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Transcranial magnetic resonance imaging (MRI)-guided histotripsy has been demonstrated to treat various locations in in vivo swine brain through a human skull. To ensure that the histotripsy treatment is delivered to the intended target location, accurate pre-treatment targeting is necessary. In this work, we investigate the feasibility of MR-thermometry and MR-acoustic radiation force imaging (MR-ARFI) to perform pre-treatment targeting of histotripsy in ex vivo bovine brain through a human skull. A 700 kHz, 128-element MR-compatible histotripsy array was used to generate histotripsy and tone-burst sonications. The array's electronic drivers were modified to also generate low-amplitude tone-burst sonications to perform MR-thermometry and MR-ARFI–based targeting. Twelve ex vivo bovine brains were treated with histotripsy at 35 MPa, 75 MPa and through a skull at 36 MPa. Before treating the tissue, both MR-ARFI and MR-thermometry were used to estimate the lesion location. Finally, the location of the histotripsy lesion was compared with the focus estimated by MR-thermometry and MR-ARFI. MR-thermometry and MR-ARFI were able to successfully perform pre-treatment targeting of histotripsy using the modified histotripsy array driver. Histotripsy focus was estimated with mean absolute errors along the transverse/longitudinal axis of 2.06/2.95 mm and 2.13/2.51 mm for MR-ARFI and MR-thermometry, respectively. The presence of the human skull reduced the pressure at the focal region, but it did not compromise the targeting accuracy of either of the two methods with a mean absolute error of 1.10/2.91 mm and 1.29/2.91 mm for MR-ARFI and MR-thermometry, respectively. This study demonstrated that transcranial histotripsy pre-treatment targeting is feasible with MR-thermometry and MR-ARFI. [ABSTRACT FROM AUTHOR]

2-(piperazin-1-yl) N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid β aggregation inhibitors. Formation of synthesized compounds (P1 P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aβ aggregation and Cu(II)-mediated Aβ aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC 50 = 4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced β-amyloid (Aβ) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aβ 1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aβ disaggregation, antioxidation, metal-chelation activity. Image 1 • 2-(piperazin-1-yl)-N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as new multifunctional anti-Alzheimer's agents. • They possess AChE and BChE inhibition, Aβ aggregation inhibition, Aβ disaggregation, antioxidation and metal-chelation properties. • The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity with IC50 = 4.8 nM. • In vitro study revealed compounds to be capable of inhibiting self-induced β-amyloid aggregation with the highest inhibition percentage 81.65%. • Aβ 1-42 aggregation was ascertained by TEM analysis. [ABSTRACT FROM AUTHOR]

In an attempt to construct potential anti-Alzheimer's agents Naphthalene-triazolopyrimidine hybrids were synthesized and screened in vitro against the two cholinesterases (ChE)s, amyloid β aggregation and for antioxidation activity. Single-crystal X-ray crystallography was utilized for crystal structure determination of one of the compounds. In vitro study of compounds revealed that most of the compounds are capable of inhibiting acetylcholinesterase and Butyrylcholinesterase activity. Particularly, the compounds 4e and 4d exhibited IC 50 values ranging from 8.6 to 14 nM against AChE lower than the standard drug Donepezil (IC 50 49 nM). Best result was found for compound 4e with IC 50 of 8.6 nM (for AChE) and 150 nM (for BuChE). Selectivity upto that of Donepezil and even more was observed for 4a , 4c and 4h. Investigation by electron microscopy, transmission electron microscopy and ThT fluorescence assay unveils the fact that synthesized hybrids exhibit amyloid β self-aggregation inhibition. The compounds 4i and 4j revealed highest inhibitory potential, 85.46% and 72.77% at 50 μM respectively; above the standard Aβ disaggregating agent, Curcumin. Their antioxidation profile was also analyzed. Studies from DPPH free radical scavenging assay and ORAC assay depicts molecules to possess low antioxidation profile. Results suggest that triazolopyrimidines are potential candidate for Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), and amyloid β aggregation inhibition. In silico ADMET profiling indicates drug-like properties with a very low toxic influence. Such synthesized compounds provide a strong vision for further development of potential anti-Alzheimer's agents. [ABSTRACT FROM AUTHOR]

Blends of cottonseed and sunflower oils with vacuum gasoil were catalytically cracked in fixed bed microreactor using commercial high alumina zeolite FCC catalyst and halloysite nanotubes as a catalyst. Halloysite occurs in nature as clay nanotube with large 5–20 nm inner lumen that provides cost-effective way to produce mesoporous cracking catalysts with low environmental footprint. Performance of the cracking catalyst was significantly improved in terms of gasoline yield and coke formation upon addition of halloysite. Hydrocarbon content of the gasoline fraction was analyzed in detail and efficiency of the skeletal isomerization within halloysite pores was observed to be significantly higher than with the FCC catalyst alone, increasing the yield of the branched hydrocarbons in produced gasoline and hence octane rating. [ABSTRACT FROM AUTHOR]

