摘要:

Fluid secretion from the pulmonary epithelium may play a significant role in determining intrauterine lung development. We used suspensions of distal pulmonary epithelial cells isolated from rat fetuses to assess a shift in secretory mechanisms occurring in the lung of this species during late gestation. The impact of cAMP on distal airway epithelial cells isolated from d 18 to d 21 rat fetuses was evaluated with measurements of cell volume and36Cl efflux rates. At d 18, 8-Br-cAMP stimulated a volume reduction measured by electronic cell sizing that was prevented by the Cl−channel blocker anthracene-9-carboxylate (A-9C) and reflected in an increased rate of A-9C sensitive36Cl efflux. Because the cystic fibrosis trans-membrane conductance regulator (CFTR) is thought to be a cAMP-regulated Cl−channel, we measured the effect of prior cell incubation with oligodeoxynucleotides antisense to the transcription site of the human CFTR gene on these events. We found that in antisense oligomer-treated cells, but not in sense oligomer-treated controls, volume and36Cl efflux responses to 8-Br-cAMP were prevented in d 18 cells. In d 21 cells, 8-Br-cAMP did not stimulate volume reduction but the calcium ionophore A23187 did elicit cell volume reduction in cells suspended in an isotonic Ca2+-containing medium that was prevented by A-9C. This response to the ionophore was not found in the d 18 cells, and incubation with the antisense CFTR oligomer had no effect on the ionophore-induced responses in d 21 cells. Our results suggest that CFTR mediates cAMP-stimulated Cl−conductance in d 18 rat fetal distal pulmonary epithelial cells. Furthermore, during fetal growth between d 18 and 21 there is a reciprocal pattern whereby Ca2+-activated Cl−conductance appears whereas CFTR disappears in the distal pulmonary epithelium.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Cerebral blood flow velocity was recorded for an average of 23 4-min epochs during natural sleep in 11 normal full-term newborn babies. Intracranial pressure, core temperature, and respiration were simultaneously and non-invasively monitored. Sleep state was classified using information from EEG, pattern of respiration, and eye and body movements by a trained observer. From a total of 238 epochs, 66 were considered to occur in quiet sleep, 101 in active sleep, and in 77 the baby was awake, in a transitional state or moving excessively. Slow cyclical variations in cerebral blood flow velocity were observed with a frequency of between 2 and 6 cycles/min, and these were of significantly greater amplitude during quiet sleep (24%) compared to active sleep (16%;p< 0.0001, Mann Whitney U test). There was no difference in median cerebral blood flow velocity (7.5 cm/s). The cyclical variation observed in normal babies were similar to those described in preterm babies and adults, at a similar frequency to B waves in intracranial pressure. They may represent vasomotor waves in the small autoregulatory arteries of the brain. Reduction in sensitivity of the receptors initiating the waves may occur in active sleep or there may be competition from other oscillatory mechanisms.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We have previously demonstrated that vagal phase-response curves (PRC), which characterize the effects of critically timed, brief vagal stimuli on sinus node automaticity, exhibit a fundamentally different shape in the canine newborn than in the adult. In this study we analyzed the changes in sinus cycle length in response to critically timed, brief vagal stimuli, delivered to the decentralized cervical right and left vagosympathetic trunks, in two older age groups: 14 1-mo-old puppies (ages 21–36 d), and eight 2-mo-old puppies (ages 56–62 d). Vagal PRC were constructed by plotting the magnitude (percent change) of the vagal chronotropic response as a function of the phase of the cardiac cycle at which the vagus nerve was stimulated. At 1 mo of age adult-type PRC were observed, but in only six of the puppies (43%) and only in response to right vagal stimulation. By 2 mo of age adult-type PRC were observed in seven of eight puppies (88%) in response to right vagal stimulation and in three of eight (38%) in response to left vagal stimulation. Thus, clear developmental changes in the phase dependence of the vagal chronotropic response can be tracked over the first 2 mo of life in the dog.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We evaluated the effects ofEscherichia coliendotoxin on the peripheral vascular hemodynamics and myocardial function of the newborn lamb to understand how gram-negative endotoxemia can lead to cardiovascular collapse in newborn infants. Fifteen lambs, 0–3 d old, were acutely instrumented with a micromanometer-tipped catheter and two pairs of ultrasonic crystals to measure left ventricular (LV) pressure and LV anterior-posterior and septal-free wall dimensions, a fluid-filled catheter for monitoring aortic pressure, and an electromagnetic flow probe to measure systemic blood flow. Cardiovascular performance was evaluated by measuring or deriving the following variables: mean arterial blood pressure (MABP), LV pressure, heart rate, stroke volume, systemic vascular resistance, LV