Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Since we have been a dialogue: Blanchot's 'Entretiens'

At the turn of the 1960s, Maurice Blanchot began publishing texts that he named entretiens, this change in his writing responding to what deconstruction sees as the closure of logocentric or continuous discourse. Paradoxically, this closure does not prevent such discourse, in which philosophical enquiry and technological change are intertwined, from dominating the modern world. By changing his writing, and by reiterating the dialogical form so central to metaphysical tradition since Plato, Blanchot gives voice to the tensions between continuity and its ‘outside’, between philosophy and literature. This is one sense in which his entretiens do not engage in a representation of difference, but instead open themselves to the inflections of what Jean-Luc Nancy calls le partage des voix.

Theoretical insight into diagnosing observation error correlations using observation-minus-background and observation-minus-analysis statistics

To improve the quantity and impact of observations used in data assimilation it is necessary to take into account the full, potentially correlated, observation error statistics. A number of methods for estimating correlated observation errors exist, but a popular method is a diagnostic that makes use of statistical averages of observation-minus-background and observation-minus-analysis residuals. The accuracy of the results it yields is unknown as the diagnostic is sensitive to the difference between the exact background and exact observation error covariances and those that are chosen for use within the assimilation. It has often been stated in the literature that the results using this diagnostic are only valid when the background and observation error correlation length scales are well separated. Here we develop new theory relating to the diagnostic. For observations on a 1D periodic domain we are able to the show the effect of changes in the assumed error statistics used in the assimilation on the estimated observation error covariance matrix. We also provide bounds for the estimated observation error variance and eigenvalues of the estimated observation error correlation matrix. We demonstrate that it is still possible to obtain useful results from the diagnostic when the background and observation error length scales are similar. In general, our results suggest that when correlated observation errors are treated as uncorrelated in the assimilation, the diagnostic will underestimate the correlation length scale. We support our theoretical results with simple illustrative examples. These results have potential use for interpreting the derived covariances estimated using an operational system.

Application of data assimilation to ocean and climate prediction

Ocean prediction systems are now able to analyse and predict temperature, salinity and velocity structures within the ocean by assimilating measurements of the ocean’s temperature and salinity into physically based ocean models. Data assimilation combines current estimates of state variables, such as temperature and salinity, from a computational model with measurements of the ocean and atmosphere in order to improve forecasts and reduce uncertainty in the forecast accuracy. Data assimilation generally works well with ocean models away from the equator but has been found to induce vigorous and unrealistic overturning circulations near the equator. A pressure correction method was developed at the University of Reading and the Met Office to control these circulations using ideas from control theory and an understanding of equatorial dynamics. The method has been used for the last 10 years in seasonal forecasting and ocean prediction systems at the Met Office and European Center for Medium-range Weather Forecasting (ECMWF). It has been an important element in recent re-analyses of the ocean heat uptake that mitigates climate change.

A joint state and parameter estimation scheme for nonlinear dynamical systems

We present a novel algorithm for concurrent model state and parameter estimation in nonlinear dynamical systems. The new scheme uses ideas from three dimensional variational data assimilation (3D-Var) and the extended Kalman filter (EKF) together with the technique of state augmentation to estimate uncertain model parameters alongside the model state variables in a sequential filtering system. The method is relatively simple to implement and computationally inexpensive to run for large systems with relatively few parameters. We demonstrate the efficacy of the method via a series of identical twin experiments with three simple dynamical system models. The scheme is able to recover the parameter values to a good level of accuracy, even when observational data are noisy. We expect this new technique to be easily transferable to much larger models.

A moving-point approach to model shallow ice sheets: a study case with radially symmetrical ice sheets

Predicting the evolution of ice sheets requires numerical models able to accurately track the migration of ice sheet continental margins or grounding lines. We introduce a physically based moving-point approach for the flow of ice sheets based on the conservation of local masses. This allows the ice sheet margins to be tracked explicitly. Our approach is also well suited to capture waiting-time behaviour efficiently. A finite-difference moving-point scheme is derived and applied in a simplified context (continental radially symmetrical shallow ice approximation). The scheme, which is inexpensive, is verified by comparing the results with steady states obtained from an analytic solution and with exact moving-margin transient solutions. In both cases the scheme is able to track the position of the ice sheet margin with high accuracy.

