Cystic fibrosis and calcium oxalate nephrolithiasis.

During the past six years, we have treated eight patients with cystic fibrosis (CF) for nephrolithiasis. In seven patients, the stones were comprised of calcium oxalate. Another six patients had calcium oxalate crystalluria. In our CF population of 140 patients, this represents a cumulative incidence of calcium oxalate nephrolithiasis of 5.7 percent and an additional 4.2 percent incidence of crystalluria. Experience with these patients is reviewed. Pancreatic insufficiency was universally associated with nephrolithiasis or crystalluria. Diabetes and cirrhosis were also common. Predisposing factors and potential mechanisms of stone disease in pancreatic insufficient CF patients are discussed, focusing on the relationship between fat malabsorption in CF to oxalate metabolism.

Unusual inheritance of primary ciliary dyskinesia (Kartagener's syndrome).

Primary ciliary dyskinesia syndrome is characterised by chronic sinusitis, bronchiectasis, and, in 50% of cases, dextrocardia. It is generally believed to be inherited as an autosomal recessive disorder. In this report, we describe a family consisting of a mother and her five male children, the offspring of three different fathers, all of whom have this syndrome. This argues for either an X linked or autosomal dominant pattern of inheritance. Cytogenetic and FISH (fluorescent in situ hybridisation) analyses were done on the mother and one son and were found to be normal.

Abnormal sweat chloride in auto-immune hypothyroidism.

A case of an 11-year-old girl with autoimmune hypothyroidism and a positive sweat test is presented. When the hypothyroidism was corrected the sweat test reverted to normal.

Visceral leishmaniasis: resistance to reinfection in the liver following chemotherapy in the BALB/c mouse.

The ability of BALB/c mice to resist reinfection with Leishmania donovani following chemotherapy was studied. BALB/c mice, infected with L. donovani, were treated on Days 7 and 8 postinfection with free, niosomal, or liposomal sodium stibogluconate. It was found that all three drug treatments caused a dramatic reduction in liver parasite burdens as measured on Days 6 and 29 post-treatment. On Day 6 postdrug treatment infection with L. donovani amastigotes, of mice from infected, drug-treated groups, along with age- and sex-matched uninfected controls, showed that at 23 days later, significantly fewer parasites were recovered from the livers of reinfected animals compared with controls given their first infection. Treatment of mice with sodium stibogluconate 6 days prior to a primary infection significantly reduced the number of parasites recovered 14 days later, especially using the carrier form of the drug. In vivo macrophage activity in the liver, as measured by the uptake of radiolabeled horseradish peroxidase immune complex, was significantly raised following stibogluconate treatment of infected but not uninfected mice. These results suggest that a state of resistance persists in the liver of infected mice following chemotherapy which may in part be due to local macrophage activation but also to an unsuspected persistance of the drug.

Visceral leishmaniasis: drug carrier system characteristics and the ability to clear parasites from the liver, spleen and bone marrow in Leishmania donovani infected BALB/c mice.

The efficacy of various sodium stibogluconate formulations against Leishmania donovani has been investigated using a BALB/c mouse model of visceral leishmaniasis. Only one therapy, multiple dosing with drug loaded sonicated vesicles, liposomes or niosomes, was found to be effective against parasites in the liver, spleen and bone marrow. Other treatments significantly reduced parasite liver burdens but either failed to effect spleen and bone marrow parasites, or were effective but toxic. Prophylactic treatment with sodium stibogluconate preparations, six days before infection, reduced parasite multiplication in the liver (free, niosomal and liposomal drug) and the spleen (sonicated, drug loaded niosomes only), but had no suppressive effect on bone marrow parasite burdens compared with controls. These results indicate that in-vivo sodium stibogluconate persists in some compartments at parasiticidal concentrations and that failure to reach this concentration at some sites of infection such as bone marrow, is the cause of treatment failure and relapse.

The therapeutic effect of sodium stibogluconate in BALB/c mice infected with Leishmania donovani is organ-dependent.

