A Novel Mutation of VPS13D-related Disorders with Parkinsonism.

We herein report a case of VPS13D-related disorder with a novel homogeneous variant. A 58-year-old Japanese woman was referred to our hospital with slowly progressive gait disturbance and cognitive impairment. A neurological examination revealed decreased spontaneity, recent memory impairment, Parkinsonism, cerebellar ataxia, pyramidal signs, and autonomic dysfunction. Dopamine transporter single-photon-emission computed tomography showed a markedly reduced uptake in the striatum bilaterally. Whole-exome sequencing revealed a novel homozygous missense variant of the VPS13D gene (Arg3267Pro). Our case suggests that mutations in VPS13D may cause parkinsonism, in addition to the previously reported cerebellar ataxia and spastic paraplegia.

Effects of an environmental endocrine disruptor, para-nonylphenol on the cell growth of Euglena gracilis: association with the cellular oxidative stress.

Effects of an environmental endocrine disruptor, para-nonylphenol (NP) on the cell growth of a photosynthetic eukaryotic microorganism, Euglena gracilis were analysed under different cell culture conditions. Although NP did not show significant inhibitory effects on the cell growth of E. gracilis (Z and SM strains) under light culture condition, NP exhibited significant suppressive effects under dark culture condition. Exogenous supplementation with lipophilic antioxidants (α-tocopherol, ß-carotene or 6-O-palmitoyl-ascorbic acid) to E. gracilis caused strong preventive effects against NP-induced cell growth inhibition under dark culture condition, but hydrophilic antioxidants [ascorbic acid, glutathione and epigallocatechin gallate (EGCG)] did not show significant preventive effects. NP caused significant generation of reactive oxygen species (ROS) in E. gracilis under dark culture condition, but E. gracilis under light culture condition did not show significant increase in ROS generation. Supplementation with lipophilic antioxidants to E. gracilis caused significant suppressive effects against NP-induced cellular ROS generation under dark culture condition, but hydrophilic antioxidants did not show significant suppressive effects. Furthermore, the productivities of typical cellular antioxidants (α-tocopherol, ß-carotene and ascorbic acid) in E. gracilis under light culture conditions were much higher than those under dark culture conditions.

Establishment of a mouse- and egg-adapted strain for the evaluation of vaccine potency against H3N2 variant influenza virus in mice.

Sporadic spreads of swine-origin influenza H3N2 variant (H3N2v) viruses were reported in humans, resulting in 437 human infections between 2011 and 2021 in the USA. Thus, an effective vaccine is needed to better control a potential pandemic for these antigenically distinct viruses from seasonal influenza. In this study, a candidate vaccine strain with efficient growth capacity in chicken embryos was established through serial blind passaging of A/Indiana/08/2011 (H3N2)v in mice and chicken embryos. Seven amino acid substitutions (M21I in PA; A138T, N165K, and V226A in HA; S312L in NP; T167I in M1; G62A in NS1 proteins) were found in the passaged viruses without a major change in the antigenicity. This mouse- and egg-adapted virus was used as a vaccine and challenge strain in mice to evaluate the efficacy of the H3N2v vaccine in different doses. Antibodies with high neutralizing titers were induced in mice immunized with 100 µg of inactivated whole-virus particles, and those mice were significantly protected from the challenge of homologous strain. The findings indicated that the established strain in the study was useful for vaccine study in mouse models.

Low urine pH associated with sarcopenia in the elderly: A multi-center observational study.

