Safety and efficacy of first-in-man intrathecal injection of human astrocytes (AstroRx®) in ALS patients: phase I/IIa clinical trial results.

BACKGROUND: Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients. METHODS: We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx® in patients with ALS. Five patients were injected intrathecally with a single dose of 100 × 106 AstroRx® cells and 5 patients with 250 × 106 cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3 months pre-treatment (run-in period) and 12 months post-treatment (follow-up period). RESULTS: A single administration of AstroRx® at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx® itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100 × 106 AstroRx® arm, the ALSFRS-R rate of deterioration was attenuated from - 0.88/month pre-treatment to - 0.30/month in the first 3 months post-treatment (p = 0.039). In the 250 × 106 AstroRx® arm, the ALSFRS-R slope decreased from - 1.43/month to - 0.78/month (p = 0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study. CONCLUSIONS: Overall, these findings suggest that a single IT administration of AstroRx® to ALS patients at a dose of 100 × 106 or 250 × 106 cells is safe. A signal of beneficial clinical effect was observed for the first 3 months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx®, e.g., every 3 months. TRIAL REGISTRATION: NCT03482050.

Astrocytes Downregulate Inflammation in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome: Applicability to COVID-19.

Background: An acute respiratory distress syndrome (ARDS) is caused by the increased amounts of pro-inflammatory cytokines and neutrophil-mediated tissue injury. To date, there is no effective treatment for the ARDS available, while the need for one is growing due to the most severe complications of the current coronavirus disease-2019 (COVID-19) pandemic. The human astrocytes (AstroRx) have shown immunomodulatory properties in the central nervous system (CNS). This study aimed to evaluate the capacity of astrocytes to decrease lung inflammation and to be applied as a treatment therapy in ARDS. Methods: First, we assessed the ability of clinical-grade AstroRx to suppress T-cell proliferation in a mixed lymphocyte reaction test. Next, we tested the therapeutical potential of AstroRx cells in a lipopolysaccharide (LPS)-based ARDS mouse model by injecting AstroRx intravenously (i.v). We determined the degree of lung injury by using a severity scoring scale of 0-2, based on the American Thoracic Society. The scoring measured the presence of neutrophils, fibrin deposits, and the thickening of alveolar walls. The state of inflammation was further assessed by quantifying the immune-cell infiltration to the bronchoalveolar lavage fluid (BALF) and by the presence of proinflammatory cytokines and chemokines in the BALF and serum. Results: We detected that AstroRx cells were capable to suppress T-cell proliferation in vitro after exposure to the mitogen concanavalin A (ConA). In vivo, AstroRx cells were able to lower the degree of lung injury in LPS-treated animals compared with the sham injected animals (P = 0.039). In this study, 30% of AstroRx treated mice showed no lung lesions (responder mice), these mice presented a steady number of eosinophils, T cells, and neutrophils comparable with the level of naïve control mice. The inflammatory cytokines and chemokines, such as TNFα, IL1b, IL-6, and CXCL1, were also kept in check in responder AstroRx-treated mice and were not upregulated as in the sham-injected mice (P < 0.05). As a result, the LPS-treated ARDS mice had a higher survival rate when they were treated with AstroRx. Conclusions: Our results demonstrate that the immunosuppressive activity of AstroRx cells support the application of AstroRx cells as a cell therapy treatment for ARDS. The immunoregulatory activity may also be a part of the mechanism of action of AstroRx reported in the amyotrophic lateral sclerosis (ALS) neurodegenerative disease.

Selection for CD26- and CD49A+ Cells From Pluripotent Stem Cells-Derived Islet-Like Clusters Improves Therapeutic Activity in Diabetic Mice.

