MRI in adult patients with aortic coarctation: diagnosis and follow-up.

Aortic coarctation is a disease that usually presents in infancy; however, a proportion of patients present for the first time in adulthood. These lesions generally require repair with either surgery or interventional techniques. The success of these techniques means that increasing numbers of patients are presenting for follow-up imaging in adulthood, whether their coarctation was initially repaired in infancy or as adults. Thus, the adult presenting to the radiologist for assessment of possible coarctation or follow-up of coarctation repair is not an uncommon scenario. In this review, we present details of the MRI protocols and MRI findings in these patients so that a confident and accurate assessment can be made.

Evidence supporting nutritional interventions for persons in early stage Alzheimer's disease (AD).

The purpose of this paper is to grade research evidence supporting nutritional interventions for persons with early stage dementias and to report the recommendations of a consensus panel. Thirty four studies were reviewed in the areas of dietary restriction, antioxidants, and Mediterranean diet with strong support from epidemiological studies found in all three areas. The body of evidence to support nutritional interventions in the prevention and treatment of AD is growing and has potential as a treatment modality following translational studies.

Human squamous cell carcinomas lose a mortality gene from chromosome 6q14.3 to q15.

Normal human keratinocytes possess a finite replicative lifespan. Most advanced squamous cell carcinomas (SCCs), however, are immortal, a phenotype that is associated with p53 and INK4A dysfunction, high levels of telomerase and loss of heterozygosity (LOH) at several genetic loci, suggestive of the dysfunction of other mortality genes. We show here that human chromosome 6 specifically reduces the proliferation or viability of a human SCC line, BICR31, possessing LOH across the chromosome. This was determined by an 88% reduction in colony yield (P<0.001), following the reintroduction of an intact normal chromosome 6 by monochromosome transfer. Deletion analysis of immortal segregants using polymorphic markers revealed the loss of a 2.9 Mbp interval, centred on marker D6S1045 at 6q14.3-q15, in 6/19 segregants. Crucially, allelic losses of this region were not identified in control hybrids constructed between chromosome 6 and the BICR6 SCC cell line that is heterozygous for chromosome 6 and which showed no reduction in colony formation relative to the control chromosome transfers. This indicates that the minimally deleted region at D6S1045 is not the result of fragile sites, a recombination hot spot, or a feature of the monochromosome transfer technique. LOH of D6S1045 was found in 2/9 immortal SCC lines and was part of a minimally deleted region of line BICR19. Furthermore, allelic imbalance, consistent with LOH, was detected in 3/17 advanced SCCs of the tongue. These results suggest the existence of a suppressor of SCC immortality and tumour development at chromosome 6q14.3-q15, which is important to a subset of human SCCs.

Survival effect of lung transplantation among patients with cystic fibrosis.

CONTEXT: Patients with cystic fibrosis (CF) are the second largest group of lung transplant recipients in the United States. The survival effect of transplantation on a general CF population has not previously been measured. OBJECTIVE: To determine the impact of bilateral lung transplantation on survival in patients with CF. DESIGN, SETTING, AND PATIENTS: Retrospective observational cohort study of 11 630 CF patients who did not undergo lung transplantation (controls) and 468 transplant recipients with CF from 115 CF centers in the United States, 1992-1998. Patients were stratified into 5 groups based on a 5-year survival prediction model (survival group 1: <30%; survival group 2: 30 to <50%; survival groups 3-5: 50 to <100%.) MAIN OUTCOME MEASURE: Five-year survival from date of transplantation in 1992-1997 in the transplant group and from January 1, 1993, in the control group. RESULTS: Lung transplantation increased 5-year survival of CF patients in survival group 1. Survival group 2 had equivocal survival effects, and groups 3-5 had negative survival effects from transplantation. From 1994-1997, there was a mean annual prevalence of 238 patients in survival group 1 and mean annual incidence of 154 patients entering the group, approximately 1.5 times the number of lung transplantations performed each year in CF patients (mean, 104). Use of the criterion of forced expiratory volume in 1 second of less than 30% resulted in an equivocal survival benefit and identified 1458 potential candidates for transplantation in 1993. CONCLUSIONS: Cystic fibrosis patients in group 1 have improved 5-year survival after lung transplantation. The majority of patients with CF have equivocal or negative survival effects from the procedure. Selection of patients with CF for transplantation based on group 1 survival predictions maximizes survival benefits to individuals and may reduce the demand for scarce donor organs.

