Intra-individual variation of serum prostate specific antigen levels in men with benign prostate biopsies

To determine the intra-individual (physiological) variation of prostate-specific antigen (PSA) measurements in men after a benign prostatic biopsy. Sixty-four men were prospectively assessed, all of whom had a benign prostatic biopsy within the preceding 13 months. The degree of intra-individual variability was established by calculating the coefficient of variation on four PSA levels obtained from each patient weekly over a month. Six patients were subsequently diagnosed with prostate cancer and their data are presented separately. In the remaining 58 patients the median (range) individual mean PSA value was 6.3 (0.5-34.1) ng/mL. The median (range) coefficient of variation within the group was 9.5 (2.4-76.1)%. There was a clear linear relationship between mean PSA level and the standard deviation. In 48 of the 63 patients analysed, the coefficient of variation for serum PSA values in the group as a whole was greater than the variation claimed for the assay technique. The significance of the linear relationship between PSA and the standard deviation is discussed, with particular reference to those men who had a benign prostate biopsy.

Variability in fecal water genotoxicity, determined using the Comet assay, is independent of endogenous N-nitroso compound formation attributed to red meat consumption

Red meat consumption causes a dose-dependent increase in fecal apparent total N-nitroso compounds (ATNC). The genotoxic effects of these ATNCs were investigated using two different Comet assay protocols to determine the genotoxicity of fecal water samples. Fecal water samples were obtained from two studies of a total of 21 individuals fed diets containing different amounts of red meat, protein, heme, and iron. The first protocol incubated the samples with HT-29 cells for 5 min at 4 degrees C, whereas the second protocol used a longer exposure time of 30 min and a higher incubation temperature of 37 degrees C. DNA strand breaks were quantified by the tail moment (DNA in the comet tail multiplied by the comet tail length). The results of the two Comet assay protocols were significantly correlated (r = 0.35, P = 0.003), however, only the second protocol resulted in detectable levels of DNA damage. Inter-individual effects were variable and there was no effect on fecal water genotoxicity by diet (P > 0.20), mean transit time (P = 0.588), or weight (P = 0.705). However, there was a highly significant effect of age (P = 0.019). There was no significant correlation between concentrations of ATNCs in fecal homogenates and fecal water genotoxicity (r = 0.04, P = 0.74). ATNC levels were lower in fecal water samples (272 microg/kg) compared to that of fecal homogenate samples (895 microg/kg) (P < 0.0001). Failure to find dietary effects on fecal water genotoxicity may therefore be attributed to individual variability and low levels of ATNCs in fecal water samples.

Personalized nutrition for the prevention of cardiovascular disease: a future perspective

Cardiovascular disease (CVD) is responsible for significant morbidity and mortality in the Western and developing world. This multifactorial disease is influenced by many environmental and genetic factors. At present, public health advice involves prescribed population-based recommendations, which have been largely unsuccessful in reducing CVD risk. This is, in part, due to individual variability in response to dietary manipulations, that arises from nutrient-gene interactions (defined by the term 'nutrigenetics'). The shift towards personalized nutritional advice is a very attractive proposition, where, in principle, an individual can be given dietary advice specifically tailored to their genotype. However, the evidence-base for the impact of interactions between nutrients and fixed genetic variants on biomarkers of CVD risk is still very limited. This paper reviews the evidence for interactions between dietary fat and two common polymorphisms in the apolipoprotein E and peroxisome proliferator-activated receptor-gamma genes. Although an increased understanding of how these and other genes influence response to nutrients should facilitate the progression of personalized nutrition, the ethical issues surrounding its routine use need careful consideration.

