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SrTiO 3-δ is a well-known metal oxide with cubic perovskite structure. In this work, we have synthesized SrTiO 3-δ via conventional solid-state reaction route (SSR) and studied its electrochemical behaviour in three different pH media viz. 1 M aqueous solution of Na 2 SO 4, (pH 7, neutral medium), KOH (pH 14, basic medium) and 0.5 M solution of H 2 SO 4 (pH 1, acidic medium). The cubic phase with lattice constant, a = 3.905 Å is confirmed through XRD measurements. The electrical characterization of the sample was done in the frequency range 1Hz to 1 MHz and temperature range 25 oC–700 oC. The dynamics of the charged particles in the sample was studied using Jonscher power law. The scaling behaviour of the system has been investigated to understand the conduction mechanism. Further, charge carrier kinetics was also studied to understand the ionic contribution. Electrocatalysis was studied by cyclic voltammetry confirming the redox process in neutral and basic media, which was further confirmed in the XPS study. A better redox coupling occurs that was related to the Ti d-orbital and the O p-orbital interaction. The conductivity and catalytic properties of these materials indicated their use in different applications such as in fuel cells, sensors as well as in electrochemical devices. [Display omitted] • Charge carrier dynamics of SrTiO 3 is explained by conductivity spectra. • Electrochemical performance was studied in neutral (Na 2 SO 4), basic (KOH) and acidic (H 2 SO 4) media. • Observed better redox activity in neutral medium against basic and acidic media with high specific capacitance value. • A high Corrosion rate observed in SrTiO 3 sample in basic medium in comparison to neutral medium. [ABSTRACT FROM AUTHOR]

Dynamic contrast enhanced MRI (DCEMRI), diffusion weighted imaging (DWI) and in vivo proton (1H) magnetic resonance spectroscopy (MRS) provides functional and molecular nature of breast cancer. This study evaluates the potential of the combination of three MR parameters [curve kinetics, apparent diffusion coefficient (ADC) and total choline (tCho) concentration] determined from these techniques in increasing the sensitivity of breast cancer detection. MR investigations were carried out at 1.5 T on 56 patients with cytologically/histologically confirmed breast carcinoma. Single-voxel MRS was used to determine the tCho concentration. 3D FLASH was used for DCEMRI while single shot EPI based DWI was used for ADC determination. On DCEMRI, one patient showed type I curve, while 8 showed type II and 47 showed type III curve thus giving a sensitivity of 83.9% as detection rate of malignancy. tCho concentration was above cut-off value (2.54 mmol/kg) for 50/56 cases giving a sensitivity of 89.3%. Among 9 indeterminate DCEMRI cases, tCho showed malignancy in 6 cases with type II curve. DWI detected malignancy in 54/56 cases that included 9 cases that were false negative on DCEMRI, yielding a sensitivity of 96.4%. A total of 54 cases showed malignancy when any two of the three MR parameters was positive for malignancy yielding a sensitivity of 96.4% while it increased to 100% when any one parameters showed positive result. DWI showed highest sensitivity of detection compared to DCEMRI and MRS. Multi-parametric approach yielded 96.4% and 100% sensitivity when any two or one of the three parameters was taken as positive for malignancy, respectively. Also the results demonstrated that addition of DWI and MRS play a significant role in establishing the final diagnosis of malignancy, especially in cases where DCEMRI is indeterminate. [ABSTRACT FROM AUTHOR]

Abstract Metanil yellow, an azo dye, is a non-permitted synthetic food colour used extensively in India and other developing countries as food additive. Present communication reports the toxic effects of metanil yellow on hepatic and kidney tissues and its amelioration by eugenol, vitamin E and vitamin C. Oral administration of metanil yellow in albino Wistar rats for 28 days caused elevation in serum enzymes (glutamate oxaloacetate transaminase, gluatamate pyruvate transaminase, alkaline phosphatase), and total bilirubin along with decline in albumin and total protein levels. At tissue level, activities of oxidative stress markers viz., superoxide dismutase, catalase and reduced glutathione in liver and kidney were reduced to about half while malondialdehyde level increased significantly under the influence of metanil yellow. Co-administration of eugenol/vitamin E/vitamin C in metanil yellow intoxicated rats exhibited considerable restoration of oxidative stress as well as hepatic and renal function markers in serum and tissues. The study revealed that eugenol has antioxidant, hepatoprotective and renoprotective activities. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the utility of fat fraction (FF) for the differentiation of different breast tissues and in various breast tumor subtypes using in vivo proton ( 1 H) magnetic resonance spectroscopy (MRS). Methods 1 H MRS was performed on 68 malignant, 35 benign, and 30 healthy volunteers at 1.5 T. Malignant breast tissues of patients were characterized into different subtypes based on the differences in the expression of hormone receptors and the FF was calculated. Further, the sensitivity and specificity of FF to differentiate malignant from benign and from normal breast tissues of healthy volunteers was determined using receiver operator curve (ROC) analysis. Results A significantly lower FF of malignant (median 0.12; range 0.01–0.70) compared to benign lesions (median 0.28; range 0.02–0.71) and normal breast tissue of healthy volunteers (median 0.39; range 0.06–0.76) was observed. No significant difference in FF was seen between benign lesions and normal breast tissues of healthy volunteers. Sensitivity and specificity of 75% and 68.6%, respectively was obtained to differentiate malignant from benign lesions. For the differentiation of malignant from healthy breast tissues, 76% sensitivity and 74.5% specificity was achieved. Higher FF was seen in patients with ER−/PR− status as compared to ER+/PR+ patients. Similarly, FF of HER2neu+ tumors were significantly higher than in HER2neu− breast tumors. Conclusion The results showed the potential of in vivo 1 H MRS in providing insight into the changes in the fat content of different types of breast tissues and in various breast tumor subtypes. [ABSTRACT FROM AUTHOR]

