Image-Based Personalization of Cardiac Anatomy for Coupled Electromechanical Modeling.

Computational models of cardiac electromechanics (EM) are increasingly being applied to clinical problems, with patient-specific models being generated from high fidelity imaging and used to simulate patient physiology, pathophysiology and response to treatment. Current structured meshes are limited in their ability to fully represent the detailed anatomical data available from clinical images and capture complex and varied anatomy with limited geometric accuracy. In this paper, we review the state of the art in image-based personalization of cardiac anatomy for biophysically detailed, strongly coupled EM modeling, and present our own tools for the automatic building of anatomically and structurally accurate patient-specific models. Our method relies on using high resolution unstructured meshes for discretizing both physics, electrophysiology and mechanics, in combination with efficient, strongly scalable solvers necessary to deal with the computational load imposed by the large number of degrees of freedom of these meshes. These tools permit automated anatomical model generation and strongly coupled EM simulations at an unprecedented level of anatomical and biophysical detail.

A new protocol for evaluating the efficacy of some dispensing systems of a packaging in the microbial protection of water-based preservative-free cosmetic products.

OBJECTIVE: A new protocol is described for assessing the efficacy of the dispenser of some packaging systems (PSs) of preservative-free cosmetic products in protecting both their contained formula and their delivered doses. METHODS: Practically, aiming at mimicking contacts with a non-sterile skin or fingers, the dispensing system is put into contact with a pre-contaminated fabric by a standardized colonization of P. aeruginosa. RESULTS: When applied to three different types of packaging, results show clear differences in both criteria between these conditioning articles, that is variable efficacies in protecting the contained product and the delivered doses, knowing that the first aspect is of paramount importance. CONCLUSION: The proposed protocol is proved being able to discriminate between different PSs and provides information on strong and weak features of certain types dispensing technologies prone to efficiently decrease either the dose contamination or to prevent contamination in reaching the contained product. Therefore, the proposed protocol can contribute to an objective selection of a PS for protecting a cosmetic care product with a low content of preservative or preservative free.

Anti-estrogenic activity of a human resveratrol metabolite.

BACKGROUND AND AIMS: Resveratrol, the most investigated dietary compound in studies aimed at linking wine consumption to human health, is an extremely minor component of this beverage and it is generally studied in vitro as the unconjugated aglycone at concentrations largely exceeding those found in the human circulatory system after dietary intake. Moreover, following intestinal absorption, trans-resveratrol and its glucoside, which are naturally present in wine and other food sources, are converted to sulphate and glucuronide metabolites. An estrogenic activity has previously been documented for resveratrol, yet nothing is known about the activity of its blood-circulating metabolic derivatives. METHODS AND RESULTS: Using a yeast two-hybrid detection system relying on the interaction between the ligand-binding domain of the human oestrogen receptors α and ß and the human coactivator Tif2, we have systematically examined the oestrogen agonist and antagonist activities of the two main resveratrol forms present in planta (trans-resveratrol and trans-resveratrol-3-O-glucoside) and of the three main metabolites found in human plasma (trans-resveratrol-3-O-sulphate, trans-resveratrol-3-O-glucuronide and trans-resveratrol-4'-O-glucuronide). Only resveratrol-3-O-sulphate was found to display a fairly strong and oestrogen receptor α-preferential antagonistic activity, which was confirmed in a human breast adenocarcinoma cell line containing a luciferase reporter gene under the control of an oestrogen-responsive promoter. CONCLUSIONS: We show, for the first time, that resveratrol-3-O-sulphate, but neither of its metabolites, is endowed with anti-estrogenic activity and how human metabolism of phenolic substances plays a pivotal role in modulating their biological effect.

Reduction of monocyte chemoattractant protein 1 and macrophage migration inhibitory factor by a polyphenol-rich extract in subjects with clustered cardiometabolic risk factors.

