BACKGROUND. A randomized clinical trial from 1984-1992 indicated that vitamin A supplementation had a beneficial effect on the progression of retinitis pigmentosa (RP), while vitamin E had an adverse effect. METHODS. Sequencing of banked DNA samples from that trial provided the opportunity to determine if certain genotypes responded preferentially to vitamin supplementation. RESULTS. The genetic solution rate was 587/765 (77%) of sequenced samples. Combining genetic solutions with electroretinogram outcomes showed that there were systematic differences in severity and progression seen among different genetic subtypes of RP, extending findings made for USH2A, RHO, RPGR, PRPF31, and EYS. Baseline electroretinogram 30Hz flicker implicit time was an independent strong predictor of progression rate. Using additional data and baseline implicit time as a predictor, the deleterious effect of vitamin E was still present. Surprisingly, the effect of vitamin A progression in the cohort as a whole was not detectable, with or without data from subsequent trials. Subgroup analyses are also discussed. CONCLUSION. Overall, genetic subtype and implicit time have significant predictive power for a patient’s rate of progression, which is useful prognostically. While vitamin E supplementation should still be avoided, these data do not support a generalized neuroprotective effect of vitamin A for all types of RP. TRAIL REGISTRATION. ClinicalTrials.gov NCT00000114, NCT00000116, NCT00346333 FUNDING. the Foundation Fighting Blindness and the National Eye Institute: RO1 EY012910 (EAP), R01 EY031036 (JC), R01EY026904 (KMB/EAP), and P30EY014104.
Jason Comander, Carol Weigel DiFranco, Kit Green Sanderson, Emily M. Place, Matthew Maher, Erin Zampaglione, Yan Zhao, Rachel M. Huckfeldt, Kinga M. Bujakowska, Eric A. Pierce
BACKGROUND/AIMS. The effects of diet-induced weight loss (WL) and WL after Roux-en-Y gastric bypass (RYGB) surgery on β-cell function are unclear because of conflicting results from different studies, presumably because of differences in the methods used to measure β-cell function, the amount of WL between treatment groups, and baseline β-cell function. The goal of this study was to evaluate the effect of WL after RYGB surgery or reduced energy intake alone on β-cell function in people with obesity with and without type 2 diabetes. METHODS. β-cell function (insulin secretion in relationship to plasma glucose) was assessed before and after glucose or mixed-meal ingestion before and after: i) progressive amounts (6%, 11%, 16%) of WL induced by a low-calorie diet (LCD) in people with obesity without diabetes, ii) ~20% WL after RYGB surgery or laparoscopic adjustable gastric banding (LAGB) in people with obesity without diabetes, and iii) ~20% WL after RYGB surgery or LCD alone in people with obesity and diabetes. RESULTS. Diet-induced progressive WL in people without diabetes progressively decreased β-cell function. Marked WL after LAGB or RYGB in people without diabetes did not alter β-cell function. Marked WL after LCD or RYGB in people with diabetes markedly increased β-cell function, without a difference between the two groups. CONCLUSION. Marked WL increases β-cell function in people with obesity and diabetes but not in people with obesity without diabetes. The effect of RYGB-induced WL on β-cell function is not different from the effect of matched WL after LAGB or LCD alone. CLINICAL TRIAL REGISTRATION NUMBERS. NCT00981500, NCT02207777, NCT01299519 FUNDING. This study was supported by NIH grants R01 DK037948, R01 DK101578, P30 DK056341 (Washington University Nutrition and Obesity Research Center), P30 DK020579 (Washington University Diabetes Research Center), and UL1 TR002345 (Washington University Institute of Clinical and Translational Sciences), and grants from the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation (2019-011).
