Search

Abstract Background The impact of simultaneous conversion of dialysate calcium (DCa) concentration from 3.0 to 2.6 mEq/L and dialysate magnesium (DMg) concentration from 1.0 to 1.2 mEq/L on mineral and bone metabolism in patients undergoing hemodialysis remains unknown. Methods We retrospectively recruited 52 patients undergoing hemodialysis who experienced a conversion of dialysates from dialysate A (DCa 3.0 mEq/L and DMg 1.0 mEq/L) to dialysate B (DCa 2.6 mEq/L and DMg 1.2 mEq/L) at a hemodialysis center. The effects of changing the DCa and DMg concentrations on serum bone and mineral parameters were examined over 7 months. Results A total of 48 patients were finally analyzed. After changing the dialysate, serum magnesium (Mg) levels increased significantly from 2.31 ± 0.38 at 0 months to 2.54 ± 0.43 mg/L at 7 months, and serum calcium (Ca) levels decreased significantly from 9.51 ± 0.80 at 0 months to 9.14 ± 0.57 mg/dL at 7 months, with no change in serum intact parathyroid hormone levels. Notably, the serum Ca-to-serum-Mg ratio and serum Ca × inorganic phosphate-to-serum-Mg ratio decreased significantly after dialysate conversion. Around 10% of patients started or increased the dose of vitamin D receptor activators, and 18% of patients started or increased the dose of Ca-based phosphate binders. Notably, the serum Mg levels in three patients exceeded 3.5 mg/dL during the observation period. Conclusions Conversion of DCa from 3.0 to 2.6 mEq/L and DMg from 1.0 to 1.2 mEq/L lowers serum Ca levels and increases serum Mg levels, possibly leading to decreased Ca loading and increased Mg storage among patients undergoing hemodialysis.

Abstract Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generate a full-length isoform annotation of human immune cells from an individual by long-read sequencing for 29 cell subsets. This contains a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE in the Alzheimer’s disease locus. We profile characteristics of isoforms and show that repetitive elements significantly explain the diversity of unannotated isoforms, providing insight into the human genome evolution. In addition, some of the isoforms are expressed in a cell-type specific manner, whose alternative 3’-UTRs usage contributes to their specificity. Further, we identify disease-associated isoforms by isoform switch analysis and by integration of several quantitative trait loci analyses with genome-wide association study data. Our findings will promote the elucidation of the mechanism of complex diseases via alternative splicing.

Background: Biallelic variants in PARK7, which encodes protein-nucleic acid deglycase DJ-1, can cause early-onset Parkinson's disease (PD). Although many patients with PARK7 variants have been identified from European and Middle Eastern ethnic groups, there have been no reports in the Japanese population. Objectives: To determine the prevalence and clinical features of patients with PD harboring PARK7 variants in Japan. Methods: We performed a molecular genetic analysis of PD patients with PARK7 variants identified using comprehensive panel sequencing, to explore the details of variants. Moreover, clinical neurological features were investigated, including neuroimaging analyses. This study followed STROBE guidelines. Results: Four patients with biallelic rare variants of PARK7 were identified in the cohort. All four patients presented with levodopa-responsive parkinsonism, with an age at onset in the early 30s. Furthermore, two of the four patients had psychiatric complications. Dopamine transporter imaging revealed nigrostriatal pathway dysfunction. Conclusions: To our knowledge, this is the first report of Japanese patients with PARK7 variants. We identified a relatively low frequency of PARK7 variants in patients in Japan. As opposed to typical patients with sporadic PD, the identified patients developed the disease in their 30s and presented with a variety of non-motor symptoms and complications. Further studies are needed to identify the clinical features related to PARK7 variants in Japanese patients with PD, and to analyze the pathophysiology of how the variants identified in the present study might affect DJ-1 function.

