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1.  Effect of increased fruit and vegetable consumption on physical function and muscle strength in older adults 
Age  2013;35(6):2409-2422.
Fruit and vegetable (FV) intake, which is often low in older people, may be associated with improved muscle strength and physical function. However, there is a shortage of intervention trial evidence to support this. The current study examined the effect of increased FV consumption on measures of muscle strength and physical function among healthy, free-living older adults. A randomized controlled intervention study was undertaken. Eighty-three participants aged 65–85 years, habitually consuming ≤2 portions of FV/day, were randomised to continue their normal diet (≤2 portions/day), or to consume ≥5 portions of FV/day for 16 weeks. FV were delivered to all participants each week, free of charge. Compliance was monitored at baseline, 6, 12 and 16 weeks by diet history and by measuring biomarkers of micronutrient status. Grip strength was measured by a hand-held dynamometer, while lower-extremity physical function was assessed by performance-based measures. Eighty-two participants completed the intervention. The 5 portions/day group showed greater change in daily FV consumption compared to the 2 portions/day group (P < 0.001). This was reflected in significant increases in biomarkers of micronutrient status. No significant differences were evident in change in physical function between the two groups. However, there was a trend towards a greater change in grip strength in the 5 portions/day compared to the 2 portions/day group (mean change at 16 weeks ± SD, 2.04 ± 5.16 and 0.11 ± 3.26 kg, respectively, P = 0.06). Increased FV consumption may modestly increase grip strength but has no effect on physical function in healthy older adults.
PMCID: PMC3825010  PMID: 23543264
Physical function; Muscle strength; Fruit and vegetables; Ageing
2.  Dose-Response Effect of Fruit and Vegetables on Insulin Resistance in People at High Risk of Cardiovascular Disease 
Diabetes Care  2013;36(12):3888-3896.
The purpose of this randomized controlled trial was to investigate the dose-response effect of fruit and vegetable (F&V) intake on insulin resistance (IR) in people who are overweight and at high risk of cardiovascular disease (CVD).
A total of 105 participants (mean age 56 years) followed a 4-week washout diet (one to two portions of F&Vs per day). Ninety-two participants completed the washout and were randomized to receive one to two, four, or seven portions of F&Vs per day for 12 weeks. IR was assessed at the start and end of this 12-week period by the two-step euglycemic-hyperinsulinemic clamp. Compliance was monitored using a combination of 4-day food diaries and plasma biomarkers of F&V intake.
A total of 89 participants completed the study. Participants attained self-reported F&V intakes of 1.8, 3.8, and 7.0 portions per day (P < 0.001) per group. There was a significant linear increase in serum lutein status across the groups, indicating good compliance (P < 0.001), and body weight was maintained (P = 0.77). No significant difference was found between groups in terms of a change in measures of whole-body, peripheral, or hepatic IR or adiponectin multimers.
Increased consumption of F&Vs, as advocated in public-health advice, has no effect on IR in overweight individuals who are at high risk of CVD when body weight is maintained. Recent evidence from systematic reviews indicates that particular classes or types of F&Vs may have particular antidiabetic properties; hence, it is possible that benefits may only be observed in response to a more specific fruit or vegetable intervention.
PMCID: PMC3836143  PMID: 24130354
3.  Differences in Nuclear DNA Organization Between Lymphocytes, Hodgkin and Reed–Sternberg Cells Revealed by Structured Illumination Microscopy 
Journal of Cellular Biochemistry  2014;115(8):1441-1448.
Advances in light microscopy have enabled the visualization of DNA in the interphase nucleus with more detail than is visible with conventional light microscopy. The nuclear architecture is assumed to be different in cancer cells compared to normal cells. In this paper we have studied, for the first time, the organization of nuclear DNA and that of DNA-free space in control lymphocytes, Hodgkin cells and Reed–Sternberg cells using 3D structured illumination microscopy (SIM). We have observed detail in these SIM images that was not observed in conventional widefield images. We have measured the size distribution of the DNA structure using granulometry and noted a significant, progressive increase in the amount of sub-micron structures from control lymphocytes to Hodgkin cells to Reed–Sternberg cells. The DNA-free space changes as well; “holes” in the DNA distribution start to appear in the malignant cells. We have studied whether these “holes” are nucleoli by staining for upstream binding factor (UBF), a protein associated with the nucleolus. We have found that the relative UBF content progressively and significantly decreases—or is absent—in the DNA-free space when measured as either the Pearson correlation coefficient with the DNA-free space or as the number of “holes” that contain UBF. Similar differences exist within the population of Reed–Sternberg cells between binucleated and multinucleated cells with four or more subnuclei. To our knowledge, this is the first study that investigates the changes of the nuclear DNA structure in any disease with superresolution light microscopy. J. Cell. Biochem. 115: 1441–1448, 2014. © 2014 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
PMCID: PMC4231252  PMID: 24590512
4.  The Role of Angiogenic and Antiangiogenic Factors in the Second Trimester in the Prediction of Preeclampsia in Pregnant Women With Type 1 Diabetes 
Diabetes Care  2013;36(11):3671-3677.
