Mutant Tof11 alleles are highly accumulated in early planting-adaptable Japanese summer type soybeans.

To avoid crop failure because of climate change, soybean (Glycine max (L.) Merrill) cultivars adaptable to early planting are required in western Japan. Because current Japanese cultivars may not be adaptable, genetic resources with high early-planting adaptability, and their genetic information must be developed. In the present study, summer type (ST) soybeans developed for early planting were used as plant materials. We examined their phenological characteristics and short reproductive period as an indicator of early planting adaptability and performed genetic studies. Biparental quantitative trait loci (QTL) analysis of a representative ST cultivar revealed a principal QTL for the reproductive period duration on chromosome 11. The results of resequencing analysis suggested that circadian clock-related Tof11 (soybean orthologue of PRR3) is a candidate QTL. Additionally, all 25 early planting-adaptable germplasms evaluated in this study possessed mutant alleles in Tof11, whereas 15 conventional cultivars only had wild-type alleles. These results suggest that mutant alleles in Tof11 are important genetic factors in the high adaptability to early planting of these soybeans, and thus, these alleles were acquired and accumulated in the ST soybean population.

Metabolic changes in the plasma of mild Alzheimer's disease patients treated with Hachimijiogan.

Background: Alzheimer's disease (AD), the most prevalent form of dementia, is a debilitating, progressive neurodegeneration. Amino acids play a wide variety of physiological and pathophysiological roles in the nervous system, and their levels and disorders related to their synthesis have been related to cognitive impairment, the core feature of AD. Our previous multicenter trial showed that hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), has an adjuvant effect for Acetylcholine estelase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of female patients with mild AD. However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear. Objectives: To elucidate through metabolomic analysis the mechanism(s) of HJG for mild AD based on changes in plasma metabolites. Methods: Sixty-seven patients with mild AD were randomly assigned to either an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI (HJG:33, Control:34). Blood samples were collected before, 3 months, and 6 months after the first drug administration. Comprehensive metabolomic analyses of plasma samples were done by optimized LC-MS/MS and GC-MS/MS methods. The web-based software MetaboAnalyst 5.0 was used for partial least square-discriminant analysis (PLS-DA) to visualize and compare the dynamics of changes in the concentrations of the identified metabolites. Results: The VIP (Variable Importance in Projection) score of the PLS-DA analysis of female participants revealed a significantly higher increase in plasma metabolite levels after HJG administration for 6 months than was seen in the control group. In univariate analysis, the aspartic acid level of female participants showed a significantly higher increase from baseline after HJG administration for 6 months when compared with the control group. Conclusion: Aspartic acid was a major contributor to the difference between the female HJG and control group participants of this study. Several metabolites were shown to be related to the mechanism of HJG effectiveness for mild AD.

Static and Dynamic Functional Connectivity Alterations in Alzheimer's Disease and Neuropsychiatric Diseases.

Background: To date, numerous studies have documented various alterations in resting brain activity in Alzheimer's disease (AD) and other neuropsychiatric diseases. In particular, disease-related alterations of functional connectivity (FC) in the resting state networks (RSN) have been documented. Altered FC in RSN is useful not only for interpreting the phenotype of diseases but also for diagnosing the diseases. More recently, several studies proposed the dynamics of resting-brain activity as a useful marker for detecting altered RSNs related to AD and other diseases. Objectives: In this article, we review recent studies exploring alterations of static and dynamic functional connectivity in AD and other neuropsychiatric diseases. We then discuss how to utilize and interpret dynamics of FC for studying resting brain activity in diseases. Results: In contrast to previous studies, which focused on FC calculated using an entire fMRI scan (static FC), newer studies focused on the temporal dynamics of FC within the scan (dynamic FC) to provide more sensitive measures to characterize RSNs. However, despite the increasing popularity of dynamic FC, several statistical investigations of dynamic FC cautioned that the results obtained in commonly used analyses for dynamic FC require careful interpretation. Conclusions: Although static and dynamic FC are likely to be a useful tool to detect altered RSN in patients affected by AD and other neuropsychiatric disorders, interpretation of altered dynamic FC in patients require special care. Impact statement We review recent studies of static and dynamic functional connectivity (dFC) in Alzheimer's disease and discuss interpretation of dFC.

