Clinical Research and Public Health
Abstract
BACKGROUND. Neuronal remodeling in human heart disease is not well understood. METHODS. Stellate ganglia from patients with cardiomyopathy (CMY) and refractory ventricular arrhythmias undergoing cardiac sympathetic denervation (n = 8), and from organ donors with normal hearts (n = 8) collected at the time of organ procurement were compared. Clinical data on all subjects were reviewed. Electron microscopy (EM), histologic, and immunohistochemical assessments of neurotransmitter profiles, glial activation and distribution, and lipofuscin deposition, a marker of oxidative stress, were quantified. RESULTS. In CMY specimens, lipofuscin deposits were larger, and present in more neurons (26.3% ± 6.3% vs. 16.7% ± 7.6%, P < 0.043), than age-matched controls. EM analysis revealed extensive mitochondrial degeneration in CMY specimens. T cell (CD3+) infiltration was identified in 60% of the CMY samples, with one case having large inflammatory nodules, while none were identified in controls. Myeloperoxidase-immunoreactive neutrophils were also identified at parenchymal sites distinct from inflammatory foci in CMY ganglia, but not in controls. The adrenergic phenotype of pathologic samples revealed a decrease in tyrosine hydroxylase staining intensity compared with controls. Evaluation of cholinergic phenotype by staining for the vesicular acetylcholine transporter revealed a low but comparable number of cholinergic neurons in ganglia from both groups and demonstrated that preganglionic cholinergic innervation was maintained in CMY ganglia. S100 staining (a glial cell marker) demonstrated no differences in glial distribution and relationship to neurons; however, glial activation demonstrated by glial fibrillary acidic protein (GFAP) staining was substantially increased in pathologic specimens compared with controls. CONCLUSIONS. Stellate ganglia from patients with CMY and arrhythmias demonstrate inflammation, neurochemical remodeling, oxidative stress, and satellite glial cell activation. These changes likely contribute to excessive and dysfunctional efferent sympathetic tone, and provide a rationale for sympathectomy as a treatment for arrhythmias in this population. FUNDING. This work was made possible by support from NIH grants HL125730 to OAA, GM107949 to DBH, and HL084261 and OT2OD023848 to KS.
Authors
Olujimi A. Ajijola, Donald B. Hoover, Thomas M. Simerly, T. Christopher Brown, Jane Yanagawa, Reshma M. Biniwale, Jay M. Lee, Ali Sadeghi, Negar Khanlou, Jeffrey L. Ardell, Kalyanam Shivkumar
Abstract
BACKGROUND. In obese subjects with obstructive sleep apnea (OSA), chronic intermittent hypoxia (CIH) may be linked to systemic and adipose tissue inflammation. METHODS. We obtained abdominal subcutaneous adipose tissue biopsies from OSA and non-OSA obese (BMI > 35) subjects at baseline and after 24 weeks (T1) of weight-loss intervention plus continuous positive airway pressure (c-PAP) or weight-loss intervention alone, respectively. OSA subjects were grouped according to good (therapeutic) or poor (subtherapeutic) adherence to c-PAP. RESULTS. At baseline, anthropometric and metabolic parameters, serum cytokines, and adipose tissue mRNA levels of obesity-associated chemokines and inflammatory markers were not different in OSA and non-OSA subjects. At T1, body weight was significantly reduced in all groups. Serum concentrations of IL-2, IL-4, IL-6, MCP-1, PDGFβ, and VEGFα were reduced by therapeutic c-PAP in OSA subjects and remained unaltered in non-OSA and subtherapeutic c-PAP groups. Similarly, adipose tissue mRNA levels of macrophage-specific (CD68, CD36) and ER stress (ATF4, CHOP, ERO-1) gene markers, as well as of IL-6, PDGFβ, and VEGFα, were decreased only in the therapeutic c-PAP group. CONCLUSION. CIH does not represent an additional factor increasing systemic and adipose tissue inflammation in morbid obesity. However, in subjects with OSA, an effective c-PAP therapy improves systemic and obesity-associated inflammatory markers. FUNDING. Ministero dell’Università e della Ricerca and Progetti di Rilevante Interesse Nazionale.
