Anupam Guleria

Metabolite characterisation in peritoneal dialysis effluent using high-resolution 1H and 1H–13C NMR spectroscopy

Metabolite analysis of peritoneal dialysis (PD) effluent may provide information regarding onset and progression of complications associated with prolonged PD therapy. In this context, the nuclear magnetic resonance detectable small metabolites of PD effluent samples were characterised using high‐resolution 1H and 1H–13C NMR spectroscopy. The various spectra were recorded (at 800 MHz proton frequency) on PD effluent samples obtained after 4‐h (intraperitoneal) dwell time from patients with end‐stage renal failure and continuing normally on PD therapy. In spite of devastating spectral feature of PD effluent due to the presence of intense resonances from glucose and lactate, we were able to identify 53 small endogenous metabolites (including many complex coupled spin systems) and more than 90% of the total CH cross peaks of 1H–13C heteronuclear single‐quantum correlation spectrum specific to various metabolites of PD effluent. We foresee that the characteristic fingerprints of various metabolites of control PD effluent samples will be used to identify and distinguish metabolic differences from PD‐related complications. Copyright

NMR-Based Serum Metabolomics Discriminates Takayasu Arteritis from Healthy Individuals: A Proof-of-Principle Study.

Takayasu arteritis (TA) is a debilitating, systemic disease that involves the aorta and large arteries in a chronic inflammatory process that leads to vessel stenosis. Initially, the disease remains clinically silent (or remains undetected) until the patients present with vascular occlusion. Therefore, new methods for appropriate and timely diagnosis of TA cases are needed to start proper therapy on time and also to monitor the patients response to the given treatment. In this context, NMR-based serum metabolomic profiling has been explored in this proof-of-principle study for the first time to determine characteristic metabolites that could be potentially helpful for diagnosis and prognosis of TA. Serum metabolic profiling of TA patients (n = 29) and healthy controls (n = 30) was performed using 1D (1)H NMR spectroscopy, and possible biomarker metabolites were identified. Using projection to least-squares discriminant analysis, we could distinguish TA patients from healthy controls. Compared to healthy controls, TA patients had (a) increased serum levels of choline metabolites, LDL cholesterol, N-acetyl glycoproteins (NAGs), and glucose and (b) decreased serum levels of lactate, lipids, HDL cholesterol, and glucogenic amino acids. The results of this study are preliminary and need to be confirmed in a prospective study.

NMR based serum metabolomics reveals a distinctive signature in patients with Lupus Nephritis

Management of patient with Lupus Nephritis (LN) continues to remain a challenge for the treating physicians because of considerable morbidity and even mortality. The search of biomarkers in serum and urine is a focus of researchers to unravel new targets for therapy. In the present study, the utility of NMR-based serum metabolomics has been evaluated for the first time in discriminating LN patients from non-nephritis lupus patients (SLE) and further to get new insights into the underlying disease processes for better clinical management. Metabolic profiling of sera obtained from 22 SLE patients, 40 LN patients and 30 healthy controls (HC) were performed using high resolution 1D 1H-CPMG and diffusion edited NMR spectra to identify the potential molecular biomarkers. Using multivariate analysis, we could distinguish SLE and LN patients from HC and LN from SLE patients. Compared to SLE patients, the LN patients had increased serum levels of lipid metabolites (including LDL/VLDL lipoproteins), creatinine and decreased levels of acetate. Our results revealed that metabolic markers especially lipids and acetate derived from NMR spectroscopy has high sensitivity and specificity to distinguish LN among SLE patients and has the potential to be a useful adjunctive tool in diagnosis and clinical management of LN.

Learning to read alters cortico-subcortical cross-talk in the visual system of illiterates

As little as 6 months of literacy instruction leads to neuroplastic changes in deep structures of the brain of illiterate adults. Learning to read is known to result in a reorganization of the developing cerebral cortex. In this longitudinal resting-state functional magnetic resonance imaging study in illiterate adults, we show that only 6 months of literacy training can lead to neuroplastic changes in the mature brain. We observed that literacy-induced neuroplasticity is not confined to the cortex but increases the functional connectivity between the occipital lobe and subcortical areas in the midbrain and the thalamus. Individual rates of connectivity increase were significantly related to the individual decoding skill gains. These findings crucially complement current neurobiological concepts of normal and impaired literacy acquisition.

