Oligodendrogliopathy in Multiple Sclerosis: Low Glycolytic Metabolic Rate Promotes Oligodendrocyte Survival.

UNLABELLED: Multiple sclerosis (MS) lesions feature demyelination with limited remyelination. A distinct injury phenotype of MS lesions features dying back of oligodendrocyte (OL) terminal processes, a response that destabilizes myelin/axon interactions. This oligodendrogliopathy has been linked with local metabolic stress, similar to the penumbra of ischemic/hypoxic states. Here, we developed an in vitro oligodendrogliopathy model using human CNS-derived OLs and related this injury response to their distinct bioenergetic properties. We determined the energy utilization properties of adult human surgically derived OLs cultured under either optimal or metabolic stress conditions, deprivation of growth factors, and glucose and/or hypoxia using a Seahorse extracellular flux analyzer. Baseline studies were also performed on OL progenitor cells derived from the same tissue and postnatal rat-derived cells. Under basal conditions, adult human OLs were less metabolically active than their progenitors and both were less active than the rat cells. Human OLs and progenitors both used aerobic glycolysis for the majority of ATP production, a process that contributes to protein and lipid production necessary for myelin biosynthesis. Under stress conditions that induce significant process retraction with only marginal cell death, human OLs exhibited a significant reduction in overall energy utilization, particularly in glycolytic ATP production. The stress-induced reduction of glycolytic ATP production by the human OLs would exacerbate myelin process withdrawal while favoring cell survival, providing a potential basis for the oligodendrogliopathy observed in MS. The glycolytic pathway is a potential therapeutic target to promote myelin maintenance and enhance repair in MS. SIGNIFICANCE STATEMENT: The neurologic deficits that characterize multiple sclerosis (MS) reflect disruption of myelin (demyelination) within the CNS and failure of repair (remyelination). We define distinct energy utilization properties of human adult brain-derived oligodendrocytes and oligodendrocyte progenitor cells under conditions of metabolic stress that model the initial relapsing and subsequent progressive phases of MS. The observed changes in energy utilization affect both cell survival and myelination capacity. These processes may be amenable to therapeutic interventions to limit the extent of cumulative tissue injury and to promote repair in MS.

Safety and efficacy of initial combination of linagliptin and metformin in patients with type 2 diabetes: A subgroup analysis of Indian patients from a randomized, double-blind, placebo-controlled study.

CONTEXT AND OBJECTIVES: The number of people with diabetes is increasing exponentially in India. Owing to a unique "Asian Indian Phenotype," Indians develop diabetes a decade earlier and have an earlier onset of complications than Western populations. Therefore, it is essential to evaluate more effective treatment strategies at an earlier stage of disease progression, such as initial combination therapy, in Indian patients. In this study, we evaluated the efficacy and safety of initial combination therapy with linagliptin plus metformin in comparison to linagliptin or metformin monotherapy in Indian patients with type 2 diabetes mellitus. METHODS: This is a subgroup analysis of Indian patients who participated in a Phase III, 24-week, double-blind, placebo-controlled, trial. Overall, 249 Indian patients were randomized to one of six treatment arms (Two free combination therapy arms: Linagliptin 2.5 mg twice daily [bid] + either low [500 mg, n = 36] or high [1000 mg, n = 44] dose metformin bid and four monotherapy arms: Linagliptin 5 mg once daily [qd, n = 40], metformin 500 mg [n = 49] or 1000 mg bid [n = 45], or placebo [n = 23]). RESULTS: The placebo-corrected mean change in glycated hemoglobin from baseline (8.9%) to week 24 was -1.83% for linagliptin + metformin 1000 mg bid; -1.46% for linagliptin + metformin 500 mg bid; -1.30% for metformin 1000 mg bid; -1.00% for metformin 500 mg bid; and -0.77% for linagliptin 5 mg qd. None of the patients in the combination therapy arms had hypoglycemia, whereas there was one event in the metformin 1000 mg bid arm. Rates of adverse event were similar across various treatments. CONCLUSIONS: In this subgroup analysis of Indian patients, initial combination therapy with linagliptin + metformin was more efficacious in improving glycemic control than the monotherapy arms, with a comparable tolerability profile. The results were comparable to the overall population.

A randomised study of dabigatran in elective percutaneous coronary intervention in stable coronary artery disease patients.

AIMS: Patients receiving long-term anticoagulant treatment with dabigatran may need to undergo a percutaneous coronary intervention (PCI). We studied markers of coagulation activation during elective PCI in patients using dabigatran in order to investigate whether coagulation activation upon balloon inflation and stenting is suppressed by dabigatran without additional heparin treatment. METHODS AND RESULTS: This phase IIa, exploratory, multicentre, randomised, open-label study included 50 stable patients having an elective PCI. Patients on standard dual antiplatelet therapy (DAPT) were randomised (2:2:1) to either pre-procedural dabigatran 110 mg BID (n=19) or 150 mg BID (n=21), as compared to standard intraprocedural unfractionated heparin (UFH) (n=10). Following PCI, a significant increase in the levels of prothrombin fragment 1+2 (F1+2) in the combined dabigatran group was observed compared to the level just before the start of PCI (159.1 [1.4] pmol/l; geometric mean [gSD]). Levels at 0.5, 1.0, 1.5 and 2 hrs after the start of PCI ranged from 193.5 (1.4) to 270.6 pmol/l (1.7); (p-value for paired analysis=0.015, 0.022, 0.2342, 0.0379, respectively). Also, thrombin-antithrombin (TAT) complexes were increased significantly in the combined dabigatran group compared to pre-PCI levels (4.2 [2.2] ug/l). Levels ranged from 5.2 (2.5) to 8.5 (2.3) (p=0.0497, 0.0343, 0.005 and 0.1628, respectively). In contrast, in the control group of patients treated with UFH, no increase was observed in F1+2 and TAT complexes during PCI. Five out of 40 (12.5%) patients required bail-out anticoagulation in the dabigatran group, of whom four experienced a procedural myocardial infarction (MI), versus one out of 10 in the UFH group, who had a stent thrombosis without MI prior to the study-PCI. One minor access-site bleeding occurred in the dabigatran group. CONCLUSIONS: Dabigatran treatment (110 mg or 150 mg BID) may not provide sufficient anticoagulation during PCI. EudraCT. No: 2007-007536-25.

