Conformational, Dimensional, and Hydrodynamic Properties of Amylose Tris(n-butylcarbamate) in Tetrahydrofuran, Methanol, and Their Mixtures

This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Macromolecules, copyright © American Chemical Society after peer review. To access the final edited and published work see https://doi.org/10.1021/ma902200z

Intracoronary Autologous Cardiac Progenitor Cell Transfer in Patients With Hypoplastic Left Heart Syndrome (TICAP) : A Prospective Phase 1 Controlled Trial

RATIONALE: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. OBJECTIVE: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. METHODS AND RESULTS: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lower incidence of coil occlusion for collaterals (P=0.007). CONCLUSIONS: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes

Effects of the Amino Acid Constituents of Microcystin Variants on Cytotoxicity to Primary Cultured Rat Hepatocytes

Microcystins, which are cyclic heptapeptides produced by some cyanobacterial species from algal blooms, strongly inhibit serine/threonine protein phosphatase and are known as hepatotoxins. Microcystins have many structural variations, yet insufficient information is available on the differences in the cytotoxic potentials among the structural variants. In this study, the cytotoxicities of 16 microcystin variants at concentrations of 0.03–10 μg/mL to primary cultured rat hepatocytes were determined by measuring cellular ATP content, and subsequently determined by their 50% inhibitory concentration (IC50). Differences in the amino acid constituents were associated with differences in cytotoxic potential. [d-Asp3, Z-Dhb7] microcystin-LR exhibited the strongest cytotoxicity at IC50 of 0.053 μg/mL among the microcystin variants tested. Furthermore, [d-Asp3, Z-Dhb7] microcystin-HtyR was also highly cytotoxic. These results suggest that both d-Asp and Z-Dhb residues are important in determining the cytotoxic potential of microcystin variants

Anti-Allergic Effects of Vernonia amygdalina Leaf Extracts in Hapten-Induced Atopic Dermatitis-Like Disease in Mice

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic and ec- zematous skin lesions. In this study, AD-like disease was induced in NC/Nga mice so as to evaluate the antiallergic effects of Vernonia amygdalina leaf extracts (VAM). Methods: Forty NC/Nga mice were purchased for each of the two protocols (prophylactic and curative) of the study. Mice were randomly divided in groups of five or six after sensitization with 5% trinitrochlorobenzene (TNCB): aqueous extracts (VAM1), methanolic extracts (VAM2), hydrocortisone (HCT), buffer for the control (TNCB) and the normal mice (NORM) groups. Results: As for HCT, VAM1 and VAM2-pretreated mice showed significantly lower number of scratching behavior episodes (p<0.01; vs. TNCB) following TNCB challenge. In addition, VAM1, VAM2 exerted a significant inhibitory effect on the development of AD skin symptoms (vs. TNCB group; p<0.001), the production of IgE, TNF-alpha (p<0.05), IL-5 and IFN-gamma (p<0.01) (vs. TNCB group) and on the increase in ear thickness (p<0.05) in prophylactic protocol. In the AD curative protocol, topical VAM1, VAM2 markedly improved skin lesions such as erythema/hemorrhage (p<0.05), scaling/dryness, erosion/excoriation (p<0.01) (vs. TNCB mice). Furthermore, a significant decrease in ear thickness was noted in VAM1, VAM2, HCT groups (vs. TNCB group; p<0.05) as well as the serum total IgE, MCP-1 (p<0.01) and eotaxin (p<0.05). VAM2 also improved chronic eczema dermatitis skin symptoms in a patient. Conclusions: Results from this report suggest that VAM extracts, known as ERK pathway inhibitor, prevent and improve atopic/eczema dermatitis syndrome

Associations of the tau protein and oxidative stress to apathy levels in patients with progressive supranuclear palsy.