Introduction to the DISRUPT postprandial database: subjects, studies and methodologies

Dysregulation of lipid and glucose metabolism in the postprandial state are recognised as important risk factors for the development of cardiovascular disease and type 2 diabetes. Our objective was to create a comprehensive, standardised database of postprandial studies to provide insights into the physiological factors that influence postprandial lipid and glucose responses. Data were collated from subjects (n = 467) taking part in single and sequential meal postprandial studies conducted by researchers at the University of Reading, to form the DISRUPT (DIetary Studies: Reading Unilever Postprandial Trials) database. Subject attributes including age, gender, genotype, menopausal status, body mass index, blood pressure and a fasting biochemical profile, together with postprandial measurements of triacylglycerol (TAG), non-esterified fatty acids, glucose, insulin and TAG-rich lipoprotein composition are recorded. A particular strength of the studies is the frequency of blood sampling, with on average 10-13 blood samples taken during each postprandial assessment, and the fact that identical test meal protocols were used in a number of studies, allowing pooling of data to increase statistical power. The DISRUPT database is the most comprehensive postprandial metabolism database that exists worldwide and preliminary analysis of the pooled sequential meal postprandial dataset has revealed both confirmatory and novel observations with respect to the impact of gender and age on the postprandial TAG response. Further analysis of the dataset using conventional statistical techniques along with integrated mathematical models and clustering analysis will provide a unique opportunity to greatly expand current knowledge of the aetiology of inter-individual variability in postprandial lipid and glucose responses.

The role of monounsaturated fatty acids in the mitigation of insulin resistance

With the rising rate of obesity, there is considerable interest in dietary strategies to reduce insulin resistance, a major characteristic of the metabolic syndrome and type 2 diabetes. Diets rich in monounsaturated fatty acids (MUFA) have been suggested as an alternative to low-fat, high-carbohydrate diets to improve glycemic control. However, inconsistent effects have been observed with MUFA-rich diets in both healthy and insulin-resistant individuals. In studies that have reported favorable effects on insulin sensitivity, Mediterranean-style diets have been used that are rich not only in MUFA but also whole-grain foods, fiber, and carbohydrates with a low glycemic index. There is a need for intervention studies to examine the true impact of MUFA-rich oils on glycemic control in both Mediterranean and non-Mediterranean populations. In addition, the metabolic and genotypic status of the participants may also play a role in the inter-individual variability in insulin sensitivity in response to MUFA-rich diets.

A double-blind, placebo-controlled, crossover-designed probiotic feeding study in children diagnosed with autistic spectrum disorders

There is growing interest in the role of gastrointestinal (GI) pathology and clinical expression of autism. Recent studies have demonstrated differences in the faecal clostridial populations harboured by autistic and non-autistic children. The potential of Lactobacillus plantarum WCSF1 (a probiotic) to modulate the gut microbiota of autistic subjects was investigated during a double-blind, placebo-controlled, crossover-designed feeding study. The faecal microbiota, gut function and behaviour scores of subjects were examined throughout the 12-week study. Lactobacillus plantarum WCFS1 feeding significantly increased Lab158 counts (lactobacilli and enterococci group) and significantly reduced Erec482 counts (Clostridium cluster XIVa) compared to placebo. Probiotic feeding also resulted in significant differences in the stool consistency compared to placebo and behaviour scores (total score and scores for some subscales) compared to baseline. The major finding of this work was the importance of study protocol in relation to the specific considerations of this subject population, with an extremely high dropout rate seen (predominantly during the baseline period). Furthermore, the relatively high inter-individual variability observed suggests that subsequent studies should use defined subgroups of autistic spectrum disorders, such as regressive or late-onset autism. In summary, the current study has highlighted the potential benefit of L. plantarum WCFS1 probiotic feeding in autistic individuals.

