Publications by authors named "Benjamin Atkinson"

25 Publications

  • Page 1 of 1

Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling.

J Med Chem 2021 04 30;64(8):4289-4311. Epub 2021 Mar 30.

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.

Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (), ABC99 (), and ARUK3001185 (), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172013PMC
April 2021

Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity.

J Med Chem 2020 09 18;63(17):9464-9483. Epub 2020 Aug 18.

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, United Kingdom.

The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole , guided by structure-based drug design, identified as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine gave acid . This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable ADME profiles.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00660DOI Listing
September 2020

The ditungsten decacarbonyl dianion.

Dalton Trans 2020 Jul 25;49(27):9330-9335. Epub 2020 Jun 25.

Department of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK.

We report the synthesis and structural authentication of the ditungsten decarbonyl dianion in [(OC)W-W(CO)][K(18-crown-6)(THF)] (1), completing the group 6 dianion triad over half a century since the area began. The W-W bond is long [3.2419(8) Å] and, surprisingly, in the solid-state the dianion adopts a D eclipsed rather than D staggered geometry, the latter of which dominates the structural chemistry of binary homobimetallic carbonyls. Computational studies at levels of theory from DFT to CCSD(T) confirm that the D geometry is energetically preferred in the gas-phase, being ∼18 kJ mol more stable than the D form, since slight destabilisation of the degenerate W-CO π 5d and 5d orbitals is outweighed by greater stabilisation of the W-W σ-bond orbital. The gas-phase D structure displays a single imaginary vibrational mode, intrinsic reaction coordinate analysis of which links the D isomer directly to the D forms, which are produced by rotation around the W-W bond by ±45°. It is therefore concluded that the gas-phase transition state becomes a minimum on the potential energy surface when subjected to crystal packing in the solid-state.
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http://dx.doi.org/10.1039/d0dt01921fDOI Listing
July 2020

DietSensor: Automatic Dietary Intake Measurement Using Mobile 3D Scanning Sensor for Diabetic Patients.

Sensors (Basel) 2020 Jun 15;20(12). Epub 2020 Jun 15.

Sensors Energy and Automation Laboratory (SEAL), Department of Electrical and Computer Engineering, The University of Washington, Paul Allen Center, 185 E Stevens Way NE AE100R, Seattle, WA 98195, USA.

Diabetes is a global epidemic that impacts millions of people every year. Enhanced dietary assessment techniques are critical for maintaining a healthy life for a diabetic patient. Moreover, hospitals must monitor their diabetic patients' food intake to prescribe a certain amount of insulin. Malnutrition significantly increases patient mortality, the duration of the hospital stay, and, ultimately, medical costs. Currently, hospitals are not fully equipped to measure and track a patient's nutritional intake, and the existing solutions require an extensive user input, which introduces a lot of human errors causing endocrinologists to overlook the measurement. This paper presents DietSensor, a wearable three-dimensional (3D) measurement system, which uses an over the counter 3D camera to assist the hospital personnel with measuring a patient's nutritional intake. The structured environment of the hospital provides the opportunity to have access to the total nutritional data of any meal prepared in the kitchen as a cloud database. DietSensor uses the 3D scans and correlates them with the hospital kitchen database to calculate the exact consumed nutrition by the patient. The system was tested on twelve volunteers with no prior background or familiarity with the system. The overall calculated nutrition from the DietSensor phone application was compared with the outputs from the 24-h dietary recall (24HR) web application and MyFitnessPal phone application. The average absolute error on the collected data was 73%, 51%, and 33% for the 24HR, MyFitnessPal, and DietSensor systems, respectively.
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http://dx.doi.org/10.3390/s20123380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349497PMC
June 2020

Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors.

Bioorg Med Chem Lett 2020 02 28;30(3):126751. Epub 2019 Oct 28.

Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, UK. Electronic address:

The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.
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http://dx.doi.org/10.1016/j.bmcl.2019.126751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961116PMC
February 2020

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent.