The association of socioeconomic status with outcomes in cystic fibrosis patients in the United States.

There is considerable variability in the clinical course of disease in cystic fibrosis (CF). Although currently unidentified modifier genes might explain some of this heterogeneity, other factors are probably contributory. Socioeconomic status (SES) is an important predictor of health status in many chronic polygenic diseases, but its role in CF has not been systematically evaluated. We performed a historical cohort analysis of pediatric CF patients in the United States using National Cystic Fibrosis Foundation Patient Registry (NCFPR) data for 1986 to 1994, and used Medicaid status as a proxy for low SES. The adjusted risk of death was 3.65 times higher (95% confidence interval [CI]: 3.03 to 4.40) for Medicaid patients than for those not receiving Medicaid. The percent predicted FEV(1) of surviving Medicaid patients was less by 9.1% (95% CI: 6.9 to 11.2). Medicaid patients were 2.19 times more likely to be below the 5th percentile for weight (95% CI: 1.91 to 2.51) and 2.22 times more likely to be below the 5th percentile for height (95% CI: 1.95 to 2.52) than were non-Medicaid patients. Medicaid patients were 1.60 times more likely to require treatment for a pulmonary exacerbation (95% CI: 1.29 to 1.98). There was no difference in the number of outpatient clinic visits for Medicaid and non-Medicaid patients. We conclude that low SES is associated with significantly poorer outcomes in children with CF. Barriers in access to specialty health care do not seem to explain this difference. Further study is indicated to determine what adverse environmental factors might cluster in CF patients of low SES to cause worse outcomes.

Effect of choice of reference equation on analysis of pulmonary function in cystic fibrosis patients.

Pulmonary function is an important measure of disease severity and prognosis in cystic fibrosis (CF). It is generally expressed as a percentage of a predicted value, calculated using regression equations derived from a reference population. A number of reference equations are in widespread use. The purposes of this study were to determine: 1) the extent to which, for a given absolute FEV(1) value, percent of predicted (PPFEV(1)) values vary when derived by different reference equations; and 2) whether these differences affect conclusions of longitudinal and cross-sectional analyses. Subjects were all Caucasians 6-18 years old in the 1990 Cystic Fibrosis Foundation Registry. We found clinically important discrepancies in PPFEV(1) when calculated by the methods of Dockery et al. [Am Rev Respir Dis 1983;128:405-412] and Wang et al. [Pediatr Pulmonol 1993;15:75-78] as compared to Knudson et al. [Am Rev Respir Dis 1983;127:725-734] or Polgar and Promadhat [Pulmonary Function Testing in Children 1971; Philadelphia: W.B. Saunders]. In longitudinal analyses, the choice of reference equation resulted in varying apparent rates of decline in FEV(1). For example, among subjects ages 12-14 years in 1990, the decline in PPFEV(1) from 1990-1995 varied between 2-11%, depending on the choice of reference equation. In cross-sectional analyses, the choice of reference equation affected the distribution of subjects classified as having mild, moderate, or severe lung disease. CF physicians should be aware of the impact of choice of reference equation in both clinical care and research.

Predictive 5-year survivorship model of cystic fibrosis.

The objective of this study was to create a 5-year survivorship model to identify key clinical features of cystic fibrosis. Such a model could help researchers and clinicians to evaluate therapies, improve the design of prospective studies, monitor practice patterns, counsel individual patients, and determine the best candidates for lung transplantation. The authors used information from the Cystic Fibrosis Foundation Patient Registry (CFFPR), which has collected longitudinal data on approximately 90% of cystic fibrosis patients diagnosed in the United States since 1986. They developed multivariate logistic regression models by using data on 5,820 patients randomly selected from 11,630 in the CFFPR in 1993. Models were tested for goodness of fit and were validated for the remaining 5,810 patients for 1993. The validated 5-year survivorship model included age, forced expiratory volume in 1 second as a percentage of predicted normal, gender, weight-for-age z score, pancreatic sufficiency, diabetes mellitus, Staphylococcus aureus infection, Burkerholderia cepacia infection, and annual number of acute pulmonary exacerbations. The model provides insights into the complex nature of cystic fibrosis and supplies a rigorous tool for clinical practice and research.

Early diagnosis of cystic fibrosis in the newborn period and risk of Pseudomonas aeruginosa acquisition in the first 10 years of life: A registry-based longitudinal study.

