Incidence, population, and survival of cystic fibrosis in the UK, 1968-95. UK Cystic Fibrosis Survey Management Committee

The UK Cystic Fibrosis Survey holds data on all people resident in the UK who were diagnosed as having cystic fibrosis and born either since 1968 or before 1968 and alive in 1977. Thus, incidence may be reported from 1968 and prevalence from 1977. The previous estimates are updated to the end of 1995 from data held in the database on 23 August 1996. The incidence is now calculated as one in 2415 live births. The 1992 mid-year population was 6500 people with 65% aged under 16 years. Births outnumber deaths by 160 per year, which suggests a population of 7750 by the year 2000, with all the increase being in the adult age range. The survival of successive cohorts continues to be better than earlier cohorts, the linear descent of the curves is still evident. The infant mortality rate for cystic fibrosis is now under 20 per thousand per year and early childhood mortality is under five per thousand per year. The crude mortality rate for 1995 was 21 per thousand per year, but the standardised mortality ratio was about 3300.     

The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients

OBJECTIVES: To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. PATIENTS: The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. OUTCOME MEASUREMENTS: The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. CONCLUSIONS: Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.     

Computed tomography in chronic inflammatory bowel disease

In children with complicated inflammatory bowel disease, conventional ultrasound imaging may not define the extent of extraluminal disease and the involvement of other viscera. Three children with chronic inflammatory bowel disease are presented, where computed tomography was well tolerated and provided valuable information on extraluminal disease, involvement of other organs, and the state of the bowel wall and mesentery. In children in whom ultrasound examination is inconclusive or limited by gas or tenderness, computed tomography can provide important information that may determine clinical management.     

Confidential inquiry into families with two siblings with cystic fibrosis

OBJECTIVE: To audit the care that had been provided to couples before the birth of a child with cystic fibrosis where a sibling had been previously diagnosed. DESIGN: Retrospective review of case notes. SAMPLE: Families where at least one affected child had been born between 1 January 1991 and 30 June 1995 and the diagnosis in the first child was made before the second affected pregnancy reached 20 weeks. The combination of information on these families with data from the prenatal diagnosis register allowed the reconstruction of a cohort of pregnancies in women with a previous affected child. MAIN RESULTS: Forty six eligible families with a second affected child were identified. Details from the paediatrician who had diagnosed the first affected child were obtained in 43 cases: all 43 couples were offered genetic counselling, but where provided by a paediatrician this was difficult to assess as no couple was sent a summary letter. Details were obtained from the obstetrician in the subsequent affected pregnancy in 42 cases: prenatal diagnosis was not offered in 10 (24%), offered and declined in 24 (57%), offered and accepted but termination declined in eight (19%). In the overall cohort of at risk pregnancies, the estimated rate of prenatal diagnosis offer was 97%, prenatal diagnosis uptake 86%, false negative prenatal diagnosis rate 0%, and uptake of termination 95%. CONCLUSIONS: (1) Parental choice was an important determinant of second affected births. (2) Despite widespread availability, prenatal diagnosis was not offered in an estimated 3% of at risk pregnancies. (3) There were shortcomings in counselling documentation, in particular failure to send a summary letter to counselled couples.     

Functional characterization of the rat mdr1b encoded P-glycoprotein: not all inducing agents are substrates

The multidrug resistance (mdr) genes encode P-glycoproteins, integral membrane proteins which function as drug efflux transporters. Exposure of animals in vivo and cells in vitro to a variety of xenobiotics leads to increased mdr1 gene expression and higher levels of P-glycoprotein. This response may protect cells from the cytotoxic effects of these compounds. In this investigation we functionally expressed the rat mdr1b gene in NIH 3T3 cells and assessed the ability of the encoded P- glycoprotein to protect these cells from the cytotoxicity of xenobiotics known to induce mdr1b expression. In long-term colony survival assays, stably expressed mdr1b conferred resistance to cytotoxic drugs such as colchicine, vinblastine and doxorubicin, but not to 5-fluorouracil nor to the carcinogens aflatoxin B1 and N-hydroxy- acetylaminofluorene. The mdr reversal agent verapamil restored cytotoxicity of colchicine, doxorubicin, actinomycin D, vinblastine and taxol, but had no effect on the sensitivity of these cells to 5- fluorouracil, aflatoxin B1 or N-hydroxy-acetylaminofluorene. In a competitive transport assay, verapamil and, to a lesser extent, colchicine blocked the increased efflux of the fluorescent dye rhodamine 123 from mdr1b-transfected cells, whereas aflatoxin B1 did not compete for this export. These data demonstrate that expression of the rat mdr1b encoded P-glycoprotein can protect cells from a diverse group of compounds previously identified to be mdr substrates, however, other effective inducers of mdr expression, such as aflatoxin B1 and N- hydroxy-acetylaminofluorene, remain potent cytotoxins despite high levels of P-glycoprotein. The fact that compounds which are not themselves substrates can induce P-glycoprotein expression may have implications for pharmacokinetic interactions and chemotherapy.      

