Early development of accelerated graft coronary artery disease: Risk factors and course

AbstractObjectives. This study assessed the time of first appearance of angiographic graft coronary artery disease in relation to clinical and laboratory variables and clinical events in heart transplant recipients.Background. Graft coronary artery disease is the main factor limiting long-term survival after heart transplantation, and it is important to understand its natural history.Methods. One hundred thirty-nine consecutive patients who developed angiographic coronary artery disease after heart transplantation were classified according to early (≤2 years) versus late (>2 years) posttransplantation initial detection of coronary artery disease. These subgroups were analyzed for differences in clinical and laboratory demographics, incidence of progression to ischemic events and incidence of antecedent cytomegalovirus infection.Results. The early-onset group (64 patients) had more rapid progression to ischemic events than the late-onset group (75 patients), with 59% of the late group and only 35% of the early group free from ischemic events by 5 years after initial detection (p = 0.02), but there were no significantly correlated clinical or laboratory predictors of ischemic events. The early group had a significantly higher incidence of antecedent cytomegalovirus infection.Conclusions. We conclude that 1) accelerated graft coronary artery disease develops at variable times after heart transplantation; 2) the early appearance of graft coronary artery disease may be a marker of intrinsically more aggressive disease; 3) cytomegalovirus infection is associated with earlier onset of graft coronary artery disease. Patients with early development of graft coronary artery disease should potentially be given priority for interventional strategies as they are developed

Gas emissions, minerals, and tars associated with three coal fires, Powder River Basin, USA.

Ground-based surveys of three coal fires and airborne surveys of two of the fires were conducted near Sheridan, Wyoming. The fires occur in natural outcrops and in abandoned mines, all containing Paleocene-age subbituminous coals. Diffuse (carbon dioxide (CO(2)) only) and vent (CO(2), carbon monoxide (CO), methane, hydrogen sulfide (H(2)S), and elemental mercury) emission estimates were made for each of the fires. Additionally, gas samples were collected for volatile organic compound (VOC) analysis and showed a large range in variation between vents. The fires produce locally dangerous levels of CO, CO(2), H(2)S, and benzene, among other gases. At one fire in an abandoned coal mine, trends in gas and tar composition followed a change in topography. Total CO(2) fluxes for the fires from airborne, ground-based, and rate of fire advancement estimates ranged from 0.9 to 780mg/s/m(2) and are comparable to other coal fires worldwide. Samples of tar and coal-fire minerals collected from the mouth of vents provided insight into the behavior and formation of the coal fires

Design, Synthesis, and Evaluation of Hydroxamic Acid-Based Molecular Probes for In Vivo Imaging of Histone Deacetylase (HDAC) in Brain

Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging.Chemistry and Chemical Biolog

Host affinity of endophytic fungi and the potential for reciprocal interactions involving host secondary chemistry

PREMISE: Interactions between fungal endophytes and their host plants present useful systems for identifying important factors affecting assembly of host-associated microbiomes. Here we investigated the role of secondary chemistry in mediating host affinity of asymptomatic foliar endophytic fungi using Psychotria spp. and Theobroma cacao (cacao) as hosts. METHODS: First, we surveyed endophytic communities in Psychotria species in a natural common garden using culture-based methods. Then we compared differences in endophytic community composition with differences in foliar secondary chemistry in the same host species, determined by liquid chromatography–tandem mass spectrometry. Finally, we tested how inoculation with live and heat-killed endophytes affected the cacao chemical profile. RESULTS: Despite sharing a common environment and source pool for endophyte spores, different Psychotria host species harbored strikingly different endophytic communities that reflected intrinsic differences in their leaf chemical profiles. In T. cacao, inoculation with live and heat-killed endophytes produced distinct cacao chemical profiles not found in uninoculated plants or pure fungal cultures, suggesting that endophytes, like pathogens, induce changes in secondary chemical profiles of their host plant. CONCLUSIONS: Collectively our results suggest at least two potential processes: (1) Plant secondary chemistry influences assembly and composition of fungal endophytic communities, and (2) host colonization by endophytes subsequently induces changes in the host chemical landscape. We propose a series of testable predictions based on the possibility that reciprocal chemical interactions are a general property of plant–endophyte interactionsPREMISE: Interactions between fungal endophytes and their host plants present useful systems for identifying important factors affecting assembly of host-associated microbiomes. Here we investigated the role of secondary chemistry in mediating host affinity of asymptomatic foliar endophytic fungi using Psychotria spp. and Theobroma cacao (cacao) as hosts. METHODS: First, we surveyed endophytic communities in Psychotria species in a natural common garden using culture-based methods. Then we compared differences in endophytic community composition with differences in foliar secondary chemistry in the same host species, determined by liquid chromatography–tandem mass spectrometry. Finally, we tested how inoculation with live and heat-killed endophytes affected the cacao chemical profile. RESULTS: Despite sharing a common environment and source pool for endophyte spores, different Psychotria host species harbored strikingly different endophytic communities that reflected intrinsic differences in their leaf chemical profiles. In T. cacao, inoculation with live and heat-killed endophytes produced distinct cacao chemical profiles not found in uninoculated plants or pure fungal cultures, suggesting that endophytes, like pathogens, induce changes in secondary chemical profiles of their host plant. CONCLUSIONS: Collectively our results suggest at least two potential processes: (1) Plant secondary chemistry influences assembly and composition of fungal endophytic communities, and (2) host colonization by endophytes subsequently induces changes in the host chemical landscape. We propose a series of testable predictions based on the possibility that reciprocal chemical interactions are a general property of plant–endophyte interaction

