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.

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.

[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.

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.

Survival, differentiation, and reversal of heroin neurobehavioral teratogenicity in mice by transplanted neural stem cells derived from embryonic stem cells.

Cell therapies in animal models of neurobehavioral defects are normally derived from neural stem cells (NSC) of the developing cortex. However, the clinical feasibility of NSC therapies would be greatly improved by deriving transplanted cells and from a tissue culture source that is self-renewing, containing cells that potentially differentiate into the desired neuronal phenotypes. These cultures can be engineered to contain the appropriate factors to support their therapeutic action and likely evoke lesser immune reactions. In the current study, we employed our model of mice neurobehaviorally impaired via prenatal exposure to heroin, to test the therapeutic efficacy of NSC derived from murine embryonic stem cells culture (ESC). The culture contained elongated bipolar cells, 90% of which are positive for nestin, the intermediate filament protein found in neural precursors. After removal of growth factors, the NSC differentiated into neurons (34.0% +/- 3.8% NF-160 positive), including cholinergic cells (ChAT positive), oligodendrocytes (29.9% +/- 4.2% O(4)), and astrocytes (36.1% +/- 4.7% GFAP positive). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis confirmed the immunocytochemical findings. Mice made deficient in Morris maze behavior by prenatal heroin exposure (10 mg/kg heroin s.c. on gestational days 9-18) were transplanted into the hippocampus region on postnatal day 35 with the ES culture-derived NSC (ES-NSC) labeled with dialkylcarbocyanine (Dil) cell tracker. Dil+ and NF160+ cells were detected in the hippocampal region (50% +/- 8% survival). The transplantation completely restored maze performance to normal; e.g., on day 3, transplantation improved the behavior from the deficient level of 11.9-sec latency to the control of 5.6-sec latency (44.5% improvement).

Employment status and socio-economic burden in systemic sclerosis: a cross-sectional survey.

OBJECTIVE: To assess employment status and socio-economic burden in SSc patients. METHODS: Eighty-seven SSc patients (72 females), fulfilling the ACR or the Leroy and Medsger criteria, or both, were evaluated for employment status, socio-economic burden and handicap. Statistical analysis involved Mann-Whitney U-test and Fisher's exact test and backward stepwise regression analysis. RESULTS: In total, 60.9% of the SSc patients were on full-time sick leave and 35.6% were receiving a disability pension. On univariate analysis, myalgia was the only clinical manifestation more frequently encountered in sick-leave patients than others (73.6 vs 47.1%; P = 0.012). Karnofsky performance status (KPS) was lower in SSc patients who were on sick leave or were receiving a disability pension than others [78.5 (10.6) vs 85.8 (9.0); P = 0.004 and 78.1 (8.7) vs 83.1 (11.2); P = 0.016, respectively]. In addition, greater global, hand and mouth handicaps and depression were observed in patients on sick leave [HAQ 0.9 (0.7) vs 0.6 (0.5); P = 0.021; Cochin Hand Function Scale 21.7 (18.9) vs 10.7 (12.1); P = 0.003; mouth handicap scale 20.2 (10.8) vs 14.6 (10.0); P = 0.014; and depression dimension of the hospital anxiety and depression scale 7.1 (3.9) vs 4.8 (3.4); P = 0.003]. On multivariate analysis, factors associated with sick leave were KPS [odds ratio (OR) 0.92; 95%CI 0.88, 0.98] and myalgias (OR 3.19; 95% CI 1.19, 8.58), and the factor associated with receiving a disability pension was decreased income (OR 8.19; 95% CI 2.67, 25.12). CONCLUSIONS: SSc patients commonly have to take full-time sick leave from work. Despite such patients receiving disability pensions, the socio-economic burden is considerable.

Splint for base-of-thumb osteoarthritis: a randomized trial.