ABSTRACT: The pathophysiology of sarcopenia is complex and must be further explored. While metabolic acidosis may be a risk factor for sarcopenia, it remains unclear whether acidic urine is related to sarcopenia. The purpose of the present study was to investigate the association between sarcopenia and urine pH in the elderly.An elderly population (n = 123 [male = 46]; mean age = 81.7 years) was classified into 2 groups based on the sarcopenia status according to their strength, requirement of assistance in walking, their ability to rise from a chair their ability to climb stairs, and their history of falls. Urinalysis was measured using dipstick tests.The sarcopenia group (n = 32) was significantly older, had less exercise habit and showed a lower urine pH (mean pH = 5.5) in comparison to the nonsarcopenia group (mean pH = 6.2, P < .01). A multivariate analysis that was adjusted for age, male sex, body mass index, uro-renal variables and exercise habit revealed that urine pH (odds ratio, 0.43; 95% confidence interval, 0.22-0.85, P = .02), age and less exercise habit were independently and significantly associated with sarcopenia.The findings of the present study suggest a potential association between metabolic acidosis and the pathophysiology of sarcopenia in the elderly. As urine pH is a simple biomarker that can be obtained using dipstick tests, it is therefore expected to be helpful for detecting sarcopenia in the clinical setting.

Re-Invasion of H5N8 High Pathogenicity Avian Influenza Virus Clade 2.3.4.4b in Hokkaido, Japan, 2020.

Global dispersion of high pathogenicity avian influenza (HPAI), especially that caused by H5 clade 2.3.4.4, has threatened poultry industries and, potentially, human health. An HPAI virus, A/northern pintail/Hokkaido/M13/2020 (H5N8) (NP/Hok/20) belonging to clade 2.3.4.4b, was isolated from a fecal sample collected at a lake in Hokkaido, Japan where migratory birds rested, October 2020. In the phylogenetic trees of all eight gene segments, NP/Hok/20 fell into in the cluster of European isolates in 2020, but was distinct from the isolates in eastern Asia and Europe during the winter season of 2017-2018. The antigenic cartography indicates that the antigenicity of NP/Hok/20 was almost the same as that of previous isolates of H5 clade 2.3.4.4b, whereas the antigenic distances from NP/Hok/20 to the representative strains in clade 2.3.4.4e and to a strain in 2.3.4 were apparently distant. These data imply that HPAI virus clade 2.3.4.4b should have been delivered by bird migration despite the intercontinental distance, although it was not defined whether NP/Hok/20 was transported from Europe via Siberia where migratory birds nest in the summer season. Given the probability of perpetuation of transmission in the northern territory, periodic updates of intensive surveys on avian influenza at the global level are essential to prepare for future outbreaks of the HPAI virus.

Potency of an Inactivated Influenza Vaccine against a Challenge with A/Swine/Missouri/A01727926/2015 (H4N6) in Mice for Pandemic Preparedness.

H4 influenza viruses have been isolated from birds across the world. In recent years, an H4 influenza virus infection has been confirmed in pigs. Pigs play an important role in the transmission of influenza viruses to human hosts. Therefore, it is important to develop a new vaccine in the case of an H4 influenza virus infection in humans, considering that this virus has a different antigenicity from seasonal human influenza viruses. In this study, after selecting vaccine candidate strains based on their antigenic relation to one of the pig isolates, A/swine/Missouri/A01727926/2015 (H4N6) (MO/15), an inactivated whole-particle vaccine was prepared from A/swan/Hokkaido/481102/2017 (H4N6). This vaccine showed high immunogenicity in mice, and the antibody induced by the vaccine showed high cross-reactivity to the MO/15 virus. This vaccine induced sufficient neutralizing antibodies and mitigated the effects of an MO/15 infection in a mouse model. This study is the first to suggest that an inactivated whole-particle vaccine prepared from an influenza virus isolated from wild birds is an effective countermeasure in case of a future influenza pandemic caused by the H4 influenza virus.

Oral Supplementation of the Vitamin D Metabolite 25(OH)D3 Against Influenza Virus Infection in Mice.