Mapping the platelet profile for functional genomic studies and demonstration of the effect size of the GP6 locus

BACKGROUND: Evidence suggests the wide variation in platelet response within the population is genetically controlled. Unraveling the complex relationship between sequence variation and platelet phenotype requires accurate and reproducible measurement of platelet response. OBJECTIVE: To develop a methodology suitable for measuring signaling pathway-specific platelet phenotype, to use this to measure platelet response in a large cohort, and to demonstrate the effect size of sequence variation in a relevant model gene. METHODS: Three established platelet assays were evaluated: mobilization of [Ca(2+)](i), aggregometry and flow cytometry, each in response to adenosine 5'-diphosphate (ADP) or the glycoprotein (GP) VI-specific crosslinked collagen-related peptide (CRP). Flow cytometric measurement of fibrinogen binding and P-selectin expression in response to a single, intermediate dose of each agonist gave the best combination of reproducibility and inter-individual variability and was used to measure the platelet response in 506 healthy volunteers. Pathway specificity was ensured by blocking the main subsidiary signaling pathways. RESULTS: Individuals were identified who were hypo- or hyper-responders for both pathways, or who had differential responses to the two agonists, or between outcomes. 89 individuals, retested three months later using the same methodology, showed high concordance between the two visits in all four assays (r(2) = 0.872, 0.868, 0.766 and 0.549); all subjects retaining their phenotype at recall. The effect of sequence variation at the GP6 locus accounted for approximately 35% of the variation in the CRP-XL response. CONCLUSION: Genotyping-phenotype association studies in a well-characterized, large cohort provides a powerful strategy to measure the effect of sequence variation in genes regulating the platelet response.

Development of personalised functional foods needs metabolic profiling

Purpose of review There is growing interest in applying metabolic profiling technologies to food science as this approach is now embedded into the foodomics toolbox. This review aims at exploring how metabolic profiling can be applied to the development of functional foods. Recent findings One of the biggest challenges of modern nutrition is to propose a healthy diet to populations worldwide that must suit high inter-individual variability driven by complex gene-nutrient-environment interactions. Although a number of functional foods are now proposed in support of a healthy diet, a one-size-fits-all approach to nutrition is inappropriate and new personalised functional foods are necessary. Metabolic profiling technologies can assist at various levels of the development of functional foods, from screening for food composition to identification of new biomarkers of food intake to support diet intervention and epidemiological studies. Summary Modern ‘omics’ technologies, including metabolic profiling, will support the development of new personalised functional foods of high relevance to twenty-first-century medical challenges such as controlling the worldwide spread of metabolic disorders and ensuring healthy ageing.

The APOB insertion/deletion polymorphism (rs17240441) influences postprandial lipaemia in healthy adults

BACKGROUND: Apolipoprotein (apo)B is the structural apoprotein of intestinally- and liver- derived lipoproteins and plays an important role in the transport of triacylglycerol (TAG) and cholesterol. Previous studies have examined the association between the APOB insertion/deletion (ins/del) polymorphism (rs17240441) and postprandial lipaemia in response to a single meal; however the findings have been inconsistent with studies often underpowered to detect genotype-lipaemia associations, focused mainly on men, or with limited postprandial characterisation of participants. In the present study, using a novel sequential test meal protocol which more closely mimics habitual eating patterns, we investigated the impact of APOB ins/del polymorphism on postprandial TAG, non-esterified fatty acids, glucose and insulin levels in healthy adults. FINDINGS: Healthy participants (n = 147) consumed a standard test breakfast (0 min; 49 g fat) and lunch (330 min; 29 g fat), with blood samples collected before (fasting) and on 11 subsequent occasions until 480 min after the test breakfast. The ins/ins homozygotes had higher fasting total cholesterol, LDL-cholesterol, TAG, insulin and HOMA-IR and lower HDL-cholesterol than del/del homozygotes (P < 0.017). A higher area under the time response curve (AUC) was evident for the postprandial TAG (P < 0.001) and insulin (P = 0.032) responses in the ins/ins homozygotes relative to the del/del homozygotes, where the genotype explained 35% and 7% of the variation in the TAG and insulin AUCs, respectively. CONCLUSIONS: In summary, our findings indicate that the APOB ins/del polymorphism is likely to be an important genetic determinant of the large inter-individual variability in the postprandial TAG and insulin responses to dietary fat intake.

