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Abstract SIS-g-PB copolymers were successfully synthesized by grafting living polybutadiene (PB) lithium macroanions onto epoxidized SIS copolymers. Their molecular structures and thermal properties were characterized by TGA, 1H-NMR and DSC, respectively. SIS, epoxidized SIS (ESIS) and SIS-g-PB copolymers were melt-blended with tackifiers to develop hot-melt pressure-sensitive adhesives (HMPSAs), respectively (named of H-SIS, H-ESIS and H-SIS-g-PB). Their adhesive performances were measured in terms of 180° peel strength and holding power. A modified Franz type horizontal diffusion cell was used to carry out In vitro drug release experiments, in which geniposides were chosen as hydrophilic model drugs. The results showed that H-SIS-g-PB has two times as high a 180° peel strength as H-SIS. Meanwhile H-SIS-g-PB has a slightly lower drug cumulative release rate than H-ESIS. It is indicated that the PB branches not only could impart good adhesive performance to H-SIS-g-PB via improving the compatibility between the epoxidized main chains and tackifier resins but also provide release channels to hydrophilic drugs by retaining most of the epoxide groups in the SIS-g-PB copolymers. [ABSTRACT FROM AUTHOR]

Abstract Background Therapeutic strategies for traumatic brain injury (TBI) in the last three decades have failed to show significant benefit in large scale studies. Given the multitude of pathological mechanisms involved in TBI, strategies focusing on multimodality regimen have gained interest as promising future interventions. Hypothesis We hypothesized that combining noninvasive transcranial magnetic stimulation (TMS) with rehabilitative training in an environmental enrichment (EE) can facilitate post-TBI recovery in rats via cortical excitability and reorganization. Methods We subjected rats to controlled cortical impact, and then assigned them to one of four groups: 1. No treatments (TBI), 2. EE after injury (TBI + EE), 3. TMS for one week (TBI + TMS), and 4. TMS for one week combined with EE (TBI + TMS/EE). For TMS, a 10 Hz repetitive TMS protocol was used. Results At 7 days, TBI + TMS and TBI + TMS/EE groups had significantly increased primary somatosensory cortex local field potential (LFP) compared to TBI and TBI + EE groups (P < 0.05). Also, TBI + TMS/EE group had significantly improved performance on beam walk test compared to TBI group (P < 0.005). At 6 weeks, there was significantly higher response in TBI + TMS/EE group compared to TBI + TMS for somatosensory cortex LFP (P < 0.05), bicep motor evoked potentials (MEP) (P < 0.05), challenge ladder test performance (P < 0.01), and fMRI responses to tactile forepaw stimulation. Conclusions We demonstrate here for the first time the mechanism by which combined therapy using TMS and EE after TBI leads to functional improvement, possibly via cortical excitability and reorganization. Highlights • Combined therapy with TMS and environmental enrichment is assessed for TBI recovery. • This significantly improves motor behavior function compared to either therapy alone. • Motor evoked potentials are enhanced for animals with combined therapy. • Somatosensory cortex local field potential and fMRI response are also enhanced. [ABSTRACT FROM AUTHOR]

Because oxidative metabolism is the primary form of energy production in the brain, the amount of oxygen consumed by the brain, denoted by a physiological parameter termed cerebral metabolic rate of oxygen (CMRO 2 ), represents a key marker for tissue viability and brain function. Quantitative assessment of cerebral oxygen metabolism in the neonate may provide an important marker in better understanding normal brain development and in making diagnosis and treatment decisions in neonatal brain injuries. Measurement of CMRO 2 in humans has been a challenging task, particularly in neonates. Recently, several promising techniques have been proposed to quantify neonatal CMRO 2 and the purpose of this article is to provide a technical review of these techniques. Among these, we will focus the review on the NIRS optic based methods and MRI methods which are non-invasive, have been applied in normal and sick newborns and show great potentials. Potential clinical prospects of CMRO 2 techniques are discussed in the context of their advantages, challenges and limitations. [ABSTRACT FROM AUTHOR]

Abstract: A series of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) were examined in which the pendant imidazole moiety was replaced to improve selectivity for IGF-1R inhibition over cytochrome P450 (CYP). Synthesis and SAR of these compounds is presented. [Copyright &y& Elsevier]

Cerebral venous oxygenation (Y v) is a key parameter for the brain's oxygen utilization and has been suggested to be a valuable biomarker in various brain diseases including hypoxic ischemic encephalopathy in neonates and Alzheimer's disease in older adults. T 2 -Relaxation-Under-Spin-Tagging (TRUST) MRI is a widely used technique to measure global Y v level and has been validated against gold-standard PET. However, subject motion during TRUST MRI scan can introduce considerable errors in Y v quantification, especially for noncompliant subjects. The aim of this study was to develop an Automatic Rejection based on Tissue Signal (ARTS) algorithm for automatic detection and exclusion of motion-contaminated images to improve the precision of Y v quantification. TRUST MRI data were collected from a neonatal cohort (N = 37, 16 females, gestational age = 39.12 ± 1.11 weeks, postnatal age = 1.89 ± 0.74 days) and an older adult cohort (N = 223, 134 females, age = 68.02 ± 9.01 years). Manual identification of motion-corrupted images was conducted for both cohorts to serve as a gold-standard. 9.3% of the images in the neonatal datasets and 0.4% of the images in the older adult datasets were manually identified as motion-contaminated. The ARTS algorithm was trained using the neonatal datasets. TRUST Y v values, as well as the estimation uncertainty (ΔR 2) and test-retest coefficient-of-variation (CoV) of Y v , were calculated with and without ARTS motion exclusion. The ARTS algorithm was tested on datasets of older adults: first on the original adult datasets with little motion, and then on simulated adult datasets where the percentage of motion-corrupted images matched that of the neonatal datasets. In the neonatal datasets, the ARTS algorithm exhibited a sensitivity of 0.95 and a specificity of 0.97 in detecting motion-contaminated images. Compared to no motion exclusion, ARTS significantly reduced the ΔR 2 (median = 3.68 Hz vs. 4.89 Hz, P = 0.0002) and CoV (median = 2.57% vs. 6.87%, P = 0.0005) of Y v measurements. In the original older adult datasets, the sensitivity and specificity of ARTS were 0.70 and 1.00, respectively. In the simulated adult datasets, ARTS demonstrated a sensitivity of 0.91 and a specificity of 1.00. Additionally, ARTS significantly reduced the ΔR 2 compared to no motion exclusion (median = 2.15 Hz vs. 3.54 Hz, P < 0.0001). ARTS can improve the reliability of Y v estimation in noncompliant subjects, which may enhance the utility of Y v as a biomarker for brain diseases. [ABSTRACT FROM AUTHOR]