Effect of SOHAM Meditation on Human Brain: A Voxel-Based Morphometry Study

The anatomical correlates of long‐term meditators involved in practice of “SOHAM” meditation have been studied using voxel‐based morphometry (VBM). The VBM analysis indicates significantly higher gray matter density in brain stem, ventral pallidum, and supplementary motor area in the meditators as compared with age‐matched nonmeditators. The observed changes in brain structure are compared with other forms of meditation.

Metabolomics approach discriminates toxicity index of pyrazinamide and its metabolic products, pyrazinoic acid and 5-hydroxy pyrazinoic acid:

Pyrazinamide (PYZ)—an essential component of primary drug regimen used for the treatment and management of multidrug resistant or latent tuberculosis—is well known for its hepatoxicity. However, the mechanism of PYZ-induced hepatotoxicity is still unknown to researchers. Studies have shown that the drug is metabolized in the liver to pyrazinoic acid (PA) and 5-hydroxy pyrazinoic acid (5-OHPA) which individually may cause different degrees of hepatotoxicity. To evaluate this hypothesis, PYZ, PA, and 5-OHPA were administered to albino Wistar rats orally (respectively, at 250, 125, and 125 mg kg−1 for 28 days). Compared to normal rats, PYZ and its metabolic products decreased the weights of dosed rats and induced liver injury and a status of oxidative stress as assessed by combined histopathological and biochemical analysis. Compared to normal controls, the biochemical and morphological changes were more aberrant in PA- and 5-OHPA-dosed rats with respect to those dosed with PYZ. Finally, the serum metabolic profiles of rats dosed with PYZ, PA, and 5-OHPA were measured and compared with those of normal control rats. With respect to normal control rats, the rats dosed with PYZ and 5-OHPA showed most aberrant metabolic perturbations in their sera as compared to those dosed with PA. Altogether, the study suggests that PYZ-induced hepatotoxicity might be associated with its metabolized products, where 5-OHPA contributes to a higher degree in its overall toxicity than PA.

1H NMR-based serum metabolomics reveals erythromycin-induced liver toxicity in albino Wistar rats

Introduction: Erythromycin (ERY) is known to induce hepatic toxicity which mimics other liver diseases. Thus, ERY is often used to produce experimental models of drug-induced liver-toxicity. The serum metabolic profiles can be used to evaluate the liver-toxicity and to further improve the understanding of underlying mechanism. Objective: To establish the serum metabolic patterns of Erythromycin induced hepatotoxicity in albino wistar rats using 1H NMR based serum metabolomics. Experimental: Fourteen male rats were randomly divided into two groups (n = 7 in each group): control and ERY treated. After 28 days of intervention, the metabolic profiles of sera obtained from ERY and control groups were analyzed using high-resolution 1D 1H CPMG and diffusion-edited nuclear magnetic resonance (NMR) spectra. The histopathological and SEM examinations were employed to evaluate the liver toxicity in ERY treated group. Results: The serum metabolic profiles of control and ERY treated rats were compared using multivariate statistical analysis and the metabolic patterns specific to ERY-induced liver toxicity were established. The toxic response of ERY was characterized with: (a) increased serum levels of Glucose, glutamine, dimethylamine, malonate, choline, phosphocholine and phospholipids and (b) decreased levels of isoleucine, leucine, valine, alanine, glutamate, citrate, glycerol, lactate, threonine, circulating lipoproteins, N-acetyl glycoproteins, and poly-unsaturated lipids. These metabolic alterations were found to be associated with (a) decreased TCA cycle activity and enhanced fatty acid oxidation, (b) dysfunction of lipid and amino acid metabolism and (c) oxidative stress. Conclusion and Recommendations: Erythromycin is often used to produce experimental models of liver toxicity; therefore, the established NMR-based metabolic patterns will form the basis for future studies aiming to evaluate the efficacy of anti-hepatotoxic agents or the hepatotoxicity of new drug-formulations.

