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.     

Oxygen saturation and breathing patterns in preterm infants with cyanotic episodes

The pathophysiology of cyanotic/apnoeic episodes in preterm infants was investigated using overnight tape recordings of beat-to-beat arterial oxygen saturation (SaO2), plethysmographic waveforms from the oximeter, breathing movements and nasal airflow. Recordings were made in 16 preterm infants with recurrent cyanotic episodes of unknown cause that had received stimulation or resuscitation, and 15 preterm controls, matched for birth weight, post-conceptional and postnatal age. The recordings were analysed for baseline SaO2, the number of hypoxaemic episodes (SaO2 < or = 80% for > or = 4 s) and the breathing patterns associated with each episode. There was a significant difference in the total number of hypoxaemic episodes between patients and controls (520 versus 100; p < 0.01), but no difference was found for mean baseline SaO2 (98.6 versus 99.0%; p > 0.05). The mean duration of each hypoxaemic episode in the patients was 9.5 s compared with 5.8 s in the controls (p < 0.01). Although most hypoxaemic episodes (62 and 76%) were associated with pauses in breathing movements, a proportion (8 and 18%, respectively) occurred despite continuous airflow and breathing movements in both patients (6 of 16) and preterm controls (2 of 15). The rate of decrease in SaO2 was significantly more rapid during these latter hypoxaemic episodes than during episodes associated with isolated apnoeic pauses (8.5 versus 3.2% per second, p = 0.02). Preterm infants with cyanotic episodes have increased numbers of clinically unapparent hypoxaemic episodes, some of which have continued ventilation and rapid desaturation. The pathogenesis of these episodes warrants further investigation.     

Variation in serum C-reactive protein across the clinical spectrum of meningococcal disease

In a multicentre prospective study, 124 cases of meningococcal disease were classified into the clinical categories, meningitis alone (n = 15), meningitis and septicaemia (n= 79) and septicaemia alone (n = 30). A further 60 children referred with other illnesses served as controls. Serial measurements of serum C-reactive protein (admission, day 1, day 2, days 5–7) were compared. Children with septicaemia had significantly lower C-reactive protein levels on admission than those with meningitis alone or meningitis and septicaemia which were unexplained by differences in the duration of the presenting illness or severity of the disease. Within each clinical category of meningococcal disease, significant changes in C-reactive protein concentration occurred during the course of the disease. Four control children had other types of septic meningitis: admission C-reactive protein concentrations did not differ from those with meningitis or meningitis and septicaemia, but were significantly higher than those with septicaemia alone. The other 56 patients had a significantly lower admission C-reactive protein concentration compared with all cases of meningococcal disease. For the diagnosis of meningococcal disease, admission C-reactive protein levels of ≥ 40 mg/l had a sensitivity of 79%, specificity of 80% and positive predictive value of 87%. For the prognostic prediction of death in meningococcal disease (or meningococcal disease with shock) CRP < 100 mg/l on admission had a sensitivity of 69% (69%), specificity of 50% (56%) and positive predictive value of 18% (53%). In children with suspected meningococcal disease, serum C-reactive protein, measured on admission, has diagnostic value but not prognostic value. The C-reactive protein concentration on admission varies with the clinical category of meningococcal disease and the day of illness.     

Renal osteodystrophy in nondialysed adolescents. Long-term treatment with 1alpha-hydroxycholecalciferol

The effects of small oral doses (1-2 microgram/day) of 1alpha-hydroxycholecalciferol, given for 1 to 2 years, have been examined in four nondialysed adolescents with chronic renal failure and bone disease. Treatment increased calcium retention and plasma calcium, and decreased plasma levels of alkaline phosphatase, hydroxyproline, and immunoreactive parathyroid hormone. X-ray abnormalities of bone regressed, and 2 patients underwent successful surgical correction of knock-knees; bone histology in these 2 was normal at the time of operation. 2 patients developed hypercalcaemia which promptly reversed when 1alpha-hydroxycholecalciferol was withdrawn. In one patient treatment was initially successful, but later there was biochemical, radiographic, and histological evidence of relapse. Long-term treatment of such patients with 1alpha-hydroxycholecalciferol may be effective and facilitate the surgical correction of deformities, but this is not invariable. Toxic effects are similar to those of vitamin D itself, but are more readily reversible.     

Biopterin derivatives in normal and phenylketonuric patients after oral loads of L-phenylalanine, L-tyrosine, and L-tryptophan

Plasma biopterin derivatives studied in 10 normal and 21 phenylketonuric children showed a significantly high concentration in the latter group. Biopterin derivatives correlated with plasma phenylalanine concentration, but in normal adults given an oral phenylalanine load the rate of increase with phenylalanine differed from that in phenylketonuric patients. A patient with hyperphenylalaninaemia, not due to phenylketonuria, had an abnormal biopterin derivatives response to phenylalanine distinct from that of patients with classical phenylketonuria. This may be a useful investigation to differentiate some variants of phenylketonuria.