An exploratory, open-label, randomized, multicenter trial of hachimijiogan for mild Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurodegeneration and is the most prevalent form of dementia. Intervention at an early stage is imperative. Although three acetylcholinesterase inhibitors (AChEIs) are currently approved for the treatment of mild AD, they are not sufficiently effective. Novel treatments for mild AD are of utmost importance. Objective: To assess the effectiveness of hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), in the treatment of mild AD. Methods: This exploratory, open-label, randomized, multicenter trial enrolled patients with mild AD whose score on the Mini Mental State Examination (MMSE) was over 21points. All participants had been taking the same dosage of AChEI for more than 3 months. The participants were randomly assigned to an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI. The primary outcome was the change from baseline to 6 months post treatment initiation on the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version(ADAS-Jcog). The secondary outcomes were change from baseline of the Instrumental Activity of Daily Life (IADL), Apathy scale, and Neuropsychiatric Inventory (NPI) -Q score. Results: Among the 77 enrollees, the data of 69(34 HJG and 35 control)were available for analysis. The difference in the change of ADAS-Jcog from baseline to 6 months of the HJG and control groups was 1.29 (90% Confidence interval (CI), -0.74 to 3.32 p = 0.293). In the subgroup analysis, the differences in the change from baseline to 3 and 6 months for women were 3.70 (90% CI ,0.50 to 6.91, p = 0.059) and 2.90 (90% CI,0.09 to 5.71, p = 0.090), respectively. For patients over 65 years, the difference at 3 months was 2.35 (90%CI, 0.01 to 4.68 p = 0.099). No significant differences were found between the HJG and control groups in IADL score, Apathy scale, or NPI-Q score. Conclusion: Although not conclusive, our data indicate that HJG has an adjuvant effect for acetylcholinesterase inhibitors and that it delays the deterioration of the cognitive dysfunction of mild Altzheimer's disease patients. Clinical Trial Registration: http://clinicaltrials.gov Japan Registry of clinical trials, identifier jRCTs 071190018.

Long-Term Effect of Acetylcholinesterase Inhibitors on the Dorsal Attention Network of Alzheimer's Disease Patients: A Pilot Study Using Resting-State Functional Magnetic Resonance Imaging.

Background: Alzheimer's disease (AD) is the most common condition of all neurodegenerative diseases and is characterized by various cognitive dysfunctions. Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have revealed the physiological dynamics of functionally connected brain networks, which are called resting-state networks (RSNs). Associations between impairments of RSNs and various neuropsychiatric diseases, such as AD, have been reported. Acetylcholinesterase inhibitors (AChEIs) have been used as a pharmacological treatment for mild-to-moderate moderate AD, and short-term improvements in cognitive functions and RSNs in restricted areas have been reported. Objective: We aimed to characterize AChEI-related RSN changes by acquiring two sets of rs-fMRI data separated by approximately 3 to 6 months. Methods: Seventeen patients with AD and nine healthy subjects participated in this study. Independent component analysis was performed on the rs-fMRI data of AChEI-responsive and non-responsive AD patients, stratified according to change in Mini-Mental State Examination (MMSE) scores after 3 to 6 months of AChEI therapy. In addition, a region of interest-based analysis of the rs-fMRI data before therapy was performed to explore the functional connectivity (FC) changes associated with AchEI therapy. Results: Responders showed a significantly greater increase in MMSE scores, especially for orientation for time, than that of non-responders following AChEI therapy. A subtraction map of MMSE score differences (responders minus non-responders) in the independent component analysis revealed higher FC of the dorsal attention network in responders compared with that in non-responders. Moreover, in the region of interest analysis of untreated status data, the dorsal attention network showed significant negative FC with the right planum temporale, which belongs to the ventral attention network, proportional to MMSE score change. Conclusion: The negative correlation of the FC of the dorsal attention network and right planum temporale before AChEI therapy and MMSE score change may be a biomarker of the therapeutic effect of AChEIs for AD.

Anti-Donor Regulatory T-Cell Therapy in Adult-to-Adult Living Donor Liver Transplantation: A Case Report.