Background: Cell therapy of diabetes aims at restoring the physiological control of blood glucose by transplantation of functional pancreatic islet cells. A potentially unlimited source of cells for such transplantations would be islet cells derived from an in vitro differentiation of human pluripotent stem cells (hESC/hiPSC). The islet-like clusters (ILC) produced by the known differentiation protocols contain various cell populations. Among these, the ß-cells that express both insulin and the transcription factor Nkx6.1 seem to be the most efficient to restore normoglycemia in diabetes animal models. Our aim was to find markers allowing selection of these efficient cells. Methods: Functional Cell-Capture Screening (FCCS) was used to identify markers that preferentially capture the cells expressing both insulin and Nkx6.1, from hESC-derived ILC cells. In order to test whether selection for such markers could improve cell therapy in diabetic mouse models, we used ILC produced from a clinical-grade line of hESC by a refined differentiation protocol adapted to up-scalable bioreactors. Re-aggregated MACS sorted cells were encapsulated in microspheres made of alginate modified to reduce foreign body reaction. Implantation was done intraperitoneally in STZ-treated C57BL/6 immuno-competent mice. Results: CD49A (integrin alpha1) was identified by FCCS as a marker for cells that express insulin (or C-peptide) as well as Nkx6.1 in ILC derived by hESC differentiation. The ILC fraction enriched in CD49A + cells rapidly reduced glycemia when implanted in diabetic mice, whereas mice receiving the CD49A depleted population remained highly diabetic. CD49A-enriched ILC cells also produced higher levels of human C-peptide in the blood of transplanted mice. However, the difference between CD49A-enriched and total ILC cells remained small. Another marker, CD26 (DPP4), was identified by FCCS as binding insulin-expressing cells which are Nkx6.1 negative. Depletion of CD26 + cells followed by enrichment for CD49A + cells increased insulin+/Nkx6.1+ cells fraction to ~70%. The CD26 - /CD49A + enriched ILC exhibited improved function over non-sorted ILC or CD49A + cells in diabetic mice and maintain prolonged blood C-peptide levels. Conclusions: Refining the composition of ILC differentiated from hPSC by negative selection to remove cells expressing CD26 and positive selection for CD49A expressing cells could enable more effective cell therapy of diabetes.

Rising Stars: Astrocytes as a Therapeutic Target for ALS Disease.

Amyotrophic lateral sclerosis (ALS) is a multifactorial disease, characterized by a progressive loss of motor neurons that eventually leads to paralysis and death. The current ALS-approved drugs modestly change the clinical course of the disease. The mechanism by which motor neurons progressively degenerate remains unclear but entails a non-cell autonomous process. Astrocytes impaired biological functionality were implicated in multiple neurodegenerative diseases, including ALS, frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer disease (AD). In ALS disease patients, A1 reactive astrocytes were found to play a key role in the pathology of ALS disease and death of motor neurons, via loss or gain of function or acquired toxicity. The contribution of astrocytes to the maintenance of motor neurons by diverse mechanisms makes them a promising therapeutic candidate for the treatment of ALS. Therapeutic approaches targeting at modulating the function of endogenous astrocytes or replacing lost functionality by transplantation of healthy astrocytes, may contribute to the development of therapies which might slow down or even halt the progression ALS diseases. The proposed mechanisms by which astrocytes can potentially ameliorate ALS progression and the status of ALS clinical studies involving astrocytes are discussed.

Safety and efficacy of human embryonic stem cell-derived astrocytes following intrathecal transplantation in SOD1G93A and NSG animal models.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron (MN) disease characterized by the loss of MNs in the central nervous system. As MNs die, patients progressively lose their ability to control voluntary movements, become paralyzed and eventually die from respiratory/deglutition failure. Despite the selective MN death in ALS, there is growing evidence that malfunctional astrocytes play a crucial role in disease progression. Thus, transplantation of healthy astrocytes may compensate for the diseased astrocytes. METHODS: We developed a good manufacturing practice-grade protocol for generation of astrocytes from human embryonic stem cells (hESCs). The first stage of our protocol is derivation of astrocyte progenitor cells (APCs) from hESCs. These APCs can be expanded in large quantities and stored frozen as cell banks. Further differentiation of the APCs yields an enriched population of astrocytes with more than 90% GFAP expression (hES-AS). hES-AS were injected intrathecally into hSOD1G93A transgenic mice and rats to evaluate their therapeutic potential. The safety and biodistribution of hES-AS were evaluated in a 9-month study conducted in immunodeficient NSG mice under good laboratory practice conditions. RESULTS: In vitro, hES-AS possess the activities of functional healthy astrocytes, including glutamate uptake, promotion of axon outgrowth and protection of MNs from oxidative stress. A secretome analysis shows that these hES-AS also secrete several inhibitors of metalloproteases as well as a variety of neuroprotective factors (e.g. TIMP-1, TIMP-2, OPN, MIF and Midkine). Intrathecal injections of the hES-AS into transgenic hSOD1G93A mice and rats significantly delayed disease onset and improved motor performance compared to sham-injected animals. A safety study in immunodeficient mice showed that intrathecal transplantation of hES-AS is safe. Transplanted hES-AS attached to the meninges along the neuroaxis and survived for the entire duration of the study without formation of tumors or teratomas. Cell-injected mice gained similar body weight to the sham-injected group and did not exhibit clinical signs that could be related to the treatment. No differences from the vehicle control were observed in hematological parameters or blood chemistry. CONCLUSION: Our findings demonstrate the safety and potential therapeutic benefits of intrathecal injection of hES-AS for the treatment of ALS.