To assess the association between circulating angiogenic and antiangiogenic factors in the second trimester and risk of preeclampsia in women with type 1 diabetes.
Maternal plasma concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) were available at 26 weeks of gestation in 540 women with type 1 diabetes enrolled in the Diabetes and Preeclampsia Intervention Trial.
Preeclampsia developed in 17% of pregnancies (n = 94). At 26 weeks of gestation, women in whom preeclampsia developed later had significantly lower PlGF (median [interquartile range]: 231 pg/mL [120–423] vs. 365 pg/mL [237–582]; P < 0.001), higher sFlt-1 (1,522 pg/mL [1,108–3,393] vs. 1,193 pg/mL [844–1,630] P < 0.001), and higher sEng (6.2 ng/mL [4.9–7.9] vs. 5.1 ng/mL[(4.3–6.2]; P < 0.001) compared with women who did not have preeclampsia. In addition, the ratio of PlGF to sEng was significantly lower (40 [17–71] vs. 71 [44–114]; P < 0.001) and the ratio of sFlt-1 to PlGF was significantly higher (6.3 [3.4–15.7] vs. 3.1 [1.8–5.8]; P < 0.001) in women who later developed preeclampsia. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to a logistic model containing established risk factors (area under the curve [AUC], 0.813) significantly improved the predictive value (AUC, 0.850 and 0.846, respectively; P < 0.01) and significantly improved reclassification according to the integrated discrimination improvement index (IDI) (IDI scores 0.086 and 0.065, respectively; P < 0.001).
These data suggest that angiogenic and antiangiogenic factors measured during the second trimester are predictive of preeclampsia in women with type 1 diabetes. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to established clinical risk factors significantly improves the prediction of preeclampsia in women with type 1 diabetes.
PMCID: PMC3816852  PMID: 23920083
5.  Haptoglobin Phenotype, Preeclampsia and Response to Vitamin C and E Supplementation in Pregnant Women with Type 1 Diabetes 
The phenotype of the anti-oxidant and pro-angiogenic protein haptoglobin (Hp) predicts cardiovascular disease risk and treatment response to antioxidant vitamins in individuals with diabetes. Our objective was to determine whether the Hp phenotype influences preeclampsia risk, or the efficacy of vitamins C and E in preventing preeclampsia, in women with Type 1 diabetes.
This is a secondary analysis of a randomized controlled trial in which women with diabetes received daily vitamins C and E, or placebo, from 8–22 weeks gestation until delivery.
25 antenatal metabolic clinics across the UK (northwest England, Scotland, and Northern Ireland).
Pregnant women with Type 1 diabetes.
Hp phenotype was determined in white women who completed the study, and had plasma samples available (n=685). \
Main Outcome Measures
Compared to Hp 2-1, Hp 1-1 (odds ratio: 0.59 (95% confidence interval: 0.30–1.16)) and Hp 2-2 (0.93 (0.60–1.45)) were not associated with significantly decreased preeclampsia risk after adjusting for treatment group and HbA1c at randomization. Our study was not powered to detect an interaction between Hp phenotype and treatment response. However, our preliminary analysis suggests that vitamins C and E did not prevent preeclampsia in women of any Hp phenotype (Hp 1-1: 0.77 (0.22–2.71); Hp 2-1: 0.81 (0.46–1.43); Hp 2-2: 0.67 (0.34–1.33)) after adjusting for HbA1c at randomization.
Hp phenotype did not significantly affect preeclampsia risk in women with Type 1 diabetes.
PMCID: PMC3860176  PMID: 23718253
pregnancy; preeclampsia; Type 1 diabetes; haptoglobin phenotype; vitamin C; vitamin E
6.  Dry needling: a literature review with implications for clinical practice guidelines1 
Physical Therapy Reviews  2014;19(4):252-265.
Wet needling uses hollow-bore needles to deliver corticosteroids, anesthetics, sclerosants, botulinum toxins, or other agents. In contrast, dry needling requires the insertion of thin monofilament needles, as used in the practice of acupuncture, without the use of injectate into muscles, ligaments, tendons, subcutaneous fascia, and scar tissue. Dry needles may also be inserted in the vicinity of peripheral nerves and/or neurovascular bundles in order to manage a variety of neuromusculoskeletal pain syndromes. Nevertheless, some position statements by several US State Boards of Physical Therapy have narrowly defined dry needling as an ‘intramuscular’ procedure involving the isolated treatment of ‘myofascial trigger points’ (MTrPs).
To operationalize an appropriate definition for dry needling based on the existing literature and to further investigate the optimal frequency, duration, and intensity of dry needling for both spinal and extremity neuromusculoskeletal conditions.