Beilstein J Org Chem 2019 19;15:2790-2797. Epub 2019 Nov 19.

Alzheimer's Research UK UCL Drug Discovery Institute, The Cruciform Building, University College London, Gower Street, London WC1E 6BT, UK.

The carboxylesterase Notum has been shown to act as a key negative regulator of the Wnt signalling pathway by mediating the depalmitoleoylation of Wnt proteins. LP-922056 () is an orally active inhibitor of Notum. We are investigating the role of Notum in modulating Wnt signalling in the central nervous system and wished to establish if would serve as a peripherally restricted control. An accessible and improved synthetic route would allow to become more readily available as a chemical tool to explore the fundamental biology of Notum and build target validation to underpin new drug discovery programs. An improved, scalable synthesis of is reported. Key modifications include: (1) the introduction of the C7-cyclopropyl group was most effectively achieved with a Suzuki-Miyaura cross-coupling reaction with MIDA-boronate ( → ), and (2) C6 chlorination was performed with 1-chloro-1,2-benziodoxol-3-one () ( → ) as a mild and selective electrophilic chlorination agent. This 7-step route from has been reliably performed on large scale to produce multigram quantities of in good efficiency and high purity. Pharmacokinetic studies in mouse showed CNS penetration of is very low with a brain/plasma concentration ratio of just 0.01. A small library of amides were prepared from acid to explore if could be modified to deliver a CNS penetrant tool by capping off the acid as an amide. Although significant Notum inhibition activity could be achieved, none of these amides demonstrated the required combination of metabolic stability along with cell permeability without evidence of P-gp mediated efflux. Mouse pharmacokinetic studies demonstrate that is unsuitable for use in models of disease where brain penetration is an essential requirement of the compound but would be an ideal peripherally restricted control. These data will contribute to the understanding of drug levels of to overlay with appropriate in vivo efficacy endpoints, i.e., the PK-PD relationship. The identification of a suitable analogue of (or ) which combines Notum inhibition with CNS penetration would be a valuable chemical probe for investigating the role of Notum in disease models.
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http://dx.doi.org/10.3762/bjoc.15.271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880826PMC
November 2019

Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center.

Circ Heart Fail 2019 11 29;12(11):e006214. Epub 2019 Oct 29.

Division of Cardiovascular Medicine, and Department of Medicine (E.F..L.), Brigham and Women's Hospital, Boston, MA.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality.

Results: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84-0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72-0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race.

Conclusions: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183732PMC
November 2019

Controlling Engineered P2X Receptors with Light.

Methods Mol Biol 2020 ;2041:301-309

Wolfson Institute for Biomedical Research, University College London, London, UK.

This chapter details methods to express and modify ATP-gated P2X receptor channels so that they can be controlled using light. Following expression in cells, a photoswitchable tool compound can be used to covalently modify mutant P2X receptors, as previously demonstrated for homomeric P2X2 and P2X3 receptors, and heteromeric P2X2/3 receptors. Engineered P2X receptors can be rapidly and reversibly opened and closed by different wavelengths of light. Light-activated P2X receptors can be mutated further to impart ATP-insensitivity if required. This method offers control of specific P2X receptor channels with high spatiotemporal precision to study their roles in physiology and pathophysiology.
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http://dx.doi.org/10.1007/978-1-4939-9717-6_22DOI Listing
April 2020

Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen.

Medchemcomm 2019 Aug 29;10(8):1361-1369. Epub 2019 Apr 29.

Alzheimer's Research UK UCL Drug Discovery Institute , University College London , Cruciform Building, Gower Street , London , WC1E 6BT , UK . Email: ; Tel: +44 (0)20 7679 6971.