Kinematic analysis of the shoulder complex after anatomic and reverse total shoulder arthroplasty: A cross-sectional study.

BACKGROUND: The movement of the arm relative to the trunk results from coordinated 3D glenohumeral and scapulothoracic movements. Changes in scapula kinematics may occur after total shoulder arthroplasty and could affect clinical and functional outcomes. OBJECTIVES: To assess the 3D movement of the scapula during arm elevation after anatomic and reverse total shoulder arthroplasty. DESIGN/METHODS: This was a single-centre, non-randomized, controlled cross-sectional study. Patients with anatomic (n = 14) and reverse total shoulder arthroplasty (n = 9) were prospectively enrolled and were compared to age-matched asymptomatic controls (n = 23). 3D scapular kinematics were assessed by a non-invasive, electromagnetic method during arm abduction and flexion. 3D scapular rotations and 3D linear displacements of the barycentre (geometrical centre) at rest and at 30°, 60° and 90° arm elevation; as well as scapulohumeral rhythm were analysed. Participant groups were compared using one-way ANOVA and Bonferroni post-hoc testing for normally distributed data, and Mann-Whitney U test for non-normally distributed data. RESULTS/FINDINGS: Total range of scapular lateral rotation and barycentre displacement were increased, and scapulohumeral rhythm was reduced, in patients with anatomic and reverse total shoulder arthroplasty compared with age-matched controls; however, the global scapular kinematic pattern was preserved. CONCLUSION/INTERPRETATION: For patients after total shoulder arthroplasty, the increased contribution of the scapula to arm elevation is consistent with a compensatory mechanism for the reduced glenohumeral mobility. The stability of the global scapula kinematic pattern reflects its mechanical and neuromotor strength.

Compact MRI for the detection of teratoma development following intrathecal human embryonic stem cell injection in NOD-SCID mice.

Stem cells are emerging as a promising new treatment modality for a variety of central nervous system disorders. However, their use is hampered by the potential for the development of teratomas and other tumors. Therefore, there is a crucial need for the development of methods for detecting teratomas in preclinical safety studies. The aim of the current study is to assess the ability of a compact Magnetic Resonance Imaging (MRI) system to detect teratoma formation in mice. Five NOD-SCID mice were injected intrathecally with human embryonic stem cells (hESCs), with two mice serving as controls. In vivo MRI was performed on days 25 and 48, and ex vivo MRI was performed after scheduled euthanization (day 55). MRI results were compared to histopathology findings. Two animals injected with hESCs developed hind-limb paresis and paralysis, necessitating premature euthanization. MRI examination revealed abnormal pale areas in the spinal cord and brain, which correlated histopathologically with teratomas. This preliminary study shows the efficacy of compact MRI systems in the detection of small teratomas following intrathecal injection of hESCs in a highly sensitive manner. Although these results should be validated in larger studies, they provide further evidence that the use of MRI in longitudinal studies offers a new monitoring strategy for preclinical testing of stem cell applications.

Tumor necrosis factor-α blockade in recurrent and disabling chronic sciatica associated with post-operative peridural lumbar fibrosis: results of a double-blind, placebo randomized controlled study.

