■ AbstractThe bone marrow is an invaluable source of adult pluripotent stem cells, as it gives rise to hematopoietic stem cells, endothelial progenitor cells, and mesenchymal cells, amongst others. The use of bone marrow-derived stem cell (BMSC) transplantation (BMT) may assist in achieving tissue repair and regeneration, and in modulating immune responses in the context of autoimmunity and transplantation. Ongoing clinical trials are evaluating the effects of BMSC to preserve functional beta-cell mass in subjects with type 1 and type 2 diabetes, and to favor engraftment and survival of transplanted islets. Additional trials are evaluating the impact of BMT (i.e., mesenchymal stem cells) on the progression of diabetes complications. This article reviews the progress in the field of BMSC for the treatment of subjects with insulindependent diabetes, by combining allogeneic islet transplantation with donor-specific BMSC. Clinical data is summarized from pilot studies performed at our research center over the last two decades.

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Mitochondria modulate inflammatory processes in various model organisms, but it is unclear how much mitochondria regulate immune responses in human blood leukocytes. Here, we examine the effect of i) experimental perturbations of mitochondrial respiratory chain function, and ii) baseline inter-individual variation in leukocyte mitochondrial energy production capacity on stimulated cytokine release and glucocorticoid (GC) sensitivity. In a first cohort, whole blood from 20 healthy women and men was stimulated with increasing concentrations of the immune agonist lipopolysaccharide (LPS). Four inhibitors of mitochondrial respiratory chain Complexes I, III, IV, and V were used (LPS + Mito-Inhibitors) to acutely perturb mitochondrial function, GC sensitivity was quantified using the GC-mimetic dexamethasone (DEX) (LPS + DEX), and the resultant cytokine signatures mapped with a 20-cytokine array. Inhibiting mitochondrial respiration caused large inter-individual differences in LPS-stimulated IL-6 reactivity (Cohen’s d = 0.72) and TNF-α ( d = 1.55) but only minor alteration in EC 50 -based LPS sensitivity ( d = 0.21). Specifically, inhibiting mitochondrial Complex IV potentiated LPS-induced IL-6 levels by 13%, but inhibited TNF-α induction by 72%, indicating mitochondrial regulation of the IL-6/TNF-α ratio. As expected, DEX treatment suppressed multiple LPS-induced pro-inflammatory cytokines (IFN-γ, IL-6, IL-8, IL-1β, .TNF-α) by >85% and increased the anti-inflammatory cytokine IL-10 by 80%. Inhibiting Complex I potentiated DEX suppression of IL-6 by a further 12% ( d = 0.73), indicating partial mitochondrial modulation of glucocorticoid sensitivity. Finally, to examine if intrinsic mitochondrial respiratory capacity may explain a portion of immune reactivity differences across individuals, we measured biochemical respiratory chain enzyme activities and mitochondrial DNA copy number in isolated peripheral blood mononuclear cells (PBMCs) from a second cohort of 44 healthy individuals in parallel with LPS-stimulated IL-6 and TNF-α response. Respiratory chain .function, particularly Complex IV activity, was positively correlated with LPS-stimulated IL-6 levels (r = 0.45, p = 0.002). Overall, these data provide preliminary evidence that mitochondrial behavior modulates LPS-induced inflammatory cytokine signatures in human blood.

With the world's population aging, age-related memory decline is an impending cognitive epidemic. Assessing the impact of diet on cognitive aging, we conducted a controlled, randomized, parallel-arm dietary intervention with 211 healthy adults (50–75 years) investigating effects of either a placebo or 260, 510 and 770 mg/day of cocoa flavanols for 12-weeks followed by 8-weeks washout. The primary outcome was a newly-developed object-recognition task localized to the hippocampus’ dentate gyrus. Secondary outcomes included a hippocampal-dependent list-learning task and a prefrontal cortex-dependent list-sorting task. The alternative Healthy Eating Index and a biomarker of flavanol intake (gVLM) were measured. In an MRI substudy, hippocampal cerebral blood volume was mapped. Object-recognition and list-sorting performance did not correlate with baseline diet quality and did not improve after flavanol intake. However, the hippocampal-dependent list-learning performance was directly associated with baseline diet quality and improved after flavanol intake, particularly in participants in the bottom tertile of baseline diet quality. In the imaging substudy, a region-of-interest analysis was negative but a voxel-based-analysis suggested that dietary flavanols target the dentate gyrus. While replication is needed, these findings suggest that diet in general, and dietary flavanols in particular, may be associated with memory function of the aging hippocampus and normal cognitive decline.