Bettina Mittendorfer, Bruce W. Patterson, Faidon Magkos, Mihoko Yoshino, David P. Bradley, J. Christopher Eagon, Samuel Klein
Fasting is associated with increased susceptibility to hypoglycemia in people with type 1 diabetes, thereby making it a significant health risk. To date, the relationship between fasting and insulin-induced hypoglycemia has not been well characterized, so our objective was to determine whether insulin-independent factors, such as counterregulatory hormone responses, are adversely impacted by fasting in healthy control subjects. Counterregulatory responses to insulin-induced hypoglycemia were measured in twelve healthy people during two metabolic studies. During one study, subjects ate breakfast and lunch, after which they underwent a two-hour bout of insulin-induced hypoglycemia (FED). During the other study, subjects remained fasted prior to hypoglycemia (FAST). As expected, hepatic glycogen concentrations were lower in FAST, and associated with diminished peak glucagon levels and reduced endogenous glucose production (EGP) during hypoglycemia. Accompanying lower EGP in FAST was a reduction in peripheral glucose utilization, and a resultant reduction in the amount of exogenous glucose required to maintain glycemia. These data suggest that whereas a fasting-induced lowering of glucose utilization could potentially delay the onset of insulin-induced hypoglycemia, subsequent reductions in glucagon levels and EGP are likely to encumber recovery from it. As a result of this diminished metabolic flexibility in response to fasting, susceptibility to hypoglycemia could be enhanced in patients with type 1 diabetes under similar conditions.
Shana O. Warner, Yufei Dai, Nicole Sheanon, Michael V. Yao, Rebecca L. Cason, Shahriar Arbabi, Shailendra B. Patel, Diana M. Lindquist, Jason J. Winnick
BACKGROUND. Current studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in CKD patients. METHODS. We conducted a randomized placebo-controlled, double blind, cross-over trial comparing CoQ10, NR, and placebo in 25 patients with eGFR of <60ml/min/1.73m2. Subjects received NR (1000 mg/day), CoQ10 (1200 mg/day), or placebo for 6 weeks each. Primary outcomes were aerobic capacity (VO2 peak) and work efficiency measured using graded cycle ergometry testing. We performed semi-targeted plasma metabolomics and lipidomics. RESUTS. Participant mean age was 61.0 ± 11.6 years and mean eGFR was 36.9±9.2 ml/min/1.73m2. Compared to placebo, we found no differences in VO2 peak (P=0.30, 0.17), total work (P=0.47, 0.77), and total work efficiency (P=0.46, 0.55) post NR or CoQ10 supplementation. NR decreased submaximal VO2 at 30W (P=0.03) and VO2 at 60W (P=0.07) compared to placebo. No changes in eGFR were observed post-NR or CoQ10 (P=0.14, 0.88). CoQ10 increased free fatty acids and decreased complex medium/long chain triglycerides. NR supplementation significantly altered TCA cycle intermediates and glutamate that are involved in reactions that exclusively use NAD+ and NADP+ as cofactors. NR decreased a broad range of lipid groups including triglycerides and ceramides. CONCLUSIONS. Six-weeks of treatment with NR or CoQ10 improved markers of systemic mitochondrial metabolism and lipid profiles but did not improve VO2 peak or total work efficiency. TRIAL REGISTRATION. ClinicalTrials.gov (NCT03579693) FUNDING. This study was supported by National Institutes of Diabetes and Digestive Kidney Diseases R01 DK101509 (to BK), R03 DK114502 (to BR), R01 DK125794 (to BR), R01 DK101509 (to JG), Dialysis Clinics Incorporated C-4112 (to BR), Northern California VA Health Care System (BR).