INTRODUCTION: The aim of this study was to assess the efficacy and safety of tumor necrosis factor (TNF)-α inhibition with infliximab (IFX) in treating recurrent and disabling chronic sciatica pain associated with post-operative peridural lumbar fibrosis. METHOD: A double-blind, placebo-controlled study randomized 35 patients presenting with sciatica pain associated with post-operative peridural lumbar fibrosis to two groups: IFX (n = 18), a single intravenous injection of 3 mg/kg IFX; and placebo (n = 17), a single saline serum injection. The primary outcome was a 50 % reduction in sciatica pain on a visual analog scale (VAS) at day 10. Secondary outcomes were radicular and lumbar VAS pain at day 0 and radicular and lumbar VAS pain, Québec disability score, drug-sparing effect and tolerance at days 10, 30, 90, and 180. RESULTS: At day 10, the placebo and IFX groups did not differ in the primary outcome (50 % reduction in sciatica pain observed in three (17.6 %) versus five (27.8 %) patients; p = 0.69). The number of patients reaching the patient acceptable symptom state for radicular pain was significantly higher in the placebo than IFX group after injection (12 (70.6 %) versus five (27.8 %) patients; p = 0.01). The two groups were comparable for all other secondary outcomes. CONCLUSION: Treatment with a single 3 mg/kg IFX injection for post-operative peridural lumbar fibrosis-associated sciatica pain does not significantly reduce radicular symptoms at day 10 after injection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00385086 ; registered 4 October 2006 (last updated 15 October 2015).

Clinical, functional and health-related quality of life correlates of clinically significant symptoms of anxiety and depression in patients with systemic sclerosis: a cross-sectional survey.

OBJECTIVES: To identify clinical, functional and health-related quality of life (HRQoL) correlates of clinically significant symptoms of anxiety and depression in patients with systemic sclerosis (SSc). METHODS: Three-hundred-and-eighty-one patients fulfilling the American College of Rheumatology and/or the Leroy and Medsger criteria for SSc were assessed for visceral involvement, disability and HRQoL (assessed by SF-36). Clinically significant symptoms of anxiety and depression were evaluated with the Hospital Anxiety Depression Scale (HAD) (defined cut-off≥8). RESULTS: 9.2% the patients had limited SSc, 50.5% limited cutaneous SSc (lcSSc), and 40.3% diffuse cutaneous SSc (dcSSc). Overall, 40.4% and 58.8% of the patients had clinically significant symptoms of depression and anxiety, respectively. Compared to patients without clinically significant symptoms of depression, patients with clinically significant symptoms of depression had poorer health status, HRQoL mental and physical component, and greater global disability, hand disability and aesthetic impairment. Compared to patients without clinically significant symptoms of anxiety, patients with clinically significant symptoms of anxiety had poorer SF-36 mental and physical component scores. On multivariable analysis, excluding mental component score of SF-36, variables independently associated with clinically significant symptoms of depression and anxiety were global disability and physical component of SF-36, plus female gender for clinically significant symptoms of anxiety only. Remarkably, patients with and without clinically significant psychiatric symptoms were comparable for all disease-related clinical features assessed. CONCLUSION: High levels of clinically significant symptoms of anxiety and depression are observed among SSc patients. Clinically significant psychiatric symptoms are rather associated with increased disability and altered HRQoL, than with disease-specific organ manifestations.

Scheuermann's disease: an update.

Scheuermann's disease is a juvenile osteochondrosis of the spine. It is a disease of the growth cartilage endplate, probably due to repetitive strain on the growth cartilage weakened by a genetic background. The radiographic aspects are related to the vertebral endplate lesions and include vertebral wedging, irregularity of the vertebral endplate, and Schmorl's node (intraossous disk herniation). Disc alterations are frequent and may be secondary to dysfunction of the disc-vertebra complex. The definitions of Scheuermann's disease are varied; it can refer to the classical form of juvenile kyphosis, described by Scheuermann as well as asymptomatic radiographic abnormalities. Lumbar involvement is probably as frequent as the thoracic form and might be more painful. The first-line treatment is medical and includes rehabilitation and bracing. The earlier the start of treatment, the better the outcome, which highlights the importance of early diagnosis. Surgery is uncommon and must be limited to severe involvement after failure of conservative treatment. The natural history of Scheuermann's disease is unknown, but it might be associated with increased risk of back pain. The evolution of thoracolumbar and lumbar disease is unknown.

Specific scapular kinematic patterns to differentiate two forms of dynamic scapular winging.