BACKGROUND: Some guidelines recommend splinting for base-of-thumb osteoarthritis, despite lack of evidence of efficacy. OBJECTIVE: To assess the efficacy and acceptability of a splint for base-of-thumb osteoarthritis. DESIGN: Multicenter, randomized trial. Randomization was computer-generated, and allocation was concealed by faxing centralized treatment assignment to investigators at the time of enrollment. Patients and investigators were not blinded to assignment, and patients self-reported outcomes. SETTING: 2 tertiary care hospitals in France. PATIENTS: 112 patients (101 women) with base-of-thumb osteoarthritis. INTERVENTION: Custom-made neoprene splint (n = 57) or usual care (n = 55). MEASUREMENTS: Primary outcome was change in pain level assessed on a visual analogue scale (VAS) (range, 0 to 100 mm) from baseline to 1 month. Secondary outcomes were change in measures of hand disability at 1 month and change in pain level and measures of disability at 12 months. Tolerance and adherence with the splint were recorded. RESULTS: At 1 month, no difference in change occurred in pain level from baseline in the intervention and control groups (adjusted mean change, -10.1 vs. -10.7; between-group difference, 0.6 [95% CI, -7.9 to 9.1]; P = 0.89). Disability was assessed by the Cochin Hand Function Scale score (range, 0 to 90) or patient-perceived disability (VAS, 0 to 100 mm). At 12 months, change in pain from baseline was greater in the intervention group than in the control group (adjusted mean change, -22.2 vs. -7.9; between-group difference, -14.3 [CI, -23.4 to -5.2]; P = 0.002). The Cochin Hand Function Scale score was -1.9 versus 4.3 (between-group difference, -6.3 [CI, -10.9 to -1.7]; P = 0.008) and patient-perceived disability was -11.6 versus 1.5 (between-group difference, -13.1 [CI, -21.8 to -4.4]; P = 0.003). At 12 months, 86% of the intervention group had worn the splint for more than 5 nights a week, and no adverse effects were observed. LIMITATION: Patients, health care providers, and outcome assessors were not blinded. CONCLUSION: For patients with base-of-thumb osteoarthritis, wearing a splint had no effect on pain at 1 month but improved pain and disability at 12 months. PRIMARY FUNDING SOURCE: Programme Hospitalier de Recherche Clinique National.

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.

The trunk as a part of the kinematic chain for arm elevation in healthy subjects and in patients with frozen shoulder.

During arm elevation, the trunk may have both a postural and synergic role, but few 3-D experimental studies exist of the phenomenon, and the contribution of trunk rotations to arm elevation has not been studied in patients with frozen shoulder. Thirty healthy volunteers performed maximal dominant arm elevation in 2 planes, sagittal (anteflexion) and frontal (abduction), and 13 patients with unilateral frozen shoulder performed arm elevation on the unaffected then affected side. Trunk rotations and humeral elevation were measured with use of an electromagnetic system (Polhemus Fastrak). Flexion/extension, inclination (lateral bending) and torsion (rotation around the main axis) of the trunk were measured at intermediate (45 degrees and 60 degrees ) and maximal levels of arm elevation. For patients, trunk rotations were also measured during elevation on the unaffected side at a level corresponding to maximal arm elevation of the contralateral affected side. Healthy volunteers made a small (4 degrees -9 degrees ) but consistent pattern of trunk rotations characterized mainly by extension during anteflexion and torsion during abduction associated with biphasic inclination (ipsilateral then contralateral). As expected, patients showed restricted arm elevation of the affected shoulder but performed larger trunk extension and torsion at intermediate levels of elevation with a similar pattern as above. Inclination range was limited during elevation of the affected shoulder, with no initial ipsilateral inclination on any side. Our results suggest that the trunk contributes to the kinematic chain for arm elevation in both groups. Trunk extension and torsion may compensate for impaired arm elevation. Conversely, the irregularities in trunk inclination may contribute to the impairment and be a target for rehabilitative management.

Three-dimensional scapular kinematics and scapulohumeral rhythm in patients with glenohumeral osteoarthritis or frozen shoulder.