Authors
Sebastio Perrini, Angelo Cignarelli, Vitaliano Nicola Quaranta, Vito Antonio Falcone, Stella Kounaki, Stefania Porro, Alessandro Ciavarella, Romina Ficarella, Maria Barbaro, Valentina Annamaria Genchi, Pasquale Nigro, Pierluigi Carratù, Annalisa Natalicchio, Luigi Laviola, Onofrio Resta, Francesco Giorgino
Abstract
BACKGROUND. The impact of resistance exercise training (RE-T) across the life span is poorly defined. METHODS. To resolve this, we recruited three distinct age cohorts of young (18–28 years; n = 11), middle-aged (45–55 years; n = 20), and older (nonsarcopenic; 65–75 years; n = 17) individuals to a cross-sectional intervention study. All subjects participated in 20 weeks of fully supervised whole-body progressive RE-T, undergoing assessment of body composition, muscle and vascular function, and metabolic health biomarkers before and after RE-T. Individuals also received stable isotope tracer infusions to ascertain muscle protein synthesis (MPS). RESULTS. There was an age-related increase in adiposity, but only young and middle-age groups demonstrated reductions following RE-T. Increases in blood pressure with age were attenuated by RE-T in middle-aged, but not older, individuals, while age-related increases in leg vascular conductance were unaffected by RE-T. The index of insulin sensitivity was reduced by RE-T in older age. Despite being matched at baseline, only younger individuals increased muscle mass in response to RE-T, and there existed a negative correlation between age and muscle growth; in contrast, increases in mechanical quality were preserved across ages. Acute increases in MPS (upon feeding plus acute RE-T) were enhanced only in younger individuals, perhaps explaining greater hypertrophy. CONCLUSION. Our data indicate that RE-T offsets some, but not all, negative characteristics of ageing — some of which are apparent in midlife. FUNDING. Biotechnology and Biological Sciences Research Council (BB/C516779/1).
Authors
Bethan E. Phillips, John P. Williams, Paul L. Greenhaff, Kenneth Smith, Philip J. Atherton
Abstract
BACKGROUND. Cross-reactive immunological material–negative (CRIM-negative) infantile Pompe disease (IPD) patients develop an immune response against enzyme replacement therapy (ERT) with alglucosidase alfa that nullifies ERT efficacy. Prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG successfully prevents development of deleterious rhGAA IgG antibodies; however, safety, likelihood of success, and long-term efficacy of ITI in a larger cohort remain unknown. METHODS. Clinical data were analyzed for 19 CRIM-negative IPD patients who received ITI with rituximab, methotrexate, and IVIG in the ERT-naive setting (ERT+ITI) and compared to a historical cohort of 10 CRIM-negative IPD patients on ERT monotherapy. RESULTS. ITI was safely tolerated, although infections were reported in 4 patients. Fourteen (74%) ERT+ITI patients were alive, with a median age of 44.2 months at their final assessment. The eldest survivor was 103.9 months old, with 100.2 months of follow-up after initiation of ERT+ITI. Death (n = 5) occurred at a median age of 29.2 months and was unrelated to the administration of ITI. Fifteen patients either did not seroconvert (n = 8) or maintained low titers (n = 7; defined as titers of ≤6,400 throughout the course of ERT) following ERT+ITI. Only one patient developed high and sustained antibody titers (defined as titers of ≥51,200 at or beyond 6 months on ERT). Left ventricular mass index (LVMI) decreased from a median of 248.5 g/m2 at baseline to 76.8 g/m2 at a median time from ERT+ITI initiation to 59 weeks. ERT+ITI significantly improved overall survival (P = 0.001), eliminated/reduced antibodies at values of ≤6,400 at week 52 on ERT (P = 0.0004), and improved LVMI at week 52 on ERT (P = 0.02) when compared with ERT monotherapy. CONCLUSION. Evidence from this international cohort of CRIM-negative IPD patients further supports the safety, feasibility, and efficacy of ITI in the prevention of immune responses to ERT. TRIAL REGISTRATION. Clinicaltrials.gov NCT01665326. FUNDING. This research was supported in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network, and by a grant from Genzyme, a Sanofi company.
