A Pilot Study of A2NTX, a Novel Low-Molecular-Weight Neurotoxin Derived from Subtype A2 for Post-Stroke Lower Limb Spasticity: Comparison with OnabotulinumtoxinA.

All the currently used type A botulinum neurotoxins for clinical uses are of subtype A1. We compared the efficacy and safety for the first time head-to-head between a novel botulinum toxin A2NTX prepared from subtype A2 and onabotulinumtoxinA (BOTOX) derived from A1 for post-stroke spasticity. We assessed the modified Ashworth scale (MAS) of the ankle joint, the mobility scores of Functional Independence Measure (FIM), and the grip power of the unaffected hand before and after injecting 300 units of BOTOX or A2NTX into calf muscles. The procedure was done in a blinded manner for the patient, the injecting physician, and the examiner. Stroke patients with chronic spastic hemiparesis (15 for A2NTX and 16 for BOTOX) were enrolled, and 11 for A2NTX and 13 for BOTOX (MAS of ankle; > or = 2) were entered for the MAS study. Area-under-curves of changes in MAS (primary outcome) were greater for A2NTX by day 30 (p = 0.044), and were similar by day 60. FIM was significantly improved in the A2NTX group (p = 0.005), but not in the BOTOX group by day 60. The hand grip of the unaffected limb was significantly decreased in the BOTOX-injected group (p = 0.002), but was unaffected in the A2NTX-injected group by day 60, suggesting there was less spread of A2NTX to the upper limb than there was with BOTOX. Being a small-sized pilot investigation with an imbalance in the gender of the subjects, the present study suggested superior efficacy and safety of A2NTX, and warrants a larger scale clinical trial of A2NTX to confirm these preliminary results.

Clinical Safety and Tolerability of A2NTX, a Novel Low-Molecular-Weight Neurotoxin Derived from Botulinum Neurotoxin Subtype A2, in Comparison with Subtype A1 Toxins.

All the botulinum type A neurotoxins available for clinical use are of the A1 subtype. We developed a subtype A2 low-molecular-weight (150 kD (kilo Dalton)) neurotoxin (A2NTX) with less spread and faster entry into the motor nerve terminal than A1 in vitro and in vivo. Preliminary clinical studies showed that its efficacy is superior to A1 toxins. We conducted an open study exploring its safety and tolerability profile in comparison with A1LL (LL type A1 toxin, or onabotulinumtoxinA) and a low-molecular-weight (150 kD) A1 neurotoxin (A1NTX). Those who had been using A1LL (n = 90; 50-360 mouse LD50 units) or A1NTX (n = 30; 50-580 units) were switched to A2NTX (n = 120; 25-600 units) from 2010 to 2018 (number of sessions ~27, cumulative doses ~11,640 units per patient). The adverse events for A2NTX included weakness (n = 1, ascribed to alcoholic polyneuropathy), dysphagia (1), local weakness (4), and spread to other muscles (1), whereas those for A1LL or A1NTX comprised weakness (n = 2, A1NTX), dysphagia (8), ptosis (6), local weakness (7), and spread to other muscles (15). After injections, 89 out of 120 patients preferred A2NTX to A1 for the successive sessions. The present study demonstrated that A2NTX had clinical safety up to the dose of 500 units and was well tolerated compared to A1 toxins.

Clinical Uses of a Robot (Hybrid-Assisted Limb or HAL™) in Patients with Post-stroke Spasticity after Botulinum Toxin Injections.

Spasticity is the major cause of disabilities in stroke-survivors. Botulinum neurotoxin (BoNT) injections have been used to reduce the muscle tone in those patients, but its efficacy in functional outcome is not well delineated. We have studied the effect of a robot (Hybrid-Assisted Limb or HAL™) designed for assisting the elbow flexion and extension in those who underwent BoNT injections with reduced muscle tone. We enrolled 15 post stroke patients who had BoNT injections for more than 12 months. They were measured for active ROM (range of motion) with video recordings before and after the use of HAL for 40 minutes. Active ROM was measured by a rater who were blinded as to the use of the robot. Significant increase of active ROM was observed immediately after the use of HAL, and the effect was maintained for another 12 months by repeating the sessions. It is suggested from present study that the combined use of BoNT and robotics is effective efficacious for regaining the active function of the upper limb in stroke survivors. J. Med. Invest. 68 : 297-301, August, 2021.