NOTUM is a carboxylesterase that has been shown to act by mediating the -depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide as binding in the palmitoleate pocket with modest inhibition activity (IC 33 μM). Optimization of hit by SAR studies guided by SBDD identified indazole (IC 0.032 μM) and isoquinoline (IC 0.085 μM) as potent inhibitors of NOTUM. The binding of to NOTUM was rationalized through an X-ray co-crystal structure determination which showed a flipped binding orientation compared to . However, it was not possible to combine NOTUM inhibition activity with metabolic stability as the majority of the compounds tested were rapidly metabolized in an NADPH-independent manner.
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http://dx.doi.org/10.1039/c9md00096hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727465PMC
August 2019

Back-bonding between an electron-poor, high-oxidation-state metal and poor π-acceptor ligand in a uranium(V)-dinitrogen complex.

Nat Chem 2019 09 19;11(9):806-811. Epub 2019 Aug 19.

School of Chemistry, The University of Manchester, Manchester, UK.

A fundamental bonding model in coordination and organometallic chemistry is the synergic, donor-acceptor interaction between a metal and a neutral π-acceptor ligand, in which the ligand σ donates to the metal, which π back-bonds to the ligand. This interaction typically involves a metal with an electron-rich, mid-, low- or even negative oxidation state and a ligand with a π* orbital. Here, we report that treatment of a uranium-carbene complex with an organoazide produces a uranium(V)-bis(imido)-dinitrogen complex, stabilized by a lithium counterion. This complex, which was isolated in a crystalline form, involves an electron-poor, high-oxidation-state uranium(V) 5f ion that is π back-bonded to the poor π-acceptor ligand dinitrogen. We propose that this is made possible by a combination of cooperative heterobimetallic uranium-lithium effects and the presence of suitable ancillary ligands that render the uranium ion unusually electron rich. This electron-poor back-bonding could have implications for the field of dinitrogen activation.
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http://dx.doi.org/10.1038/s41557-019-0306-xDOI Listing
September 2019

Post Hartree-Fock calculations of pnictogen-uranium bonding in EUF (E = N-Bi).

Chem Commun (Camb) 2018 Oct;54(79):11100-11103

School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK.

NUF3 is identified as having a N[triple bond, length as m-dash]U triple bond, as has been previously found (Andrews et al., Angew. Chem. Int. Ed., 2008, 47, 5366). By contrast, while previously reported calculations on PUF3 and AsUF3 (Andrews et al., Inorg. Chem., 2009, 48, 6594) gave a E[triple bond, length as m-dash]U triple bond, our calculations suggest a single bond for both molecules, with antibonding π* and non-bonding 5fU orbitals significantly occupied, and highly multiconfigurational wavefunctions. We propose this difference to be due to the smaller [6,6] active space used (σ, π, π* and σ*) in the previous studies. In our calculations, a [6,16] active space was employed in order to include uranium f-orbitals and pnictogen d-orbitals.
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http://dx.doi.org/10.1039/c8cc05581eDOI Listing
October 2018

Regioselective and enantiospecific synthesis of the HSP co-inducer arimoclomol from chiral glycidyl derivatives.

Org Biomol Chem 2017 Nov;15(46):9794-9799

Alzheimer's Research UK UCL Drug Discovery Institute, The Cruciform Building, University College London, Gower Street, London, WC1E 6BT, UK.

A new efficient chiral synthesis of enantiopure arimoclomol (2) is reported from (R)-(-)-glycidyl nosylate (11) with complete retention of chiral integrity. Off-target pharmacology of arimoclomol (2) was evaluated against a representative set of drug targets and showed modest binding to a few kinases. Pharmacokinetic data was generated in vivo in mouse and showed a low brain : plasma ratio. These studies will be helpful towards a better understanding of the PK-PD relationship of 2 in disease models.
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http://dx.doi.org/10.1039/c7ob02578eDOI Listing
November 2017

Lesion complexity drives the cost of superficial femoral artery endovascular interventions.

J Vasc Surg 2015 Oct 21;62(4):998-1002. Epub 2015 Jul 21.

Section of Vascular Surgery, Dartmouth Hitchcock Medical Center, Lebanon, NH. Electronic address:

Objective: Patients who undergo endovascular treatment of superficial femoral artery (SFA) disease vary greatly in lesion complexity and treatment options. This study examined the association of lesion severity and cost of SFA stenting and to determine if procedure cost affects primary patency at 1 year.