Inflammation is a hallmark of the metabolic syndrome, which also contributes to a pro-atherogenic state. NF-κB activation, a critical step in regulating inflammatory reactions, can be inhibited by polyphenol (PF) extracts, at least in vitro. In the present study, we set out to study whether a PF-rich extract could attenuate the chronic inflammatory state and/or an acute immune response in vivo in subjects with clustered metabolic risk factors. A commercially available, PF-rich extract (500 mg daily) or placebo was administered for 4 weeks to thirty-four subjects with two or more metabolic risk factors using a randomised, double-blind, cross-over design. During the final study visit, an acute inflammatory challenge (lipopolysaccharide (LPS) 1 ng/kg body weight) was administered to a random subgroup of subjects (PF-rich extract (n 12) and placebo (n 12)). The PF-rich extract modestly reduced the inflammatory chemokines monocyte chemoattractant protein 1 (MCP-1) and macrophage migration inhibitory factor (MIF) (MCP-1 - 6.5 % (PF, median 116 (interquartile range 97-136) pg/ml v. placebo, median 124 (interquartile range 105-153) pg/ml; P < 0.05); MIF - 10.8 % (PF, median 2512 (interquartile range 1898-3972) pg/ml v. placebo, median 2814.5 (interquartile range 2296-3852) pg/ml; P < 0.05); however, other measured markers of inflammation and cardiometabolic disease, such as C-reactive protein, IL-6, HDL-cholesterol, adiponectin and oxidised LDL, remained unaffected. Following the LPS challenge, we found a statistically significant 48 % reduction of MCP-1 production in the PF-rich extract group (n 12) v. placebo (n 12) over 6 h (PF 766 (sd 155) v. placebo 1466 (sd 989) ng/ml; P < 0.05, area under the curve). In conclusion, short-term oral administration of the PF-rich extract caused a modest anti-inflammatory effect in subjects with clustered metabolic risk factors. Further dose-ranging studies are needed to evaluate whether and to what extent PF-rich extracts can be used to reduce the pro-inflammatory state in subjects with metabolic diseases at increased cardiovascular risk.

Polyphenols and health: what compounds are involved?

On the basis of prospective, cross-sectional and intervention studies linking polyphenols to human health, several experimental papers in the literature have tried to evaluate the molecular mechanisms involved in their bioactivity. Polyphenols are reported to in vitro inhibit cancer cell proliferation, reduce vascularisation, protect neurons, stimulate vasodilation and improve insulin secretion, but are often studied as aglycones or as sugar conjugates and at non-physiological concentration. However, it is now well established that polyphenols undergo substantial metabolism after being ingested by humans in dietary relevant amount and that concentrations of plasma metabolites after a normal dietary intake rarely exceed nmol/L. This viewpoint intends to highlight that uncritical judgements made on the basis of the published literature, particularly about toxicity and bioactivity, may sometimes have been misled and misleading and to conclude that i) bioavailability values reported in the literature for phenolic compounds should be strongly reconsidered in the light of the large number of newly identified circulating and excreted metabolites, with particular attention to colonic ring-fission products which are obviously contributing much more than expected to the percentage of their absorption; ii) it is phenolic metabolites, formed in the small intestine and hepatic cells, and low molecular weight catabolic products of the colonic microflora to travel around the human body in the circulatory system or reach body tissues to elicit bioactive effects. Understanding these compounds certainly carries interest for drug-discovery but also for dietary prevention of disease.

Increasing antioxidant intake from fruits and vegetables: practical strategies for the Scottish population.

BACKGROUND: Increasing intakes of dietary antioxidants may help to reduce oxidative damage caused by free radicals and provide protection against the progression of a number of chronic diseases. The present study aimed to estimate the antioxidant intake from fruits and vegetables in the UK and Scottish population and to examine consumption models to identify potential strategies to optimize antioxidant intake from these foods. METHODS: This was a retrospective study of cross-sectional data on fruit and vegetable intake in relation to antioxidant intake. Antioxidant capacity of individual fruits and vegetables was determined by the ferric reducing antioxidant power assay and data on quantity and frequency of consumption of fruits and vegetables determined from National Diet and Nutrition Survey 2000-2001. RESULTS: Mean antioxidant intake in UK population from fruits and vegetables varied by region. In the Scottish sample (n = 123), mean antioxidant intake was estimated at 680 +/- 689 micromol day(-1) with 92% subjects consuming <400 g of fruits and vegetables per day. Consumption data showed that strawberries, apples, orange citrus fruits, purple broccoli and cauliflower were the top five sources of antioxidants from fruits and vegetables in the Scottish population. CONCLUSIONS: Appropriate selection of fruits and vegetables would help to achieve a higher antioxidant intake with the potential to produce significant health benefits.