BackgroundConsensus panels regularly recommend aerobic exercise for its health‐promoting properties, due in part to presumed anti‐inflammatory effects, but many studies show no such effect, possibly related to study differences in participants, interventions, inflammatory markers, and statistical approaches. This variability makes an unequivocal determination of the anti‐inflammatory effects of aerobic training elusive.Methods and ResultsWe conducted a randomized controlled trial of 12 weeks of aerobic exercise training or a wait list control condition followed by 4 weeks of sedentary deconditioning on lipopolysaccharide (0, 0.1, and 1.0 ng/mL)‐inducible tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6), and on toll‐like receptor 4 in 119 healthy, sedentary young adults. Aerobic capacity by cardiopulmonary exercise testing was measured at study entry (T1) and after training (T2) and deconditioning (T3). Despite a 15% increase in maximal oxygen consumption, there were no changes in inflammatory markers. Additional analyses revealed a differential longitudinal aerobic exercise training effect by lipopolysaccharide level in inducible TNF‐α (P=0.08) and IL‐6 (P=0.011), showing T1 to T2 increases rather than decreases in inducible (lipopolysaccharide 0.1, 1.0 versus 0.0 ng/mL) TNF‐α (51% increase, P=0.041) and IL‐6 (42% increase, P=0.11), and significant T2 to T3 decreases in inducible TNF‐α (54% decrease, P=0.007) and IL‐6 (55% decrease, P<0.001). There were no significant changes in either group at the 0.0 ng/mL lipopolysaccharide level for TNF‐α or IL‐6.ConclusionsThe failure to support the primary hypotheses and the unexpected post hoc findings of an exercise‐training–induced proinflammatory response raise questions about whether and under what conditions exercise training has anti‐inflammatory effects.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01335737.

OBJECTIVETo evaluate if baseline serum lipids are associated with islet graft survival in type 1 diabetes islet transplant (ITx) recipients.RESEARCH DESIGN AND METHODSBaseline fasting lipid profile was collected from 44 ITx recipients. Comparisons were performed between subjects below and above the median values of each lipid fraction. Differences in outcomes were compared by Kaplan-Meier curves and Cox regression analysis.RESULTSSubjects with baseline fasting plasma triglycerides and VLDL cholesterol above the median had shorter islet graft survival (triglycerides: 39.7 ± 6.1 vs. 61.3 ± 6.6 months, P = 0.029, and VLDL: 41.5 ± 5.7 vs. 62.8 ± 7.3 months, P = 0.032). Total, LDL, and HDL cholesterol did not influence islet function. Triglycerides (odds ratio 2.97 [95% CI 1.03–8.52], P = 0.044) maintained its association with graft failure after adjustments for confounders.CONCLUSIONSHigher baseline triglycerides are associated with earlier decline in islet graft function. Prospective clinical trials should address whether it is directly caused by lipotoxicity and if strategies focusing on lowering serum lipids may prolong islet graft survival.

Objective Elevated cardiovascular reactivity to, and reduced recovery from, challenging events may increase the risk of cardiovascular disease, and exercise training may reduce this reactivity. However, in a randomized controlled trial of aerobic versus strength training in sedentary, healthy young adults, we found no training group differences in reactivity or recovery. Because strength training also may have a reactivity-reducing effect, we conducted a secondary analysis of data from another trial, this time with a wait-list control condition. Methods One hundred nineteen healthy, young, sedentary adults were randomized to a 12-week aerobic training program or wait-list control. Before (T1) and after (T2) training and after 4 weeks of sedentary deconditioning (T3), we measured heart rate (HR), heart rate variability, and blood pressure at rest and in response to and recovery from psychological and orthostatic challenge. Data were analyzed using a group (aerobic versus wait-list) by session (T1, T2, and deconditioning) and by period (baseline, psychological challenge, recovery, standing) three-way analysis of variance with prespecified contrasts. Results Aerobic capacity significantly increased at T2 and decreased at T3 only in the aerobic training group. The groups did not differ on HR, heart rate variability, or blood pressure reactivity to or recovery from challenge. Without baseline adjustment, there were no significant treatment differences in response to challenges. With baseline adjustment, there were significant treatment by session effects for HR (Cohen d = 0.54, p = .002), systolic blood pressure (d = 0.44, p = .014), diastolic blood pressure (d = 0.74, p = .002), and root mean squared successive difference (d = 0.48, p = .006) reactivity from T1 to T2 only for orthostatic challenge: at T2, reactivity in the aerobic group was nonsignificantly reduced, compared with T1. In the wait-list group, reactivity significantly increased after T1. Conclusions This study raises further doubt about attenuation of cardiovascular reactivity or enhancement of recovery as a cardioprotective mechanism of aerobic exercise training. Clinical Trial Registration: ClinicalTrials.gov Unique identifier: NCT01335737.