Objective: Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) is an ionotropic transmembrane receptor for glutamate. AMPA receptor blockers have been reported to prevent neurological damage and enhance the post stroke recovery in rats. Decanoic acid, a medium-chain fatty acid, has been reported to exhibit non-competitive AMPA receptor antagonism. This study evaluated the effect of decanoic acid administered before and after ischemia reperfusion injury on neurological damage and post stroke recovery in rats. Methods: Middle cerebral artery occlusion (MCAo) was performed by using the intraluminal method to induce focal cerebral ischemia. Decanoic acid (120 mg/kg) was administered orally for 1 day (5-10 min post reperfusion) in one group and for 2 days (24 h pre and 5-10 min post reperfusion) in the other group. Effect on neurological damage and post stroke recovery was assessed by neurobehavioral parameters, MRI and TTC staining along with inflammatory, oxidative, apoptotic, and neuroprotective biomarkers. Results: Decanoic acid significantly reduced the MCAo induced neurological damage and infarct size. Decanoic acid treatment increased the motor coordination and grip strength. Furthermore, levels of inflammatory (TNFα, IL-1β and IL-6), oxidative stress (MDA), apoptotic (TUNEL positive cells) and neurological injury (GFAP) biomarkers were reduced after decanoic acid treatment. Anti-inflammatory cytokine (IL-10) and neuroprotective markers (NT-3, BDNF and TrkB) were found to be significantly increased with decanoic acid treatment. Conclusion: This study showed protective effects of decanoic acid against ischemia reperfusion injury in rats. Anti-inflammatory, antioxidant, neuroprotective, and anti-apoptotic properties may be responsible for the beneficial effects of decanoic acid observed in the study. [ABSTRACT FROM AUTHOR]

Purpose The potential of diffusion weighted imaging (DWI) in assessing pathologic response and surgical margins in locally advanced breast cancer patients (n = 38) undergoing neoadjuvant chemotherapy was investigated. Methods DWI was performed at pre-therapy (Tp0), after I (Tp1) and III (Tp3) NACT at 1.5 T. Apparent diffusion coefficient (ADC) of whole tumor (ADC WT ), solid tumor (ADC ST ), intra-tumoral necrosis (ADC Nec ) was determined. Further, ADC of 6 consecutive shells (5 mm thickness each) including tumor margin to outside tumor margins (OM1 to OM5) was calculated and the data analyzed to define surgical margins. Results Of 38 patients, 6 were pathological complete responders (pCR), 19 partial responders (pPR) and 13 were non-responders (pNR). Significant increase was observed in ADC ST and ADC WT in pCR and pPR following therapy. Pre-therapy ADC was significantly lower in pCR compared to pPR and pNR indicating the heterogeneous nature of tumor which may affect drug perfusion and consequently the response. ADC of outside margins (OM1, OM2, and OM3) was significantly different among pCR, pPR and pNR at Tp3 which may serve as response predictive parameter. Further, at Tp3, ADC of outside margins (OM1, OM2, and OM3) was significantly lower compared to that seen at Tp0 in pCR, indicating the presence of residual disease in these shells. Conclusion Pre-surgery information may serve as a guide to define cancer free margins and the extent of residual disease which may be useful in planning breast conservation surgery. [ABSTRACT FROM AUTHOR]

Theranostics has received considerable attention since both therapy and imaging modalities can be integrated into a single nanocarrier. In this study, fluorescent iron oxide (FIO) nanoparticles and gemcitabine (G) encapsulated poly(lactide- co -glycolide) (PLGA) nanospheres (PGFIO) conjugated with human epidermal growth factor receptor 2, (HER-2) antibody (HER-PGFIO) were prepared and characterized. HER-PGFIO showed the magnetic moment of 10 emu/g, relaxivity ( r 2 ) of 773 mM −1 s −1 and specific absorption rate (SAR) of 183 W/g. HER-PGFIO showed a sustained release of gemcitabine for 11 days in PBS (pH 7.4). In vitro cytotoxicity evaluation of HER-PGFIO in 3D MIAPaCa-2 cultures showed 50% inhibitory concentration (IC 50 ) of 0.11 mg/mL. Subcutaneous tumor xenografts of MIAPaCa-2 in SCID mice were developed and the tumor regression study at the end of 30 days showed significant tumor regression (86 ± 3%) in the HER-PGFIO with magnetic hyperthermia (MHT) treatment group compared to control group. In vivo MRI imaging showed the enhanced contrast in HER-PGFIO + MHT treated group compared to control. HER-PGFIO showed significant tumor regression and enhanced MRI in treatment groups, which could be an effective nanocarrier system for the treatment of pancreatic cancer. Statement of Significance Combination therapies are best suitable to treat pancreatic cancer. Theranostics are the next generation therapeutics with both imaging and treatment agents encapsulated in a single nanocarrier. The novelty of the present work is the development of targeted nanocarrier that provides chemotherapy, thermotherapy and MRI imaging properties. The present work is the next step in developing the nanocarriers for pancreatic cancer treatment. Different treatment modalities embedding into a single nanocarrier is the biggest challenge that was achieved without compromising the functionality of each other. The surface modification of polymeric nanocarriers for antibody binding and their multifunctional abilities will appeal to wider audience. [ABSTRACT FROM AUTHOR]

