Omics biomarkers and an approach for their practical implementation to delineate health status for personalized nutrition strategies.

Personalized nutrition (PN) has gained much attention as a tool for empowerment of consumers to promote changes in dietary behavior, optimizing health status and preventing diet related diseases. Generalized implementation of PN faces different obstacles, one of the most relevant being metabolic characterization of the individual. Although omics technologies allow for assessment the dynamics of metabolism with unprecedented detail, its translatability as affordable and simple PN protocols is still difficult due to the complexity of metabolic regulation and to different technical and economical constrains. In this work, we propose a conceptual framework that considers the dysregulation of a few overarching processes, namely Carbohydrate metabolism, lipid metabolism, inflammation, oxidative stress and microbiota-derived metabolites, as the basis of the onset of several non-communicable diseases. These processes can be assessed and characterized by specific sets of proteomic, metabolomic and genetic markers that minimize operational constrains and maximize the information obtained at the individual level. Current machine learning and data analysis methodologies allow the development of algorithms to integrate omics and genetic markers. Reduction of dimensionality of variables facilitates the implementation of omics and genetic information in digital tools. This framework is exemplified by presenting the EU-Funded project PREVENTOMICS as a use case.

Tunable Optical Molecular Thermometers Based on Metallacrowns.

The effect of ligands' energy levels on thermal dependence of lanthanide emission was examined to create new molecular nanothermometers. A series of Ln2Ga8L8'L8″ metallacrowns (shorthand Ln2L8'), where Ln = Gd3+, Tb3+, or Sm3+ (H3L' = salicylhydroxamic acid (H3shi), 5-methylsalicylhydroxamic acid (H3mshi), 5-methoxysalicylhydroxamic acid (H3moshi), and 3-hydroxy-2-naphthohydroxamic acid (H3nha)) and H2L″ = isophthalic acid (H2iph), was synthesized and characterized. Within the series, ligand-centered singlet state (S1) energy levels ranged from 23,300 to 27,800 cm-1, while triplet (T1) energy levels ranged from 18,150 to 21,980 cm-1. We demonstrated that the difference between T1 levels and relevant energies of the excited 4G5/2 level of Sm3+ (17,800 cm-1) and 5D4 level of Tb3+ (20,400 cm-1) is the major parameter controlling thermal dependence of the emission intensity via the back energy transfer mechanism. However, when the energy difference between S1 and T1 levels is small (below 3760 cm-1), the S1 → T1 intersystem crossing (and its reverse, S1 ← T1) mechanism contributes to the thermal behavior of metallacrowns. Both mechanisms affect Ln3+-centered room-temperature quantum yields with values ranging from 2.07(6)% to 31.2(2)% for Tb2L8' and from 0.0267(7)% to 2.27(5)% for Sm2L8'. The maximal thermal dependence varies over a wide thermal range (ca. 150-350 K) based on energy gaps between relevant ligand-based and lanthanide-based electronic states. By mixing Tb2moshi8' with Sm2moshi8' in a 1:1 ratio, an optical thermometer with a relative thermal sensitivity larger than 3%/K at 225 K was created. Other temperature ranges are also accessible with this approach.

Comparative analysis of striatal [18 F]FDOPA uptake in a partial lesion model of Parkinson's disease in rats: Ratio method versus graphical model.

Animal models of Parkinson's disease are useful to evaluate new treatments and to elucidate the etiology of the disease. Hence, it is necessary to have methods that allow quantification of their effectiveness. [18 F]FDOPA-PET (FDOPA-PET) imaging is outstanding for this purpose because of its capacity to measure changes in the dopaminergic pathway noninvasively and in vivo. Nevertheless, PET acquisition and quantification is time-consuming making it necessary to find faster ways to quantify FDOPA-PET data. This study evaluated Male Wistar rats by FDOPA, before and after being partially injured with 6-OHDA unilaterally. MicroPET scans with a duration of 120 min were acquired and Patlak reference plots were created to estimate the influx constant Kc in the striatum using the full dynamic scan data. Additionally, simple striatal-to-cerebral ratios (SCR) of short static acquisitions were computed and compared with the Kc values. Good correlation (r > 0.70) was obtained between Kc and SCR, acquired between 80-120 min after FDOPA administration with frames of 10 or 20 min and both methods were able to separate the FDOPA-uptake of healthy controls from that of the PD model (SCR -28%, Kc -71%). The present study concludes that Kc and SCR can be trustfully used to discriminate partially lesioned rats from healthy controls.