Abstract: A novel mesoporous catalyst has been developed based on tubule halloysite clay and commercial Y-zeolite. The catalyst was tested for the pyrolysis of cottonseed oil in combination with heavy vacuum gasoil and performed better than the original zeolite, in terms of gasoline yield and coke formation. In depth analysis of hydrocarbon content in gasoline fraction revealed that the efficiency of skeletal isomerization is higher in the proposed catalyst than Y-zeolite alone, yielding the gasoline with better octane rating. Blending halloysite clay with Y-zeolite provides cost-effective way for the preparation of mesoporous cracking catalysts. [Copyright &y& Elsevier]

Abstract: Oro-antral communications (OAC) greater than 4–5mm in diameter can seldom be counted on to heal spontaneously without the necessity for surgical closure. The initial experience in applying an absorbable polyglactin/polydioxanon implant (Ethisorb®), in non-surgical closure of OAC ranging from 5 to 7mm in diameter, is presented. Twelve patients of varying ages with OAC up to72h in duration, have been treated with Ethisorb®. Failures were not demonstrated in the form of the creation of an oro-antral fistula (OAF), and in all patients, OAC-s were closed with the epithelization of post-extraction wounds up to 21 days after implantation of Ethisorb®. Based on these initial encouraging results, we propose that an Ethisorb® biopolymeric absorbable implant can be used in selected clinical cases for non-surgical closure of OAC. [Copyright &y& Elsevier]

Background & Aims: Diclofenac is a widely used nonsteroidal anti-inflammatory drug and is among the most common drugs causing idiosyncratic hepatotoxicity in several recent series with up to 20% mortality in jaundiced subjects. We hypothesized that susceptibility to hepatotoxicity would be associated with genetic polymorphisms in the genes encoding the enzymes UGT2B7 and CYP2C8, which determine the formation of reactive diclofenac metabolites and in ABCC2 encoding the transporter MRP2 contributing to the biliary excretion of the reactive metabolite. Methods: Twenty-four patients (19 female) aged 24–70 (mean, 50.8) years who had suffered diclofenac hepatotoxicity, 48 subjects (35 female) aged 22–77 (mean, 52) years who were taking diclofenac for 0.3–20 (mean, 4) years without developing hepatotoxicity (hospital controls), and 112 healthy controls were investigated. Genotyping for several polymorphisms in the genes encoding UGT2B7, CYP2C8, and ABCC2 was performed and haplotypes assigned. Results: The UGT2B7*2 allele was more common in diclofenac hepatotoxicity patients compared with hospital controls (odds ratio [OR], 8.5, P = .03) and healthy controls (OR, 7.7, P = .03). The ABCC2 C-24T variant was more common in hepatotoxicity patients compared with hospital (OR, 5.0, P = .005) and healthy controls OR: 6.3, P = .0002). Haplotype distributions for CYP2C8 were different in patients compared with hospital controls (P = .04). Conclusions: Allelic variants of UGT2B7, CYP2C8, and ABCC2, which may predispose to the formation and accumulation of reactive diclofenac metabolites are associated with diclofenac hepatotoxicity. Increased level of reactive metabolites may lead to higher levels of protein-diclofenac adducts and subsequently hepatotoxicity. [Copyright &y& Elsevier]

Microcystin-LR (MCLR) is a liver and kidney toxin produced by cyanobacteria. Recently, it was demonstrated that MCLR exposure drives the progression of high fat/high cholesterol (HFHC) induced nonalcoholic fatty liver disease (NAFLD) to a more severe state. NAFLD is also a risk factor for chronic kidney disease (CKD), and the current study investigated MCLR renal toxicity in the context of an HFHC diet. Sprague Dawley rats were fed either a control diet or an HFHC diet for 10 weeks. After 6 weeks of diet, animals were administered either vehicle, 10 μg/kg, or 30 μg/kg MCLR via intraperitoneal injection every other day for 4 weeks. HFHC diet alone increased the renal glomerular change histopathology score, and 30 μg/kg MCLR exposure increased this score in both the control group and the HFHC group. In contrast, 30 μg/kg MCLR caused greater proteinuria and cast formation and decreased protein phosphatase 1 and 2A protein expression in the HFHC group. Urinary excretion of KIM-1 increased, but albumin and tamm-horsfall protein did not change after MCLR exposure. The general concordance between KIM-1, polyuria, proteinuria, and renal casts after MCLR exposure suggests that proximal tubule cell damage contributed to these connected pathologies. The control group adapted to repeated MCLR exposure by increasing the urinary elimination of MCLR and its metabolites, whereas this adaptation was blunted in the HFHC group. These data suggest an HFHC diet may increase the severity of certain MCLR-elicited renal toxicities. • HFHC diet increased severity of MCLR induced casts and proteinuria. • Urinary KIM-1 levels increased after MCLR exposure. • PP1 and PP2A protein levels decreased after MCLR exposure only in the HFHC group. • HFHC diet decreased the metabolism and total urinary elimination of MCLR. [ABSTRACT FROM AUTHOR]