We assessed and correlated neurochemical levels and cognitive functions in left dorsolateral prefrontal cortex (DLPFC) and left hippocampus in euthymic patients with bipolar disorder and compared these with healthy controls Twenty-five right-handed euthymic patients (HAM-D score < 7, and YMRS score < 7) with bipolar disorder and 20 age and gender matched controls were compared for neurometabolites (n-acetylaspartate – tNAA, choline – Cho, creatinine – Cr, myoinositol – Ins, and glutamine/glutamate – Glu/Gln) measured in left DLPFC and left hippocampus using single voxel magnetic resonance spectroscopy (MRS) and cognitive functions assessed using trail making test (TMT – A and B), wisconsin card sorting test (WCST), and wechsler memory scale (WMS-III Indian adaptation). The two groups were comparable on socio-demographic variables. tNAA levels in DLPFC and hippocampus, and glutamate levels in hippocampus were found to be significantly lower and Inositol and glutamine levels in hippocampus were found to be significantly higher in patients as compared to controls. Patients performed significantly poorly as compared to controls on TMT A & B, all subscales of WMS – III, 5 subscales of WCST, including perseverative responses and errors. The tNAA and glutamate levels in left DLPFC in patients correlated with scores on TMT A & B, and several subscales of WCST and WMS-III. tNAA concentration in left hippocampus in patients correlated with scores on subscales of WMS-III. Neurochemical dysfunction in select brain areas directly correlates with impairment in cognitive functions seen in patients with bipolar disorder in euthymic phase. • Brain MRS in left DLPFC and left hippocampus in euthymic patients with bipolar disorder (BD) shows abnormalities in neurochemical levels. • In BD, ↓ tNAA levels in DLPFC and hippocampus, ↓ glutamate levels in hippocampus and ↑ Inositol and glutamine levels in hippocampus. • In BD, tNAA and glutamate levels in DLPFC correlate with TMT A & B and several subscales of WCST and WMS-III. • In BD, tNAA concentration in hippocampus correlates with subscales of WMS-III. • In BD, neurochemical levels correlate significantly with the extent of cognitive dysfunction even in euthymic phase. [ABSTRACT FROM AUTHOR]

Abstract: We carried out retrospective analysis of apparent diffusion coefficient (ADC) values in 48 infiltrating ductal breast cancer patients who had dynamic contrast-enhanced magnetic resonance imaging (DCEMRI; Group I) and in 53 patients (Group II) for whom DCEMRI data were not available. Twenty-three patients of Group I showed no necrosis (Group Ia), while in 25 patients, both viable (nonnecrotic) and necrotic tumor areas (Group Ib) were observed on DCEMRI. T1-weighted, fat-suppressed and short inversion recovery images were used to identify the viable and necrotic tumor areas in Group II patients, and necrosis was not seen in 11 patients (Group IIa), while 42 (Group IIb) showed both viable and necrotic tumor areas. The ADCs of the necrotic area of Group Ib (1.79±0.30 ×10−3 mm2/s) and Group IIb (1.83±0.40 ×10−3 mm2/s) patients were similar and significantly higher (P<.01) compared to the ADCs of the viable tumor area of Group Ia (0.96±0.21 ×10−3 mm2/s) and Group IIa (0.90±0.17 ×10−3 mm2/s) patients. Proton MR spectroscopy (MRS) data were also available in these patients, and the ADC values were retrospectively determined from the voxel from which MR spectrum was obtained. These values were compared with the ADC obtained for the viable and necrotic areas of the tumor. ADC of the MRS voxel was similar to that obtained for the viable tumor area in patients of both groups. This interesting observation reveals the potential utility of using ADC values to identify viable tumor area for positioning of voxel for MRS in the absence of DCEMRI data. [Copyright &y& Elsevier]

A series of redo switched anthraquinone substituted receptors (R1-R4) have been synthesized and used as a carrier for transport of glucose through supported liquid membrane system using different membrane supports, i.e. egg shell, PTFE and dialysis membrane. These membranes were impregnated with receptors using chloroform as a solvent. The efficacy of different receptors for glucose transport through egg-shell, PTFE and dialysis membranewas found to be R1 >R4 >R2 >R3. It is found that the receptor R1 shows maximum amount of glucose transport with egg-shell membrane. Effects of various parameters such as concentration of glucose, concentration of receptors and the nature of supported membranes have been studied. The objective of the present study is to investigate the carrier ability of the receptors (R1-R4) with different membrane supports (egg-shell, PTFE and dialysis). Upon investigating the best membrane amongst all, egg-shell membrane is found to be the best membrane support. Altering the structure of receptors (R1-R4), this can be correlated to QSPR that helps in fabrication of glucose sensors. [ABSTRACT FROM AUTHOR]

Abstract: Background: The histological extent of inflammatory bowel disease (IBD) is greater than that evident by colonoscopic evaluation. We hypothesized that metabolic profile in macroscopically un-involved colonic mucosa in IBD is similar to that of controls with healthy colon. We thus assessed the differences in metabolic profile in macroscopically involved and un-involved colonic mucosa of IBD patients to further substantiate the extent of disease. Patients and Methods: Colonic mucosal biopsies were obtained and snap frozen from both the macroscopically un-involved and involved colonic mucosa of IBD patients and macroscopically normal colonic mucosa of controls and were subjected to in-vitro high-resolution proton (1H) magnetic resonance (MR) spectroscopy and the concentrations of metabolites were determined. Results: Thirty-two metabolites were assigned in the proton MR spectrum of colonic mucosa of IBD patients. The concentrations of amino acids (isoleucine, leucine, valine, arginine, lysine, glutamine/glutamate, alanine), membrane metabolites (choline, glycerophosphorylcholine/phosphorylcholine), glycolytic product (lactate) and short chain fatty acid (formate) were significantly lower while significantly high level of glucose were observed in the macroscopically un-involved colonic mucosa of IBD patients compared to the macroscopically normal mucosa of controls. There was no significant difference in the concentrations of metabolites in macroscopically involved and un-involved colonic mucosa of IBD patients. Conclusions: The metabolic profile in macroscopically un-involved colonic mucosa of IBD patients is similar to that of macroscopically involved mucosa but different from colonic mucosa of controls. This suggests that even macroscopically un-involved colonic mucosa is metabolically abnormal and may explain the increase in extent of disease with time. [ABSTRACT FROM AUTHOR]