Components of frailty, sarcopenia and their association with vitamin D deficiency. Cross-sectional, analytical study.

INTRODUCTION: In older adults, the association of frailty and sarcopenia with vitamin D deficiency is well known, but the association of the components of frailty syndrome has been poorly studied. OBJECTIVE: To determine the association of the components of frailty and sarcopenia with vitamin D insufficiency in older adults. METHODS: Adults were studied, in whom age, education, marital status, history of fractures, hospitalizations, anthropometric indicators, sarcopenia, Charlson index, polypharmacy, Fried's frailty phenotype, and plasma vitamin D were recorded; figures < 30 ng/mL were considered indicative of vitamin D insufficiency. Descriptive and inferential statistics were used for statistical analysis. The association was determined by binary logistic regression. RESULTS: One-hundred and seventy-five adults with a mean age of 71.7 ± 6.7 years (95% CI = 60-90 years) were studied. Binary logistic regression showed that the variables associated with vitamin D deficiency were exhaustion (OR = 2.6, 95% CI = 1.0-6.5, p = 0.03), frailty (OR = 9.2, 95% CI = 2.5-34.1, p = 0.001) and pre-frailty (OR = 4.6, 95% CI = 2.1-10.0, p < 0.001). CONCLUSION: The frail and pre-frail phenotypes, as well as exhaustion, are associated with vitamin D insufficiency.

INTRODUCCIÓN: En adultos mayores, la asociación de fragilidad y sarcopenia con deficiencia de vitamina D es conocida, pero poco se ha estudiado la asociación de los componentes del síndrome de fragilidad. OBJETIVO: Determinar la asociación entre los componentes de fragilidad, sarcopenia e insuficiencia de vitamina D en adultos mayores. MÉTODOS: Se estudiaron adultos de quienes se registró edad, escolaridad, estado civil, antecedentes de fracturas, hospitalizaciones, indicadores antropométricos, sarcopenia, índice de Charlson, polifarmacia, fenotipo de fragilidad de Fried y vitamina D plasmática; cifras < 30 ng/mL se consideraron indicativas de insuficiencia de vitamina D. Para el análisis estadístico se utilizó estadística descriptiva e inferencial. La asociación fue determinada mediante regresión logística binaria. RESULTADOS: Se estudiaron 175 adultos con un promedio de edad de 71.7 ± 6.7 años (IC 95 % = 60-90 años). La regresión logística binaria demostró que las variables asociadas a insuficiencia de vitamina D fueron agotamiento (RM = 2.6, IC 95 % = 1.0-6.5, p = 0.03), fragilidad (RM = 9.2, IC 95 % = 2.5-34.1, p = 0.001) y prefragilidad (RM = 4.6, IC 95 % = 2.1-10.0, p < 0.001). CONCLUSIÓN: Los fenotipos frágil, prefrágil y agotamiento se asocian a insuficiencia de vitamina D.

Nitrous oxide versus lidocaine versus no analgesic for in-office hysteroscopy: a randomised clinical trial.

OBJECTIVE: To compare the effect of inhaled nitrous oxide (INO) on pain control during in-office hysteroscopy with 1% lidocaine paracervical infiltration and no analgesic. DESIGN: Single-blind stratified randomised clinical trial with masked assessment by a third party. SETTING: Department of Obstetrics and Gynaecology in a Spanish hospital. POPULATION: Women who underwent hysteroscopy. METHODS: Patients were stratified into three groups according to the purpose of the hysteroscopy (biopsy, polypectomy or tubal sterilisation) and then assigned to different treatment groups through a permuted-blocks randomisation within strata. Pain scale was provided by a gynaecologist totally blinded to procedures and treatments. Effects were assessed using a one-way analysis of variance following an intention-to-treat approach. MAIN OUTCOME MEASURES: Visual analogue scale (VAS) from 0 to 100 mm. RESULTS: A total of 314 women were included: 105 to INO, 104 to 1% lidocaine and 105 to no analgesic. Baseline characteristics were comparable. Mean VAS score after the procedure was 34.7 ± 25.8 mm, 36.1 ± 22.9 mm (P = 1.0) and 47.3 ± 28.2 mm (P = 0.001) for INO, 1% lidocaine and no analgesic, respectively. No adverse events were reported in 91 (86.7%) patients in the INO group compared with 79 (76%) in the 1%-lidocaine group (P = 0.04) and 85 (81%) in the no-analgesic group (P = 0.26). CONCLUSION: INO was as effective as 1% lidocaine in pain control for in-office hysteroscopy and was better tolerated. The no-analgesic group presented the poorer results, so was the least recommended clinical option.

