Cross Sectional Analysis of Patients with Alpha-1 Antitrypsin Deficiency Enrolled in a Disease Management and Prevention Program

Background: Alpha-1 antitrypsin deficiency is a heritable genetic condition that is largely underdiagnosed and has been estimated to affect 1 out of every 5,000-7,000 people in North America. The condition is characterized by a decrease in the production or activity of the alpha-1 antitrypsin protein, increasing risk for chronic lung or liver inflammation, that may lead to disease. Currently, there is no cure for the condition and augmentation therapy, which replaces the lost protein, has shown mixed results, meaning preventive measures taken by the patient are a large component of the prescribed treatment. Thus, patients with the condition are strongly encouraged to quit smoking, reduce drinking, avoid occupations or areas that have high levels of particulate matter or toxic air pollutants as well as maintain active vaccinations against lung and liver infections like pneumonia, hepatitis A and B, and the flu to prevent complications from the condition. Objectives: This study aims to 1) Access the associations between adherence to the AlphaNet disease management and prevention program and the prophylactic measures that are encouraged by the program and; 2) determine if any of these associations are a result of demographic and health differences between individuals who are adherent ADMAPP and those who are not. Methods: This is a cross-sectional study of 3,526 individuals with alpha-1 antitrypsin deficiency who answered a questionnaire administered by AlphaNet from May 29th 2008 to February 14th 2015 as part of the Alpha-1 Antitrypsin Management and Prevention Program. This study focused on questions related to adherence to the program and prophylactic measures taken by the individual that are encouraged by the literature given out by the program. Only individuals who 3 answered questions about their adherence to the program were included in this current study. Demographic differences between the two stratified populations and an index for comorbidities were used for logistic regression analysis. Results: After adjustment for sex, age, income, and comorbidies, compared with individuals who self-reported as being non-adherent to the disease management and prevention program, adherent individuals were more likely to be comfortable with their knowledge of the disease (ORadj=4.95, 95% CI: 3.24-7.57), have read any part of the literature provided by the program (ORadj=6.44, 95% CI: 5.45-7.62), and use augmentation therapy (ORadj=2.08, 95% CI: 1.53-2.82). These individuals were also more likely to be vaccinated for the flu (ORadj=1.34, 95% CI: 1.08-1.68), Hepatitis A (ORadj=1.41, 95% CI: 1.20-1.66), and Hepatitis B (ORadj=1.62, 95% CI: 1.37-1.91), as well as exercise (ORadj=2.07, 95% CI: 1.74-2.47), while being less likely to be active smokers (ORadj=0.47, CI: 0.31-0.70). Conclusions: This study suggests that AlphaNet program may be a useful tool for informing and improving preventive measures taken by individuals with alpha-1 antitrypsin deficiency. Individuals who self-reported their percent adherence to the program as being nonzero were more likely to be informed about their condition and taking preventive measures, such as smoking cessation, getting vaccinated for conditions that could magnify the effects of AATD, and increases in self-reported exercise. Future studies are needed to show causality and improvement in participant outcomes such as mortality and quality of life

An Open-Sourced Statistical Application for Identifying Complex Toxicological Interactions of Environmental Pollutants

The rising number of chemicals that humans are exposed to on a daily basis, as well as advances in biomonitoring and detection technologies have highlighted the diversity of individual exposure profiles (complex body burdens). To address this, the toxicological sciences have begun to shift away from examining toxic agents or stressors individually to focusing on more complex models with multiple agents or stressors present. Literature on interactions between chemicals is fairly limited in comparison with dose-response studies on individual toxicants, which is largely due to experimental and statistical challenges. Experimental designs capable of identifying these complex interactions are often avoided or not evaluated to their fullest potential because of the difficulty associated with appropriate analysis as well as logistical factors. To assist with statistical analysis of these types of experiments, an online, open-sourced statistical application was created for investigators to use to analyze and interpret potential toxicant interactions in laboratory experimental data using a full-factorial three-way analysis of variance (ANOVA). This model utilizes backward selection on interaction terms to model main effects and interactions