A study of the antileishmanial efficacy of sodium stibogluconate was carried out in BALB/c mice. The drug was administered to Leishmania donovani-infected animals on days 7 and 8 post-infection in one of three forms; free (40-50 mg Sbv Kg-1), liposomal, or niosomal (6.4-8.0 mg Sbv Kg-1) drug. On day 14 post-infection counts of the number of parasites present in the liver, spleen and bone marrow of treated and control animals showed that although all three drug preparations significantly reduced parasite numbers in the liver (approximately equal to 99% suppression) they had little effect on those residing in the spleen or bone marrow. The carrier forms of the drug were therefore significantly more effective than free drug in reducing liver parasite burdens. Increasing the concentration and the number of doses of free drug (maximum of 500 mg Sbv Kg-1), and reducing the size of the vesicles used to deliver the drug had a minimal effect on parasite numbers in the spleen and bone marrow. It is proposed that because of the resistance of spleen and bone marrow parasites to drug therapy, the BALB/c mouse infected with L. donovani provides an excellent model system for the study of drug delivery to these deeper tissue sites.

Vesicular systems (niosomes and liposomes) for delivery of sodium stibogluconate in experimental murine visceral leishmaniasis.

Suppression of Leishmania donovani liver amastigotes by sodium stibogluconate has been determined in a murine model of experimental visceral leishmaniasis. Niosomal and liposomal drug formulations were equiactive and both increased drug efficacy by an order of magnitude compared with that of free drug. Niosomes containing 30 mol % cholesterol were prepared from three different non-ionic surfactants and no significant difference in activity was detected among the different drug-loaded niosomes. Both negatively charged and neutral vesicles were found to be equally effective. However, vesicle cholesterol content had a slight influence on the antiparasitic activity of the drug-loaded niosomes. Empty vesicles produced a dose-dependent parasite suppression for all vesicles studied. Studies of antimony distribution in the mouse using neutron activation analysis showed high liver levels after i.v. administration of the carrier forms of the drug.

Biodegradable microspheres: polyacryl starch microparticles as a delivery system for the antileishmanial drug, sodium stibogluconate.

Liver parasite burdens of Leishmania donovani in the mouse have been determined after treatment with intravenous administration of sodium stibogluconate in the free or carrier form. The carrier form, in which the drug was covalently bound to polyacryl starch microparticles, was up to 100x more effective than the free form in this murine model of visceral leishmaniasis. Empty microparticles had no effect on liver parasite burdens and the enhanced in-vivo antileishmanial activity of the carrier form of the drug was apparently due to passive drug delivery to the infected liver.

Non-ionic surfactant vesicles, niosomes, as a delivery system for the anti-leishmanial drug, sodium stibogluconate.

Liver and serum concentrations of antimony in the mouse have been determined after administration of sodium stibogluconate in the free, liposomal and niosomal form. High liver and low serum values were attained by the use of both vesicular formulations. Niosomal sodium stibogluconate was shown to be more active than free drug against experimental murine visceral leishmaniasis, an effect apparently dependent on maintaining high drug levels in the infected reticuloendothelial system.

Clinical features as predictors of functional status in children with cystic fibrosis.

Previous clinical studies in patients with cystic fibrosis have demonstrated substantial variability in the symptoms present at diagnosis and in subsequent survival rates. In this study we assessed the association between features present at diagnosis and the clinical course of cystic fibrosis in 89 patients. The 5- and 10-year outcomes for children with cystic fibrosis were better than has been generally appreciated. Overall, two thirds of the patients had either improved or remained at the same level of morbidity 5 years after diagnosis. Children who presented with isolated gastrointestinal symptoms had a good clinical course; some actually improved clinically during the first 5 to 10 years after diagnosis. In contrast, children who presented with respiratory disease frequently had clinical deterioration during the follow-up period. Neither age at presentation nor the initial level of morbidity was significantly related to subsequent outcome. We conclude that clinical features apparent at diagnosis are valuable prognostic indicators in children with cystic fibrosis.

Spirometry with positive airway pressure. A simple method of evaluating obstructive lung disease in children.