We aimed to describe 3D scapular kinematics and scapulohumeral rhythm (SHR) in glenohumeral (GH) osteoarthritis shoulders compared to unaffected shoulders and to compare the abnormal scapular kinematic schema for GH osteoarthritis with that for frozen shoulder. Thirty-two patients with stiff shoulder (16 with GH osteoarthritis and 16 with frozen shoulder) performed maximal arm elevation in two planes, sagittal and frontal. Scapular rotations and humeral elevation of the affected and unaffected shoulders were measured by the Polhemus Fastrak electromagnetic system. Patients with GH osteoarthritis were older, had longer disease duration (p<0.001) and less restricted humeral elevation in the frontal plane (p=0.01). Protraction was significantly lower for the affected shoulders except for arm elevation in the frontal plane in the GH osteoarthritis group. Furthermore, protraction was lower with frozen shoulder than GH osteoarthritis during arm elevation in the frontal plane. Scapular lateral rotation and SHR were significantly higher for the affected shoulders in both groups whatever the plane of elevation. SHR showed a fair to moderate negative correlation with maximal humeral elevation in both groups and appears to be higher with frozen shoulder than GH osteoarthritis. In addition, SHR of the affected shoulder showed a fair to moderate correlation with disease duration only with GH osteoarthritis. Scapular tilt did not differ between affected and unaffected sides and was not influenced by type of disease. In conclusion, the increased scapular lateral rotation described in frozen shoulder is also observed in GH osteoarthritis. SHR of the affected shoulder is inversely related to severity of limitation of shoulder range of motion, which suggests a compensatory pattern.

Relationship of glenohumeral elevation and 3-dimensional scapular kinematics with disability in patients with shoulder disorders.

OBJECTIVE: To determine variables among glenohumeral elevation and 3-dimensional scapular rotations that are related to shoulder function as assessed by the Disability of the Arm, Shoulder and Hand-Disability/Symptom (DASH-D/S) scale. DESIGN: Prospective, cross-sectional study. PATIENTS: Eighty-eight patients with shoulder pain and limited range of motion were included. METHODS: Each patient performed 2 full active range of motion activities, forward flexion and abduction, and 2 activities of daily living, combing hair and simulating washing the back. Glenohumeral elevation and scapular rotations were measured by the Polhemus Fastrak electromagnetic system. RESULTS: On multiple regression analysis, glenohumeral elevation in combing hair and scapular lateral rotation in both abduction and simulating washing the back were the best predictors of shoulder function and explained 39.7% of the variance of the DASH-D/S score. CONCLUSION: These findings support the classical rehabilitation of the shoulder based on glenohumeral elevation and suggest the importance of attention paid to scapular lateral rotation.

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.

HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver.

Hematopoietic stem cells rarely contribute to hepatic regeneration, however, the mechanisms governing their homing to the liver, which is a crucial first step, are poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1), which attracts human and murine progenitors, is expressed by liver bile duct epithelium. Neutralization of the SDF-1 receptor CXCR4 abolished homing and engraftment of the murine liver by human CD34+ hematopoietic progenitors, while local injection of human SDF-1 increased their homing. Engrafted human cells were localized in clusters surrounding the bile ducts, in close proximity to SDF-1-expressing epithelial cells, and differentiated into albumin-producing cells. Irradiation or inflammation increased SDF-1 levels and hepatic injury induced MMP-9 activity, leading to both increased CXCR4 expression and SDF-1-mediated recruitment of hematopoietic progenitors to the liver. Unexpectedly, HGF, which is increased following liver injury, promoted protrusion formation, CXCR4 upregulation, and SDF-1-mediated directional migration by human CD34+ progenitors, and synergized with stem cell factor. Thus, stress-induced signals, such as increased expression of SDF-1, MMP-9, and HGF, recruit human CD34+ progenitors with hematopoietic and/or hepatic-like potential to the liver of NOD/SCID mice. Our results suggest the potential of hematopoietic CD34+/CXCR4+cells to respond to stress signals from nonhematopoietic injured organs as an important mechanism for tissue targeting and repair.

Fear-avoidance beliefs about back pain in patients with acute LBP.

OBJECTIVE: We aimed to assess fear-avoidance beliefs in patients with acute low back pain (LBP) and to identify features of patients and general practitioners (GPs) associated with patients' fear-avoidance beliefs. METHODS: A cross-sectional study conducted in primary care practice in France. A total of 709 GPs completed a self-administered questionnaire assessing fear-avoidance beliefs [the Fear-Avoidance Beliefs Questionnaire (FABQ)] and 2,727 patients with acute LBP completed a self-administered questionnaire assessing pain, perceived handicap and disability (on the Quebec Back Pain Disability Scale) and fear-avoidance beliefs (on the FABQ). RESULTS: Patients' FABQ mean scores were 16.8+/-5.0 for physical activities (FABQ Physical) and 19.5+/-10.9 for occupational activities (FABQ Work). From multivariate analysis, the following factors were associated with patients' FABQ Phys and Work scores: having a GP with a high rating on the FABQ Phys (P=0.0001 and 0.02 for FABQ Phys and Work, respectively), no sport practice (vs. occasional: P=0.0003 and 0.03; vs. usual/competition: P=0.0001 and 0.004), disability score (Quebec) (P=0.0001 for both FABQ scores), and pain intensity (P=0.0012 and 0.0013). CONCLUSIONS: High levels of fear-avoidance beliefs occur early in LBP patients, and key messages on this topic should probably be delivered at a very early stage of the disease.

