Development of Benziodarone Analogues with Enhanced Potency for Selective Binding to Transthyretin in Human Plasma.

Transthyretin amyloidosis is a fatal disorder caused by transthyretin amyloid aggregation. Stabilizing the native structure of transthyretin is an effective approach to inhibit amyloid aggregation. To develop kinetic stabilizers of transthyretin, it is crucial to explore compounds that selectively bind to transthyretin in plasma. Our recent findings demonstrated that the uricosuric agent benziodarone selectively binds to transthyretin in plasma. Here, we report the development of benziodarone analogues with enhanced potency for selective binding to transthyretin in plasma compared to benziodarone. These analogues featured substituents of chlorine, bromine, iodine, a methyl group, or a trifluoromethyl group, at the 4-position of the benzofuran ring. X-ray crystal structure analysis revealed that CH···O hydrogen bonds and a halogen bond are important for the binding of the compounds to the thyroxine-binding sites. The bioavailability of benziodarone analogues with 4-Br, 4-Cl, or 4-CH3 was comparable to that of tafamidis, a current therapeutic agent for transthyretin amyloidosis.

CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.

Benziodarone and 6-hydroxybenziodarone are potent and selective inhibitors of transthyretin amyloidogenesis.

Transthyretin amyloidosis is a progressive systemic disorder that is caused by the amyloid deposition of transthyretin in various organs. Stabilization of the native transthyretin is an effective strategy for the treatment of transthyretin amyloidosis. In this study we demonstrate that the clinically used uricosuric agent benziodarone is highly effective to stabilize the tetrameric structure of transthyretin. An acid-induced aggregation assay showed that benziodarone had strong inhibitory activity similar to that of tafamidis, which is currently used as a therapeutic agent for transthyretin amyloidosis. Moreover, a possible metabolite, 6-hydroxybenziodarone, retained the strong amyloid inhibitory activity of benziodarone. An ex vivo competitive binding assay using a fluorogenic probe showed that benziodarone and 6-hydroxybenziodarone were highly potent for selective binding to transthyretin in human plasma. An X-ray crystal structure analysis revealed that the halogenated hydroxyphenyl ring was located at the entrance of the thyroxine binding channel of transthyretin and that the benzofuran ring was located in the inner channel. These studies suggest that benziodarone and 6-hydroxybenziodarone would potentially be effective against transthyretin amyloidosis.

A case of thymoma-associated myasthenia gravis accompanied with myositis showing the clusters of histiocyte along the fascicles in perimysium.

Patients with myasthenia gravis (MG) often have other autoimmune disorders. However, the coexistence of MG and myositis is rare. Here, we report a case of a 77-year-old woman who developed mild fatigable muscle weakness and diplopia in 3 months. Serum creatine kinase was elevated to 1385 IU/L. Antibodies to acetylcholine receptor (AChR), titin and voltage-gated potassium channel 1.4 (Kv 1.4) were all positive while all tested myositis-specific autoantibodies were negative. Standard needle electromyography showed fibrillation potential and early recruitment of motor units. The repetitive nerve stimulations were consistent with a disorder of the neuromuscular junction. Muscle biopsy showed that the clusters of histiocyte were present along the fascicles in perimysium and some of them invaded into endomysium.

Identification of a novel mutation and genotype-phenotype relationship in MEGF10 myopathy.

Mutations in MEGF10 are associated with early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). Recently, a mild variant phenotype of EMARDD has been reported in patients with multiple minicores in the myofibers. However, some reported patients had no clear cores. We present a patient who had progressive weakness since his 30 s and then developed severe respiratory failure at the age of 66 years and found that he had a novel mutation, p.G739R, in MEGF10. He had no clear core in the biopsied muscle. We summarize the clinical and genetic characteristics of the current and reported patients with MEGF10 and statistically evaluate the genotype-phenotype correlation. Results show that patients with missense mutations in at least one allele had significantly later onset than those with biallelic truncation mutations.

Nurses' experience in providing care at shelters following natural hazards and disasters: a qualitative systematic review protocol.

OBJECTIVE: The review will synthesize current evidence regarding the experiences of nurses who care for people living in shelters following natural hazards and disasters. INTRODUCTION: Over the last decade, due to climate change and global warming, the damage caused by natural hazards and disasters like hurricanes, floods and heavy rainfall has been steadily growing. Following natural hazards and disasters, many who lose their homes reside in evacuation shelters for prolonged periods. The loss of medical infrastructure in disaster-stricken areas can result in evacuees' health being compromised and the spread of disease and/or infection. Under such circumstances, disaster relief nurses can play a critical role in supporting these victims. This review aims to provide useful information for nurses who are working in disaster shelters. INCLUSION CRITERIA: The review will include qualitative studies examining experiences of nurses caring for people living in shelters following natural hazards and disasters, published in either English or Japanese. Studies published from 2000 to the present will be considered. METHODS: The review will follow the meta-aggregation approach developed by JBI. Published and unpublished studies will be searched using major international databases and other relevant databases for gray literature in either English or Japanese. Two reviewers will independently appraise studies and extract qualitative data using the JBI standardized critical appraisal and extraction instruments. Findings from the review will be categorized according to their similarity in meaning and their categories subjected to a meta-synthesis to produce a single comprehensive set of synthesized findings. The final synthesized findings will be graded according to the ConQual approach.