Mapping of Brain Activations to Rectal Balloon Distension Stimuli in Male Patients with Irritable Bowel Syndrome Using Functional Magnetic Resonance Imaging

Background/Aims Irritable bowel syndrome (IBS) is associated with exaggerated cerebral response including emotional processing following visceral stimulation; though data on this issue is available in female IBS patients, it is scanty among males. Hence, we aimed to study brain response of male IBS patients following rectal balloon distension as compared to healthy controls using functional magnetic resonance imaging (fMRI). Data between diarrhea and constipation predominant IBS (IBS-D and IBS-C) were also compared. Methods Rectal balloon distension threshold was assessed in 20 male IBS patients (10 IBS-C and 10 IBS-D) and 10 age-matched male healthy controls. Subsequently, fMRI on all the participants was performed at their respective rectal pain threshold. The fMRI data were analysed using the Statistical Parametric Mapping software. Results IBS patients showed greater cerebral activations in insula, middle temporal gyrus, and cerebellum in the left hemisphere compared to healthy controls. Neural activation was found in bilateral precuneus/superior parietal lobules in controls but not in patients with IBS. The brain activation differed among IBS-C and IBS-D patients; while the right mid-cingulate cortex was activated in IBS-C, the left inferior orbito-frontal cortex, left calcarine, and bilateral fusiform gyri were activated among patients with IBS-D following rectal balloon distension. Conclusions Brain response to rectal balloon distension differed among male patients with IBS and controls and among patients with IBS-C and IBS-D. Differential activation among patients with IBS-C and IBS-D was seen in the brain regions controlling affective motivation, homeostatic emotions, and autonomic responses to pain.

Neuro-cognitive aspects of “OM” sound/syllable perception: A functional neuroimaging study

The sound “OM” is believed to bring mental peace and calm. The cortical activation associated with listening to sound “OM” in contrast to similar non-meaningful sound (TOM) and listening to a meaningful Hindi word (AAM) has been investigated using functional magnetic resonance imaging (MRI). The behaviour interleaved gradient technique was employed in order to avoid interference of scanner noise. The results reveal that listening to “OM” sound in contrast to the meaningful Hindi word condition activates areas of bilateral cerebellum, left middle frontal gyrus (dorsolateral middle frontal/BA 9), right precuneus (BA 5) and right supramarginal gyrus (SMG). Listening to “OM” sound in contrast to “non-meaningful” sound condition leads to cortical activation in bilateral middle frontal (BA9), right middle temporal (BA37), right angular gyrus (BA 40), right SMG and right superior middle frontal gyrus (BA 8). The conjunction analysis reveals that the common neural regions activated in listening to “OM” sound during both conditions are middle frontal (left dorsolateral middle frontal cortex) and right SMG. The results correspond to the fact that listening to “OM” sound recruits neural systems implicated in emotional empathy.

Biomedical Applications of Magnetic Nanomaterials

Abstract Magnetic nanoparticles (MNPs) have gained significant attention in recent years due to their specific physical properties and ability to function at bio-interfaces, which makes them a useful tool for clinical diagnostics and therapeutics. Furthermore, one can tailor the features and properties of these MNPs by the use of recent advances in nanotechnology, such as through the control of particle size and architecture, nonfouling surfaces, and increased functionalities, by conjugating them with highly specific targeting agents and other functional ligands. This last step of surface modification plays an important role in the production of multifunctional magnetic nanomaterials with widespread diagnostic and therapeutic capabilities. In this chapter, the promising biomedical applications of MNPs, such as their use in contrast enhancement in magnetic resonance imaging (MRI), site specific magnetic targeting, magnetic hyperthermia treatment, multimodal imaging, magnetic field-dependent controlled drug delivery, and MNPs mediated transfection will be discussed in detail. More novel avenues of research opening up in these areas will also be highlighted.