BACKGROUND: Dynamic scapular winging (DSW) is a rare and misdiagnosed disorder causing considerable disability due to reduced scapular stability and abnormal motion. Two common causes are long thoracic nerve lesions resulting in serratus anterior muscle palsy and spinal accessory nerve lesions resulting in trapezius muscle palsy. The aim of this study was to analyse 3D scapular kinematic patterns in patients with DSW due to long thoracic (LTNL) or spinal accessory nerve lesions (SANL). METHODS: 3D scapular kinematics were assessed using a non invasive method involving an electromagnetic device during arm elevation in the frontal and sagittal planes in 9 patients (4 with SANL and 5 with LTNL) with unilateral DSW confirmed by electrical evidence. Within subject affected-unaffected differences were measured and compared between pathological groups (Mann-Whitney). FINDINGS: Differences between affected and unaffected shoulders were significantly greater for scapular posterior tilt (at rest and 30° for sagittal arm elevation, at rest, 30° and 60° for frontal arm elevation) in the LTNL compared to the SANL group. Differences between affected and unaffected shoulders were significantly greater for scapular protraction (at rest and 60° of sagittal arm elevation, at rest, 30° and 60° of frontal arm elevation) and scapular lateral rotation at 60° for frontal arm elevation in the SANL compared to the LTNL group. INTERPRETATIONS: These kinematic findings show two different scapular patterns that are specific to the neurological lesion. Moreover our kinematic data relate to specific clinical signs and the functional roles of the muscles involved.

Precision of 3D scapular kinematic measurements for analytic arm movements and activities of daily living.

Electromagnetic devices allow the non invasive and accurate measurement of 3D scapula kinematics. The acromial method allows continuous dynamic measurement using a skin surface sensor fixed to the acromion. Inter-session intra and inter-observer repeatability of 3D scapular kinematics have only been partially assessed for analytical movements and never for functional tasks. Inter-session intra and inter-observer repeatability of 3D scapular kinematics were assessed for arm elevation in the sagittal and frontal planes and for two activities of daily living (ADL), hair combing and back washing, in both shoulders of 15 healthy subjects, using the intraclass correlation coefficient (ICC), the standard error of measurement (SEM), the small real difference (SRD) and the Bland and Altman's graphical method. Intra-observer repeatability was good to excellent for every scapular rotation for both arm elevation in isolated planes and ADL (ICC ranged from 0.64 to 0.95). Inter-observer repeatability of scapular rotations was fair to excellent for arm elevation in isolated planes (ICC ranged from 0.49 to 0.92) and poor to excellent for ADL (ICC ranged from 0.35 to 0.89). Inter-observer repeatability of scapular protraction/retraction had the lowest ICC. For both inter-session intra and inter-observer reliability, the SEM and SRD remained low and Bland and Altman's graphical method showed a good repeatability of the measurement method. Longitudinal monitoring of a subject's scapular kinematics by a trained observer is reliable. The inter-observer repeatability of scapular protraction/retraction must be improved.

Modified 3D scapular kinematic patterns for activities of daily living in painful shoulders with restricted mobility: a comparison with contralateral unaffected shoulders.

There is a lack of studies of 3D scapular kinematic patterns for patients with shoulder conditions comparing affected and contralateral nonaffected shoulders during self-care activities of daily living (ADL). In this study, we compared 48 patients - 11 with glenohumeral osteoarthritis (GHOA), 20 with frozen shoulder (FS) and 17 with rotator cuff tendinopathies (RCT) - as they performed two ADL: hair combing and back washing. 3D scapular rotations and humerothoracic elevation (HTE) of the affected and contralateral nonaffected shoulders were recorded with use of a 6 degrees-of-freedom electromagnetic device. The HTE of affected and nonaffected shoulders were compared for each pathology group at rest and at the HTE used to perform the ADL: 30°, 45° and 60° of HTE for hair combing, and 30° of HT elevation for back washing. For hair combing, mean peak HTE was significantly lower for affected than nonaffected shoulders. Mean scapular lateral rotation was significantly greater at each HTE degree for GHOA and RCT groups, and mean scapular posterior tilt was significantly lower at 30° of HTE for the FS group. For back washing, mean peak HTE was lower for affected than nonaffected shoulders for the FS group only. Mean scapular medial rotation was significantly lower at 30° of HTE for the RCT group. 3D scapular kinematics appear to be specific to the shoulder pathology and to the task studied. Specific scapular kinematic patterns must be considered for appropriate therapeutic management.

