Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.

Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4A exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4 and CD3CD4CD8 double-negative T cells over CD8 T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice.

mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.

Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency.

Metabolic pathways mediate pathogenesis and offer targets for treatment in rheumatic diseases.

Purpose Of Review: The cause of autoimmune diseases remains incompletely understood. Here, we highlight recent advances in the role of proinflammatory metabolic pathways in autoimmune disease, including treatment with antioxidants and mechanistic target of rapamycin (mTOR) inhibitors.

Recent Findings: Recent studies show that mTOR pathway activation, glucose utilization, mitochondrial oxidative phosphorylation, and antioxidant defenses play critical roles in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, immune thrombocytopenia, Sjögren's syndrome, large vessel vasculitis, and systemic lupus erythematosus.

Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials.

Background: Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer's disease (AD).

Methods: Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.

Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques.

Objectives: To explore the effects of tofacitinib-an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)-with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand.

Methods: In this exploratory, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score (RAMRIS), quantitative RAMRIS (RAMRIQ) and dynamic contrast-enhanced (DCE) MRI) were assessed using a mixed-effect model for repeated measures.

Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Individuals with Early Alzheimer's Disease: Amyloid Imaging Positron Emission Tomography and Safety Results from a Phase 2 Study.

Background: ACC-001 is an investigational therapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease.

Objectives: To evaluate safety, immunogenicity, impact on brain amyloid, and other exploratory endpoints in participants receiving ACC-001.

Design: Randomized, phase 2, interventional study.

Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer's Disease.

Background: Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE*ɛ4 carriers and noncarriers, respectively, with Alzheimer's disease.

Objectives: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change.

Methods: Bapineuzumab dosages included 0.

Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity.

The serotonergic system is widely distributed throughout the central nervous system. It is well known as a mood regulating system, although it also contributes to many other functions. With resting state functional magnetic resonance imaging (RS-fMRI) it is possible to investigate whole brain functional connectivity.

Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials.

Objective: To evaluate the effects of bapineuzumab on brain β-amyloid (Aβ) burden using (11)C-Pittsburgh compound B ((11)C-PiB)-PET.

Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE ε4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aβ monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks.

Carotid magnetic resonance imaging for monitoring atherosclerotic plaque progression: a multicenter reproducibility study.

This study sought to determine the multicenter reproducibility of magnetic resonance imaging (MRI) and the compatibility of different scanner platforms in assessing carotid plaque morphology and composition. A standardized multi-contrast MRI protocol was implemented at 16 imaging sites (GE: 8; Philips: 8). Sixty-eight subjects (61 ± 8 years; 52 males) were dispersedly recruited and scanned twice within 2 weeks on the same magnet.

Changes in MR relaxation times of the meniscus with acute loading: an in vivo pilot study in knee osteoarthritis.

Purpose: To prospectively evaluate changes in T1ρ and T2 relaxation times in the meniscal body with acute loading using MRI in osteoarthritic knees and to compare these findings with those of age-matched healthy controls.

Materials And Methods: Female subjects above 40 years of age with (N1  = 20) and without osteoarthritis (OA) (N2  = 10) were imaged on a 3 Tesla MR scanner using a custom made loading device. MR images were acquired, with the knee flexed at 20°, with and without a compressive load of 50% of the subject's bodyweight.

Differences between X-ray and MRI-determined knee cartilage thickness in weight-bearing and non-weight-bearing conditions.

Objective: Determine the effect of loading upon MRI-based mean medial femorotibial cartilage thickness (mMFT_th) and radiograph-based minimum joint space width (mJSW), and determine loading's effect on the relationship between these measures.

Methods: MRI and radiographs were analyzed of 25 knees in weight-bearing and non-weight-bearing conditions. Eight subjects had a Kellgren-Lawrence (KL) grade of 0, indicating no evidence of radiographic OA.

Relationship between knee pain and the presence, location, size and phenotype of femorotibial denuded areas of subchondral bone as visualized by MRI.

Objective: Conflicting associations between imaging biomarkers and pain in knee osteoarthritis (OA) have been reported. A relation between pain and denuded areas of subchondral bone (dABs) has been suggested and this study explores this relationship further by relating the presence, phenotype, location and size of dABs to different measures of knee pain.

Methods: 633 right knees from the Osteoarthritis Initiative (OAI) (250 men, age 61.

Disease progression modeling using Hidden Markov Models.

The development of novel treatments for many slowly progressing diseases, such as Alzheimer's disease (AD), is dependent on the ability to monitor and detect changes in disease progression. In some diseases the distinct clinical stages of the disease progress far too slowly to enable a quick evaluation of the efficacy of a given proposed treatment. To help improve the assessment of disease progression, we propose using Hidden Markov Models (HMM's) to model, in a more granular fashion, disease progression as compared to the clinical stages of the disease.

Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study.