OBJECTIVE: Controlled clinical trial data have suggested that identifying asymptomatic cystic fibrosis (CF) patients through newborn screening improves health outcomes of affected children in the first decade of life. However, it is unclear whether these improvements also include a reduction in risk for bronchial infection, the major determinant of CF morbidity. The authors therefore investigated the association between early CF diagnosis and acquisition of Pseudomonas aeruginosa, the major bronchial pathogen, in the first decade of life. METHODOLOGY: Longitudinal data on 3625 CF patients diagnosed between 1982 and 1990 and before 36 months of age were ascertained from the National Cystic Fibrosis Patient Registry. We compared P aeruginosa acquisition in the first 10 years of life among 4 groups: EAD (early asymptomatic diagnosis)-<6 weeks, by pre/neonatal screening, genotype, family history (n = 157); ESD (early symptomatic diagnosis) (n = 227); LAD (late asymptomatic diagnosis)-6 weeks to 36 months (n = 161); and LSD (late symptomatic diagnosis) (n = 3080). P aeruginosa acquisition was determined from yearly sputum and/or bronchoscopy cultures. Children whose CF diagnoses followed meconium ileus or whose cultures were obtained only from nasal samples were excluded from the study. RESULTS: Kaplan Meier analyses for P aeruginosa acquisition were conducted for each diagnostic group. Regression models were used to generate adjusted relative hazards with EAD as the referent group. Relative hazards were 0.9 (95% confidence interval [CI]: 0.7-1.2) for ESD, 0.8 (95% CI: 0.6-1.2) for LAD, and 1.0 (95% CI: 0.7-1.2) for LSD. The risk of acquiring P aeruginosa was therefore not significantly different between children diagnosed early, late, asymptomatically, or symptomatically. CONCLUSIONS: These data suggest that, despite improvements in other health outcomes from newborn screening for CF, early asymptomatic diagnosis of CF does not affect P aeruginosa acquisition.

Easy rider wheelchair biking. A nursing-recreation therapy clinical trial for the treatment of depression.

Depression is a common condition among long-term care residents with limited treatment options available. There are few nonpharmacological interventions available to this population. This study examined the use of a prescribed, therapeutic recreation-nursing intervention, wheelchair biking, for treatment of symptoms of depression in older adults in a long-term care setting. A classical experimental design was used and was guided by the Roy Adaptation Model. Forty residents were pretested for depression and randomly assigned to two groups. A 2-week trial of biking therapy was provided to the treatment group. All participants were posttested. Findings indicated there was a statistically significant improvement in depression scores for the treatment group and no significant change for the control group. This study contributes to the body of knowledge of nursing regarding options for the treatment of depression in older adults, and is an encouraging indicator that psychosocial interventions may be effective in reducing depression.

Longitudinal relationship among growth, nutritional status, and pulmonary function in children with cystic fibrosis: analysis of the Cystic Fibrosis Foundation National CF Patient Registry.

OBJECTIVE: To determine prospectively the relationship among growth, nutritional status, and pulmonary function over a 4-year period in a large cohort of children with cystic fibrosis (CF). STUDY DESIGN: CF Foundation National CF Patient Registry data collected from 1991 to 1995 for 968 children (507 male) aged 5 to 8 years with pancreatic insufficiency and forced expiratory volume in 1 second within 60% to 140% of predicted values (FEV(1)%) were analyzed longitudinally. Variables hypothesized to affect FEV(1)% included age, sex, z scores for height, weight, percent of height-appropriate body weight, and annual number of days hospitalized. RESULTS: The significant decline in FEV(1)% was curvilinear and dependent on baseline FEV(1)%; children with initial FEV(1)% > or = 90 declined 2.6 U/y more than those with initial FEV(1)% <90. Boys gained but girls declined in z scores for height. Girls decreased in z scores for weight at a greater rate than boys. The z scores for weight and percent of height-appropriate body weight were significantly associated with longitudinal changes in FEV(1)%, after adjustment was done for hospitalizations. CONCLUSIONS: Growth, nutritional status, and pulmonary function are not stable in prepubertal children with CF and pancreatic insufficiency. Important sex-related differences in growth occur before puberty. Growth and nutritional status are associated with changes in FEV(1)%, suggesting that nutritional intervention may slow the decline in pulmonary function in children with CF.

Inhibition of tetanus toxin fragment C binding to ganglioside G(T1b) by monoclonal antibodies recognizing different epitopes.

