normal controls in protein or SCFA excretion. Fat excretion as percentage of fat intake was significantly increased in CF patients: 35.3 +/- 10.2% versus 8.0 +/- 3.0%, respectively. These data suggest that carbohydrate supplementation could be more widely used to increase caloric intake in CF patients without causing secondary osmotic diarrhea.

Myeloproliferative disease of childhood associated with a trisomy 21 clone.

Myeloproliferative disease of childhood is frequently associated with chromosomal anomalies, usually of the C group. Clinical features are similar to those of the juvenile type of chronic myeloid leukemia. A child with this disease is described. Marked myeloid proliferation, anemia, thrombocytopenia and hepatosplenomegaly were present; leukocyte alkaline phosphatase and fetal hemoglobin were moderately elevated. Chromosome analysis of bone marrow cells revealed a mosaicism 47,XX,+21/46,XX. Down's syndrome was ruled out by the child's normal phenotype and dermatoglyphic analysis. The cytogenetic finding is probably evidence for the clonal origin of the trisomy 21 cell line.

Thrombus in the left ventricle of a child with systemic emboli: an unusual presentation of hereditary protein C deficiency.

We present a case of left ventricular thrombus in a child with a normal functioning left ventricle. The diagnosis was made by 2-dimensional echocardiography after 2 episodes of systemic emboli. Hereditary protein C deficiency diagnosed in the patient provides the probable pathogenesis of the thrombus formation. Systemic emboli necessitates cardiac examination, and in cases of unusual thrombi, hereditary or acquired thrombophilic risk factors should be considered.

Impaired brainstem auditory evoked potentials in patients with cystic fibrosis.

Brainstem auditory evoked potentials (BAEPs) were measured in 11 young patients with cystic fibrosis (CF). Though none had clinical evidence of neurological impairment, all had various abnormal components of brainstem auditory evoked potentials (BAEPs). Abnormal BAEPs may be attributed to nutritional deficiencies including deficiencies of vitamins E and B6. As patients with CF are often deficient in vitamin E despite daily supplementation and normal serum levels, the authors suggest that the abnormal BAEPs demonstrated in the present study may reflect prolonged intracellular vitamin E deficiency. This finding suggests that BAEP studies may be useful in the neurological evaluation of patients with CF.

Measurement of ventilation in children using the respiratory inductive plethysmograph.

A new technique to measure ventilation, based on the separate contributions of rib cage and abdomen to tidal volume, the respiratory inductive plethysmograph was evaluated in 20 healthy children. The accuracy of the method was determined by simultaneously measuring tidal volume with a pneumotachograph in the standing, sitting, supine, left lateral decubitus, and prone postures. Comparison of these two techniques showed mean correlation coefficients greater than 0.96, mean slopes between 0.98 and 1.11, and mean SEE of less than 8% in all postures studied. Breathing through a mouthpiece connected to a pneumotachograph resulted in a substantial change in the pattern of breathing and a mean increase in tidal volume of 32% (P less than 0.05). In the standing and sitting postures, rib cage contribution to tidal volume was predominant (greater than 65%) whereas in the recumbent postures abdominal contribution was predominant (greater than 61%). We conclude that the RIP is an accurate means of measuring ventilation in children and that it avoids the artifacts caused by using a conventional respiratory measuring apparatus.

Erythrocyte glutathione peroxidase activity in asthmatic children.

Erythrocyte glutathione peroxidase (GPX) levels were determined in 56 asthmatic children. Lowest levels were found during acute asthmatic attack (13.53 +/- 2.94 IU) which were significantly less than controls (20.4 +/- 5.44 IU) (P less than .001). Post-attack levels 1 week later rose significantly (16.77 +/- 2.63 IU), but were still less than normal values (P = .001). GPX levels (16.96 +/- 3.28 IU) were less than controls (P less than .03) even in patients with mild symptomatology. Asymptomatic patients receiving theophylline had normal levels. Low GPX activity in asthmatic patients may play a role in the pathogenesis of the disease.