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1.  Frail HDLs and Stiff Arteries in Type 2 Diabetes in Juveniles 
Diabetes  2013;62(8):2662-2664.
doi:10.2337/db13-0784
PMCID: PMC3717845  PMID: 23881197
2.  Environmental tobacco smoke exposure and diabetes in adult never-smokers 
Environmental Health  2014;13(1):74.
Background
Active smoking has been linked to type 2 diabetes mellitus (T2DM) but only few recent studies have shown environmental tobacco smoke (ETS) to be associated with DM in never-smokers. We assessed the association between long term ETS exposure and DM, and explored effect modifications of this association in our sample.
Methods
We analysed 6392 participants of the Swiss study on air pollution and lung and heart diseases in adults (SAPALDIA). We used mixed logistic regression models to assess the cross-sectional association between ETS and DM. Selected variables were tested for effect modification and several sensitivity analyses were performed, mostly treating participants’ study area as a random effect.
Results
The prevalence of DM and ETS in the sample was 5.5% and 47% respectively. There were 2779 never-smokers with 4% diabetes prevalence. Exposure to ETS increased risk of DM in never-smokers by 50% [95% confidence interval (CI): 1.00, 2.26], and we observed a positive dose–response relationship between ETS exposure level and DM in never-smokers. Associations were strengthened (more than three-folds) by older age and chronic obstructive pulmonary disease, and were stronger in post-menopausal, obese, hypertriglyceridaemic and physically inactive participants. Estimates of association were robust across all sensitivity analyses (including inverse probability weighting for participation bias and fixed-effect analysis for study area). ETS had no substantial associations in current and ex-smokers in our study.
Conclusions
We found a positive association between ETS exposure and DM in never smokers. Additional longitudinal studies involving biomarkers are needed to further explore underlying mechanisms and susceptibilities.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-069X-13-74) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-069X-13-74
PMCID: PMC4192739  PMID: 25253088
Passive smoke; Type 2 diabetes; Cross-sectional study; Respiratory obstruction; Never-smokers
3.  ICG-liver test versus new biomarkers as prognostic markers for prolonged length of stay in critically ill patients - a prospective study of accuracy for prediction of length of stay in the ICU 
Background
Prognostic abilities of medical parameters, which are scoring systems, measurements and biomarkers, are important for stratifying critically ill patients. Indocyanine green plasma disappearance (ICG-PDR) is an established clinical tool for the assessment of liver perfusion and function. Copeptin, MR-proANP and pro-ADM are biomarkers whose prognostic value is still unclear. The goal of this prospective study was to evaluate ICG-PDR, copeptin, MR-proANP and pro-ADM to predict prolonged length of stay (pLOS) in the ICU.
Methods
This study was conducted as a prospective single center study including 110 consecutively admitted ICU patients. Primary endpoint was prolonged length of stay (pLOS) in the ICU, defined as more than three days of stay there.
Results
ROC analysis showed an AUC of 0.73 for ICG-PDR, 0.70 for SAPS II, 0.65 for MR-proANP, 0.64 for pro-ADM and 0.54 for copeptin for pLOS in the ICU.
Conclusions
The prediction of pLOS in the ICU might be better by means of ICG-PDR than with the new biomarkers copeptin, MR-proANP or pro-ADM. Nevertheless, there is more need for research to evaluate whether ICG-PDR is an overall prognostic marker for pLOS.
Trial registration
(ClinicalTrials.gov number, NCT01126554).
doi:10.1186/s13613-014-0019-7
PMCID: PMC4100565  PMID: 25045579
Copeptin; MR-proANP; pro-ADM; ICG-Liver test; ICG-PDR; pLOS; Length of stay in the ICU
4.  Clinical Criteria Replenish High-Sensitive Troponin and Inflammatory Markers in the Stratification of Patients with Suspected Acute Coronary Syndrome 
PLoS ONE  2014;9(6):e98626.
