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Find video protocols related to scientific articles indexed in Pubmed.
Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B.
N. Engl. J. Med.
PUBLISHED: 11-20-2014
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Background In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. Methods We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. Results A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. Conclusions In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238 .).
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Community-onset Staphylococcus aureus Surveillance Programme annual report, 2012.
Commun Dis Intell Q Rep
PUBLISHED: 11-20-2014
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In 2012, the Australian Group on Antimicrobial Resistance (AGAR) conducted a community-onset period-prevalence survey of clinical Staphylococcus aureus isolated from hospital outpatients and general practice patients including nursing homes, long term care facilities and hospice patients. Day surgery and dialysis patients were excluded. Twenty-nine medical microbiology laboratories from all state and mainland territories participated. Isolates were tested by Vitek2® (AST-P612 card). Results were compared with previous AGAR community surveys. Nationally, the proportion of S. aureus that were methicillin-resistant S. aureus (MRSA) increased significantly from 11.5% in 2000 to 17.9% in 2012 (P<0.0001). Resistance to the non-ß-lactam antimicrobials varied between regions. No resistance was detected to vancomycin, teicoplanin or linezolid. Resistance in methicillin susceptible S. aureus was rare apart from erythromycin (12.8%) and was absent for vancomycin, teicoplanin, linezolid and daptomycin. The proportion of S. aureus characterised as health care-associated MRSA (HA-MRSA) was 5.1%. Three HA-MRSA clones were characterised, with 72.9% and 26.4% of HA-MRSA classified as ST22-IV [2B] (EMRSA-15) and ST239-III [3A] (Aus-2/3 EMRSA) respectively. Multi-clonal community-associated MRSA (CA-MRSA) accounted for 12.5% of all S. aureus. Regional variation in resistance in MRSA was primarily due to the differential distribution of the 2 major HA-MRSA clones; ST239-III [3A] (Aus-2/3 EMRSA), which is resistant to multiple non-ß-lactam antimicrobials, and ST22-IV [2B] (EMRSA-15), which is resistant to ciprofloxacin and typically erythromycin. Although the majority of CA-MRSA were non-multi-resistant, a significant expansion of Panton-Valentine leukocidin (PVL) positive CA-MRSA clones has occurred nationally. The mean age of patients (31.7 years, 95% CI 28.9-34.5) with a PVL positive CA-MRSA infection was significantly lower (P<0.0001), than the mean age of patients with a PVL negative CA-MRSA infection (55.7 years, 95% CI 50.7-60.6). This shift in the molecular epidemiology of MRSA clones in the Australian community will potentially increase the number of young Australians with skin and soft tissue infections requiring hospitalisation. Commun Dis Intell 2014;38(1):E59-E69.
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Addressing the Knowledge Gap in Clinical Recommendations for Management and Complete Excision of Clinically Atypical Nevi/Dysplastic Nevi: Pigmented Lesion Subcommittee Consensus Statement.
JAMA Dermatol
PUBLISHED: 11-20-2014
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The management of clinically atypical nevi/dysplastic nevi (CAN/DN) is controversial, with few data to guide the process. Management recommendations for DN with positive histologic margins were developed by the Delphi method to achieve consensus among members of the Pigmented Lesion Subcommittee (PLS) of the Melanoma Prevention Working Group (MPWG) after reviewing the current evidence.
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Synthesis and Characterization of the Platinum-Substituted Keggin Anion ?-H2SiPtW11O40(4-)
Inorg Chem
PUBLISHED: 11-20-2014
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Acidification of an aqueous solution of K8SiW11O39 and K2Pt(OH)6 to pH 4 followed by addition of excess tetramethylammonium (TMA) chloride yielded a solid mixture of TMA salts of H2SiPtW11O40(4-) (1) and SiW12O40(4-) (2). The former was separated from the latter by extraction into an aqueous solution and converted into tetra-n-butylammonium (TBA) and potassium salts TBA-1 and K-1. The ?-H2SiPtW11O40(4-) was identified as a monosubstituted Keggin anion using elemental analysis, IR spectroscopy, X-ray crystallography, electrospray ionization mass spectrometry, (195)Pt NMR spectroscopy, (183)W NMR spectroscopy, and (183)W-(183)W 2D INADEQUATE NMR spectroscopy. Both TBA-1 and K-1 readily cocrystallized with their unsubstituted Keggin anion salts, TBA-2 and K-2, respectively, providing an explanation for the historical difficulty of isolating certain platinum-substituted heteropolyanions in pure form.
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Discovery and Characterization of the Tuberculosis Drug Lead Ecumicin.
Org. Lett.
PUBLISHED: 11-20-2014
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The new tuberculosis (TB) lead ecumicin (1), a cyclic tridecapeptide, was isolated from Nonomuraea sp. MJM5123, following a high-throughput campaign for anti-TB activity. The large molecular weight of 1599 amu detected by LC-HR-MS precluded the initial inference of its molecular formula. The individual building blocks were identified by extensive NMR experiments. The resulting two possible planar structures were distinguished by LC-MS(2). Determination of absolute configuration and unambiguous structural confirmation were carried out by X-ray crystallography and Marfey's analysis.
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Assessing the spatial and temporal variability of diffusive methane and nitrous oxide emissions from subtropical freshwater reservoirs.
Environ. Sci. Technol.
PUBLISHED: 11-20-2014
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Surface water methane (CH4) and nitrous oxide (N2O) concentrations were measured and diffusive fluxes were estimated in three subtropical freshwater reservoirs (Little Nerang Dam (LND), Lake Wivenhoe (LW) and Lake Baroon (LB)) in southeast Queensland, Australia, during four seasons in 2011 - 2012. All reservoirs were strong sources of CH4 in all seasons. Surface water CH4 varied between 1,350 and 524,000% saturation, and was overall highest in spring and summer, and lowest in winter, however, with no clear patterns common to all reservoirs. In contrast, all reservoirs switched from weak N2O sinks in spring to strong N2O sources for the rest of the year. N2O saturation in all reservoirs varied between 70 and 1,230%. There were significant differences for CH4 concentrations and fluxes between the reservoirs. Within each reservoir, there was strong spatial CH4 variability but minimal N2O saturation variability. CH4 saturation was higher in inflow zones than in the main body. Area-weighted average fluxes were estimated using six water-air gas transfer velocity estimation models and resulted in fluxes in the range 4.8 - 20.5, 2.3 - 5.4, and 2.3 - 7.5 mg CH4 m(-2) d(-1) while N2O was 0.07 - 0.41, 0.09 - 0.22 and 0.03 - 0.09 mg N2O m(-2) d(-1) for LND, LW and LB, respectively. Total emissions, in carbon dioxide equivalents, from all measurement campaigns were CH4 dominated (67 - 86%). The measured degree of CH4 saturation and fluxes are among the highest reported thus far indicating that subtropical freshwater reservoirs could be significant aquatic greenhouse gas sources. This paper provides a comprehensive assessment of the interplay between biogeochemical processes and the physical forcing driving the water-air gas emissions. The high variability coupled with the lack of consensus amongst estimation models calls for concerted efforts to address uncertainty of measurements for reliable emissions accounting.
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Evaluating Public Housing Residents for Knowledge, Attitudes, and Practices Following Dengue Prevention Outreach in Key West, Florida.
Vector Borne Zoonotic Dis.
PUBLISHED: 11-20-2014
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Abstract Background: In 2009-2010, 93 cases of dengue were identified in Key West, Florida. This was the first outbreak of autochthonous transmission of dengue in Florida since 1934. In response to this outbreak, a multifaceted public education outreach campaign was launched. The aim of this study is to compare dengue prevention knowledge, attitudes, perceptions, and prevention practices among residents of subsidized public housing to the general population in Key West and to assess whether there were barriers preventing effective outreach from reaching specific vulnerable populations. Methods: A randomized population-based evaluation of knowledge, attitudes, and behaviors toward dengue prevention consisting of 521 separate household interviews was undertaken in July of 2011. A subset analysis was performed on interviews collected from 28 public housing units within four subsidized public housing complexes. Analysis was performed to determine whether knowledge, attitudes, and behaviors exhibited by public housing residents differed from the non-public housing study population. Results: Public housing residents recalled fewer outreach materials (p=0.01) and were 3.4 times (95% confidence interval [CI] 1.4-8.3) more likely not to recall any outreach materials. Public housing residents were less likely to correctly identify how dengue transmission occurs (61% vs. 89%), where mosquitoes lay their eggs (54% vs. 85%), or to identify any signs or symptoms related to dengue (36% vs. 64%). Public housing residents were less likely to perform dengue prevention practices such as removing standing water or always using air conditioning. Conclusions: Examination of public housing residents identified an at-risk population that recalled less exposure to outreach materials and had less knowledge about dengue infection and prevention than the randomized study population. This provides public health systems the opportunity to target or modify future health messages and interventions to this group. Differences identified in the demographics of this population suggest that alternative methods or non-English materials may be required to reach desired outcomes.