Diabetic uremic syndrome has been rarely reported in patients on maintenance dialysis for diabetic nephropathy who present subacutely with neurological symptoms and bilateral basal ganglia lesions. There are also a few reports on metformin-induced encephalopathy, which is clinically similar to diabetic uremic syndrome. Because some patients with each of these diseases also have metabolic acidosis, it is speculated that these two diseases may have the same pathology. Recently, the term “extrapyramidal syndromes of chronic kidney disease and dialysis” (EPS-CKDD), with associated diagnostic criteria, has been proposed to describe these conditions, and metformin use is considered a risk factor for developing these syndromes. We report a case of a patient on maintenance hemodialysis for diabetic nephropathy who was taking metformin and developed subacute parkinsonism and bilateral basal ganglia lesions that rapidly improved after discontinuation of metformin with continued maintenance hemodialysis. We should ascertain whether patients with EPS-CKDD are taking metformin because it may be inappropriately prescribed for end-stage renal disease. If metformin has been prescribed, it should be discontinued immediately; its discontinuation may lead to rapid symptom recovery and improved prognosis.

Modulated pulsed power magnetron sputtering (MPPMS) of titanium was investigated as a function of argon gas pressure using optical emission spectroscopy (OES). Delays in discharge and the formation of comb-like discharge current waveforms due to splitting and pulsing were observed with a decrease in pressure. This observation corresponds to the evolution from MPPMS condition to deep-oscillation-magnetron-sputtering (DOMS)-like condition by changing discharge gas pressure. The optical emission intensities of the ionic species (Ar+ and Ti+) increased as the comb-like current waveforms were formed with decreasing Ar pressure. This behavior showed a marked contrast to that of the neutral species (Ar and Ti). The Ar pressure dependence of OES was revealed to be due to the plasma build-up stage, which is the initial generation process of plasma discharge in pulsed dc magnetron sputtering, from the temporal profile for the atomic-line intensities of the optically emitting species in MPPMS and DOMS-like plasmas.

Delayed discharges due to electrical breakdown are observed in modulated pulsed pow er magnetron sputtering (MPPMS) plasma of titanium. The delayed discharge, which is remarkable with decreasing argon gas pressure, transforms the discharge current waveform from a standard modulated pulsed discharge current waveform to a comb-like discharge current waveform consisting of several pulses with high power. In addition, the delay times, consisting of statistical times and formative times in the delayed MPPMS discharges, are experimentally measured with the help of Laue plot analysis. The pressure dependence of delay times observed indicates that the delayed discharge behavior matches the breakdown characteristics well. In the present study, the delayed discharge dynamics of the comb-like discharge current waveform, which can be the origin of deep oscillation magnetron sputtering, are investigated based on measurement of the delay times and the characteristics of discharge current waveforms.

Abstract This study examined whether forced postural change from prone to supine during toddlers’ nap, a preventative measure taken in Japan for sudden unexplained death in childhood (SUDC), disturbs toddlers’ sleep. When the "Back to Sleep" campaign (BSC) was introduced to Japan in 1996, its recommendations were also applied to infants aged 1 year old and over with the expectation that the BSC recommendations may also contribute to a decrease in the occurrence rate of SUDC. Since then, Japanese nurseries have routinely conducted sleeping position checks and positional adjustments of toddlers every 5–10 min during naps. A total of 52 toddlers (age 18.4 ± 3.3 months, means ± SD) were continuously monitored for 8 h during daytime at nursery schools for wake-sleep status and body position (prone, supine and lateral) with actigraphs and 3-orthogonal-axis accelerometers. Out of the 52 toddlers, 24 toddlers adopted prone positions during naps, which were adjusted by nursery staff back to supine. When nursery staff manually changed the toddlers position from prone to supine, the toddlers either did not wake or woke only briefly (3.1 ± 4.9 min) and returned to sleep soon after the positional change. Our study indicates that manual change of toddlers’ sleeping position from prone to supine, a potential SUDC prevention method, does not disturb toddlers’ sleep during their naps.

Many adult tissues are composed of differentiated cells and stem cells, each working in a coordinated manner to maintain tissue homeostasis during physiological cell turnover. Old differentiated cells are believed to typically die by apoptosis. Here, we discovered a previously uncharacterized, new phenomenon, which we name erebosis based on the ancient Greek word erebos (“complete darkness”), in the gut enterocytes of adult Drosophila. Cells that undergo erebosis lose cytoskeleton, cell adhesion, organelles and fluorescent proteins, but accumulate Angiotensin-converting enzyme (Ance). Their nuclei become flat and occasionally difficult to detect. Erebotic cells do not have characteristic features of apoptosis, necrosis, or autophagic cell death. Inhibition of apoptosis prevents neither the gut cell turnover nor erebosis. We hypothesize that erebosis is a cell death mechanism for the enterocyte flux to mediate tissue homeostasis in the gut. It has been believed that gut enterocytes continuously die through apoptosis. However, this study shows that gut enterocytes die through a novel cell death mechanism, named erebosis. Erobotic cells lack the characteristic features of apoptotic, necrotic or autophagic cell death; instead they lose their cytoskeleton, cell adhesion and organelles, and their nuclei become flat and indistinct.