Objectives
In patients with suspected acute coronary syndrome (ACS), rapid triage is essential. The aim of this study was to establish a tool for risk prediction of 30-day cardiac events (CE) on admission. 30-day cardiac events (CE) were defined as early coronary revascularization, subsequent myocardial infarction, or cardiovascular death within 30 days.
Methods and Results
This single-centre, prospective cohort study included 377 consecutive patients presenting to the emergency department with suspected ACS and for whom troponin T measurements were requested on clinical grounds. Fifteen biomarkers were analyzed in the admission sample, and clinical parameters were assessed by the TIMI risk score for unstable angina/Non-ST myocardial infarction and the GRACE risk score. Sixty-nine (18%) patients presented with and 308 (82%) without ST-elevations, respectively. Coronary angiography was performed in 165 (44%) patients with subsequent percutaneous coronary intervention – accounting for the majority of CE – in 123 (33%) patients, respectively. Eleven out of 15 biomarkers were elevated in patients with CE compared to those without. High-sensitive troponin T (hs-cTnT) was the best univariate biomarker to predict CE in Non-ST-elevation patients (AUC 0.80), but did not yield incremental information above clinical TIMI risk score (AUC 0.80 vs 0.82, p = 0.69). Equivalence testing of AUCs of risk models and non-inferiority testing demonstrated that the clinical TIMI risk score alone was non-inferior to its combination with hs-cTnT in predicting CE.
Conclusions
In patients presenting without ST-elevations, identification of those prone to CE is best based on clinical assessment based on TIMI risk score criteria and hs-cTnT.
doi:10.1371/journal.pone.0098626
PMCID: PMC4043791  PMID: 24892556
5.  A Three-Dimensional Engineered Artery Model for In Vitro Atherosclerosis Research 
PLoS ONE  2013;8(11):e79821.
The pathogenesis of atherosclerosis involves dysfunctions of vascular endothelial cells and smooth muscle cells as well as blood borne inflammatory cells such as monocyte-derived macrophages. In vitro experiments towards a better understanding of these dysfunctions are typically performed in two-dimensional cell culture systems. However, these models lack both the three-dimensional structure and the physiological pulsatile flow conditions of native arteries. We here describe the development and initial characterization of a tissue engineered artery equivalent, which is composed of human primary endothelial and smooth muscle cells and is exposed to flow in vitro. Histological analyses showed formation of a dense tissue composed of a tight monolayer of endothelial cells supported by a basement membrane and multiple smooth muscle cell layers. Both low (LDL) and high density lipoproteins (HDL) perfused through the artery equivalent were recovered both within endothelial cells and in the sub-endothelial intima. After activation of the endothelium with either tumour necrosis factor alpha (TNFα) or LDL, monocytes circulated through the model were found to adhere to the activated endothelium and to transmigrate into the intima. In conclusion, the described tissue engineered human artery equivalent model represents a significant step towards a relevant in vitro platform for the systematic assessment of pathogenic processes in atherosclerosis independently of any systemic factors.