Authors
Zoheb B. Kazi, Ankit K. Desai, Kathryn L. Berrier, R. Bradley Troxler, Raymond Y. Wang, Omar A. Abdul-Rahman, Pranoot Tanpaiboon, Nancy J. Mendelsohn, Eli Herskovitz, David Kronn, Michal Inbar-Feigenberg, Catherine Ward-Melver, Michelle Polan, Punita Gupta, Amy S. Rosenberg, Priya S. Kishnani
Abstract
BACKGROUND. Right-sided heart failure is the leading cause of death in pulmonary arterial hypertension (PAH). Similar to left heart failure, sympathetic overactivation and β-adrenoreceptor (βAR) abnormalities are found in PAH. Based on successful therapy of left heart failure with β-blockade, the safety and benefits of the nonselective β-blocker/vasodilator carvedilol were evaluated in PAH. METHODS. PAH Treatment with Carvedilol for Heart Failure (PAHTCH) is a single-center, double-blind, randomized, controlled trial. Following 1-week run-in, 30 participants were randomized to 1 of 3 arms for 24 weeks: placebo, low-fixed-dose, or dose-escalating carvedilol. Outcomes included clinical measures and mechanistic biomarkers. RESULTS. Decreases in heart rate and blood pressure with carvedilol were well tolerated; heart rate correlated with carvedilol dose. Carvedilol-treated groups had no decrease in exercise capacity measured by 6-minute walk, but had lower heart rates at peak and after exercise, and faster heart rate recovery. Dose-escalating carvedilol was associated with reduction in right ventricular (RV) glycolytic rate and increase in βAR levels. There was no evidence of RV functional deterioration; rather, cardiac output was maintained. CONCLUSIONS. Carvedilol is likely safe in PAH over 6 months of therapy and has clinical and mechanistic benefits associated with improved outcomes. The data provide support for longer and larger studies to establish guidelines for use of β-blockers in PAH. TRIAL REGISTRATION. ClinicalTrials.gov NCT01586156 FUNDING. This project was supported by NIH R01HL115008 and R01HL60917 and in part by the National Center for Advancing Translational Sciences, UL1TR000439.
Authors
Samar Farha, Didem Saygin, Margaret M. Park, Hoi I. Cheong, Kewal Asosingh, Suzy A.A. Comhair, Olivia R. Stephens, Emir C. Roach, Jacqueline Sharp, Kristin B. Highland, Frank P. DiFilippo, Donald R. Neumann, W.H. Wilson Tang, Serpil C. Erzurum
Abstract
BACKGROUND. Lack of investigatory and diagnostic tools has been a major contributing factor to the failure to mechanistically understand lymphedema and other lymphatic disorders in order to develop effective drug and surgical therapies. One difficulty has been understanding the true changes in lymph vessel pathology from standard 2D tissue sections. METHODS. VIPAR (volume information-based histopathological analysis by 3D reconstruction and data extraction), a light-sheet microscopy–based approach for the analysis of tissue biopsies, is based on digital reconstruction and visualization of microscopic image stacks. VIPAR allows semiautomated segmentation of the vasculature and subsequent nonbiased extraction of characteristic vessel shape and connectivity parameters. We applied VIPAR to analyze biopsies from healthy lymphedematous and lymphangiomatous skin. RESULTS. Digital 3D reconstruction provided a directly visually interpretable, comprehensive representation of the lymphatic and blood vessels in the analyzed tissue volumes. The most conspicuous features were disrupted lymphatic vessels in lymphedematous skin and a hyperplasia (4.36-fold lymphatic vessel volume increase) in the lymphangiomatous skin. Both abnormalities were detected by the connectivity analysis based on extracted vessel shape and structure data. The quantitative evaluation of extracted data revealed a significant reduction of lymphatic segment length (51.3% and 54.2%) and straightness (89.2% and 83.7%) for lymphedematous and lymphangiomatous skin, respectively. Blood vessel length was significantly increased in the lymphangiomatous sample (239.3%). CONCLUSION. VIPAR is a volume-based tissue reconstruction data extraction and analysis approach that successfully distinguished healthy from lymphedematous and lymphangiomatous skin. Its application is not limited to the vascular systems or skin. FUNDING. Max Planck Society, DFG (SFB 656), and Cells-in-Motion Cluster of Excellence EXC 1003.
Authors
René Hägerling, Dominik Drees, Aaron Scherzinger, Cathrin Dierkes, Silvia Martin-Almedina, Stefan Butz, Kristiana Gordon, Michael Schäfers, Klaus Hinrichs, Pia Ostergaard, Dietmar Vestweber, Tobias Goerge, Sahar Mansour, Xiaoyi Jiang, Peter S. Mortimer, Friedemann Kiefer
Abstract
BACKGROUND. Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1–blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years). METHODS. Six mutation-positive DIRA patients (children, ages 3–6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months. RESULTS. Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported. CONCLUSION. Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. TRIAL REGISTRATION. ClinicalTrials.gov NCT01801449. FUNDING. NIH, NIAMS, and NIAID.
Authors
Megha Garg, Adriana A. de Jesus, Dawn Chapelle, Paul Dancey, Ronit Herzog, Rafael Rivas-Chacon, Theresa L. Wampler Muskardin, Ann Reed, James C. Reynolds, Raphaela Goldbach-Mansky, Gina A. Montealegre Sanchez
Abstract
BACKGROUND. Noninvasive detection of Alzheimer’s disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS. Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS. Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson’s r = 0.84–0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION. The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring. FUNDING. National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.