Characteristics and variability of storm tracks in the north Pacific, Bering Sea, and Alaska

The North Pacific and Bering Sea regions represent loci of cyclogenesis and storm track activity. In this paper climatological properties of extratropical storms in the North Pacific/Bering Sea are presented based upon aggregate statistics of individual storm tracks calculated by means of a feature-tracking algorithm run using NCEP–NCAR reanalysis data from 1948/49 to 2008, provided by the NOAA/Earth System Research Laboratory and the Cooperative Institute for Research in Environmental Sciences, Climate Diagnostics Center. Storm identification is based on the 850-hPa relative vorticity field (ζ) instead of the often-used mean sea level pressure; ζ is a prognostic field, a good indicator of synoptic-scale dynamics, and is directly related to the wind speed. Emphasis extends beyond winter to provide detailed consideration of all seasons. Results show that the interseasonal variability is not as large during the spring and autumn seasons. Most of the storm variables—genesis, intensity, track density—exhibited a maxima pattern that was oriented along a zonal axis. From season to season this axis underwent a north–south shift and, in some cases, a rotation to the northeast. This was determined to be a result of zonal heating variations and midtropospheric moisture patterns. Barotropic processes have an influence in shaping the downstream end of storm tracks and, together with the blocking influence of the coastal orography of northwest North America, result in high lysis concentrations, effectively making the Gulf of Alaska the “graveyard” of Pacific storms. Summer storms tended to be longest in duration. Temporal trends tended to be weak over the study area. SST did not emerge as a major cyclogenesis control in the Gulf of Alaska.

Intraclonal variability in Daphnia acetylcholinesterase activity: The implications for its applicability as a biomarker

The relationship between individual growth and acetylcholinesterase (AChE).activity was evaluated for Daphnia magna. Analysis on the influence of two different culture media on baseline AChE activity was performed with Daphnia similis. The results indicated an inverse relationship between D. magna body length and AChE activity. An increase in total protein, which was not proportional to an increase in the rate of the substrate hydrolysis (Delta absorbance/min), seems to be the reason for this inverse size versus AChE activity relationship. Therefore, toxicants such as phenobarbital, which affect protein and size but not AChE activity directly, have an overall affect on AChE activity. In contrast, the AChE inhibitor parathion altered AChE activity but not protein. Culture medium also had a significant affect on AChE activity in D. similis. Changes in total protein seem to be the main reason for the variations in baseline AChE activity in Daphnia observed in the different evaluations performed in this work. Therefore, AChE activity in Daphnia must be interpreted carefully, and variations related to changes in total protein must be taken into account when applying this enzyme as a biomarker in biological monitoring.

Phonological similarity effects without a phonological store: an individual differences model

The feature model of immediate memory (Nairne, 1990) is applied to an experiment testing individual differences in phonological confusions amongst a group (N=100) of participants performing a verbal memory test. By simulating the performance of an equivalent number of “pseudo-participants” the model fits both the mean performance and the variability within the group. Experimental data show that high-performing individuals are significantly more likely to demonstrate phonological confusions than low performance individuals and this is also true of the model, despite the model’s lack of either an explicit phonological store or a performance-linked strategy shift away from phonological storage. It is concluded that a dedicated phonological store is not necessary to explain the basic phonological confusion effect, and the reduction in such an effect can also be explained without requiring a change in encoding or rehearsal strategy or the deployment of a different storage buffer.