Oncogenes often promote cell death as well as proliferation. How oncogenes drive these diametrically opposed phenomena remains to be solved. A key question is whether cell death occurs as a response to aberrant proliferation signals or through a proliferation-independent mechanism. Here, we reveal that Src, the first identified oncogene, simultaneously drives cell proliferation and death in an obligatorily coupled manner through parallel MAPK pathways. The two MAPK pathways diverge from a lynchpin protein Slpr. A MAPK p38 drives proliferation whereas another MAPK JNK drives apoptosis independently of proliferation signals. Src-p38-induced proliferation is regulated by methionine-mediated Tor signaling. Reduction of dietary methionine uncouples the obligatory coupling of cell proliferation and death, suppressing tumorigenesis and tumor-induced lethality. Our findings provide an insight into how cells evolved to have a fail-safe mechanism that thwarts tumorigenesis by the oncogene Src. We also exemplify a diet-based approach to circumvent oncogenesis by exploiting the fail-safe mechanism.

A 75-year-old male was admitted to our hospital because of bile duct stenosis. He had no medical history of autoimmune disease. The level of tumor markers, serum IgG, and IgG4 were within normal ranges. Computed tomography showed perihilar and distal bile duct stenosis and wall thickening without swelling or abnormal enhancement of the pancreas. Endoscopic retrograde cholangiopancreatography showed perihilar and distal bile duct stenosis. A biopsy and cytology from the distal bile duct stenosis suggested adenocarcinoma, and cytology from the perihilar bile duct also suggested adenocarcinoma. A preoperative diagnosis of perihilar and distal bile duct cancer was made, and the patient underwent left hepatectomy and pancreaticoduodenectomy. Resected specimens showed wall thickening in the perihilar and distal bile duct; however, tumors were unclear. A histopathological examination revealed lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis in the perihilar and distal bile ducts. Immunohistochemistry revealed diffuse infiltration of IgG4-positive plasma cells in the perihilar and distal bile ducts. Lymphoplasmacytic infiltration, inflammatory change, storiform fibrosis, and obliterative phlebitis were shown in the pancreas. A final diagnosis of IgG4-related sclerosing cholangitis (IgG4-SC) with autoimmune pancreatitis was made. We herein report a case in which a preoperative diagnosis of IgG4-SC was difficult due to normal serum IgG4 levels and no obvious pancreatic lesion.

Objectives Recent meta-analyses of eradication therapy in Helicobacter pylori-infected adults reported significant reductions in gastric carcinoma risk. However, concerns about supporting unfocused screening and eradication programme in healthy, asymptomatic populations have arisen. We performed a systematic review and Bayesian meta-analysis to provide an accurate interpretation of randomised evidence on the preventive effectiveness of eradication therapy on gastric carcinoma risk.Methods We searched databases including PubMed, Cochrane Central and Embase for reference and citation tracking without language restrictions, from inception through 31 July 2018. Paired investigators independently selected randomised controlled trials (RCTs) comparing eradication therapy with placebo or no treatment for asymptomatic or dyspeptic H. pylori-infected adults with no previous gastric carcinoma. The main outcome was gastric carcinoma incidence; secondary outcomes included gastric carcinoma-specific, non-gastric carcinoma and all-cause mortality.Results A total of 5 population-based and 2 outpatient care-based RCTs involving 7303 adults were eligible. Eradication algorithms were heterogeneous, and unsuccessful eradication and reinfection were frequently observed. A Bayesian meta-analysis with competing risk outcomes found low-certainty evidence that eradication therapy might be more likely than control to reduce gastric carcinoma risk (HR=0.65; 95% credible interval (CrI) 0.41 to 1.0; I2=11%). The CrIs included the null effects across the subgroup and sensitivity analyses, apart from those based on particular models that excluded two RCTs that enrolled subjects with specific histological findings only (HR=0.55; CrI 0.30 to 0.89; I2=14%). The uncertainty of the average 41% risk reduction in gastric carcinoma-specific mortality included a clinically important mortality risk increase (HR=0.59 favouring eradication therapy; CrI 0.25 to 1.20; I2=13%; low certainty).Conclusions There is insufficient evidence to support or refute the effectiveness of eradication therapy in preventing gastric carcinoma in H. pylori-infected, high-risk populations. Rigorously conducted large RCTs of healthy infected adults only would provide evidence of the true efficacy of successful eradication.PROSPERO registration number: CRD42014009245.

