TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Interactive effects of soil acidity and fluoride on soil solution aluminium chemistry and barley (Hordeum vulgare L.) root growth.

A greenhouse study was conducted to determine if concentrations of fluoride (F), which would be added to acid soils via P fertilisers, were detrimental to barley root growth. Increasing rates of F additions to soil significantly increased the soil solution concentrations of aluminium (Al) and F irrespective of the initial adjusted soil pH, which ranged from 4.25 to 5.48. High rates of F addition severely restricted root growth; the effect was more pronounced in the strongly acidic soil. Speciation calculations demonstrated that increasing rates of F additions substantially increased the concentrations of Al-F complexes in the soil. Stepwise regression analysis showed that it was the combination of the activities of AlF2(1+) and AlF(2+) complexes that primarily controlled barley root growth. The results suggested that continuous input of F to soils, and increased soil acidification, may become an F risk issue in the future.

Drug-induced ototoxicity: Mechanisms, Pharmacogenetics, and protective strategies.

Drug ototoxicity limits the quality of life of patients after treatment, having serious consequences, especially for psychosocial development of children. Although the ototoxicity of many drugs resolves after treatment discontinuation, the use of platinum derivatives and aminoglycosides is associated with permanent hearing loss. In this review, we have listed ototoxic drugs and the mechanisms by which they damage the ears. Moreover, possible protective strategies and important methods for early detection of ototoxic effects are discussed.

Synthesis, stereochemistry, and analgesic activity of 4-mono- and 4,4-disubstituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines.

The synthesis of 4-alkyl-, 4-aralkyl-, and 4-alkenyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines is described together with some 4,4-disubstituted and 8-hydroxy derivatives. Evidence of the stereochemistry of the 4-substituent was from 1H and 13C NMR. In the 4-methyl series the equatorial epimer 1b has a higher analgesic (hot-plate) potency than 1a, and 10a, 10c, and 10f are also good agonists. 5a afforded analgesic properties without an antagonist component. Surprisingly 10d, bearing an 8-OH function, was without analgesic activity, contrasting with the significant hot-plate activity exhibited by 1,2,3,4,5,6-hexahydro-3,5,6-trimethyl-2,6-methano-3-benzazocine. If the assumption is made that the more active enantiomorph in members of this series is configurationally related to (-)-morphine, then it may be that the enantiotopic edge in hexahydro-2,6-methano-3-benzazocines has a narrow steric requirement for analgesic responses.

Analgesic actions of 3-substituted 6-tert-butyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines.

The synthesis of four 3-substituted 6-tert-butyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines is described. Derivatives with N-Me or N-phenethyl substituents do not differ significantly in their antinociceptive properties from compounds bearing 6-H or 6-Me; however, they are less active than 6-Ph analogues.

Preparation and analgesic activity of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines.

Dihydrocodeinone oxime (1) under Beckmann rearrangement conditions gave a product (2) that facilitated the preparation of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines, a hitherto little-examined series of morphine partial structures. Compounds 7a and 12 gave good levels of agonist antinociceptive activity. Masking of the 8-oxygen function, as in 6 and 8, dramatically reduced mouse hot-plate activity, as did its loss (9).

Familial paracentric inversion of 1p.

We report a paracentric inversion of 1p in a boy with mild mental retardation. The chromosome aberration was identified by high resolution chromosome banding, and was also present in his phenotypically normal mother and other relatives. The boy's karyotype was considered to be 46,XY,inv(1) (p31,2p36.22) ISCN (1981).

Direct intrachromosomal duplication of 16q and heritable fragile site fra (10) (q25) in the same patient.

We describe a woman with profound mental retardation and a direct duplication of 16q and fragile site fra(10)(q25). The identification and possible origin of the duplicated 16q is discussed along with the clinical manifestations. To our knowledge this is the first direct duplication of 16q to be reported. The karyotype is shown to be 46,XX, dir dup (16) (q11.2----q13).

Translocation (2;14) associated with complex rearrangements of the Ig heavy chain in non-Hodgkin lymphoma.

