Pregnancy outcomes in cystic fibrosis: a 10-year experience from a UK centre.

BACKGROUND: Cystic fibrosis manifests as a multisystem disease, despite this female fertility is relatively preserved with levels approaching that of the non-cystic fibrosis population. We reviewed pregnancies in cystic fibrosis patients over a 10-year period from a UK adult cystic fibrosis centre by considering maternal and fetal outcomes. METHODS: We conducted a retrospective case-note review of pregnancies during 2003-2013 using respiratory and obstetric records. RESULTS: We observed moderate falls in lung function immediately after delivery, which persisted at 12 months postpartum. We found that a decline in lung function at delivery was a marker for further decline in function during the subsequent postpartum period. We found baseline lung function was predictive of gestational age at delivery. We observed a high incidence of haemoptysis. CONCLUSION: Consistent with current guidance we found pregnancy is feasible and well tolerated in the majority of patients with cystic fibrosis. There was a high incidence of haemoptysis, which warrants further study.

The effects of an anabolic agent on body composition and pulmonary function in tetraplegia: a pilot study.

STUDY DESIGN: Prospective repeated-measures longitudinal study. OBJECTIVES: To determine if an 8-week course of an oral anabolic steroid can positively effect body composition or pulmonary function in healthy individuals with chronic tetraplegia. SETTING: United States. METHODS: Oxandrolone (20 mg per day) was administered for 8 weeks to 10 men with motor complete tetraplegia. Dual X-ray absorptiometry scans, pulmonary function tests (PFTs), serum lipids and liver function tests (LFTs) were obtained at baseline, 4, 8, 12 and 20 weeks. To analyze change over time, a repeated measures General Linear Model and nonparametric tests were utilized. RESULTS: Following treatment, total lean body mass (LBM) increased 1.9% and LBM of the arms increased 5.4%. Total body fat decreased 1.5%, and increased 3.9% in the arms and, on average, combined measures of PFTs improved 2.2%. High-density lipoprotein cholesterol decreased 31.8%, low density lipoprotein cholesterol increased 41.2%, and LFTs increased 9.7-65.6% while on therapy but all trended to baseline at 20 weeks. CONCLUSION: Baseline body composition was characterized by a high proportion of fat and a body mass index that underestimated chronic disease risk. Treatment with oxandrolone was associated with modest improvements in PFTs and in arm and total body LBM. Unfavorable changes in serum lipids and LFTs indicate that reported benefits of using oxandrolone in this population must be carefully weighed against potential adverse effects.

A limited association of generalized osteoarthritis with alleles at the type II collagen locus: COL2A1.

A significant genetic influence in osteoarthritis has been observed in the combination of Heberden's nodes and generalized osteoarthritis. We examined whether mutation in the gene encoding the major cartilage matrix protein type II collagen was responsible by comparing allele frequencies at the locus (COL2A1) in a group of 61 patients with nodal GOA with a control population and by analysing the COL2A1 genotypes of 21 affected sibling pairs. There were no significant allele differences but a slightly increased tendency over chance alone for affected siblings to have inherited the same COL2A1 alleles from their parents.

Prenatal diagnosis of osteogenesis imperfecta by identification of the concordant collagen 1 allele.

Dominantly inherited osteogenesis imperfecta is consistently linked to the two loci encoding the alpha 1 and alpha 2 subunits of collagen 1, the predominant bone collagen. We have performed several prenatal diagnoses based on identification of the segregating allele at the concordant locus in chorionic villus samples both in families where the linkage can be independently shown and in those where it cannot. Especially in the latter category, calculation of the final risk must incorporate an estimate of genetic heterogeneity within the OI population to give a prior probability of linkage. This figure can then be modified for each family by additional information from concordant meioses.

Basal metabolic rate in monozygotic and dizygotic twins.

The basal metabolic rate (BMR) was determined in 14 pairs of monozygotic (MZ; 11 females, 3 males) and 12 pairs of dizygotic (DZ; 10 females, 2 males) twins, with mean ages of 22.7 and 26 years. Zygosity was confirmed using DNA fingerprinting. When BMR was expressed as kJ/d, kJ/kg/d and kJ/kg FFM/d significant intra-class correlation coefficients were observed in the MZ twins of 0.82, 0.79 and 0.85, respectively. The DZ twins showed much lower intra-class correlations coefficients of 0.1, 0.07 and -0.04. Although the results of the study suggest a likely genetic component to the variation in BMR, they should be interpreted with caution as heritability estimates vary with the method of calculation. These will be critically discussed in the paper.

Amplification of the COL2A1 3' variable region used for segregation analysis in a family with the Stickler syndrome.

Amplification of a variable region 3' to the human type II collagen gene (COL2A1) has permitted segregation analysis in a three generation Stickler syndrome pedigree. This family had previously proved uninformative for the known restriction fragment length dimorphisms. Amplification of the variable region revealed five distinguishable alleles, of which three were segregating in this family. The lod score in favour of linkage was 2.86 at zero recombination.