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Low-cost and Scalable Classroom Equipment to Promote Physical Activity and Improve Education.
J Phys Act Health
PUBLISHED: 11-20-2014
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We tested a low-cost and scalable set of classroom equipment, called Active Classroom Equipment, which was designed to promote physical activity while children learn. We hypothesized the Active Classroom Equipment would be associated with increased physical activity without impairing learning.
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Australian enterococcal sepsis outcome progamme, 2011.
Commun Dis Intell Q Rep
PUBLISHED: 11-14-2014
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From 1 January to 31 December 2011, 29 institutions around Australia participated in the Australian Enterococcal Sepsis Outcome Programme (AESOP). The aim of AESOP 2011 was to determine the proportion of enterococcal bacteraemia isolates in Australia that are antimicrobial resistant, with particular emphasis on susceptibility to ampicillin and the glycopeptides, and to characterise the molecular epidemiology of the Enterococcus faecalis and E. faecium isolates. Of the 1,079 unique episodes of bacteraemia investigated, 95.8% were caused by either E. faecalis (61.0%) or E. faecium (34.8%). Ampicillin resistance was detected in 90.4% of E. faecium but not detected in E. faecalis. Using Clinical and Laboratory Standards Institute breakpoints (CLSI), vancomycin non-susceptibility was reported in 0.6% and 31.4% of E. faecalis and E. faecium respectively and was predominately due to the acquisition of the vanB operon. Approximately 1 in 6 vanB E. faecium isolates however, had an minimum inhibitory concentration at or below the CLSI vancomycin susceptible breakpoint of ? 4 mg/L. Overall, 37% of E. faecium harboured vanA or vanB genes. Although molecular typing identified 126 E. faecalis pulsed-field gel electrophoresis (PFGE) pulsotypes, more than 50% belonged to 2 pulsotypes that were isolated across Australia. E. faecium consisted of 73 PFGE pulsotypes from which 43 multilocus sequence types were identified. Almost 90% of the E. faecium were identified as clonal complex 17 clones, of which approximately half were characterised as sequence type 203, which was isolated Australia-wide. In conclusion, the AESOP 2011 has shown that although polyclonal, enterococcal bacteraemias in Australia are frequently caused by ampicillin-resistant vanB E. faecium.
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Mimicking the hierarchical functions of dentin collagen cross-links with plant derived phenols and phenolic acids.
Langmuir
PUBLISHED: 11-08-2014
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Proanthocyanidins (PACs) are secondary plant metabolites that mediate non-enzymatic collagen cross-linking and enhance the properties of collagen based tissue, such as dentin. The extent and nature of cross-linking is influenced by the composition and specific chemical structure of the bioactive compounds present in certain PAC-rich extracts. This study investigated the effect of the molecular weight and stereochemistry of polyphenol compounds on two important properties of dentin, biomechanics and biostability. For that, purified phenols, a phenolic acid and some of its derivatives were selected: PACs dimers (A1, A2, B1 and B2) and a trimer (C1), gallic acid (Ga), its esters methyl gallate (MGa) and propyl gallate (PGa), and a pentagalloyl ester of glucose (PGG). Synergism was assessed by combination of the most active PAC and gallic acid derivative. Mechanical properties of dentin organic matrix were determined by the modulus of elasticity obtained in a flexural test. Biostability was evaluated by resistance to collagenase degradation. PACs significantly enhanced dentin mechanical properties and decreased collagen digestion. Among the gallic acid derivatives, only PGG had a significant enhancing effect. The lack of observed C1:PGG synergy indicates that both compounds have similar mechanisms of interaction with the dentin matrix. These findings reveal that the molecular weight of polyphenols have a determinant effect on their interaction with type I collagen and modulate the mechanism of cross-linking at the molecular, inter-molecular, and inter-micro-fibrillar levels.
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Importance of Purity Evaluation and the Potential of Quantitative (1)H NMR as a Purity Assay.
J. Med. Chem.
PUBLISHED: 10-09-2014
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In any biomedical and chemical context, a truthful description of chemical constitution requires coverage of both structure and purity. This qualification affects all drug molecules, regardless of development stage (early discovery to approved drug) and source (natural product or synthetic). Purity assessment is particularly critical in discovery programs and whenever chemistry is linked with biological and/or therapeutic outcome. Compared with chromatography and elemental analysis, quantitative NMR (qNMR) uses nearly universal detection and provides a versatile and orthogonal means of purity evaluation. Absolute qNMR with flexible calibration captures analytes that frequently escape detection (water, sorbents). Widely accepted structural NMR workflows require minimal or no adjustments to become practical (1)H qNMR (qHNMR) procedures with simultaneous qualitative and (absolute) quantitative capability. This study reviews underlying concepts, provides a framework for standard qHNMR purity assays, and shows how adequate accuracy and precision are achieved for the intended use of the material.
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IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo.
Nature
PUBLISHED: 09-30-2014
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TP53 is commonly altered in human cancer, and Tp53 reactivation suppresses tumours in vivo in mice (TP53 and Tp53 are also known as p53). This strategy has proven difficult to implement therapeutically, and here we examine an alternative strategy by manipulating the p53 family members, Tp63 and Tp73 (also known as p63 and p73, respectively). The acidic transactivation-domain-bearing (TA) isoforms of p63 and p73 structurally and functionally resemble p53, whereas the ?N isoforms (lacking the acidic transactivation domain) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53, TAp63 and TAp73 to inhibit their tumour-suppressive functions. The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy, thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway. Here we show that deletion of the ?N isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregulation of IAPP, the gene that encodes amylin, a 37-amino-acid peptide co-secreted with insulin by the ? cells of the pancreas. We found that IAPP is causally involved in this tumour regression and that amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes, caused rapid tumour regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers.
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Lack of Impact of Mild Obstructive Sleep Apnea on Sleepiness, Mood and Quality of Life.
Southwest J Pulm Crit Care
PUBLISHED: 09-19-2014
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Obstructive sleep apnea (OSA) is associated with sleepiness, depression and reduced quality of life. However, it is unclear whether mild OSA has these negative impacts. Using data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), this study determined whether participants with mild OSA had greater sleepiness, more depressive symptoms and poorer quality of life in comparison to those without OSA.
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Physiology of Sedentary Behavior and Its Relationship to Health Outcomes.
Med Sci Sports Exerc
PUBLISHED: 09-16-2014
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This paper reports on the findings and recommendations of the "Physiology of Sedentary Behavior and its Relationship to Health Outcomes" group, a part of a larger workshop entitled Sedentary Behavior: Identifying Research Priorities sponsored by the National Heart, and Lung and Blood Institute and the National Institute on Aging, which aimed to establish sedentary behavior research priorities.
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A randomized controlled trial of mindfulness meditation for chronic insomnia.
Sleep
PUBLISHED: 09-01-2014
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To evaluate the efficacy of mindfulness meditation for the treatment of chronic insomnia.
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Antibody-mediated immune suppression of erythrocyte alloimmunization can occur independently from red cell clearance or epitope masking in a murine model.
