Correlations between clinical motor scores and CMAP in patients with type 2 spinal muscular amyotrophy treated with nusinersen.

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of the anterior horn cells of the spinal cord. Nusinersen for the treatment of SMA has been covered by public healthcare in France since May 2017. OBJECTIVE: Our aim was to investigate whether there is a correlation between clinical and compound motor action potential (CMAP) measurements in SMA patients treated with nusinersen after 3  years' follow-up. METHOD: Motor skills were evaluated regularly between M0 and M36 using the Motor Function Measure (MFM) score. CMAP measurements were collected regularly between M0 and M22. RESULTS: Data for 10 patients with SMA type 2 were collected and divided into two age groups (< 5 years and > 5 years). Motor function improved, but not significantly, regarding distal motor skills (D3) in both groups, and in axial and proximal motor function (D2) in the younger group. CMAP measurements improved in all patients. CMAP increased significantly for the median nerve, and this improvement correlated significantly with global MFM and with axial and proximal tone (D2). CONCLUSION: Our study shows gain in distal motor function with nusinersen, especially in younger patients with SMA type 2. These results encourage the screening of SMA patients and treatment as early as possible. CMAP measurements of the median nerve show clear improvement in patients treated with nusinersen and could be performed as routine follow-up.

A new score combining compound muscle action potential (CMAP) amplitudes and motor score is predictive of motor outcome after AVXS-101 (Onasemnogene Abeparvovec) SMA therapy.

Spinal muscular atrophy 1 (SMA1) is a severe early genetic disease with degeneration of motor neurons. Motor development is still suboptimal after gene replacement therapy in symptomatic patients. In this study, compound muscle action potential (CMAP) amplitudes were explored as predictors of motor recovery after gene therapy. Thirteen symptomatic SMA1 patients were prospectively included at the Necker Enfants Malades Hospital, Paris, France (Cohort 1) and 12 at the other pediatric neuromuscular reference centers of the French Filnemus network (Cohort 2). In Cohort 1, median CMAP amplitudes showed the best improvement between baseline and the 12 months visit compared to the other tested nerves (ulnar, fibular and tibial). High median CMAP amplitudes at baseline was associated with unaided sitting achievement at M6 (AUC 90%). None of the patients with CHOPINTEND at M0 < 30/64 and median CMAP < 0.5 mV achieved unaided sitting at M6 and this result was confirmed on Cohort 2 used as an independent validation data. Thus, median CMAP amplitude is a valid biomarker for routine practice to predict sitting at M6. A median CMAP amplitude over 0.5 mV at baseline may predict better motor recovery.

An Automated Recording Method in Clinical Consultation to Rate the Limp in Lower Limb Osteoarthritis.

For diagnosis and follow up, it is important to be able to quantify limp in an objective, and precise way adapted to daily clinical consultation. The purpose of this exploratory study was to determine if an inertial sensor-based method could provide simple features that correlate with the severity of lower limb osteoarthritis evaluated by the WOMAC index without the use of step detection in the signal processing. Forty-eight patients with lower limb osteoarthritis formed two severity groups separated by the median of the WOMAC index (G1, G2). Twelve asymptomatic age-matched control subjects formed the control group (G0). Subjects were asked to walk straight 10 meters forward and 10 meters back at self-selected walking speeds with inertial measurement units (IMU) (3-D accelerometers, 3-D gyroscopes and 3-D magnetometers) attached on the head, the lower back (L3-L4) and both feet. Sixty parameters corresponding to the mean and the root mean square (RMS) of the recorded signals on the various sensors (head, lower back and feet), in the various axes, in the various frames were computed. Parameters were defined as discriminating when they showed statistical differences between the three groups. In total, four parameters were found discriminating: mean and RMS of the norm of the acceleration in the horizontal plane for contralateral and ipsilateral foot in the doctor's office frame. No discriminating parameter was found on the head or the lower back. No discriminating parameter was found in the sensor linked frames. This study showed that two IMUs placed on both feet and a step detection free signal processing method could be an objective and quantitative complement to the clinical examination of the physician in everyday practice. Our method provides new automatically computed parameters that could be used for the comprehension of lower limb osteoarthritis. It may not only be used in medical consultation to score patients but also to monitor the evolution of their clinical syndrome during and after rehabilitation. Finally, it paves the way for the quantification of gait in other fields such as neurology and for monitoring the gait at a patient's home.

Action of metformin on erythrocyte membrane fluidity in vitro and in vivo.