Vitamin D is a fat-soluble vitamin that is metabolized by the liver into 25-hydroxyvitamin D [25(OH)D] and then by the kidney into 1,25-dihydroxyvitamin D [1,25(OH)2D], which activates the vitamin D receptor expressed in various cells, including immune cells, for an overall immunostimulatory effect. Here, to investigate whether oral supplementation of 25-hydroxyvitamin D3 [25(OH)D3], a major form of vitamin D metabolite 25(OH)D, has a prophylactic effect on influenza A virus infection, mice were fed a diet containing a high dose of 25(OH)D3 and were challenged with the influenza virus. In the lungs of 25(OH)D3-fed mice, the viral titers were significantly lower than in the lungs of standardly fed mice. Additionally, the proinflammatory cytokines IL-5 and IFN-γ were significantly downregulated after viral infection in 25(OH)D3-fed mice, while anti-inflammatory cytokines were not significantly upregulated. These results indicate that 25(OH)D3 suppresses the production of inflammatory cytokines and reduces virus replication and clinical manifestations of influenza virus infection in a mouse model.

5-Hydroxy-7-methoxyflavone derivatives from Kaempferia parviflora induce skeletal muscle hypertrophy.

Skeletal muscle plays a critical role in locomotion and energy metabolism. Maintenance or enhancement of skeletal muscle mass contributes to the improvement of mobility and prevents the development of metabolic diseases. The extracts from Kaempferia parviflora rhizomes contain at least ten methoxyflavone derivatives that exhibit enhancing effects on ATP production and glucose uptake in skeletal muscle cells. In the present study, we investigated the effects of ten K. parviflora-derived methoxyflavone derivatives (six 5,7-dimethoxyflavone (DMF) derivatives and four 5-hydroxy-7-methoxyflavone (HMF) derivatives) on skeletal muscle hypertrophy. Murine C2C12 myotubes and senescence-accelerated mouse-prone 1 (SAMP1) mice treated with methoxyflavones were used as experimental models to determine the effects of HMF derivatives on myotube diameter and size and muscle mass. The four HMF derivatives, but not the six DMF derivatives, increased myotube diameter. The 5-hydroxyflavone, 7-methoxyflavone, and 5,7-dihydroxyflavone had no influence on myotube size, a result that differed from HMF. Dietary administration of the mixture composed of the four HMF derivatives resulted in increase in the soleus muscle size and mass in SAMP1 mice. HMF derivatives also promoted protein synthesis in myotubes, and treatment with the intracellular Ca2+ chelator BAPTA-AM, which depletes intracellular Ca2+ levels, inhibited this promotion. Furthermore, BAPTA-AM inhibited HMF-promoted protein synthesis even when myotubes were incubated in Ca2+-free medium. These results indicate that HMF derivatives induce myotube hypertrophy and that both the 5-hydroxyl group and the 7-methoxy group in the flavones are necessary for myotube hypertrophy. Furthermore, these results suggest that HMF-induced protein synthesis requires intracellular Ca2+, but not extracellular Ca2+.

Suppression of benign prostate hyperplasia by Kaempferia parviflora rhizome.

BACKGROUND: Kaempferia parviflora rhizome is used as a folk medicine in Thailand for the treatment of various symptoms. In the present study, the inhibitory activities of extract from K. parviflora rhizome against 5α-reductase (5αR) were subjected. Furthermore, the effects of the extract from K. parviflorar hizome in benign prostate hyperplasia (BPH) were studied using the model mice. MATERIALS AND METHODS: Preparations of extracts from the rhizomes of K. parviflora, Curcuma zedoaria and Zingiber officinale, and methoxyflavones isolated from K. parviflora was used for 5αR inhibition assay. The effects of K. parviflora extract on growth suppression for the prostates and seminal vesicles were performed based on the Hershberger's method. The K. parviflora extract was administered to castrated mice for 14 days. RESULTS: K. parviflora extract showed more potent inhibitory activity on 5αR than C. zedoaria and Z. officinale extracts. The active principles were identified as 3,5,7,3',4'-pentamethoxyflavone and 5,7,3',4'-tetramethoxyflavone by activity guided fractionation. Furthermore, K. parviflora extract suppressed the weights of prostates and seminal vesicles in BPH model rats by daily administration for 14 days. CONCLUSION: These results indicate that K. parviflora extract can be a promising agent for the treatment of BPH.

ent-Rosane and abietane diterpenoids as cancer chemopreventive agents.