We report on the case of a 50-year-old female patient with symptomatic polycystic liver disease who underwent living donor liver transplantation (LDLT) using right liver graft from her ABO-identical husband. To achieve operational tolerance, regulatory T-cell (T-reg)-based cell therapy was applied, following the protocol introduced by Todo et al. Briefly, donor lymphocytes were collected by leukapheresis 20 days before LDLT without any adverse events, and the cells were irradiated with a dose of 30 Gy and kept frozen. Lymphopheresis of the recipient was conducted in a similar manner 1 day before LDLT, and donor cells and recipient cells were cultured with anti-CD80/86 antibodies to induce the donor-specific T-reg. At 14 days of culture, the CD4+CD25+Foxp3+ cells had increased from 1.51% to 5.21%, and mixed lymphocyte reaction assay using an intracellular fluorescent dye carboxyfluorescein diacetate succinimidyl ester-labeling technique revealed donor-specific hyporesponsiveness of CD4-positive lymphocytes. On postoperative day (POD) 13 (14 days of culture), these cells were infused to the recipient intravenously without any adverse events. Initial immunosuppression consisted of tacrolimus, steroid and mycophenolate mofetil (MMF), and cyclophosphamide (40 mg/kg) administered on POD 5. Both the steroid and MMF were continued until 4 weeks after LDLT, and the patient was discharged on POD 30 with normal liver function. On POD 52, the patient developed acute cellular rejection and received appropriate reinforcement of immunosuppressive therapy and is currently doing well with normal liver function 30 months after LDLT with reduced anti-donor allo-activity. In summary, T-reg therapy was safely performed in adult LDLT, and we are following the patient carefully to determine whether she can achieve operational tolerance in the future.

Construction of a high-density linkage map and graphical representation of the arrangement of transcriptome-based unigene markers on the chromosomes of onion, Allium cepa L.

BACKGROUND: Genomic information for Allium cepa L. is limited as it is heterozygous and its genome is very large. To elucidate potential SNP markers obtained by NGS, we used a complete set of A. fistulosum L.-A. cepa monosomic addition lines (MALs) and doubled haploids (DHs). These were the parental lines of an A. cepa mapping population for transcriptome-based SNP genotyping. RESULTS: We mapped the transcriptome sequence reads from a series of A. fistulosum-A. cepa MALs onto the unigene sequence of the doubled haploid shallot A. cepa Aggregatum group (DHA) and compared the MAL genotype call for parental bunching onion and shallot transcriptome mapping data. We identified SNP sites with at least four reads on 25,462 unigenes. They were anchored on eight A. cepa chromosomes. A single SNP site was identified on 3,278 unigenes and multiple SNPs were identified on 22,184 unigenes. The chromosome marker information was made public via the web database Allium TDB ( http://alliumtdb.kazusa.or.jp/ ). To apply transcriptome based genotyping approach for genetic mapping, we gathered RNA sequence data from 96 lines of a DHA × doubled haploid bulb onion A. cepa common onion group (DHC) mapping population. After selecting co-dominant SNP sites, 16,872 SNPs were identified in 5,339 unigenes. Of these, at least two SNPs with identical genotypes were found in 1,435 unigenes. We developed a linkage map using genotype information from these unigenes. All unigene markers mapped onto the eight chromosomes and graphical genotyping was conducted based on the unigene order information. Another 2,963 unigenes were allocated onto the eight chromosomes. To confirm the accuracy of this transcriptome-based genetic linkage map, conventional PCR-based markers were used for linkage analysis. All SNP - and PCR-based markers were mapped onto the expected linkage groups and no inconsistency was found among these chromosomal locations. CONCLUSIONS: Effective transcriptome analysis with unique Allium resources successfully associated numerous chromosome markers with unigene information and a high-density A. cepa linkage map. The information on these unigene markers is valuable in genome sequencing and useful trait detection in Allium.

Triazolopyrimidine derivative NK026680 and donor-specific transfusion induces CD4+CD25+Foxp3+ T cells and ameliorates allograft rejection in an antigen-specific manner.