Armin Ahmadi, Gwenaelle Begue, Ana P. Valencia, Jennifer E. Norman, Benjamin Lidgard, Brian J. Bennett, Matthew P. Van Doren, David J. Marcinek, Sili Fan, David K. Prince, Jorge L. Gamboa, Jonathan Himmelfarb, Ian H. de Boer, Bryan R. Kestenbaum, Baback Roshanravan
BACKGROUND. There is considerable heterogeneity in the effect of weight loss on metabolic function in people with obesity. METHODS. We evaluated muscle and liver insulin sensitivity, body composition, and circulating factors associated with insulin action before and after ~20% weight loss in women identified as “Responders” (n=11) or “Non-responders” (n=11), defined as the top (>75% increase) and bottom (<5% increase) quartiles of the weight loss-induced increase in glucose disposal rate (GDR) during a hyperinsulinemic-euglycemic clamp procedure, among 43 women with obesity (BMI: 44.1±7.9 kg/m2). RESULTS. At baseline, GDR, which provides an index of muscle insulin sensitivity, and the hepatic insulin sensitivity index were >50% lower in Responders than Non-Responders, but both increased much more after weight loss in Responders than Non-responders, which eliminated the differences between groups. Weight loss also caused greater decreases in intrahepatic triglyceride content and plasma adiponectin and PAI-1 concentrations in Responders than Non-Responders and greater insulin-mediated suppression of plasma free fatty acids, branched-chain amino acids and C3/C5 acylcarnitines in Non-Responders than Responders, so that differences between groups at baseline were no longer present after weight loss. The effect of weight loss on total body fat mass, intra-abdominal adipose tissue volume, adipocyte size, and circulating inflammatory markers were not different between groups. CONCLUSION. The results from our study demonstrate the heterogeneity in the effects of marked weight loss on muscle and hepatic insulin sensitivity in people with obesity is determined by baseline insulin action, and reaches a ceiling when “normal” insulin action is achieved. CLINICAL TRIAL REGISTRATION. NCT00981500, NCT01299519, NCT02207777 FUNDING. This study was supported by National Institutes of Health grants P30 DK056341 (Washington University Nutrition and Obesity Research Center), P30 DK020579 (Washington University Diabetes Research Center), P30 DK052574 (Washington University Digestive Disease Research Center), and UL1 TR002345 (Washington University Institute of Clinical and Translational Sciences), T32 HL130357 (Obesity and Cardiovascular Disease Postdoctoral Training Program), grants from the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation (2019-011), and the Atkins Philanthropic Trust.
Bettina Mittendorfer, Brandon D. Kayser, Mihoko Yoshino, Jun Yoshino, Jeramie D. Watrous, Mohit Jain, J. Christopher Eagon, Bruce W. Patterson, Samuel Klein
BACKGROUND. The Omicron BA.5 subvariant of SARS-CoV-2 markedly escapes neutralizing antibodies induced by vaccination due to mutations in the Spike (S) protein. Solid organ transplant recipients (SOTRs) suffer high COVID-19 morbidity and demonstrate poor Omicron strain recognition after COVID-19 vaccination. T cell responses may provide a crucial second line of defense. Therefore, it is critical to understand which vaccine regimens induce robust, conserved T cell responses. METHODS. We evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4+ and CD8+ T cell responses from SOTRs in a national, prospective observational trial (n=75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or two doses of mRNA followed by Ad26.COV2.S (heterologous boosting). RESULTS. Homologous boosting with three mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated significantly lower pseudo-neutralization against BA.5 compared to the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared to ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4+ T cell responses, with polyfunctional IL-21+ peripheral T follicular helper cells increased in mRNA-1273 compared to BNT¬¬162b2. IL-21+ cells robustly correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8+ responses compared to homologous boosting. CONCLUSIONS. These data demonstrate that boosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants of concern in SOTRs, but alterative vaccine strategies are required to induce robust CD8+ T cell responses. TRIAL REGISTRATION. IRB00248540 FUNDING. U01AI138897, U54CA260492, Emory COVID-19 research repository
Elizabeth A. Thompson, Wabathi Ngecu, Laila Stoddart, T. Scott Johnston, Amy Chang, Katherine Cascino, Jennifer L. Alejo, Aura T. Abedon, Hady Samaha, Nadine Rouphael, Aaron A.R. Tobian, Dorry L. Segev, William A. Werbel, Andrew H. Karaba, Joel N. Blankson, Andrea L. Cox
BACKGROUND Elevated circulating branched chain amino acids (BCAAs), measured at a single time point in middle life, are strongly associated with an increased risk of developing type 2 diabetes mellitus (DM). However, the longitudinal patterns of change in BCAAs through young adulthood and their association with DM in later life are unknown.METHODS We serially measured BCAAs over 28 years in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective cohort of apparently healthy Black and White young adults at baseline. Trajectories of circulating BCAA concentrations from years 2–30 (for prevalent DM) or years 2–20 (for incident DM) were determined by latent class modeling.RESULTS Among 3,081 apparently healthy young adults, trajectory analysis from years 2–30 revealed 3 distinct BCAA trajectory groups: low-stable (n = 1,427), moderate-stable (n = 1,384), and high-increasing (n = 270) groups. Male sex, higher body mass index, and higher atherogenic lipid fractions were more common in the moderate-stable and high-increasing groups. Higher risk of prevalent DM was associated with the moderate-stable (OR = 2.59, 95% CI: 1.90–3.55) and high-increasing (OR = 6.03, 95% CI: 3.86–9.43) BCAA trajectory groups in adjusted models. A separate trajectory group analysis from years 2–20 for incident DM after year 20 showed that moderate-stable and high-increasing trajectory groups were also significantly associated with higher risk of incident DM, after adjustment for clinical variables and glucose levels.CONCLUSION BCAA levels track over a 28-year span in most young adults, but serial clinical metabolomic measurements identify subpopulations with rising levels associated with high risk of DM in later life.FUNDING This research was supported by the NIH, under grants R01 HL146844 (JTW) and T32 HL069771 (MRC). The CARDIA study is conducted and supported by the NIH National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), the University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I).
