Urinary and Plasma Metabolomics Identify the Distinct Metabolic Profile of Disease State in Chronic Mouse Model of Multiple Sclerosis

Identification of non-invasive biomarkers of disease progression in multiple sclerosis (MS) is critically needed for monitoring the disease progression and for effective therapeutic interventions. Urine is an attractive source for non-invasive biomarkers because it is easily obtained in the clinic. In search of a urine metabolite signature of progression in chronic experimental autoimmune encephalomyelitis (EAE), we profiled urine at the chronic stage of the disease (day 45 post immunization) by global untargeted metabolomics. Using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry, we found 105 metabolites (P < 0.05) significantly altered at the chronic stage, indicating a robust alteration in the urine metabolite profile during disease. Assessment of altered metabolites against the Kyoto Encyclopedia of Genes and Genomes revealed distinct non-overlapping metabolic pathways and revealed phenylalanine-tyrosine and associated metabolism being the most impacted. Combined with previously performed plasma profiling, eight common metabolites were significantly altered in both of the biofluids. Metaboanalyst analysis of these common metabolites revealed that phenylalanine metabolism and Valine, leucine, and isoleucine biosynthetic pathways are central metabolic pathways in both bio-fluids and could be analyzed further, either for the discovery of therapeutics or biomarker development. Overall, our study suggests that urine and plasma metabolomics may contribute to the identification of a distinct metabolic fingerprint of EAE disease discriminating from the healthy control which may aid in the development of an objective non-invasive monitoring method for progressive autoimmune diseases like MS.

Untargeted urinary metabolomics of a chronic mouse model of multiple sclerosis identified Phenylalanine, tyrosine & tryptophan metabolism as the significantly altered metabolic pathway. Eight common metabolites were identified when we combined urinary and plasma metabolic signature, which revealed a perturbation of Phenylalanine metabolism and valine, leucine & isoleucine metabolic pathways, involved in CNS dysfunction during diseases. The identified eight metabolic signature of urine and plasma may be of clinical relevance as potential biomarkers and guide towards the identification of specific metabolic pathways as novel drug targets.

     

Personalized treatment selection using data from crossover designs with carry-over effects

In this work, we propose a semiparametric method for estimating the optimal treatment for a given patient based on individual covariate information for that patient when data from a crossover design are available. Here, we assume there are carry-over effects for patients switching from one treatment to another. For the K treatment (K ≥ 2) scenario, we show that nonparametric estimation of carry-over effects can have the undesirable property that comparison of treatment means can only be done using independent outcome measurements from different groups of patients rather than using available joint measurements for each patient. To overcome this barrier, we compare probabilities of outcome variable of each treatment dominating outcome variables for all other treatments conditional on patient-specific scores constructed from patient covariates. We suggest single-index models as appropriate models connecting outcome variables to covariates and our empirical investigations show that frequencies of correct treatment assignments are highly accurate. The proposed method is also rather robust against departures from a single-index model structure. We also conduct a real data analysis to show the applicability of the proposed procedure.     

Analgesia in labour and delivery

Pain is defined as “an unpleasant sensory or emotional experience associated with actual or potential tissue injury”. Labour pain is encountered during contractions in labour, and patient satisfaction correlates closely to how well it is managed. Doctors commonly encounter acute pain in clinical practice which can be treated simply by applying some basic rules. However, pain due to labour requires specific management which falls outside the basic principles of acute pain management and it is important for practitioners who look after these patients to understand what can be offered. This review considers the basic principles of each of these techniques using some common clinical scenarios. The type of analgesia given will determine where labour takes place and this will be reflected in each case. Specifically, the World Health Organisation (WHO) analgesia ladder is not applicable in these patients because the periodic nature and the intensity of labour pain renders this model obsolete, although is applicable after delivery or after a caesarean section (CS) under general anaesthetic.     

Exploring two contrasting surface‐active exopolysaccharides from a single strain of Ochrobactrum utilizing different hydrocarbon substrates