Methods: A retrospective record review identified patients undergoing initial SFA stenting between January 1, 2010, and February 1, 2012. Medical records were reviewed to collect data on demographics, comorbidities, indication for the procedure, TransAtlantic Inter-Society Consensus (TASC) II severity, and primary patency. The interventional radiology database and hospital accounting database were queried to determine cost drivers of SFA stenting. Procedure supply cost included any item with a bar code used for the procedure. Associations between cost drivers and lesion characteristics were explored. Primary patency was determined using Kaplan-Meier survival curves and a log-rank test.

Results: During the study period, 95 patients underwent stenting in 98 extremities; of these, 61% of SFA stents were performed for claudication, with 80% of lesions classified as TASC II A or B. Primary patency at 1 year was 79% for the entire cohort. The mean total cost per case was $10,333. Increased procedure supply cost was associated with adjunct device use, the number of stents, and TASC II severity. Despite higher costs of treating more complex lesions, primary patency at 1 year was similar at 80% for high-cost (supply cost >$4000) vs 78% for low-cost (supply cost <$4000) interventions.

Conclusions: SFA lesion complexity, as defined by TASC II severity, drives the cost of endovascular interventions but does not appear to disadvantage patency at 1 year. Reimbursement agencies should consider incorporating disease severity into reimbursement algorithms for lower extremity endovascular interventions.
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http://dx.doi.org/10.1016/j.jvs.2015.04.450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292273PMC
October 2015

Antibodies to infliximab are associated with lower infliximab levels and increased likelihood of surgery in pediatric IBD.

Inflamm Bowel Dis 2015 Feb;21(2):307-14

*Pediatric Inflammatory Bowel Disease Center, Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts; †Boston Children's Hospital Clinical Research Center, Boston, Massachusetts; and ‡Prometheus Laboratories Inc., San Diego, California.

Background: Adult studies suggest antibodies to infliximab (ATI) correlate with loss of response in inflammatory bowel disease but pediatric data are limited.

Methods: We conducted a cross-sectional study of trough infliximab levels and ATI in 134 pediatric and young adult patients receiving infliximab. At the time serum was obtained demographics, disease phenotype, duration of infliximab therapy, use of combination therapy (methotrexate or 6-mercaptopurine with infliximab), and surgery were recorded.

Results: Assays were performed on 134 subjects currently receiving infliximab (85 male; mean age, 17.3 ± 4.3 years; 114 Crohn's disease and 20 ulcerative colitis). Infliximab use ranged from 12 days to 12 years: median 2.0 (interquartile range [1.1-4.3]) years. Twenty-seven of 134 (20%) patients had ATI ≥5 U/mL. Of patients with ATI ≥5 U/mL, 59% had infliximab levels <5 μg/mL, compared with 14% of patients with ATI <5 U/mL (P < 0.001). Ten (7%) patients (9 Crohn's disease, 1 ulcerative colitis) underwent bowel resections after beginning infliximab infusions. Sixty percent who underwent surgery had ATI ≥12 U/mL; in contrast, only 8% of patients who did not undergo surgery had ATI ≥12 U/mL (P = 0.01). At the time of serum sampling, 50 (37%) patients were receiving combination therapy, compared with 84 (63%) on infliximab alone. Combination therapy at the time of serum sampling did not correlate with either increase infliximab levels or lower ATI compared with infliximab monotherapy. However, prior immunomodulator use was associated with lower antibody levels (P = 0.007).

Conclusions: ATI correlates with reduction in infliximab level and a higher risk of surgery in patients with inflammatory bowel disease.
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http://dx.doi.org/10.1097/MIB.0000000000000284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5279914PMC
February 2015

Changes in metabolic syndrome status after initiation of antiretroviral therapy.