Risk of acute myocardial infarction among new users of bisphosphonates: a nested case-control study.

OBJECTIVE: To test the hypothesis that bisphosphonates reduce AMI risk among new users and to assess whether the effect depends on the duration of treatment. METHODS: Case-control study nested in a primary cohort composed of patients aged 40 to 99 years, with at least 1-year registry in the BIFAP database throughout the study period 2002-2015. Out of this cohort, incident AMI cases were identified and five controls per case were randomly selected, matched by exact age, sex, and index date. The association of AMI with current, recent and past use of bisphosphonates was assessed by computing adjusted odds ratios (AOR) and their corresponding 95% confidence interval (CI) through an unconditional logistic regression. Only initiators of bisphosphonates were considered. RESULTS: A total of 23,590 cases of AMI and 117,612 controls were included. The mean age was 66.8 (SD 13.4) years, and 72.52% was male, in both groups. About 276 (1.17%) cases and 1458 (1.24%) controls were current users of bisphosphonates yielding an AOR of 0.98 (95% CI 0.854-1.14). Recent and past use were not associated with a reduced risk, either, nor was it found a reduction with treatment duration (AOR less than 1 year = 0.92; 95% CI 0.73-1.15; AOR more than 1 year = 1.03; 95% CI 0.86-1.23). Stratified analysis by age, sex and background cardiovascular risk did not show an effect modification by these variables. CONCLUSION: The results do not support a cardioprotective effect of bisphosphonates regardless of the duration of treatment, age, sex or background cardiovascular risk. However, a small protective effect could have been masked if patients with osteoporosis have had a background higher risk of AMI.

[Ga3+ 8 Sm3+ 2 , Ga3+ 8 Tb3+ 2 ] Metallacrowns are Highly Promising Ratiometric Luminescent Molecular Nanothermometers Operating at Physiologically Relevant Temperatures.

Nanothermometry is the study of temperature at the submicron scale with a broad range of potential applications, such as cellular studies or electronics. Molecular luminescent-based nanothermometers offer a non-contact means to record these temperatures with high spatial resolution and thermal sensitivity. A luminescent-based molecular thermometer comprised of visible-emitting Ga3+ /Tb3+ and Ga3+ /Sm3+ metallacrowns (MCs) achieved remarkable relative thermal sensitivity associated with very low temperature uncertainty of Sr =1.9 % K-1 and δT<0.045 K, respectively, at 328 K, as an aqueous suspension of polystyrene nanobeads loaded with the corresponding MCs. To date, they are the ratiometric molecular nanothermometers offering the highest level of sensitivity in the physiologically relevant temperature range.

IAEA contribution to the development of 64Cu radiopharmaceuticals for theranostic applications.

Copper-64 is a very attractive radioisotope with unique nuclear properties that allow using it as both a diagnostic and therapeutic agent, thus providing an almost ideal example of a theranostic radionuclide. A characteristic of Cu-64 stems from the intrinsic biological nature of copper ions that play a fundamental role in a large number of cellular processes. Cu-64 is a radionuclide that reflects the natural biochemical pathways of Cu-64 ions, therefore, can be exploited for the detection and therapy of certain malignancies and metabolic diseases. Beside these applications of Cu-64 ions, this radionuclide can be also used for radiolabelling bifunctional chelators carrying a variety of pharmacophores for targeting different biological substrates. These include peptide-based substrates and immunoconjugates as well as small-molecule bioactive moieties. Fueled by the growing interest of Member States (MS) belonging to the International Atomic Energy Agency (IAEA) community, a dedicated Coordinated Research Project (CRP) was initiated in 2016, which recruited thirteen participating MS from four continents. Research activities and collaborations between the participating countries allowed for collection of an impressive series of results, particularly on the production, preclinical evaluation and, in a few cases, clinical evaluation of various 64Cu-radiopharmaceuticals that may have potential impact on future development of the field. Since this CRP was finalized at the beginning of 2020, this short review summarizes outcomes, outputs and results of this project with the purpose to propagate to other MS and to the whole scientific community, some of the most recent achievements on this novel class of theranostic 64Cu-pharmaceuticals.