Abstract Microcystin-LR (MCLR) is a cyanotoxin produced by blue-green algae that causes liver and kidney toxicities. MCLR toxicity is dependent on cellular uptake through the organic anion transporting polypeptide (OATP) transporters. Nonalcoholic fatty liver disease (NAFLD) progresses through multiple stages, alters expression of hepatic OATPs, and is associated with chronic kidney disease. The purpose of this study was to determine whether NAFLD increases systemic exposure to MCLR and influences acute liver and kidney toxicities. Rats were fed a control diet or two dietary models of NAFLD; methionine and choline deficient (MCD) or high fat/high cholesterol (HFHC). Two studies were performed in these groups: 1) a single dose intravenous toxicokinetic study (20 μg/kg), and 2) a single dose intraperitoneal toxicity study (60 μg/kg). Compared to control rats, plasma MCLR area under the concentration-time curve (AUC) in MCD rats doubled, whereas biliary clearance (Cl bil) was unchanged; in contrast, plasma AUC in HFHC rats was unchanged, whereas Cl bil approximately doubled. Less MCLR bound to PP2A was observed in the liver of MCD rats. This shift in exposure decreased the severity of liver pathology only in the MCD rats after a single toxic dose of MCLR (60 μg/kg). In contrast, the single toxic dose of MCLR increased hepatic inflammation, plasma cholesterol, proteinuria, and urinary KIM1 in HFHC rats more than MCLR exposed control rats. In conclusion, rodent models of NAFLD alter MCLR toxicokinetics and acute toxicity and may have implications for liver and kidney pathologies in NAFLD patients. Highlights • Systemic exposure to MCLR increased approximately two-fold in MCD-induced NAFLD. • Biliary clearance of MCLR increased approximately two-fold in HFHC-induced NAFLD. • MCD-induced NAFLD had the lowest hepatic MCLR levels and hepatic toxicity. • HFHC-induced NAFLD exposed to MCLR had the highest plasma cholesterol, proteinuria, and urinary KIM1. [ABSTRACT FROM AUTHOR]

Targeted adenoviral tropism and improved viral biodistribution can be achieved by alteration of genes encoding viral capsid proteins. However, manipulation of such late viral genes is difficult due to the potential problems of altering Major Late Transcriptional Unit (MLTU) splicing, capsid protein folding, multimerization, and assembly into a working virus. Further, the viral genome is large and therefore cloning strategies are limited to low efficiency homologous recombination. We have therefore generated a novel and robust vector system, based on unidirectional Cre/lox recombination, which is capable of altering the fiber gene region of adenovirus with high efficiency. The system, termed pFex for Fiber EXchange, applies a small shuttle vector containing a floxed fiber gene cassette (lox 66 & lox M2/71) and a large acceptor Ad5 viral vector containing a floxed negative selectable marker (SacB, Lox M2/66 & lox 71) in place of fiber. The modified fiber gene cassettes can be efficiently recombined back into the large viral vectors in bacteria or mammalian cells that express the Cre enzyme. Finally, modified fiber genes can be shuttled into linear, pseudotyped, viral genomes with previously unachievable efficiency. Dilution experiments demonstrate that one wild type fiber shuttle can generate working adenovirus in the background of 40,000 mutant abortive fiber shuttles. The lox-modified virus show no negative effects when compared to AdEasy generated vectors. Here we demonstrate the ability to generate re-targeted and Fiber- IRES-reporter adenovirus with this system.Molecular Therapy (2006) 13, S56–S56; doi: 10.1016/j.ymthe.2006.08.163 [ABSTRACT FROM AUTHOR]

Abstract: N-(2-hydroxynaphtalidene)β-alanine (I) forms two type complexes with Co(II) ions: binuclear complex [Co2(Napβala)2 ·2H2O]·H2O (III) and trinuclear mixed-valence complex {[Co(Napβala)2]2 ·Co(H2O)4}·4H2O·2C2H5OH (IV). X-ray data and magnetic measurements indicated that trinuclear complex had CoIII–CoII–CoIII distribution of oxidation states. Co(III) ions has weak distorted octahedric environment of four oxygen and two nitrogen atoms due to two ligand molecules per each. The tetrahydrate envelope of Co(II) ion is upgraded to octahedra with two oxygen atoms of two bridge carboxylic group of the ligand molecules which coordinates Co(III) ions. The azomethine bond in I is reduced to secondary amine group by sodium borohydride in dimethylformamide solution, which contains water. Cobalt (II) complex of the reduced Schiff base Co(RNaphβala)·2H2O (V) has been synthesized and its spectroscopic and magnetic properties are reported. Binuclear cobalt (II) complex of Schiff base is reduced by NaBH4 and complex V is obtained. Trinuclear mixed-valence complex IV could not be reduced under similar conditions. [Copyright &y& Elsevier]