J. Immunol.
PUBLISHED: 08-13-2014
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Anti-D can prevent immunization to the RhD Ag on RBCs, a phenomenon commonly termed Ab-mediated immune suppression (AMIS). The most accepted theory to explain this effect has been the rapid clearance of RBCs. In mouse models using SRBC, these xenogeneic cells are always rapidly cleared even without Ab, and involvement of epitope masking of the SRBC Ags by the AMIS-inducing Ab (anti-SRBC) has been suggested. To address these hypotheses, we immunized mice with murine transgenic RBCs expressing the HOD Ag (hen egg lysozyme [HEL], in sequence with ovalbumin, and the human Duffy transmembrane protein) in the presence of polyclonal Abs or mAbs to the HOD molecule. The isotype, specificity, and ability to induce AMIS of these Abs were compared with accelerated clearance as well as steric hindrance of the HOD Ag. Mice made IgM and IgG reactive with the HEL portion of the molecule only. All six of the mAbs could inhibit the response. The HEL-specific Abs (4B7, IgG1; GD7, IgG2b; 2F4, IgG1) did not accelerate clearance of the HOD-RBCs and displayed partial epitope masking. The Duffy-specific Abs (MIMA 29, IgG2a; CBC-512, IgG1; K6, IgG1) all caused rapid clearance of HOD RBCs without steric hindrance. To our knowledge, this is the first demonstration of AMIS to erythrocytes in an all-murine model and shows that AMIS can occur in the absence of RBC clearance or epitope masking. The AMIS effect was also independent of IgG isotype and epitope specificity of the AMIS-inducing Ab.
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Home Circadian Phase Assessments with Measures of Compliance Yield Accurate Dim Light Melatonin Onsets.
Sleep
PUBLISHED: 08-06-2014
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There is a need for the accurate assessment of circadian phase outside of the clinic/laboratory, particularly with the gold standard dim light melatonin onset (DLMO). We tested a novel kit designed to assist in saliva sampling at home for later determination of the DLMO. The home kit includes objective measures of compliance to the requirements for dim light and half-hourly saliva sampling.
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Notes from the field: Outbreak of pertussis in a school and religious community averse to health care and vaccinations--columbia County, Florida, 2013.
MMWR Morb. Mortal. Wkly. Rep.
PUBLISHED: 08-01-2014
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On August 30, 2013, the Florida Department of Health in Columbia County was notified of a Bordetella pertussis laboratory-positive unimmunized child attending a local charter school (316 students from pre-K through 8th grade) in a large religious community averse to health care and vaccinations. Kindergarten immunization records showed that only five (15%) of 34 students were fully immunized with pertussis-antigen-containing vaccines. In seventh grade, only one (5%) of 22 students was fully immunized with pertussis-antigen-containing vaccines. Of the children who were not fully immunized in these two grades, 84% had religious exemptions.
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Effect of dietary adherence on the body weight plateau: a mathematical model incorporating intermittent compliance with energy intake prescription.
Am. J. Clin. Nutr.
PUBLISHED: 07-30-2014
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Clinical weight loss in individuals typically stabilizes at 6 mo. However, validated models of dynamic energy balance have consistently shown weight plateaus between 1 and 2 y. The cause for this discrepancy is unclear.
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Do inflammatory pathways drive melanomagenesis?
Exp. Dermatol.
PUBLISHED: 07-13-2014
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Inflammatory pathways serve to protect the host and promote tissue healing/repair; however, over-activation or dysregulation can be pathological with unintended consequences including malignant progression. A correlation between inflammation and cancer has been well established, and anti-inflammatory medications have been shown to be chemopreventive in certain malignancies. Data are now becoming available that outline an inflammatory pathway that may have a critical role in melanomagenesis. ATP-regulated membrane channels/receptors P2X7 and PANX1 have been directly implicated in melanoma tumor growth. Among other potential effects, opening of the P2X7/PANX1 channel results in activation of the NALP3 inflammasome, which in turn leads to caspase-1 activation and increased levels of activated IL-1?. Elevated levels of caspase-1 and IL-1? have been correlated with melanoma progression, and inhibitors of the inflammasome, caspase and IL-1? activity have all been shown to inhibit melanoma growth. Among many other potential actions, IL-1? increases cyclooxygenase-2 expression leading to local increases in inflammatory mediators such as prostaglandin E2 (PGE2). Anti-inflammatory medications targeting the end of this pathway have had positive results for certain cancers but overall remain mixed for melanoma. A better understanding of the pathways and appropriate intervention points may help direct future therapies. In this viewpoint, we will review data and attempt to model an inflammatory pathway that may be critical for melanomagenesis and propose future directions for exploration.
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Reducing RIP140 Expression in Macrophage Alters ATM Infiltration, Facilitates White Adipose Tissue Browning, and Prevents High-Fat Diet-Induced Insulin Resistance.
Diabetes
PUBLISHED: 06-26-2014
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Adipose tissue macrophage (ATM) recruitment and activation play a critical role in obesity-induced inflammation and insulin resistance (IR). The mechanism regulating ATM activation and infiltration remains unclear. In this study, we found receptor interacting protein 140 (RIP140) can regulate the dynamics of ATM that contribute to adipose tissue remodeling. A high-fat diet (HFD) elevates RIP140 expression in macrophages. We generated mice with RIP140 knockdown in macrophages using transgenic and bone marrow transplantation procedures to blunt HFD-induced elevation in RIP140. We detected significant white adipose tissue (WAT) browning and improved systemic insulin sensitivity in these mice, particularly under an HFD feeding. These mice have decreased circulating monocyte population and altered ATM profile in WAT (a dramatic reduction in inflammatory classically activated macrophages [M1] and expansion in alternatively activated macrophages [M2]), which could improve HFD-induced IR. These studies suggest that reducing RIP140 expression in monocytes/macrophages can be a new therapeutic strategy in treating HFD-induced and inflammation-related diseases.
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Essential parameters for structural analysis and dereplication by (1)H NMR spectroscopy.
J. Nat. Prod.
PUBLISHED: 06-04-2014
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The present study demonstrates the importance of adequate precision when reporting the ? and J parameters of frequency domain (1)H NMR (HNMR) data. Using a variety of structural classes (terpenoids, phenolics, alkaloids) from different taxa (plants, cyanobacteria), this study develops rationales that explain the importance of enhanced precision in NMR spectroscopic analysis and rationalizes the need for reporting ?? and ?J values at the 0.1-1 ppb and 10 mHz level, respectively. Spectral simulations paired with iteration are shown to be essential tools for complete spectral interpretation, adequate precision, and unambiguous HNMR-driven dereplication and metabolomic analysis. The broader applicability of the recommendation relates to the physicochemical properties of hydrogen ((1)H) and its ubiquity in organic molecules, making HNMR spectra an integral component of structure elucidation and verification. Regardless of origin or molecular weight, the HNMR spectrum of a compound can be very complex and encode a wealth of structural information that is often obscured by limited spectral dispersion and the occurrence of higher order effects. This altogether limits spectral interpretation, confines decoding of the underlying spin parameters, and explains the major challenge associated with the translation of HNMR spectra into tabulated information. On the other hand, the reproducibility of the spectral data set of any (new) chemical entity is essential for its structure elucidation and subsequent dereplication. Handling and documenting HNMR data with adequate precision is critical for establishing unequivocal links between chemical structure, analytical data, metabolomes, and biological activity. Using the full potential of HNMR spectra will facilitate the general reproducibility for future studies of bioactive chemicals, especially of compounds obtained from the diversity of terrestrial and marine organisms.
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Melanoma's high C>T mutation rate: is deamination playing a role?
Exp. Dermatol.
PUBLISHED: 05-08-2014
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The majority of melanoma mutations are C>T transitions, and most bear UV signatures. However, other process may contribute to the high C>T mutation rate. Okura et al., have demonstrated immunohistochemical evidence of deaminating enzymes, activation-induced cytidine deaminase (AID) and apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3B (APOBEC3B) in melanoma. Both have been implicated in cancer. While further validation is necessary, these findings warrant consideration of a role for deamination in melanomagenesis. Deamination primarily drives C>T transitions. Compared with trunk/extremity melanomas, acral melanomas display a significantly higher percentage of 'spontaneous' and 'AID' mutation signature events suggesting deamination may be particularly important in this subgroup.
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Using sit-stand workstations to decrease sedentary time in office workers: a randomized crossover trial.
Int J Environ Res Public Health
PUBLISHED: 04-11-2014
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This study was conducted to determine whether installation of sit-stand desks (SSDs) could lead to decreased sitting time during the workday among sedentary office workers.
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Dark homogeneous streak dermoscopic pattern correlating with specific KIT mutations in melanoma.
JAMA Dermatol
PUBLISHED: 04-04-2014
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Mutations driving melanoma growth have diagnostic, prognostic, and therapeutic implications. Traditional classification systems do not correlate optimally with underlying melanoma growth-promoting mutations. Our objective was to determine whether unique dermoscopic growth patterns directly correlate with driving mutations.