Efficacy of Istradefylline for the Treatment of ADCY5-Related Disease.

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Co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis: a clinical-pathological case report.

BACKGROUND: The coexistence of distinct neurodegenerative diseases in single cases has recently attracted greater attention. The phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, the clinicopathological comorbidity of these two diseases has not been demonstrated. CASE PRESENTATION: A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5 months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP. CONCLUSIONS: Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course.

[Use of Sports in the Rehabilitation of Parkinson's Disease].

Parkinson's disease is a slowly progressing disease where motor function gradually worsens. It is a well-known fact that neuronal plasticity is said to be said, and rehabilitation after developing a cerebrovascular disorder is important. After a stroke, the patient's condition start from its worst state and a goal for improvement can be set for the rehabilitation period However, in Parkinson's disease, rehabilitation is effective in preventing the patient's condition from worsening further, making it difficult to set a goal. Sports are very useful as a long-term and sustainable rehabilitation tool.

The effect of an L/N-type calcium channel blocker on intradialytic blood pressure in intradialytic hypertensive patients.

BACKGROUND: Intradialytic hypertension (HTN), which is one of the poor prognostic markers in patients undergoing hemodialysis, may be associated with sympathetic overactivity. The L/N-type calcium channel blocker, cilnidipine, has been reported to suppress sympathetic nerves activity in vivo. Therefore, we hypothesized that cilnidipine could attenuate intradialytic systolic blood pressure (SBP) elevation. METHODS: Fifty-one patients on chronic hemodialysis who had intradialytic-HTN (SBP elevation ≥10 mmHg during hemodialysis) and no fluid overload were prospectively randomized into two groups: control and cilnidipine groups. Cilnidipine group patients took cilnidipine (10 mg/day) for 12 weeks. The primary endpoint was the change in the intradialytic SBP elevation before and after the 12-week intervention. RESULTS: Before the intervention, no differences were observed in age, sex or pre-dialytic SBP (148.5 ± 12.9 vs. 148.3 ± 19.3 mmHg) between the two groups. Intradialytic SBP elevation was unchanged in the control group. Cilnidipine significantly lowered the post-dialytic SBP with an attenuation of the intradialytic SBP elevation from 12.0 ± 15.4 mmHg to 4.8 ± 10.1 mmHg. However, the observed difference in the intradialytic SBP elevation by cilnidipine did not reach statistical significance (group×time interaction effect p = 0.25). Cathecolamine levels were unaffected by the intervention in both groups. CONCLUSION: Cilnidipine lowers both the pre- and post-dialytic SBP and might attenuate intradialytic SBP elevation. Therefore, cilnidipine may be effective in lowering SBP during HD in patients with intradialytic-HTN.

[A Case of Colon Cancer with DPD Deficiency That Showed Severe Myelosuppression by CapeOX Adjuvant Chemotherapy after Colon Resection].

A 57-year-old female patient received ileocecal colon resection because of colon cancer. Pathological findings showed pSSN2M0(pStage III b). After surgery, CapeOX was administered as an adjuvant chemotherapy. On day 13 of CapeOX treatment, severe oral mucositis and Grade 4 myelosuppression appeared, and the CapeOX treatment was immediately stopped. However, these adverse effects continued for 19 days, and she gradually recovered. The severe myelosuppression was caused bydeficiencyof DPD, which is a keyenzy me that metabolizes 5-FU. While DPD deficiencyis veryrare, we need to consider that 5-FU causes severe adverse events in patients with DPD deficiency.

[Long-Term Successful Management of Recurrent Rectal Cancer in the Predialysis State with FOLFIRI Chemotherapy].