D2 receptor-expressing medium spiny neurons (D2-MSNs) are thought to suppress goal-directed behaviours. Here authors ablate D2-MSNs specifically in the ventrolateral striatum, and find that surprisingly, it leads to a reduction in goal-directed motivation in mice.

We have previously reported that schisandrin B (SchB) is a specific inhibitor of ATR (ataxia telangiectasia and Rad-3-related) protein kinase. Since SchB consists of a mixture of its diastereomers gomisin N (GN) and γ-schisandrin (γ-Sch), the inhibitory action of SchB might result from a stereospecific interaction between one of the stereoisomers of SchB and ATR. Therefore, we investigated the effect of GN and γ-Sch on UV (UVC at 254 nm)-induced activation of DNA damage checkpoint signaling in A549 cells. UV-induced cell death (25 – 75 J/m2) was amplified by the presence of the diastereomers, especially GN. At the same time, GN, but not γ-Sch, inhibited the phosphorylation of checkpoint proteins such as p53, structural maintenance of chromosomes 1, and checkpoint kinase 1 in UV-irradiated cells. Moreover, GN inhibited the G2/M checkpoint during UV-induced DNA damage. The in vitro kinase activity of immunoaffinity-purified ATR was dose-dependently inhibited by GN (IC50: 7.28 μM) but not by γ-Sch. These results indicate that GN is the active component of SchB and suggest that GN inhibits the DNA damage checkpoint signaling by stereospecifically interacting with ATR. Keywords:: schisandrin B, gomisin N, ataxia telangiectasia and Rad-3-related (ATR), checkpoint, DNA damage

Ataxia telangiectasia mutated (ATM) kinase plays a crucial role as a master controller in the cellular DNA damage response. Inhibition of ATM leads to inhibition of the checkpoint signaling pathway. Hence, addition of checkpoint inhibitors to anticancer therapies may be an effective targeting strategy. A recent study reported that Wip1, a protein phosphatase, de-phosphorylates serine 1981 of ATM during the DNA damage response. Squalene has been proposed to complement anticancer therapies such as chemotherapy and radiotherapy; however, there is little mechanistic information supporting this idea. Here, we report the inhibitory effect of squalene on ATM-dependent DNA damage signals. Squalene itself did not affect cell viability and the cell cycle of A549 cells, but it enhanced the cytotoxicity of gamma-irradiation (γIR). The in vitro kinase activity of ATM was not altered by squalene. However, squalene increased Wip1 expression in cells and suppressed ATM activation in γIR-treated cells. Consistent with the potential inhibition of ATM by squalene, IR-induced phosphorylation of ATM effectors such as p53 (Ser15) and Chk1 (Ser317) was inhibited by cell treatment with squalene. Thus, squalene inhibits the ATM-dependent signaling pathway following DNA damage through intracellular induction of Wip1 expression.

Cellular and tissue injury associated with reactive oxygen species (ROS) has been reported in many kinds of disorders. While the antioxidant enzymes play critical roles in inhibiting the ROS-mediated injury, glutathione peroxidase (GPx) is scavenging hydroperoxides including H2O2. We previously reported that Shengmai-san (SMS), a traditional Chinese medicine, prevented ischemia/reperfusion injury of the brain and other organs in rats. To clarify the effect of SMS on intracellular responses of muscle cells against oxidative stress, C2C12 myoblasts were subjected to H2O2 abuse. SMS pre-incubation prevented the decreasing cell viability after H2O2 treatment. The accumulations of cellular protein carbonyl associated with apoptotic cell death were also inhibited by the SMS pre-incubation prior to oxidative damage induction. At the same time, enhanced activity, protein, and mRNA expression levels of GPx were observed in cells pre-incubated with SMS prior to H2O2 abuse. Moreover, intracellular GSH was subsequently decreased after H2O2 treatment. These findings suggest that SMS improved the antioxidant capacity against acute oxidative stress through the constitutive enhancement of GPx expression in C2C12 myoblasts. Because of its antioxidative property, SMS might be useful not only for the oxidative damage associated diseases but also for the transplantation of myoblasts into muscular dystrophy patients. Keywords:: oxidative stress, Shengmai-san, glutathione peroxidase, skeletal muscle

