Numerical simulation of the cardiovascular system

In this article, we aim at giving a non-technical overview of some mathematical models currently used in the numerical simulation of the cardiovascular system. A hierarchy of models for blood flows in large arteries is briefly described as well as an electromechanical model for the heart. We discuss some possible applications of the numerical simulations of such models, for example the optimization of prostheses. We also address the issue of the data assimilation for the calibration of the models.     

CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease

CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.     

Olive tree varieties cultivated for the great Baetican oil trade between the 1st and the 4th centuries <Emphasis Type="SmallCaps">ad</Emphasis>: morphometric analysis of olive stones from Las Delicias (Ecija,Province of Seville,Spain)

During the excavations of a Roman amphora workshop and oil mill of the 1st–4th century ad in Las Delicias, Genil valley, Ecija, Spain, large quantities of charred olive stones were recovered. The assemblages discovered in the pottery kilns demonstrate the use as fuel of olive residues, which were obtained from the extraction of the oil in the nearby mill. The abundance of material offered the opportunity to study the infra-specific diversity of the olives growing in the province of Baetica, which is known to have been an important oil-producing region during the Roman Empire. In total, 335 intact charred archaeological olive stones were analysed using geometric morphometry (outline analysis) and compared with several current morphotypes. These have been identified within a set of dimensional references of the stones established from the morphometric study of current varieties and wild populations, including genuinely wild and feral forms of olives, from various areas around the Mediterranean. The morphotype mainly found in wild populations was widely represented among the olive stones from Las Delicias. A large proportion of the archaeological stones were however close to various domesticated forms, which reflect the history of the region and of its varied cultural Mediterranean influences, Punic, Greek and Roman. Moreover, intermediate forms between two distinct morphotypes were identified. They suggest that hybrid olive trees derived from crosses among domesticated varieties and also between domesticated and wild forms, were grown in Las Delicias. In the Genil valley, Roman olive cultivation was based on a set of local olives which included wild and domesticated varieties from various origins, and whose diversity arose from breeding for improvement of varieties.     

In vitro characterization of four novel non-functional variants of the thiopurine S-methyltransferase

Human thiopurine S-methyltransferase (TPMT) is an enzyme responsible for the detoxification of widely used thiopurine drugs such as azathioprine (Aza). Its activity is inversely related to the risk of developing severe hematopoietic toxicity in certain patients treated with standard doses of thiopurines. DNA samples from four leucopenic patients treated with Aza were screened by PCR-SSCP analysis for mutations in the 10 exons of the TPMT gene. Four missense mutations comprising two novel mutations, A83T (TPMT*13, Glu(28)Val) and C374T (TPMT*12, Ser(125)Leu), and two previously described mutations, G430C (TPMT*10, Gly(144)Arg) and T681G (TPMT*7, His(227)Gln) were identified. Using a recombinant yeast expression system, kinetic parameters (K(m) and V(max)) of 6-thioguanine S-methylation of the four TPMT variants were determined and compared to those obtained with wild-type TPMT. This functional analysis suggests that these rare allelic variants are defective TPMT alleles. The His(227)Gln variant retained only 10% of the intrinsic clearance value (V(max)/K(m) ratio) of the wild-type enzyme. The Ser(125)Leu and Gly(144)Arg variants were associated with a significant decrease in intrinsic clearance values, retaining about 30% of the wild-type enzyme, whereas the Glu(28)Val variant produced a more modest decrease (57% of the wild-type enzyme). The data suggest that the sporadic contribution of the rare Glu(28)Val, Ser(125)Leu, Gly(144)Arg, and His(227)Gln variants may account for the occurrence of altered metabolism of TPMT substrates. These findings improve our knowledge of the genetic basis of interindividual variability in TPMT activity and would enhance the efficiency of genotyping methods to predict patients at risk of inadequate responses to thiopurine therapy.     