We have previously demonstrated the unique properties of a new triazolopyrimidine derivative, NK026680, which exerts immunosuppressive effects in rat heart transplant model and confers tolerogeneic properties on ex vivo-conditioned dendritic cells in mice. We herein demonstrate that NK026680 promotes the expansion of regulatory T cells (Tregs) with potent immunoregulatory effects when used in combination with donor-specific transfusion (DST). BALB/c (H-2d) heart graft were transplanted into C57BL/6 (H-2b) mice following intravenous injection of donor splenocytes (DST) and oral administration of NK026680. The NK026680 plus DST treatment markedly prolonged the survival time of the donor-graft, but not that of the 3rd party-graft (C3H; H-2k). Treg cells in the recipient spleen on day 0 expanded when stimulated with donor-antigens in vivo and in vitro. After heart transplantation, Treg cells accumulated into the graft and increased in the spleen. NK026680 plus DST also decreased activated CD8+ T cells in the spleen and inhibited infiltration of CD8+ T cells into the graft. Depletion of CD25+ cells inhibited the graft prolonging effect of the NK026680 plus DST treatment. NK026680 administration together with DST induces potent immunoregulatory effects in an antigen-specific manner, likely due to the in vivo generation of donor-specific Tregs.

Optic, trigeminal, and facial neuropathy related to anti-neurofascin 155 antibody.

OBJECTIVE: To characterize the frequency and patterns of optic, trigeminal, and facial nerve involvement by neuroimaging and electrophysiology in IgG4 anti-neurofascin 155 antibody-positive (NF155+ ) chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Thirteen IgG4 NF155+ CIDP patients with mean onset age of 34 years (11 men) were subjected to neurological examination, blink reflex, and visual-evoked potential (VEP) testing, and axial and/or coronal T2-weighted head magnetic resonance imaging (MRI). RESULTS: Among 13 patients, facial sensory impairment, facial weakness, and apparent visual impairment were observed in three (23.1%), two (15.4%), and two (15.4%) patients, respectively. All 12 patients tested had blink reflex abnormalities: absent and/or delayed R1 in 11 (91.7%), and absent and/or delayed R2 in 10 (83.3%). R1 latencies had strong positive correlations with serum anti-NF155 antibody levels (r = 0.9, P ≤ 0.0001 on both sides) and distal and F wave latencies of the median and ulnar nerves. Absent and/or prolonged VEPs were observed in 10/13 (76.9%) patients and 17/26 (65.4%) eyes. On MRI, hypertrophy, and high signal intensity of trigeminal nerves were detected in 9/13 (69.2%) and 10/13 (76.9%) patients, respectively, whereas optic nerves were normal in all patients. The intra-orbital trigeminal nerve width on coronal sections showed a significant positive correlation with disease duration. INTERPRETATION: Subclinical demyelination frequently occurs in the optic, trigeminal, and facial nerves in IgG4 NF155+ CIDP, suggesting that both central and peripheral myelin structures of the cranial nerves are involved in this condition, whereas nerve hypertrophy only develops in myelinated peripheral nerve fibers.

The efficacy and safety of hachimijiogan for mild Alzheimer disease in an exploratory, open standard treatment controlled, randomized allocation, multicenter trial: A study protocol.

BACKGROUND: Dementia among the Japanese aged 65 years or over population is estimated to approach about 700 million cases by 2025, and a corresponding rapid increase in Alzheimer disease (AD) can also be expected. The ballooning number of dementia patients, including AD, is creating major medical and social challenges. At present, only 3 drugs are recognized for the treatment of mild AD, and these are only used to alleviate symptoms. Although new therapies are needed to treat mild AD, insufficient development of disease-modifying drugs is being done. METHODS/DESIGN: The aim of this exploratory, open standard, treatment-controlled, randomized allocation, multicenter trial is to determine the efficacy of the traditional Japanese Kampo medicine hachimijiogan (HJG) on the cognitive dysfunction of mild AD.Eighty-six patients with AD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and as mild AD according to the Mini Mental State Examination (MMSE ≥21) will be included. All will already have been taking the same dose of Donepezil, Galantamine, or Rivastigmine for more than 3 months. The patients will be randomly assigned to receive additional treatment with HJG or to continue mild AD treatment without additional HJG. The primary endpoint is the change from baseline of the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version (ADAS-Jcog). ADAS-Jcog is a useful index for detecting change over time that investigates memory and visuospatial cognition injury from the early stage. The secondary endpoints are the changes from baseline of the Instrumental Activity of Daily Life, Apathy scale, and Nueropsychiatric Inventory scores. In this protocol, we will examine the Geriatric depression scale and do Metabolome analysis as exploratory endpoints. The recruitment period will be from August 2019 to July 2021. DISCUSSION: This is the first trial of Kampo medicine designed to examine the efficacy of HJG for the cognitive dysfunction of patients with mild AD. TRIAL REGISTRATION: This trial was registered on the Japan Registry of Clinical trials on 2 August 2, 2019 (jRCTs 071190018).