Abstract: Randomized, placebo-controlled single blinded study was carried out to evaluate the effect of oral creatine supplementation on cellular energetics, manual muscle test (MMT) score and functional status in steroid-naive, ambulatory boys suffering with Duchenne muscular dystrophy (DMD; n=33). Eighteen patients received creatine monohydrate (Cr; 5 g/day for 8 weeks), while 15 received placebo (500 mg of vitamin C). Phosphorus metabolite ratios were determined from the right calf muscle of patients using phosphorus magnetic resonance spectroscopy (31P MRS) both prior to (baseline) and after supplementation of Cr or placebo. In addition, metabolite ratios were determined in normal calf muscle of age and sex matched controls (n=8). Significant differences in several metabolite ratios were observed between controls and DMD patients indicating a lower energy state in these patients. Analysis using analysis of covariance adjusted for age and stature showed that the mean phosphocreatine (PCr)/inorganic phosphate (Pi) ratio in patients treated with Cr (4.7; 95% CI; 3.9–5.6) was significantly higher (P=.03) compared to the placebo group (3.3; 95% CI; 2.5–4.2). The mean percentage increase in PCr/Pi ratio was also more in patients <7 years of age compared to older patients after Cr supplementation indicating variation in therapeutic effect with the age. In the placebo group, significant reduction in PCr/Pi (P=.0009), PCr/t-ATP (P=.05) and an increase in phosphodiester (PDE)/PCr ratios was observed after supplementation. Further, in the placebo group, patients <7 years showed reduction of PCr/t-ATP and Pi/t-ATP compared to older patients (>7 years), after supplementation. These results imply that the significant difference observed in PCr/Pi ratio between the Cr and the placebo groups after supplementation may be attributed to a decrease of PCr in the placebo group and an increase in PCr in the Cr group. Changes in MMT score between the two groups was significant (P=.04); however, no change in functional scale (P=.19) was observed. Parents reported subjective improvement on Cr supplementation versus worsening in placebo (P=.02). Our results indicated that Cr was well tolerated and oral Cr significantly improved the muscle PCr/Pi ratio and preserved the muscle strength in short term. However, this study provides no evidence that creatine will prove beneficial after long-term treatment, or have any positive effect on patient lifespan. [Copyright &y& Elsevier]

Abstract: Purpose: To investigate the alterations in water–fat (W-F) ratio of the normal breast tissue of female volunteers as a function of the histological phases of the menstrual cycle. Methods: Image-guided volume localized in vivo proton (1H) magnetic resonance spectroscopy (MRS) at 1.5 T was carried out in the para-areolar region and the upper and lower quadrants of the normal breast tissue of volunteers (n=29; mean age 33.7±6 years) during five histological phases of the menstrual cycle. Results: A W-F value of 0.90±0.41 was observed for the para-areolar region during the proliferative phase, which reduced to 0.46±0.21 and 0.45±0.25 during follicular and luteal phases, respectively. The value increased to 0.76±0.61 during secretory and to 0.87±0.37 during menstrual phases. No significant difference was observed in the W-F value for the upper and the lower quadrants of the breast during various phases of the menstrual cycle. However, the W-F ratio of the para-areolar region was significantly higher compared to the upper and the lower quadrants during all phases. This reflects the dependence of W-F value on the amount of glandular and adipose tissues and the heterogeneous nature of the breast. Conclusions: Our results indicate that changes in the normal breast tissue characteristics occur due to physiological factors like menstrual cycle that strongly influences the W-F value especially the para-areolar region in a cyclic manner. Thus any assessment of breast pathology using W-F values should be carried out carefully taking into consideration the location of the tumor within the breast as well as the time of menstruation. [Copyright &y& Elsevier]

Objectives: Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, gets activated and worsen stroke outcome after ischemia/reperfusion (I/R) injury by inducing inflammation and apoptosis. In this study, tideglusib, a selective irreversible and non-ATP competitive inhibitor of GSK-3β, was explored in cerebral I/R damage using middle cerebral artery occlusion (MCAo) model in rats.Materials and Methods: MCAo was done for 90 min in male Wistar rats (250-280 g) using doccol suture. In pre-treatment group, tideglusib (50 mg/kg) was administered once daily for 2 days and on the day of surgery, 30 min before MCAo. Next day, rats were examined for neurobehavioral parameters and MRI was performed to assess brain damage. In post-treatment group, tideglusib was started at 30 min after MCAo and continued for the next 2 days. After 72 h of MCAo, behavioral parameters and brain damage by MRI were assessed. Further, oxidative stress markers (MDA and GSH), inflammatory cytokines (TNF-α, IL-1β and IL-10) and expression levels of pGSK-3β S9, Bcl-2 and Bax were estimated in pre-treatment group.Results: Tideglusib pre-treatment but not post-treatment significantly improved neurobehavioral parameters (p < 0.05) and reduced brain damage (p < 0.01) when compared with MCAo group. I/R induced changes in MDA (p < 0.01), TNF-α and IL-1β (p < 0.05) were significantly attenuated by pre-treatment. Further, tideglusib pre-treatment ameliorated MCAo induced altered expressions of pGSK-3β S9, Bcl-2 and Bax.Conclusion: The results of our exploratory study indicated prophylactic potential of tideglusib in I/R injury by modulating pGSK-3β S9, apoptosis and neuro-inflammation. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of the study was to assess the efficacy and safety of pregabalin monotherapy in patients with fibromyalgia in a randomized, double-blinded, placebo-controlled trial. After 1 week of single-blinded administration of placebo, 750 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to pregabalin (300 mg/d, 450 mg/d, 600 mg/d) or placebo, administered twice daily for 14 weeks. The primary outcome variable was comparison of end point mean pain scores, derived from daily diary ratings of pain intensity (0 to 10 scale), between each of the pregabalin groups and the placebo group. If positive, additional primary efficacy parameters included the Patient Global Impression of Change (PGIC) and the Fibromyalgia Impact Questionnaire (FIQ) total score. Compared with placebo-treated patients, mean changes in pain scores at the end point in pregabalin-treated patients were significantly greater (P < .001: 300 mg/d, −0.71; 450 mg/d, −0.98; 600 mg/d, −1.00). Compared with placebo, significantly more pregabalin-treated patients reported improvement on PGIC (P < .01 for all 3 pregabalin doses) and significant improvements in total FIQ score for the 450 mg/d (P = .004) and the 600 mg/d (P = .003) doses. Compared with placebo, all 3 doses of pregabalin were associated with significant improvement in sleep. The most commonly reported pregabalin-related adverse events were dizziness and somnolence, which tended to be dose-related. Perspective: This randomized, placebo-controlled trial of 300, 450, and 600 mg/d of pregabalin monotherapy demonstrated that all 3 doses were efficacious for up to 14 weeks for the treatment of fibromyalgia and were well tolerated by most patients. These results provide evidence that pregabalin is an important treatment option for patients with fibromyalgia. [Copyright &y& Elsevier]