Two ent-rosane- (cuzcol, 1 and 6-dehydroxycuzcol, 2) and a abietatriene- (salvadoriol, 3) type diterpenoids have been isolated from Maytenus cuzcoina and Crossopetalum uragoga, respectively, along with five known diterpene compounds (4-8). Their stereostructures have been elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques, and computational data. The absolute configuration of cuzcol was determined by application of Riguera ester procedure. This is the first instance of isolation of ent-rosane diterpenoids from species of the Celastraceae. The isolated diterpenes were found to be potent anti-tumour-promoter agents, and carnosol (7) also showed a remarkable chemopreventive effect in an in vivo two-stage carcinogenesis model.

Sesquiterpenes from Maytenus jelskii as potential cancer chemopreventive agents.

Seven new (1-4 and 7-9) sesquiterpenes with a dihydro-beta-agarofuran skeleton, along with four known compounds (5, 6, 10, and 11), have been isolated from the leaves of Maytenus jelskii. The structures of the new compounds were elucidated by means of spectroscopic data analysis, including 1D and 2D NMR techniques, and their absolute configurations were determined by circular dichroism and chemical correlations. The compounds have been tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Compound 10 was found to be an effective antitumor-promoting agent and also showed a potent chemopreventive effect in an in vivo two-stage carcinogenesis model.

Preoperative Diagnosis of Adult Intussusception Caused by Small Bowel Lipoma.

Adult intussusception is rare, accounting for only 5% of all intussusceptions, for which preoperative diagnosis is difficult. We herein report a preoperatively diagnosed case of adult intussusception caused by a small bowel lipoma. A 33-year-old man was admitted to our hospital with three weeks history of colicky epigastric pain. Computed tomography revealed thickening of the ileal wall suggestive of intussusception. Colonoscopy revealed an ileocolic intussusception. Barium enema for reduction of ileocolic intussusception demonstrated a small bowel tumor in the ileum 15 cm proximal to the ileocecal valve. The intussusception was reduced, and the patient underwent partial resection of the ileum encompassing the small bowel tumor. Histological findings confirmed the diagnosis of lipoma of the small bowel. The patient made a satisfactory recovery and remains well.

Light dependency of resistance to ionizing radiation in Euglena gracilis.

The resistance of Euglena gracilis strains Z (wild type) and SM-ZK (chloroplast-deficient mutant) to ionizing radiation was investigated. The colony forming ability of E. gracilis strain Z was higher than that of strain SM-ZK after 60Cogamma-irradiation. For both strains, the resistance of light-grown cells was higher than that of dark-grown cells, suggesting that the light conditions during culture contribute to the radiation resistance of E. gracilis. The comet assay showed that the ability of rejoining DNA double-strand breaks (dsb) was much higher in the light-grown cells. These results suggest that E. gracilis possesses a light-induced repair system to cope with DNA dsb.

Evaluation of the resistance of Euglena gracilis to ion beam radiation.

The resistance of Euglena (E.) gracilis to ionizing radiation was investigated using seven kinds of ion beams each with different energy characteristics. The minimum effective dose of the most lethal ion beams was 40 Gy. Given its substantially high resistance to heavy ion beams, E. gracilis possesses great potential in acting as an effective support system to produce food and regenerate oxygen in a space station. The lethal effect of ionizing radiation was dependent on the linear energy transfer value of the heavy ion beams, and reached a maximum at 196 keV/micron. This value was different from those obtained by previous irradiation experiments using mammalian and plant cells, suggesting that the radiation response of E. gracilis is distinct from that of mammalian and plant cells.