doi:10.1371/journal.pone.0079821
PMCID: PMC3828234  PMID: 24244566
6.  Genome-wide association analyses identify 18 new loci associated with serum urate concentrations 
Köttgen, Anna | Albrecht, Eva | Teumer, Alexander | Vitart, Veronique | Krumsiek, Jan | Hundertmark, Claudia | Pistis, Giorgio | Ruggiero, Daniela | O’Seaghdha, Conall M | Haller, Toomas | Yang, Qiong | Tanaka, Toshiko | Johnson, Andrew D | Kutalik, Zoltán | Smith, Albert V | Shi, Julia | Struchalin, Maksim | Middelberg, Rita P S | Brown, Morris J | Gaffo, Angelo L | Pirastu, Nicola | Li, Guo | Hayward, Caroline | Zemunik, Tatijana | Huffman, Jennifer | Yengo, Loic | Zhao, Jing Hua | Demirkan, Ayse | Feitosa, Mary F | Liu, Xuan | Malerba, Giovanni | Lopez, Lorna M | van der Harst, Pim | Li, Xinzhong | Kleber, Marcus E | Hicks, Andrew A | Nolte, Ilja M | Johansson, Asa | Murgia, Federico | Wild, Sarah H | Bakker, Stephan J L | Peden, John F | Dehghan, Abbas | Steri, Maristella | Tenesa, Albert | Lagou, Vasiliki | Salo, Perttu | Mangino, Massimo | Rose, Lynda M | Lehtimäki, Terho | Woodward, Owen M | Okada, Yukinori | Tin, Adrienne | Müller, Christian | Oldmeadow, Christopher | Putku, Margus | Czamara, Darina | Kraft, Peter | Frogheri, Laura | Thun, Gian Andri | Grotevendt, Anne | Gislason, Gauti Kjartan | Harris, Tamara B | Launer, Lenore J | McArdle, Patrick | Shuldiner, Alan R | Boerwinkle, Eric | Coresh, Josef | Schmidt, Helena | Schallert, Michael | Martin, Nicholas G | Montgomery, Grant W | Kubo, Michiaki | Nakamura, Yusuke | Tanaka, Toshihiro | Munroe, Patricia B | Samani, Nilesh J | Jacobs, David R | Liu, Kiang | D’Adamo, Pio | Ulivi, Sheila | Rotter, Jerome I | Psaty, Bruce M | Vollenweider, Peter | Waeber, Gerard | Campbell, Susan | Devuyst, Olivier | Navarro, Pau | Kolcic, Ivana | Hastie, Nicholas | Balkau, Beverley | Froguel, Philippe | Esko, Tõnu | Salumets, Andres | Khaw, Kay Tee | Langenberg, Claudia | Wareham, Nicholas J | Isaacs, Aaron | Kraja, Aldi | Zhang, Qunyuan | Wild, Philipp S | Scott, Rodney J | Holliday, Elizabeth G | Org, Elin | Viigimaa, Margus | Bandinelli, Stefania | Metter, Jeffrey E | Lupo, Antonio | Trabetti, Elisabetta | Sorice, Rossella | Döring, Angela | Lattka, Eva | Strauch, Konstantin | Theis, Fabian | Waldenberger, Melanie | Wichmann, H-Erich | Davies, Gail | Gow, Alan J | Bruinenberg, Marcel | Study, LifeLines Cohort | Stolk, Ronald P | Kooner, Jaspal S | Zhang, Weihua | Winkelmann, Bernhard R | Boehm, Bernhard O | Lucae, Susanne | Penninx, Brenda W | Smit, Johannes H | Curhan, Gary | Mudgal, Poorva | Plenge, Robert M | Portas, Laura | Persico, Ivana | Kirin, Mirna | Wilson, James F | Leach, Irene Mateo | van Gilst, Wiek H | Goel, Anuj | Ongen, Halit | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, Andre G | Imboden, Medea | von Eckardstein, Arnold | Cucca, Francesco | Nagaraja, Ramaiah | Piras, Maria Grazia | Nauck, Matthias | Schurmann, Claudia | Budde, Kathrin | Ernst, Florian | Farrington, Susan M | Theodoratou, Evropi | Prokopenko, Inga | Stumvoll, Michael | Jula, Antti | Perola, Markus | Salomaa, Veikko | Shin, So-Youn | Spector, Tim D | Sala, Cinzia | Ridker, Paul M | Kähönen, Mika | Viikari, Jorma | Hengstenberg, Christian | Nelson, Christopher P | Consortium, CARDIoGRAM | Consortium, DIAGRAM | Consortium, ICBP | Consortium, MAGIC | Meschia, James F | Nalls, Michael A | Sharma, Pankaj | Singleton, Andrew B | Kamatani, Naoyuki | Zeller, Tanja | Burnier, Michel | Attia, John | Laan, Maris | Klopp, Norman | Hillege, Hans L | Kloiber, Stefan | Choi, Hyon | Pirastu, Mario | Tore, Silvia | Probst-Hensch, Nicole M | Völzke, Henry | Gudnason, Vilmundur | Parsa, Afshin | Schmidt, Reinhold | Whitfield, John B | Fornage, Myriam | Gasparini, Paolo | Siscovick, David S | Polašek, Ozren | Campbell, Harry | Rudan, Igor | Bouatia-Naji, Nabila | Metspalu, Andres | Loos, Ruth J F | van Duijn, Cornelia M | Borecki, Ingrid B | Ferrucci, Luigi | Gambaro, Giovanni | Deary, Ian J | Wolffenbuttel, Bruce H R | Chambers, John C | März, Winfried | Pramstaller, Peter P | Snieder, Harold | Gyllensten, Ulf | Wright, Alan F | Navis, Gerjan | Watkins, Hugh | Witteman, Jacqueline C M | Sanna, Serena | Schipf, Sabine | Dunlop, Malcolm G | Tönjes, Anke | Ripatti, Samuli | Soranzo, Nicole | Toniolo, Daniela | Chasman, Daniel I | Raitakari, Olli | Kao, W H Linda | Ciullo, Marina | Fox, Caroline S | Caulfield, Mark | Bochud, Murielle | Gieger, Christian
Nature genetics  2012;45(2):145-154.