Abstract: The muscle metabolism of at-rest patients with varying degrees of postpolio residual paralysis (PPRP) was studied and compared with that of controls using in vivo phosphorus magnetic resonance spectroscopy. The phosphocreatine (PCr)/inorganic phosphate (Pi) and PCr/adenosine triphosphate ratios were lower in patients than in controls. Reduction in PCr/Pi suggests abnormalities in oxidative phosphorylation. A significant increase was observed in the phosphomonoester/PCr ratio in patients, indicating the accumulation of intermediary compounds of the glycolytic pathway. Furthermore, the phosphodiester/PCr ratio was also significantly increased in patients. In general, the observed changes in metabolite ratios were found to be related to the degree of residual paralysis, suggesting that metabolic changes are secondary to chronic neurogenic processes. These metabolic alterations appear to be the possible cause of energy deficit and underlying muscle fatigue in PPRP patients. The present results provide an insight into the metabolic impairment and degree of muscle damage in patients with PPRP. [Copyright &y& Elsevier]

Abstract: The anthracycline antibiotic daunomycin, having four fused rings and an amino sugar, is being used in the treatment of acute leukemia. Binding to DNA is generally believed to be essential for its activity. We have studied the interaction of daunomycin with DNA hexamer sequence d-(TGATCA)2 by titrating up to two drug molecules per duplex using nuclear magnetic resonance spectroscopy. The solution structure of 2:1 drug to DNA complex based on two dimensional nuclear Overhauser enhancement (NOE) spectroscopy and molecular dynamics calculations has been studied. The change in conformation of drug molecule on binding to DNA, deoxyribose conformation and glycosidic bond rotation has been obtained. The absence of sequential NOE connectivities at d-T1pG2 and d-C5pA6 sites shows that the drug chromophore intercalates between these two base pairs. This is substantiated by intermolecular NOEs observed between nucleotide base protons and aromatic ring protons of drug molecule. A set of 17 intermolecular NOE interactions allowed the structure to be derived by restrained molecular dynamics simulations, which have been compared with that obtained by X-ray analysis. Several specific interactions between the drug and DNA protons are found to stabilize the formation of drug–DNA complex. [Copyright &y& Elsevier]

Using one-dimensional (1D) and two-dimensional (2D) proton nuclear magnetic resonance (NMR) methods, the perchloric acid extract of involved (n = 11) and noninvolved (n = 12) axillary lymph nodes (ALN) of breast cancer patients was investigated. Resonances from 40 metabolites such as lactate (Lac), glucose, several amino acids (alanine, lysine, glutamic acid, glutamine, etc.), nucleotides (adenosine triphosphate, guanosine triphosphate, uridine triphosphate, uridine monophosphate, etc.), membrane metabolites [glycerophosphocholine (GPC), phosphocoline (PC), phosphoethanolamine (PE), choline] were unambiguously assigned in both the involved and noninvolved ALN. The concentration of PC/GPC (p = 0.002) was significantly higher in the involved compared to noninvolved nodes. In addition, the concentration of glycolytic product Lac (p = 0.0001) was also found to be significantly higher in involved nodes. Increased concentration of membrane metabolites PC/GPC may be attributed to increased membrane synthesis in malignant cells and, therefore, suggests the presence of metastatic cells in lymph nodes. The higher concentration of Lac is indicative of the presence of malignant cells that derive energy via anaerobic glycolytic pathway. Present results demonstrate the potentials of in vitro proton NMR in detecting malignant cells in ALN and such studies may have an important bearing in determining the prognosis of breast cancer patients. [Copyright &y& Elsevier]

The metabolic differences in the skeletal muscle of patients with Duchenne muscular dystrophy (DMD) and normal subjects (controls) were investigated using in-vitro high-resolution proton NMR spectroscopy. In all, 56 metabolites were unambiguously identified in the perchloric acid extract of muscle tissue using one- and two-dimensional NMR. The concentrations of glycolytic substrate glucose (Glc; p < 0.05), gluconeogenic amino acids such as glutamine (Gln; p < 0.05) and alanine (Ala; p < 0.05) and the glycolytic product lactate (Lac; p < 0.05) were statistically significantly lower in DMD patients as compared to controls. A significant reduction in the concentrations of total creatine (TCr; p < 0.05), glycerophosphoryl choline + phosphoryl choline + carnitine (GPC/PC/Car; p < 0.05), choline (Cho; p < 0.05) and acetate (Ace; p < 0.05) was also observed in these patients. Decrease in the level of glucose may be attributed to the reduction in the concentrations of gluconeogenic substrates or membrane abnormalities in degenerated muscle of DMD patients. Lower levels of choline containing compounds indicate membrane abnormalities. Decrease in the concentration of lactate in the muscle of DMD patients may be due to the reduction in anaerobic glycolytic activity or lower substrate concentration. The decrease in the concentration of acetate may reflect reduced transport of fatty acids into mitochondria due to decreased concentration of carnitine in DMD patients. Kreb’s cycle intermediate α-ketoglutarate was observed only in the diseased muscle, which is suggestive of predominant oxidative metabolism for energy generation. [Copyright &y& Elsevier]