Anti-tetanus toxoid monoclonal antibodies would be useful in exploring the relationship of tetanus toxin structure to its function. Tetanus toxin fragment C has been shown to be responsible for binding to neurons via gangliosides. Eleven new and two previously derived monoclonal antibodies specific for tetanus toxin fragment C were shown to recognize five different fragment C epitopes, two of which were overlapping. Three of these epitopes participate in the binding to ganglioside G(T1b). One epitope was defined by a monoclonal antibody that did not inhibit the interaction between fragment C and ganglioside. This antibody however, was blocked from binding to fragment C by antibodies that were able to inhibit the fragment C-ganglioside interaction.

Underutilization of the V kappa 10C gene in the B cell repertoire is due to the loss of productive VJ rearrangements during B cell development.

The V kappa10 family of murine light chain Ig genes is composed of three members, two of which (V kappa 10A and V kappa 10B) are well used. V kappa 10C, the third member of this family, is not detected in any expressed Abs. Our previous work showed that V kappa 10C is structurally functional and can recombine, but mRNA levels in spleen were extremely low relative to those of V kappa 10A and V kappa 10B. Furthermore, while the V kappa 10C promoter was efficient in B cells, it was shown to work inefficiently in pre-B cell lines. Here, we extend our analysis of the V kappa 10 family and examine V kappa 10 gene accessibility, their representation in V kappa cDNA phage libraries, and the frequency and nature of rearrangements during different stages of B cell development. We demonstrate that V kappa 10C is under-represented in V kappa cDNA libraries, but that the frequency of its sterile transcripts in pre-B cells surpasses both V kappa 10A and V kappa 10B, indicating that the gene is as accessible as V kappa 10A and V kappa 10B to the recombination machinery. We also demonstrate that V kappa 10C recombines at a frequency equal to that of V kappa 10A in pre-B cells and has a normal nonproductive to productive recombination ratio. As B cells develop, however, both the frequency of V kappa 10C rearrangements and the presence of productive rearrangements decline, indicating that these cells are in some fashion being eliminated.

Replicative senescence as a barrier to human cancer.

There is evidence that one critically short telomere may be recognized as DNA damage and, as a consequence, induce a p53/p21WAF- and p16INK4A-dependent G1 cell cycle checkpoint to cause senescence. Additionally, senescence via a p53- and p16(INK4A)-dependent mechanism can be induced by the over- or under-stimulation of certain signalling pathways that are involved in cancer. Central to this alternative senescence mechanism is the p14ARF protein, which connects oncogene activation, but not DNA damage, to p53 activation and senescence. We find that immortal keratinocytes almost invariably have dysfunctional p53 and p16 and have high levels of telomerase, but very often express a wild-type p14(ARF). Furthermore, when normal keratinocytes senesce they show a striking elevation of p16 protein, but not of p14(ARF) or its downstream targets p53 and p21(WAF). These results suggest that p16, rather than p14(ARF), is the more important gene in human keratinocyte senescence, but do not exclude a co-operative role for p14(ARF), perhaps in the induction of senescence by activated oncogenes in neoplasia. Regardless of mechanism, these results suggest that replicative senescence acts as a barrier to human cancer development.

Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis.

BACKGROUND: It is uncertain whether the growth impairment that occurs in children during long-term treatment with glucocorticoids persists after the medication is discontinued and ultimately affects adult height. METHODS: We evaluated growth six to seven years after alternate-day treatment with prednisone had been discontinued in 224 children 6 to 14 years of age with cystic fibrosis who had participated in a multicenter trial of this therapy from 1986 through 1991. Of the children, 151 had been randomly assigned to receive prednisone (either 1 or 2 mg per kilogram of body weight) and 73 to receive placebo. We obtained data on growth up to 1997 from the Cystic Fibrosis Foundation Patient Registry and standardized the data to sex- and age-specific norms from the National Center for Health Statistics. We used z scores to compare growth patterns among treatment groups. RESULTS: In 1997, 68 percent of the patients were 18 years of age or older. The z scores for height declined during prednisone therapy; catch-up growth began two years after treatment with prednisone was discontinued. Among the boys, the z scores for height in those treated with prednisone remained lower than the scores for those who received placebo (P=0.02). The mean heights for boys 18 years of age or older were 4 cm less in the prednisone groups than in the placebo group, an equivalent of 13 percentile points (P=0.03). Among the girls, differences in height between those who were treated with prednisone and those who received placebo were no longer present two to three years after prednisone therapy was discontinued. CONCLUSIONS: Among children with cystic fibrosis who have received alternate-day treatment with prednisone, boys, but not girls, have persistent growth impairment after treatment is discontinued.

