Management of chronic sinusitis in cystic fibrosis

Chronic rhinosinusitis is extremely common in patients with cystic fibrosis. It causes numerous problems in these patients and can put them at risk for life-threatening illness. Potential problems include nasal obstruction, congestion, sinus pain and pressure, infection (usually with Pseudomonas organisms), hyposmia or anosmia, and the seeding of bacteria into the lower respiratory tract. Cystic fibrosis patients with chronically infected sinuses are at increased risk for pneumonia following lung transplantation. A prophylactic protocol has been developed for the management of chronic sinusitis in patients with cystic fibrosis. These patients are fully evaluated at the Nasal Dysfunction Clinic of the University of California, San Diego (UCSD), Medical Center. Based on the results of the evaluation, they are treated with endoscopic sinus surgery, partial middle turbinectomy, septoplasty, and a large middle meatal maxillary antrostomy. Surgery is followed by a rigorous regimen of pulsatile hypotonic saline nasal irrigation to wash away tenacious cystic secretions. Tobramycin (Nebcin®) is given once daily in the nasal irrigant to inhibit the growth of Pseudomonas organisms. At the USCD Nasal Dysfunction Clinic, this prepulmonary transplantation protocol is now used in all cystic fibrosis patients with chronic sinusitis.     

Faecal interleukin-8 and tumour necrosis factor-alpha concentrations in cystic fibrosis.

Interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) concentrations were measured in faecal samples from nine patients with cystic fibrosis and nine healthy age matched controls. The patients were assessed with Shwachman score, apparent energy absorption, pancreatic enzyme dosage, simple spirometry, and presence of pseudomonal colonisation. Median (range) wet stool IL-8 and TNF-alpha concentrations in patients were 32,113 pg/g (21,656-178,128) and 3187 pg/g (368-17,611) respectively, compared with < 43.5 pg (IL-8)/g (< 22-4079) and 99 pg (TNF-alpha)/g (< 0.26-231) in controls. IL-8 concentration was negatively correlated with Shwachman score (r = -0.79) and pancreatic enzyme dosage (r = -0.77), but not with energy absorption. Seven patients were mature enough to cooperate with spirometry. Their IL-8 concentrations correlated with percentage predicted forced expiratory volume in one second (r = -0.78). IL-8 concentration was greater in four patients with, than five without, established pseudomonal colonisation: median difference 134,583 pg/g. TNF-alpha concentration was not correlated with measures of disease severity. Faecal IL-8 concentration might reflect the severity of pulmonary inflammation in cystic fibrosis and could provide an easily obtainable marker of disease activity.     

Vinblastine and erythromycin: an unrecognized serious drug interaction

Vinblastine and erythromycin are among the most commonly used chemotherapeutic and antimicrobial agents, respectively. No interaction between the two has ever been reported. Towards the end of a phase I study of vinblastine plus oral cyclosporin (to reverse multidrug resistance), three patients also received erythromycin to raise their cyclosporin levels. All developed severe toxicity consistent with a much higher vinblastine dose than was actually given. This apparent potentiation of vinblastine toxicity has not been previously described.     

Effect of Helicobacter mustelase infection on ferret gastric epithelial cell proliferation

The effect of Helicobacter mustelae infection on gastric epithelialproliferation was studied in ferrets colonized with H.mustelaeand specific pathogen-free (SPF) ferrets not infected with H.mustelae.Thirteen H.mustelae-infected ferrets between the ages of 13and 32 months and 16 SPF ferrets between 6 and 18 months wereanalyzed. Bacterial cultures, urease tests and Warthin-Starrystains were used to identify H.mustelae. Tissues obtained fromthe antrum and the body regions of the stomach were assayedby proliferating cell nuclear antigen (PCNA) immunohisto-chemistryand measured using a computerized color image analysis system.PCNA-expressing gastric epithelia in the antrum and the bodyregions were significantly increased in the H.mustelae-infectedferrets versus the SPF ferrets (P <0.001). PCNA positivityin the antrum regions of both the H.mustelae-infected ferretsand SPF ferrets was significantly higher than that of the bodyregions (P <0.001). Comparison of the histopathology of infectedferrets indicated that PCNA positivity correlated with the histologicalseverity of gastritis. This study suggests that cell proliferationin ferret gastric mucosa increases with H.mustelae infectionand provides evidence that PCNA is a useful biomarker for studyingthe changes in cell kinetics in the ferret stomach. The dataalso further support the use of the H.mustelae-infected ferretas an animal model for studying the pathogenesis of Helicobacterpylori-induced gastric diseases of humans.     

