Coastal response to late-stage transgression and sea-level highstand

Coastal morphologic features associated with past shoreline transgressions and sea-level highstands can provide insight into the rates and processes associated with coastal response to the modern global rise in sea level. Along the eastern and southern Brazilian coasts of South America, 6000 years of sea-level fall have preserved late-stage transgressive and sea-level highstand features 1-4 m above present mean sea level and several kilometers landward of modern shorelines. GPS with real-time kinematics data, ground-penetrating radar, stratigraphy, and radiocarbon dating within a 2-3-km-wide river-associated strandplain in central Santa Catarina (southern Brazil) uncovered a diverse set of late-stage transgressive and highstand deposits. Here, the highstand took the forms of (1) an exposed bedrock coast in areas of high wave energy and low sediment supply; (2) a 3.8-m-high transgressive barrier ridge where landward barrier migration was prohibited by the presence of shallow bedrock; and (3) a complete barrier-island complex containing a 5.2-m-high barrier ridge, wash-over deposits, a paleo-inlet, and a backbarrier lowland, formed in a protected cove with ample sediment supply from small local streams and the erosion of upland sediments. Similar signatures of the mid-Holocene highstand can be traced across all coastal Brazilian states. This study presents the first complete compilation of the diversity of these sedimentary sequences. They are broadly classified here as exposed bedrock coasts (type A), back barrier deposits (type B), transgressive barrier ridges (type C), and barrier-island complexes (type D), according to localized conditions of upland migration potential, wave exposure, and sediment supply. These Brazilian systems present a paradigm for understanding future coastal response to climate change and accelerated sea-level rise: the recognition of a minimum threshold sea-level-rise rate of similar to 2 mm yr(-1) above which transgression proceeded too rapidly for the formation of these stable accretionary shoreline features demonstrates the nonlinearity of coastal response to sea-level change, and the site specificity of conditions associated with the formation of each highstand deposit type, even within a single small embayment, demonstrates the non-uniformity of that response

MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

The changing association between socioeconomic circumstances and the incidence of colorectal cancer: a population-based study

Background:There is emerging evidence to suggest that the association between socioeconomic circumstances and colorectal cancer incidence has changed over recent decades.Methods:We conducted a descriptive population-based study to describe the relationship between socioeconomic circumstances and the incidence of colorectal cancer in a pre-screened population. Incident cases of colorectal cancer from the West of Scotland were identified from the Scottish Cancer Registry and European age-standardised incidence rates (EASR) were calculated. Socioeconomic circumstances were measured using the area-based Scottish Index of Multiple Deprivation (SIMD).Results:In total, 14?051 incident cases of colorectal cancer were recorded from 1999 to 2007. Incidence of colorectal cancer was associated with increased deprivation in men but not among women; an association that became evident from 2005 onwards. From 2005 to 2007, the deprivation gap in incidence among men was 13.3 per 100?000 (95% confidence interval 3.2-23.4), with rates 19.5% lower among the least deprived compared with the most deprived. This deprivation gap now accounts for an estimated 75 excess cases per year of male colorectal cancer in the West of Scotland.Conclusion:Deprivation was associated with higher incidence rates of male, but not female, colorectal cancer before the implementation of a national bowel screening programme

Global quantitative indices reflecting provider process-of-care: data-base derivation

Background: Controversy has attended the relationship between risk-adjusted mortality and process-of-care. There would be advantage in the establishment, at the data-base level, of global quantitative indices subsuming the diversity of process-of-care. Methods: A retrospective, cohort study of patients identified in the Australian and New Zealand Intensive Care Society Adult Patient Database, 1993-2003, at the level of geographic and ICU-level descriptors (n = 35), for both hospital survivors and non-survivors. Process-of-care indices were established by analysis of: (i) the smoothed time-hazard curve of individual patient discharge and determined by pharmaco-kinetic methods as area under the hazard-curve (AUC), reflecting the integrated experience of the discharge process, and time-to-peak-hazard (TMAX, in days), reflecting the time to maximum rate of hospital discharge; and (ii) individual patient ability to optimize output (as length-of-stay) for recorded data-base physiological inputs; estimated as a technical production-efficiency (TE, scaled [0,(maximum)1]), via the econometric technique of stochastic frontier analysis. For each descriptor, multivariate correlation-relationships between indices and summed mortality probability were determined. Results: The data-set consisted of 223129 patients from 99 ICUs with mean (SD) age and APACHE III score of 59.2(18.9) years and 52.7(30.6) respectively; 41.7% were female and 45.7% were mechanically ventilated within the first 24 hours post-admission. For survivors, AUC was maximal in rural and for-profit ICUs, whereas TMAX (≥ 7.8 days) and TE (≥ 0.74) were maximal in tertiary-ICUs. For non-survivors, AUC was maximal in tertiary-ICUs, but TMAX (≥ 4.2 days) and TE (≥ 0.69) were maximal in for-profit ICUs. Across descriptors, significant differences in indices were demonstrated (analysisof- variance, P ≤ 0.0001). Total explained variance, for survivors (0.89) and non-survivors (0.89), was maximized by combinations of indices demonstrating a low correlation with mortality probability. Conclusions: Global indices reflecting process of care may be formally established at the level of national patient databases. These indices appear orthogonal to mortality outcome.John L Moran, Patricia J Solomon and the Adult Database Management Committee (ADMC) of the Australian and New Zealand Intensive Care Society (ANZICS