Major findings:
According to recent findings in the literature, the needle tip touches, taps, or pricks tiny nerve endings or neural tissue (i.e. ‘sensitive loci’ or ‘nociceptors’) when it is inserted into a MTrP. To date, there is a paucity of high-quality evidence to underpin the use of direct dry needling into MTrPs for the purpose of short and long-term pain and disability reduction in patients with musculoskeletal pain syndromes. Furthermore, there is a lack of robust evidence validating the clinical diagnostic criteria for trigger point identification or diagnosis. High-quality studies have also demonstrated that manual examination for the identification and localization of a trigger point is neither valid nor reliable between-examiners.
Several studies have demonstrated immediate or short-term improvements in pain and/or disability by targeting trigger points (TrPs) using in-and-out techniques such as ‘pistoning’ or ‘sparrow pecking’; however, to date, no high-quality, long-term trials supporting in-and-out needling techniques at exclusively muscular TrPs exist, and the practice should therefore be questioned. The insertion of dry needles into asymptomatic body areas proximal and/or distal to the primary source of pain is supported by the myofascial pain syndrome literature. Physical therapists should not ignore the findings of the Western or biomedical ‘acupuncture’ literature that have used the very same ‘dry needles’ to treat patients with a variety of neuromusculoskeletal conditions in numerous, large scale randomized controlled trials. Although the optimal frequency, duration, and intensity of dry needling has yet to be determined for many neuromusculoskeletal conditions, the vast majority of dry needling randomized controlled trials have manually stimulated the needles and left them in situ for between 10 and 30 minute durations. Position statements and clinical practice guidelines for dry needling should be based on the best available literature, not a single paradigm or school of thought; therefore, physical therapy associations and state boards of physical therapy should consider broadening the definition of dry needling to encompass the stimulation of neural, muscular, and connective tissues, not just ‘TrPs’.
PMCID: PMC4117383  PMID: 25143704
Dry needling; Literature review; Trigger point; Practice guidelines; Physical therapy
7.  Influence of the cystathionine β-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations 
A high homocysteine, low folate phenotype is a feature of many diseases. The effect of the cystathionine β-synthase (CBS) 844ins68 polymorphism on homocysteine and folate concentrations was examined alone and in the context of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in a Northwestern European male population. The MTHFR 677TT genotype is known to be associated with increased homocysteine and decreased folate relative to CT heterozygotes and CC homozygotes in this and other populations. MTHFR 677TT homozygotes who were also CBS 844ins68 carriers had homocysteine and folate concentrations similar to those of individuals with the MTHFR 677CT and CC genotypes. Homocysteine levels in MTHFR 677TT subjects carrying the CBS 844ins68 allele were 24.1% lower than in non-carriers (6.66 vs 8.77 μmol/l, P=0.045), and serum folate levels were 27.7% higher (11.16 vs 8.74 nmol/l, P=0.034). These findings suggest that the CBS 844ins68 allele ‘normalizes’ homocysteine and folate levels in MTHFR 677TT individuals.
PMCID: PMC4051220  PMID: 18398434
folate; homocysteine; hyperhomocysteinemia; MTHFR; CBS
8.  Identification of MicroRNAs Regulating the Developmental Pathways of Bone Marrow Derived Mast Cells 
PLoS ONE  2014;9(5):e98139.
MicroRNAs (miRNAs) play important roles in leukocyte differentiation, although those utilised for specific programs and key functions remain incompletely characterised. As a global approach to gain insights into the potential regulatory role of miRNA in mast cell differentiation we characterised expression in BM cultures from the initiation of differentiation. In cultures enriched in differentiating mast cells we characterised miRNA expression and identified miRNA targeting the mRNA of putative factors involved in differentiation pathways and cellular identity. Detailed pathway analysis identified a unique miRNA network that is intimately linked to the mast cell differentiation program.
Methodology/Principal Findings
We identified 86 unique miRNAs with expression patterns that were up- or down- regulated at 5-fold or more during bone marrow derived mast cells (BMMC) development. By employing TargetScan and MeSH databases, we identified 524 transcripts involved in 30 canonical pathways as potentially regulated by these specific 86 miRNAs. Furthermore, by applying miRanda and IPA analyses, we predict that 7 specific miRNAs of this group are directly associated with the expression of c-Kit and FcεRIα and likewise, that 18 miRNAs promote expression of Mitf, GATA1 and c/EBPα three core transcription factors that direct mast cell differentiation. Furthermore, we have identified 11 miRNAs that may regulate the expression of STATs-3, -5a/b, GATA2 and GATA3 during differentiation, along with 13 miRNAs that target transcripts encoding Ndst2, mMCP4 and mMCP6 and thus may regulate biosynthesis of mast cell secretory mediators.
This investigation characterises changes in miRNA expression in whole BM cultures during the differentiation of mast cells and predicts functional links between miRNAs and their target mRNAs for the regulation of development. This information provides an important resource for further investigations of the contributions of miRNAs to mast cell differentiation and function.