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
doi:10.1038/ng.2500
PMCID: PMC3663712  PMID: 23263486
7.  Effect of physical activity on heart rate variability in normal weight, overweight and obese subjects: results from the SAPALDIA study 
Many studies have demonstrated an association of both a sedentary lifestyle and a high body mass index (BMI) with greater risk for cardiovascular disease. Within the prospective SAPALDIA cohort (Swiss cohort study on Air Pollution and Lung Diseases in Adults), we investigated whether regular exercise was protective against reduced heart rate variability (HRV), a clinically relevant predictor of cardiovascular morbidity and mortality, and whether adverse effects of obesity and weight gain on HRV were modified by regular exercise. 24-hour electrocardiograms were recorded in 1712 randomly selected SAPALDIA participants aged ≥50, for whom BMI was assessed in the years 1991 and 2001–2003. Other examinations included an interview investigating health status (especially respiratory and cardiovascular health and health relevant behaviours including physical activity) and measurements of blood pressure, body height and weight. The association between regular physical activity and HRV and interactions with BMI and BMI change was assessed in multivariable linear regression analyses.
Compared to sedentary obese subjects, SDNN (standard deviation of all RR intervals) was 14% (95% CI: 8–20%) higher in sedentary normal weight subjects; 19% (CI: 12–27%) higher in normal weight subjects exercising regularly ≥ 2h/week; and 19% (CI:11–28%) higher in obese subjects exercising regularly ≥ 2h/week.
Compared with sedentary subjects who gained weight, those who gained weight but did exercise regularly had a 13% higher SDNN (CI: 7–20%).
Regular physical exercise has strong beneficial effects on cardiac autonomic nervous function and thus appears to offset the negative effect of obesity on HRV.
doi:10.1007/s00421-008-0800-0
PMCID: PMC3705554  PMID: 18597107
heart rate variability; autonomic nervous system; body mass index; obesity; body weight change; exercise
8.  Peripheral Blood Monocyte Sirt1 Expression Is Reduced in Patients with Coronary Artery Disease 
PLoS ONE  2013;8(1):e53106.
Background
Inflammation plays a key role in atherosclerosis. Sirt1 regulates transcription factors involved in inflammatory processes and blunts atherosclerosis in mice. However, its role in humans remains to be defined. This study was therefore designed to investigate the role of Sirt1 in the development of atherosclerosis.
Methods and Results
48 male subjects admitted for cardiac catheterization were subdivided into healthy subjects, patients with stable coronary artery disease (CAD), and with acute coronary syndromes (ACS). Monocytes were isolated and Sirt1 mRNA levels were determined. Sirt1 gene expression was higher in healthy subjects as compared to patients with CAD or ACS (P<0.05), respectively. Interestingly, HDL levels correlated positively with Sirt1 expression. Thus, HDL from the three groups was isolated and incubated with THP-1 monocytes to determine the effects of HDL on Sirt1 protein in controlled experimental conditions. HDL from healthy subjects stimulated Sirt1 expression in THP-1 monocytes to a higher degree than HDL from CAD and ACS patients (P<0.05). Paraoxonase-1 (PON-1), a HDL-associated enzyme, showed a reduced activity in HDL isolated from CAD and ACS patients as compared to the controls (P<0.001).