Objective: The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported.

Methods: In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily.

Standardization of analysis sets for reporting results from ADNI MRI data.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) three-dimensional T1-weighted magnetic resonance imaging (MRI) acquisitions provide a rich data set for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data.

A computational neurodegenerative disease progression score: method and results with the Alzheimer's disease Neuroimaging Initiative cohort.

While neurodegenerative diseases are characterized by steady degeneration over relatively long timelines, it is widely believed that the early stages are the most promising for therapeutic intervention, before irreversible neuronal loss occurs. Developing a therapeutic response requires a precise measure of disease progression. However, since the early stages are for the most part asymptomatic, obtaining accurate measures of disease progression is difficult.

A simple strategy for jumping straight up.

Jumping from a stationary standing position into the air is a transition from a constrained motion in contact with the ground to an unconstrained system not in contact with the ground. A simple case of the jump, as it applies to humans, robots and humanoids, is studied in this paper. The dynamics of the constrained rigid body are expanded to define a larger system that accommodates the jump.

Association of MR relaxation and cartilage deformation in knee osteoarthritis.

We assessed the relationship between cartilage MR relaxation times and biomechanical response of tibiofemoral articular cartilage to physiological loading in healthy subjects and patients with osteoarthritis (OA). Female subjects above 40 years of age with (N(1)  = 20) and without (N(2)  = 10) OA were imaged on a 3T MR scanner using a custom made loading device. MR images were acquired with the knee flexed at 20° with and without a compressive load of 50% of the subject's bodyweight.

In vivo tibiofemoral cartilage-to-cartilage contact area of females with medial osteoarthritis under acute loading using MRI.

Purpose: To investigate the effect of acute loading on in vivo tibiofemoral contact area changes in both compartments, and to determine whether in vivo tibiofemoral contact area differs between subjects with medial knee osteoarthritis (OA) and healthy controls.

Materials And Methods: Ten subjects with medial knee OA (KL3) and 11 control subjects (KL0) were tested. Coronal three-dimensional spoiled gradient-recalled (3D-SPGR) and T(2) -weighted fast spin-echo FSE magnetic resonance imaging (MRI) of the knee were acquired under both unloaded and loaded conditions.

Loading of the knee during 3.0T MRI is associated with significantly increased medial meniscus extrusion in mild and moderate osteoarthritis.

Purpose: Standard knee MRI is performed under unloading (ULC) conditions and not much is known about changes of the meniscus, ligaments or cartilage under loading conditions (LC). The aim is to study the influence of loading of different knee structures at 3Tesla (T) in subjects with osteoarthritis (OA) and normal controls.

Materials And Methods: 30 subjects, 10 healthy and 20 with radiographic evidence of OA (10 mild and 10 moderate) underwent 3T MRI under ULC and LC at 50% body weight.

Clinical, radiographic, molecular and MRI-based predictors of cartilage loss in knee osteoarthritis.

Objective: To examine the relationship of baseline clinical, radiographic, molecular and MRI measures with structural progression (subregional MRI-based femorotibial cartilage loss) in knee osteoarthritis (OA).

Methods: Single knees of 75 female participants with radiographic knee OA (and 77 healthy control participants) were examined over 24 months using MRI. Subregional femorotibial cartilage thickness was determined at baseline and follow-up.

The relationship between prevalent medial meniscal intrasubstance signal changes and incident medial meniscal tears in women over a 1-year period assessed with 3.0 T MRI.

Objective: Intrasubstance meniscal signal changes not reaching the articular surface on fast spin echo (FSE) sequences are considered to represent mucoid degeneration on MRI. The aim of this study was to evaluate the association of prevalent intrasubstance signal changes with incident tears of the medial meniscus detected on 3.0 T MRI over a 1-year period.

Osteoarthritis of the knee at 3.0 T: comparison of a quantitative and a semi-quantitative score for the assessment of the extent of cartilage lesion and bone marrow edema pattern in a 24-month longitudinal study.

Objective: To compare a semi-quantitative and a quantitative morphological score for assessment of early osteoarthritis (OA) evolution.

Materials And Methods: 3.0 T MRI of the knee was performed in 60 women, 30 with early OA (each 15 with Kellgren-Lawrence grade 2 and 3) and 30 age-matched controls at baseline and at 12 and 24 months.

In vivo measures of cartilage deformation: patterns in healthy and osteoarthritic female knees using 3T MR imaging.

Objective: To explore and to compare the magnitude and spatial pattern of in vivo femorotibial cartilage deformation in healthy and in osteoarthritic (OA) knees.

Methods: One knee each in 30 women (age: 55 ± 6 years; BMI: 28 ± 2.4 kg/m(2); 11 healthy and 19 with radiographic femorotibial OA) was examined at 3Tesla using a coronal fat-suppressed gradient echo SPGR sequence.