Konrad T. Sawicki, Hongyan Ning, Norrina B. Allen, Mercedes R. Carnethon, Amisha Wallia, James D. Otvos, Issam Ben-Sahra, Elizabeth M. McNally, Janet K. Snell-Bergeon, John T. Wilkins
BACKGROUND. People living with HIV (PLHIV) on antiretroviral therapy (ART) exhibit persistent immune dysregulation and microbial dysbiosis, leading to the development of cardiovascular diseases (CVD). We initially compared plasma proteomic profiles between 205 PLHIV and 120 healthy controls (HCs) and validated the results in an independent cohort of 639 PLHIV and 99 HCs. Differentially expressed proteins (DEPs) were then associated to microbiome data. Finally, we assessed which proteins were linked with CVD development in PLHIV. METHOD. Proximity extension assay technology was utilized to measure 1472 plasma proteins. Markers of systemic inflammation (CRP, D-Dimer, IL6, sCD14, and sCD163) and microbial translocation (IFABP) were measured by ELISA, and gut bacterial species were identified using shotgun metagenomic sequencing. Baseline CVD data were available for all PLHIV, and 205 PLHIV were recorded for the development of CVD during a 5-year follow-up. RESULTS. PLHIV on ART displayed systemic dysregulation of protein concentrations compared to HCs. Most of the DEPs originated from the intestine and lymphoid tissues, while they enriched in immune- and lipid metabolism-related pathways. Furthermore, we observed that DEPs originating from the intestine were associated with specific gut bacterial species. Finally, we identified upregulated proteins in PLHIV (GDF15, PLAUR, RELT, NEFL, COL6A3, and EDA2R), unlike most markers of systemic inflammation, associated with the presence and risk of developing CVD in 5-year follow-up. CONCLUSIONS. Our findings suggest a systemic dysregulation of protein concentrations in PLHIV, of which some proteins were associated with CVD development. Most of DEPs originated from the gut and were related to specific gut bacterial species. TRIAL REGISTRATION. Cohorts included in this study are part of the Human Functional Genomics Project (HFGP) (www.humanfunctionalgenomics.org). The 2000HIV Human Functional Genomics Partnership Program is registered at ClinicalTrials.gov: (ID: NCT03994835). FUNDING. The 200HIV and 2000HIV studies are supported by the AIDS-fonds (#P-29001, Netherlands) and a ViiV healthcare grant (A18-1052), respectively; The ViiV healthcare grant was awarded to A.V., M.G.N., L.A.B.J., and Q.d.M; The Spinoza Prize (NWO SPI94-212) and ERC Advanced grant (no. 833247) were awarded to M.G.N; The Indonesia Endowment Fund for Education (LPDP) given by the Ministry of Finance of the Republic of Indonesia was awarded to N.V.