PMCID: PMC4029961  PMID: 24848502
9.  Expression Profiling of Differentiating Eosinophils in Bone Marrow Cultures Predicts Functional Links between MicroRNAs and Their Target mRNAs 
PLoS ONE  2014;9(5):e97537.
MicroRNAs (miRNAs) are small non-coding RNAs that regulate complex transcriptional networks underpin immune responses. However, little is known about the specific miRNA networks that control differentiation of specific leukocyte subsets. In this study, we profiled miRNA expression during differentiation of eosinophils from bone marrow (BM) progenitors (bmEos), and correlated expression with potential mRNA targets involved in crucial regulatory functions. Profiling was performed on whole BM cultures to document the dynamic changes in miRNA expression in the BM microenvironment over the differentiation period. miRNA for network analysis were identified in BM cultures enriched in differentiating eosinophils, and chosen for their potential ability to target mRNA of factors that are known to play critical roles in eosinophil differentiation pathways or cell identify.
Methodology/Principal Findings
We identified 68 miRNAs with expression patterns that were up- or down- regulated 5-fold or more during bmEos differentiation. By employing TargetScan and MeSH databases, we identified 348 transcripts involved in 30 canonical pathways as potentially regulated by these miRNAs. Furthermore, by applying miRanda and Ingenuity Pathways Analysis (IPA), we identified 13 specific miRNAs that are temporally associated with the expression of IL-5Rα and CCR3 and 14 miRNAs associated with the transcription factors GATA-1/2, PU.1 and C/EBPε. We have also identified 17 miRNAs that may regulate the expression of TLRs 4 and 13 during eosinophil differentiation, although we could identify no miRNAs targeting the prominent secretory effector, eosinophil major basic protein.
This is the first study to map changes in miRNA expression in whole BM cultures during the differentiation of eosinophils, and to predict functional links between miRNAs and their target mRNAs for the regulation of eosinophilopoiesis. Our findings provide an important resource that will promote the platform for further understanding of the role of these non-coding RNAs in the regulation of eosinophil differentiation and function.
PMCID: PMC4019607  PMID: 24824797
10.  A randomised controlled trial of increasing fruit and vegetable intake and how this influences the carotenoid concentration and activities of PON-1 and LCAT in HDL from subjects with type 2 diabetes 
High density lipoproteins (HDL) have many cardioprotective roles; however, in subjects with type 2 diabetes (T2D) these cardioprotective properties are diminished. Conversely, increased fruit and vegetable (F&V) intake may reduce cardiovascular disease risk, although direct trial evidence of a mechanism by which this occurs in subjects with T2D is lacking. Therefore, the aim of this study was to examine if increased F&V consumption influenced the carotenoid content and enzymes associated with the antioxidant properties of HDL in subjects with T2D.
Eighty obese subjects with T2D were randomised to a 1- or ≥6-portion/day F&V diet for 8-weeks. Fasting serum was collected pre- and post-intervention. HDL was subfractionated into HDL2 and HDL3 by rapid ultracentrifugation. Carotenoids were measured in serum, HDL2 and HDL3 by high performance liquid chromatography. The activity of paraoxonase-1 (PON-1) was measured in serum, HDL2 and HDL3 by a spectrophotometric assay, while the activity of lecithin cholesterol acyltransferase (LCAT) was measured in serum, HDL2 and HDL3 by a fluorometric assay.
In the ≥6- vs. 1-portion post-intervention comparisons, carotenoids increased in serum, HDL2 and particularly HDL3, (α-carotene, p = 0.008; β-cryptoxanthin, p = 0.042; lutein, p = 0.012; lycopene, p = 0.016), as did the activities of PON-1 and LCAT in HDL3 (p = 0.006 and 0.044, respectively).
To our knowledge, this is the first study in subjects with T2D to demonstrate that increased F&V intake augmented the carotenoid content and influenced enzymes associated with the antioxidant properties of HDL. We suggest that these changes would enhance the cardioprotective properties of this lipoprotein.
Clinical trial registration
PMCID: PMC3898240  PMID: 24423117
Type-2 diabetes; Fruit and vegetables; High density lipoprotein; Carotenoids; Paraoxonase-1; Lecithin cholesterol acyltransferase
Background and Purpose:
Neck pain is a significant problem and many treatment options exist. While some studies suggest exercise is beneficial for individuals with non‐specific neck pain clinicians have few tools to assist in the decision making process. Therefore, the purpose of this study was to derive a preliminary clinical prediction rule (CPR) for identifying patients with neck pain (NP) who may respond to an exercise‐based treatment program. Exercise‐based interventions have demonstrated positive outcomes in patients with NP, however it is unclear which patients are more likely to respond to this treatment approach.
Consecutive patients with a primary report of nonspecific NP with or without arm pain were recruited. All patients participated in a standardized exercise program and then were classified as having a successful or non‐successful outcome at 6 weeks. Potential predictor variables were entered into a stepwise regression analysis. Variables retained in the regression model were used to develop a multivariate CPR that can be used to classify patients with NP that may benefit from exercise‐based treatment. A 6‐month follow up of the patients was used to evaluate the long‐term effects.