dp/dt, end-diastolic area, arterial elastance, and end-systolic elastance (the slope of the end-systolic pressure-area relationship) as an index of contractility independent of loading conditions and heart rate. Once instrumented, nine lambs received endotoxin, 0.5 mg/kg i.v., and six animals, serving as controls, received a saline infusion. Of the endotoxin-treated lambs, five survived the duration of the study (120 min from the beginning of the endotoxin infusion), and four died by 90 min from the beginning of the endotoxin infusion. No significant changes in any of the cardiovascular variables occurred in the control group. A significant decrease in MABP was seen in all endotoxin-treated animals by 45 min after the beginning of the endotoxin infusion. MABP decreased by 52% from baseline in the survivors and 38% in the nonsurvivors. In the survivors, the MABP stabilized with saline boluses, whereas in the nonsurvivors MABP continued to decrease until death. In the survivors, end-systolic elastance remained stable, and, despite changes in afterload, LV dp/dt also remained stable throughout the study. In the nonsurvivors, the end-systolic elastance and LV dp/dt exhibited a progressive decline until death, with the changes in the end-systolic elastance preceding the changes in LV dp/dt. End-diastolic area and stroke volume remained stable during the study in both groups of endotoxin-treated animals, decreasing in the nonsurvivors just before death. Because the changes in end-systolic elastance and LV dp/dt clearly preceded the decreases in end-diastolic area and stroke volume in the nonsurvivors, we conclude that the myocardial depression in the nonsurvivors was primarily due to depressed myocardial contractility, not decreased preload.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Because the expression of IgG Fc receptors and complement receptors on macrophages may vary in a tissue-specific manner, we used monoclonal antibodies and flow cytometry to define the expression and function of opsonin receptors on fresh normal and cystic fibrosis (CF) bronchoalveolar lavage (BAL) macrophages. Using flow cytometry to separately analyze individual types of cells, we then determined the relative contributions of IgG and complement to phagocytosis ofPseudomonas aeruginosaby fresh BAL cells, avoiding alterations in receptor expression due toin vitropurification or culturing techniques. Neither normal nor CF BAL macrophages express appreciable amounts of the complement receptors CRI, CR2, or CR3. These results were confirmed by immunohistochemical staining of fixed lung sections. BAL macrophages express a high-affinity IgG receptor, Fc γRI, that is not found on neutrophils (PMN). In contrast, chemoattractant-stimulated blood PMN express large amounts of CR1 and CR3 but do not express Fc γRI. These results correlate with phagocytosis assays, which show that phagocytosis by macrophages is enhanced by relatively low concentrations of IgG but that the addition of complement does not further increase their phagocytosis. In contrast, low concentrations of IgG alone do not promote phagocytosis by PMN, whereas addition of complement markedly enhances phagocytosis by PMN. These results may explain the previously reported sensitivity of macrophages rather than PMN to the “blocking” effects ofanti-Pseudomonasantibodies from CF patients, and emphasize the pathologic significance of interference with IgG and complement mediated opsonization in the lung in CF.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Current guidelines for heparin therapy in pediatric patients have been extrapolated from trials in adult patients without rigorous evaluation of efficacy and safety. We prospectively monitored consecutive pediatric patients receiving systemic doses of heparin over 10 mo at one institution using a predetermined nomogram to monitor maintenance therapy. Sixty-five consecutive children; 38 males and 27 females, received systemic doses of heparin. Thirty children had deep venous thrombosis and/or pulmonary embolism; 11 had arterial thrombi, most frequently after diagnostic angiography; and the remaining 24 received heparin prophylactically, for congenital heart disease. Twenty-nine (45%) of the 65 patients were less than 1 y of age and 22 (34%) were 10 y or older. Congenital heart disease was the predominant diagnosis under 1 y and deep venous thrombosis in older children. After a bolus dose of 50 U/kg, 39% of children (n= 30) achieved a minimal level activated partial thromboplastin time (APTT). Sixty-eight percent of children achieved a minimal level APTT by 24 h and 81% by 48 h. For all 65 children, APTT values were within the therapeutic range 43% of the time. APTT values outside the therapeutic range were twice as likely to be low as high. The average amount of heparin required to maintain therapeutic APTT values for children was 22 U/kg/h: 28 U/kg/h for infants <1 y and 20 U/kg/h for the rest. Bleeding was rare (2%) and mild. Documented recurrent thrombotic disease was more common (7%) with associated morbidity. In summary, a commonly used protocol for administration of heparin to children was rigorously evaluated and shown to provide insufficient amounts of heparin in the first days of treatment. Average requirements of heparin per kilogram per hour were determined and will form the bases of future studies.