Disconnection of the right superior parietal lobule from the precuneus is associated with memory impairment in oldest-old Alzheimer's disease patients.

There is a wide range of onset age in Alzheimer's disease (AD). Emerging evidence indicates variation of AD manifestations in oldest-old AD (OOAD); however, the pattern of cognitive dysfunctions remains unclear. We aimed to reveal cognitive performance characteristics and changes in brain functional connectivity in OOAD patients by a resting-state fMRI (rs-fMRI) study. We enrolled AD patients who had been referred to Kyushu University Hospital (KUH) or Sanno Hospital, and classified them into middle-old AD (MOAD) (65-79 years old) and OOAD (≥80 years old) according to the age of onset. Our subjects consisted of 19 OOAD, 17 MOAD, and 8 normal subjects. Cognitive performance was evaluated using Mini Mental State Examination-Japanese (MMSE-J) and Clinical Dementia Rating (CDR). rs-fMRI scanning and independent component analysis (ICA) were performed on Sanno Hospital patients and MOAD vs. OOAD patients were compared. The resulting significant regions were used as seeds for ROI-to-ROI analysis of the KUH dataset. Collectively, MMSE-J delayed recall sub-scores were significantly lower in OOAD patients compared with MOAD patients. ICA of the Sanno Hospital data indicated significant connectivity decrease in the default mode network (DMN) in the OOAD group compared with the MOAD group in the right superior parietal lobule (SPL). ROI-to-ROI analysis of the KUH dataset indicated significant disconnection in the OOAD group of the right SPL from the precuneus (p < 0.01). The functional connectivity from the right SPL to the precuneus was positively correlated with the MMSE-J delayed recall sub-score (p = 0.03) and negatively correlated with the CDR memory sub-scale (p = 0.04). These findings indicate that disconnection between the right SPL and the precuneus may contribute to worse memory capability in OOAD compared with MOAD.

The severity of obstructive sleep apnea syndrome cannot predict the accumulation of brain amyloid by imaging with [11C]-Pittsburgh compound B PET computed tomography in patients with a normal cognitive function.

OBJECTIVE: Disturbed sleep due to obstructive sleep apnea syndrome (OSAS) might accelerate amyloidß (Aß) deposition, which can be a crucial factor in Alzheimer's disease. We studied Aß deposition in untreated OSAS patients with normal cognition. METHOD: We performed polysomnography (PSG) and Aß imaging with [11C]-Pittsburgh compound B PET computed tomography (11C-PiB PET CT) in 14 untreated OSAS patients (apnea-hypopnea index: 43.8 ± 26.3/h). RESULTS: The abnormal accumulation of enhanced 11C-PiB PET was observed only one patient with severe, but not the most severe. CONCLUSIONS: The OSAS severity alone may not predict Aß deposition in OSAS patients with normal cognition.

Functional connectivity change between posterior cingulate cortex and ventral attention network relates to the impairment of orientation for time in Alzheimer's disease patients.

Alzheimer's disease (AD) patients exhibit various cognitive dysfunctions, including impairment of orientation for time (OT). The brain regions underlying OT impairment remain to be elucidated. A previous single-photon emission computed tomography study has indicated hypoperfusion of the posterior cingulate cortex (PCC) in relation to deterioration of OT. In this study, we investigated whole brain functional connectivity changes of PCC using resting-state functional magnetic resonance imaging. Voxel-based functional connectivity with PCC was analyzed in OT-poor or OT-good AD patients, classified according to the mean OT scores of the Mini-Mental State Examination subscale. The connectivities of dorsal frontal lobe, and lateral parietal and lateral temporal lobes with PCC in the right hemisphere were reduced in the OT-poor AD group compared with the OT-good AD group. A subtraction connectivity map of OT score differences (OT-good minus OT-poor) revealed the right middle temporal gyrus near the temporo-parietal junction as a significantly connected region with PCC. These results suggest that the right posterior part of the middle temporal gyrus may play an important role in OT in conjunction with PCC, and that disconnection between PCC and the right ventral attention network may cause OT disturbance in AD patients.