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Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial.
Lancet Neurol
PUBLISHED: 03-27-2014
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Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment.
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2D NMR barcoding and differential analysis of complex mixtures for chemical identification: the Actaea triterpenes.
Anal. Chem.
PUBLISHED: 03-27-2014
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The interpretation of NMR spectroscopic information for structure elucidation involves decoding of complex resonance patterns that contain valuable molecular information (? and J), which is not readily accessible otherwise. We introduce a new concept of 2D-NMR barcoding that uses clusters of fingerprint signals and their spatial relationships in the ?-? coordinate space to facilitate the chemical identification of complex mixtures. Similar to widely used general barcoding technology, the structural information of individual compounds is encoded as a specifics pattern of their C,H correlation signals. Software-based recognition of these patterns enables the structural identification of the compounds and their discrimination in mixtures. Using the triterpenes from various Actaea (syn. Cimicifuga) species as a test case, heteronuclear multiple-bond correlation (HMBC) barcodes were generated on the basis of their structural subtypes from a statistical investigation of their ?H and ?C data in the literature. These reference barcodes allowed in silico identification of known triterpenes in enriched fractions obtained from an extract of A. racemosa (black cohosh). After dereplication, a differential analysis of heteronuclear single-quantum correlation (HSQC) spectra even allowed for the discovery of a new triterpene. The 2D barcoding concept has potential application in a natural product discovery project, allowing for the rapid dereplication of known compounds and as a tool in the search for structural novelty within compound classes with established barcodes.
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Tumor lysing genetically engineered T cells loaded with multi-modal imaging agents.
Sci Rep
PUBLISHED: 03-04-2014
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Genetically-modified T cells expressing chimeric antigen receptors (CAR) exert anti-tumor effect by identifying tumor-associated antigen (TAA), independent of major histocompatibility complex. For maximal efficacy and safety of adoptively transferred cells, imaging their biodistribution is critical. This will determine if cells home to the tumor and assist in moderating cell dose. Here, T cells are modified to express CAR. An efficient, non-toxic process with potential for cGMP compliance is developed for loading high cell number with multi-modal (PET-MRI) contrast agents (Super Paramagnetic Iron Oxide Nanoparticles - Copper-64; SPION-(64)Cu). This can now be potentially used for (64)Cu-based whole-body PET to detect T cell accumulation region with high-sensitivity, followed by SPION-based MRI of these regions for high-resolution anatomically correlated images of T cells. CD19-specific-CAR(+)SPION(pos) T cells effectively target in vitro CD19(+) lymphoma.
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How, and from which cell sources, do nevi really develop?
Exp. Dermatol.
PUBLISHED: 02-27-2014
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Melanocytic neoplasms are a diverse group of benign and malignant tumors with variable clinical features. While some models still promote the epidermal melanocyte as the origin of melanocytic neoplasms, clinical findings are inconsistent with this theory for the majority of tumors. Despite advances in naevus and melanoma biology, the location and differentiation status of the cell of origin remains undefined. Germ line genetics, biological state and cellular location of the mutated cell, as well as local environmental factors all likely play a role in the development of melanocytic neoplasms. Herein, we will review potential models for melanocytic neoplasia and discuss research challenges and opportunities.
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Feasibility of multianimal hyperpolarized (13) C MRS.
Magn Reson Med
PUBLISHED: 02-19-2014
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There is great potential for real-time investigation of metabolism with MRS and hyperpolarized (HP) (13) C agents. Unfortunately, HP technology has high associated costs and efficiency limitations that may constrain in vivo studies involving many animals. To improve the throughput of preclinical investigations, we evaluate the feasibility of performing HP MRS on multiple animals simultaneously.
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Universal quantitative NMR analysis of complex natural samples.
Curr. Opin. Biotechnol.
PUBLISHED: 02-04-2014
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Nuclear Magnetic Resonance (NMR) is a universal and quantitative analytical technique. Being a unique structural tool, NMR also competes with metrological techniques for purity determination and reference material analysis. In pharmaceutical research, applications of quantitative NMR (qNMR) cover mostly the identification and quantification of drug and biological metabolites. Offering an unbiased view of the sample composition, and the possibility to simultaneously quantify multiple compounds, qNMR has become the method of choice for metabolomic studies and quality control of complex natural samples such as foods, plants or herbal remedies, and biofluids. In this regard, NMR-based metabolomic studies, dedicated to both the characterization of herbal remedies and clinical diagnosis, have increased considerably.
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An ERK/Cdk5 axis controls the diabetogenic actions of PPAR?
Nature
PUBLISHED: 01-16-2014
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Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPAR? (peroxisome proliferator-activated receptor ?) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPAR?, such as the thiazolidinediones and PPAR? partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPAR? phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPAR? phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPAR? in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPAR? function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.
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Quantification of a botanical negative marker without an identical standard: ginkgotoxin in Ginkgo biloba.
J. Nat. Prod.
PUBLISHED: 01-16-2014
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A new strategy for the analysis of natural products uses a combination of quantitative (1)H NMR (qHNMR) and adsorbent-free countercurrent separation (CS) methodology to establish a quantification method for ginkgotoxin (4'-O-methylpyridoxine) in Ginkgo biloba preparations. The target analyte was concentrated in a one-step CS process using the ChMWat +2 solvent system (CHCl3-MeOH-H2O, 10:5:5) and subsequently assayed by qHNMR. While commercial G. biloba seeds contained 59 ?g of ginkgotoxin per seed, the compound was below the limit of detection (9 ppm) in a typical leaf extract. Due to the enrichment potential and loss-free operation of CS, the combination of CS and qHNMR is a generally suitable approach for threshold assays aimed at quantifying target compounds such as botanical negative markers at the low ppm level. As the proof of principle is demonstrated for relatively small CS capacities (20 mL, 1:40 loading) and modest NMR sensitivity (n = 16, 400 MHz, 5 mm RT probe), the approach can be adapted to quantification at the ppb level. The procedure enables the quantification of a botanical negative marker in the absence of identical reference material, which otherwise is a prerequisite for LC-based assays.
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The effect of two benzodiazepine receptor agonist hypnotics on sleep-dependent memory consolidation.
J Clin Sleep Med
PUBLISHED: 01-16-2014
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Numerous studies have demonstrated that sleep promotes memory consolidation, but there is little research on the effect of hypnotics on sleep-dependent memory consolidation. We compared bedtime administration of zolpidem-ER 12.5 mg (6- to 8-h duration of action), middle-of-the-night administration of zaleplon 10 mg (3- to 4-h duration of action), and placebo to examine the effect of different durations of hypnotic drug exposure on memory consolidation during sleep.
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Galloyl moieties enhance the dentin biomodification potential of plant-derived catechins.
Acta Biomater
PUBLISHED: 01-10-2014
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Proanthocyanidin-rich plant-derived agents have been shown to enhance dentin biomechanical properties and resistance to collagenase degradation. This study systematically investigated the interaction of chemically well-defined monomeric catechins with dentin extracellular matrix components by evaluating dentin mechanical properties as well as activities of matrix metalloproteinases (MMPs) and cysteine-cathepsins (CTs). Demineralized dentin beams (n=15) were incubated for 1h with 0.65% (+)-catechin (C), (-)-catechin gallate (CG), (-)-gallocatechin gallate (GCG), (-)-epicatechin (EC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin (EGC) and (-)-epigallocatechin-3-gallate (EGCG). The modulus of elasticity (E) and the fold increase in E were determined by comparing specimens at baseline and after treatment. Biodegradation rates were assessed by differences in percentage of dry mass before and after incubation with bacterial collagenase. The inhibition of MMP-9 and CT-B by 0.65, 0.065 and 0.0065% of each catechin was determined using fluorimetric proteolytic assay kits. All monomeric catechins led to a significant increase in E. EGCG showed the highest fold increase in E, followed by ECG, CG and GCG. EGCG, ECG, GCG and CG significantly lowered biodegradation rates and inhibited both MMP-9 and CT-B at a concentration of 0.65%. Overall, the 3-O-galloylated monomeric catechins are clearly more potent than their non-galloylated analogues in improving dentin mechanical properties, stabilizing collagen against proteolytic degradation, and inhibiting the activity of MMPs and CTs. The results indicate that galloylation is a key pharmacophore in the monomeric and likely also in the oligomeric proanthocyanidins that exhibit high cross-linking potential for dentin extracellular matrix.