Effect of RISUG™, a newly developed male contraceptive, on various amino acids of seminal plasma ejaculates was studied by proton magnetic resonance spectroscopy at 400 MHz. Levels of amino acids were compared with the seminal plasma of obstructive azoospermia and controls. Glutamic acid, glutamine, and arginine were found to be high in concentration in human seminal plasma. The concentration of aromatic amino acids such as tyrosine, histidine, and phenylalanine in RISUG-injected subjects showed no significant difference compared to controls (p > 0.1); however, there was a statistically significant decrease in the concentration of these amino acids in obstructive azoospermia. The concentration of some prominent amino acids that showed overlapping resonances, such as isoleucine+leucine+valine (p < 0.01), alanine+isoleucine+lysine (p < 0.01), arginine+lysine+leucine (p < 0.01), and glutamic acid+glutamine (p < 0.01), showed a statistically significant decrease in RISUG-injected subjects compared to controls. Overlap of these amino acid resonances were noticed even at 600 MHz. In general, the total amino acids concentration in RISUG-injected subjects was found to be higher than in azoospermic subjects, confirming the occurrence of ‘partial’ obstructive azoospermia in subjects injected with this contraceptive. [Copyright &y& Elsevier]

Post stroke recanalization has been associated with increased risk of oxidative stress. Stimulating endogenous antioxidant pathway by activation of nuclear factor erythroid-2-related factor-2 (Nrf2) plays a key role in neuronal defense against inflammation and oxidative stress in penumbra. Here, we explored whether monomethyl fumarate (MMF) could produce neuro-protection after ischemia/reperfusion (I/R) injury via Nrf2/HO1 activation. In male SD rats, middle cerebral artery was occluded for 90 min and confirmed using Laser Doppler flowmeter. MMF (10, 20 and 40 mg/kg) was administered in two divided doses at 30 min post ischemia and 5–10 min after reperfusion. After 24 h, effect on neurobehavioral parameters, infarct damage by TTC staining and MRI, oxidative stress and inflammatory cytokines were assessed. Expression studies of nuclear Nrf2 and cytoplasmic HO1 were performed in peri-infarct cortex and striatum; followed by dual immunofluorescence study to check the specific cell type. I/R induced neurobehavioral deficits and infarct damage were significantly (p < 0.05) attenuated by MMF (20 and 40 mg/kg). MMF, 20 mg/kg, significantly normalized I/R induced altered redox status and increased levels of TNF-α, IL-1β in the ipsilateral cortex. MRI data showed significantly reduced infarct in cortex but not in striatum after MMF treatment. Expression of nuclear Nrf2 and cytoplasmic HO1 were significantly (p < 0.05) increased in peri-infarct cortex after treatment with MMF. Additionally, dual immunofluorescence showed increased Nrf2 expression in neurons and HO1 expression in neurons as well as astrocytes in peri-infarct cortex after MMF treatment. Our results show the neuro-protective potential of MMF probably by restricting the progression of damage from striatum to cortex through activation of Nrf2/HO1 pathway in peri-infarct cortex. Image 1 • Monomethyl fumarate (MMF) attenuated I/R induced neurological deficits, motor incoordination and cortical infarct. • Oxidative stress and inflammatory cytokines were normalized mainly in cortex after MMF treatment. • MMF increased Nrf2 expression in neurons and HO1 expression in neurons as well as astrocytes in peri-infarct cortex. • Nrf2/HO1 activation and inhibition of inflammation in peri-infarct region may be responsible for protective effect of MMF. [ABSTRACT FROM AUTHOR]

Proper functional development of the auditory cortex (ACx) critically depends on early relevant sensory experiences. Exposure to high intensity noise (industrial/traffic) and music, a current public health concern, may disrupt the proper development of the ACx and associated behavior. The biochemical mechanisms associated with such activity dependent changes during development are poorly understood. Here we report the effects of prenatal chronic (last 10 days of incubation), 110 dB sound pressure level (SPL) music and noise exposure on metabolic profile of the auditory cortex analogue/field L (AuL) in domestic chicks. Perchloric acid extracts of AuL of post hatch day 1 chicks from control, music and noise groups were subjected to high resolution (700 MHz) 1 H NMR spectroscopy. Multivariate regression analysis of the concentration data of 18 metabolites revealed a significant class separation between control and loud sound exposed groups, indicating a metabolic perturbation. Comparison of absolute concentration of metabolites showed that overstimulation with loud sound, independent of spectral characteristics (music or noise) led to extensive usage of major energy metabolites, e.g., glucose, β-hydroxybutyrate and ATP. On the other hand, high glutamine levels and sustained levels of neuromodulators and alternate energy sources, e.g., creatine, ascorbate and lactate indicated a systems restorative measure in a condition of neuronal hyperactivity. At the same time, decreased aspartate and taurine levels in the noise group suggested a differential impact of prenatal chronic loud noise over music exposure. Thus prenatal exposure to loud sound especially noise alters the metabolic activity in the AuL which in turn can affect the functional development and later auditory associated behaviour. [ABSTRACT FROM AUTHOR]

Abstract: Background: Biosimilars are defined as biologic products that are highly similar to reference products, notwithstanding minor differences in clinically inactive components, with no clinically meaningful differences between the biologic product and the reference product in terms of safety profile, purity, and potency. Due to the high cost of innovator biologics, as well as an increase in the number of these products reaching patent expiry, the development of a process for approving biosimilar products has become a crucial regulatory issue in the United States. Objective: This commentary explores the relationship between structural/biophysical variation and the risk/benefit profile of biosimilars and reference biologics that have undergone process changes in the context of the most recent biophysical, nonclinical, and clinical data available. Methods: The search strategy used PubMed, EMBASE, and MEDLINE for the retrieval of documents pertaining to biologic manufacturing, comparative analysis of biosimilars and originator biologics, and relevant review articles on biosimilars. For regulatory documents pertaining to the processes of the approval of biosimilars, biologics, and generics, a search for legislative decisions, briefing summaries, concept papers, guidance, and evaluations of approved and rejected applications for biosimilars published by the World Health Organization, US Food and Drug Administration, European Medicines Agency (EMA), and other national regulatory authorities was conducted. Selected articles from key opinion leaders and manufacturers were also reviewed. These searches were conducted to provide a review of historical and contemporary issues in the consideration of the current status of worldwide biosimilar use and regulation. Results: A total of 18 marketing applications covering 9 development programs were surveyed. Of these, 14 applications were approved and 4 were rejected by the EMA. None of the biosimilars were reported to have evidence of significant clinical variation relative to reference compounds in the absence of corresponding differences in biophysical properties. A single biosimilar (Omnitrope® [somatropin]) was reported to have evidence of significant variation in both biophysical and clinical parameters in premarketing studies. Biophysical variation in the absence of relevant differences in the efficacy and safety profiles compared with the reference brands was noted for 2 biosimilar epoetin products. Conclusions: This commentary provides evidence that current EU guidelines have resulted in the approval of biosimilar therapeutics with comparable efficacy and safety profiles for the recommended indications of their respective reference originator biologics. It is anticipated that these precedents will serve as a starting point in the development of a process for approving biosimilars in the United States and worldwide to provide efficacious and tolerable biotherapeutics with a significant cost advantage for national health care programs and consumers. [Copyright &y& Elsevier]