Variational approach to KPZ: Fluctuation theorems and large deviation function for entropy production.

Motivated by the time behavior of the functional arising in the variational approach to the Kardar-Parisi-Zhang (KPZ) equation, and in order to study fluctuation theorems in such a system, we have adapted a path-integral scheme that adequately fits to this kind of study dealing with unstable systems. As the KPZ system has no stationary probability distribution, we show how to proceed for obtaining detailed as well as integral fluctuation theorems. This path-integral methodology, together with the variational approach, in addition to allowing analyze fluctuation theorems, can be exploited to determine a large deviation function for entropy production.

Quantitative Analysis of [18F]FFMZ and [18F]FDG PET Studies in the Localization of Seizure Onset Zone in Drug-Resistant Temporal Lobe Epilepsy.

BACKGROUND: Positron emission tomography (PET) imaging in epilepsy is an in vivo technique that allows the localization of a possible seizure onset zone (SOZ) during the interictal period. Stereo-electro-encephalography (SEEG) is the gold standard to define the SOZ. The objective of this research was to evaluate the accuracy of PET imaging in localizing the site of SOZ compared with SEEG. METHODS: Seven patients with refractory temporal lobe epilepsy (Ep) and 2 healthy controls (HC) underwent 2 PET scans, one with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and another with 2'-[18F]fluoroflumazenil (FFMZ), acquired 1 day apart. FDG was acquired for 10 min (static scan) 1 h after administration. An FFMZ scan was acquired for 60 min from radiopharmaceutical administration in a dynamic mode. Each brain PET image was segmented using a standard template implemented in PMOD 3.8. The pons was used as the reference region for modeling of the nondisplaceable binding potential (BPND)for FFMZ, and to obtain uptake ratios for FDG. SEEG studies of patients were performed as a part of their surgical evaluation to define the SOZ. RESULTS: Well-defined differences between HC and Ep were found with both radiopharmaceuticals, showing the utility to identify abnormal brain regions using quantitative PET imaging. Lateralization of the SOZ findings by PET (lower uptake/binding in a specific brain hemisphere) matched in 86% for FFMZ and 71% for FDG with SEEG data. CONCLUSION: Quantitative PET imaging is an excellent complementary tool that matches reasonably well with SEEG to define SOZ in presurgical evaluation.

Geography and major host evolutionary transitions shape the resource use of plant parasites.

The evolution of resource use in herbivores has been conceptualized as an analog of the theory of island biogeography, assuming that plant species are islands separated by phylogenetic distances. Despite its usefulness, this analogy has paradoxically led to neglecting real biogeographical processes in the study of macroevolutionary patterns of herbivore-plant interactions. Here we show that host use is mostly determined by the geographical cooccurrence of hosts and parasites in spider mites (Tetranychidae), a globally distributed group of plant parasites. Strikingly, geography accounts for most of the phylogenetic signal in host use by these parasites. Beyond geography, only evolutionary transitions among major plant lineages (i.e., gymnosperms, commelinids, and eudicots) shape resource use patterns in these herbivores. Still, even these barriers have been repeatedly overcome in evolutionary time, resulting in phylogenetically diverse parasite communities feeding on similar hosts. Therefore, our results imply that patterns of apparent evolutionary conservatism may largely be a byproduct of the geographic cooccurrence of hosts and parasites.

In Silico Study of the Resistance to Organophosphorus Pesticides Associated with Point Mutations in Acetylcholinesterase of Lepidoptera: B. mandarina, B. mori, C. auricilius, C. suppressalis, C. pomonella, H. armígera, P. xylostella, S. frugiperda, and S. litura.