Fat transforms ascorbic acid from inhibiting to promoting acid-catalysed N-nitrosation.

BACKGROUND: The major potential site of acid nitrosation is the proximal stomach, an anatomical site prone to a rising incidence of metaplasia and adenocarcinoma. Nitrite, a pre-carcinogen present in saliva, can be converted to nitrosating species and N-nitroso compounds by acidification at low gastric pH in the presence of thiocyanate. AIMS: To assess the effect of lipid and ascorbic acid on the nitrosative chemistry under conditions simulating the human proximal stomach. METHODS: The nitrosative chemistry was modelled in vitro by measuring the nitrosation of four secondary amines under conditions simulating the proximal stomach. The N-nitrosamines formed were measured by gas chromatography-ion-trap tandem mass spectrometry, while nitric oxide and oxygen levels were measured amperometrically. RESULTS: In absence of lipid, nitrosative stress was inhibited by ascorbic acid through conversion of nitrosating species to nitric oxide. Addition of ascorbic acid reduced the amount of N-nitrosodimethylamine formed by fivefold, N-nitrosomorpholine by >1000-fold, and totally prevented the formation of N-nitrosodiethylamine and N-nitrosopiperidine. In contrast, when 10% lipid was present, ascorbic acid increased the amount of N-nitrosodimethylamine, N-nitrosodiethylamine and N-nitrosopiperidine formed by approximately 8-, 60- and 140-fold, respectively, compared with absence of ascorbic acid. CONCLUSION: The presence of lipid converts ascorbic acid from inhibiting to promoting acid nitrosation. This may be explained by nitric oxide, formed by ascorbic acid in the aqueous phase, being able to regenerate nitrosating species by reacting with oxygen in the lipid phase.

A study of the safety of current gastrointestinal endoscopy (EGD).

BACKGROUND AND STUDY AIMS: Previous attempts at assessing the safety of upper gastrointestinal endoscopy have been hampered by incomplete data collection. We aimed to assess the 30-day mortality associated with esophagogastroduodenoscopy (EGD) and assess the important risk factors. PATIENTS AND METHODS: A retrospective cohort study was conducted of patients who underwent endoscopy at Ninewells Hospital in Dundee between 1 June 2000 and 31 May 2003. A total of 11 501 EGDs were performed in 8926 patients. These patients were record-linked to the death registry and the database of hospital admissions in order to calculate the all-cause 30-day mortality. An expert panel judged whether EGD had caused or contributed to the deaths. Logistic regression analysis was performed on outcomes of all-cause and EGD-contributed mortality. RESULTS: The median age of the patients was 62 years (interquartile range 48 - 74 years), 54 % were women, and 94 % of procedures were diagnostic. A total of 395 patients died within 30 days (all-cause 30-day mortality rate 4.4 %). One patient death was caused directly by the EGD (procedure-caused mortality rate 1 in 9000). EGD was judged to have contributed to patient deaths at a rate of 1 in 182, based on majority agreement of experts: some factors associated with these deaths were percutaneous endoscopic gastrostomy insertion (odds ratio [OR] 18.39, 95 % confidence interval [CI] 5.71 - 59.22), melena or hematemesis indications (OR 9.01, 95 % CI 3.53 - 22.99), and esophageal varices (OR 6.28, 95 % CI 1.54 - 25.60). CONCLUSIONS: A causal death rate of 1 in 9000 suggests that EGD is very safe. However, certain patient groups have an increased mortality, and the risks and benefits of EGD should be carefully evaluated in each patient.

Growth, survival and inactivation of Pseudomonas aeruginosa and Staphylococcus aureus strains of various origin in the presence of ethanol.

The influence of ethanol on the behaviour of Pseudomonas aeruginosa and Staphylococcus aureus strains was evaluated throughout this study. Strains of different origin were used: collection, clinical and industrial strains were selected. Concentrations of ethanol from 0 to 20% (v/v) were evaluated by automated optical density measurements and by enumeration. When growth conditions were observed, predictive microbiology models were used to assess quantitatively for the ethanol effect. Primary modelling of kinetics was performed to determine growth rate values; secondary modelling was performed on these growth rates as influenced by ethanol, and minimum inhibitory concentrations of ethanol were determined for each strain. Staphylococcus aureus strains were more resistant to ethanol than P. aeruginosa strains, in growth conditions as well as in inactivation conditions. Furthermore, clinical S. aureus strains were more resistant than the collection strain. The method was promising for management of microbiological safety in cosmetics.