The lipid domains of the cell membrane are believed to be one of the sites where biguanides exert their antihyperglycemic effect. We have examined the effects of metformin on the membrane fluidity of intact erythrocytes in vivo and in vitro. Membrane fluidity was measured by monitoring changes in the anisotropy of the fluorescent probe 6-antroyloxystearic acid (6-AS). The erythrocyte membranes from patients with non-insulin dependent diabetes mellitus treated with metformin were more fluid than those from non-insulin dependent diabetes mellitus patients treated by diet or healthy controls. There was no correlation between membrane fluidity and the plasma lipids or the parameters of metabolic control, suggesting that the high fluidity is an effect of metformin itself. Incubation of erythrocytes from healthy controls and diabetic patients treated by diet or glibenclamide with metformin in vitro confirmed that metformin increases the fluidity of erythrocyte membranes. In vitro metformin did not alter the fluidity of membranes from diabetic patients treated with metformin, perhaps because the basal high fluidity due to their in vivo interaction with plasma metformin could be increased no further. Since insulin appears to be required for the antihyperglycemic effect of metformin, the effect of insulin on membrane fluidity was also evaluated. Insulin generally had a small fluidizing effect on erythrocytes in vitro. The fluidizing action of both insulin and metformin could represent a membrane event common to the hormone and drug leading to additive or synergistic effects in vivo.

Immunoadsorption procedure as a potential method for the specific beta 2-microglobulin removal from plasma of patients with chronic renal failure.

beta 2-Microglobulin (beta 2-M), which accumulates in the plasma of patients undergoing long-term dialysis, has been identified as the principal precursor protein of amyloid fibrils in dialysis-related amyloidosis. As no specific treatment for this affection has been yet established, an extracorporeal immunoadsorption procedure appears to be an attractive therapeutic approach to remove beta 2-M. Several murine monoclonal antibodies to human beta 2-M were developed and compared as affinity ligands. One of them was selected on the basis of its specificity and adsorption capacity. In order to achieve maximum efficiency in protein removal, different parameters of the procedure were studied and optimized: effect of antibody coupling density, determination of maximum adsorption capacity of the immunoadsorbents and influence of antigen concentration and of flow-rate on antigen capture efficiency. The conditions of regeneration of immunoaffinity sorbents were also investigated to allow their multiple use without loss of adsorption capacity. The results show the validity of the proposed technique in removing beta-M from plasma of patients with chronic renal failure.

Migration of peripheral T and B cells into the thymus of aging (NZB X SJL)F1 female mice.

Aging NZB X SJL (NS) female mice provide a unique model of thymus pathology characterized by the intrathymic accumulation of large numbers of mature T and B cells. The purpose of the present work was to examine the possibility that this phenomenon results from the invasion of the thymus by cells from the periphery. Lymphoid cells labeled with chromium-51 or indium-111 were injected into syngeneic recipients to study their patterns of in vivo migration. Lymph node (LN) or spleen cells were found to localize significantly (1-2% of injected radioactivity) into the thymus of 12-month-old NS females but not into that of young recipients or of old NS males. However, intrathymic localization of injected LN cells was observed in castrated NS males which exhibit the same thymus pathology as NS females. Both radiolabeled T and B cells were found to enter the thymus of aged NS females but the latter cells about three times less efficiently than the former. Moreover, while thymocytes from young NS females were unable to recirculate to LN, those of old NS females showed increased LN-seeking capacity and part (1%) of them did migrate back into the thymus of old but not young NS females. In additional cell transfer experiments, the intrathymic migration of B cells into old NS females was further documented by using the antibody response to sheep erythrocytes as a tracer. Taken together, these observations indicate that the thymus of aging NS female mice is permeable to recirculating lymphocytes, suggesting that at least part of the mature T and B cells detected in this thymus are migrants from the periphery.

Prepubertal orchidectomy induces thymic abnormalities in aging (NZB X SJL)F1 male mice.