Anorexia nervosa is a serious psychiatric disorder characterized by restricted eating, a pursuit of thinness, and altered perceptions of body shape and size. Neuroimaging in anorexia nervosa has revealed morphological and functional alterations in the brain. A better understanding of physiological changes in anorexia nervosa could provide a brain-specific health marker relevant to treatment and outcomes. In this study, we applied several advanced magnetic resonance imaging (MRI) techniques to quantify regional and global cerebral blood flow (CBF) in 25 healthy women (HC), 23 patients currently with anorexia (AN-C) and 19 patients in long-term weight recovery following anorexia (AN-WR). Specifically, CBF was measured with pseudo-continuous arterial spin labeling (pCASL) MRI and then verified by a different technique, phase contrast (PC) MRI. Venous T 2 values were determined by T 2 relaxation under spin tagging (TRUST) MRI, and were used to corroborate the CBF results. These novel techniques were implemented on a standard 3T MRI scanner without any exogenous tracers, and the total scan duration was less than 10 min. Voxel-wise comparison revealed that the AN-WR group showed lower CBF in bilateral temporal and frontal lobes than the AN-C group. Compared with the HC group, the AN-C group also showed higher CBF in the right temporal lobe. Whole-brain-averaged CBF was significantly decreased in the AN-WR group compared with the AN-C group, consistent with the PC-MRI results. Venous T 2 values were lower in the AN-WR group than in the AN-C group, consistent with the CBF results. A review of prior work examining CBF in anorexia nervosa is included in the discussion. This study identifies several differences in the cerebral physiological alterations in anorexia nervosa, and finds specific differences relevant to the current state of the disorder. [ABSTRACT FROM AUTHOR]

Abstract: The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented. [Copyright &y& Elsevier]

Abstract Purpose To demonstrate the feasibility of mapping cerebrovascular reactivity (CVR) using resting-state functional MRI (fMRI) data without gas or other challenges in patients with cerebrovascular diseases and to show that brain regions affected by the diseases have diminished vascular reactivity. Materials and methods Two sub-studies were performed on patients with stroke and Moyamoya disease. In Study 1, 20 stroke patients (56.3 ± 9.7 years, 7 females) were enrolled and resting-state blood‑oxygenation-level-dependent (rs-BOLD) fMRI data were collected, from which CVR maps were computed. CVR values were compared across lesion, perilesional and control ROIs defined on anatomic images. Reproducibility of the CVR measurement was tested in 6 patients with follow-up scans. In Study 2, rs-BOLD fMRI and dynamic susceptibility contrast (DSC) MRI scans were collected in 5 patients with Moyamoya disease (32.4 ± 8.2 years, 4 females). Cerebral blood flow (CBF), cerebral blood volume (CBV), and time-to-peak (TTP) maps were obtained from the DSC MRI data. CVR values were compared between stenotic brain regions and control regions perfused by non-stenotic arteries. Results In stroke patients, lesion CVR (0.250 ± 0.055 relative unit (r.u.)) was lower than control CVR (0.731 ± 0.088 r.u., p = 0.0002). CVR was also lower in the perilesional regions in a graded manner (perilesion 1 CVR = 0.422 ± 0.051 r.u., perilesion 2 CVR = 0.492 ± 0.046 r.u.), relative to that in the control regions (p = 0.005 and 0.036, respectively). In the repeatability analysis, a strong correlation was observed between lesion CVR (r2 = 0.91, p = 0.006) measured at two time points, as well as between control CVR (r2 = 0.79, p = 0.036) at two time points. In Moyamoya patients, CVR in the perfusion deficit regions delineated by DSC TTP maps (0.178 ± 0.189 r.u.) was lower than that in the control regions (0.868 ± 0.214 r.u., p = 0.013). Furthermore, the extent of reduction in CVR was significantly correlated with the extent of lengthening in TTP (r2 = 0.91, p = 0.033). Conclusion Our findings suggested that rs-BOLD data can be used to reproducibly evaluate CVR in patients with cerebrovascular diseases without the use of any vasoactive challenges. [ABSTRACT FROM AUTHOR]

[Display omitted] We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study. [ABSTRACT FROM AUTHOR]

Abstract: A series of 3-[6-(4-substitued-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure–activity and structure–solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions. [Copyright &y& Elsevier]

Abstract: A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17β-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate. [Copyright &y& Elsevier]