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SMART DOCS: A New Patient-Centered Outcomes and Coordinated-Care Management Approach for the Future Practice of Sleep Medicine.
Sleep
PUBLISHED: 01-07-2014
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The practice of medicine is currently undergoing a transformation to become more efficient, cost-effective, and patient centered in its delivery of care. The aim of this article is to stimulate discussion within the sleep medicine community in addressing these needs by our approach as well as other approaches to sleep medicine care. The primary goals of the Sustainable Methods, Algorithms, and Research Tools for Delivering Optimal Care Study (SMART DOCS) are: (1) to introduce a new Patient-Centered Outcomes and Coordinated-Care Management (PCCM) approach for the future practice of sleep medicine, and (2) to test the PCCM approach against a Conventional Diagnostic and Treatment Outpatient Medical Care (CONV) approach in a randomized, two-arm, single-center, long-term, comparative effectiveness trial. The PCCM approach is integrated into a novel outpatient care delivery model for patients with sleep disorders that includes the latest technology, allowing providers to obtain more accurate and rapid diagnoses and to make evidence-based treatment recommendations, while simultaneously enabling patients to have access to personalized medical information and reports regarding their diagnosis and treatment so that they can make more informed health care decisions. Additionally, the PCCM approach facilitates better communication between patients, referring primary care physicians, sleep specialists, and allied health professionals so that providers can better assist patients in achieving their preferred outcomes. A total of 1,506 patients 18 y or older will be randomized to either the PCCM or CONV approach and will be followed for at least 1 y with endpoints of improved health care performance, better health, and cost control.
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"Go4Life" exercise counseling, accelerometer feedback, and activity levels in older people.
Arch Gerontol Geriatr
PUBLISHED: 01-04-2014
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Older people are more sedentary than other age groups. We sought to determine if providing an accelerometer with feedback about activity and counseling older subjects using Go4Life educational material would increase activity levels. Participants were recruited from independent living areas within assisted living facilities and the general public in the Rochester, MN area. 49 persons aged 65-95 (79.5±7.0 years) who were ambulatory but sedentary and overweight participated in this randomized controlled crossover trial for one year. After a baseline period of 2 weeks, group 1 received an accelerometer and counseling using Go4Life educational material (www.Go4Life.nia.nih.gov) for 24 weeks and accelerometer alone for the next 24 weeks. Group 2 had no intervention for the first 24 weeks and then received an accelerometer and Go4Life based counseling for 24 weeks. There were no significant baseline differences between the two groups. The intervention was not associated with a significant change in activity, body weight, % body fat, or blood parameters (p>0.05). Older (80-93) subjects were less active than younger (65-79) subjects (p=0.003). Over the course of the 48 week study, an increase in activity level was associated with a decline in % body fat (p=0.008). Increasing activity levels benefits older patients. However, providing an accelerometer and a Go4Life based exercise counseling program did not result in a 15% improvement in activity levels in this elderly population. Alternate approaches to exercise counseling may be needed in elderly people of this age range.
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Frequency and Fitness Consequences of Bacteriophage ?6 Host Range Mutations.
PLoS ONE
PUBLISHED: 01-01-2014
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Viruses readily mutate and gain the ability to infect novel hosts, but few data are available regarding the number of possible host range-expanding mutations allowing infection of any given novel host, and the fitness consequences of these mutations on original and novel hosts. To gain insight into the process of host range expansion, we isolated and sequenced 69 independent mutants of the dsRNA bacteriophage ?6 able to infect the novel host, Pseudomonas pseudoalcaligenes. In total, we found at least 17 unique suites of mutations among these 69 mutants. We assayed fitness for 13 of 17 mutant genotypes on P. pseudoalcaligenes and the standard laboratory host, P. phaseolicola. Mutants exhibited significantly lower fitnesses on P. pseudoalcaligenes compared to P. phaseolicola. Furthermore, 12 of the 13 assayed mutants showed reduced fitness on P. phaseolicola compared to wildtype ?6, confirming the prevalence of antagonistic pleiotropy during host range expansion. Further experiments revealed that the mechanistic basis of these fitness differences was likely variation in host attachment ability. In addition, using computational protein modeling, we show that host-range expanding mutations occurred in hotspots on the surface of the phage's host attachment protein opposite a putative hydrophobic anchoring domain.
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Low Message Sensation Health Promotion Videos Are Better Remembered and Activate Areas of the Brain Associated with Memory Encoding.
PLoS ONE
PUBLISHED: 01-01-2014
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Greater sensory stimulation in advertising has been postulated to facilitate attention and persuasion. For this reason, video ads promoting health behaviors are often designed to be high in "message sensation value" (MSV), a standardized measure of sensory intensity of the audiovisual and content features of an ad. However, our previous functional Magnetic Resonance Imaging (fMRI) study showed that low MSV ads were better remembered and produced more prefrontal and temporal and less occipital cortex activation, suggesting that high MSV may divert cognitive resources from processing ad content. The present study aimed to determine whether these findings from anti-smoking ads generalize to other public health topics, such as safe sex. Thirty-nine healthy adults viewed high- and low MSV ads promoting safer sex through condom use, during an fMRI session. Recognition memory of the ads was tested immediately and 3 weeks after the session. We found that low MSV condom ads were better remembered than the high MSV ads at both time points and replicated the fMRI patterns previously reported for the anti-smoking ads. Occipital and superior temporal activation was negatively related to the attitudes favoring condom use (see Condom Attitudes Scale, Methods and Materials section). Psychophysiological interaction (PPI) analysis of the relation between occipital and fronto-temporal (middle temporal and inferior frontal gyri) cortices revealed weaker negative interactions between occipital and fronto-temporal cortices during viewing of the low MSV that high MSV ads. These findings confirm that the low MSV video health messages are better remembered than the high MSV messages and that this effect generalizes across public health domains. The greater engagement of the prefrontal and fronto-temporal cortices by low MSV ads and the greater occipital activation by high MSV ads suggest that that the "attention-grabbing" high MSV format could impede the learning and retention of public health messages.
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Complex Changes in von Willebrand Factor-Associated Parameters Are Acquired during Uncomplicated Pregnancy.
PLoS ONE
PUBLISHED: 01-01-2014
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The coagulation protein von Willebrand Factor (VWF) is known to be elevated in pregnancy. However, the timing and nature of changes in VWF and associated parameters throughout pregnancy are not well understood.
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Evaluation of hyperpolarized [1-¹³C]-pyruvate by magnetic resonance to detect ionizing radiation effects in real time.
PLoS ONE
PUBLISHED: 01-01-2014
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Ionizing radiation (IR) cytotoxicity is primarily mediated through reactive oxygen species (ROS). Since tumor cells neutralize ROS by utilizing reducing equivalents, we hypothesized that measurements of reducing potential using real-time hyperpolarized (HP) magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) can serve as a surrogate marker of IR induced ROS. This hypothesis was tested in a pre-clinical model of anaplastic thyroid carcinoma (ATC), an aggressive head and neck malignancy. Human ATC cell lines were utilized to test IR effects on ROS and reducing potential in vitro and [1-¹³C] pyruvate HP-MRS/MRSI imaging of ATC orthotopic xenografts was used to study in vivo effects of IR. IR increased ATC intra-cellular ROS levels resulting in a corresponding decrease in reducing equivalent levels. Exogenous manipulation of cellular ROS and reducing equivalent levels altered ATC radiosensitivity in a predictable manner. Irradiation of ATC xenografts resulted in an acute drop in reducing potential measured using HP-MRS, reflecting the shunting of reducing equivalents towards ROS neutralization. Residual tumor tissue post irradiation demonstrated heterogeneous viability. We have adapted HP-MRS/MRSI to non-invasively measure IR mediated changes in tumor reducing potential in real time. Continued development of this technology could facilitate the development of an adaptive clinical algorithm based on real-time adjustments in IR dose and dose mapping.
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Altered regulation of energy homeostasis in older rats in response to thyroid hormone administration.
FASEB J.