Oculoauriculovertebral spectrum: report of nine familial cases with evidence of autosomal dominant inheritance and review of the literature

Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is a complex condition characterized by defects of aural, oral, mandibular and vertebral development. The aetiology of this condition is likely to be heterogeneous; most cases are sporadic, however, familial cases suggesting autosomal recessive end autosomal dominant inheritance have been reported. In this study, we describe the clinical aspects of nine familial cases with evidence of autosomal dominant inheritance and compare them with reports in the literature. Interfamilial and intrafamilial clinical variabilities were observed in this study (reinforcing the necessity of careful examination of familial members). We suggest that oculoauriculovertebral spectrum with autosomal dominant inheritance is characterized mainly by bilateral auricular involvement and rarely presents extracranial anomalies. Clin Dysmorphol 18:67-77 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

22q11 deletion syndrome and limb anomalies: Report on two Brazilian patients

Objective: To report on two Brazilian patients with chromosome 22q11 deletion who presented with velopharyngeal insufficiency, congenital heart anomalies, developmental delay, and limb anomalies. The pattern of limb anomalies in these patients, which range from ectrodactyly to limb synostosis, is very uncommon in 22q11 deletion syndrome. Conclusion: These patients widen the spectrum of clinical signs of the 22q11 deletion syndrome and alert researchers to conduct additional investigation in patients with limb involvement with velopharyngeal insufficiency and/or cardiac anomalies, along with developmental delay.

Phylogenetic group distribution among Escherichia coli isolated from rivers in Sao Paulo State, Brazil

The phylogenetic group distribution of Escherichia coli strains isolated from the Sorocaba and Jaguari Rivers located in the State of Sao Paulo, Brazil, is described. E. coli strains from group D were found in both rivers while one strain from group B2 was isolated from the Sorocaba river. These two groups often include strains that can cause extraintestinal diseases. Most of the strains analyzed were allocated into the phylogenetic groups A and B1, supporting the hypothesis that strains from these phylogenetic groups are more abundant in tropical areas. Though both rivers are located in urbanized and industrialized areas where the main source of water pollution is considered to derive from domestic sewage, our results suggest that the major sources of contamination in the sampling sites of both rivers might have originated from animals and not humans.

Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies

Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype (similar to 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.

NHE1, NHE2, and NHE4 contribute to regulation of cell pH in T84 colon cancer cells

The isoforms of the Na+/H+ exchanger present in T84 human colon cells were identified by functional and molecular methods. Cell pH was measured by fluorescence microscopy using the probe BCECF. Based on the pH recovery after an ammonium pulse and determination of buffering capacity of these cells, the rate of H+ extrusion (J(H)) was 3.68 mM/min. After the use of the amiloride derivative HOE-694 at 25 mu M, which inhibits the isoforms NHE1 and NHE2, there remained 43% of the above transport rate, the nature of which was investigated. Evidence of the presence of NHE1, NHE2, and NHE4 was obtained by reverse transcriptase polymerase chain reaction (RT-PCR) (mRNA) and Western blot. There was no decrease of J(H) by the NHE3 inhibitor S3226 (1 mu M) and no evidence of this isoform by RT-PCR was found. The following functional evidence for the presence of NHE4 was obtained: 25 mu M EIPA abolished J(H) entirely, but NHE4 was not inhibited at 10 mu M; substitution of Na by K increased the remainder, a property of NHE4; hypertonicity also increased this fraction of J(H). Cl--dependent NHE was not detected: in 0 Cl- solutions J(H) was increased and not reduced. In 0 Cl- cell volume decreased significantly, which was abolished by the Cl- channel blocker NPPB, indicating that the 0 Cl- effect was because of reduction of cell volume. In conclusion, T84 human colon cells contain three isoforms of the Na+/H+ exchanger, NHE1, NHE2, and NHE4, but not the Cl-dependent NHE.