J Acquir Immune Defic Syndr 2015 Jan;68(1):73-80

*Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA; †Department of Surgery, University of Washington School of Medicine, Seattle, WA; ‡Harborview Medical Center, Seattle, WA; §Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University, Baltimore, MD; ‖AIDS Clinical Trials Unit, University of North Carolina, Chapel Hill, NC; ¶Division of Pediatric Infectious Diseases and Rheumatology, Case School of Medicine, Cleveland, OH; #Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York, NY; **Hawaii Center for AIDS, University of Hawaii, Honolulu, HI; and ††University of California San Diego, San Diego, CA.

Background: Data on changes in metabolic syndrome (MetS) status in HIV-infected adults on antiretroviral therapy (ART) are limited.

Methods: MetS was assessed at ART initiation and every 48 weeks on ART in ART-naive HIV-infected individuals from the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) cohort. MetS, defined using the Adult Treatment Panel III criteria, required at least 3 of the following: elevated fasting glucose, hypertension, elevated waist circumference, elevated triglycerides, low high-density lipoprotein (HDL) cholesterol. Prevalence of MetS and the individual criteria were compared between ART initiation and during follow-up using McNemar test.

Results: At ART initiation, 450 (20%) ALLRT participants had MetS. After 96 weeks of ART, 37% of the 411 with MetS at ART initiation and with available data at this time point did not meet the MetS criteria. Among these participants, there was a dramatic decline in the proportion with low HDL (95% versus 26%, P < 0.0001). Among the 63% who continued to meet MetS criteria at week 96, the proportion with ≥4 criteria was higher at week 96 compared to at the time of ART initiation (48% versus 40%, P = 0.03); at week 96, the proportion with high triglycerides was greater (87% versus 69%, P < 0.0001) as was the proportion with high glucose (59% versus 42%, P < 0.0001).

Conclusions: One in 5 ART-naive subjects met criteria for MetS at ART initiation. Although more than half of these individuals continued to have MetS after 96 weeks of ART, 37% with MetS at ART initiation no longer met criteria for MetS; this decrease was driven largely by increases in HDL cholesterol.
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http://dx.doi.org/10.1097/QAI.0000000000000397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262682PMC
January 2015

Characterization of adherent bacteroidales from intestinal biopsies of children and young adults with inflammatory bowel disease.

PLoS One 2013 11;8(6):e63686. Epub 2013 Jun 11.

Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

There is extensive evidence implicating the intestinal microbiota in inflammatory bowel disease [IBD], but no microbial agent has been identified as a sole causative agent. Bacteroidales are numerically dominant intestinal organisms that associate with the mucosal surface and have properties that both positively and negatively affect the host. To determine precise numbers and species of Bacteroidales adherent to the mucosal surface in IBD patients, we performed a comprehensive culture based analysis of intestinal biopsies from pediatric Crohn's disease [CD], ulcerative colitis [UC], and control subjects. We obtained biopsies from 94 patients and used multiplex PCR or 16S rDNA sequencing of Bacteroidales isolates for species identification. Eighteen different Bacteroidales species were identified in the study group, with up to ten different species per biopsy, a number higher than demonstrated using 16S rRNA gene sequencing methods. Species diversity was decreased in IBD compared to controls and with increasingly inflamed tissue. There were significant differences in predominant Bacteroidales species between biopsies from the three groups and from inflamed and uninflamed sites. Parabacteroides distasonis significantly decreased in inflamed tissue. All 373 Bacteroidales isolates collected in this study grew with mucin as the only utilizable carbon source suggesting this is a non-pathogenic feature of this bacterial order. Bacteroides fragilis isolates with the enterotoxin gene [bft], previously associated with flares of colitis, were not found more often at inflamed colonic sites or within IBD subjects. B. fragilis isolates with the ability to synthesize the immunomodulatory polysaccharide A [PSA], previously shown to be protective in murine models of colitis, were not detected more often from healthy versus inflamed tissue.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063686PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679120PMC
January 2014

Anthropometric differences between HIV-infected individuals prior to antiretroviral treatment and the general population from 1998-2007: the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) cohort and NHANES.