Abstract: Focused pathological evaluation of axillary lymph nodes in breast cancer is gaining importance. Nuclear magnetic resonance (NMR) spectroscopy that assesses the whole of the specimen has the potential in evaluating micrometastases. The biochemical changes associated with breast cancer metastases in axillary nodes by in vitro NMR and its use in the detection of axillary metastases in a clinical setting in comparison with conventional histopathology is presented in this study. Eighty-eight lymph nodes obtained from 30 patients with breast cancer were investigated. Histopathology revealed metastases in 20 nodes from 11 patients, while in vitro NMR spectroscopy revealed metastases in 22 nodes. Out of these 22 nodes, 16 were the same, which showed metastases on histopathology, while 6 nodes have shown metastases only on in vitro magnetic resonance spectroscopy (MRS). These 6 nodes with suspicion of metastases on MRS were subjected to reevaluation with serial sectioning and immunohistochemistry, but no additional metastases were revealed. Forty metabolites could be identified from the MR spectrum of lymph nodes. The levels of the glycerophosphocholine-phosphocholine (GPC-PC), choline, lactate, alanine and uridine diphosphoglucose were elevated significantly in nodes with metastases. In addition, the intensity ratio of GPC-PC/threonine (Thr) was higher in nodes with metastases, and using this as marker, MRS detected the axillary metastases with a sensitivity, specificity and accuracy of 80%, 91% and 88%, respectively. Neoadjuvant chemotherapy (NACT) lowered the concentrations of GPC-PC and GPC-PC/Thr ratio. The accuracy of MRS in detecting metastases was 75% in patients who received NACT (n=9) as compared to 96% in those who did not (n=21). Our results demonstrate the potential of in vitro MRS in characterizing the metabolite profile of the axillary nodes with breast cancer metastases. It detected axillary metastases with reasonable accuracy and can be complementary to histopathological evaluation and immunohistochemistry. [Copyright &y& Elsevier]

Abstract: Stroke causes brain injury in millions of people world wide each year. Despite the enormity of problem, currently there is no established therapy, which can restore the blood flow at infracted area and also improve the neurological deficit. The present study was carried out to investigate the effect of an endothelin antagonist (TAK-044) in middle cerebral artery (MCA) occlusion model of acute ischemic stroke in rats. Male Wistar rats were pretreated with TAK-044 (5 mg/kg, i.p.) for 7 days and thereafter subjected to focal ischemia by occlusion of MCA using intraluminal thread for two hours. 30 min after reperfusion the animals were subjected to diffusion-weighted imaging (DWI) for assessment of protective effect. Twenty-four hours later the motor performance was tested and subsequently the animals were sacrificed for estimation of markers of oxidative stress; malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD). Control group received vehicle (saline) and similar experimental protocol was followed. In the TAK-044 pretreated group, percent hemispheric lesion area (% HLA) in DWI was significantly attenuated 17.5 ± 0.5% as compared to control group 61.2 ± 5.9%. Significant motor impairment, with significant elevated levels of MDA, decrease in GSH and SOD were observed in the vehicle treated MCA occluded rats. Pretreatment with TAK-044 prevented the motor impairment and significantly reversed the changes in markers of oxidative stress (MDA, GSH and SOD). In addition to well-known vasodilatory effect, TAK-044 has recently been documented to have antioxidant and anti-inflammatory properties. These effects can contribute to the protection afforded by TAK-044 in the present study. [Copyright &y& Elsevier]

Poly (ADP-ribose) polymerase- (PARP)-1 is predominantly triggered by DNA damage. Overexpression of PARP-1 is known for its association with the pathogenesis of several CNS disorders, such as Stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington (HD) and Amyotrophic lateral sclerosis (ALS). NAD+ depletion resulted PARP related cell death only happened when the trial used extreme high oxidization treatment. Inhibition of PARP1/2 may induce replication related cell death due to un-repaired DNA damage. This review has discussed PARP-1 modulated downstream pathways in neurodegeneration and various FDA approved PARP-1 inhibitors. A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on mechanistic role of Poly (ADP-ribose) polymerase and its inhibition in Neurodegenerative diseases. Several researchers have put forward number of potential treatments, of which PARP-1 enzyme has been regarded as a potent target intended for the handling of neurodegenerative ailments. Targeting PARP using its chemical inhibitors in various neurodegenerative may have therapeutic outcomes by reducing neuronal death mediated by PARPi. Numerous PARP-1 inhibitors have been studied in neurodegenerative diseases but they haven't been clinically evaluated. In this review, the pathological role of PARP-1 in various neurodegenerative diseases has been discussed along with the therapeutic role of PARP-1 inhibitors in various neurodegenerative diseases. Unlabelled Image • Parthanatos involves cell death mechanism which is dependent on PARP activation in response to any stress and toxic stimuli. • Parthanatos and its cellular responses such as apoptosis, cell survival, and differentiation are involved in this study. • Involvement of PARP-1 in various neurodegenerative diseases such as such as Parkinson's, Alzheimer, Huntington and ALS. • Downstream pathways (Caspase, PI3K, NF-κB and ASK-1 signalling) are modulated by PARP-1 in neurodegeneration. • Various PARP-1 inhibitors in neuroprotection proved to be a potential target in NDD. [ABSTRACT FROM AUTHOR]