Vitamin B12 (cobalamin) deficiency in elderly patients

VITAMIN B₁₂ OR COBALAMIN DEFICIENCY occurs frequently (> 20%) among elderly people, but it is often unrecognized because the clinical manifestations are subtle; they are also potentially serious, particularly from a neuropsychiatric and hematological perspective. Causes of the deficiency include, most frequently, food-cobalamin malabsorption syndrome (> 60% of all cases), pernicious anemia (15%–20% of all cases), insufficent dietary intake and malabsorption. Food-cobalamin malabsorption, which has only recently been identified as a significant cause of cobalamin deficiency among elderly people, is characterized by the inability to release cobalamin from food or a deficiency of intestinal cobalamin transport proteins or both. We review the epidemiology and causes of cobalamin deficiency in elderly people, with an emphasis on food-cobalamin malabsorption syndrome. We also review diagnostic and management strategies for cobalamin deficiency. Vitamin B₁₂ or cobalamin deficiency occurs frequently among elderly patients,¹ but it is often unrecognized or not investigated because the clinical manifestations are subtle. However, the potential seriousness of the complications (particularly neuropsychiatric and hematological)^1,2,3,4 requires investigation of all patients who present with vitamin or nutritional deficiency. We summarize the current state of knowledge on cobalamin deficiency, with a particular focus on deficiency in elderly people.In gathering information for this article, we systematically searched PubMed for articles published from 1990 to July 2003 (the search strategy is outlined in online Appendix 1 [www.cmaj.ca/cgi/content/full/171/3/251/DC1]). We have also included unpublished data from our working group, the Groupe d''étude des carences en vitamine B12 des Hôpitaux Universitaires de Strasbourg.     

Survival to Parasitoids in an Insect Hosting Defensive Symbionts: A Multivariate Approach to Polymorphic Traits Affecting Host Use by Its Natural Enemy

Insect parasitoids and their insect hosts represent a wide range of parasitic trophic relations that can be used to understand the evolution of biotic diversity on earth. Testing theories of coevolution between hosts and parasites is based on factors directly involved in host susceptibility and parasitoid virulence. We used controlled encounters with potential hosts of the Aphidius ervi wasp to elucidate behavioral and other phenotypic traits of host Acyrthosiphon pisum that most contribute to success or failure of parasitism. The host aphid is at an advanced stage of specialization on different crop plants, and exhibits intra-population polymorphism for traits of parasitoid avoidance and resistance based on clonal variation of color morph and anti-parasitoid bacterial symbionts. Randomly selected aphid clones from alfalfa and clover were matched in 5 minute encounters with wasps of two parasitoid lineages deriving from hosts of each plant biotype in a replicated transplant experimental design. In addition to crop plant affiliation (alfalfa, clover), aphid clones were characterized for color morph (green, pink), Hamiltonella defensa and Regiella insecticola symbionts, and frequently used behaviors in encounters with A. ervi wasps. A total of 12 explanatory variables were examined using redundancy analysis (RDA) to predict host survival or failure to A. ervi parasitism. Aphid color was the best univariate predictor, but was poorly predictive in the RDA model. In contrast, aphid host plant and symbionts were not significant univariate predictors, but significant predictors in the multivariate model. Aphid susceptibility to wasp acceptance as reflected in host attacks and oviposition clearly differed from its suitability to parasitism and progeny development. Parasitoid progeny were three times more likely to survive on clover than alfalfa host aphids, which was compensated by behaviorally adjusting eggs invested per host. Strong variation of the predictive power of intrinsic (body color) and extrinsic traits (symbionts, host plant), indicate that host variables considered as key predictors of outcomes strongly interact and cannot be considered in isolation.     

Diagnosing Nodular Regenerative Hyperplasia of the Liver Is Thwarted by Low Interobserver Agreement

Background and Aims

Nodular regenerative hyperplasia (NRH) of the liver is associated with several diseases and drugs. Clinical symptoms of NRH may vary from absence of symptoms to full-blown (non-cirrhotic) portal hypertension. However, diagnosing NRH is challenging. The objective of this study was to determine inter- and intraobserver agreement on the histopathologic diagnosis of NRH.