PLoS One 2013 3;8(6):e65306. Epub 2013 Jun 3.

Madison Clinic, Harborview Medical Center, Seattle, Washington, United States of America.

Objective: To assess differences in body circumferences and body mass index (BMI, kg/m(2)) between antiretroviral treatment (ART) naïve HIV-infected and HIV-uninfected persons.

Methods: Waist, arm, and thigh circumferences and BMI were measured within the ALLRT and NHANES cohorts between 1998 and 2007. ALLRT is a prospective, longitudinal study of U.S. participants enrolled in randomized HIV treatment studies conducted by the AIDS Clinical Trials Group (ACTG). NHANES is a representative group of the US population. The cohorts were analyzed in two time periods, to account for trends towards increased adiposity. Anthropometrics were displayed in percentiles by age and sex. Multiple linear regression models examined differences between cohorts.

Results: ALLRT had more males (82% versus 48%, p<0.0001), more black participants (32% versus 23%, p<0.0001), and less Hispanics (21% versus 30%, p<0.0001) than NHANES. Mean BMI was smaller in ALLRT males and females compared to NHANES by 1.6-2.4 kg/m(2) (p<0.0001). Mean waist and arm circumferences in both sexes and time periods were significantly smaller in ALLRT than in NHANES (p<0.0001). Mean thigh circumference in ALLRT was also smaller than NHANES among males (p<0.0001 in both time periods) and females (p = 0.01 in the early time period).

Conclusions: Differences in anthropometrics existed prior to ART initiation, in this large national cohort of HIV-infected individuals, compared to a representative HIV-uninfected cohort, indicating that HIV and its complications have important effects on body shape. Further longitudinal examination of anthropometrics in this HIV-infected cohort may provide additional insight into disease risk.

Trial Registration: NCT00001137 at www.clinicaltrials.gov.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065306PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670846PMC
January 2015

Risk factors, morbidity, and treatment of thrombosis in children and young adults with active inflammatory bowel disease.

J Pediatr Gastroenterol Nutr 2013 Sep;57(3):343-7

Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA.

Objectives: Pediatric inpatients with inflammatory bowel disease (IBD) are rarely considered for thromboprophylaxis because of concerns about safety and underappreciation of thrombotic risk. We characterized thromboembolism (TE) in children and young adults with inflammatory bowel disease (IBD) at a single tertiary care hospital.

Methods: We performed a retrospective review of an inpatient billing database for all IBD admissions with colonic involvement and an anticoagulation database for thrombotic complications from 2006 to 2011.

Results: Of 532 patients admitted with IBD with colonic involvement, 10 (1.9%) had TE (9 venous, 1 arterial), 2 of whom had recurrent thrombosis. Many of the events resulted in considerable morbidity, including 4 cerebrovascular events and 2 pulmonary emboli. Established risk factors in IBD colitis inpatients with TE included: indwelling catheter (4/10), first-degree family member with TE (2/10), hereditary thrombophilia (3/10), smoking (1/10), oral contraceptive (1/5 females), and thalidomide (1/10). Additionally, most (8/10) patients had acquired thrombophilia, mostly elevation of factor VIII and anticardiolipin antibodies. Patients with IBD and TE received therapeutic anticoagulation without significantly increased bleeding. Thrombus resolution was documented in 7 cases, persistence in 2 cases and recurrence in 2 cases.

Conclusions: Pediatric inpatients hospitalized with IBD with colonic involvement have increased risk of TE, including complications of pulmonary embolism, recurrence, persistence, and indefinite long-term anticoagulation. Therapeutic anticoagulation in patients with IBD with active colitis appears safe. We identified both inherited thrombophilias and acquired risk factors in patients with IBD and TE. We presently use risk stratification and recommend prophylactic anticoagulation in high-risk patients.
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http://dx.doi.org/10.1097/MPG.0b013e31829ce5cdDOI Listing
September 2013

Transamidation of primary amides with amines catalyzed by zirconocene dichloride.

