Exon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency

CONTEXT AND OBJECTIVE: Alteration of exon splice enhancers (ESE) may cause autosomal dominant GH deficiency (IGHD II). Disruption analysis of a (GAA) (n) ESE motif within exon 3 by introducing single-base mutations has shown that single nucleotide mutations within ESE1 affect pre-mRNA splicing. DESIGN, SETTING, AND PATIENTS: Confirming the laboratory-derived data, a heterozygous splice enhancer mutation in exon 3 (exon 3 + 2 A-->C) coding for GH-E32A mutation of the GH-1 gene was found in two independent pedigrees, causing familial IGHD II. Because different ESE mutations have a variable impact on splicing of exon 3 of GH and therefore on the expression of the 17.5-kDa GH mutant form, the GH-E32A was studied at the cellular level. INTERVENTIONS AND RESULTS: The splicing of GH-E32A, assessed at the protein level, produced significantly increased amounts of 17.5-kDa GH isoform (55% of total GH protein) when compared with the wt-GH. AtT-20 cells coexpressing both wt-GH and GH-E32A presented a significant reduction in cell proliferation as well as GH production after forskolin stimulation when compared with the cells expressing wt-GH. These results were complemented with confocal microscopy analysis, which revealed a significant reduction of the GH-E32A-derived isoform colocalized with secretory granules, compared with wt-GH. CONCLUSION: GH-E32A mutation found within ESE1 weakens recognition of exon 3 directly, and therefore, an increased production of the exon 3-skipped 17.5-kDa GH isoform in relation to the 22-kDa, wt-GH isoform was found. The GH-E32A mutant altered stimulated GH production as well as cell proliferation, causing IGHD II.

Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.

Associations with multiple pituitary hormone deficiency in patients with an ectopic posterior pituitary gland

INTRODUCTION: The presence of an ectopic posterior pituitary gland (EPP) on magnetic resonance imaging (MRI) is associated with hypopituitarism with one or more hormone deficiencies. We aimed to identify risk factors for having multiple pituitary hormone deficiency (MPHD) compared to isolated growth hormone deficiency (IGHD) in patients with an EPP. METHODS: In 67 patients (45 male) with an EPP on MRI, the site (hypothalamic vs. stalk) and surface area (SA) [ x (maximum diameter/2) x (maximum height/2), mm(2)] of the EPP were recorded and compared in patients with IGHD and MPHD in relation to clinical characteristics. RESULTS: In MPHD (n = 32) compared to IGHD (n = 35) patients: age of presentation was younger (1.4 [0.1-10.7]vs. 4.0 [0.1-11.3] years, P = 0.005), major incidents during pregnancy were increased (47%vs. 20%, P = 0.02) as were admissions to a neonatal intensive care unit (NICU) (60%vs. 26%, P = 0.04), whilst EPP SA was lower (12.3 [2.4-34.6]vs. 25.7 [6.9-48.2] mm(2), P < 0.001). In patients with a hypothalamic (n = 56) compared to a stalk sited EPP (n = 11): prevalence of MPHD was greater (55%vs. 9%,P = 0.05) and EPP surface area was smaller (17.3 [2.4-48.2]vs. 25.3 [11.8-38.5] mm(2), P < 0.001). In regression analysis, after adjusting for age, presence of MPHD was associated with: major incidents during pregnancy (RR 6.8 [95%CI 1.2-37.7]), hypothalamic EPP site (RR 10.9 [1.0-123.9]) and small EPP SA (RR 2.5 [1.0-5.0] for tertiles of SA). CONCLUSION: In patients with an EPP, adverse antenatal events, size (small) and position (hypothalamic) of the posterior pituitary gland on MRI were associated with MPHD. These findings suggest that adverse factors during pregnancy may be important for the development of an EPP.

Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency

CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

Numerical study of Anderson localization of terahertz waves in disordered waveguides

We present a numerical study of electromagnetic wave transport in disordered quasi-one-dimensional waveguides at terahertz frequencies. Finite element method calculations of terahertz wave propagation within LiNbO3 waveguides with randomly arranged air-filled circular scatterers exhibit an onset of Anderson localization at experimentally accessible length scales. Results for the average transmission as a function of waveguide length and scatterer density demonstrate a clear crossover from diffusive to localized transport regime. In addition, we find that transmission fluctuations grow dramatically when crossing into the localized regime. Our numerical results are in good quantitative agreement with theory over a wide range of experimentally accessible parameters both in the diffusive and localized regime opening the path towards experimental observation of terahertz wave localization.

Adults Can Be Trained to Acquire Synesthetic Experiences

Synesthesia is a condition where presentation of one perceptual class consistently evokes additional experiences in different perceptual categories. Synesthesia is widely considered a congenital condition, although an alternative view is that it is underpinned by repeated exposure to combined perceptual features at key developmental stages. Here we explore the potential for repeated associative learning to shape and engender synesthetic experiences. Non-synesthetic adult participants engaged in an extensive training regime that involved adaptive memory and reading tasks, designed to reinforce 13 specific letter-color associations. Following training, subjects exhibited a range of standard behavioral and physiological markers for grapheme-color synesthesia; crucially, most also described perceiving color experiences for achromatic letters, inside and outside the lab, where such experiences are usually considered the hallmark of genuine synesthetes. Collectively our results are consistent with developmental accounts of synesthesia and illuminate a previously unsuspected potential for new learning to shape perceptual experience, even in adulthood.

Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone.

BACKGROUND The long-term safety of growth hormone treatment is uncertain. Raised risks of death and certain cancers have been reported inconsistently, based on limited data or short-term follow-up by pharmaceutical companies. PATIENTS AND METHODS The SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study assembled cohorts of patients treated in childhood with recombinant human growth hormone (r-hGH) in 8 European countries since the first use of this treatment in 1984 and followed them for cause-specific mortality and cancer incidence. Expected rates were obtained from national and local general population data. The cohort consisted of 24,232 patients, most commonly treated for isolated growth failure (53%), Turner syndrome (13%) and growth hormone deficiency linked to neoplasia (12%). This paper describes in detail the study design, methods and data collection and discusses the strengths, biases and weaknesses consequent on this. CONCLUSION The SAGhE cohort is the largest and longest follow-up cohort study of growth hormone-treated patients with follow-up and analysis independent of industry. It forms a major resource for investigating cancer and mortality risks in r-hGH patients. The interpretation of SAGhE results, however, will need to take account of the methods of cohort assembly and follow-up in each country.

Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases.

Biomarkers of disease activity have come into wide use in the study of mechanisms of human disease and in clinical medicine to both diagnose and predict disease course; as well as to monitor response to therapeutic intervention. Here we review biomarkers of the involvement of mast cells, basophils, and eosinophils in human allergic inflammation. Included are surface markers of cell activation as well as specific products of these inflammatory cells that implicate specific cell types in the inflammatory process and are of possible value in clinical research as well as within decisions made in the practice of allergy-immunology.

A Bayesian analysis for spatial processes with application to mapping

In geographical epidemiology, maps of disease rates and disease risk provide a spatial perspective for researching disease etiology. For rare diseases or when the population base is small, the rate and risk estimates may be unstable. Empirical Bayesian (EB) methods have been used to spatially smooth the estimates by permitting an area estimate to "borrow strength" from its neighbors. Such EB methods include the use of a Gamma model, of a James-Stein estimator, and of a conditional autoregressive (CAR) process. A fully Bayesian analysis of the CAR process is proposed. One advantage of this fully Bayesian analysis is that it can be implemented simply by using repeated sampling from the posterior densities. Use of a Markov chain Monte Carlo technique such as Gibbs sampler was not necessary. Direct resampling from the posterior densities provides exact small sample inferences instead of the approximate asymptotic analyses of maximum likelihood methods (Clayton & Kaldor, 1987). Further, the proposed CAR model provides for covariates to be included in the model. A simulation demonstrates the effect of sample size on the fully Bayesian analysis of the CAR process. The methods are applied to lip cancer data from Scotland, and the results are compared. ^

d18O, lithologies, mineralogy and determination of temperature and depth of formation of DSDP Site 69-504 siliceous rocks