Oenology: red wine procyanidins and vascular health.

Regular, moderate consumption of red wine is linked to a reduced risk of coronary heart disease and to lower overall mortality, but the relative contribution of wine's alcohol and polyphenol components to these effects is unclear. Here we identify procyanidins as the principal vasoactive polyphenols in red wine and show that they are present at higher concentrations in wines from areas of southwestern France and Sardinia, where traditional production methods ensure that these compounds are efficiently extracted during vinification. These regions also happen to be associated with increased longevity in the population.

The effects of cranberry juice consumption on antioxidant status and biomarkers relating to heart disease and cancer in healthy human volunteers.

BACKGROUND: Consumption of fruit and vegetables is associated with a decreased risk of heart disease and cancer. This has been ascribed in part to antioxidants in these foods inactivating reactive oxygen species involved in initiation or progression of these diseases. Non-nutritive anthocyanins are present in significant amounts in the human diet. However, it is unclear whether they have health benefits in humans. AIM: To determine whether daily consumption of anthocyanin-rich cranberry juice could alter plasma antioxidant activity and biomarkers of oxidative stress. METHODS: 20 healthy female volunteers aged 18-40 y were recruited. Subjects consumed 750 ml/day of either cranberry juice or a placebo drink for 2 weeks. Fasted blood and urine samples were obtained over 4 weeks. The total phenol, anthocyanin and catechin content of the supplements and plasma were measured. Anthocyanin glycosides were identified by tandem mass spectrometry (MS-MS). Vitamin C, homocysteine (tHcy) and reduced glutathione (GSH) were measured by HPLC. Total antioxidant ability was determined using electron spin resonance (ESR) spectrometry and by the FRAP assay. Plasma total cholesterol, high density lipoprotein (HDL), and low density lipoprotein (LDL) cholesterol and triglycerides (TG) were measured. Glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) activities were measured in erythrocytes. Urine was collected for analysis of malondialdehyde (MDA) by HPLC and 8-oxo-deoxyguanosine (8-oxo-dG) by ELISA. Endogenous and induced DNA damage were measured by single cell gel electrophoresis (SCGE) in lymphocytes. RESULTS: Vitamin C, total phenol, anthocyanin and catechin concentrations and FRAP and ESR values were significantly higher in the cranberry juice compared with the placebo. Cyanidin and peonidin glycosides comprised the major anthocyanin metabolites [peonidin galactoside (29.2%) > cyanidin arabinoside (26.1%) > cyanidin galactoside (21.7%) > peonidin arabinoside (17.5%) > peonidin glucoside (4.1%) > cyanidin glucoside (1.4 %)]. Plasma vitamin C increased significantly (P<0.01) in volunteers consuming cranberry juice. No anthocyanins (plasma) or catechins (plasma or urine) were detectable and plasma total phenols, tHcy,TC,TG,HDL and LDL were unchanged. The antioxidant potential of the plasma, GSH-Px, CAT and SOD activities, and MDA were similar for both groups. Supplementation with cranberry juice did not affect 8-oxo-deoxyguanosine in urine or endogenous or H(2)O(2)-induced DNA damage in lymphocytes. CONCLUSIONS: Cranberry juice consumption did not alter blood or cellular antioxidant status or several biomarkers of lipid status pertinent to heart disease. Similarly, cranberry juice had no effect on basal or induced oxidative DNA damage. These results show the importance of distinguishing between the in vitro and in vivo antioxidant activities of dietary anthocyanins in relation to human health.

Extraction of phenolics and changes in antioxidant activity of red wines during vinification.