An in silico analysis of the interaction between the complex-ligands of nine acetylcholinesterase (AChE) structures of Lepidopteran organisms and 43 organophosphorus (OPs) pesticides with previous resistance reports was carried out. To predict the potential resistance by structural modifications in Lepidoptera insects, due to proposed point mutations in AChE, a broad analysis was performed using computational tools, such as homology modeling and molecular docking. Two relevant findings were revealed: (1) Docking results give a configuration of the most probable spatial orientation of two interacting molecules (AChE enzyme and OP pesticide) and (2) a predicted ΔGb. The mutations evaluated in the form 1 acetylcholinesterase (AChE-1) and form 2 acetylcholinesterase (AChE-2) structures of enzymes do not affect in any way (there is no regularity of change or significant deviations) the values of the binding energy (ΔGb) recorded in the AChE-OPs complexes. However, the mutations analyzed in AChE are associated with a structural modification that causes an inadequate interaction to complete the phosphorylation of the enzyme.

High pressure luminescence of Nd3+ in YAlO3 perovskite nanocrystals: A crystal-field analysis.

Pressure-induced energy blue- and red-shifts of the 4F3/2 → 4I9/2,11/2 near-infrared emission lines of Nd3+ ions in YAlO3 perovskite nano-particles have been measured from ambient conditions up to 29 GPa. Different positive and negative linear pressure coefficients have been calibrated for the emission lines and related to pressure-induced changes in the interactions between those Nd3+ ions and their twelve oxygen ligands at the yttrium site. Potentiality of the simple overlap model, combined with ab initio structural calculations, in the description of the effects of these interactions on the energy levels and luminescence properties of the optically active Nd3+ ion is emphasized. Simulations show how the energies of the 4f3 ground configuration and the barycenters of the multiplets increase with pressure, whereas the Coulomb interaction between f-electrons decreases and the crystal-field strength increases. All these effects combined explain the wavelength blue-shifts of some near-infrared emission lines of Nd3+ ions. Large pressure rates of various emission lines suggest that a YAlO3 perovskite nano-crystal can be a potential candidate for near-infrared optical pressure sensors.

Anaerobic ammonium oxidation linked to sulfate and ferric iron reduction fuels nitrogen loss in marine sediments.

Availability of fixed nitrogen is a pivotal driver on primary productivity in the oceans, thus the identification of key processes triggering nitrogen losses from these ecosystems is of major importance as they affect ecosystems function and consequently global biogeochemical cycles. Denitrification and anaerobic ammonium oxidation coupled to nitrite reduction (Anammox) are the only identified marine sinks for fixed nitrogen. The present study provides evidence indicating that anaerobic ammonium oxidation coupled to the reduction of sulfate, the most abundant electron acceptor present in the oceans, prevails in marine sediments. Tracer analysis with 15N-ammonium revealed that this microbial process, here introduced as Sulfammox, accounts for up to 5 µg 15N2 produced g-1 day-1 in sediments collected from the eastern tropical North Pacific coast. Raman and X-ray diffraction spectroscopies revealed that elemental sulfur and sphalerite (ZnFeS) were produced, besides free sulfide, during the course of Sulfammox. Anaerobic ammonium oxidation linked to Fe(III) reduction (Feammox) was also observed in the same marine sediments accounting for up to 2 µg 15N2 produced g-1 day-1. Taxonomic characterization, based on 16S rRNA gene sequencing, of marine sediments performing the Sulfammox and Feammox processes revealed the microbial members potentially involved. These novel nitrogen sinks may significantly fuel nitrogen loss in marine environments. These findings suggest that the interconnections among the oceanic biogeochemical cycles of N, S and Fe are much more complex than previously considered.

Revisiting phylogenetic signal; strong or negligible impacts of polytomies and branch length information?