Seven opal-CT-rich and five quartz-rich porcellanites and cherts from Site 504 have a range in oxygen-isotope values of 24.4 and 29.4 per mil. In opal-CT rocks, d18O becomes larger with sub-bottom depth and with age. Quartz-rich rocks do not show these trends. Boron, in general, increases with decreasing d18O for porcellanites and cherts considered together, supporting the conclusion that boron is incorporated within the quartz crystal structure during precipitation of the SiO2. Silicification of the chalks at Site 504 began 1 m.y. ago - that is, 5 m.y. after sedimentation commenced on the oceanic crust. Temperatures of chert formation determined from oxygen-isotope compositions reflect diagenetic temperatures rather than bottom-water temperatures, and are comparable to temperatures of formation determined by down-hole measurements. Opal-A in the chalks began conversion to opal-CT when a temperature of 50°C was reached in the sediment column. Conversion of opal-CT to quartz started at 55 °C. Silicification occurred over a stratigraphic thickness of about 10 meters when the temperature at the top of the 10 meters reached about 50°C. It took about 250,000 years to complete the silica transformation within each 10-meter interval of sediment at Site 504. Quartz formed over a stratigraphic range of at least 30 meters, at temperatures of about 54 to 60°C. The time and temperatures of silicification of Site 504 rocks are more like those at continental margins than those in deep-sea, open-ocean deposits.

Lead and strontium isotopic composition of some metalliferous and pelagic sediments and basalts at DSDP Leg 70 Holes

In recent years, metalliferous sediments have been discovered overlying newly generated oceanic crust in the East Pacific, North Atlantic, Indian Ocean, Red Sea, Gulf of Aden, and elsewhere (e.g., Boström, 1973; Lalou et al., 1977; Bischoff, 1969; Boström and Fisher, 1971; Cann et al., 1977, respectively). Such material has also been recovered by drilling from sediments lying upon older oceanic crust (Boström et al., 1972, 1976; Horowitz and Cronan, 1976). Hydrothermal circulation of seawater at a spreading ridge results in the leaching of Fe, Mn, and possibly other elements from the basaltic volcanic layer and their transport and discharge into ocean bottom waters, whereupon fine-grained Fe-Mn-rich precipitates form and settle into the ambient sediment (cf. Corliss, 1971; Dasch et al., 1971; Spooner and Fyfe, 1973; Bischoff and Dickson, 1975; Heath and Dymond, 1977; Corliss et al., 1979, Edmond et al., 1979). Mn-rich crusts have also been recovered from active ridges and are inferred to have formed in the vicinity of hydrothermal discharge areas (Scott et al., 1974; Moore and Vogt, 1976; Corliss et al., 1978; Hoffert et al., 1978). The source of the trace elements in the metalliferous deposits is generally not clear. They may be derived from seawater by adsorption onto the precipitates or crusts, or from hydrothermal solutions which have leached them from the basalts. Pb, however, can be used as a geochemical tracer because of the known isotopic compositional differences between oceanic basalts and seawater. Isotopic investigations of Pb in ferruginous sediments from the East Pacific have shown that it has been derived partly or mostly from a basaltic source (Bender et al., 1971; Dasch et al., 1971; Dymond et al., 1973). In the present study, Pb isotopic analyses have been made of a suite of metalliferous sediments (nontronite, Mn-oxide crust, Mn-Fe-oxide mud), pelagic sediments, and basalts from the Galapagos mounds area. The main purposes of the Pb study were to determine the source or sources of Pb in the metalliferous sediments, and whether or not stratigraphic variations exist in the isòtopic composition of Pb in the sediments.