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Children with glycogen storage disease (GSD) type 1b are susceptible to recurrent bacterial infections and have chronic neutropenia accompanied by phagocytic cell dysfunction including decreased superoxide anion (O2−) generation, calcium (Ca2+) mobilization, and chemotactic activity. Granulocyte colony-stimulating factor (G-CSF), a cytokine that corrects neutropenia in other diseases,in vitroenhances f-Met-Leu-Phe-triggered neutrophil O2−generation. Short-term pretreatment (15 min) of GSD 1b neutrophils with G-CSF increased the rate of O2−production (p< 0.01); however, this rate was still significantly below the rate of O2−production in control neutrophils. Recombinant human G-CSF (5 μg/kg/d) was administered s.c. to a GSD 1b patient. Before treatment, absolute neutrophil counts were < 500/mm3. Two d after G-CSF administration, the absolute neutrophil counts increased to 1333 and remained in the normal range during a 12-mo follow-up period.In vivo, G-CSF therapy increased f-Met-Leu-Phe-stimulated O2−production to 52% of control after 1 mo, and by mo 4, O2−production reached control levels. Our previous studies (J Clin Invest 56:196–202, 1990) demonstrated that decreased O2−production in neutrophils was associated with impaired Ca2+mobilization.In vivoadministration of G-CSF increased f-Met-Leu-Phe-triggered Ca2+mobilization by neutrophils to 43% of control by mo 1 of G-CSF therapy and to 93% of control by mo 4, thus paralleling the improvements in O2−generation. In contrast, G-CSF therapy had no effect on the defective neutrophil chemotaxis. In summary, G-CSF therapy produced a rapid increase in circulating neutrophils and a gradual correction of O2−production. Long-term exposure to G-CSF may be required for correction of both neutropenia and O2−production in GSD 1b patients.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We studied the effect of iopanoic acid (IOP), an iodinated contrast medium, on iodothyronine 5′-deio-dinase (5'D) and nuclear T3 content (nT3) in fetal tissues. In 18− and 20 day-old fetuses from control dams, nT3was higher in interscapular brown adipose tissue (IBAT, 69 ± 5 and 281 ± 8 fmol/mg of DNA) than in brain (16 ± 2 and 42 ± 3 fmol/mg of DNA) or liver (5.6 ± 1 and 27 ± 2 fmol/mg of DNA). IOP administration (10 mg, twice daily) to pregnant rats on days 18 and 19 postconception significantly blocked 5'D activity in fetal IBAT and brain at day 20. Liver 5'D was not affected. The rise in nT3was not modified by IOP treatment in IBAT, but it was enhanced in brain and liver of IOP-treated fetuses on day 20. In contrast, in adult rats, IOP treatment reduced IBAT nT3. Prolongation of IOP treatment until day 21 decreased fetal body weight on day 22 and inhibited IBAT 5'D. No change was produced in mitochondrial oxidative capacity, the subunit II of cytochrome oxidase, or uncoupling protein mRNA expression in IBAT from IOP-treated fetuses. Thus, the finding that IOP does not decrease the nT3of fetal IBAT explains the lack of effect of IOP on uncoupling protein expression in fetuses, in contrast with the known decrease in adults. Present results also show that IOP increases nT3in brain and liver, indicating a general incapacity of IOP to decrease nT3in fetal tissues. It is concluded that the effects of IOP during fetal life differ from those in adults.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The purpose of this study was to determine whether treatment with L-carnitine or acetyl-L-carnitine enhances the turnover of lipid or branched-chain amino acid oxidation in patients with inborn errors of metabolism. Increasing i.v. doses of L-carnitine and acetyl-L-carnitine were given to one patient with medium-chain acyl-CoA dehydrogenase deficiency and to another with isovaleric acidemia. Both patients were in stable condition and receiving oral L-carnitine supplements. The excretion of carnitine and disease-specific metabolites was measured. The incorporation of L-carnitine in the intracellular pool was demonstrated using stable isotopes and mass spectrometry. Increasing doses of either i.v. L-carnitine or acetyl-L-carnitine did not stimulate the excretion of octanoylcarnitine in the patient with medium-chain acyl-CoA dehydrogenase deficiency, nor did it raise the plasma levels of eithercis-4-decenoate or octanoylcarnitine. Similarly, increasing doses of either i.v. L-carnitine or acetyl-L-carnitine did not enhance the excretion of isovalerylcarnitine in a patient with isovaleric acidemia. The excretion of isovalerylglycine actually decreased. We conclude that there was no evidence of enhanced fatty acid β-oxidation or enhanced branched-chain amino acid oxidationin vivoby the administration of high doses of L-carnitine or acetyl-L-carnitine in these two patients. Because only one individual with each disorder was studied, the data are only indicative and may not necessarily be representative of all individuals with these disorders. Definite settlement of this issue will require further studies in additional subjects.

ISSN:0031-3998    

出版商:OVID    

年代:1994

数据来源: OVID