[New possibilities resulting from oocyte banking].

Oocyte cryopreservation solves the legal and ethical problems associated with the cryopreservation of embryos in patients undergoing in vitro fertilization procedures. Furthermore, it may also offer the possibility of extending the reproductive capability of young women with malignant diseases in cases where the treatment may compromise the ovarian reserve. Moreover, it may also offer alternatives for infertile patients who are subject to ovarian hyper-stimulation syndrome or premature ovarian faiLure or who require oocyte donation. The creation of banks for cryopreserved oocytes avoids the need for cycle synchronization or the formation of an over-supply of embryos destined for cryopreservation. If a Large number of oocytes is obtained it could possibly enable women and couples the opportunity to postpone childbirth according to their wishes. This paper reviews the revolution obtained by oocyte vitrification, reports on ethical issues and discusses the pros and cons of oocyte banking and its potential effects on society.

McMaster-Toronto Arthritis Patient Preference Disability Questionnaire sensitivity to change in low back pain: influence of shifts in priorities.

OBJECTIVE: To assess the sensitivity to change of the McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) in chronic low back pain (CLBP) and shifts in patients' priorities of disabling activities over time. METHODS: A prospective longitudinal survey of 100 patients (38 males) with CLBP in a tertiary care teaching hospital. Evaluation at baseline and 6 months by the MACTAR, Quebec Back Pain Disability Questionnaire (QUEBEC), Hospital Anxiety and Depression scale (HAD), Fear-Avoidance Beliefs Questionnaire (FABQ), Coping Strategies Questionnaire (CSQ), and pain and handicap visual analogue scales (VASs). Patients' perceived improvement or worsening of condition was assessed at 6 months. Effect size (ES) and Standardized response mean (SRM) and effect size (ES) were used to evaluate sensitivity to change of the MACTAR. RESULTS: The MACTAR SRM and ES values (SRM = 0.25; ES = 0.37) were among the highest for the instruments evaluated. For patients considering their condition as improved, the SRM was 0.66 and the ES 1. The 3 disability domains, classified by the International Classification of Functioning, Disability and Health (ICF), most often cited as priorities at baseline remained the most cited at follow-up: mobility (40.9% of patients); community, social and civic life (22.7%); and domestic life (22.4%). At 6 months, 48 patients shifted their priorities, for a decrease in MACTAR SRM and ES values for patients considering their condition improved and an increase in these values for those considering their condition deteriorated. CONCLUSIONS: Although the MACTAR has similar sensitivity to change as other outcome measures widely used in CLBP, shifts in patient priorities over time are common and influence scores and sensitivity to change.

Association of accelerated switch from vertebral end-plate Modic I to Modic 0 signal changes with clinical benefit of intradiscal corticosteroid injection for chronic low back pain.

Modic I vertebral end-plate signal changes detected by magnetic resonance imaging (MRI) are associated with chronic low back pain. Typically, Modic I signal changes in untreated patients switch to non-Modic I signal changes within 3 years, which reflect spontaneous healing. Recent findings suggest that Modic I signal changes may be related to local inflammatory changes, providing a rationale for treatment with intradiscal injections of antiinflammatory drugs. In the present report, we describe a 31-year-old man with 1-year history of chronic low back pain associated with vertebral end-plate Modic I signal changes, who received 1 intradiscal corticosteroid injection in L5-S1. Local treatment led to rapid pain relief and was associated with an accelerated switch from Modic I to Modic 0 signal changes, as seen on lumbar MRI at 1-month followup. This is the first report of an effective local treatment for both the symptoms and the structural changes of chronic low back pain that are associated with Modic I signal changes. Additionally, this case reinforces the hypothesis that local inflammation has a pathogenic role.

Association of gender with clinical expression, quality of life, disability, and depression and anxiety in patients with systemic sclerosis.

