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The prognostic value of minimal/measurable residual disease (MRD) detection in autografts of patients with multiple myeloma (MM) in an autologous stem-cell transplantation setting has been reported. Next-generation flow (NGF) cytometry has lower sensitivity (2 × 10 -6 ) to detect MRD than next-generation sequencing (NGS) (<10 -6 ). We compared the clinical value of high-sensitivity NGF (cutoff: <10 -6 ) and NGS (cutoff: 10 -6 ) for the detection of MRD in the cryopreserved autografts of 49 patients with newly diagnosed MM. The sensitivity test using frozen/thawed autografts revealed a strong correlation among MRD levels of 5 × 10 -7 and 1 × 10 -4 ( r  = 0.9997, p  < 0.0001) when an adequate number of cells were analyzed. Autograft MRD levels determined using NGF and NGS were highly correlated ( r  = 0.811, p  < 0.0001). MRD-negative patients identified with NGF (cutoff: <10 -6 ) showed significantly longer progression-free survival (PFS) than MRD-positive patients ( p  = 0.026). The PFS of MRD-negative patients determined by NGS (cutoff: 10 -6 ) was similar to that determined by NGF. These results show that the high-sensitivity NGF method can assess MRD in frozen/thawed autografts, and its prognostic value is comparable to that of NGS., Competing Interests: H.T. received honoraria from Janssen Pharmaceutical K.K., Bristol‐Myers Squibb company, Sanofi, Takeda Pharmaceutical Company Limited and Ono Pharmaceutical Co., Ltd. T. Yamashita received honoraria from Bristol‐Myers Squibb company, Sanofi, Takeda Pharmaceutical Company Limited and Ono Pharmaceutical Co., Ltd. The rest of authors do not have any relationships to disclose., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

To determine whether antigen presentation by HLA-DR on hematopoietic stem progenitor cells (HSPCs) is involved in the development of acquired aplastic anemia (AA), we studied the HLA-DR expression on CD45 dim CD34 + CD38 + cells in the peripheral blood of 61 AA patients including 23 patients possessing HLA-class I allele-lacking (HLA-class I[-]) leukocytes. HLA-DR-lacking (DR[-]) cells accounted for 13.0-57.1% of the total HSPCs in seven (11.5%) patients with HLA-DR15 who did not possess HLA-class I(-) leukocytes. The incubation of sorted DR(-) HSPCs in the presence of IFN-γ for 72 h resulted in the full restoration of the DR expression. A comparison of the transcriptome profile between DR(-) and DR(+) HSPCs revealed the lower expression of immune response-related genes including co-stimulatory molecules (e.g., CD48, CD74, and CD86) in DR(-) cells, which was not evident in HLA-class I(-) HSPCs. DR(-) cells were exclusively detected in GPI(+) HSPCs in four patients whose HSPCs could be analyzed separately for GPI(+) and GPI(-) HSPCs. These findings suggest that CD4 + T cells specific to antigens presented by HLA-DR15 on HSPCs may contribute to the development of AA as well as the immune escape of GPI(-) HSPCs in a distinct way from CD8 + T cells recognizing HLA-class I-restricted antigens., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Although a glycosylphosphatidylinositol-anchored protein (GPI-AP) CD109 serves as a TGF-β co-receptor and inhibits TGF-β signaling in keratinocytes, the role of CD109 on hematopoietic stem progenitor cells (HSPCs) remains unknown. We studied the effect of CD109 knockout (KO) or knockdown (KD) on TF-1, a myeloid leukemia cell line that expresses CD109, and primary human HSPCs. CD109-KO or KD TF-1 cells underwent erythroid differentiation in the presence of TGF-β. CD109 was more abundantly expressed in hematopoietic stem cells (HSCs) than in multipotent progenitors and HSPCs of human bone marrow (BM) and cord blood but was not detected in mouse HSCs. Erythroid differentiation was induced by TGF-β to a greater extent in CD109-KD cord blood or iPS cell-derived megakaryocyte-erythrocyte progenitor cells (MEPs) than in wild-type MEPs. When we analyzed the phenotype of peripheral blood MEPs of patients with paroxysmal nocturnal hemoglobinuria who had both GPI(+) and GPI(-) CD34 + cells, the CD36 expression was more evident in CD109 - MEPs than CD109 + MEPs. In summary, CD109 suppresses TGF-β signaling in HSPCs, and the lack of CD109 may increase the sensitivity of PIGA-mutated HSPCs to TGF-β, thus leading to the preferential commitment of erythroid progenitor cells to mature red blood cells in immune-mediated BM failure., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: The establishment of biomarkers for amyotrophic lateral sclerosis (ALS) will be useful for early diagnosis and may provide evidence about pathogenesis. To elucidate whether high-field magnetic resonance (MR) findings and multimodal analysis of cerebrospinal fluid (CSF) levels of cystatin C could be indicators of upper motor neuron (UMN) involvement in ALS., Patients and Methods: Patients with ALS (n = 20), multiple sclerosis (n = 15), immune mediated chronic polyneuropathy (n = 17), and acute polyneuropathy (n = 12) were included in this retrospective study. Clinical indices including UMN signs were assessed, and 3.0-Tesla diffusion tensor imaging and MR spectroscopy were performed in patients with ALS. CSF levels of cystatin C were measured using enzyme-linked immunosorbent assay., Results: MR findings indicated that decreased anisotropy, increased diffusion, and increased myo-inositol/creatine ratio were also significantly correlated with UMN involvement in patients with ALS. The CSF cystatin C levels were significantly lower in patients with ALS than in the other three groups. The reduction of CSF cystatin C levels was significantly correlated with clinical UMN involvement (r = -0.505, p =  0.023)., Conclusions: Reduced cystatin C in CSF can reflect UMN involvement as shown in high-field MR of ALS, potentially providing a new biomarker for UMN degeneration in ALS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