A 71-year-old man with predialysis terminal renal insufficiency experienced peritoneal dissemination 1.5 years after low anterior resection for advanced rectal cancer. He received FOLFIRI therapy (70% dose); he achieved partial response (PR) under computed tomography and stable disease (SD) was maintained over a long term. Although Grade 3 myelosuppression was occasionally noted, he was treated with FOLFIRI for 2 years without other severe complications and without requiring the initiation of hemodialysis. After the initiation of hemodialysis, FOLFIRI treatment was continued for 1 year until progressive disease (PD). He received mFOLFOX6 as second-line therapy for 6 months, followed by LV-5-FU and a molecular targeting agent. These treatments prolonged his survival for 1 year and 8 months. FOLFIRI can be administered as an effective first-line therapy even for patients with predialysis terminal renal impairment without major renal damage. FOLFOX and molecular targeting agents should be made available and prolonged survival can be expected for advanced colorectal cancer patients with terminal renal disease after the initiation of hemodialysis.

[Successful management using laparoscopic splenectomy for splenomegaly and thrombocytopenia caused by oxaliplatin-based chemotherapy for advanced rectal cancer].

We report a case of advanced rectal cancer treated with chemotherapy, for which laparoscopic splenectomy had been effective for thrombocytopenia. A 56-year-old man suffered from advanced rectal cancer with multiple lung metastases. He underwent Hartmann's procedure and received chemotherapy with FOLFOX and FOLFIRI with bevacizumab. After 3 years and 2 months, he also suffered from splenomegaly and thrombocytopenia. Laparoscopic splenectomy produced and increased the thrombocyte count, allowing for a restart of chemotherapy. Oxaliplatin-based chemotherapy might produce hepatic sinusoid injury and induce splenomegaly owing to portal hypertension. Laparoscopic splenectomy seemed to be useful for treating thrombocytopenia, and allowed the continuation of chemotherapy.

Lung adenocarcinoma in a patient with plasmacytoma.

An increased risk of second malignancy is well recognized in patients treated for plasma cell neoplasms. However, second solid tumor is very rare in such patients. We report a case of a 68-year-old woman with plasmacytoma who developed lung adenocarcinoma.

[A case of status epilepticus with a possible therapeutic effect by dantrolene sodium].

We report a 62-year-old man who have taken major tranquilizer for schizophrenia for the past 24 years. He had sudden generalized tonic-clonic seizure and consciousness loss on April 2010. He was administered diazepam, phenytoin, phenobarbital intravenously and drip-infused with midazolam continuously, but the seizure persisted. For a possible comorbidity of neuroleptic malignant syndrome, we administered dantrolene sodium intravenously and bromocriptine through a nasal gastric tube. The refractory status epilepticus disappeared immediately after the administration. Status epilepticus remitted 2 days later but again disappeared with repeated injection of dantrolene. These results suggested that intravenous administration of dantrolene may have alleviated the refractory symptoms of status epilepticus.

Deletion of chromosome arm 15q in a case of minimally differentiated hypoplastic AML-M0.

Deletion of the long arm of chromosome 15 is known as a rare but recurrent chromosomal abnormality in myeloid malignancies. We report a novel case of minimally differentiated hypoplastic acute myeloid leukemia (AML M0) in a patient who initially had a normal karyotype, but clonal interstitial deletion of chromosome 15, del(15)(q11.2q22), coincided with increment of leukemic cells a year later. We also summarize 18 published cases with myeloid malignancies and this chromosomal abnormality.

Preliminary study of psychological factors affecting clinic attendance and glycemic control of Japanese patients with type 2 diabetes mellitus.

We studied 50 Japanese patients who were first diagnosed with type 2 diabetes mellitus. Psychological functioning was assessed by using the Rorschach test and the Yatabe-Guilford Personality test. Analysis indicated that patients who discontinued clinic attendance during the 2-yr. study period had more depression, lower general activity and less extraversion, more negative self-attitudes, and more concern about being helpless than those who continued having regular followups. This study also found that patients who had worse glycemic control 2 yr. after being first diagnosed reported more inferiority feelings, lower general activity, more need for closeness to others, and more emotional demands than those who had better glycemic control. In conclusion, understanding the psychological functioning would be helpful in the management of Japanese patients with type 2 diabetes mellitus.