A novel approach to investigate tissue-specific trinucleotide repeat instability

Abstract Background In Huntington's disease (HD), an expanded CAG repeat produces characteristic striatal neurodegeneration. Interestingly, the HD CAG repeat, whose length determines age at onset, undergoes tissue-specific somatic instability, predominant in the striatum, suggesting that tissue-specific CAG length changes could modify the disease process. Therefore, understanding the mechanisms underlying the tissue specificity of somatic instability may provide novel routes to therapies. However progress in this area has been hampered by the lack of sensitive high-throughput instability quantification methods and global approaches to identify the underlying factors. Results Here we describe a novel approach to gain insight into the factors responsible for the tissue specificity of somatic instability. Using accurate genetic knock-in mouse models of HD, we developed a reliable, high-throughput method to quantify tissue HD CAG repeat instability and integrated this with genome-wide bioinformatic approaches. Using tissue instability quantified in 16 tissues as a phenotype and tissue microarray gene expression as a predictor, we built a mathematical model and identified a gene expression signature that accurately predicted tissue instability. Using the predictive ability of this signature we found that somatic instability was not a consequence of pathogenesis. In support of this, genetic crosses with models of accelerated neuropathology failed to induce somatic instability. In addition, we searched for genes and pathways that correlated with tissue instability. We found that expression levels of DNA repair genes did not explain the tissue specificity of somatic instability. Instead, our data implicate other pathways, particularly cell cycle, metabolism and neurotransmitter pathways, acting in combination to generate tissue-specific patterns of instability. Conclusion Our study clearly demonstrates that multiple tissue factors reflect the level of somatic instability in different tissues. In addition, our quantitative, genome-wide approach is readily applicable to high-throughput assays and opens the door to widespread applications with the potential to accelerate the discovery of drugs that alter tissue instability

Population Genetics of Streptococcus dysgalactiae Subspecies equisimilis Reveals Widely Dispersed Clones and Extensive Recombination

Streptococcus dysgalactiae subspecies equisimilis (SDSE) is an emerging global pathogen that can colonize and infect humans. Although most SDSE isolates possess the Lancefield group G carbohydrate, a significant minority have the group C carbohydrate. Isolates are further sub-typed on the basis of differences within the emm gene. To gain a better understanding of their molecular epidemiology and evolutionary relationships, multilocus sequence typing (MLST) analysis was performed on SDSE isolates collected from Australia, Europe and North America.The 178 SDSE isolates, representing 37 emm types, segregate into 80 distinct sequence types (STs) that form 17 clonal complexes (CCs). Eight STs recovered from all three continents account for >50% of the isolates. Thus, a small number of STs are highly prevalent and have a wide geographic distribution. Both ST and CC strongly correlate with group carbohydrate. In contrast, eleven STs were associated with >1 emm type, suggestive of recombinational replacements involving the emm gene; furthermore, 35% of the emm types are associated with genetically distant STs. Data also reveal a history of extensive inter- and intra-species recombination involving the housekeeping genes used for MLST. Sequence analysis of single locus variants identified through goeBURST indicates that genetic change mediated by recombination occurred approximately 4.4 times more frequently than by point mutation.A few genetic lineages with an intercontinental distribution dominate among SDSE causing infections in humans. The distinction between group C and G isolates reflects recent evolution, and no long-term genetic isolation between them was found. Lateral gene transfer and recombination involving housekeeping genes and the emm gene are important mechanisms driving genetic variability in the SDSE population

Evaluating comorbidities in total hip and knee arthroplasty: available instruments