Nadira Vadaq, Yue Zhang, Wilhelm A.J.W. Vos, Albert L. Groenendijk, Martinus J.T. Blaauw, Louise E. van Eekeren, Maartje C.P. Jacobs-Cleophas, Lisa Van de Wijer, Jéssica Cristina dos Santos, Muhammad Hussein Gasem, Leo A.B. Joosten, Mihai G. Netea, Quirijn de Mast, Jingyuan Fu, André J.A.M. van der Ven, Vasiliki Matzaraki
BACKGROUND. Currently, no laboratory tests exist to stratify for the risk of developing sinusoidal obstruction syndrome (SOS), an early endothelial complication after hematopoietic cell transplantation (HCT). Risk biomarkers of SOS have not been verified in a prospective cohort accounting for differences between practices across institutions. Herein, we aimed to define risk groups for SOS occurrence using three proteins: L-Ficolin, Hyaluronic Acid (HA), and Stimulation-2 (ST2). METHODS. Between 2017 to 2021, we prospectively accrued 80 pediatric patients across 4 US centers. Biomarkers were tested by ELISA blind to patient groupings and associated with SOS incidence at day 35 post-HCT, and overall survival (OS) at day 100 post-HCT. Cutpoints were identified using retrospective cohorts and applied to the prospective cohort. RESULTS. Combination of the three biomarkers measured at day 3 post-HCT in the prospective cohort provided 80% (95%CI, 55-100%) sensitivity and 73% (95%CI, 62-83%) specificity for risk of SOS occurrence. Patients with low L-Ficolin were 9 times (95%CI 3-32) more likely to develop SOS, while patients with high HA and ST2 were 6.5 (95%CI 1.9-22.0) and 5.5 (95%CI 2.3-13.1) times more likely to develop SOS. These three markers also predicted worse day 100 OS [L-Ficolin: HR, 10.0 (95%CI 2.2-45.1), P=0.0002; HA: HR, 4.1 (95%CI 1.0-16.4), P=0.031; ST2: HR, 3.9 (95%CI 0.9-16.4), P=0.04]. CONCLUSION. L-Ficolin, HA, and ST2 levels measured as early as three days post-HCT improved risk stratification for SOS occurrence and OS and may guide risk-adapted preemptive therapy. TRIAL REGISTRATION. ClinicalTrials.gov NCT03132337. FUNDING. NICHD P50HD090215, R01HD074587, NCI R01CA168814 and NHLBI K24HL156896.
Yan Han, Alan Bidgoli, Brittany P. DePriest, Alejandra Méndez, Khadijeh Bijangi-Vishehsaraei, Evelio D. Perez-Albuerne, Robert A. Krance, Jamie Renbarger, Jodi L. Skiles, Sung W. Choi, Hao Liu, Sophie Paczesny
BACKGROUND. Due to their immunoregulatory and tissue regenerative features, mesenchymal stromal cells (MSCs) are a promising novel tool for the management of ulcerative proctitis (UP). Here we report on a phase IIa clinical study to evaluate the impact of local MSC therapy in UP. METHODS. Thirteen refractory UP patients, with endoscopic Mayo score (EMS) 2 or 3, were included. Seven patients received 20-40 x 106 allogeneic MSCs (cohort 1), while six patients received 40-80 x 106 MSCs (cohort 2). Adverse events (AEs) were assessed at baseline and week 2, 6, 12, and 24. Clinical, endoscopic, and biochemical parameters were assessed at baseline, week 2 and 6. Furthermore, we evaluated the engraftment of MSCs, presence of donor-specific human leukocyte antigen (HLA) antibodies (DSAs), and we determined the impact of MSC therapy on the local immune compartment. RESULTS. No serious AEs were observed. The clinical Mayo score was significantly improved at week 2 and 6, and the EMS was significantly improved at week 6, compared to baseline. At week 6, donor MSCs were still detectable in rectum biopsies of 4/9 patients and DSAs against both HLA-class I and -class II were found. Mass cytometry showed a reduction of activated CD8+ T cells and CD16+ monocytes and an enrichment in mononuclear phagocytes and natural killer cells in biopsies after local MSC therapy. CONCLUSION. Local administration of allogeneic MSCs is safe, tolerable, and feasible for treatment of refractory UP and shows encouraging signs of clinical efficacy and modulation of local immune responses. This sets the stage for larger clinical trials. TRIAL REGISTRATION. clinicaltrialsregister.eu, EudraCT: 2017-003524-75, Dutch Trial register: NTR7205. FUNDING. ECCO grant 2020.
Laura F. Ouboter, Marieke C. Barnhoorn, Hein W. Verspaget, Leonie Plug, Emma S. Pool, Karoly Szuhai, Lukas J.A.C. Hawinkels, Melissa van Pel, Jaap Jan Zwaginga, Dave Roelen, Frits Koning, M. Fernanda Pascutti, Andrea van der Meulen - de Jong
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