Structure-Activity Relationship for the Oxadiazole Class of Antibacterials

A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for in vitro toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) infection. Oxadiazole 72c shows potent in vitro antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.Fil: Boudreau, Marc A.. University of Notre Dame; Estados UnidosFil: Ding, Derong. University of Notre Dame; Estados UnidosFil: Meisel, Jayda E.. University of Notre Dame; Estados UnidosFil: Janardhanan, Jeshina. University of Notre Dame; Estados UnidosFil: Spink, Edward. University of Notre Dame; Estados UnidosFil: Peng, Zhihong. University of Notre Dame; Estados UnidosFil: Qian, Yuanyuan. University of Notre Dame; Estados UnidosFil: Yamaguchi, Takao. University of Notre Dame; Estados UnidosFil: Testero, Sebastian Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. University of Notre Dame; Estados UnidosFil: O'Daniel, Peter I.. University of Notre Dame; Estados UnidosFil: Leemans, Erika. University of Notre Dame; Estados UnidosFil: Lastochkin, Elena. University of Notre Dame; Estados UnidosFil: Song, Wei. University of Notre Dame; Estados UnidosFil: Schroeder, Valerie A.. University of Notre Dame; Estados UnidosFil: Wolter, William R.. University of Notre Dame; Estados UnidosFil: Suckow, Mark A.. University of Notre Dame; Estados UnidosFil: Mobashery, Shahriar. University of Notre Dame; Estados UnidosFil: Chang, Mayland. University of Notre Dame; Estados Unido

Structure-Activity Relationship for the Oxadiazole Class of Antibiotics

The structure-activity relationship (SAR) for the newly discovered oxadiazole class of antibiotics is described with evaluation of 120 derivatives of the lead structure. This class of antibiotics was discovered by in silico docking and scoring against the crystal structure of a penicillin-binding protein. They impair cell-wall biosynthesis and exhibit activities against the Gram-positive bacterium Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant and linezolid-resistant S. aureus. 5-(1H-Indol-5-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazole (antibiotic 75b) was efficacious in a mouse model of MRSA infection, exhibiting a long half-life, a high volume of distribution, and low clearance. This antibiotic is bactericidal and is orally bioavailable in mice. This class of antibiotics holds great promise in recourse against infections by MRSA.Fil: Spink, Edward. University of Notre Dame-Indiana; Estados UnidosFil: Ding, Derong. University of Notre Dame-Indiana; Estados UnidosFil: Peng, Zhihong. University of Notre Dame-Indiana; Estados UnidosFil: Boudreau, Marc A.. University of Notre Dame-Indiana; Estados UnidosFil: Leemans, Erika. University of Notre Dame-Indiana; Estados UnidosFil: Lastochkin, Elena. University of Notre Dame-Indiana; Estados UnidosFil: Song, Wei. University of Notre Dame-Indiana; Estados UnidosFil: Lichtenwalter, Katerina. University of Notre Dame-Indiana; Estados UnidosFil: O’Daniel, Peter I.. University of Notre Dame-Indiana; Estados UnidosFil: Testero, Sebastian Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. University of Notre Dame-Indiana; Estados UnidosFil: Pi, Hualiang. University of Notre Dame-Indiana; Estados UnidosFil: Schroeder, Valerie A.. University of Notre Dame-Indiana; Estados UnidosFil: Wolter, William R.. University of Notre Dame-Indiana; Estados UnidosFil: Antunes, Nuno T.. University of Notre Dame-Indiana; Estados UnidosFil: Suckow, Mark A.. University of Notre Dame-Indiana; Estados UnidosFil: Vakulenko, Sergei. University of Notre Dame-Indiana; Estados UnidosFil: Chang, Mayland. University of Notre Dame-Indiana; Estados UnidosFil: Mobashery, Shahriar. University of Notre Dame-Indiana; Estados Unido

Conference on Best Practices for Managing \u3cem\u3eDaubert\u3c/em\u3e Questions

This article is a transcript of the Philip D. Reed Lecture Series Conference on Best Practices for Managing Daubert Questions, held on October 25, 2019, at Vanderbilt Law School under the sponsorship of the Judicial Conference Advisory Committee on Evidence Rules. The transcript has been lightly edited and represents the panelists’ individual views only and in no way reflects those of their affiliated firms, organizations, law schools, or the judiciary

Light Element Depletion in Contracting Brown Dwarfs and Pre--Main-Sequence Stars

We present an analytic calculation of the thermonuclear depletion of the light elements lithium, beryllium, and boron in fully convective, low-mass stars. Under the presumption that the pre--main-sequence star is always fully mixed during contraction, we find that the burning of these rare light elements can be computed analytically, even when the star is degenerate. Using the effective temperature as a free parameter, we constrain the properties of low-mass stars from observational data, independently of the uncertainties associated with modeling their atmospheres and convection. Our analytic solution explains the dependence of the age at a given level of elemental depletion on the stellar effective temperature, nuclear cross sections, and chemical composition. Most importantly, our results allow observers to translate lithium non-detections in young cluster members into a model-independent minimum age for that cluster. Using this procedure, we have found lower limits to the ages of the Pleiades (100 Myr) and Alpha Persei (60 Myr) clusters. Recent experimental work on the low energy resonance in the ^10B(p,\alpha)^7Be reaction has greatly enhanced estimates of the destruction rate of ^10B, making it possible for stars with M>0.1 M_sun to deplete both ^10B and ^11B before reaching the main sequence. Moreover, there is an interesting range of masses, 0.085 M_sun < M < 0.13 M_sun, where boron depletion occurs on the main sequence in less than a Hubble time, providing a potential ``clock'' for dating low-mass stars.Comment: 34 pages, including 6 figures; Accepted to Ap

Antimicrobial Drug–Resistant Escherichia coli from Humans and Poultry Products, Minnesota and Wisconsin, 2002–2004

Similarities were found between drug-resistant E. coli from humans and poultry products