An economic analysis of developmental detection methods

OBJECTIVE: To assess the costs and benefits of various approaches to early detection of developmental disabilities. DESIGN: Cost-benefit analyses based on data from previously published studies of developmental screening tests. SETTING: General pediatric practices and day care centers. PATIENTS AND OTHER PARTICIPANTS: A total of 247 parents and their 0- to 6-year-old children-103 from day care centers and 144 from pediatric practices. MAIN OUTCOME MEASURES: Licensed psychological examiners administered a screening test of parents' concerns about children's development and one or two direct screening tests: the Denver-II and/or the Battelle Developmental Inventory Screening Test. For the day care sample, examiners also administered to each child measures of intelligence, adaptive behavior, and language. In the pediatric sample, children were administered additional assessments. At the same time, diagnostic measures were administered to a randomly selected subsample to make determinations about developmental status. Each screening method was evaluated for its short-term costs (administration, interpretation, diagnosis, and treatment) and long-term benefits (impact of early intervention on adult functioning as inferred from longitudinal studies by other researchers). RESULTS: When the long-term costs and benefits were considered, none of the approaches emerged as markedly superior to another. When viewing the short-term costs, the various screening approaches differed markedly. The use of parents' concerns was by far the least costly for physicians to administer and interpret. CONCLUSION: Physicians can incur tremendous expenses when attempting to detect children with developmental problems. Although the benefits of early detection and intervention are substantial, physicians are not well-compensated for providing a critical service to society. Health policymakers and third-party payers must reconsider their minimal investment in early detection by health care providers. Nevertheless, our findings have encouraging implications for practice, because the use of parents' concerns as a screening technique offers substantial savings over and above other methods.     

Contribution of genetic and nutritional factors to DNA damage in heavy smokers

Prior epidemiological evidence suggests that genes controlling the metabolism of carcinogens and antioxidant/nutritional status are associated with lung cancer risk, possibly through their ability to modulate DNA damage by carcinogens. We performed a cross-sectional analysis of 159 heavy smokers from a cohort of subjects enrolled in a smoking cessation program. A total of 159 blood samples were analyzed to determine the relative contributions of genetic polymorphisms [CYP1A1 MspI and exon 7 and glutathione S-transferase M1 (GSTM1)] and plasma micronutrients to polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adduct levels. DNA damage in smokers was affected by genetic polymorphisms and nutritional status. Smokers with the CYP1A1 exon 7 valine polymorphism had significantly higher (2-fold, P < or = 0.03) levels of DNA damage than those without. In parallel models, PAH-DNA adducts were inversely associated with plasma levels of retinol (beta = -0.93, P = 0.01), beta-carotene (beta = -0.18, P = 0.09), and alpha- tocopherol (beta = -0.28, P = 0.21) in 159 subjects. The association between smoking-adjusted plasma beta-carotene levels and DNA damage was only significant in those subjects lacking the GSTM1 detoxification gene (beta = -0.30, P = 0.05, n = 75). There was a statistical interaction between beta-carotene and alpha-tocopherol; when beta- carotene was low, alpha-tocopherol had a significant protective effect (beta = -0.78, P = 0.04) on adducts, but not when beta-carotene was high (beta = -0.16, P = 0.57). Plasma alpha-tocopherol was significantly correlated with beta-carotene (r = 0.36, P = 0.0005) and less strongly with retinol (r = 0.20, P = 0.0005). These results suggest that several micronutrients may act in concert to protect against DNA damage and highlight the importance of assessing overall antioxidant status. In conclusion, a subset of smokers may be at increased risk of DNA damage and possibly lung cancer due to the combined effect of low plasma micronutrients and genetic susceptibility factors. The use of biological markers to assess efficacy of interventions and to study mechanisms of micronutrients is timely given the current debate regarding the use of chemopreventive agents in high risk populations.      

P53 expression in stage iii-iv squamous-cell carcinoma of the larynx - an immunohistochemical study related to clinicopathological, flow-cytometric DNA analysis and prognosis

A series of 71 patients undergoing radical surgical resection for stage III and IV laryngeal carcinoma (LC) consecutively diagnosed was prospectively studied in order to evaluate the relative weight of p53 expression in predicting clinical outcome, All the patients taking part in this study were followed up for a median of 18 months (range: 6-41 months). Positive staining for p53 protein was detected in 44 of 71 (62%) of these tumors on paraffin-embedded tissue, even in dysplastic areas. Among the clinico-pathological and biological parameters analyzed, only flow-cytometric S-phase (FCM-S) Values of turners showed a significant relationship to p53 immunostaining (p=0.01). With Kaplan-Meier estimation, in multivariate analysis only high FCM-S (>15.1) was independently related to risk of relapse (RR=5.82), while both FCM-S and site (subglottis) were related to risk of death (RR=6.83 and RR=14.3, respectively). These findings indicate that p53 immunoreactivity, though of no utility as a prognostic indicator, probably plays a role in the early stages of LC tumorigenesis.     

