Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with heterogeneous presentations ranging from moderate constitutional symptoms to life-threatening multiorgan system involvement. iMCD patients present with vastly different clinical subtypes, with some patients demonstrating thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly (TAFRO) and others demonstrating more mild/moderate symptoms with potential for severe disease (not otherwise specified, NOS). Due to its rarity and heterogeneity, the natural history and long-term burden of iMCD are poorly understood. We investigated real-world medical data from ACCELERATE, a large natural history registry of Castleman disease patients, to better characterize the long-term disease burden experienced by these patients. We found that iMCD-TAFRO patients face significant hospitalization burden, requiring more time in the hospital than iMCD-NOS patients during the year surrounding diagnosis (median [IQR] 36 [18, 61] days vs. 0 [0, 4] days;

Myogenin Regulates Exercise Capacity and Skeletal Muscle Metabolism in the Adult Mouse

Although skeletal muscle metabolism is a well-studied physiological process, little is known about how it is regulated at the transcriptional level. The myogenic transcription factor myogenin is required for skeletal muscle development during embryonic and fetal life, but myogenin's role in adult skeletal muscle is unclear. We sought to determine myogenin's function in adult muscle metabolism. A Myog conditional allele and Cre-ER transgene were used to delete Myog in adult mice. Mice were analyzed for exercise capacity by involuntary treadmill running. To assess oxidative and glycolytic metabolism, we performed indirect calorimetry, monitored blood glucose and lactate levels, and performed histochemical analyses on muscle fibers. Surprisingly, we found that Myog-deleted mice performed significantly better than controls in high- and low-intensity treadmill running. This enhanced exercise capacity was due to more efficient oxidative metabolism during low- and high-intensity exercise and more efficient glycolytic metabolism during high-intensity exercise. Furthermore, Myog-deleted mice had an enhanced response to long-term voluntary exercise training on running wheels. We identified several candidate genes whose expression was altered in exercise-stressed muscle of mice lacking myogenin. The results suggest that myogenin plays a critical role as a high-level transcriptional regulator to control the energy balance between aerobic and anaerobic metabolism in adult skeletal muscle

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Non-emphysematous chronic obstructive pulmonary disease is associated with diabetes mellitus

Background: Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients. Methods: Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%). Results: Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5-10% and were not categorized. Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St. George's Respiratory Questionnaire score 43 vs 31, p < 0.0001). Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use. The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study. Conclusions: Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes. COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa

Solvent Self-diffusion and Transverse Relaxation in Concentrated Polymer Solutions

The self-diffusion coefficients of chloroform in poly(isopropyl acrylate)-chloroform solutions have been studied as a function of concentration and temperature using the pulsed field-gradient spin-echo NMR method. It is found that the self-diffusion coefficients of the solvent can be adequately fit using a simple free volume approach with either a concentration or temperature superposition. It was noted that the free volume parameters derived from the self-diffusion data are the same as those which can be derived from deuterium NMR transverse relaxation time measurements of the polymer in the same systems

NMR Relaxation, Polymer Dynamics, and Free Volume in Polyacrylate Solutions

The chain dynamics of polymer molecules in solution has been the subject of much scientific study. Polymer reorientation is important because the microscopic dynamics of polymer chains often dictates the physical properties of polymer solutions. NMR techniques can be used to probe the dynamics of polymers over many orders of magnitude in the frequency domain. In dilute solution, NMR results have provided insight into microscopic polymer dynamics. Carbon-13 and proton studies have shown that the relaxation times T//1 and T//2 are dominated by local segmental motions. These motions have been quantitatively described by invoking either jump or diffusion-like models, most of which have been reviewed by Heatley. Unfortunately, in more concentrated solutions, these models no longer fit NMR relaxation data in a physically meaningful manner. In this study the authors report **2H NMR relaxation results on solutions of polyacrylates in chloroform as a function of temperature and composition. The polyacrylates have been specifically deuterated at the backbone methine positions. Deuterium NMR is useful because the relaxation mechanism for a C-D species is well defined and simplified spectra (one resonance per spectrum) result. This is especially useful in concentrated solutions where the line widths can be very large and the overlap of resonances would normally occur in **1H or **1**3C NMR

Free Volume and Transverse Relaxation in Polymer Solutions

NMR has proven to be a very effective tool for the study of polymer motions. In this study, we have labeled poly(isopropyl acrylate), (PIPA) in the backbone methine position with deuterium. Thus only one resonance per spectrum is observed and the results of the relaxation time measurements can be used to probe polymer motions. It is found that T//2 measurements can be used to study the transition from semi-dilute to concentrated solution. T//2 values can also be seen to exhibit either a concentration or temperature superposition predicted by simple-free volume approaches

Solvent Self-diffusion, Polymer Nmr Relaxation, and Free Volume in Polymer Solutions

The self-diffusion coefficient of chloroform in poly(isopropyl acrylate-chloroform solutions has been studied as a function of concentration and temperature by using the pulsed-field-gradient spin-echo NMR method. It is found that the self-diffusion coefficient of the solvent can be adequately fitted by using a simple free-volume approach with either a concentration or temperature superposition. It was noted that the free-volume parameters derived from the self-diffusion data are the same as those derived from deuterium NMR transverse relaxation-time measurements of the polymer in the same system. the equality of these two sets of experiments suggests a fundamental relationship between the two different processes. the simplest explanation is that the free volume necessary for the local segmental motion of the polymer and the translation of the solvent are similar

Backbone Dynamics of Poly(isopropyl Acrylate) in Chloroform

The backbone dynamics of poly(isopropyl acrylate) (PIPA) in chloroform have been studied over a wide composition and temperature range using deuterium NMR. The polymer was specifically labeled with deuterium in the methine position so that only one resonance would be seen. The results of T1 and T2 measurements were used to test the log χ2, VJGM, Bendler-Yaris (BY), and Skolnick-Yaris (SY) models of polymer reorientation. It was found that, even though all the models could mimic the data, they did not always fit the data in a physically realistic way. The log χ2 model yielded results which were not physically realistic even in dilute solution. The results from the VJGM, BY, and SY models were roughly indistinguishable despite their different formulations. All three models contain two parameters, each of which are dominated by either fast or slow motions. Further, it was seen that in dilute solution, the fast motion has an energy of activation of about 5 kcal/mol which is independent of concentration. In more concentrated solutions the energies of activation for the slow-motion parameters are concentration dependent and range from 12 to 30 kcal/mol. In concentrated solutions, it was found that T1 and T2 cannot be represented by a single model but the T2 measurements can be used to define a division between semidilute and concentrated solution when [η]Cc ≅ 30 for PIPA-CHCl3. It was also found that the T2 values for the concentrated solutions could be fit by using a free volume approach. The free volume parameters were calculated and judged to be reasonable when compared to the other systems. © 1984 American Chemical Society