Conclusions
Monocytic Sirt1 expression is reduced in patients with stable CAD and ACS. Experiments on THP-1 monocytes suggest that this effect is HDL-dependent and is mediated by a reduced activity of HDL-associated enzyme PON1.
doi:10.1371/journal.pone.0053106
PMCID: PMC3558418  PMID: 23382833
9.  APOLIPOPROTEIN E (APOE) INDUCES ANTI-INFLAMMATORY PHENOTYPE IN MACROPHAGES 
Objectives
Apolipoprotein E (apoE) exerts potent anti-inflammatory effects. We here investigated the effect of apoE on the functional phenotype of macrophages.
Methods and Results
Human apoE receptors VLDL-R or apoER2 were stably expressed in RAW264.7 mouse macrophages. In these cells apoE downregulated markers of the pro-inflammatory M1 phenotype (iNOS, IL-12, MIP-1α), but upregulated markers of the anti-inflammatory M2 phenotype (arginase-I, SOCS3, IL-1RA). In addition, M1 macrophage responses (migration, generation of reactive oxygen species, antibody-dependent cell cytotoxicity, phagocytosis) as well as poly(I:C)- and/or IFN-γ-induced production of pro-inflammatory cytokines, COX-2 expression, and activation of NF-κB, IκB and STAT1 were suppressed in VLDL-R- or apoER2-expressing cells. Conversely, the suppression of M2 phenotype and the enhanced response to poly(I:C) were observed in apoE-producing bone marrow macrophages derived from VLDL-R-deficient mice, but not wild type or LDL receptor-deficient mice. The modulatory effects of apoE on macrophage polarization were inhibited in apoE receptor-expressing RAW264.7 cells exposed to SB220025, a p38MAP kinase inhibitor, and PP1, a tyrosine kinase inhibitor. Accordingly, apoE induced tyrosine kinase-dependent activation of p38MAP kinase in VLDL-R- or apoER2-expressing macrophages. Under in vivo conditions, apoE−/− mice transplanted with apoE-producing wild-type bone marrow showed increased plasma IL-1RA levels and peritoneal macrophages of transplanted animals were shifted to the M2 phenotype (increased IL-1RA production and CD206 expression).
Conclusion
ApoE signaling via VLDL-R or apoER2 promotes macrophage conversion from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. This effect may represent a novel anti-inflammatory activity of apoE.
doi:10.1161/ATVBAHA.111.222745
PMCID: PMC3529398  PMID: 21350196
Apolipoprotein E (apoE); macrophage; inflammation; atherosclerosis
10.  Percentiles of Percentage Body Fat in German Children and Adolescents: An International Comparison 
Background:
Age- and gender-specific percentiles of body mass index in children and adolescents are a cornerstone categorizing overweight and obesity in youths worldwide. Since corresponding worldwide growth curves of percent body fat (% BF) are missing, the purpose was to contribute smoothed percentiles of percentage body fat from a large urban sample of German youths and to include them in actual national and international percentile curves.
Methods:
We estimated % BF in 22 113 German youths aged 3 to 18 years participating in yearly cross-sectional surveys of the PEP Family Heart Study Nuremberg between 1993 and 2007. Percentage body fat was calculated from skinfold thickness using Slaughter equations. Ten smoothed percentile curves were constructed for % BF using the LMS method significant.
Results:
The age- and gender-specific reference curves demonstrate a continuous age-dependent increase of percentage body fat from age 3 to 18 years in girls; whereas in boys, the percentile curves steeply increase from 5 to 11 years and thereafter slightly decrease. The shape of the percentile curves, the maxima among boys at puberty and the median % BF at age 18 years are consistent with most of the current growth curves. % BF in urban studies seems to be lower than in national surveys .