• We study a cluster-randomized health and nutrition intervention delivered through self-help groups (SHGs) in Bihar. • The intervention was two-pronged, with a behavior change and a convergence component. • We find few impacts on women or children's anthropometry but large significant impacts on their dietary diversity. • We investigate multiple pathways to impact and compare the cost of this intervention to similar programs. • Despite potential of SHGs, information-only interventions in resource-constrained settings will likely have limited impact. India accounts for a large proportion of the global prevalence of maternal and child undernutrition, and recent trends have renewed the call for large-scale concerted efforts to improve outcomes. With their reach to millions of rural Indian women, self-help groups (SHGs) offer a possible solution. We provide evidence from a cluster-randomized controlled trial in the state of Bihar of the impact of a health and nutrition intervention that provided behavior change communication to SHG members and worked to strengthen utilization of services. Over the course of 2.5 years, the intervention resulted in a 7% increase in the number of food groups consumed by children and a 30% increase in the proportion of women achieving minimum dietary diversity but had no impact on women's body mass index or child underweight and wasting. Both knowledge and adoption of key behaviors along the impact pathway improved as a result of the treatment. SHGs certainly have the potential to effect social change and accelerate improvements in maternal and child health and nutrition outcomes, but in resource-constrained settings such as these, information-only interventions delivered through these platforms will likely have limited impact. [ABSTRACT FROM AUTHOR]

Abstract: On March 2003, IBIS, the γ-ray imager on board the INTEGRAL satellite, detected an outburst from a new source, IGR J17464-3213, that turned out to be an HEAO-1 transient, namely H1743-322. The spectral and temporal evolutions of the source were observed by INTEGRAL in different periods. Also RXTE observed the source for the first time on 2003 March 29 during a PCA Galactic bulge scan. The source flux decayed below the RXTE PCA sensitivity limit in November 2003, then in April 2004 it was again detected by INTEGRAL. On July 3, 2004 the source was again detected by RXTE/PCA at a 2–10keV intensity of 16 mCrab and on July 7, reached 69 mCrab. Recently, a new outburst was observed on August 2005. We briefly summarise here the behaviour of the source observed by INTEGRAL from March 2003 to August 2005. The new outbursts of the source and the analysis of all the data collected (now public) give a global view of the spectral and time behaviour of this X-ray transient. [Copyright &y& Elsevier]

Abstract: In this paper, we present the spectral characteristics of a sample of Black Hole Candidates observed with the IBIS, SPI and JEM-X instruments on board the INTEGRAL Gamma-ray Observatory. This work is part of the long term, systematic, spectral study programme of intermediate intensity BHC (<500 mCrab) within the INTEGRAL Core Programme observations. The basic data set is from Galactic Plane Scan (GPS) and Galactic Centre Deep Exposure (GCDE), collected from the beginning of the Integral scientific observation programme. We will address in particular the behaviour of IGR J17464-3213, 1E 1740.7-294 and XTE J1720-318. [Copyright &y& Elsevier]

Objective Research methods are described for developing a food and physical activity behaviors questionnaire for the Expanded Food and Nutrition Education Program (EFNEP), a US Department of Agriculture nutrition education program serving low-income families. Design Mixed-methods observational study. The questionnaire will include 5 domains: (1) diet quality, (2) physical activity, (3) food safety, (4) food security, and (5) food resource management. A 5-stage process will be used to assess the questionnaire's test-retest reliability and content, face, and construct validity. Setting Research teams across the US will coordinate questionnaire development and testing nationally. Participants Convenience samples of low-income EFNEP, or EFNEP-eligible, adult participants across the US. Interventions A 5-stage process: (1) prioritize domain concepts to evaluate (2) question generation and content analysis panel, (3) question pretesting using cognitive interviews, (4) test-retest reliability assessment, and (5) construct validity testing. Main Outcome Measure A nationally tested valid and reliable food and physical activity behaviors questionnaire for low-income adults to evaluate EFNEP's effectiveness. Analysis Cognitive interviews will be summarized to identify themes and dominant trends. Paired t tests ( P ≤ .05) and Spearman and intra-class correlation coefficients ( r > .5) will be conducted to assess reliability. Construct validity will be assessed using Wilcoxon t test ( P ≤ .05), Spearman correlations, and Bland-Altman plots. [ABSTRACT FROM AUTHOR]