PUBLISHED: 12-16-2013
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Hyperthyroidism causes increased energy intake and expenditure, although anorexia and higher weight loss have been reported in elderly individuals with hyperthyroidism. To determine the effect of age on energy homeostasis in response to experimental hyperthyroidism, we administered 200 ?g tri-iodothyronine (T3) in 7- and 27-mo-old rats for 14 d. T3 increased energy expenditure (EE) in both the young and the old rats, although the old rats lost more weight (147 g) than the young rats (58 g) because of the discordant effect of T3 on food intake, with a 40% increase in the young rats, but a 40% decrease in the old ones. The increased food intake in the young rats corresponded with a T3-mediated increase in the appetite-regulating proteins agouti-related peptide, neuropeptide Y, and uncoupling protein 2 in the hypothalamus, but no increase occurred in the old rats. Evidence of mitochondrial biogenesis in response to T3 was similar in the soleus muscle and heart of the young and old animals, but less consistent in old plantaris muscle and liver. Despite the comparable increase in EE, T3s effect on mitochondrial function was modulated by age in a tissue-specific manner. We conclude that older rats lack compensatory mechanisms to increase caloric intake in response to a T3-induced increase in EE, demonstrating a detrimental effect of age on energy homeostasis.-Walrand, S., Short, K. R., Heemstra, L. A., Novak, C. M., Levine, J. A., Coenen-Schimke, J. M., Nair, K. S. Altered regulation of energy homeostasis in older rats in response to thyroid hormone administration.
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Hytramycins V and I, Anti-Mycobacterium tuberculosis Hexapeptides from a Streptomyces hygroscopicus Strain.
J. Nat. Prod.
PUBLISHED: 11-13-2013
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Thirty-five thousand actinomycete extracts were screened for anti-Mycobacterium tuberculosis (M. tb) activity, followed by C18 cartridge fractionation of 37 prioritized extracts. Based on MICs against replicating and nonreplicating M. tb, and IC50 values against Vero cells to generate selectivity indices, seven fractions from seven different strains were selected for further examination. When cultured in G.S.S. media and extracted with ethyl acetate, the Streptomyces hygroscopicus strain ECUM 14046 yielded an extract with promising anti-M. tb activity and a well-defined chromatographic profile. Fractionation by preparative HPLC and subsequent structure elucidation of two active fractions using 1D- and 2D-NMR and MS methods revealed the presence of two cyclohexapeptides, hytramycins V and I, each containing three unusual piperazic acid moieties. The use of (1)H iterative full spin analysis (HiFSA) on both hytramycins confirmed that quantum mechanics-simulated spectra match the experimental data, and all JH,H and ?H values are consistent with the proposed structures. The absolute configuration of each amino acid moiety was determined by Marfeys method. The MICs against replicating and, more importantly, nonreplicating M. tb fall into the range of some existing second-line anti-TB drugs, such as streptomycin and capreomycin, respectively. The activities were maintained against M. tb strains that represent the major global clades, as well as H37Rv-isogenic strains that are resistant to individual clinical anti-TB drugs.
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Impact of treatment with continuous positive airway pressure (CPAP) on weight in obstructive sleep apnea.
J Clin Sleep Med
PUBLISHED: 10-16-2013
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To determine the impact of continuous positive airway pressure (CPAP) on weight change in persons with obstructive sleep apnea (OSA).
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Chlorinated coumarins from the polypore mushroom Fomitopsis officinalis and their activity against Mycobacterium tuberculosis.
J. Nat. Prod.
PUBLISHED: 10-02-2013
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An EtOH extract of the polypore mushroom Fomitopsis officinalis afforded two new naturally occurring chlorinated coumarins, which were identified as the previously synthesized compounds 6-chloro-4-phenyl-2H-chromen-2-one (1) and ethyl 6-chloro-2-oxo-4-phenyl-2H-chromen-3-carboxylate (2). The structures of the two isolates were deduced by ab initio spectroscopic methods and confirmed by chemical synthesis. In addition, an analogue of each was synthesized as 7-chloro-4-phenyl-2H-chromen-2-one (3) and ethyl 7-chloro-2-oxo-4-phenyl-2H-chromen-3-carboxylate (4). All four compounds were characterized physicochemically, and their antimicrobial activity profiles revealed a narrow spectrum of activity with lowest MICs against the Mycobacterium tuberculosis complex.
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Proton fingerprints portray molecular structures: enhanced description of the 1H NMR spectra of small molecules.
J. Org. Chem.
PUBLISHED: 09-06-2013
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The characteristic signals observed in NMR spectra encode essential information on the structure of small molecules. However, extracting all of this information from complex signal patterns is not trivial. This report demonstrates how computer-aided spectral analysis enables the complete interpretation of 1D (1)H NMR data. The effectiveness of this approach is illustrated with a set of organic molecules, for which replicas of their (1)H NMR spectra were generated. The potential impact of this methodology on organic chemistry research is discussed.
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Physical activity measured by physical activity monitoring system correlates with glucose trends reconstructed from continuous glucose monitoring.
Diabetes Technol. Ther.
PUBLISHED: 08-14-2013
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In type 1 diabetes mellitus (T1DM), physical activity (PA) lowers the risk of cardiovascular complications but hinders the achievement of optimal glycemic control, transiently boosting insulin action and increasing hypoglycemia risk. Quantitative investigation of relationships between PA-related signals and glucose dynamics, tracked using, for example, continuous glucose monitoring (CGM) sensors, have been barely explored.
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Methane and nitrous oxide emissions from a subtropical estuary (the Brisbane River estuary, Australia).
Sci. Total Environ.
PUBLISHED: 08-13-2013
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Methane (CH4) and nitrous oxide (N2O) are two key greenhouse gases. Their global atmospheric budgeting is, however, flout with challenges partly due to lack of adequate field studies determining the source strengths. Knowledge and data limitations exist for subtropical and tropical regions especially in the southern latitudes. Surface water methane and nitrous oxide concentrations were measured in a subtropical estuarine system in the southern latitudes in an extensive field study from 2010 to 2012 and water-air fluxes estimated using models considering the effects of both wind and flow induced turbulence. The estuary was found to be a strong net source of both CH4 and N2O all-year-round. Dissolved N2O concentrations ranged between 9.1±0.4 to 45.3±1.3nM or 135 to 435% of atmospheric saturation level, while CH4 concentrations varied between 31.1±3.7 to 578.4±58.8nM or 1210 to 26,430% of atmospheric saturation level. These results compare well with measurements from tropical estuarine systems. There was strong spatial variability with both CH4 and N2O concentrations increasing upstream the estuary. Strong temporal variability was also observed but there were no clear seasonal patterns. The degree of N2O saturation significantly increased with NOx concentrations (r(2)=0.55). The estimated water-air fluxes varied between 0.1 and 3.4mgN2Om(-2)d(-1) and 0.3 to 27.9mgCH4m(-2)d(-1). Total emissions (CO2-e) were N2O (64%) dominated, highlighting the need for reduced nitrogen inputs into the estuary. Choice of the model(s) for estimation of the gas transfer velocity had a big bearing on the estimated total emissions.
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Comparison of physical activity sensors and heart rate monitoring for real-time activity detection in type 1 diabetes and control subjects.
Diabetes Technol. Ther.
PUBLISHED: 08-12-2013
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Currently, patients with type 1 diabetes decide on the amount of insulin to administer based on several factors, including current plasma glucose value, expected meal input, and physical activity (PA). One future therapeutic modality for patients with type 1 diabetes is the artificial endocrine pancreas (AEP). Incorporation of PA could enhance the efficacy of AEP significantly. We compared the main technologies used for PA quantitation.
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Radial spectroscopic MRI of hyperpolarized [1-(13) C] pyruvate at 7 tesla.
Magn Reson Med
PUBLISHED: 07-09-2013
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The transient and nonrenewable signal from hyperpolarized metabolites necessitates extensive sequence optimization for encoding spatial, spectral, and dynamic information. In this work, we evaluate the utility of radial single-timepoint and cumulative spectroscopic MRI of hyperpolarized [1-(13) C] pyruvate and its metabolic products at 7 Tesla (T).
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Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity.
