Cost-effectiveness of fibronectin testing in a triage in women with threatened preterm labor: alleviation of pregnancy outcome by suspending tocolysis in early labor (APOSTEL-I trial)

BACKGROUND: At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective. METHODS/DESIGN: We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, beta 0.2, alpha 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin. DISCUSSION: This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor. TRIAL REGISTRATION: Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl

Localization of DNA probes with tight linkage to the cystic fibrosis locus by in situ hybridization using fibroblasts with a 7q22 deletion

Five DNA probes known to originate from the region 7q22-q31 were sublocalized by in situ hybridization to metaphase preparations of fibroblasts having besides a normal chromosome 7, a homologue 7 with an apparent interstitial deletion of a large part of band q22. A flow cytometric chromosome analysis confirmed a loss of material from one of the homologues of chromosome 7. Four of the probes, B79a, 7C22, metH, and pJ3.11, have been shown to be closely linked to the cystic fibrosis (CF) locus. We localized probes B79a and 7C22 to the part of 7q22 involved in the deletion, whereas metH and pJ3.11 could be assigned to band 7q31. Probe pJu28, for which polymorphisms have not yet been described, also appeared to derive from the latter band. Since pJ3.11 and metH are most tightly linked to the CF locus, this disease locus is indirectly assigned to 7q31. A comparison of our findings with linkage data suggests a discrepancy between genetic and physical distances in the region 7q22-q31

Localization at a subband level of polymorphic 13q14 DNA probes for diagnosis of hereditary retinoblastoma and Wilson disease

Two single-copy DNA sequences, pG24E6.8 (D13S21) detecting a low-frequency MspI RFLP and pG14E1.9 (D13S22) detecting a high-frequency DraI RFLP, have been isolated and cloned from a human chromosome 13-specific phage library and localized at 13q14. Their subband localization was described using a panel of cell lines from patients with different chromosome 13 deletions. A quantitative analysis of hybridization signals was carried out, taking for reference a single-copy DNA sequence from another chromosome. D13S21 and D13S22 were both assigned to q14.1-14.2, which also harbors the genes responsible for retinoblastoma and Wilson disease. The DraI polymorphism detected by pG14E1.9 is a very suitable one for linkage studies in families with either diseas

FISH and array-CGH analysis of a complex chromosome 3 aberration suggests that loss of CNTN4 and CRBN contributes to mental retardation in 3pter deletions

Imbalances of 3p telomeric sequences cause 3p- and trisomy 3p syndrome, respectively, showing distinct, but also shared clinical features. No causative genes have been identified in trisomy 3p patients, but for the 3p- syndrome, there is growing evidence that monosomy for one or more of four genes at 3pter, CHL1, CNTN4, CRBN and MEGAP/srGAP3, may play a causative role. We describe here an analysis of a complex chromosome 3p aberration in a severely mentally retarded patient that revealed two adjacent segments with different copy number gains and a distal deletion. The deletion in this patient included the loci for CHL1, CNTN4, and CRBN, and narrowed the critical segment associated with the 3p- syndrome to 1.5 Mb, including the loci for CNTN4 and CRBN. We speculate that the deletion contributes more to this patient's phenotype than the gains that were observed. We suggest that 3p- syndrome associated features are primarily caused by loss of CNTN4 and CRBN, with loss of CHL1 probably having an additional detrimental effect on the cognitive functioning of the present patient. (c) 2006 Wiley-Liss, Inc

Functional analysis of lung tumor suppressor activity at 3p21.3

The early and frequent occurrence of deletions at 3p21.3 in lung cancer has led to the consideration of this chromosomal region as a lung cancer (LUCA) critical region with tumor suppressor activity. We covered this 19 genes-containing region with overlapping PI artificial chromosomes (PACs), in which genes are likely accompanied by their own promoters or other regulatory sequences. With these PACs we transfected cells from a small cell lung cancer (SCLC) cell line which readily caused tumors in nude mice. Per PAC we selected two cell clones with a low number of PAC copies integrated at a single genomic site. The selected clones were s.c. injected into nude mice to investigate whether the integrated genes suppressed the tumor-inducing capacity of the original SCLC cell line. We could demonstrate PAC-specific gene expression in the transfected cells. All of the PAC integration sites were different. It appeared that introduction of a PAC or even an empty PAC vector causes some chromosomal instability, which in principle may either promote or inhibit cell growth. However, both cell clones with integration of the same PAC from the centromeric part of the LUCA region in different genomic sites were the sole pair of clones that caused smaller tumors than did the original SCLC cell line. This suggests that rather than the induced chromosomal instability, the DNA sequence of that PAC, which in addition to two protein-encoding genes contains at least one potential miRNA gene, is responsible for the tumor suppressor activity. (c) 2006 Wiley-Liss, Inc

Analysis of a new homozygous deletion in the tumor suppressor region at 3p12.3 reveals two novel intronic noncoding RNA genes

Homozygous deletions or loss of heterozygosity (LOH) at human chromosome band 3p12 are consistent features of lung and other malignancies, suggesting the presence of a tumor suppressor gene(s) (TSG) at this location. Only one gene has been cloned thus far from the overlapping region deleted in lung and breast cancer cell lines U2020, NCI H2198, and HCC38. It is DUTTI (Deleted in U Twenty Twenty), also known as ROBO1, FLJ21882, and SAX3, according to HUGO. DUTTI, the human ortholog of the fly gene ROBO, has homology with NCAM proteins. Extensive analyses of DUTTI in lung cancer have not revealed any mutations, suggesting that another gene(s) at this location could be of importance in lung cancer initiation and progression. Here, we report the discovery of a new, small, homozygous deletion in the small cell lung cancer (SCLC) cell line GLC20, nested in the overlapping, critical region. The deletion was delineated using several polymorphic markers and three overlapping PI phage clones. Fiber-FISH experiments revealed the deletion was approximately 130 kb. Comparative genomic sequence analysis uncovered short sequence elements highly conserved among mammalian genomes and the chicken genome. The discovery of two EST clusters within the deleted region led to the isolation of two noncoding RNA (ncRNA) genes. These were subsequently found differentially expressed in various tumors when compared to their normal tissues. The ncRNA and other highly conserved sequence elements in the deleted region may represent miRNA targets of importance in cancer initiation or progression. Published 2006 Wiley-Liss, Inc.(dagger)