Occupational therapy using a robotic-assisted glove ameliorates finger dexterity and modulates functional connectivity in amyotrophic lateral sclerosis.

INTRODUCTION: Although rehabilitation is recommended for amyotrophic lateral sclerosis (ALS), improvement of functional decline has hardly been achieved. We investigated the effect of occupational therapy that uses a robotic-assisted glove (RAG) on hand dexterity and the functional connectivities found in the brain of ALS patients. METHOD: Ten patients diagnosed with ALS and admitted to the Shiga University of Medical Science (SUMS) Hospital from December 2018 to December 2021 participated in the study. These participants chose the hand side to wear RAG and exercised for two weeks. A sham movement was performed on the other side. We administered several functional assessments, including the Simple Test for Evaluating Hand Function (STEF), grip strength, pinch meter for grip strength, Canadian occupational performance measure (COPM), as well as nerve conduction study (NCS) before and after the exercise, and evaluated the results. We also analyzed six patients' resting-state functional magnetic resonance imaging (rs-fMRI). RESULTS: Two-week robotic rehabilitation improved the STEF, grip strength, and COPM scores when compared with those of the other side. However, no significant effect was observed in the pinch meter and the NCS results. The rs-fMRI data analysis revealed that the robotic rehabilitation augmented two functional connectivities between the left pallidum-right supplementary motor cortex and right insular cortex-right sensorimotor network among the patients, which had beneficial effects. CONCLUSION: The occupational therapy using RAG displayed improved hand dexterity. The enhanced functional connectivities around the sensorimotor network might be associated with the improvement in hand dexterity because of the RAG.

Clinicopathologic Features of Oculopharyngodistal Myopathy With LRP12 CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes.

Importance: Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective: To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, Setting, and Participants: This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main Outcomes and Measures: Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results: Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and Relevance: This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

The Effect of Intravenous Methylprednisolone on Recurrent Exacerbation in Hematologic Malignancy-associated Progressive Multifocal Leukoencephalopathy.

We herein report a 65-year-old man with progressive multifocal leukoencephalopathy (PML) after 2-year remission from acute myeloid leukemia who developed recurrent episodes of left hemiparesis with gadolinium enhancement on magnetic resonance imaging. Steroid pulse therapy for each exacerbation induced clinical and radiological improvement, suggesting that exacerbations are an excessive immune response to the JC virus and distinct from immune reconstitution inflammatory syndrome (IRIS). Although glucocorticoids are recommended only for IRIS, steroid pulse therapy should be considered as a therapeutic option in cases of exacerbation of hematologic malignancy-associated PML. Importantly, neuroimaging is not sufficient to differentiate excessive inflammation from a controlled inflammatory response, for which steroids are not recommended.

Rheumatoid meningitis developed in patient with stable rheumatoid arthritis and myasthenia gravis-detailed analysis of intracranial inflammation using flow cytometry.

BACKGROUND: Rheumatoid meningitis (RM) is a rare disorder that often develops during a remission phase of rheumatoid arthritis (RA). This is the first study to demonstrate differences in regard to immunological disturbance between blood and cerebrospinal fluid (CSF) samples obtained from a patient with RM using flow cytometry. CASE PRESENTATION: A 36-year-old woman with RA and generalized myasthenia gravis (MG) developed RM during a remission phase. Although both RA and MG were stable and well controlled, she noticed fever, headache, and transient sensory disturbance. Blood and CSF examination findings suggested aseptic meningitis, while brain magnetic resonance imaging revealed restricted portions of meningitis and associated cortical lesions, compatible with a diagnosis of RM. The dose of oral prednisolone was increased, which ameliorated the symptoms within 1 week along with improvement in CSF findings. This patient exhibited features of RM that were manifested in a manner independent of the activity of RA. An investigation of cellular immunity using CSF specimens with flow cytometry showed differences in regard to the pathogenesis of inflammation in the CSF as compared to outside of the central nervous system. In contrast to results obtained with paired blood samples, CSF cells at the peak stage of RM showed a marked increase in CCR3+ Th2 cells and marked decrease in CD8+ cells, suggesting an immunoregulatory disturbance in the CSF. Those findings indicated a CSF-specific activation of humoral immunity, resulting in augmentation of meningeal inflammation, as shown by excess synthesis of intrathecal IgG and markedly elevated interleukin-6 level. Results of the present detailed investigation of lymphocyte subsets revealed a discrepancy regarding the process of inflammation in this RM patient between CSF and blood samples. CONCLUSIONS: RM is not a simple reflection of the immune status of RA, as the pathogenesis seems related to, at least in part, CSF-specific immunological dysregulation.