Sci Transl Med
PUBLISHED: 05-31-2013
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Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor used in the treatment of human malignancies. A substantial number of sunitinib-treated patients develop cardiac dysfunction, but the mechanism of sunitinib-induced cardiotoxicity is poorly understood. We show that mice treated with sunitinib develop cardiac and coronary microvascular dysfunction and exhibit an impaired cardiac response to stress. The physiological changes caused by treatment with sunitinib are accompanied by a substantial depletion of coronary microvascular pericytes. Pericytes are a cell type that is dependent on intact platelet-derived growth factor receptor (PDGFR) signaling but whose role in the heart is poorly defined. Sunitinib-induced pericyte depletion and coronary microvascular dysfunction are recapitulated by CP-673451, a structurally distinct PDGFR inhibitor, confirming the role of PDGFR in pericyte survival. Thalidomide, an anticancer agent that is known to exert beneficial effects on pericyte survival and function, prevents sunitinib-induced pericyte cell death in vitro and prevents sunitinib-induced cardiotoxicity in vivo in a mouse model. Our findings suggest that pericytes are the primary cellular target of sunitinib-induced cardiotoxicity and reveal the pericyte as a cell type of concern in the regulation of coronary microvascular function. Furthermore, our data provide preliminary evidence that thalidomide may prevent cardiotoxicity in sunitinib-treated cancer patients.
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Orthogonal analytical methods for botanical standardization: Determination of green tea catechins by qNMR and LC-MS/MS.
J Pharm Biomed Anal
PUBLISHED: 05-02-2013
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The development of analytical methods for parallel characterization of multiple phytoconstituents is essential to advance the quality control of herbal products. While chemical standardization is commonly carried out by targeted analysis using gas or liquid chromatography-based methods, more universal approaches based on quantitative (1)H NMR (qHNMR) measurements are being used increasingly in the multi-targeted assessment of these complex mixtures. The present study describes the development of a 1D qHNMR-based method for simultaneous identification and quantification of green tea constituents. This approach utilizes computer-assisted (1)H iterative Full Spin Analysis (HiFSA) and enables rapid profiling of seven catechins in commercial green tea extracts. The qHNMR results were cross-validated against quantitative profiles obtained with an orthogonal LC-MS/MS method. The relative strengths and weaknesses of both approaches are discussed, with special emphasis on the role of identical reference standards in qualitative and quantitative analyses.
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Content matters: neuroimaging investigation of brain and behavioral impact of televised anti-tobacco public service announcements.
J. Neurosci.
PUBLISHED: 04-26-2013
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Televised public service announcements are video ads that are a key component of public health campaigns against smoking. Understanding the neurophysiological correlates of anti-tobacco ads is an important step toward novel objective methods of their evaluation and design. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the brain and behavioral effects of the interaction between content ("argument strength," AS) and format ("message sensation value," MSV) of anti-smoking ads in humans. Seventy-one nontreatment-seeking smokers viewed a sequence of 16 high or 16 low AS ads during an fMRI scan. Dependent variables were brain fMRI signal, the immediate recall of the ads, the immediate change in intentions to quit smoking, and the urine levels of a major nicotine metabolite cotinine at a 1 month follow-up. Whole-brain ANOVA revealed that AS and MSV interacted in the inferior frontal, inferior parietal, and fusiform gyri; the precuneus; and the dorsomedial prefrontal cortex (dMPFC). Regression analysis showed that the activation in the dMPFC predicted the urine cotinine levels 1 month later. These results characterize the key brain regions engaged in the processing of persuasive communications and suggest that brain fMRI response to anti-smoking ads could predict subsequent smoking severity in nontreatment-seeking smokers. Our findings demonstrate the importance of the quality of content for objective ad outcomes and suggest that fMRI investigation may aid the prerelease evaluation of televised public health ads.
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Lipidated steroid saponins from Dioscorea villosa (wild yam).
Fitoterapia
PUBLISHED: 04-09-2013
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Two groups of lipidated steroid saponins including seven new compounds (2, 3, 5, and 7-10) were isolated from the widely used botanical, wild yam (Dioscorea villosa), employing a fractionation protocol of metabolomic mining. This methodology recently led to the isolation of 14 diarylheptanoids from the same plant. Together with these lipidated steroid saponins, they establish additional new markers for D. villosa. The lipidation of steroids with analog long-chain fatty acids containing different degrees of unsaturation generates an entire series of compounds which are difficult to purify and analyze. The structures of the two series of lipidated steroid saponins (series A and B) were established by a combination of 1D and 2D NMR as well as GC-MS after chemical modification. Series A was determined to be a mixture of lipidated spirostanol glycosides (1-5), while series B (6-10) was proved to be a mixture of five lipidated clionasterol glucosides. The latter group represents the first derivatives of clionasterol to be found in D. villosa. The discovery of this specific structural type of aliphatic esters of steroid saponins expands the characterization of the secondary metabolome of D. villosa. It may also inspire biological studies which take into account the lipophilic character and significantly altered physiochemical characteristics of these otherwise relatively polar phytoconstituents.
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Potential role of meiosis proteins in melanoma chromosomal instability.
J Skin Cancer
PUBLISHED: 03-29-2013
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Melanomas demonstrate chromosomal instability (CIN). In fact, CIN can be used to differentiate melanoma from benign nevi. The exact molecular mechanisms that drive CIN in melanoma have yet to be fully elucidated. Cancer/testis antigens are a unique group of germ cell proteins that are found to be primarily expressed in melanoma as compared to benign nevi. The abnormal expression of these germ cell proteins, normally expected only in the testis and ovaries, in somatic cells may lead to interference with normal cellular pathways. Germ cell proteins that may be particularly critical in CIN are meiosis proteins. Here, we review pathways unique to meiosis with a focus on how the aberrant expression of meiosis proteins in normal mitotic cells "meiomitosis" could impact chromosomal instability in melanoma and other cancers.
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A confirmed Ehrlichia ewingii infection likely acquired through platelet transfusion.
Clin. Infect. Dis.
PUBLISHED: 03-19-2013
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Ehrlichiosis is a tick-borne disease that ranges in severity from asymptomatic infection to fatal sepsis. Ehrlichiosis acquired from transfusion of blood products has not been documented in the literature to date. A case of Ehrlichia ewingii infection likely transmitted by transfusion of leukoreduced platelets is described, and public health implications are discussed.
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The critical role of sleep spindles in hippocampal-dependent memory: a pharmacology study.
J. Neurosci.
PUBLISHED: 03-08-2013
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An important function of sleep is the consolidation of memories, and features of sleep, such as rapid eye movement (REM) or sleep spindles, have been shown to correlate with improvements in discrete memory domains. Because of the methodological difficulties in modulating sleep, however, a causal link between specific sleep features and human memory consolidation is lacking. Here, we experimentally manipulated specific sleep features during a daytime nap via direct pharmacological intervention. Using zolpidem (Ambien), a short-acting GABAA agonist hypnotic, we show increased sleep spindle density and decreased REM sleep compared with placebo and sodium oxybate (Xyrem). Naps with increased spindles produced significantly better verbal memory and significantly worse perceptual learning but did not affect motor learning. The experimental spindles were similar to control spindles in amplitude and frequency, suggesting that the experimental intervention enhanced normal sleep processes. Furthermore, using statistical methods, we demonstrate for the first time a critical role of spindles in human hippocampal memory performance. The gains in memory consolidation exceed sleep-alone or control conditions and demonstrate the potential for targeted, exceptional memory enhancement in healthy adults with pharmacologically modified sleep.
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HiFSA fingerprinting applied to isomers with near-identical NMR spectra: the silybin/isosilybin case.
J. Org. Chem.
PUBLISHED: 03-05-2013
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This study demonstrates how regio- and diastereo-isomers with near-identical NMR spectra can be distinguished and unambiguously assigned using quantum mechanical driven (1)H iterative Full Spin Analysis (HiFSA). The method is illustrated with four natural products, the flavonolignans silybin A, silybin B, isosilybin A, and isosilybin B, which exhibit extremely similar coupling patterns and chemical shift differences well below the commonly reported level of accuracy of 0.01 ppm. The HiFSA approach generated highly reproducible (1)H NMR fingerprints that enable distinction of all four isomers at (1)H frequencies from 300 to 900 MHz. Furthermore, it is demonstrated that the underlying numeric (1)H NMR profiles, combined with iterative computational analysis, allow parallel quantification of all four isomers, even in difficult to characterize reference materials and mixtures. The results shed new light on the historical challenges to the qualitative and quantitative analysis of these therapeutically relevant flavonolignans and open new opportunities to explore hidden diversity in the chemical space of organic molecules.
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Visualizing the prostate gland by MR imaging in young and old mice.