A QTL associated with high seed coat cracking rate of a leading Japanese soybean variety.

Seed coat cracking in soybeans [Glycine max (L). Merr.] leads to commercial and agronomic losses. The Japanese elite soybean cultivar 'Fukuyutaka' is often used as a parent for breeding, but its high rate of seed coat cracking is an obstacle to its further use in breeding programs. To establish a DNA marker-assisted selection system for seed coat cracking, genetic factors related to high rates of seed coat cracking were surveyed, and a quantitative trait locus (QTL) with a stable effect on seed coat cracking in both years of a two-year replication experiment was detected on chromosome 20. Comparison of a set of near-isogenic lines (NILs) around this locus verified that the presence of the 'Fukuyutaka' allele significantly increased seed coat cracking in the kernel. The locus is located in a genomic region spanning 3.2 Mb. Marker-assisted selection for the locus will improve the selection efficiency of 'Fukuyutaka'-derived breeding populations.

Chronic Inflammatory Demyelinating Polyneuropathy With Concurrent Membranous Nephropathy: An Anti-paranode and Podocyte Protein Antibody Study and Literature Survey.

Background: Several case reports have described the concurrence of chronic inflammatory demyelinating polyneuropathy (CIDP) and membranous nephropathy (MN). The presence of autoantibodies against podocyte antigens phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain containing 7A (THSD7A) in MN suggests an autoimmune mechanism. Some CIDP patients also harbor autoantibodies against paranodal proteins such as neurofascin 155 (NF155) and contactin-1 (CNTN1). We investigated the relationship between CIDP and MN by assaying autoantibodies against paranodal and podocyte antigens in a CIDP patient with MN, and by a literature survey on the clinical features of CIDP with MN. Methods: Anti-CNTN1 and NF155 antibodies were measured by flow cytometry using HEK293 cell lines stably expressing human CNTN1 or NF155. Binding capacity of antibodies was validated by immunostaining mouse teased sciatic nerve fibers. Anti-PLA2R antibodies were measured by enzyme-linked sorbent assay and anti-THSD7A antibodies by indirect immunofluorescence assay. Clinical features between 14 CIDP with MN cases including two with anti-CNTN1 antibodies and 20 anti-CNTN1 antibody-positive CIDP cases were compared. Results: A patient whose ages was in the late 70 s complained of progressive weakness and superficial and deep sensory impairment in four extremities over 6 months. Nerve conduction studies showed prominent demyelination patterns. The patient presented with nephrotic syndrome. Renal biopsy disclosed basement membrane thickening with local subepithelial projections and glomerular deposits of IgG4, compatible with MN. Autoantibody assays revealed the presence of IgG4 and IgG1 anti-CNTN1 antibodies, but an absence of anti-NF155, anti-PLA2R, and anti-THSD7A antibodies. The patient's serum stained paranodes of teased sciatic nerves. CIDP with MN and anti-CNTN1 antibody-positive CIDP commonly showed male preponderance, relatively higher age of onset, acute to subacute onset in 35-50% of cases, distal dominant sensorimotor neuropathy, proprioceptive impairment leading to sensory ataxia, and very high cerebrospinal fluid protein levels. However, 11 of 13 CIDP patients with MN had a favorable response to mono- or combined immunotherapies whereas anti-CNTN1 antibody-positive CIDP was frequently refractory to corticosteroids and intravenous immunoglobulin administration. Conclusion: CIDP with MN and anti-CNTN1 antibody-positive CIDP show considerable overlap but are not identical. CIDP with MN is probably heterogeneous and some cases harbor anti-CNTN1 antibodies.

A novel carbohydrate-binding surface layer protein from the hyperthermophilic archaeon Pyrococcus horikoshii.

In Archaea and Bacteria, surface layer (S-layer) proteins form the cell envelope and are involved in cell protection. In the present study, a putative S-layer protein was purified from the crude extract of Pyrococcus horikoshii using affinity chromatography. The S-layer gene was cloned and expressed in Escherichia coli. Isothermal titration calorimetry analyses showed that the S-layer protein bound N-acetylglucosamine and induced agglutination of the gram-positive bacterium Micrococcus lysodeikticus. The protein comprised a 21-mer structure, with a molecular mass of 1,340 kDa, as determined using small-angle X-ray scattering. This protein showed high thermal stability, with a midpoint of thermal denaturation of 79 °C in dynamic light scattering experiments. This is the first description of the carbohydrate-binding archaeal S-layer protein and its characteristics.