Ninety‐one patients were enrolled in the study of which 50 had a successful outcome. A CPR with 5 variables was identified (Neck Disability Index score < 18/50, presence of shoulder protraction during static postural assessment, patient does not bicycle for exercise, cervical side bending < 32°, and Fear Avoidance Belief Questionnaire–Physical Activity Score < 15). If 4 of the 5 variables were present, the probability of a successful outcome shifted from 56% to 78% (+LR 2.97). At 6 months no significant difference existed in self‐reported outcomes between those considered positive on the rule for a successful outcome and those negative on the rule for a successful outcome.
The proposed CPR may identify patients with NP likely to benefit from exercise‐based treatment in the short term. However, long‐term follow up did not demonstrate a significant difference between groups.
Level of Evidence:
PMCID: PMC3867069  PMID: 24377062
Clinical prediction rule; exercise; neck pain
12.  High Yield Production of a Soluble Human Interleukin-3 Variant from E. coli with Wild-Type Bioactivity and Improved Radiolabeling Properties 
PLoS ONE  2013;8(8):e74376.
Human interleukin-3 (hIL-3) is a polypeptide growth factor that regulates the proliferation, differentiation, survival and function of hematopoietic progenitors and many mature blood cell lineages. Although recombinant hIL-3 is a widely used laboratory reagent in hematology, standard methods for its preparation, including those employed by commercial suppliers, remain arduous owing to a reliance on refolding insoluble protein expressed in E. coli. In addition, wild-type hIL-3 is a poor substrate for radio-iodination, which has been a long-standing hindrance to its use in receptor binding assays. To overcome these problems, we developed a method for expression of hIL-3 in E. coli as a soluble protein, with typical yields of >3mg of purified hIL-3 per litre of shaking microbial culture. Additionally, we introduced a non-native tyrosine residue into our hIL-3 analog, which allowed radio-iodination to high specific activities for receptor binding studies whilst not compromising bioactivity. The method presented herein provides a cost-effective and convenient route to milligram quantities of a hIL-3 analog with wild-type bioactivity that, unlike wild-type hIL‑3, can be efficiently radio-iodinated for receptor binding studies.
PMCID: PMC3753260  PMID: 23991218
13.  Scoping Review on Search Queries and Social Media for Disease Surveillance: A Chronology of Innovation 
The threat of a global pandemic posed by outbreaks of influenza H5N1 (1997) and Severe Acute Respiratory Syndrome (SARS, 2002), both diseases of zoonotic origin, provoked interest in improving early warning systems and reinforced the need for combining data from different sources. It led to the use of search query data from search engines such as Google and Yahoo! as an indicator of when and where influenza was occurring. This methodology has subsequently been extended to other diseases and has led to experimentation with new types of social media for disease surveillance.
The objective of this scoping review was to formally assess the current state of knowledge regarding the use of search queries and social media for disease surveillance in order to inform future work on early detection and more effective mitigation of the effects of foodborne illness.
Structured scoping review methods were used to identify, characterize, and evaluate all published primary research, expert review, and commentary articles regarding the use of social media in surveillance of infectious diseases from 2002-2011.
Thirty-two primary research articles and 19 reviews and case studies were identified as relevant. Most relevant citations were peer-reviewed journal articles (29/32, 91%) published in 2010-11 (28/32, 88%) and reported use of a Google program for surveillance of influenza. Only four primary research articles investigated social media in the context of foodborne disease or gastroenteritis. Most authors (21/32 articles, 66%) reported that social media-based surveillance had comparable performance when compared to an existing surveillance program. The most commonly reported strengths of social media surveillance programs included their effectiveness (21/32, 66%) and rapid detection of disease (21/32, 66%). The most commonly reported weaknesses were the potential for false positive (16/32, 50%) and false negative (11/32, 34%) results. Most authors (24/32, 75%) recommended that social media programs should primarily be used to support existing surveillance programs.
The use of search queries and social media for disease surveillance are relatively recent phenomena (first reported in 2006). Both the tools themselves and the methodologies for exploiting them are evolving over time. While their accuracy, speed, and cost compare favorably with existing surveillance systems, the primary challenge is to refine the data signal by reducing surrounding noise. Further developments in digital disease surveillance have the potential to improve sensitivity and specificity, passively through advances in machine learning and actively through engagement of users. Adoption, even as supporting systems for existing surveillance, will entail a high level of familiarity with the tools and collaboration across jurisdictions.
PMCID: PMC3785982  PMID: 23896182
disease; surveillance; social media; review
14.  Reproducibility and validity of a food frequency questionnaire among pregnant women in a Mediterranean area 
Nutrition Journal  2013;12:26.