OBJECTIVES: To assess the association of gender with clinical expression, health-related quality of life (HRQoL), disability, and self-reported symptoms of depression and anxiety in patients with systemic sclerosis (SSc). METHODS: SSc patients fulfilling the American College of Rheumatology and/or the Leroy and Medsger criteria were assessed for clinical symptoms, disability, HRQoL, self-reported symptoms of depression and anxiety by specific measurement scales. RESULTS: Overall, 381 SSc patients (62 males) were included. Mean age and disease duration at the time of evaluation were 55.9 (13.3) and 9.5 (7.8) years, respectively. One-hundred-and-forty-nine (40.4%) patients had diffuse cutaneous SSc (dcSSc). On bivariate analysis, differences were observed between males and females for clinical symptoms and self-reported symptoms of depression and anxiety, however without reaching statistical significance. Indeed, a trend was found for higher body mass index (BMI) (25.0 [4.1] vs 23.0 [4.5], p = 0.013), more frequent dcSSc, echocardiography systolic pulmonary artery pressure >35 mmHg and interstitial lung disease in males than females (54.8% vs 37.2%, p = 0.010; 24.2% vs 10.5%, p = 0.003; and 54.8% vs 41.2%, p = 0.048, respectively), whereas calcinosis and self-reported anxiety symptoms tended to be more frequent in females than males (36.0% vs 21.4%, p = 0.036, and 62.3% vs 43.5%, p = 0.006, respectively). On multivariate analysis, BMI, echocardiography PAP>35 mmHg, and anxiety were the variables most closely associated with gender. CONCLUSIONS: In SSc patients, male gender tends to be associated with diffuse disease and female gender with calcinosis and self-reported symptoms of anxiety. Disease-associated disability and HRQoL were similar in both groups.

Assessment of ankylosing spondylitis criteria in patients with chronic low back pain and vertebral endplate Modic I signal changes.

OBJECTIVE: Patients with chronic low back pain (cLBP) and vertebral endplate Modic I signal changes on lumbar magnetic resonance imaging (MRI) have clinical features that could mimic inflammatory back pain related to spondyloarthritis (SpA) and/or ankylosing spondylitis (AS). We aimed to assess whether such patients fulfilled criteria for SpA and/or AS. METHODS: For 5 months in 2008, all patients (n = 314) referred to a tertiary care physical medicine and rehabilitation facility in France were consecutively screened. A total of 185 hospitalized for non-specific cLBP were prospectively assessed. Forty patients fulfilling inclusion criteria were consecutively enrolled and included in 2 groups according to MRI findings: Modic I (n = 15) and non-Modic I (n = 25). MRI findings were assessed independently by 2 spine specialists and a radiologist. HLA-B27 status was determined. Data were collected on clinical measurements and fulfillment of Amor criteria (AC) and modified New York criteria (mNYC). All assessors were blinded to HLA-B27 status. RESULTS: Whatever the Modic group, no patient fulfilled AC or mNYC, and mean total scores were comparable [3 ± 2 (range 0-22; p = 0.977), 1 ± 1 (range 0-3; p = 1.000), and 0 ± 0 (range 0-1; p = 1.000) for AC and clinical and radiological mNYC, respectively]. HLA-B27 status was similar in both groups [n = 2 (13%) vs n = 0 (0%); p = 0.135]. CONCLUSION: Patients with cLBP and Modic I vertebral endplate signal changes on lumbar MRI do not fulfill widely used and validated criteria for SpA and/or AS. Such cases are clinically distinct from SpA and AS.

Suspension culture of undifferentiated human embryonic and induced pluripotent stem cells.

Alongside their contribution to research, human embryonic stem cells (hESC) may also prove valuable for cell-based therapies. Traditionally, these cells have been grown in adhesion culture either with or without feeder cells, allowing for their continuous growth as undifferentiated cells. However, to be applicable in therapy and industry they must be produced in a scalable and controlled process. Here we present for the first time a suspension culture system for undifferentiated hESC and induced pluripotent stem cells (iPSC), based on medium supplemented with the IL6RIL6 chimera (interleukin-6 receptor fused to interleukin-6), and basic fibroblast growth factor. Four hESC lines cultured in this system maintained all ESC features after 20 passages, including stable karyotype and pluripotency. Similar results were obtained when hESC were replaced with iPSC from two different cell lines. We demonstrate that the IL6RIL6 chimera supports the self-renewal and expansion of undifferentiated hESC and iPSC in suspension, and thus present another efficient system for large-scale propagation of undifferentiated pluripotent cells for clinical and translational applications.