The moderate consumption of alcoholic beverages has been associated with protection against the development of coronary heart disease. Although alcohol itself can help prevent coronary heart disease through a number of mechanisms, red wine appears to offer protection above and beyond that attributable to alcohol alone. Red wine is a complex fluid containing grape, yeast, and wood-derived phenolic compounds, the majority of which have been recognized as potent antioxidants. The aim of this study was to investigate the major phenolic contributors to the antioxidant activity of wine. To this end, four wines were followed during the first 7-9 days of vinification. Individual phenolic compounds were quantified by HPLC, and antioxidant activity was determined by electron spin resonance spectroscopy. The extraction of the phenolics was found to be influenced by vinification procedure, grape quality, and grape variety. Although fermenting wines reached a total phenolic content comparable to that of a bottled wine after 9 days of vinification, the antioxidant activity was significantly lower than that of a finished wine. This suggests that the larger polyphenolic complexes and condensation products that appear during aging make a sizable contribution to the overall antioxidant activity of red wines.

Caffeine: a well known but little mentioned compound in plant science.

Caffeine, a purine alkaloid, is a key component of many popular drinks, most notably tea and coffee, yet most plant scientists know little about its biochemistry and molecular biology. A gene from tea leaves encoding caffeine synthase, an N-methyltransferase that catalyses the last two steps of caffeine biosynthesis, has been cloned and the recombinant enzyme produced in E. coli. Similar genes have been isolated from coffee leaves but the recombinant protein has a different substrate specificity to the tea enzyme. The cloning of caffeine biosynthesis genes opens up the possibility of using genetic engineering to produce naturally decaffeinated tea and coffee.

Profiles of purine and pyrimidine nucleotides in fresh and manufactured tea leaves.

Profiles of nucleotide levels in two varieties of Japanese green teas (cv. Yabukita and Saemidori), a Chinese green tea (Longjing), and two Japanese black teas (cv. Benifuuki and Benihikari) were determined and compared with that of fresh tea leaves. The concentration of 5'-nucleotides in green tea was much higher than in black tea. Nucleoside diphosphates were present in larger amounts than nucleoside triphosphates in manufactured green and black teas, whereas the triphosphates predominated in fresh tea leaves. Low levels of 3'-nucleotides were found in green and black teas. Inosine 5'-monophosphate, which is utilized as a seasoning component, was found in all manufactured teas in concentrations ranging from 50 to 200 nmol/g of dry weight. The levels of both inosine 5'-monophosphate and guanosine 5'-monophosphate were high in Chinese Longjing green tea. The unique profiles of nucleotides in manufactured teas may be a consequence of the action of degradation enzymes, such as ribonuclease, apyrase, phosphatase, nucleotidase, and adenosine 5'-monophsphate deaminase during the commercial processing of the young leaves.

A new caffeine biosynthetic pathway in tea leaves: utilisation of adenosine released from the S-adenosyl-L-methionine cycle.

The four-step caffeine biosynthetic pathway includes three methylation steps that utilise S-adenosyl-L-methionine (SAM) as the methyl donor. In the process SAM is converted to S-adenosyl-L-homocysteine (SAH) which in turn is hydrolysed to L-homocysteine and adenosine. Significant amounts of radioactivity from [methyl-(14)C]methionine and [methyl-(14)C]SAM were incorporated into theobromine and caffeine in young tea leaf segments, and very high SAH hydrolase activity was found in cell-free extracts from young tea leaves. Substantial amounts of radioactivity from [adenosyl-(14)C]SAH were also recovered as theobromine and caffeine in tea leaf segments, indicating that adenosine derived from SAH is utilised for the synthesis of the purine ring of caffeine. From the profiles of activity of related enzymes in tea leaf extracts, it is proposed that the major route from SAM to caffeine is a SAM-->SAH-->adenosine-->adenine-->AMP-->IMP-->XMP-->xanthosine-->7-methylxanthosine-->7-methylxanthine-->theobromine-->caffeine pathway. In addition, direct adenosine kinase-catalysed formation of AMP from adenosine may participate as an alternative minor route. The activity of two of the three N-methyltransferase activities involved in caffeine biosynthesis and part of the activities of SAH hydrolase, adenosine nucleosidase, adenine phosphoribosyltransferase and adenosine kinase were located in tea chloroplasts. In contrast, no detectable activity of SAM synthetase was associated with the purified chloroplast fraction. This is a first demonstration that the purine skeleton of caffeine is synthesised from adenosine released from the SAM cycle.

Alcohol consumption and mortality: is wine different from other alcoholic beverages?