Conclusions:
More than these nine studies should contribute to worldwide-standardized growth charts for % BF to better define overweight and obesity in youth.
PMCID: PMC3530302  PMID: 23272283
Youths; Germany; international comparison; percentage body fat; reference curves
11.  Antibody Phage Display Assisted Identification of Junction Plakoglobin as a Potential Biomarker for Atherosclerosis 
PLoS ONE  2012;7(10):e47985.
To date, no plaque-derived blood biomarker is available to allow diagnosis, prognosis or monitoring of atherosclerotic vascular diseases. In this study, specimens of thrombendarterectomy material from carotid and iliac arteries were incubated in protein-free medium to obtain plaque and control secretomes for subsequent subtractive phage display. The selection of nine plaque secretome-specific antibodies and the analysis of their immunopurified antigens by mass spectrometry led to the identification of 22 proteins. One of them, junction plakoglobin (JUP-81) and its smaller isoforms (referred to as JUP-63, JUP-55 and JUP-30 by molecular weight) were confirmed by immunohistochemistry and immunoblotting with independent antibodies to be present in atherosclerotic plaques and their secretomes, coronary thrombi of patients with acute coronary syndrome (ACS) and macrophages differentiated from peripheral blood monocytes as well as macrophage-like cells differentiated from THP1 cells. Plasma of patients with stable coronary artery disease (CAD) (n = 15) and ACS (n = 11) contained JUP-81 at more than 2- and 14-fold higher median concentrations, respectively, than plasma of CAD-free individuals (n = 13). In conclusion, this proof of principle study identified and verified JUP isoforms as potential plasma biomarkers for atherosclerosis. Clinical validation studies are needed to determine its diagnostic efficacy and clinical utility as a biomarker for diagnosis, prognosis or monitoring of atherosclerotic vascular diseases.
doi:10.1371/journal.pone.0047985
PMCID: PMC3480477  PMID: 23110151
12.  Low-Dose Oral Sirolimus and the Risk of Menstrual-Cycle Disturbances and Ovarian Cysts: Analysis of the Randomized Controlled SUISSE ADPKD Trial 
PLoS ONE  2012;7(10):e45868.
Sirolimus has been approved for clinical use in non proliferative and proliferative disorders. It inhibits the mammalian target of rapamycin (mTOR) signaling pathway which is also known to regulate ovarian morphology and function. Preliminary observational data suggest the potential for ovarian toxicity but this issue has not been studied in randomized controlled trials. We reviewed the self-reported occurrence of menstrual cycle disturbances and the appearance of ovarian cysts post hoc in an open label randomized controlled phase II trial conducted at the University Hospital Zürich between March 2006 and March 2010. Adult females with autosomal dominant polycystic kidney disease, an inherited kidney disease not known to affect ovarian morphology and function, were treated with 1.3 to 1.5 mg sirolimus per day for a median of 19 months (N = 21) or standard care (N = 18). Sirolimus increased the risk of both oligoamenorrhea (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.1 to 29) and ovarian cysts (HR 4.4, CI 1.1 to 26); one patient was cystectomized five months after starting treatment with sirolimus. We also studied mechanisms of sirolimus-associated ovarian toxicity in rats. Sirolimus amplified signaling in rat ovarian follicles through the pro-proliferative phosphatidylinositol 3-kinase pathway. Low dose oral sirolimus increases the risk of menstrual cycle disturbances and ovarian cysts and monitoring of sirolimus-associated ovarian toxicity is warranted and might guide clinical practice with mammalian target of rapamycin inhibitors.
Trial Registration
ClinicalTrials.gov NCT00346918
doi:10.1371/journal.pone.0045868
PMCID: PMC3468602  PMID: 23071528
13.  Bile Acid Metabolites in Serum: Intraindividual Variation and Associations with Coronary Heart Disease, Metabolic Syndrome and Diabetes Mellitus 
PLoS ONE  2011;6(11):e25006.