Structural and segregation analysis of the type II collagen gene (COL2A1) in some heritable chondrodysplasias.

Seventy-seven persons with a variety of heritable chondrodysplasias were screened for gross rearrangements of the structural gene encoding the major cartilage collagen, collagen II. None was found. Segregation of the locus (COL2A1) was studied in 19 pedigrees using three restriction site dimorphisms (shown by PvuII, HindIII, and BamHI) and a length polymorphism as linkage markers. Discordant segregation between COL2A1 and the mutant locus was seen in pedigrees with multiple epiphyseal dysplasia, autosomal recessive spondyloepiphyseal dysplasia tarda, hypochondroplasia, pseudoachondroplasia, diaphyseal aclasis, and trichorhinophalangeal syndrome. One pedigree with diastrophic dysplasia was weakly concordant. Autosomal dominant spondyloepiphyseal dysplasia tarda and metaphyseal chondrodysplasia (type Schmid) were not informative. We conclude that mutations of the collagen II gene are not a common feature of the heritable chondrodysplasias. Since the chondrocyte binding protein, chondrocalcin, is also encoded at COL2A1 our conclusions apply equally to this gene.

Segregation of all four major fibrillar collagen genes in the Marfan syndrome.

Linkage markers at or close to the genes encoding the three major fibrillar collagens were used to analyze the segregation of these loci in six pedigrees with dominantly inherited Marfan syndrome. Four pedigrees were discordant at one of the Type I collagen loci (COL1A2), and, of these, two were discordant at the other Type I locus (COL1A1). The Marfan syndrome also segregated independently of the structural loci for Type II and Type III collagen in these two families. This is evidence against the Marfan syndrome being, in general, due to mutations in the major fibrillar collagen genes.

Common DNA polymorphism within coding sequence of apolipoprotein B gene associated with altered lipid levels.

60 of 83 middle-aged white men had an XbaI restriction site polymorphism within the coding sequence of the apolipoprotein B gene. Subjects homozygous and heterozygous for the presence of an XbaI restriction site had mean serum triglyceride levels 36% higher (p = 0.02) than those in homozygotes without the restriction site; there was a less substantial difference (p = 0.03) in serum cholesterol. The findings supported a dominant pattern of inheritance. The presence of this restriction site may increase the risk of atherosclerotic disease.

Insulin-like growth factor-II gene expression in Wilms' tumour and embryonic tissues.

Wilms' tumour (nephroblastoma) is an embryonal neoplasm occurring in hereditary and spontaneous forms. Both types show rearrangements of the short arm of chromosome 11. The germ line of children with the rare inherited triad of aniridia, genito-urinary abnormality and mental retardation carry a chromosome 11 that has a deletion in its short arm (band 11p13) and these children are at increased risk of developing Wilms' tumour. Neonates with the Beckwith-Wiedemann syndrome, in which there may be duplication of the 11p13-11p15 region, are similarly predisposed. In the spontaneous form of the tumour a deletion of the 11p14 band in tumour cells, but not in normal cells, has been reported, and the development of homozygosity for recessive mutations in the 11p region is implicated in the aetiology of Wilms' tumour. In view of these chromosomal rearrangements and because Wilms' tumour is histologically indistinguishable from the early stages of kidney development, we have now examined the expression of genes localized to 11p in Wilms' tumour and human embryonic tissue. In 12 sporadic tumours examined, the expression of the gene coding for insulin-like growth factor-II (IGF-II), localized to the 11p15 region, was markedly increased relative to adult tissues, but was comparable to the level of expression in several fetal tissues including kidney, liver, adrenals and striated muscle. This may reflect the stage of tumour differentiation, but could also contribute to the malignant process, as IGF-II is an embryonal mitogen.

The human apolipoprotein AII gene: structural organization and sites of expression.

The complete nucleotide sequence of the human apolipoprotein All gene together with 911 bases of 5' flanking sequence and 687 bases of 3' flanking sequence have been determined. The mRNA coding region is interrupted by three introns of 169, 293 and 395bp. The Intro-exon structure of the apo All gene is similar to that of the apo AI, apo CIII and apo E genes: three introns separate 4 coding sequences specifying the 5' untranslated region, pre-peptide, a short N-terminal domain and a C-terminal domain composed of a variable number of lipid-binding amphipathic helices. Intron II carries a 33bp dG-dT repetitive element adjacent to the 3' splice junction which has the potential to adopt the Z-DNA conformation. The 5' and 3' terminuses of the mRNA have been identified by primer extension and S1 nuclease mapping. A number of short direct repeats are found in the 5' flanking region and an inverted repeat occurs between the CAAT and TATA boxes. Downstream of the the gene is an Alu family repeat containing a polymorphic MspI site, the deletion of which is associated with increased circulating levels of apoAII. ApoAII gene expression was demonstrated in adult human liver and HepG2 cells but not in human small intestine. Of ten Rhesus monkey tissues examined apo All mRNA was detected only in liver.