Authors
Yosef Koronyo, David Biggs, Ernesto Barron, David S. Boyer, Joel A. Pearlman, William J. Au, Shawn J. Kile, Austin Blanco, Dieu-Trang Fuchs, Adeel Ashfaq, Sally Frautschy, Gregory M. Cole, Carol A. Miller, David R. Hinton, Steven R. Verdooner, Keith L. Black, Maya Koronyo-Hamaoui
Abstract
BACKGROUND. Dysregulated lipid and glucose metabolism in clear cell renal cell carcinoma (ccRCC) has been implicated in disease progression, and whole tumor tissue–based assessment of these changes is challenged by the tumor heterogeneity. We studied a noninvasive quantitative MRI method that predicts metabolic alterations in the whole tumor. METHODS. We applied Dixon-based MRI for in vivo quantification of lipid accumulation (fat fraction [FF]) in targeted regions of interest of 45 primary ccRCCs and correlated these MRI measures to mass spectrometry–based lipidomics and metabolomics of anatomically colocalized tissue samples isolated from the same tumor after surgery. RESULTS. In vivo tumor FF showed statistically significant (P < 0.0001) positive correlation with histologic fat content (Spearman correlation coefficient, ρ = 0.79), spectrometric triglycerides (ρ = 0.56) and cholesterol (ρ = 0.47); it showed negative correlation with free fatty acids (ρ = –0.44) and phospholipids (ρ = –0.65). We observed both inter- and intratumoral heterogeneity in lipid accumulation within the same tumor grade, whereas most aggressive tumors (International Society of Urological Pathology [ISUP] grade 4) exhibited reduced lipid accumulation. Cellular metabolites in tumors were altered compared with adjacent renal parenchyma. CONCLUSION. Our results support the use of noninvasive quantitative Dixon-based MRI as a biomarker of reprogrammed lipid metabolism in ccRCC, which may serve as a predictor of tumor aggressiveness before surgical intervention. FUNDING. NIH R01CA154475 (YZ, MF, PK, IP), NIH P50CA196516 (IP, JB, RJD, JAC, PK), Welch Foundation I-1832 (JY), and NIH P01HL020948 (JGM).
Authors
Yue Zhang, Durga Udayakumar, Ling Cai, Zeping Hu, Payal Kapur, Eun-Young Kho, Andrea Pavía-Jiménez, Michael Fulkerson, Alberto Diaz de Leon, Qing Yuan, Ivan E. Dimitrov, Takeshi Yokoo, Jin Ye, Matthew A. Mitsche, Hyeonwoo Kim, Jeffrey G. McDonald, Yin Xi, Ananth J. Madhuranthakam, Durgesh K. Dwivedi, Robert E. Lenkinski, Jeffrey A. Cadeddu, Vitaly Margulis, James Brugarolas, Ralph J. DeBerardinis, Ivan Pedrosa
Abstract
BACKGROUND. Food intake is guided by homeostatic needs and by the reward value of food, yet the exact relation between the two remains unclear. The aim of this study was to investigate the influence of different metabolic states and hormonal satiety signaling on responses in neural reward networks. METHODS. Twenty-three healthy participants underwent functional magnetic resonance imaging while performing a task distinguishing between the anticipation and the receipt of either food- or monetary-related reward. Every participant was scanned twice in a counterbalanced fashion, both during a fasted state (after 24 hours fasting) and satiety. A functional connectivity analysis was performed to investigate the influence of satiety signaling on activation in neural reward networks. Blood samples were collected to assess hormonal satiety signaling. RESULTS. Fasting was associated with sensitization of the striatal reward system to the anticipation of food reward irrespective of reward magnitude. Furthermore, during satiety, individual ghrelin levels were associated with increased neural processing during the expectation of food-related reward. CONCLUSIONS. Our findings show that physiological hunger stimulates food consumption by specifically increasing neural processing during the expectation (i.e., incentive salience) but not the receipt of food-related reward. In addition, these findings suggest that ghrelin signaling influences hedonic-driven food intake by increasing neural reactivity during the expectation of food-related reward. These results provide insights into the neurobiological underpinnings of motivational processing and hedonic evaluation of food reward. TRIAL REGISTRATION. ClinicalTrials.gov NCT03081585. FUNDING. This work was supported by the German Competence Network on Obesity, which is funded by the German Federal Ministry of Education and Research (FKZ 01GI1122E).
Authors
Joe J. Simon, Anne Wetzel, Maria Hamze Sinno, Mandy Skunde, Martin Bendszus, Hubert Preissl, Paul Enck, Wolfgang Herzog, Hans-Christoph Friederich
No posts were found with this tag.