• Circuit Aging Reliability Analysis Tool (CARAT) framework building. • Bias Temperature Instability (BTI) and Hot Carrier Degradation (HCD) induced degradation of FETs calculation in actual circuits using inbuilt models. • Activity Awareness under random data-path. • Dynamic Voltage Frequency Scaling(DVFS) using Ring Oscillator(RO) Circuit Aging Reliability Analysis Tool (CARAT), a framework that calculates random activity (frequency and duty) aware degradation of FETs to simulate circuit aging under real operating workloads is proposed. Bias Temperature Instability (BTI) and Hot Carrier Degradation (HCD) induced degradation of FETs is calculated in a cycle-by-cycle manner based on actual terminal waveforms grabbed from SPICE. Framework capability is demonstrated by using Level Shifter (LS) under random data-path activity, and Ring Oscillator (RO) under Dynamic Voltage Frequency Scaling (DVFS) conditions. The risk associated with the standard blanket approach is discussed. [ABSTRACT FROM AUTHOR]

Abstract: There is much interest in utilizing the intrinsic properties of magnetic nanoparticles (MNPs) for the theranostic approaches in medicine. With an aim to develop a potential therapeutics for glioma treatment, efficacy of aqueous dispersible paclitaxel loaded MNPs (Pac-MNPs) were studied in glioblastoma cell line (U-87). The identified potential receptor, glycoprotein non-metastatic melanoma protein B (GPNMB) overexpressed by glioblastoma cells, was actively targeted using GPNMB conjugated Pac-MNPs in U-87 cells. As blood brain barrier (BBB) is the primary impediment in the treatment of glioblastoma, therefore, an attempt was taken to evaluate the biodistribution and brain uptake of Pac-MNPs in rats. The bioavailability of Pac-MNPs illustrated a prolonged blood circulation in vivo, which demonstrated the presence of significant amounts of drug in rat brain tissues as compared to native paclitaxel. Further, the transmission electron microscopy (TEM) study revealed significant accumulation of the Pac-MNPs in the brain tissues. Being an effective contrast enhancement agent for magnetic resonance imaging (MRI) at tissue levels, the MNPs devoid of any surfactant demonstrated enhanced contrast effect in liver and brain imaging. Hence, the significant prevalence of drugs in the rat brain tissues, in vitro targeting potentiality as well as the augmented contrast effect elicit the non-invasive assessment and theranostic applications of MNPs for brain tumor therapy. [Copyright &y& Elsevier]

Abstract: Metabolism of the colonic mucosa of patients with ulcerative colitis (UC; n=31) and Crohn''s disease (CD; n=26) and normal mucosa (control, n=26) was investigated using in vitro high-resolution proton magnetic resonance spectroscopy. Of the 31 UC patients, 20 were in the active phase and 11 were in the remission phase of the disease. Out of 26 CD patients, 20 were in the active phase, while 6 were in the remission phase of the disease. Twenty-nine metabolites were assigned unambiguously in the perchloric acid extract of colonic mucosa. In the active phase of UC and CD, significantly lower (P≤.05) concentration of amino acids (isoleucine, leucine, valine, alanine, glutamate and glutamine), membrane components (choline, glycerophosphorylcholine and myo-inositol), lactate and succinate were observed compared to normal mucosa of controls. Patients in the active phase of UC and CD also showed increased level of α-glucose compared to normal mucosa. Altered level of metabolites indicates decreased protein and carbohydrate metabolism, thereby decreased energy status and deterioration of mucosa integrity during chronic inflammation. In the remission phase of UC and CD, the concentration of most of the metabolites was similar to controls except for lower values of lactate, glycerophosphorylcholine and myo-inositol in UC and Lac in CD. Formate was significantly lower in patients with the active phase of UC compared to patients with the active phase of CD, suggesting the potential of in vitro MRS in the differentiation of these two diseases. [Copyright &y& Elsevier]

Intracardiac injection of recombinant EphrinA1-Fc immediately following coronary artery ligation in mice reduces infarct size in both reperfused and non-reperfused myocardium, but the cellular alterations behind this phenomenon remain unknown. Herein, 10 wk-old B6129SF2/J male mice were exposed to acute ischemia/reperfusion (30minI/24hrsR) injury immediately followed by intracardiac injection of either EphrinA1-Fc or IgG-Fc. After 24 h of reperfusion, sections of the infarct margin in the left ventricle were imaged via transmission electron microscopy, and mitochondrial function was assessed in both permeabilized fibers and isolated mitochondria, to examine mitochondrial structure, function, and energetics in the early stages of repair. At a structural level, EphrinA1-Fc administration prevented the I/R-induced loss of sarcomere alignment and mitochondrial organization along the Z disks, as well as disorganization of the cristae and loss of inter-mitochondrial junctions. With respect to bioenergetics, loss of respiratory function induced by I/R was prevented by EphrinA1-Fc. Preservation of cardiac bioenergetics was not due to changes in mitochondrial J H 2 O 2 emitting potential, membrane potential, ADP affinity, efficiency of ATP production, or activity of the main dehydrogenase enzymes, suggesting that EphrinA1-Fc indirectly maintains respiratory function via preservation of the mitochondrial network. Moreover, these protective effects were lost in isolated mitochondria, further emphasizing the importance of the intact cardiomyocyte ultrastructure in mitochondrial energetics. Collectively, these data suggest that intracardiac injection of EphrinA1-Fc protects cardiac function by preserving cardiomyocyte structure and mitochondrial bioenergetics, thus emerging as a potential therapeutic strategy in I/R injury. [ABSTRACT FROM AUTHOR]