Effects of an underwear-type hip abduction orthosis on sitting balance and sit-to-stand activities in children with spastic cerebral palsy.

[Purpose] Hip dislocation and subluxation are common in patients with cerebral palsy (CP). Hip abduction orthoses are used to prevent and treat these problems. This study investigated the effects of an underwear-type hip abduction orthosis on sitting balance and sit-to-stand (STS) activity in children with spastic CP. [Participants and Methods] This trial had a cross-over design. Eight children aged 6 to 18 years old with spastic CP and Gross Motor Function Classification level III and IV were randomly allocated to groups with or without use of the underwear-type hip orthosis. The trunk impairment scale (TIS) score was evaluated and the 5-times sit-to-stand test (FTSST) was conducted with and without the underwear. [Results] The dynamic sitting balance scores in the TIS and FTSST showed significant improvement with use of the orthotic underwear. [Conclusion] The dynamic sitting balance scores of the TIS and FTSST were higher, thus indicating better stability, when wearing the orthosis underwear. Thus, it was suggested that underwear-type hip abduction orthoses are effective for promoting sitting balance and STS activities in children with spastic CP.

Validity of using multi-frequency bioelectrical impedance analysis to measure skeletal muscle mass in preschool children.

[Purposes] Although it is recommended to develop a habit of physical activities, there is no easy way to measure skeletal muscle mass in preschool children, which cause the difficulty of evaluation. The purpose of this study was to examine the validity of body composition including the skeletal muscle mass assessment using multi-frequency bioelectrical impedance analysis by comparing body fat mass obtained by using multi-frequency bioelectrical impedance analysis method and body mass index formulas. [Subjects and Methods] Ninety-four children were surveyed for age, height, weight, grip strength, maximum occlusal force, thickness of muscle and fat mass (masseter and lower limb), body fat mass, skeletal muscle mass, and calf circumference. We assessed additional parameters, which were thought to be related to skeletal muscle mass, to ensure validity. [Results] A strong correlation was found in body fat mass values obtained using the multi-frequency bioelectrical impedance analysis method and those obtained using the body mass index formulas. Additionally, strong correlation coefficients were found between the skeletal muscle mass/height obtained using the multi-frequency bioelectrical impedance analysis method and grip strength and calf circumference. [Conclusion] Our results indicate that skeletal muscle mass can be reliably measured using the multi-frequency bioelectrical impedance analysis method in preschool children.

Evaluating the effects of testing period on pollinosis symptoms using an allergen challenge chamber.

BACKGROUND: We previously built a pollen challenge test unit (allergen challenge chamber: ACC) to collect objective data about Japanese cedar pollinosis. In this study, we investigated adequate conditions for pollen challenge using the ACC. METHODS: The study consisted of two parts. The first part was conducted in November, which is not in pollen season. Subjects were exposed to Japanese cedar pollen at a concentration of 50,000 grains/m3 in the chamber for 120 min each day over the course of three consecutive days. The second part was conducted in April, which is just after pollen season. Subjects were exposed to Japanese cedar pollen at the same concentration (50,000 grains/m3) in the chamber for 90 min on a single day. Subjects recorded nasal and ocular symptoms before challenge and every 15 min after challenge initiation. The minimum cross-sectional area in the nasal cavity was measured using acoustic rhinometry before and after challenge as an indicator of nasal obstruction. Inflammatory markers in nasal lavage fluid and serum were also measured before and after challenge. RESULTS: Nasal and ocular symptoms were significantly exacerbated after challenge on all days of the single and 3-consecutive-day challenge tests, particularly on the third day of the consecutive challenge test. Nasal and ocular symptoms were also quickly induced with challenge immediately after the end of pollen season. No significant changes in inflammatory markers were seen. CONCLUSIONS: Care is needed with regard to pollen challenge conditions in the ACC, including timing of the challenge, to induce pollinosis symptoms that accurately reflect chronic inflammation.

Six secoiridoid glucosides from Adina racemosa.

Six novel secoiridoid glucosides, adinosides A (1), B (2), C (3), D (4), E (5), and grandifloroside 11-methyl ester (6) were isolated, together with 27 known compounds, from the dried leaves, flowers, and twigs of Adina racemosa. The structures of the new compounds were determined by spectroscopic (NMR, MS) and chemical means.