Studies exploring the role of diet during pregnancy are still scarce, in part due to the complexity of measuring diet and to the lack of valid instruments. The aim of this study was to examine the reproducibility and validity (against biochemical biomarkers) of a semi-quantitative food frequency questionnaire (FFQ) in pregnant women.
Participants were 740 pregnant women from a population-based birth cohort study in Valencia (INMA Study). We compared nutrient and food intakes from FFQs estimated for two periods of pregnancy (reproducibility), and compared energy-adjusted intake of several carotenoids, folate, vitamin B12, vitamin C and α-tocopherol of the FFQ in the first trimester with their concentration in blood specimens (validity).
Significant correlations for reproducibility were found for major food groups and nutrients but not for lycopene (r=0.06); the average correlation coefficients for daily intake were 0.51 for food groups and 0.61 for nutrients. For validity, statistically significant correlations were observed for vitamin C (0.18), α-carotene (0.32), β-carotene (0.22), lutein-zeaxantin (0.29) and β-cryptoxantin(0.26); non-significant correlations were observed for retinol, lycopene, α-tocopherol, vitamin B12 and folate (r≤0.12). When dietary supplement use was considered, correlations were substantially improved for folate (0.53) and to a lesser extent for vitamin B12 (0.12) and vitamin C (0.20).
This study supports that the FFQ has a good reproducibility for nutrient and food intake, and can provide a valid estimate of several important nutrients during pregnancy.
PMCID: PMC3584829  PMID: 23421854
Diet; Nutrient intake; Food frequency questionnaire; Pregnancy; Validity
15.  Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype 
Background Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case–control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
Methods To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, ‘Y402H’) with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene–smoking interaction; and 16 published studies from non-European ancestry.
Results In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10–2.45; P = 1.1 x 10−161]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
Conclusion The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.
PMCID: PMC3304526  PMID: 22253316
Age-related macular degeneration (AMD); Complement factor H gene; meta-ananlysis
16.  Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies 
Human mutation  2011;32(12):1407-1416.
Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status, has been reported. We present a pooled analysis (n=21,160) demonstrating associations between late AMD and APOε4 (OR=0.72 per haplotype; CI: 0.65–0.74; P=4.41×10−11) and APOε2 (OR=1.83 for homozygote carriers; CI: 1.04–3.23; P=0.04), following adjustment for age-group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR=1.54; CI: 1.38–1.72; P=2.8×10−15) and atrophic (OR=1.38; CI: 1.18–1.61; P=3.37×10−5) AMD but not early AMD (OR=0.94; CI: 0.86–1.03; P=0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyondε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.
PMCID: PMC3217135  PMID: 21882290
age-related macular degeneration; AMD; apolipoprotein E; APOE; case-control association study
17.  Enantioselective Total Syntheses of (−)-Palau’amine, (−)- Axinellamines, and (−)-Massadines 
Journal of the American Chemical Society  2011;133(37):14710-14726.
Dimeric pyrrole-imidazole alkaloids represent a rich and topologically unique class of marine natural products. This full account will follow the progression of efforts that culminated in the enantioselective total syntheses of the most structurally ornate members of this family: the axinellamines, the massadines, and palau’amine. A bio-inspired approach capitalizing on the pseudo-symmetry of the members of this class is recounted, delivering a deschloro derivative of the natural product core. Next, the enantioselective synthesis of the chlorocyclopentane core featuring a scalable, catalytic, enantioselective Diels–Alder reaction of a 1-siloxydiene is outlined in detail. Finally, the successful divergent conversion of this core to each of the aforementioned natural products, and the ensuing methodological developments are described.
PMCID: PMC3173569  PMID: 21861522
18.  Optimal Glycemic Control, Pre-eclampsia, and Gestational Hypertension in Women With Type 1 Diabetes in the Diabetes and Pre-eclampsia Intervention Trial 
Diabetes Care  2011;34(8):1683-1688.
To assess the relationship between glycemic control, pre-eclampsia, and gestational hypertension in women with type 1 diabetes.
Pregnancy outcome (pre-eclampsia or gestational hypertension) was assessed prospectively in 749 women from the randomized controlled Diabetes and Pre-eclampsia Intervention Trial (DAPIT). HbA1c (A1C) values were available up to 6 months before pregnancy (n = 542), at the first antenatal visit (median 9 weeks) (n = 721), at 26 weeks’ gestation (n = 592), and at 34 weeks’ gestation (n = 519) and were categorized as optimal (<6.1%: referent), good (6.1–6.9%), moderate (7.0–7.9%), and poor (≥8.0%) glycemic control, respectively.