Case-to-case variability of predictability of deep convection in a mesoscale model

Successful quantitative precipitation forecasts under convectively unstable conditions depend on the ability of the model to capture the location, timing and intensity of convection. Ensemble forecasts of two mesoscale convective outbreaks over the UK are examined with a view to understanding the nature and extent of their predictability. In addition to a control forecast, twelve ensemble members are run for each case with the same boundary conditions but with perturbations added to the boundary layer. The intention is to introduce perturbations of appropriate magnitude and scale so that the large-scale behaviour of the simulations is not changed. In one case, convection is in statistical equilibrium with the large-scale flow. This places a constraint on the total precipitation, but the location and intensity of individual storms varied. In contrast, the other case was characterised by a large-scale capping inversion. As a result, the location of individual storms was fixed, but their intensities and the total precipitation varied strongly. The ensemble shows case-to-case variability in the nature of predictability of convection in a mesoscale model, and provides additional useful information for quantitative precipitation forecasting.

Measuring significant variability characteristics: An assessment of three UK renewables

The variability of renewable energy is widely recognised as a challenge for integrating high levels of renewable generation into electricity systems. However, to explore its implications effectively, variability itself should first be clearly understood. This is particularly true for national electricity systems with high planned penetration of renewables and limited interconnection such as the UK. Variability cannot be considered as a distinct resource property with a single measurable parameter, but is a multi-faceted concept best described by a range of distinct characteristics. This paper identifies relevant characteristics of variability, and considers their implications for energy research. This is done through analysis of wind, solar and tidal current resources, with a primary focus on the Bristol Channel region in the UK. The relationship with electricity demand is considered, alongside the potential benefits of resource diversity. Analysis is presented in terms of persistence, distribution, frequency and correlation between supply and demand. Marked differences are seen between the behaviours of the individual resources, and these give rise to a range of different implications for system integration. Wind shows strong persistence and a useful seasonal pattern, but also a high spread in energy levels at timescales beyond one or two days. The solar resource is most closely correlated with electricity demand, but is undermined by night-time zero values and an even greater spread of monthly energy delivered than wind. In contrast, the tidal resource exhibits very low persistence, but also much greater consistency in energy values assessed across monthly time scales. Whilst this paper focuses primarily on the behaviour of resources, it is noted that discrete variability characteristics can be related to different system impacts. Persistence and predictability are relevant for system balancing, whereas statistical distribution is more relevant when exploring issues of asset utilisation and energy curtailment. Areas of further research are also identified, including the need to assess the value of predictability in relation to other characteristics.

Pharmacometabonomic characterization of xenobiotic and endogenous metabolic phenotypes that account for inter-individual variation in isoniazid-induced toxicological response

An NMR-based pharmacometabonomic approach was applied to investigate inter-animal variation in response to isoniazid (INH; 200 and 400 mg/kg) in male Sprague-Dawley rats, alongside complementary clinical chemistry and histopathological analysis. Marked inter-animal variability in central nervous system (CNS) toxicity was identified following administration of a high dose of INH, which enabled characterization of CNS responders and CNS non-responders. High-resolution post-dose urinary (1)H NMR spectra were modeled both by their xenobiotic and endogenous metabolic information sets, enabling simultaneous identification of the differential metabolic fate of INH and its associated endogenous metabolic consequences in CNS responders and CNS non-responders. A characteristic xenobiotic metabolic profile was observed for CNS responders, which revealed higher urinary levels of pyruvate isonicotinylhydrazone and β-glucosyl isonicotinylhydrazide and lower levels of acetylisoniazid compared to CNS non-responders. This suggested that the capacity for acetylation of INH was lower in CNS responders, leading to increased metabolism via conjugation with pyruvate and glucose. In addition, the endogenous metabolic profile of CNS responders revealed higher urinary levels of lactate and glucose, in comparison to CNS non-responders. Pharmacometabonomic analysis of the pre-dose (1)H NMR urinary spectra identified a metabolic signature that correlated with the development of INH-induced adverse CNS effects and may represent a means of predicting adverse events and acetylation capacity when challenged with high dose INH. Given the widespread use of INH for the treatment of tuberculosis, this pharmacometabonomic screening approach may have translational potential for patient stratification to minimize adverse events.