Female but not male (NZB X SJL)F1 (NS) mice develop abnormalities of their intrathymic lymphocyte population in the course of aging. To determine the role played by androgens in this sex-related difference, we monitored the evolution of the cellular composition of the thymus in NS males deprived of androgens by prepubertal orchidectomy. Although in young mice this operation resulted in a twofold enlargement of the thymus, there was no histologic alteration or major change in the surface phenotype and mitogenic reactivities of the thymocytes, which suggests that all thymocyte subsets were increased to the same extent. In 12-mo-old control (BALB/c X SJL)F1 mice, prepubertal orchidectomy also produced an equal expansion (1.4-fold increase) of all thymocyte subsets. In contrast, in 12-mo-old orchidectomized NS males, there was a marked depletion of the thymic cortex and a hyperplasia of the medullary lymphoid tissue reflecting the selective expansion of a subset of phenotypically mature T cells (dull Thy-1+, Lyt-1+2+/-, dull PNA+) together with the emergence of intrathymic surface immunoglobulin-bearing cells. These latter cells probably represented B cells because there was a concomitant augmentation of the mitogenic responsiveness in vitro of thymic cell suspensions to lipopolysaccharide. Such thymic abnormalities induced by prepubertal orchidectomy in old NS males resemble those occurring spontaneously in the NS females. This suggests that the absence of thymic disease in intact NS males is primarily due to a suppressive effect of androgens.

Electrokinetic properties and mitogen responsiveness of mouse splenic B and T lymphocytes following hydrocortisone treatment.

CBA mice recieved a single intraperitoneal injection of hydrocortisone acetate (OHC) in a dose of 125 mg/kg body weight. At various times therafter, electrophoretic mobility (EPM), surface immunoglobulin (SIG) and in vitro DNA synthetic reactivity to concanavalin A (ConA), phytohemagglutinin (PHA), lipopolysaccharide (LPS) and tuberculin (PPD) were investigated on splenic lymphocytes. OHC was found to deplete rapidly the spleen to a minimum of 18% of control cellularity by day 4 posttreatment. At this time, the proportions of low mobility (LM) and SIG-bearing lymphocytes (B cells) were reduced respectively to 28% (control 54%) and 20% (control 45%). The proportion of high mobility (HM) lymphocytes (T cells) was increased to 72% (control 45%). While the mean EPM of LM cells (0.71) was only slightly and transiently reduced, that of HM cells was significantly augmented (1.24) over control value (1.16). This latter finding was interpreted as indicating the selective removal by OHC of a T cell subpopulation with a mean EPM around 1.10. Changes in mitogenic responsiveness were consistent with these alterations of B and T cell compartments. Despite a marked drop in spontaneous 3H-thymidine uptake, the absolute response to T cell mitogens ConA and PHA remained relatively unchanged. By contrast, the reactivity to B cell mitogens LPS and PPD was strongly depressed. Starting by day 12, regeneration and normalizaiton of lymphocyte populations proceeded slowly and were not achieved before day 26-34.

Electrokinetic properties of splenic lymphocytes from the low-lipopolysaccharide responder C3H/Hej mice.

Spleen cells from C3H/Hej mice (H-2k) respond poorly to the B-cell mitogen lipopolysaccharide in vitro as compared to the related strains C3H/Tif (H-2k) and CBA/Orl (H-2k). The electrokinetic properties of splenic lymphocytes from these 3 strains were investigated in parallel, in order to both quantitate low-mobility B cell and high-mobility T cell populations and measure their mean electrophoretic mobilities. C3H/Hej mice were found to possess the same proportion (55%) of LM cells as C3H/Tif and CBA/Orl mice. Therefore, the low LPS-responsiveness of C3H/Hej is not due to a numerical deficiency in B cells. Whereas the mean EPM of HM cells was identical in the 3 strains, that of LM cells was slightly (6%) but significantly (Student's t test, P less than 0.01) lower in C3H/Hej than in the high LPS-responder controls. This suggests that the membrane-structure required for activating interaction with LPS might contribute to B-cell electronegative surface-charge.

Effect of treatment with cyclophosphamide on the electrophoretic mobility and mitogen responsiveness of mouse thymus cells.

Two days after a single intraperitoneal injection of cyclophosphamide (CY) in a dose of 300 mg/kg of body weight, the cellularity of the thymus from adult female CBA mice was reduced to 17% of its normal value. The electrophoretic mobility (EPM) analysis of the surviving cells revealed a decrease in the proportion of the slow-moving cells together with a significant diminution of their mean EPM. The proportion of fast-moving cells, which were shown to correspond to the hydrocortisone-resistant and mitogen-responsive pool of mature thymocytes, was correlatively increased by 2-3 fold. Despite this enrichment in cells with a high surface charge, the thymocytes from CY-treated mice exhibited a diminished reactivity "in vitro" to both concanavalin A and phytohemagglutinin. The possible significance of theses results is discussed with reference to the known mitostatic properties of CY.