BACKGROUND: Inaccurate estimates of phylogenetic signal may mislead interpretations of many ecological and evolutionary processes, and hence understanding where potential sources of uncertainty may lay has become a priority for comparative studies. Importantly, the sensitivity of phylogenetic signal indices and their associated statistical tests to incompletely resolved phylogenies and suboptimal branch-length information has been only partially investigated. METHODS: Here, we use simulations of trait evolution along phylogenetic trees to assess whether incompletely resolved phylogenies (polytomic chronograms) and phylogenies with suboptimal branch-length information (pseudo-chronograms) could produce directional biases in significance tests (p-values) associated with Blomberg et al.'s K and Pagel's lambda (λ) statistics, two of the most widely used indices to measure and test phylogenetic signal. Specifically, we conducted pairwise comparisons between the p-values resulted from the use of "true" chronograms and their degraded counterparts (i.e. polytomic chronograms and pseudo-chronograms), and computed the frequency with which the null hypothesis of no phylogenetic signal was accepted using "true" chronograms but rejected when using their degraded counterparts (type I bias) and vice versa (type II bias). RESULTS: We found that the use of polytomic chronograms in combination with Blomberg et al.'s K resulted in both, clearly inflated estimates of phylogenetic signal and moderate levels of type I and II biases. More importantly, pseudo-chronograms led to high rates of type I biases. In contrast, Pagel's λ was strongly robust to either incompletely resolved phylogenies and suboptimal branch-length information. CONCLUSIONS: Our results suggest that pseudo-chronograms can lead to strong overestimation of phylogenetic signal when using Blomberg et al.'s K (i.e. high rates of type I biases), while polytomies may be a minor concern given other sources of uncertainty. In contrast, Pagel's λ seems strongly robust to either incompletely resolved phylogenies and suboptimal branch-length information. Hence, Pagel's λ may be a more appropriate alternative over Blomberg et al.'s K to measure and test phylogenetic signal in most ecologically relevant traits when phylogenetic information is incomplete.

External and internal ontogenetic changes in the first rib.

OBJECTIVES: First ribs bear information about thorax morphology and are usually well preserved, compared to other ribs, in bone/fossil samples. Several studies have addressed ontogeny of the first rib by studying changes in bone microanatomy and rib morphology separately, but no studies have combined both approaches to study how internal and external changes covary during ontogeny. The aim of this project is to fill this gap in our knowledge. MATERIALS AND METHODS: We applied 3D geometric morphometrics of sliding semilandmarks to 14 first ribs of Homo sapiens to quantify rib curvature and mid-shaft cross-section outline. Ontogenetic variation was addressed throughout a principal component analysis (PCA). Additionally, we made histological sections at the mid-shaft of the same ribs and studied tissue matrix composition and compartmentalization. Finally, we performed partial least squares (PLS) and regression analyses to study covariation between rib morphology and compartmentalization variables. RESULTS: PCA shows that first ribs increase their curvature over the course of ontogeny and the rib midshaft becomes less rounded during ontogeny. In addition, the sternal end becomes more medially oriented during ontogeny and the relative head-tubercle distance becomes longer. Compartmentalization shows a decrease in the area occupied by mineralized tissues and an increase in the area occupied by non-mineralized tissues over the course of ontogeny, which covaries with mid-shaft cross-section shape. CONCLUSIONS: Our results show detailed variation in rib morphology along with histological changes in bone tissue compartmentalization and, for the first time, the correlation between the two. This could be related to muscle attachments on the 1st rib and also to changes in breathing mode, from diaphragmatic in perinatals to pulmonary in adults, which could also have implications for understanding thorax evolution.

Positional Enrichment by Proton Analysis (PEPA): A One-Dimensional 1 H-NMR Approach for 13 C Stable Isotope Tracer Studies in Metabolomics.

A novel metabolomics approach for NMR-based stable isotope tracer studies called PEPA is presented, and its performance validated using human cancer cells. PEPA detects the position of carbon label in isotopically enriched metabolites and quantifies fractional enrichment by indirect determination of 13 C-satellite peaks using 1D-1 H-NMR spectra. In comparison with 13 C-NMR, TOCSY and HSQC, PEPA improves sensitivity, accelerates the elucidation of 13 C positions in labeled metabolites and the quantification of the percentage of stable isotope enrichment. Altogether, PEPA provides a novel framework for extending the high-throughput of 1 H-NMR metabolic profiling to stable isotope tracing in metabolomics, facilitating and complementing the information derived from 2D-NMR experiments and expanding the range of isotopically enriched metabolites detected in cellular extracts.

Urine metabolome profiling of immune-mediated inflammatory diseases.

BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are a group of complex and prevalent diseases where disease diagnostic and activity monitoring is highly challenging. The determination of the metabolite profiles of biological samples is becoming a powerful approach to identify new biomarkers of clinical utility. In order to identify new metabolite biomarkers of diagnosis and disease activity, we have performed the first large-scale profiling of the urine metabolome of the six most prevalent IMIDs: rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis. METHODS: Using nuclear magnetic resonance, we analyzed the urine metabolome in a discovery cohort of 1210 patients and 100 controls. Within each IMID, two patient subgroups were recruited representing extreme disease activity (very high vs. very low). Metabolite association analysis with disease diagnosis and disease activity was performed using multivariate linear regression in order to control for the effects of clinical, epidemiological, or technical variability. After multiple test correction, the most significant metabolite biomarkers were validated in an independent cohort of 1200 patients and 200 controls. RESULTS: In the discovery cohort, we identified 28 significant associations between urine metabolite levels and disease diagnosis and three significant metabolite associations with disease activity (P FDR < 0.05). Using the validation cohort, we validated 26 of the diagnostic associations and all three metabolite associations with disease activity (P FDR < 0.05). Combining all diagnostic biomarkers using multivariate classifiers we obtained a good disease prediction accuracy in all IMIDs and particularly high in inflammatory bowel diseases. Several of the associated metabolites were found to be commonly altered in multiple IMIDs, some of which can be considered as hub biomarkers. The analysis of the metabolic reactions connecting the IMID-associated metabolites showed an over-representation of citric acid cycle, phenylalanine, and glycine-serine metabolism pathways. CONCLUSIONS: This study shows that urine is a source of biomarkers of clinical utility in IMIDs. We have found that IMIDs show similar metabolic changes, particularly between clinically similar diseases and we have found, for the first time, the presence of hub metabolites. These findings represent an important step in the development of more efficient and less invasive diagnostic and disease monitoring methods in IMIDs.

Liposcale: a novel advanced lipoprotein test based on 2D diffusion-ordered 1H NMR spectroscopy.

Determination of lipoprotein particle size and number using advanced lipoprotein tests (ALTs) is of particular importance to improve cardiovascular risk prediction. Here we present the Liposcale test, a novel ALT based on 2D diffusion-ordered (1)H NMR spectroscopy. Our method uses diffusion coefficients to provide a direct measure of the mean particle sizes and numbers. Using 177 plasma samples from healthy individuals and the concentration of ApoB and ApoA from isolated lipoprotein fractions, our test showed a stronger correlation between the NMR-derived lipoprotein particle numbers and apolipoprotein concentrations than the LipoProfile(®) test commercialized by Liposcience. We also converted LDL particle numbers to ApoB equivalents (milligrams per deciliter) and our test yielded similar values of LDL-ApoB to the LipoProfile(®) test (absolute mean bias of 8.5 and 7.4 mg/dl, respectively). In addition, our HDL particle number values were more concordant with the calibrated values determined recently using ion mobility. Finally, principal component analysis distinguished type 2 diabetic patients with and without atherogenic dyslipidemia (AD) on a second cohort of 307 subjects characterized using the Liposcale test (area under the curve = 0.88) and showed concordant relationships between variables explaining AD. Altogether, our method provides reproducible and reliable characterization of lipoprotein particles and it is applicable to pathological states such as AD.

Metabolic Changes Induced by Electrical Stimulation of Prelemniscal Radiations for the Treatment of Parkinson Disease.

OBJECTIVE: The aim of this work was to study mechanisms of action of electrical stimulation of prelemniscal radiations (Raprl) in the treatment of Parkinson disease, using 2-deoxy-2-fluoro-D-glucose (18F-FDG) Positron Emission Tomography (PET/CT). Materialand Methods: Five patients with PD and predominant unilateral tremor, rigidity and bradykinesia underwent deep brain stimulation (DBS) in contralateral Raprl that improved symptoms from 82.4 to 94.5%. 18F-FDG PET studies were performed before electrode implantation and after DBS therapy. Changes in metabolic activity in PET were evaluated by the maximal standardized uptake value (MSUV) and statistical parametric mapping (SPM) for regions of interest (ROIs) ipsilateral and contralateral to the stimulation site. ROIs were derived from a preoperative probabilistic tractography and included primary motor, supplementary motor and orbitofrontal cortices: Raprl, ventrolateral thalamus, putamen and cerebellum. RESULTS: No significant MSUV changes occurred in ROIs contralateral to Raprl-DBS. In contrast, MSUV decreased ipsilateral to DBS in Raprl, the thalamus, and the primary and supplementary motor cortices. SPM analysis showed metabolic changes which were significantly different after DBS therapy in all ROIs ipsilateral to DBS compared to those in the contralateral side. CONCLUSION: Raprl-DBS decreases the metabolic activity of areas anatomically related to its fiber composition. Improvement of symptoms may result from a decrease in pathological overactivity of circuits related to the ROIs.