Cytogenetic analysis of a patient with non-Hodgkin lymphoma revealed the following karyotype: 49,XXX,t(2;14)(q21;q32),+4,+8,del(13)(q14q21). Southern blot analysis with an Ig region probe showed non-productive rearrangements indicative of a translocation involving the Ig locus. However, molecular cloning of the abnormal rearrangements did not show novel sequences derived from chromosome 2 but showed that the BCL-6 gene was juxtaposed to the IgH enhancer. Three further clones with abnormal rearrangements involving the Ig locus, particularly Iggamma3, were isolated. This suggests that the mature lymphoid cells, in this patient, were capable of undergoing indiscriminate switch cleavage and religation.

Optical purity determination by NMR: use of chiral lanthanide shift reagents and a base line technique.

A method for optical purity determination of a range of chiral drug molecules by NMR spectroscopy is reported. This technique involves the use of optically active lanthanide shift reagents and a newly developed base line analysis. Its applicability was demonstrated for a variety of drugs including nonsteroidal antiinflammatory agents and some adrenergic agents. It is established that successful application of the method depends on a constant shift reagent to sample molar ratio, constant instrumental conditions for all solutions, and the use of a calibration curve derived from solutions containing the same total concentration of the two enantiomers. For the examples cited, the correlation coefficient is not less than 0.97, and a mathematical treatment is included which supports the basis of the method.

Modelling organic matter dynamics in New Zealand soils.

To ensure the sustainability of land systems in terms of nutrient cycling and maintenance of soil physical conditions, there is a need to understand soil organic matter (SOM) and its dynamics. It has been suggested that soil-carbon (C) models developed internationally do not perform well under New Zealand's unique climatic and soil mineralogical conditions. To test this hypothesis, we conducted 14C-labelled ryegrass decomposition studies and assessed the influence of abiotic factors on decomposition rates. These factors were characterized by estimating system mean residence times (MRTs) from estimates of first-order rate coefficients in a simple, three-compartment model. A range of MRTs obtained for decomposition was related to climatic conditions and soil properties. We summarise this work and extend this study to apply the Rothamsted soil-C turnover model, a five-compartment model, to our data with the view of testing both the model projections and the decomposability factors assumed in the model.

Studies of carbon-13 n.m.r. spectroscopy in pharmaceutical analysis: the composition of commercial samples of gentamicin sulphate.

Two procedures for applying 13C n.m.r. spectroscopy to the quantitative analysis of the C1, C1a, and C2 components of gentamicin sulphate samples are described. One is based on the use of calibration plots of peak height ratios of analyte to standard (dioxan) resonance intensities recorded under conditions of full relaxation, the other upon a steady-state experiment and the use of weighting factors. Spectrometer operating conditions are discussed, and the need for measurement of longitudinal relaxation time (T1) data described. Results for seven commercial samples are given and comparisons made between the two n.m.r. methods and an h.p.l.c. procedure in terms of accuracy, specificity and convenience.

Three approaches to define desired soil organic matter contents.

Soil organic C is often suggested as an indicator of soil quality, but desirable targets are rarely specified. We tested three approaches to define maximum and lowest desirable soil C contents for four New Zealand soil orders. Approach 1 used the New Zealand National Soils Database (NSD). The maximum C content was defined as the median value of long-term pastures, and the lower quartile defined the lowest desirable soil C content. Approach 2 used the CENTURY model to predict maximum C contents of long-term pasture. Lowest desirable content was defined by the level that still allowed recovery to 80% of the maximum C content over 25 yr. Approach 3 used an expert panel to define desirable C contents based on production and environmental criteria. Median C contents (0-20 cm) for the Recent, Granular, Melanic, and Allophanic orders were 72, 88, 98, 132 Mg ha(-1), and similar to contents predicted by the CENTURY model (78, 93, 102, and 134 Mg ha(-1), respectively). Lower quartile values (54, 78, 73, and 103 Mg ha(-1), respectively) were similar to the lowest desirable C contents calculated by CENTURY (55, 54, 67, and 104 Mg ha(-1), respectively). Expert opinion was that C contents could be depleted below these values with tolerable effects on production but less so for the environment. The CENTURY model is our preferred approach for setting soil organic C targets, but the model needs calibrating for other soils and land uses. The statistical and expert opinion approaches are less defensible in setting lower limits for desirable C contents.