A Compromised Liver Alters Polychlorinated Biphenyl-Mediated Toxicity

Exposure to environmental toxicants namely polychlorinated biphenyls (PCBs) is correlated with multiple health disorders including liver and cardiovascular diseases. The liver is important for both xenobiotic and endobiotic metabolism. However, the responses of an injured liver to subsequent environmental insults has not been investigated. The current study aims to evaluate the role of a compromised liver in PCB-induced toxicity and define the implications on overall body homeostasis. Male C57Bl/6 mice were fed either an amino acid control diet (CD) or a methionine-choline deficient diet (MCD) during the 12-week study. Mice were subsequently exposed to either PCB126 (4.9 mg/kg) or the PCB mixture, Arcolor1260 (20 mg/kg) and analyzed for inflammatory, calorimetry and metabolic parameters. Consistent with the literature, MCD diet-fed mice demonstrated steatosis, indicative of a compromised liver. Mice fed the MCD-diet and subsequently exposed to PCB126 showed observable wasting syndrome leading to mortality. PCB126 and Aroclor1260 exposure worsened hepatic fibrosis exhibited by the MCD groups. Interestingly, PCB126 but not Aroclor1260 induced steatosis and inflammation in CD-fed mice. Mice with liver injury and subsequently exposed to PCBs also manifested metabolic disturbances due to alterations in hepatic gene expression. Furthermore, PCB exposure in MCD-fed mice led to extra-hepatic toxicity such as upregulated circulating inflammatory biomarkers, implicating endothelial cell dysfunction. Taken together, these results indicate that environmental pollution can exacerbate toxicity caused by diet-induced liver injury which may be partially due to dysfunctional energy homeostasis. This is relevant to PCB-exposed human cohorts who suffer from alcohol or diet-induced fatty liver diseases

Bisphenol A and Its Analogues Activate Human Pregnane X Receptor

Background: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA and its analogues are present in environmental and human samples. Many endocrine-disrupting chemicals, including BPA, have been shown to activate the pregnane X receptor (PXR), a nuclear receptor that functions as a master regulator of xenobiotic metabolism. However, the detailed mechanism by which these chemicals activate PXR remains unknown

Observation of two-magnon bound states in the two-leg ladders of (Ca,La)14Cu24O41

Phonon-assisted 2-magnon absorption is studied at T=4 K in the spin-1/2 two-leg ladders of Ca_14-x La_x Cu_24 O_41 (x=5 and 4) for polarization of the electrical field parallel to the legs and the rungs, respectively. Two peaks at about 2140 and 2800 1/cm reflect van-Hove singularities in the density of states of the strongly dispersing 2-magnon singlet bound state, and a broad peak at about 4000 1/cm is identified with the 2-magnon continuum. Two different theoretical approaches (Jordan-Wigner fermions and perturbation theory) describe the data very well for J_parallel = 1050 - 1100 1/cm and J_parallel / J_perp = 1 - 1.1. A striking similarity of the high-energy continuum absorption of the ladders and of the undoped high T_c cuprates is observed.Comment: 4 pages, 3 figures, Revte

Kinematics and hydrodynamics of spinning particles

In the first part (Sections 1 and 2) of this paper --starting from the Pauli current, in the ordinary tensorial language-- we obtain the decomposition of the non-relativistic field velocity into two orthogonal parts: (i) the "classical part, that is, the 3-velocity w = p/m OF the center-of-mass (CM), and (ii) the so-called "quantum" part, that is, the 3-velocity V of the motion IN the CM frame (namely, the internal "spin motion" or zitterbewegung). By inserting such a complete, composite expression of the velocity into the kinetic energy term of the non-relativistic classical (i.e., newtonian) lagrangian, we straightforwardly get the appearance of the so-called "quantum potential" associated, as it is known, with the Madelung fluid. This result carries further evidence that the quantum behaviour of micro-systems can be adirect consequence of the fundamental existence of spin. In the second part (Sections 3 and 4), we fix our attention on the total 3-velocity v = w + V, it being now necessary to pass to relativistic (classical) physics; and we show that the proper time entering the definition of the four-velocity v^mu for spinning particles has to be the proper time tau of the CM frame. Inserting the correct Lorentz factor into the definition of v^mu leads to completely new kinematical properties for v_mu v^mu. The important constraint p_mu v^mu = m, identically true for scalar particles, but just assumed a priori in all previous spinning particle theories, is herein derived in a self-consistent way.Comment: LaTeX file; needs kapproc.st