Neurodegenerative brain disorders such as Alzheimer’s disease (AD) have been well investigated. However, significant methods for the treatment of the promotion and progression of AD are unavailable to date. Recent studies suggested that the redox imbalance and the accumulation of amyloid-β (Aβ) peptide occurring in the brain of AD patients lead to oxidatively-induced apoptotic cell death. Here, we show the effects of Shengmai-san (SMS) on Aβ-induced cytotoxicity in PC-12 cells. SMS dose-dependently attenuated the cytotoxicity by Aβ incubation and also prevented the morphological damage in neurites of the PC-12 cells. Heme-oxygenase-1 and glutathione peroxidase-1 expressions were increased by SMS pretreatment. SMS decreased the phosphorylation level of c-jun amino-terminal kinase (JNK) and the activity of caspase-3, which were enhanced by Aβ incubation. Of importance, SMS treatment promoted neurite outgrowth. These data demonstrated dual roles of SMS in PC-12 cells. SMS prevents the apoptosis through the enhancement of anti-oxidant enzymes and inhibition of the JNK signaling pathway with the promotion of nerve cell maturation, thus suggesting benefits of SMS for the treating of neurodegenerative diseases. It may also be beneficial not only for the treatment of brain disorders but also for other diseases caused by oxidative stress. Keywords:: Alzheimer’s disease, apoptosis, mitogen-activated protein kinase (MAPK), neurite outgrowth, Shengmai-san

Though recent studies have shown that rodents express emotions with their face, whether emotional expression in rodents has a communicative function between conspecifics is still unclear. Here, we demonstrate the ability of visual recognition of emotional expressions in laboratory rats. We found that Long-Evans rats avoid images of pain expressions of conspecifics but not those of neutral expressions. The results indicate that rats use visual emotional signals from conspecifics to adjust their behaviour in an environment to avoid a potentially dangerous place. Therefore, emotional expression in rodents, rather than just a mere ‘expression’ of emotional states, might have a communicative function.

BACKGROUND: To identify high-risk groups for gastric cancer in presumptively healthy populations, several studies have investigated the predictive ability of the pepsinogen test, H. Pylori antibodies, and a risk-prediction model based on these two tests. To investigate whether these tests accurately predict gastric cancer development, we conducted a systematic review and meta-analysis. METHODS: PubMed and other electronic databases were searched for cohort studies published in English or Japanese from January 1985 through December 2013. Six reviewers identified eligible studies, and at least two investigators extracted data on population and study-design characteristics, quality items, and outcomes of interest. Meta-analyses were performed on non-overlapping studies. RESULTS: Nine prospective cohorts from Eastern Asia reported in 12 publications, including 33,741 asymptomatic middle-aged participants of gastric cancer screening, were eligible. For discriminating between asymptomatic adults at high and low risk of gastric cancer, the pepsinogen test (summary hazard ratio [HR], 3.5; 95% confidence interval [CI], 2.7-4.7; I2 = 0%) and H. pylori antibodies (summary HR, 3.2; 95% CI, 2.0-5.2; I2 = 0%) were statistically significant predictors as standalone tests. Although the risk-prediction model was in general moderately accurate in separating asymptomatic adults into four risk groups (summary c-statistic, 0.71; 95% CI: 0.68-0.73; I2 = 7%), calibration seemed to be poor. The study validity was generally limited. CONCLUSIONS: The serum pepsinogen test, H. pylori antibodies, and the four-risk-group model for predicting gastric cancer development seem to have the potential to stratify middle-aged presumptively healthy adults. Future research needs to focus on comparative studies to evaluate the impact of screening programs adopting these tests. Also, validation, preferably with model updating, is necessary to see whether the current model performance is transferable to different populations.