Longitudinal CT study of sarcopenia due to hepatic failure after living donor liver transplantation.

BACKGROUND: The quantity and quality of skeletal muscle have been observed to be closely related with post-transplantation mortality in patients undergoing living donor liver transplantation (LDLT). However, the effect of LDLT on skeletal muscle has not been thoroughly investigated. The aim of this study was to investigate the change of trunk muscle mass and adiposity in recipients of LDLT. METHODS: The study population included LDLT recipients at Hokkaido University Hospital who underwent pre- and post-operative computed tomography (CT) scans (31 recipients; 14 males, and 17 females). The cross-sectional area of the dorsal muscle group at the 12th thoracic vertebra (Th12) was measured with the dorsal muscle group mass index (DMGMI), while the psoas muscle at the upper border of 4th lumber vertebra (L4) was measured with the psoas muscle mass index (PMI). Muscle adiposity of the dorsal muscle group was also measured with the intramuscular adipose tissue content (IMAC). For these data, the correlation between pre-operative values and follow-up changes (post-operative values minus pre-operative values) were analyzed. Each sex was evaluated separately. RESULTS: A statistically significant correlation was detected between pre-operative values and follow-up differences in DMGMI for both sexes (male: r=-0.675, P=0.008; female: r=-0.687, P=0.002) and in PMI for both sexes (males: r=-0.739, P=0.003; females: r=-0.641, P=0.006). The correlation of pre-operative values and follow-up differences for IMAC was not statistically significant with r=0.132 (P=0.700) and r=-0.498 (P=0.071) for males and females, respectively. CONCLUSIONS: Improvement of sarcopenia in recipients of LDLT can be demonstrated regardless of sex using volumetric CT.

Anti-donor regulatory T cell therapy in liver transplantation.

Liver transplantation is accepted as the most reliable therapeutic option for patients with end-stage liver failure, but lifelong administration of immunosuppressive agents continues to be problematic due to various drug-induced morbidities and the risk of mortality. Complete cessation of immunosuppressive drugs while maintaining normal graft function and histology, called operational tolerance, has the potential to overcome these long-standing problems. Previously, we reported the results of a pilot study of anti- donor regulatory T cell therapy in 10 consecutive adult patients who underwent living donor liver transplantation (LDLT), of whom 7 patients successfully stopped immunosuppression for nearly 2 years. Described herein are the clinical follow-ups of these patients, a brief description of the protocol and its theoretical background, and a possible explanation for the immunological findings.

Transparenchymal glissonean approach: a novel surgical technique for advanced perihilar bile duct cancer.

PURPOSE: To increase the surgical opportunities for locally advanced perihilar bile duct cancers that require left-sided hepatectomies, we developed the transparenchymal glissonean approach (TGA); it comprises intra-hepatic exposure and dissection of the Glisson's sheath to gain access to the hepatic artery and portal vein for reconstruction. METHODS: Following skeletonization of the hepatoduodenal ligament, the proximal portions of invaded vessels are exposed. If extra-hepatic attempts to access the distal portions of the invaded vessels fail, TGA can be used. The distal portion of the invaded right or right posterior Glisson's sheath is exposed following liver transection. The anterior portion of the wall of bile duct is cut and transected circumferentially including the fibrous plate tissue. The non-invaded portal vein and hepatic artery are isolated and dissected towards the hepatic hilum until the invaded distal portion of the vessels, and vascular reconstructions are performed. RESULTS: TGA was performed in 9 patients; 5 patients underwent left hemihepatectomy and 4 underwent left tri-sectionectomy. Eight patients needed vascular reconstruction. Clavien-Dindo classification (CDC) grades IIIa and IIIb were recorded in 6 and 1 patients, respectively. No patients had CDC grades IV and V disease. Pathologically, all cases were pT4; 3 cases were R0, 5 were R1 with microscopic positive margin, and 2 were R1 with microscopic metastasis. The overall median survival time was 25.0 months. CONCLUSIONS: TGA is feasible with acceptable prognosis and expands the surgical opportunities.