Methods

Liver specimens (n=48) previously diagnosed as NRH, were reviewed for the presence of NRH by seven pathologists without prior knowledge of the original diagnosis or clinical background. The majority of the liver specimens were from thiopurine using inflammatory bowel disease patients. Histopathologic features contributing to NRH were also assessed. Criteria for NRH were modified by consensus and subsequently validated. Interobserver agreement was evaluated by using the standard kappa index.

Results

After review, definite NRH, inconclusive NRH and no NRH were found in 35% (23-40%), 21% (13-27%) and 44% (38-56%), respectively (median, IQR). The median interobserver agreement for NRH was poor (κ = 0.20, IQR 0.14-0.28). The intraobserver variability on NRH ranged between 14% and 71%. After modification of the criteria and exclusion of biopsies with technical shortcomings, the interobserver agreement on the diagnosis NRH was fair (κ = 0.45).

Conclusions

The interobserver agreement on the histopathologic diagnosis of NRH was poor, even when assessed by well-experienced liver pathologists. Modification of the criteria of NRH based on consensus effort and exclusion of biopsies of poor quality led to a fairly increased interobserver agreement. The main conclusion of this study is that NRH is a clinicopathologic diagnosis that cannot reliably be based on histopathology alone.     

The Quebec Rural Emergency Department Project: A Cross-Sectional Study of a Potential Two-Pronged Strategy in the Knowledge Transfer Process

Introduction

Health services research generates useful knowledge. Promotion of implementation of this knowledge in medical practice is essential. Prior to initiation of a major study on rural emergency departments (EDs), we deployed two knowledge transfer strategies designed to generate interest and engagement from potential knowledge users. The objective of this paper was to review: 1) a combined project launch and media press release strategy, and 2) a pre-study survey designed to survey potential knowledge users’ opinions on the proposed study variables.

Materials and Methods

We evaluated the impact of the project launch (presentation at two conferences hosted by key stakeholders) and media press release via a survey of participants/stakeholders and by calculating the number of media interview requests and reports generated. We used a pre-study survey to collect potential key stakeholder’ opinions on the study variables.

Results

Twenty-one of Quebec’s 26 rural EDs participated in the pre-study survey (81% participation rate). The press release about the study generated 51 press articles and 20 media request for interviews, and contributed to public awareness of a major rural research initiative. In the pre-study survey, thirteen participants (46%) mentioned prior knowledge of the research project. Results from the pre-study survey revealed that all of the potential study variables were considered to be relevant for inclusion in the research project. Respondents also proposed additional variables of interest, including factors promoting retention of human resources.

Conclusions

The present study demonstrated the potential utility of a two-pronged knowledge transfer strategy, including a combined formal launch and press release, and a pre-study survey designed to ensure that the included variables were of interest to participants and stakeholders.     

Serum zinc in highly trained adolescent gymnasts

Serum zinc was measured in 20 adolescent gymnasts (9 boys, 11 girls, age 12–15 yr) explored for detecting possible adverse effects of intense training on pubertal maturation and growth. They had low serum zinc (0.599±0.026 mg/L) when compared to matched control sedentary children (n=118 mean 0.81±0.014p<0.001). Girls had lower zinc than boys (0.557±0.023 vs 0.651±0.044p<0.001). Zinc was correlated to isometric adductor strength (r=0.468p<0.05). Children with serum zinc <0.6 mg/L had lower insulin-like growth factor binding protein 3 than others (2.326±0.264 vs 2.699±0.12p<0.01). Thus, zinc is lowered in trained adolescent gymnasts and even lower in females. This reduction could play some role in abnormalities of puberty, growth, or muscular performance.     

Activity of the yeast FLP recombinase in Arabidopsis

The coding sequence for FLP recombinase, originally from the 2 plasmid of Saccharomyces cerevisiae, was introduced into Arabidopsis behind the cauliflower mosaic virus 35S promoter. FLP activity was monitored by the glucuronidase activity resulting from inversion of an antisense-oriented GUS reporter gene flanked by a pair of FRT target sites in inverted repeat. FLP-dependent Gus activity was observed in both transient assays and transgenic plants. The FLP system will be useful for a variety of in planta genetic manipulations.