Copper-Mediated Amidation of Heterocyclic and Aromatic C−H Bonds

A copper-mediated aerobic coupling reaction enables direct amidation of heterocycles or aromatics having weakly acidic C−H bonds with a variety of nitrogen nucleophiles. These reactions provide efficient access to many biologically important skeletons, including ones with the potential to serve as inhibitors of HMTs.Chemistry and Chemical Biolog

Control of Stochastic Gene Expression by Host Factors at the HIV Promoter

The HIV promoter within the viral long terminal repeat (LTR) orchestrates many aspects of the viral life cycle, from the dynamics of viral gene expression and replication to the establishment of a latent state. In particular, after viral integration into the host genome, stochastic fluctuations in viral gene expression amplified by the Tat positive feedback loop can contribute to the formation of either a productive, transactivated state or an inactive state. In a significant fraction of cells harboring an integrated copy of the HIV-1 model provirus (LTR-GFP-IRES-Tat), this bimodal gene expression profile is dynamic, as cells spontaneously and continuously flip between active (Bright) and inactive (Off) expression modes. Furthermore, these switching dynamics may contribute to the establishment and maintenance of proviral latency, because after viral integration long delays in gene expression can occur before viral transactivation. The HIV-1 promoter contains cis-acting Sp1 and NF-κB elements that regulate gene expression via the recruitment of both activating and repressing complexes. We hypothesized that interplay in the recruitment of such positive and negative factors could modulate the stability of the Bright and Off modes and thereby alter the sensitivity of viral gene expression to stochastic fluctuations in the Tat feedback loop. Using model lentivirus variants with mutations introduced in the Sp1 and NF-κB elements, we employed flow cytometry, mRNA quantification, pharmacological perturbations, and chromatin immunoprecipitation to reveal significant functional differences in contributions of each site to viral gene regulation. Specifically, the Sp1 sites apparently stabilize both the Bright and the Off states, such that their mutation promotes noisy gene expression and reduction in the regulation of histone acetylation and deacetylation. Furthermore, the NF-κB sites exhibit distinct properties, with κB site I serving a stronger activating role than κB site II. Moreover, Sp1 site III plays a particularly important role in the recruitment of both p300 and RelA to the promoter. Finally, analysis of 362 clonal cell populations infected with the viral variants revealed that mutations in any of the Sp1 sites yield a 6-fold higher frequency of clonal bifurcation compared to that of the wild-type promoter. Thus, each Sp1 and NF-κB site differentially contributes to the regulation of viral gene expression, and Sp1 sites functionally “dampen” transcriptional noise and thereby modulate the frequency and maintenance of this model of viral latency. These results may have biomedical implications for the treatment of HIV latency

Graphical models for inferring single molecule dynamics

<p>Abstract</p> <p>Background</p> <p>The recent explosion of experimental techniques in single molecule biophysics has generated a variety of novel time series data requiring equally novel computational tools for analysis and inference. This article describes in general terms how graphical modeling may be used to learn from biophysical time series data using the variational Bayesian expectation maximization algorithm (VBEM). The discussion is illustrated by the example of single-molecule fluorescence resonance energy transfer (smFRET)<it> versus</it> time data, where the smFRET time series is modeled as a hidden Markov model (HMM) with Gaussian observables. A detailed description of smFRET is provided as well.</p> <p>Results</p> <p>The VBEM algorithm returns the model’s evidence and an approximating posterior parameter distribution given the data. The former provides a metric for model selection via maximum evidence (ME), and the latter a description of the model’s parameters learned from the data. ME/VBEM provide several advantages over the more commonly used approach of maximum likelihood (ML) optimized by the expectation maximization (EM) algorithm, the most important being a natural form of model selection and a well-posed (non-divergent) optimization problem.</p> <p>Conclusions</p> <p>The results demonstrate the utility of graphical modeling for inference of dynamic processes in single molecule biophysics.</p