Inactivation of TNF-α ameliorates diabetic neuropathy in mice.

Tumor necrosis factor (TNF)-α is a potent proinflammatory cytokine involved in the pathogenesis of diabetic neuropathy. We inactivated TNF-α to determine if it is a valid therapeutic target for the treatment of diabetic neuropathy. We effected the inactivation in diabetic neuropathy using two approaches: by genetic inactivation of TNF-α (TNF-α(-/-) mice) or by neutralization of TNF-α protein using the monoclonal antibody infliximab. We induced diabetes using streptozotocin in wild-type and TNF-α(-/-) mice. We measured serum TNF-α concentration and the level of TNF-α mRNA in the dorsal root ganglion (DRG) and evaluated nerve function by a combination of motor (MNCV) and sensory (SNCV) nerve conduction velocities and tail flick test, as well as cytological analysis of intraepidermal nerve fiber density (IENFD) and immunostaining of DRG for NF-κB p65 serine-276 phosphorylated and cleaved caspase-3. Compared with nondiabetic mice, TNF-α(+/+) diabetic mice displayed significant impairments of MNCV, SNCV, tail flick test, and IENFD as well as increased expression of NF-κB p65 and cleaved caspase-3 in their DRG. In contrast, although nondiabetic TNF-α(-/-) mice showed mild abnormalities of IENFD under basal conditions, diabetic TNF-α(-/-) mice showed no evidence of abnormal nerve function tests compared with nondiabetic mice. A single injection of infliximab in diabetic TNF-α(+/+) mice led to suppression of the increased serum TNF-α and amelioration of the electrophysiological and biochemical deficits for at least 4 wk. Moreover, the increased TNF-α mRNA expression in diabetic DRG was also attenuated by infliximab, suggesting infliximab's effects may involve the local suppression of TNF-α. Infliximab, an agent currently in clinical use, is effective in targeting TNF-α action and expression and amelioration of diabetic neuropathy in mice.

Presence and functional role of the rapidly activating delayed rectifier K(+) current in left and right atria of adult mice.

Repolarization of cardiac action potentials is regulated by several types of K(+) currents. The present study examined the presence and functional significance of rapid delayed rectifier (I(Kr)) in left and right atrial myocytes of mouse heart, using whole-cell patch-clamp method. The functional role of ultrarapid delayed rectifier (I(Kur)) in the repolarization was also examined by blocking with 4-aminopyridine (50 µM). The presence of I(Kr) was detected in left and right atrial myocytes as an E-4031 (5 µM)-sensitive current that exhibited relatively rapid activation during depolarization and half activation voltage of -17.5 and -17.4 mV for left and right atrial myocytes, respectively. The current density of I(Kr) was similar between left and right atria. The prolongation of action potential measured at 50% repolarization evoked by 4-aminopyridine was significantly larger in left than in right atrium, which appears to be consistent with the larger amplitude of I(Kur) in left atrium. On the other hand, the prolongation of action potential measured at 90% repolarization caused by E-4031 was significantly larger in right than in left atrium. The longer action potential of right atrium, which may result at least partly from smaller amplitude of I(Kur), is likely to enhance the functional significance of I(Kr) in repolarization process of right atrium, despite of similar magnitude of I(Kr) in left and right atria. Our data thus identifies I(Kr) in mouse atria and indicates the presence of functional interaction between I(Kr) and I(Kur) that potentially contributes to repolarization heterogeneity in left and right atria of mouse heart.

[Case of minocycline-induced vasculitic neuropathy].