African green monkeys provide a useful nonhuman primate model for the study of human parainfluenza virus types-1, -2, and -3 infection

Human parainfluenza virus (HPIV) types-1, -2, and -3 are significant causes of both upper and lower respiratory tract disease in infants and children. Although there are two live attenuated vaccines for the prevention of HPIV-3 disease in phase 1 clinical trials, vaccines are not currently available for prevention of HPIV-1 or -2 disease. Our laboratory is developing candidate vaccines for the prevention of HPIV-1, -2, and -3 disease, and a suitable nonhuman primate model is needed for evaluation of these vaccine candidates prior to administration to humans. We evaluated the replication of HPIV-1 and -2 in six different species of nonhuman primates and found both viruses to replicate most efficiently in African green monkeys and chimpanzees. We then compared the replication of HPIV-3 in African green monkeys to that in rhesus macaques, which we have used previously, and found that HPIV-3 replicated to higher titer in African green monkeys. In summary, African green monkeys provide a very useful nonhuman primate for the evaluation of HPIV-1, -2, and -3 vaccine candidates, especially for the evaluation of various combinations of these PIV vaccines and for vaccine strategies that employ sequential immunization.     

Bronchopulmonary dysplasia and pulmonary insufficiency of prematurity. Lack of correlation of outcome with gas exchange abnormalities at 1 month of age

A review of all infants admitted to the two intensive care nurseries in Seattle from July 1, 1980, through Dec 31, 1981, was performed to evaluate the outcome of infants still requiring supplemental oxygen and/or mechanical ventilation at 1 month of age. Sixty-three infants were identified. Fifty-six infants survived to at least 2 years of age, including 11 of 13 in the subgroup of infants requiring 40% or more oxygen at 1 month of age. Eight (14%) of the 56 survivors have required prolonged rehospitalization for pneumonia or other respiratory illnesses in the first two years following birth. We conclude that the degree of gas exchange impairment assessed at 1 month of age does not predict ultimate outcome from neonatal chronic lung disease.     

Imprinted genes as potential genetic and epigenetic toxicologic targets

Genomic imprinting is an epigenetic phenomenon in eutherian mammals that results in the differential expression of the paternally and maternally inherited alleles of a gene. Imprinted genes are necessary for normal mammalian development. This requirement has been proposed to have evolved because of an interparental genetic battle for the utilization of maternal resources during gestation and postnatally. The nonrandom requisite for monoallelic expression of a subset of genes has also resulted in the formation of susceptibility loci for neurobehavioral disorders, developmental disorders, and cancer. Since imprinting involves both cytosine methylation within CpG islands and changes in chromatin structure, imprinted genes are potential targets for dysregulation by epigenetic toxicants that modify DNA methylation and histone acetylation.     

Deoxycoformycin treatment for childhood T-cell acute lymphoblastic leukemia early in second remission: A pediatric oncology group study

2-Deoxycoformycin (DCF) was added to an intensive Pediatric Oncology Group protocol ( 8303) for children with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma in first relapse. Twenty-seven patients received one or more courses of DCF at 15 mg/m²/day as a 3-day continuous infusion immediately after achieving a second remission with a four-drug reinduction regimen. Renal and neuromuscular toxicities were frequent and occasionally severe despite the provision of a source of adenosine deaminase by means of a packed red cell transfusion 1 day following the infusion of DCF. Hepatic toxicity, manifested by transaminase elevations, accompanied 62% of the courses. The median duration of the second complete re mission was 4 months (range 2-16+ months) with only two of the 27 patients still in remission at 13 + and 16 + months. Plasma concentrations of deoxyadenosine (dAdo) and the ratio of red cell deoxyadenosine triphosphate to adenosine triphosphate (dATP:ATP) were measured prior to the DCF infusion and on day 4. A dATP:ATP ratio of 1.0 or greater was seen in two patients with acute renal failure. There was no apparent correlation between toxicity or response and the plasma dAdo concentrations. DCF administered according to this dose and schedule was excessively toxic and did not appreciably prolong the duration of the second complete remission in children with T-cell lymphoblastic malignancies.     

Follow-up of infants with bilateral renal disease detected in utero. Growth and renal function

We studied 69 infants who had urinary tract abnormalities detected by antenatal ultrasound examination. There were 21 intrauterine or immediate neonatal deaths; in all 21 infants, severe bilateral renal disease incompatible with life was found at autopsy. Six of the live-born infants with abnormal results of antenatal ultrasound examinations had a normal urinary tract after birth. Of the remaining 42 infants, the prenatal diagnosis was confirmed with renal ultrasound and other studies during the first week of life. Twenty-one of 42 infants had bilateral renal disease. We obtained follow-up data on 19 of 21 of these infants. Twelve of 19 had obstructive uropathy that was treated surgically. After one to 51 (mean, 18) months of follow-up, renal function varied. Ten of 19 patients had a calculated glomerular filtration rate greater than or equal to 79 mL/min/1.73 m2. One infant required long-term ambulatory peritoneal dialysis. Renal function (glomerular filtration rate, 74 +/- 5 mL/min/1.73 m2) and growth (height percentile, 41 +/- 8) were unexpectedly good considering the severity of the urinary tract abnormalities. Prenatal detection of bilateral renal disease followed by careful medical and surgical management results in a favorable outcome with good growth and renal function.