It has been reported that negative emotional changes and conditions affect the visual faculties of humans at the neural level. On the other hand, the effects of emotion on color perception in particular, which are based on evoked potentials, are unknown. In the present study, we investigated whether different anxiety levels affect the color information processing for each of 3 wavelengths by using flash visual evoked potentials (FVEPs) and State-Trait Anxiety Inventory. In results, significant positive correlations were observed between FVEP amplitudes and state or trait anxiety scores in the long (sensed as red) and middle (sensed as green) wavelengths. On the other hand, short-wavelength-evoked FVEPs were not correlated with anxiety level. Our results suggest that negative emotional conditions may affect color sense processing in humans.

Advanced glycation end-products (AGE) have been implicated in aging and the pathogenesis of diabetic complications, inflammation, Alzheimer's disease, and cancer. AGE engage the cell surface receptor for AGE (RAGE), which in turn elicits intracellular signaling, leading to activation of NF-κB to cause deterioration of tissue homeostasis. AGE are not only formed within our bodies but are also derived from foods, endowing them with flavor. In the present study, we assessed the agonistic/antagonistic effects of food-derived AGE on RAGE signaling in a reporter assay system and found that low-molecular weight AGE can antagonize the action of AGE-BSA. Foods tested were Japanese soy sauce, coffee, cola, and red wine, all of which showed fluorescence characteristics of AGE. Soy sauce and coffee contained N(ε)-carboxymethyl-lysine (CML). Soy sauce, coffee, and red wine inhibited the RAGE ligand-induced activation of NF-κB, whereas cola had no effect on the ligand induction of NF-κB. The liquids were then fractionated into high-molecular weight (HMW) fractions and low-molecular weight (LMW) fractions. Soy sauce-, coffee-, and red wine-derived LMW fractions consistently inhibited the RAGE ligand induction of NF-κB, whereas the HMW fractions of these foods activated RAGE signaling. Using the LMW fraction of soy sauce as a model food-derived RAGE antagonist, we performed a plate-binding assay and found that the soy sauce LMW fractions competitively inhibited AGE-RAGE association. Further, this fraction significantly reduced AGE-dependent monocyte chemoattractant protein-1 (MCP-1) secretion from murine peritoneal macrophages. The LMF from soy sauce suppressed the AGE-induced RAGE trafficking to lipid rafts. These results indicate that small components in some, if not all, foods antagonize RAGE signaling and could exhibit beneficial effects on RAGE-related diseases.

In order to investigate the transcallosal effects of repetitive transcranial magnetic stimulation (rTMS), we studied median somatosensory evoked potentials (SEPs) before and after applying monophasic very low-frequency (0.2 Hz) subthreshold rTMS over the right motor cortex. For SEPs, median nerve was stimulated on each side. Sham rTMS served as the control. Twelve healthy subjects participated in this study. After rTMS over the right hemisphere, the amplitude of N34 component in right median SEPs recorded from the left parietal scalp (C3') increased significantly. Other components of right or left median SEPs or those after sham stimulation showed no changes. Monophasic 0.2 Hz subthreshold rTMS over the motor cortex predominantly affected the contralateral SEPs, probably through the transcallosal pathway.