During production and characterization of exopolysaccharides (EPS) of Ochrobactrum pseudintermedium C1, it was observed that an experimental change in the basic hydrocarbon type of substrate for bacterial utilization led to elicitation of different surface‐active properties in the EPS produced. In the sugar substrate, it elicited surfactant property, while in oil substrates it elicited emulsifying property, which indicated that the EPS might be different. Consequently, attention was focused on a detailed analysis of this substrate‐specific EPS. Utilizing waste sugar, edible, and mineral oil substrates, EPS produced in each situation was characterized. Besides estimating surface activity and thermostability, each substrate‐specific EPS was analyzed by Fourier‐transform infrared spectroscopy, gas chromatography‐mass spectroscopy, ¹H‐nuclear magnetic resonance, and matrix‐assisted laser desorption/ionization—time of flight mass spectroscopy to find any structural difference. The results were significantly contrasting although the similarity in molecular mass suggested a basic similarity in polysaccharide structure. Morphological differences were also evident both macroscopically and microscopically with scanning electron microscopy. As the surface‐active property of EPS was dependent on the substrate utilized, their structural differences might account for it. These diverse surface activities of EPS produced by a single bacterial strain simply by changing the nature of substrate would also augment their bioapplications. Moreover, utilization of waste and easily available substrates should make such applications convenient, ecofriendly, and cost‐worthy.     

Multisample adjusted U‐statistics that account for confounding covariates

Multisample U‐statistics encompass a wide class of test statistics that allow the comparison of 2 or more distributions. U‐statistics are especially powerful because they can be applied to both numeric and nonnumeric data, eg, ordinal and categorical data where a pairwise similarity or distance‐like measure between categories is available. However, when comparing the distribution of a variable across 2 or more groups, observed differences may be due to confounding covariates. For example, in a case‐control study, the distribution of exposure in cases may differ from that in controls entirely because of variables that are related to both exposure and case status and are distributed differently among case and control participants. We propose to use individually reweighted data (ie, using the stratification score for retrospective data or the propensity score for prospective data) to construct adjusted U‐statistics that can test the equality of distributions across 2 (or more) groups in the presence of confounding covariates. Asymptotic normality of our adjusted U‐statistics is established and a closed form expression of their asymptotic variance is presented. The utility of our approach is demonstrated through simulation studies, as well as in an analysis of data from a case‐control study conducted among African‐Americans, comparing whether the similarity in haplotypes (ie, sets of adjacent genetic loci inherited from the same parent) occurring in a case and a control participant differs from the similarity in haplotypes occurring in 2 control participants.     

Precision medicine in chronic disease management: The multiple sclerosis BioScreen

We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine—that is, the application of information technology to medicine—has the potential to radically transform medical practice. We introduce 3 key evolutionary phases in displaying data to health care providers, patients, and researchers: visualization (accessing data), contextualization (understanding the data), and actionable interpretation (real‐time use of the data to assist decision making). Together, these form the stepping stones that are expected to accelerate standardization of data across platforms, promote evidence‐based medicine, support shared decision making, and ultimately lead to improved outcomes. Ann Neurol 2014;76:633–642     

Assessment of vitamin D status in male osteoporosis

BACKGROUND: Clinical assessment of vitamin D status often relies on measuring total circulating 25-hydroxyvitamin D3 (25OHD3), but much of each vitamin D metabolite is bound to plasma vitamin D-binding protein (DBP), such that the percentage of free vitamin is very low. We hypothesized that measurement of free rather than total 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and 25OHD3 may provide better assessment of vitamin D status. We therefore aimed to assess vitamin D status in men with idiopathic osteoporosis, in whom possible secondary causes of osteoporosis had been excluded, and to determine the extent of change in biologically active "free" vitamin D caused by variation in plasma DBP concentrations. METHODS: We measured 1,25(OH)2D3 and 25OHD3 in plasma samples from 56 men with idiopathic osteoporosis [mean (SD) age, 59.6 (13.6) years; range, 21-86 years] and 114 male controls [62.4 (10.4) years; range, 44-82 years]. RESULTS: Mean total plasma 25OHD3 in the 56 men with osteoporosis and the 114 controls was 44.7 (21) and 43.3 (17) nmol/L, respectively; total plasma 1,25(OH)2D3 measured in randomly selected men with osteoporosis (n = 50) and controls (n = 50) was 90 (37) and 103 (39) pmol/L, respectively. Mean plasma DBP was significantly higher (P <0.001) in men with osteoporosis [224 (62) mg/L; n = 56] than in the controls [143 (34) mg/L; n = 114], but calculated free plasma 25OHD3 and 1,25(OH)2D3 were significantly lower in the osteoporotic men than in controls [6.1 (3.1) vs 9.1 (4.4) pmol/L (P <0.00001) and 77 (37) vs 142 (58) fmol/L (P <0.00001), respectively]. CONCLUSIONS: Measurement of total vitamin D metabolites alone, although providing a crude assessment of vitamin D status, may not give an accurate indication of the free (biologically active) form of the vitamin. The ratio of total 25OHD3 and 1,25(OH)2D3 to plasma DBP, rather than total circulating vitamin D metabolites, may provide a more useful index of biological activity. Further studies are required to substantiate this hypothesis.