In children with obstructive lung disease, the determination of functional resident capacity by the conventional helium dilution method [FRC(He)] often results in gross underestimations. This is due to exceptionally poor He mixing in children, which may be related to characteristics of the developing lung. We added a low level (2.5 cmH2O) of continuous positive pressure to the airway (CPAP) for 2 min beyond the end of conventional He rebreathing to evaluate its effect on gas mixing. The FRC was determined again from He concentration 1 min after CPAP was stopped. We recorded the results as an increase in measured FRC after CPAP (delta FRC) as percent of FRC(He). A total of 46 children (mean age: 13.5 yr) were studied, including those with normal lung function, those with central airway disease, and those with peripheral airway obstruction. With CPAP, delta FRC increased markedly in those with peripheral airway obstruction and was significantly correlated with volume of isoflow and the volume of trapped gas. Thus, the measurement of delta FRC is simple yet useful in detecting peripheral airway obstruction and air trapping.

Diagnostic styles of attending pediatricians, residents, and nurses in evaluating febrile children.

In order to compare the diagnostic styles of attending pediatricians (A), residents (R), and nurses (N) in judging the degree of illness of a febrile child prior to physical examination, we studied the frequency with which they used 139 different history variables and 186 observation variables in evaluating 162 consecutive children less than or equal to 24 months of age with temperature greater than or equal to 38.3 C. Because individual history and observation variables were not used with sufficient frequency, comparison of diagnostic styles based on the individual variables was not possible. The individual history and observation variables were then combined into 25 history and 30 observation categories respectively. One observation category, "Eyes," was used with sufficient frequency to allow comparison of A, R, and N diagnostic styles. In the Eyes category, there were 11 variables describing visual response to stimuli (e.g., looking at the observer) and 10 variables describing appearance of the eyes (e.g., glassy, shiny). Attendings used variables describing visual response to stimuli significantly more frequently than R or N, which may indicate a greater facility in evaluating age-appropriate behavior and/or may be a technique to increase the sensitivity of clinical judgments. These data demonstrate the variety of diagnostic styles of A, R, and N. There is a need to define valid and reliable observation data to identify serious illness in febrile children.

Occurrence of nonfermentative gram-negative rods other than Pseudomonas aeruginosa in the respiratory tract of children with cystic fibrosis.

There have been no comprehensive microbiologic studies of the frequency of respiratory colonization with nonfermentative gram-negative rods (NFGNR) other than Pseudomonas aeruginosa in patients with cystic fibrosis (CF). Records of bacteria isolated from throats and sputa of CF patients of the Yale-New Haven Hospital CF Clinic from 1975-1979 were reviewed in order to determine the incidence of these species. Thirty-one strains were recovered. Twenty patients from the CF Clinic (with an average census of 170 patients) yielded at least one isolate of non-P. aeruginosa NFGNR, and eight of them showed more than one species on at least one occasion. Two patients also carried P. aeruginosa and ten carried Staphylococcus aureus on at least one occasion. Using a standardized method of clinical scoring, our patients had a course not unlike our general CF population.

Radiographic findings and etiologic diagnosis in ambulatory childhood pneumonias.

The chest roentgenograms of 128 consecutive ambulatory children with radiologic pneumonia were read independently and without clinical information by a faculty general pediatrician (Ped), a pediatric radiologist (R-P) and a general radiologist (R-G). The films were classified as normal, indicative of a viral or bacterial process, or indeterminate. Readings were compared with results of viral titers and bacterial cultures. Agreement between any two observers in classifying films, measured by unweighted Kappa, while statistically significant (p less than 0.001) for any pair, was low. There was no significant difference between the agreement scores of Ped/R-P, Ped/R-G, and R-P/R-G. Twenty-one patients had fourfold viral titer increases (N = 16) or positive bacterial cultures of blood or pulmonary aspirate (N = 5). The sensitivity of viral readings for titers increases varied from 19% to 68% depending on observer type; the sensitivity of bacterial readings for positive bacterial cultures varied from 60% to 80%. The three observers agreed on a correct reading in only three children with viral and three with bacterial pneumonia. Because of poor observer agreement and appreciable false-negative errors when viral and bacterial readings were compared to titer increases and positive bacterial cultures, respectively, we conclude that radiographic findings are poor indicators of etiology diagnosis in ambulatory childhood pneumonias and, of themselves, are an insufficient data base for making therapeutic decisions.