Epidemiologic study of cystic fibrosis: design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada.

Cystic fibrosis (CF) is a complex illness characterized by chronic lung infection leading to deterioration in function and respiratory failure in over 85% of patients. An understanding of the risk factors for that progression and the interaction of these factors with current therapeutic strategies should materially improve the prevention of this progressive lung disease. The Epidemiologic Study of Cystic Fibrosis (ESCF) was therefore designed as a multicenter, longitudinal, observational study to prospectively collect detailed clinical, therapeutic, microbiologic, and lung function data from a large number of CF treatment sites in the U.S. and Canada. The ESCF also serves an important role as a phase-IV study of dornase alfa. To be eligible for enrollment, subjects must have the diagnosis of CF and receive the majority of their care at an ESCF site. In this paper, the authors present the ESCF study design in detail. Further, enrollment data collected at 194 study sites in 18,411 subjects enrolled from December 1, 1993 to December 31, 1995 are presented in summary form. This comprehensive study is unique in the detail of clinical data collected regarding patient monitoring and therapeutic practices in CF care. Two companion articles present data regarding practice patterns in cystic fibrosis care, including data on resource utilization and prescribing practices.

Characterization of a B cell surface antigen with homology to the S100 protein MRP8.

The S100 proteins comprise a large sub-family of the EF-hand calcium-binding proteins. Here we describe a novel monoclonal antibody recognizing a B cell surface antigen. This monoclonal antibody immunoprecipitates three proteins in the 12-18 kDa range and the smallest of these proteins has a striking homology at its amino-terminus to human MRP8, a myeloid specific member of the S100 family. Similarly to MRP8 in myeloid cells, this antigen is expressed in the cytoplasm of B cells and is secreted by LPS-induced activated B cells. This surface antigen is not B cell specific. Since MRP8 is not expressed by lymphoid cells, however, this antibody appears to recognize a new member of the S100 family.

Genetic and functional analyses exclude mortality factor 4 (MORF4) as a keratinocyte senescence gene.

Approximately 50% of immortal human keratinocyte lines show loss of heterozygosity of chromosome region 4q33-q34, and the reintroduction of chromosome 4 into one such line, BICR 6, causes proliferation arrest and features of replicative senescence. Recently, a candidate gene, mortality factor 4 (MORF4), was identified in this region and sequenced in 21 immortal keratinocyte lines. There were no mutations or deletions, and two of the seven lines that showed loss of heterozygosity at 4q33-q34 were heterozygous for MORF4 itself. Furthermore, the transfer of a chromosomal segment containing the entire MORF4 gene did not mimic the senescence effect of chromosome 4 in BICR 6. These results suggest that the inactivation of MORF4 is not required for human keratinocyte immortality.

Comparison of growth status of patients with cystic fibrosis between the United States and Canada.

BACKGROUND: Differences in growth status of patients with cystic fibrosis (CF) between the United States and Canada were reported in the 1980s based on analysis of data from 2 regional CF centers. OBJECTIVE: We evaluated the current growth status of the entire CF population in the United States and Canada in view of recent advances in the treatment of CF. DESIGN: Growth data from the 1992-1994 CF Patient Registries were analyzed. RESULTS: Mean height and weight were at approximately the 30th percentile for children with CF in the United States. Mean height and weight were 4-5 percentiles higher in children with CF in Canada than in those in the United States (P < 0.01), but percentages of ideal weight (104%) were similar in both populations. In adults with CF, mean height was similar at the 37th percentile; however, weight (26th compared with the 21st percentiles) and percentage of ideal weight (93% compared with 90%) were significantly higher in Canada than in the United States. Differences related to sex and age were similar in both countries for all indexes, which showed a high prevalence of underweight in infants and in older patients, but little sex discrepancy. CONCLUSION: We observed substantially smaller differences in the growth indexes of CF patients between the United States and Canada compared with results from the 1980s. These findings reflect significant improvements in the nutritional status of US patients in recent years. However, caution is required in the direct comparison of mean percentiles from reports using different growth standards because there are systematic differences in growth standards, which affect, in particular, the comparison of growth in males and females.