PLoS ONE
PUBLISHED: 03-01-2013
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Prostate imaging requires optimization in young and old mouse models. We tested which MR sequences and field strengths best depict the prostate gland in young and old mice; and, whether prostate MR signal, size, and architecture change with age.
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Diurnal pattern of insulin action in type 1 diabetes: implications for a closed-loop system.
Diabetes
PUBLISHED: 02-27-2013
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We recently demonstrated a diurnal pattern to insulin action (i.e., insulin sensitivity [SI]) in healthy individuals with higher SI at breakfast than at dinner. To determine whether such a pattern exists in type 1 diabetes, we studied 19 subjects with C-peptide-negative diabetes (HbA1c 7.1 ± 0.6%) on insulin pump therapy with normal gastric emptying. Identical mixed meals were ingested during breakfast, lunch, and dinner at 0700, 1300, and 1900 h in randomized Latin square of order on 3 consecutive days when measured daily physical activity was equal. The triple tracer technique enabled measurement of glucose fluxes. Insulin was administered according to the customary insulin:carbohydrate ratio for each participant. Although postprandial glucose excursions did not differ among meals, insulin concentration was higher (P < 0.01) and endogenous glucose production less suppressed (P < 0.049) at breakfast than at lunch. There were no differences in meal glucose appearance or in glucose disappearance between meals. Although there was no statistical difference (P = 0.34) in SI between meals in type 1 diabetic subjects, the diurnal pattern of SI taken across the three meals in its entirety differed (P = 0.016) from that of healthy subjects. Although the pattern in healthy subjects showed decreasing SI between breakfast and lunch, the reverse SI pattern was observed in type 1 diabetic subjects. The results suggest that in contrast to healthy subjects, SI diurnal pattern in type 1 diabetes is specific to the individual and cannot be extrapolated to the type 1 diabetic population as a whole, implying that artificial pancreas algorithms may need to be personalized.
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Treadmill desks: A 1-year prospective trial.
Obesity (Silver Spring)
PUBLISHED: 02-19-2013
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Sedentariness is associated with weight gain and obesity. A treadmill desk is the combination of a standing desk and a treadmill that allow employees to work while walking at low speed.
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Effects of experimental sleep restriction on caloric intake and activity energy expenditure.
Chest
PUBLISHED: 02-09-2013
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Epidemiologic studies link short sleep duration to obesity and weight gain. Insufficient sleep appears to alter circulating levels of the hormones leptin and ghrelin, which may promote appetite, although the effects of sleep restriction on caloric intake and energy expenditure are unclear. We sought to determine the effect of 8 days/8 nights of sleep restriction on caloric intake, activity energy expenditure, and circulating levels of leptin and ghrelin.
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A catalyzing phantom for reproducible dynamic conversion of hyperpolarized [1-¹³C]-pyruvate.
PLoS ONE
PUBLISHED: 01-01-2013
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In vivo real time spectroscopic imaging of hyperpolarized ¹³C labeled metabolites shows substantial promise for the assessment of physiological processes that were previously inaccessible. However, reliable and reproducible methods of measurement are necessary to maximize the effectiveness of imaging biomarkers that may one day guide personalized care for diseases such as cancer. Animal models of human disease serve as poor reference standards due to the complexity, heterogeneity, and transient nature of advancing disease. In this study, we describe the reproducible conversion of hyperpolarized [1-¹³C]-pyruvate to [1-¹³C]-lactate using a novel synthetic enzyme phantom system. The rate of reaction can be controlled and tuned to mimic normal or pathologic conditions of varying degree. Variations observed in the use of this phantom compare favorably against within-group variations observed in recent animal studies. This novel phantom system provides crucial capabilities as a reference standard for the optimization, comparison, and certification of quantitative imaging strategies for hyperpolarized tracers.
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The energy expenditure of an activity-promoting video game compared to sedentary video games and TV watching.
J. Pediatr. Endocrinol. Metab.
PUBLISHED: 12-08-2011
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In the present study we investigated the effect of television watching and the use of activity-promoting video games on energy expenditure in obese and lean children.
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Productivity of transcriptionists using a treadmill desk.
Work
PUBLISHED: 12-02-2011
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Time spent sitting increases all-cause mortality. Sedentary occupations are a major contributor to the obesity epidemic. A treadmill desk offers the potential to increase activity while working; however, it is important to make sure that productivity does not decline. The purpose of this study is to evaluate productivity while using a treadmill desk.
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Non-exercise physical activity in agricultural and urban people.
Urban Stud
PUBLISHED: 11-12-2011
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With evidence that urbanisation is associated with obesity, diabetes, hypertension and cardiovascular disease, this article compares daily physical activity between rural and urban dwellers. Specifically, it examines habitual daily activity levels, non-exercise activity thermogenesis (NEAT) and energy expenditure in agricultural and urban Jamaicans and urban North Americans. Ambulation was 60 per cent greater in rural Jamaicans than in the urban dwellers (4675 ± 2261 versus 2940 ± 1120 ambulation-attributed arbitrary units (AU)/day; P = 0.001). Levels of ambulation in lean urban Jamaicans were similar to those in lean urban North Americans, whereas obese urban dwellers walked less than their lean urban counterparts (2198 ± 516 versus 2793 ± 774 AU/day; P = 0.01). The data with respect to daily sitting mirrored the walking data; obese Americans sat for almost four hours more each day than rural Jamaicans (562 ± 78 versus 336 ± 68 minutes/day; P < 0.001). Urbanisation is associated with low levels of daily activity and NEAT.
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A Simple Model Predicting Individual Weight Change in Humans.
J Biol Dyn
PUBLISHED: 11-01-2011
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Excessive weight in adults is a national concern with over 2/3 of the US population deemed overweight. Because being overweight has been correlated to numerous diseases such as heart disease and type 2 diabetes, there is a need to understand mechanisms and predict outcomes of weight change and weight maintenance. A simple mathematical model that accurately predicts individual weight change offers opportunities to understand how individuals lose and gain weight and can be used to foster patient adherence to diets in clinical settings. For this purpose, we developed a one dimensional differential equation model of weight change based on the energy balance equation is paired to an algebraic relationship between fat free mass and fat mass derived from a large nationally representative sample of recently released data collected by the Centers for Disease Control. We validate the models ability to predict individual participants weight change by comparing model estimates of final weight data from two recent underfeeding studies and one overfeeding study. Mean absolute error and standard deviation between model predictions and observed measurements of final weights are less than 1.8 ± 1.3 kg for the underfeeding studies and 2.5 ± 1.6 kg for the overfeeding study. Comparison of the model predictions to other one dimensional models of weight change shows improvement in mean absolute error, standard deviation of mean absolute error, and group mean predictions. The maximum absolute individual error decreased by approximately 60% substantiating reliability in individual weight change predictions. The model provides a viable method for estimating individual weight change as a result of changes in intake and determining individual dietary adherence during weight change studies.
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Comparisons of energy intake and energy expenditure in overweight and obese women with and without binge eating disorder.
Obesity (Silver Spring)
PUBLISHED: 10-20-2011
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The purpose of this study was to determine whether there are differences in energy intake or energy expenditure that distinguish overweight/obese women with and without binge eating disorder (BED). Seventeen overweight/obese women with BED and 17 overweight/obese controls completed random 24-h dietary recall interviews, and had total daily energy expenditure (TDEE) assessed by the doubly labeled water (DLW) technique with concurrent food log data collection. Participants received two baseline dual-energy X-ray absorptiometry (DXA) scans and had basal metabolic rate (BMR) and thermic effect of food (TEF) measured using indirect calorimetry. Results indicated no between group differences in TDEE, BMR, and TEF. As in our previous work, according to dietary recall data, the BED group had significantly higher caloric intake on days when they had binge eating episodes than on days when they did not (3,255 vs. 2,343 kcal). There was no difference between BED nonbinge day intake and control group intake (2,233 vs. 2,140 kcal). Similar results were found for food log data. Dietary recall data indicated a trend toward higher average daily intake in the BED group (2,587 vs. 2,140 kcal). Furthermore, when comparing TDEE to dietary recall and food log data, both groups displayed significant under-reporting of caloric intake of similar magnitudes ranging from 20 to 33%. Predicted energy requirements estimated via the Harris-Benedict equation (HBE) underestimated measured TDEE by 23-24%. Our data suggest that increased energy intake reported by BED individuals is due to increased food consumption and not metabolic or under-reporting differences.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.