Objective: To optimize the clinical uses of repetitive transcranial magnetic stimulation (rTMS), we compared the effects of rTMS on somatosensory-evoked potentials (SEPs) and regional cerebral blood flow (rCBF) using different phases (monophasic vs. biphasic) or frequencies (0.2Hz vs. 0.8Hz) of stimulation., Methods: In the first experiment, different phases were compared (0.2Hz monophasic vs. 0.2Hz biphasic). Biphasic 1Hz or sham condition served as controls. The second experiment was to explore the effect of frequencies (0.2Hz vs. 0.8Hz) using the monophasic stimulation. Substhreshold TMS was applied 250 times over the left premotor cortex. Single photon emission computed tomography (SPECT) was performed before and after monophasic 0.2Hz or biphasic 1Hz rTMS., Results: Monophasic rTMS of both 0.2 and 0.8Hz significantly increased the ratio of N30 amplitudes as compared with sham rTMS, whereas biphasic stimulation showed no significant effects. SPECT showed increased rCBF in motor cortices after monophasic 0.2Hz rTMS, but not after biphasic 1Hz stimulation., Conclusions: Monophasic rTMS exerted more profound effects on SEPs and rCBF than biphasic rTMS over the premotor cortex., Significance: Monophasic rTMS over the premotor cortex could be clinically more useful than biphasic rTMS.

Somatosensory-evoked potentials (SEPs) are attenuated by movement. This phenomenon of 'gating' reflects sensorimotor integration for motor control. The frontal N30 component after median nerve stimulation was shown to be reduced in amplitude prior to hand movement. To investigate the mechanism of this sensory gating, we recorded median SEPs immediately before and after application of monophasic very low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) of 250 stimuli over motor cortex (MC), premotor cortex (PMC), or supplementary motor area (SMA) in 9 healthy volunteers. The stimulus intensity for MC or PMC was set 85% of the resting motor threshold for the hand muscle, and that for SMA was at the active motor threshold for the leg muscle. SEPs showed significant increases in amplitudes of the frontal N30 component after PMC stimulation, but not after SMA or MC stimulation. Low-frequency (1 Hz) biphasic stimulation over PMC showed no significant N30 changes in 6 out of 9 subjects tested, indicating the effect being specific for 0.2 Hz monophasic stimulation. To examine the functional anatomy of the N30 change, single photon emission computed tomography was performed immediately before and after monophasic 0.2 Hz rTMS over PMC in all the 9 subjects. Regional cerebral blood flow showed significant increases mainly in PMC and prefrontal cortex, indicating the involvement of these cortical areas in sensory input gating for motor control.

Basal ganglia encompass four to five distinct loops to allow parallel processing of information. Among them, the most intensively studied is the motor loop, which includes two distinct direct and indirect pathways. The direct pathway exerts facilitatory influence upon the motor cortex, whereas the indirect pathway exerts an inhibitory effect. Overall, this dual system provides a center(excitatory)-surround-(inhibitory) mechanism to focus its effect on selected cortical neurons, and several lines of evidence suggest that this center-surround mechanism is used to focus the output on a specific group of muscles required for performing a specific task. This operation is made possible through opening the sensory channel for the expected sensory feed-back afferents during movement. Thus, one of the important functions of basal ganglia seems to be the gating of sensory input for motor control. Dystonia may be caused by a mismatch between sensory input versus motor output, and parkinsonism may be viewed as a disorder of gain control of this sensorimotor integration.

Somatosensory evoked potentials (SEPs) are attenuated or gated during movement. The mechanism for this includes both centrifugal gating of afferent input and competition with other afferents caused by the movement (peripheral gating). Using a paradigm in which the signal for triggering movement is the electric stimulus for SEPs, we studied the gating of SEPs after tibial nerve stimulation prior to foot movement, and compared it with that during counting task. Significant gating was found for P40 component, which distributed centrally and ipsilaterally to the side of the stimulation, whereas the contralateral N40 component showed no changes. Dissociated gating of P40 and N40 indicates multiple generators of these components, in contrast to the previous view of a single generator dipole projecting tangentially. Together with the previous findings in median SEPs, these gating phenomena should represent a general mechanism for sensori-motor integration in preparation for limb movement.

Study Objectives: The aim of this study was to investigate the issue of whether REM sleep is involved in implicit learning through the cerebellum-related neural circuit via the use of classical eyeblink conditioning (CEC)., Design: Subjects were divided into three groups: control (sleep without interruption), REM sleep deprivation (RD), and slow wave sleep (stage 3+4) deprivation (SD). The CEC was performed after 8 hours of ordinary nocturnal sleep or sleep disrupted at a selected sleep stage., Setting: A university-based sleep laboratory., Patients or Participants: Twenty-seven healthy volunteers (all men, aged 23.2+/-0.6 years)., Interventions: The CEC was measured after selective sleep deprivation or ordinary nocturnal sleep., Measurements and Results: The eyeblink reflex was conditioned using a classical delay conditioning paradigm. The conditioned response (CR) was determined by electromyography measurements of the orbicularis oculi muscles. The rate of appearance of the CR was compared among the three groups. Compared with the control subjects, RD subjects were significantly deficient in their capacity to acquire conditioned eyeblinks, while no difference was found among the SD subjects., Conclusions: This study suggests that RD suppresses the cerebellar function in CEC and that REM sleep is closely linked with the learning function in the cerebellum.