Efficacy and safety of pimecrolimus-eluting stents in porcine coronary arteries.

OBJECTIVE: We aimed to evaluate an effective dosage and safety profile of pimecrolimus as an anti-inflammatory drug for drug-eluting stents. METHODS: In the dose finding study, coronary arteries of 20 domestic swine were randomly implanted with bare metal stents (ProKinetic and Guidant Vision), the ProKinetic stent with polylactic acid (PLLA), and pimecrolimus-eluting stents (32, 75, and 120 microg) over a period of 4 weeks. In addition, pimecrolimus (75 microg) and ProKinetic stents were randomly implanted into six swine over 3 months. In the safety study, the ProKinetic stent, the ProKinetic stent with PLLA, mid- (45 microg) and high-dose pimecrolimus (120 microg), and overlapping mid-dose stents were implanted over a period of 4 weeks. Mid-dose, ProKinetic stent, and ProKinetic stent with PLLA were implanted over a period of 3 months. RESULTS: The dose finding study revealed excellent luminal patency with low percent occlusion (approximately 29% vs. approximately 41%), injury (0.53-0.59 vs. 1.25), and inflammation (0.78-0.97 vs. 1.08) for the pimecrolimus group compared with the vision group. The safety study arm showed similar angiographic results for all tested groups, with a significantly larger minimal lumen diameter for pimecrolimus stents compared to PLLA stents. Except for the high-dose group and overlapping area of the overlapping group, promising morphometric results were found for pimecrolimus compared to bare metal stents. CONCLUSIONS: Present data suggest that pimecrolimus-eluting stents are safe and have a similar healing profile to bare metal stents. They may suppress inflammation, leading to a reduced intimal response and a milder inflammatory reaction in a porcine model.

Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction.

Antigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase Cbl-b is upregulated in T cells after tolerizing signals. Loss of Cbl-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of Cbl-b mutant mice with the tolerizing antigen results in massive lethality. Moreover, ablation of Cbl-b resulted in exacerbated autoimmunity. Mechanistically, loss of Cbl-b rescues reduced calcium mobilization of anergic T cells, which was attributed to Cbl-b-mediated regulation of PLCgamma-1 phosphorylation. Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells.

Biocompatibility and performance of the Wallstent and the Wallgraft, Jostent, and Hemobahn stent-grafts in a sheep model.

PURPOSE: Three recently developed stent-grafts and the Wallstent were compared directly in an ovine animal model with regard to performance and biocompatibility. MATERIALS AND METHODS: Three stent-grafts, the Hemobahn (polytetrafluoroethylene [ePTFE]/nitinol), Wallgraft (polyester/Ni-Co-Ti-steel alloy), and Jostent peripheral stent-graft (balloon-expandable ePTFE/stainless steel), and the Wallstent (Ni-Co-Ti-steel alloy), were implanted in sheep iliac arteries (one type of each stent or stent-graft per animal, n = 8). Pre- and postimplantation luminal diameters were measured for each prosthesis and implantation site. Angiography, intravascular ultrasonography (IVUS), and histomorphometric, histologic, and scanning electron microscopic analyses were performed at 3 months. RESULTS: Early lumen gain, late lumen loss, and patent vessel diameter at angiography were not significantly different. Two stent-grafts had significantly more neointima formation (Hemobahn, 9.88 mm(2) +/- 0.94; Wallgraft, 14.98 mm(2) +/- 0.90) than the other stent-graft (Jostent, 6.52 mm(2) +/- 0.46) and the Wallstent (5.24 mm(2) +/- 0.62; P <.01). Patent lumen area was not significantly different (Hemobahn, 42.57 mm(2) +/- 1.41; Jostent, 39.76 mm(2) +/- 2.04; Wallgraft, 40.22 mm(2) +/- 1.04; Wallstent, 41.64 mm(2) +/- 1.59; P =.57). The Hemobahn had significantly more inflammatory reaction (inflammation score of 0.83 +/- 0.03) than the Jostent (0.58 +/- 0.03), Wallgraft (0.55 +/- 0.04), or Wallstent (0.16 +/- 0.01). Angiography and IVUS demonstrated absence of anastomotic neointima formation. Endothelialization was incomplete and immature for all prostheses. CONCLUSIONS: The stent-grafts caused a greater degree of neointima formation and inflammatory vessel wall reaction than the bare stent. However, these changes did not interfere with patent lumen areas and occurred in the absence of excessive anastomotic neointima formation.