A 70-year-old woman was admitted to our hospital because of fever, numbness in her extremities and right drop foot. Because her hip prosthesis had loosened as a result of infection, she had been taking 100 mg of minocycline orally for eight months. Three months before admission, she had had melena several times and body weight loss and pyrexia developed. A month before admission, asymmetrical paresthesia and numbness appeared in her extremities and finally right drop foot developed. Laboratory tests showed elevated C-reactive protein and positive anti-nuclear antibody. Abnormalities found in nerve conduction study were compatible with mononeuritis multiplex. Sural nerve biopsy revealed an occluded medium-size artery in the epineurium and axonal degeneration in the nerve fascicles, confirming the diagnosis of vasculitic neuropathy. These manifestations met the American Congress Rheumatology criteria for polyarteritis nodosa. However, her clinical conditions markedly improved after discontinuing minocycline and therefore she was diagnosed as having minocycline-induced vasculitic neuropathy. Although minocycline-induced vasculitis is a well known adverse effect of the drug, peripheral neuropathy with biopsy findings has rarely been reported. Drug induced-vasculitis is important as a differential diagnosis for mononeuritis multiplex because the symptoms can be improved by the discontinuation of an offending drug.

Cytosolic Ca2+ under high glucose with suppressed Na+/K+ pump activity in rat sensory neurons.

Cytosolic Ca2+ concentration ([Ca2+]i) was measured in isolated rat dorsal root ganglion (DRG) neurons using the fluorescent Ca2+ indicator fura-2. Exposure to high (50 mM) extracellular K+ evoked a robust increase in [Ca2+]i, which was almost totally abolished by concomitant presence of nisoldipine (10 microM) and omega-conotoxin GVIA (10 microM). Whereas either high (30 mM) D-glucose alone or ouabain (100 microM) alone did not appreciably affect the high K+-induced [Ca2+]i elevation, neurons pretreated with high D-glucose together with ouabain exhibited a significantly larger [Ca2+]i response to high K+ stimulation, which was almost completely inhibited by nisoldipine and omega-conotoxin GVIA. These results suggest that a combination of high glucose and suppressed Na+/K+ pump activity potentiates the [Ca2+]i elevation stimulated by activation of the voltage-gated Ca2+ channels in rat DRG neurons.

Diabetic neuropathy and nerve regeneration.

Diabetic neuropathy is the most common peripheral neuropathy in western countries. Although every effort has been made to clarify the pathogenic mechanism of diabetic neuropathy, thereby devising its ideal therapeutic drugs, neither convinced hypotheses nor unequivocally effective drugs have been established. In view of the pathologic basis for the treatment of diabetic neuropathy, it is important to enhance nerve regeneration as well as prevent nerve degeneration. Nerve regeneration or sprouting in diabetes may occur not only in the nerve trunk but also in the dermis and around dorsal root ganglion neurons, thereby being implicated in the generation of pain sensation. Thus, inadequate nerve regeneration unequivocally contributes to the pathophysiologic mechanism of diabetic neuropathy. In this context, the research on nerve regeneration in diabetes should be more accelerated. Indeed, nerve regenerative capacity has been shown to be decreased in diabetic patients as well as in diabetic animals. Disturbed nerve regeneration in diabetes has been ascribed at least in part to all or some of decreased levels of neurotrophic factors, decreased expression of their receptors, altered cellular signal pathways and/or abnormal expression of cell adhesion molecules, although the mechanisms of their changes remain almost unclear. In addition to their steady-state changes in diabetes, nerve injury induces injury-specific changes in individual neurotrophic factors, their receptors and their intracellular signal pathways, which are closely linked with altered neuronal function, varying from neuronal survival and neurite extension/nerve regeneration to apoptosis. Although it is essential to clarify those changes for understanding the mechanism of disturbed nerve regeneration in diabetes, very few data are now available. Rationally accepted replacement therapy with neurotrophic factors has not provided any success in treating diabetic neuropathy. Aside from adverse effects of those factors, more rigorous consideration for their delivery system may be needed for any possible success. Although conventional therapeutic drugs like aldose reductase (AR) inhibitors and vasodilators have been shown to enhance nerve regeneration, their efficacy should be strictly evaluated with respect to nerve regenerative capacity. For this purpose, especially clinically, skin biopsy, by which cutaneous nerve pathology including nerve regeneration can be morphometrically evaluated, might be a safe and useful examination.

Properties of the Na+/K+ pump current in small neurons from adult rat dorsal root ganglia.

1 The present investigation was undertaken to characterize the Na(+)/K(+) pump current in small (