Bile acids (BAs) regulate glucose and lipid metabolism. In longitudinal and case-control-studies, we investigated the diurnal variation of serum concentrations of the 15 major BAs as well as the biosynthetic precursor 7α-hydroxy-4-cholesten-3-one (C4) and their associations, respectively, with coronary artery disease (CAD), diabetes mellitus type 2 (T2DM), and non-diabetic metabolic syndrome (MetS). In hourly taken blood samples of four healthy probands, the intraindividual 24 h variation of C4, conjugated and unconjugated BAs ranged from 42% to 72%, from 23% to 91%, and from 49% to 90%, respectively. Conjugated BA concentrations mainly increased following food intake. Serum levels of C4 and unconjugated BAs changed with daytime with maxima varying interindividually between 20h00 and 1h00 and between 3h00 and 8h00, respectively. Comparisons of data from 75 CAD patients with 75 CAD-free controls revealed no statistically significant association of CAD with BAs or C4. Comparisons of data from 50 controls free of T2DM or MetS, 50 MetS patients, and 50 T2DM patients revealed significantly increased fasting serum levels of C4 in patients with MetS and T2DM. Multiple regression analysis revealed body mass index (BMI) and plasma levels of triglycerides (TG) as independent determinants of C4 levels. Upon multivariate and principle component analyses the association of C4 with T2DM and/or MetS was not independent of or superior to the canonical MetS components. In conclusion, despite large intra- and interindividual variation, serum levels of C4,are significantly increased in patients with MetS and T2DM but confounded with BMI and TG.
doi:10.1371/journal.pone.0025006
PMCID: PMC3215718  PMID: 22110577
14.  Oral l-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1  
The Journal of Clinical Investigation  2011;121(12):4735-4745.
Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate l-serine to the alternative substrate l-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN1. In mice bearing a transgene expressing the C133W SPTLC1 mutant linked to HSAN1, a 10% l-serine–enriched diet reduced dSL levels. l-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility. In contrast, a 10% l-alanine–enriched diet increased dSL levels and led to severe peripheral neuropathy. In a pilot study with 14 HSAN1 patients, l-serine supplementation similarly reduced dSL levels. These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder.
doi:10.1172/JCI57549
PMCID: PMC3225995  PMID: 22045570
15.  Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease 
The Journal of Clinical Investigation  2011;121(7):2693-2708.
Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDLCAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKCβII activation, which in turn inhibited eNOS-activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKCβII-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX-1– and thereby PKCβII-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair–stimulating effects of HDL.
doi:10.1172/JCI42946
PMCID: PMC3223817  PMID: 21701070
16.  Deoxysphingoid bases as plasma markers in Diabetes mellitus 
Background
Sphingoid bases are formed from the precursors L-serine and palmitoyl-CoA-a reaction which is catalyzed by the serine-palmitoyltransferase (SPT). SPT metabolizes, besides palmitoyl-CoA also other acyl-CoAs but shows also variability towards the use of other amino acid substrates. The enzyme is also able to metabolize alanine, which results in the formation of an atypical deoxy-sphingoid base (DSB). This promiscuous activity is greatly increased in the case of the sensory neuropathy HSAN1, and pathologically elevated DSB levels have been identified as the cause of this disease. Clinically, HSAN1 shows a pronounced similarity to the diabetic sensory neuropathy (DSN), which is the most common chronic complication of diabetes mellitus. Since serine and alanine metabolism is functionally linked to carbohydrate metabolism by their precursors 3-phosphoglycerate and pyruvate, we were interested to see whether the levels of certain sphingoid base metabolites are altered in patients with diabetes.
Results
In a case-control study we compared plasma sphingoid base levels between healthy and diabetic individuals. DSB levels were higher in the diabetic group whereas C16 and C18 sphingoid bases were not significantly different. Plasma serine, but not alanine levels were lower in the diabetic group. A subsequent lipoprotein fractionation showed that the DSBs are primarily present in the LDL and VLDL fraction.