BACKGROUND: Alcohol has been an integral part of the diets of many cultures for thousands of years, and formed the basis of early antiseptics. However, many health professionals have been loath to recommend its moderate consumption. Fears of increased risks of cancers, strokes and coronary heart disease (CHD), as well as its role in accidents, violence, psychological and social decline (when consumed in excess) meant that alcohol was viewed as generally detrimental to health. Recent reports have examined some of these fears and suggest that the moderate consumption of alcoholic beverages, particularly red wine, may actually protect against the development of CHD. Evidence for the influence of alcoholic drinks on strokes and cancer is less clear. OBJECTIVES: This review discusses the chemical differences between red wine and other alcoholic beverages and their possible effects on the development of CHD, stroke and cancer. DATA SYNTHESIS AND CONCLUSIONS: Both clinical and experimental evidence suggest that red wine does indeed offer a greater protection to health than other alcoholic beverages. This protection has been attributed to grape-derived antioxidant polyphenolic compounds found particularly in red wine.

Ulceration of the lower leg after total knee replacement a five-year review.

Ulceration of the lower leg is considered to be a hard' clinical endpoint of venous thrombosis. Total knee replacement (TKR) is a significant risk factor for venous thrombosis of the leg and therefore potentially for ulceration. We sent a postal questionnaire to 244 patients at a minimum of five years after TKR enquiring about the development of ulceration since their TKR. The overall incidence of ulceration, both active and healed, was 8.67% which is similar to that in the age-matched general population (9.6% to 12.6%), as was the prevalence of active ulceration. We also identified no clear association between venographically-confirmed postoperative deep-venous thrombosis (DVT) and the incidence and prevalence of ulcers at five years. We suggest that after TKR DVT is not a significant risk factor for ulceration of the leg and that perioperative chemical thromboprophylaxis may not be justified on these grounds.

The relative importance of tryptophan-dependent and tryptophan-independent biosynthesis of indole-3-acetic acid in tobacco during vegetative growth.

A quantitative study of indole-3-acetic acid (IAA) turnover, and the contribution of tryptophan-dependent and tryptophan-independent IAA-biosynthesis pathways, was carried out using protoplast preparations and shoot apices obtained from wild-type and transgenic, IAA-overproducing tobacco (Nicotiana tabacum L.) plants, during a phase of growth when the level of endogenous IAA was stable. Based on the rate of disappearance of [13C6]IAA, the half-life of the IAA pool was calculated to be 1.1 h in wild-type protoplasts and 0.8 h in protoplasts from the IAA-overproducing line, corresponding to metabolic rates of 59 and 160 pg IAA (microg Chl)(-1) h(-1), respectively. The rate of conversion of tryptophan to IAA was 15 pg IAA (microg Chl)(-1) h(-1) in wild-type protoplasts and 101 pg IAA (microg Chl)(-1) h(-1) in protoplasts from IAA-overproducing plants. In both instances, IAA was metabolised more rapidly than it was synthesised from tryptophan. As the endogenous IAA pools were in a steady state, these findings indicate that IAA biosynthesis via the tryptophan-independent pathway was 44 pg IAA (microg Chl)(-1) h(-1) and 59 pg IAA (microg Chl)(-1) h(-1), respectively, in the wild-type and transformed protoplast preparations. In a parallel study with apical shoot tissue, the presumed site of IAA biosynthesis, the rate of tryptophan-dependent IAA biosynthesis exceeded the rate of metabolism of [13C6]IAA despite the steady state of the endogenous IAA pool. The most likely explanation for this anomaly is that, unlike the protoplast system, injection of substrates into the apical tissues did not result in uniform distribution of label, and that at least some of the [2H5]tryptophan was metabolised in compartments not normally active in IAA biosynthesis. This demonstrates the importance of using experimental systems where labelling of the precursor pool can be strictly controlled.

Plant-derived phenolic antioxidants.

Antioxidant nutrients are important for limiting damaging oxidative reactions in cells, which may predispose to the development of major clinical conditions such as heart disease and cancer. There is great interest in the possibility that the antioxidant potential of plant-derived phenolic compounds, such as flavonoids, may reduce the risk of developing these conditions. Antioxidant effectiveness in vivo depends on the bioavailability of these compounds, which was assumed to be low. However, recent studies with improved methodology indicate that some plant phenolics appear in plasma and body tissues and, thus, may be important nutritional antioxidants. However, this cannot be established with certainty until their effects on biomarkers of oxidative stress are established.