Pre-eclampsia and gestational hypertension developed in 17 and 11% of pregnancies, respectively. Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy compared with women who did not develop pre-eclampsia (P < 0.05, respectively). In early pregnancy, A1C ≥8.0% was associated with a significantly increased risk of pre-eclampsia (odds ratio 3.68 [95% CI 1.17–11.6]) compared with optimal control. At 26 weeks’ gestation, A1C values ≥6.1% (good: 2.09 [1.03–4.21]; moderate: 3.20 [1.47–7.00]; and poor: 3.81 [1.30–11.1]) and at 34 weeks’ gestation A1C values ≥7.0% (moderate: 3.27 [1.31–8.20] and poor: 8.01 [2.04–31.5]) significantly increased the risk of pre-eclampsia compared with optimal control. The adjusted odds ratios for pre-eclampsia for each 1% decrement in A1C before pregnancy, at the first antenatal visit, at 26 weeks’ gestation, and at 34 weeks’ gestation were 0.88 (0.75–1.03), 0.75 (0.64–0.88), 0.57 (0.42–0.78), and 0.47 (0.31–0.70), respectively. Glycemic control was not significantly associated with gestational hypertension.
Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy. These data suggest that optimal glycemic control both early and throughout pregnancy may reduce the risk of pre-eclampsia in women with type 1 diabetes.
PMCID: PMC3142058  PMID: 21636798
19.  Mitochondrial J haplogroup is associated with lower blood pressure and anti-oxidant status: findings in octo/nonagenarians from the BELFAST Study 
Age  2012;35(4):1445-1456.
Mitochondria produce cellular energy but also free-radicals, which damage cells despite an array of endogenous anti-oxidants. In Northern Europe, the mitochondrial haplogroup J has been related to longevity in nonagenarians and centenarians but also with age-related disease. Hypertension is an important contributor to atherosclerotic-related diseases and its pathogenesis is associated with increased oxidative stress. In this study, we questioned whether J haplogroup octo/nonagenarians from the Belfast Elderly Longitudinal Free-living Elderly STudy (BELFAST) study showed evidence of protective blood pressure or anti-oxidant profile which might explain their longevity advantage. Briefly, in a cross-sectional study, community-living, mentally alert (Folstein >25/30), octo/nonagenarian subjects, recruited for good health, were enlisted and consented as part of the BELFAST study, for blood pressure, anthropometric measurements and blood sampling. DNA typing for mitochondrial haplotypes was carried out with measurements for enzymatic and non-enzymatic antioxidants. J haplogroup carriers showed lower systolic blood pressure and glutathione peroxidase activity (Gpx) with higher folate measurements. There was no change in urate, bilirubin, albumin or nutrition-related antioxidants-selenium or vitamins A, C and α and β carotene. BELFAST study mtDNA J haplogroup octo/nonagenarians showed lower blood pressure and reduced glutathione peroxidase activity and higher folate, but no change for other antioxidants. These findings are of interest in view of mtDNA J haplogroup’s association with increased age in some previous studies.
PMCID: PMC3705099  PMID: 22777651
Blood pressure; J mitochondrial haplogroup; Longevity; Antioxidant status; Glutathione peroxidase activity; Vitamins A, E, C, α and β carotene; Urate
20.  Variations in Apolipoprotein E Frequency With Age in a Pooled Analysis of a Large Group of Older People 
American Journal of Epidemiology  2011;173(12):1357-1364.
Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ2 for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ2 for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.
PMCID: PMC3145394  PMID: 21498624
aged; apolipoprotein E2; apolipoprotein E3; apolipoprotein E4; apolipoproteins E; longevity; meta-analysis; multicenter study
21.  Total Synthesis of Palau’amine 
PMCID: PMC3367661  PMID: 20041464
22.  Prevalence and Risk Factors for Vitamin C Deficiency in North and South India: A Two Centre Population Based Study in People Aged 60 Years and Over 
PLoS ONE  2011;6(12):e28588.
Studies from the UK and North America have reported vitamin C deficiency in around 1 in 5 men and 1 in 9 women in low income groups. There are few data on vitamin C deficiency in resource poor countries.
To investigate the prevalence of vitamin C deficiency in India.
We carried out a population-based cross-sectional survey in two areas of north and south India. Randomly sampled clusters were enumerated to identify people aged 60 and over. Participants (75% response rate) were interviewed for tobacco, alcohol, cooking fuel use, 24 hour diet recall and underwent anthropometry and blood collection. Vitamin C was measured using an enzyme-based assay in plasma stabilized with metaphosphoric acid. We categorised vitamin C status as deficient (<11 µmol/L), sub-optimal (11–28 µmol/L) and adequate (>28 µmol/L). We investigated factors associated with vitamin C deficiency using multivariable Poisson regression.
The age, sex and season standardized prevalence of vitamin C deficiency was 73.9% (95% confidence Interval, CI 70.4,77.5) in 2668 people in north India and 45.7% (95% CI 42.5,48.9) in 2970 from south India. Only 10.8% in the north and 25.9% in the south met the criteria for adequate levels. Vitamin C deficiency varied by season, and was more prevalent in men, with increasing age, users of tobacco and biomass fuels, in those with anthropometric indicators of poor nutrition and with lower intakes of dietary vitamin C.
In poor communities, such as in our study, consideration needs to be given to measures to improve the consumption of vitamin C rich foods and to discourage the use of tobacco.