Introduction: Progressive supranuclear palsy (PSP) is one of the primary tauopathies. More than half of the patients with PSP present apathy, defined by diminished goal-directed behavior and cognition and concomitant emotions. While previous studies claimed that apathy is associated with impairment of the anterior brain regions, there is no evidence for the association among tau protein, oxidative stress (OS) as underlying mechanisms of apathy in the posterior brain regions. 1 We hypothesized that tau protein causes OS leading to brain vulnerability and apathy. To test this hypothesis, we performed positron emission tomography (PET) scans with a tau PET ligand, 18F-PM-PBB3 2 and magnetic resonance spectroscopy (MRS) for glutathione (GSH) 3, and volumetry.Materials & Methods: We enrolled 20 PSP patients and 23 healthy controls (HCs). We performed MRS by a short TE spin-echo full-intensity acquired localized single voxel spectroscopy (SPECIAL) sequence (TR/TE/number of excitations = 3000 ms / 8.5 ms / 128), PET scans with a tau PET ligand, 18F-PM-PBB3, and three-dimensional T1-weighted images. Given the importance of both the anterior and posterior cingulate cortex for apathy and GSH , volumes of interest (VOIs) for MRS were manually placed on the anterior cingulate cortex (ACC, 30 × 20 × 20 mm2) and posterior cingulate cortex (PCC, 20 × 20 × 20 mm2) regions (Figure 1). We analyzed MRS data by LCModel software and corrected metabolite values for CSF partial volumes. We examined the correlation of apathy scale (AS) score with the imaging data and the path analysis for models explaining apathy.Results: MRS The average Cramér–Rao lower bound of GSH measurements were 6.1% and 6.9% in ACC and PCC, respectively. While there was no significant difference between the PCC GSH levels of PSP patients and HCs, partial correlation analyses after controlling for age and PSP Rating Scale (PSPRS) scores showed negative correlations between the PCC GSH levels and AS scores (Figure 2). 18F-PM-PBB3 PET In PSP patients, a positive association was found between AS scores and 18F-PM-PBB3 standardized uptake value ratios (SUVRs) in the bilateral angular gyrus (AG) (Figure 3). We found significantly higher 18F-PM-PBB3 SUVRs in the bilateral AG in PSP patients compared with HCs. Partial correlation analyses with age and PSPRS scores as covariates showed negative correlations between the PCC GSH levels and 18F-PM-PBB3 SUVRs in the AG/PCC. Volumetry Voxel-based morphometry (VBM) analysis in PSP patients showed negative associations between AS scores and the GM volumes in the right inferior frontal gyrus (IFG) and the ACC. Path analysis Path analysis generated a well-fitted model between the AS scores, the 18F-PM-PBB3 SUVRs in the AG, the PCC GSH levels, and the GM volumes in the right IFG.Discussion: We found the associations of apathy with tau accumulation levels in the AG, the GSH levels in the PCC, and the brain volumes of the right IFG and ACC. We also found the negative associations between 18F-PM-PBB3 SUVRs in the AG/PCC region and the GSH levels in the PCC, suggesting the link between the tau protein accumulations and OS. Although there was no significant difference in GSH levels between PSP and HCs, our model generated by path analysis suggests that the depletion of GSH in the PCC is associated with the abnormal tau protein in the AG/PCC region, leading to a part of underlying mechanisms of apathy. Antioxidant GSH may serve as the resilience factor of the neural system by limiting the damages from OS caused by tau protein accumulation.Conclusions: The potential link among tau protein, OS, brain atrophies in both the anterior and posterior brain regions as underlying brain mechanisms for apathy in PSP patients was suggested.ISMRM JPC 202

Distinct Binding of Amyloid Imag.ing Ligands to Unique Amyloid-β Deposited in the Presubiculum of Alzheimer’s Disease.

Non-invasive determination of amyloid- peptide (Aβ) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer’s disease (AD). The polymorphic binding site on multimeric Aβ for current radioligands, however, is little understood. In the present study, we investigated the binding of several radioligands including 11C-Pittsburgh Compound B (11C-PiB), 3H-AZD2184, and two recently developed compounds, 125I-DRM106 and 125I-DRK092, with unique presubicular Aβdeposits lacking interaction with the commonly used amyloid dyes FSB. 11C-PiB, 3H-AZD2184 and 125I-DRK092 showed overt binding to presubicular Aβ deposits, while 125I-DRM106 barely bound to these aggregates, despite its strong binding in the hippocampal CA1 sector. Unlike neuritic plaques in the CA1, Aβ lesions in the presubiculum were not accompanied by inflammatory gliosis enriched with 18-kDa translocator protein (TSPO). Thus, there are at least two different components in Aβ aggregates providing distinct binding sites for the current amyloid radioligands, and one of these binding components is distinctly present in the presubicular Aβ deposits. Amyloid radioligands lacking affinity for this component, such as 125I-DRM106, may selectively capture Aβ deposits tightly associated with TSPO-positive neuroinflammation and neurodegeneration as exemplified by CA1 neuritic plaques. Hence, comparative autoradiographic assessments of radioligand binding in CA1 and presubiculum could serve for the development of an amyloid PET imaging agent visualizing neurotoxicity-related Aβ pathologies