Comet assay application in environmental monitoring: DNA damage in human leukocytes and plant cells in comparison with bacterial and yeast tests

Urban airborne particulate is a complex mixture of air pollutants, many of which have not been identified. However, short-term mutagenesis tests together with chemicophysical parameter analysis are able to better assess air quality and genotoxic load. The findings of continuous monitoring (January 1991-August 1998) of urban air genotoxicity of a Po Valley town (Italy) on Salmonella typhimurium and Saccharomyces cerevisiae are reported. During this period, various measures (catalytic devices, unleaded fuels, annual vehicle overhaul, etc.) to improve air-dispersed pollutant control were enforced. However, a continuous presence of genotoxic compounds is shown and more qualitative than quantitative changes are evident. We also demonstrate the ability of the Comet assay to detect DNA-damaging agents in airborne particulate samples. We applied the test to human leukocytes and, with major improvements, to plant cells (Allium cepa roots and epigean tissues of Impatiens balsamina). The first findings on human leukocytes confirm the sensitivity of this assay, its peculiarity and its applicability in assessing genotoxicity in environmental samples. The capability of plants to show the response of multicellular organisms to environmental pollutants largely counterbalances a probable lowering in sensitivity. Moreover, application of the Comet test to epigean tissues could be useful in estimating the bioavailability of and genotoxic damage by air pollutants, including volatile compounds (ozone, benzene, nitrogen oxides, etc.) to higher plants.     

Cloning and characterization of DXS6673E, a candidate gene for X-linked mental retardation in Xq13.1

In several families with non-specific X-linked mental retardation (XLMR) linkage analyses have assigned the underlying gene defect to the pericentromeric region of the X chromosome, but none of these genes have been isolated so far. Here, we report on the cloning and characterization of a novel gene, DXS6673E, that maps to Xq13.1, is subject to X-inactivation and is disrupted in the 5' untranslated region by a balanced X;13 translocation in a mentally retarded female. The DXS6673E gene is highly conserved among vertebrates and its expression is most abundant in brain. It encodes a hydrophilic protein of 1358 amino acids (aa) that does not show sequence homology to other known proteins. A segment of this protein consisting of neutral and hydrophobic aa with a proline residue in every second position may represent a transmembrane domain. Almost complete sequence identity was found between the 3' end of the DXS6673E gene and two expressed sequence tags (ESTs) and between the 5' end of the DXS6673E gene and a third EST. Moreover, weaker sequence similarity was observed between coding regions and two other ESTs.      

Quantitation and characterization of soluble immune complexes precipitated from sera by polyethylene glycol (PEG).

Polyethylene glycol (PEG) was used to isolate immune complexes from sera. Complexes were then quantified and partially characterized by a variety of immunological techniques. Complexes were detected in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Felty''s syndrome and vasculitis, but not in polymyositis, scleroderma or Behçets syndrome. The level of immune complexes correlated with disease activity in SLE and RA patients. Rheumatoid factors and anti-DNA antibodies were enriched by PEG precipitation of RA and SLE sera, respectively, thus these antibodies appeared to be present in the form of soluble immune complexes. Immune complexes usually contained all three immunoglobulin classes, IgG, IgM and IgA. Complexes from RA patients were generally larger and often contained Clq, while C3 was found almost exclusively in SLE complexes which also tended to be smaller. Such compositional differences may one day explain the differences in clinical manifestations of various immune complex-mediated diseases.     

Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR

Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age- related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G- >T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G- >A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.      

A Pro51Ser mutation in the COCH gene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects

We analysed a Dutch family with autosomal dominant non-syndromic progressive sensorineural hearing loss and mapped the underlying gene defect by genetic linkage analysis to a 11.0 cM region overlapping the DFNA9 interval on chromosome 14q12-q13. Clinically, the Dutch family differs from the original DFNA9 family by a later age at onset and a more clearly established vestibular impairment. A gene that is highly and specifically expressed in the human fetal cochlea and vestibule, COCH (previously described as Coch5B2 ), was mapped to the DFNA9 critical region. Sequence analysis revealed a 208C-->T mutation in the COCH gene, resulting in a Pro51Ser substitution in the predicted protein in all affected individuals of the family but not in unaffected family members and 200 control individuals. The same mutation was also identified in three apparently unrelated families with a similar phenotype, suggesting the presence of a Dutch founder mutation. The function of COCH is unknown but several characteristics of the protein point to a structural role in the extracellular matrix. The mutant serine at position 51 is situated between cysteines and possibly interferes with proper COCH protein folding or its interaction with extracellular matrix proteins.      

Evaluation of swallowing disorders in multiple sclerosis

Neurological Sciences - Swallowing disorders are present in more than one-third of multiple sclerosis (MS) patients. Dysphagia in MS usually receives limited attention, maybe because of the...