PMCID: PMC3232233  PMID: 22163038
23.  Robust nuclear lamina-based cell classification of aging and senescent cells 
Aging (Albany NY)  2011;3(12):1192-1201.
Changes in the shape of the nuclear lamina are exhibited in senescent cells, as well as in cells expressing mutations in lamina genes. To identify cells with defects in the nuclear lamina we developed an imaging method that quantifies the intensity and curvature of the nuclear lamina. We show that this method accurately describes changes in the nuclear lamina. Spatial changes in nuclear lamina coincide with redistribution of lamin A proteins and local reduction in protein mobility in senescent cell. We suggest that local accumulation of lamin A in the nuclear envelope leads to bending of the structure. A quantitative distinction of the nuclear lamina shape in cell populations was found between fresh and senescent cells, and between primary myoblasts from young and old donors. Moreover, with this method mutations in lamina genes were significantly distinct from cells with wild-type genes. We suggest that this method can be applied to identify abnormal cells during aging, in in vitro propagation, and in lamina disorders.
PMCID: PMC3273899  PMID: 22199022
cell senescence; aging cells; apoptosis; nuclear lamina; image processing
24.  Inverse Association of Vitamin C with Cataract in Older People in India 
Ophthalmology  2011;118(10):1958-1965.e2.
To examine the association between vitamin C and cataract in the Indian setting.
Population-based cross-sectional analytic study.
A total of 5638 people aged ≥60 years.
Enumeration of randomly sampled villages in 2 areas of north and south India to identify people aged ≥60 years. Participants were interviewed for socioeconomic and lifestyle factors (tobacco, alcohol, household cooking fuel, work, and diet); attended a clinical examination, including lens photography; and provided a blood sample for antioxidant analysis. Plasma vitamin C was measured using an enzyme-based assay in plasma stabilized with metaphosphoric acid, and other antioxidants were measured by reverse-phase high-pressure liquid chromatography.
Main Outcome Measures
Cataract and type of cataract were graded from digital lens images using the Lens Opacity Classification System III (LOCS III), and cataract was classified from the grade in the worse eye of ≥4 for nuclear cataract, ≥3 for cortical cataract, and ≥2 for posterior subcapsular cataract (PSC). Any cataract was defined as any unoperated or operated cataract.
Of 7518 enumerated people, 5638 (75%) provided data on vitamin C, antioxidants, and potential confounders. Vitamin C was inversely associated with cataract (adjusted odds ratio [OR] for highest to lowest quartile = 0.61; 95% confidence interval (CI), 0.51–0.74; P=1.1×10−6). Inclusion of other antioxidants in the model (lutein, zeaxanthin, retinol, β-carotene, and α-tocopherol) made only a small attenuation to the result (OR 0.68; 95% CI, 0.57–0.82; P < 0.0001). Similar results were seen with vitamin C by type of cataract: nuclear cataract (adjusted OR 0.66; CI, 0.54–0.80; P < 0.0001), cortical cataract (adjusted OR 0.70; CI, 0.54–0.90; P < 0.002), and PSC (adjusted OR 0.58; CI, 0.45–0.74; P < 0.00003). Lutein, zeaxanthin, and retinol were significantly inversely associated with cataract, but the associations were weaker and not consistently observed by type of cataract. Inverse associations were also observed for dietary vitamin C and cataract.
We found a strong association with vitamin C and cataract in a vitamin C–depleted population.
Financial Disclosure(s)
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
PMCID: PMC3185206  PMID: 21705085
25.  Elevated soluble cellular adhesion molecules are associated with increased mortality in a prospective cohort of renal transplant recipients 
BMC Nephrology  2011;12:23.
Increased plasma levels of cellular adhesion molecules (CAMs) have been shown to be predictors of all cause mortality in individuals with chronic renal failure [1,2] and patients with end-stage renal disease receiving haemodialysis [3]. In renal transplant recipients the predictive value of CAMs has not been well characterised. The aim of this study was to assess the relationship between CAMs and all-cause mortality during prospective follow-up of a renal transplant cohort.
A total of 378 renal transplant recipients were recruited between June 2000 and December 2002. Soluble vascular CAM-1 (VCAM) and soluble intercellular CAM-1 (ICAM) were measured at baseline and prospective follow-up data was collected at a median of 2441 days after enrolment.
In univariate survival analysis the renal transplant recipients with a VCAM or ICAM concentration in the lowest third were significantly more likely to have survived at follow-up (p < 0.001 and p = 0.009 respectively). In multivariate survival analysis VCAM and ICAM remained significant independent predictors of mortality following adjustment for traditional cardiovascular risk factors, hsCRP and estimated GFR (p = 0.030 and p = 0.037 respectively).
The results of this prospective study are the first to show that the CAMs, ICAM and particularly VCAM, are significant independent predictors of mortality in patients with a renal transplant.
PMCID: PMC3120748  PMID: 21600046

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