Each year millions of patients are treated for joint pain with total joint arthroplasty, and the numbers are expected to rise. Comorbid disease is known to influence the outcome of total joint arthroplasty, and its documentation is therefore of utmost importance in clinical evaluation of the individual patient as well as in research. In this paper, we examine the various methods for obtaining and assessing comorbidity information for patients undergoing joint replacement. Multiple instruments are reliable and validated for this purpose, such as the Charlson Index, Index of Coexistent Disease, and the Functional Comorbidity Index. In orthopedic studies, the Charnley classification and the American Society of Anesthesiologists physical function score (ASA) are widely used. We recommend that a well-documented comorbidity index that incorporates some aspect of mental health is used along with other appropriate instruments to objectively assess the preoperative status of the patient

Utilization patterns of Chinese medicine and Western medicine under the National Health Insurance Program in Taiwan, a population-based study from 1997 to 2003

<p>Abstract</p> <p>Background</p> <p>In 1995, Taiwan has launched a national health-care system (the National Health Insurance Program, NHI) covering the use of both Western medicine (WM) and Chinese medicine (CM). This population-based study was conducted to understand the role of CM in this dual medical system by determining the utilization patterns of CM and WM and to analyze the demographic characteristics and primary indications influencing the choice of the medical services for the development of strategies to enhance the appropriate use and reduce unnecessary use of CM.</p> <p>Methods</p> <p>This study used the NHI sample files from 1997 to 2003 consisting of comprehensive utilization and enrolment information for a random sample of 200,432 NHI beneficiaries of the total enrolees from 1995 to 2000. A total of 136,720 subjects with valid and complete enrolment and utilization data were included in this study. The logistic regression method was employed to estimate the odds ratios (ORs) for utilization of CM and WM. The usage, frequency of services, and primary indications for CM and WM were evaluated. A significance level of α = 0.05 was selected.</p> <p>Results</p> <p>Compared with WM, the odds of CM increased from 1997 to 2003. The odds of using CM (OR = 1.48; 95% CI: 1.45–1.50; p < 0.001) and WM (OR = 1.74; 95% CI: 1.72–1.77; p < 0.001) were higher in females and that of CM increased with age to a peak in the 45–54-year-group (OR = 1.75; 95% CI: 1.68–1.82; p < 0.001) and WM (OR = 1.09; 95% CI: 1.05–1.13; p < 0.001) in the elderly subjects (≥ 65 years). The odds of CM and WM were similar in all income groups. However, those of CM were higher in Central (OR = 1.65; 95% CI: 1.56–1.74; p < 0.001) and Southern Taiwan (OR = 1.18; 95% CI: 1.12–1.25; p < 0.001) and lower in the remote areas (OR = 0.57; 95% CI: 0.52–0.63; p < 0.001). Most of the patients had one ambulatory visit of both medical services annually. However, the utilization of WM predominated over CM. Over 90% of CM service was provided by clinics, whereas over 60% of WM service by hospitals. Diseases of the respiratory system was the most frequent primary indication in CM and WM. Herbal medication was the most commonly used form of CM (68.4–72.7%).</p> <p>Conclusion</p> <p>In recent years, there is an increasing trend in the utilization of CM in Taiwan. This increasing trend may be due to the covering of CM in the national health insurance system.</p

CTCF cis-Regulates Trinucleotide Repeat Instability in an Epigenetic Manner: A Novel Basis for Mutational Hot Spot Determination

At least 25 inherited disorders in humans result from microsatellite repeat expansion. Dramatic variation in repeat instability occurs at different disease loci and between different tissues; however, cis-elements and trans-factors regulating the instability process remain undefined. Genomic fragments from the human spinocerebellar ataxia type 7 (SCA7) locus, containing a highly unstable CAG tract, were previously introduced into mice to localize cis-acting “instability elements,” and revealed that genomic context is required for repeat instability. The critical instability-inducing region contained binding sites for CTCF—a regulatory factor implicated in genomic imprinting, chromatin remodeling, and DNA conformation change. To evaluate the role of CTCF in repeat instability, we derived transgenic mice carrying SCA7 genomic fragments with CTCF binding-site mutations. We found that CTCF binding-site mutation promotes triplet repeat instability both in the germ line and in somatic tissues, and that CpG methylation of CTCF binding sites can further destabilize triplet repeat expansions. As CTCF binding sites are associated with a number of highly unstable repeat loci, our findings suggest a novel basis for demarcation and regulation of mutational hot spots and implicate CTCF in the modulation of genetic repeat instability