Chem Commun (Camb) 2012 Dec;48(95):11626-8

University of Bath, UK.

Zirconocene dichloride (Cp(2)ZrCl(2)) has been shown to be an effective catalyst for the transamidation of primary amides with amines in cyclohexane at 80 °C in 5-24 hours. For favourable substrates, the reaction can be performed at temperatures as low as 30 °C.
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http://dx.doi.org/10.1039/c2cc37427gDOI Listing
December 2012

Metabolic syndrome before and after initiation of antiretroviral therapy in treatment-naive HIV-infected individuals.

J Acquir Immune Defic Syndr 2012 Nov;61(3):381-9

Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA 02115, USA.

Background: Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease and diabetes, many of which are associated with HIV and antiretroviral therapy (ART). We examined prevalence and incidence of MetS and risk factors for MetS in ART-naive HIV-infected individuals starting ART.

Methods: MetS, defined by the Adult Treatment Panel III criteria, was assessed at and after ART initiation in HIV-infected individuals who enrolled in selected AIDS Clinical Trials Group trials and were followed long-term after these trials as part of the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort. Cox proportional hazards models were used to examine risk factors of incident MetS. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) are reported.

Results: At ART initiation, the prevalence of MetS was 20%. After ART initiation, the incidence of MetS was 8.5 per 100 person-years. After adjusting for demographics and body mass index, the risk of MetS was decreased for CD4+ T-cell counts >50 cells per cubic millimeter (aHR = 0.62, 95% CI = 0.43 to 0.90 for CD4 >500), and the risk was increased for HIV-1 RNA >400 copies per milliliter (aHR = 1.55 (95% CI = 1.25 to 1.92) and use of a protease-inhibitor (PI)-based regimen [relative to no PI use, aHR = 1.25 (95% CI = 1.04 to 1.51) for any PI use].

Conclusions: In HIV-infected individuals on ART, virologic suppression and maintenance of high CD4+ T-cell counts may be potentially modifiable factors that can reduce the risk of MetS. The effect of MetS on the risk of cardiovascular disease and diabetes needs to be evaluated.
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http://dx.doi.org/10.1097/QAI.0b013e3182690e3cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480980PMC
November 2012

Transamidation of primary amides with amines using hydroxylamine hydrochloride as an inorganic catalyst.

Angew Chem Int Ed Engl 2012 Feb 30;51(6):1383-6. Epub 2011 Dec 30.

Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

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http://dx.doi.org/10.1002/anie.201107348DOI Listing
February 2012

Refractory status epilepticus secondary to CNS vasculitis, a role for epilepsy surgery.

J Neurol Sci 2012 Apr 15;315(1-2):156-9. Epub 2011 Dec 15.

Department of Neurology, Wayne State University School of Medicine, Detroit Medical Center, Detroit, MI 48201, USA.

Central nervous system (CNS) vasculitis is a rare group of disorders that affect vessels of the brain parenchyma and meninges. It presents with headache, cognitive changes, or seizures, yet without aggressive management, it carries a high degree of morbidity and mortality. Refractory status epilepticus (SE) has been reported with CNS vasculitis. Patients are treated with immunosuppression, antiepileptic drugs (AED), and anesthetic agents. Outcomes are usually poor. Epilepsy surgery for refractory partial SE has succeeded in patients. We present a comparison of two patients with refractory partial SE due to CNS vasculitis. One patient was treated medically and died, while the other underwent epilepsy surgery to remove the epileptic focus along with medical therapy and the patient had substantial recovery. We describe clinical, electrophysiological, pathological, and treatment features of both patients and discuss rationale for surgical intervention. This is the first case report of the use of epilepsy surgery for the treatment of refractory SE associated with CNS vasculitis.
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http://dx.doi.org/10.1016/j.jns.2011.11.029DOI Listing
April 2012

Comprehensive lipid management versus aggressive low-density lipoprotein lowering to reduce cardiovascular risk.