Time course comparison of cell-cycle protein expression following partial hepatectomy and WY14,643-induced hepatic cell proliferation in F344 rats

During recent years, there has been an extensive research focus in the area of cell-cycle control in eukaryotes and the relationship that exists between cell proliferation and cancer. The eukaryotic cell-cycle is governed by signal transduction pathways mediated by complexes of cyclin dependent kinases (CDK) and their partner cyclin proteins. This study was performed to identify differences in cell-cycle control protein expression following physical and chemical stimuli of hepatic cell growth. Protein levels of cell cycle mediators, cyclin dependent kinases (CDK 1,2,4,5), cyclin proteins (A,B,D1-D3 and E), proliferating cell nuclear antigen (PCNA), tumor suppressor proteins (p53 and Rb), and CDK inhibitory proteins (p16Ink4, p21Waf1 and p27Kip1) were examined in F344 rats following 70% partial hepatectomy or a single dose of WY14,643 over 96- and 48-h time courses, respectively. CDK1 (p34cdc2) and PCNA protein concentrations, quantified by ELISA, were significantly increased beginning at the 24-h time point and maximal at 48 h (6.9- and 3.7-fold for partial hepatectomy and 4.2- and 3.3-fold for WY14,643, respectively). Differential effects were observed with the G1 cell-cycle mediators CDK4, CDK5, and cyclin D3, p21Waf1 and p27Kip1 CDK inhibitory protein concentrations rose in accordance with the induction of DNA synthesis and histone H1 kinase activity. In addition, there were dramatic differences in p53 protein expression patterns following partial hepatectomy versus WY14,643 dosing. Because non-genotoxic hepatocarcinogens are known to induce cellular proliferation, data generated from this study may aid in elucidating the specific hepatocarcinogenic signal transduction pathways stimulated by non-genotoxic carcinogens.      

Body size and subcutaneous fat patterning in adolescence

Factors that influence low birth weight at term may also be associated with subcutaneous fat patterning in later life. This hypothesis was investigated in a comparative (retrospective) cohort study. The subjects, born in Cardiff between 1975 and 1977, were of mean age 15.7 years. Cases (low birth weight (< 2500 g) at term) were matched with controls (normal birth weight (3000-3800 g) at term) for sex, parity, place of birth, date of birth, and gestation. Subscapular skinfold (an index of central subcutaneous fat) and triceps skinfold (an index of peripheral subcutaneous fat) were measured using a Holtain skinfold caliper. The differences (cases minus controls) (95% confidence interval) for subscapular and triceps skinfolds were respectively -0.3 mm (-1.74 to 1.14) and -0.48 mm (-1.75 to 0.79). These findings are inconsistent with the hypothesis that low birth weight at term is associated with subcutaneous fat patterning in adolescence.     

Cystic fibrosis identified by neonatal screening: incidence, genotype, and early natural history

The incidence of cystic fibrosis over the last 10 years in East Anglia (a region of the United Kingdom with a population of 2.1 million) has halved. This has happened during the establishment of a neonatal screening programme, which has enabled early diagnosis, genetic counselling, and lately the option of prenatal diagnosis in subsequent pregnancies. One hundred and seven children were born with cystic fibrosis between 1981 and 1990, eight of whom were siblings. The Guthrie blood spots of 82 infants detected by neonatal immunoreactive trypsin screening between 1981 and 1990 were examined for the presence of the most common cystic fibrosis gene mutation (delta F508). It was present in 135 (82%) of the 164 cystic fibrosis genes analysed with 54 (66%) cases being homozygous and 27 (33%) heterozygous. Sixty nine per cent of infants were symptomatic at the time of diagnosis regardless of genotype. No association was found between the early clinical or biochemical features of the disease and homozygosity or heterozygosity for this mutation. Screening for cystic fibrosis using the blood immunoreactive trypsin assay alone remains an effective method of identifying infants with the disease soon after birth, thereby allowing early therapeutic intervention. Genetic counselling and prenatal diagnosis have contributed to a reduction in the number of children born with cystic fibrosis, but may not entirely explain the decreasing incidence of the disease.