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.

Modulation of proteoglycan production by cyclic tensile stretch in intervertebral disc cells through a post-translational mechanism.

Proteoglycan production is one of the major extracellular matrix components implicated in the dynamic process of intervertebral disc degeneration. Mechanical stress is an important modulator of the degeneration, but the underlying molecular mechanism at the proteoglycan level remains unclear. The aim of this work was to study the regulation of proteoglycan production by cyclic tensile stretch applied to intervertebral disc annulus fibrosus cells. Matrix metalloproteinases do not seem to be implicated in the regulation of proteoglycan production. By contrast, nitrite oxide production is induced by cyclic tensile stretch, in a time, intensity, and frequency dependant manner. Using a non-specific nitric oxide synthases inhibitor [NG-methyl-L-arginine (L-NMA)], we suppress totally the inhibition of proteoglycan production induced by cyclic tensile stretch suggesting the implication of nitric oxide synthases in the observed phenomenon. Introducing the transcriptional inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole or a more specific inhibitor of nitric oxide synthases II [N-iminoethyl-L-lysine (L-NIL)] did not affect the decreased proteoglycan production, which suggests a post-translational regulation. In contrast, N-omega nitro-L-arginine (L-NNA) a more specific inhibitor of NOS I and III abrogated the cyclic tensile stretch-dependant inhibition of proteoglycan production. These results suggest that cyclic tensile stretch regulates proteoglycan production through a post-translational mechanism involving nitrite oxide. This result could be of interest in the development of local therapeutic strategies aimed at controlling intervertebral disc degeneration.

Interferon-beta in the treatment of relapsing-remitting multiple sclerosis.

The role of interferon-beta as a disease-modifying drug (DMD) for the treatment of relapsing-remitting multiple sclerosis (RRMS) is now well established, and its efficacy has been demonstrated unequivocally in large-scale clinical trials. However, current evidence suggests that in order to increase the benefit of therapy, use of an effective drug and dosing regimen should be commenced early in the course of the disease, a finding that places new emphasis on the need for early diagnosis. Indeed, it is now known that MS lesions often develop at a subclinical level and that axonal damage occurs even in the very early stages of the disease. Moreover, such damage may be irreversible, and there is strong evidence to suggest that efficacy lost as a consequence of delay in the onset of treatment or the use of a suboptimal drug regimen cannot be regained. At present, the choice of interferon-beta is complicated by the availability of 3 different products, each with a different dosing regimen. Although the optimal interferon-beta dosing regimen for RRMS has been the focus of much discussion, the issues of dose, and particularly dosing frequency, have not been satisfactorily addressed in clinical trials until recently. Over the last 2 years, however, 3 comparative studies of interferon-beta products have been conducted. The results obtained from these recent trials underline the importance of both dose and dosing frequency and indicate that for improved efficacy in RRMS, interferon-beta therapy should be administered frequently at the highest tolerable, and thus most effective, dose.

[Functional disability indexes: translation difficulties and cross cultural adaptation problems]. / Les indices d'incapacité fonctionnelle: difficultés de traduction et problèmes d'adaptation transculturelle.

OBJECTIVES: To summarize the difficulties involved in translating tests in Arabic and to describe the translation methods and to apply those to functional indexes. METHOD: Four functional indexes were translated and then subjected to the following test validation methods: back translation, pre-test, and review by an expert committee. RESULTS: Translation problems were underlined. These include in particular the different types of equivalence between the source language and the target language (semantics, idioms, conceptual... equivalences). Problems related to comprehensive literal words were the most observed. CONCLUSION: The current method combining translation with back translation is not sufficient and must be used with, a pre-test and a review committee.