Am J Cardiol 2008 Apr;101(8A):48B-57B

Division of Metabolism, Endocrinology and Nutrition, Northwest Lipid Research Clinic, Seattle, Washington, USA.

Five lines of evidence justify comprehensive lipoprotein management over aggressive low-density lipoprotein (LDL) lowering alone in most cases of cardiovascular disease (CVD) prevention. First, lipoprotein lipid transport consists of a single, recycling system involving very-low-density lipoprotein, LDL, and high-density lipoprotein (HDL). Single lipid interventions affect all lipoprotein classes to varying degrees. These effects can be expanded by using different drug classes in combination. Second, observational studies support the unitary nature of lipoprotein risk. A family of curves describes increasing CVD risk from increasing LDL as other risk factors are present. Conversely, a family of curves describes increasing CVD risk from decreasing levels of HDL in mirror image to LDL. The LDL and HDL risks are additive. Third, clinical trials that raise HDL and lower triglyceride ameliorate CVD, as does lowering LDL. Lowering LDL prevents heart disease, but by only 22%-36% with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor therapy. Studies indicate that better CVD prevention is obtained when drugs for triglyceride and HDL reduction are combined with LDL reduction. Fourth, HDL and its apolipoprotein (apo), apo A-I, as well as apo A-I analogues, decrease atherosclerosis. Each modality decreases atherosclerosis in animal models, and apo A-I Milano acutely decreases human coronary luminal stenosis. Apo A-I analogues have similar promise. Fifth, combined hyperlipidemia is the most common lipid disorder, has the strongest risk for CVD, and combines elevated LDL, hypertriglyceridemia, and low HDL. This condition requires the comprehensive treatment approach described above. In conclusion, 5 lines of evidence justify comprehensive diet and drug treatment for combined hyperlipidemia and, at lesser LDL elevations, the atherogenic dyslipidemias of obesity, diabetes mellitus, and the metabolic syndrome.
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http://dx.doi.org/10.1016/j.amjcard.2008.02.038DOI Listing
April 2008

Cardiac troponin-I: a predictor of prognosis in subarachnoid hemorrhage.

Neurocrit Care 2008 ;8(3):398-403

Division of Cardiology, Harper University Hospital, Wayne State University, 1 Webber South, 3990, John R. Street, Detroit, MI 48201, USA.

Background: Release of cardiac biomarkers is reported in patients with subarachnoid hemorrhage (SAH). Data addressing the impact of cardiac injury on outcome in these patients is sparse. This study was conducted to ascertain the association of elevation of serum cardiac Troponin-I (cTnI) with mortality and neurological outcome in patients with SAH.

Methods: Medical records of all patients admitted with a diagnosis of SAH and at least one measured cTnI were reviewed. Demographic and clinical variables including admission neurological status were collected. Conservative and non-parametric statistics were used to assess association between cTnI and death or neurological outcome at discharge.

Results: The study group comprised of 83 patients with a mean age of 59 years. There was a female (60%) and African-American (60%) preponderance. At admission, the median Glasgow Coma Scale (GCS) was 9, and 47% had a severe Hunt-Hess grade (HHG) of > or =4. Elevation of cTnI was found in 31 (37%) patients and was associated with worse baseline Fisher grade (p=0.01) and neurological status: GCS score (p=0.006) and HHG (p=0.007). Patients with abnormal cTnI were more likely to die (55% vs.27%; odds ratio 1.3-8.4, p = 0.01) and had a worse GCS score (p = 0.008) and HHG (p = 0.004) on discharge. On multivariate analysis, peak cTnI (p = 0.04) and admission GCS score of <12 (p = 0.02) were independent predictors of death at discharge.

Conclusion: Patients with subarachnoid hemorrhage and elevated cTnI are found to have worse neurological status at admission. These patients have a worse neurological outcome and in-hospital mortality.
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http://dx.doi.org/10.1007/s12028-007-9038-7DOI Listing
September 2008