Conclusion
Our results suggest that DSBs are a novel category of plasma biomarkers in diabetes which reflect functional impairments of carbohydrate metabolism. Furthermore, elevated DSB levels as we see them in diabetic patients might also contribute to the progression of the diabetic sensory neuropathy, the most frequent complication of diabetes.
doi:10.1186/1476-511X-9-84
PMCID: PMC2931514  PMID: 20712864
17.  Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1 
The Journal of Neuroscience  2009;29(46):14646-14651.
Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1C133W) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knock-out mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1C133W, but not in the wild-type, double-transgenic tgSPTLC1WT + C133W or SPTLC1+/− mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.
doi:10.1523/JNEUROSCI.2536-09.2009
PMCID: PMC3849752  PMID: 19923297
18.  SPTLC1 Binds ABCA1 To Negatively Regulate Trafficking and Cholesterol Efflux Activity of the Transporter† 
Biochemistry  2008;47(23):6138-6147.
ABCA1 transport of cholesterol and phospholipids to nascent HDL particles plays a central role in lipoprotein metabolism and macrophage cholesterol homeostasis. ABCA1 activity is regulated both at the transcriptional level and at the post-translational level. To explore mechanisms involved in the post-translational regulation of the transporter, we have used affinity purification and mass spectrometry to identify proteins that bind ABCA1 and influence its activity. Previously, we demonstrated that an interaction between β 1-syntrophin stimulated ABCA1 activity, at least in part, be slowing the degradation of the transporter. This work demonstrates that one subunit of the serine palmitoyltransferase enzyme, SPTLC1, but not subunit 2 (SPTLC2), is copurified with ABCA1 and negatively regulates its function. In human THP-I macrophages and in mouse liver, the ABCA1-SPTLC1 complex was detected by co-immunoprecipitation, demonstrating that the interaction occurs in cellular settings where ABCA1 activity is critical for HDL genesis. Pharmacologic inhibition of SPTLC1 with myriocin, which resulted in the disruption of the SPTLC1-ABCA1 complex, and siRNA knockdown of SPTLC1 expression both stimulated ABCA1 efflux by nearly 60% (p < 0.05). In contrast, dominant-negative mutants of SPTLC1 inhibited ABCA1 efflux, indicating that a reduced level of sphingomyelin synthesis could not explain the effect of myriocin on ABCA1 activity. In 293 cells, the SPTLC1 inhibition of ABCA1 activity led to the blockade of the exit of ABCA1 from the endoplasmic reticulum. In contrast, myriocin treatment of macrophages increased the level of cell surface ABCA1. In composite, these results indicate that the physical interaction of ABCA1 and SPTLC1 results in reduction of ABCA1 activity and that inhibition of this interaction produces enhanced cholesterol efflux.
doi:10.1021/bi800182t
PMCID: PMC2504083  PMID: 18484747
19.  Circulating alpha1-antitrypsin in the general population: Determinants and association with lung function 
Respiratory Research  2008;9(1):35.
Background
Severe alpha1-antitrypsin (AAT) deficiency associated with low AAT blood concentrations is an established genetic COPD risk factor. Less is known about the respiratory health impact of variation in AAT serum concentrations in the general population. We cross-sectionally investigated correlates of circulating AAT concentrations and its association with FEV1.
Methods
In 5187 adults (2669 females) with high-sensitive c-reactive protein (CRP) levels ≤ 10 mg/l from the population-based Swiss SAPALDIA cohort, blood was collected at the time of follow-up examination for measuring serum AAT and CRP.
Results
Female gender, hormone intake, systolic blood pressure, age in men and in postmenopausal women, as well as active and passive smoking were positively, whereas alcohol intake and BMI inversely correlated with serum AAT levels, independent of CRP adjustment. We observed an inverse association of AAT with FEV1 in the total study population (p < 0.001), that disappeared after adjustment for CRP (p = 0.28). In addition, the AAT and FEV1 association was modified by gender, menopausal status in women, and smoking.
Conclusion
The results of this population-based study reflect a complex interrelationship between tobacco exposure, gender related factors, circulating AAT, systemic inflammatory status and lung function.
doi:10.1186/1465-9921-9-35
PMCID: PMC2413219  PMID: 18439253

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