It has been demonstrated in the rodent hippocampus that rhythmic slow activity (theta) predominantly occurs during rapid eye movement (REM) sleep, while sharp waves and associated ripples occur mainly during non-REM sleep. However, evidence is lacking for correlates of sleep stages with electroencephalogram (EEG) in the hippocampus of monkeys. In the present study, we recorded hippocampal EEG from the dentate gyrus in monkeys overnight under conditions of polysomnographical monitoring. As result, the hippocampal EEG changed in a manner similar to that of the surface EEG: during wakefulness, the hippocampal EEG showed fast, desynchronized waves, which were partly replaced with slower waves of intermediate amplitudes during the shallow stages of non-REM sleep. During the deep stages of non-REM sleep, continuous, slower oscillations (0.5-8 Hz) with high amplitudes were predominant. During REM sleep, the hippocampal EEG again showed fast, desynchronized waves similar to those found during wakefulness. These results indicate that in the monkey, hippocampal rhythmic slow activity rarely occurs during REM sleep, which is in clear contrast to that of rodents. In addition, the increase in the slower oscillations of hippocampal EEG during non-REM sleep, which resembled that of the surface EEG, may at least partly reflect cortical inputs to the dentate gyrus during this behavioral state.

The hippocampus plays an important role in learning and memory. Synaptic plasticity in the hippocampus, short-term and long-term, is postulated to be a neural substrate of memory trace. Paired-pulse stimulation is a standard technique for evaluating a form of short-term synaptic plasticity in rodents. However, evidence is lacking for paired-pulse responses in the primate hippocampus. In the present study, we recorded paired-pulse responses in the dentate gyrus of monkeys while stimulating to the medial part of the perforant path at several inter-pulse intervals (IPIs) using low and high stimulus intensities. When the stimulus intensity was low, the first pulse produced early strong depression (at IPIs of 10-30 ms) and late slight depression (at IPIs of 100-1000 ms) of field excitatory postsynaptic potentials (fEPSPs) generated by the second pulse, interposing no depression IPIs (50-70 ms). When the stimulus intensity was high, fEPSPs generated by the second pulse were depressed by the first pulse at all IPIs except for the longest one (2000 ms). Population spikes (PSs) generated by the second pulse were completely blocked or strongly depressed at shorter IPIs (10-100 or 200 ms, respectively), while no depression or slight facilitation occurred at longer IPIs (500-2000 ms). Administration of diazepam slightly increased fEPSPs, while it decreased PSs produced by the first pulse. It also enhanced the facilitation of PSs produced by the second stimulation at longer IPIs. The present results, in comparison with previous studies using rodents, indicate that paired-pulse responses of fEPSPs in the monkey are basically similar to those of rodents, although paired-pulse responses of PSs in the monkey are more delayed than those in rodents and have a different sensitivity to diazepam.

A long form (tRNase Z(L)) of tRNA 3' processing endoribonuclease (tRNase Z, or 3' tRNase) can cleave any target RNA at any desired site under the direction of artificial small guide RNA (sgRNA) that mimics a 5'-half portion of tRNA. Based on this enzymatic property, a gene silencing technology has been developed, in which a specific mRNA level can be downregulated by introducing into cells a synthetic 5'-half-tRNA that is designed to form a pre-tRNA-like complex with a part of the mRNA. Recently 5'-half-tRNA fragments have been reported to exist stably in various types of cells, although little is know about their physiological roles. We were curious to know if endogenous 5'-half-tRNA works as sgRNA for tRNase Z(L) in the cells. Here we show that human cytosolic tRNase Z(L) modulates gene expression through 5'-half-tRNA. We found that 5'-half-tRNA(Glu), which co-immunoprecipitates with tRNase Z(L), exists predominantly in the cytoplasm, functions as sgRNA in vitro, and downregulates the level of a luciferase mRNA containing its target sequence in human kidney 293 cells. We also demonstrated that the PPM1F mRNA is one of the genuine targets of tRNase Z(L) guided by 5'-half-tRNA(Glu). Furthermore, the DNA microarray data suggested that tRNase Z(L) is likely to be involved in the p53 signaling pathway and apoptosis.