Non-Gaussianity of Low Frequency Heart Rate Variability and Sympathetic Activation: Lack of Increases in Multiple System Atrophy and Parkinson Disease

The correlates of indices of long-term ambulatory heart rate variability (HRV) of the autonomic nervous system have not been completely understood. In this study, we evaluated conventional HRV indices, obtained from the daytime (12:00–18:00) Holter recording, and a recently proposed non-Gaussianity index (λ; Kiyono et al., 2008) in 12 patients with multiple system atrophy (MSA) and 10 patients with Parkinson disease (PD), known to have varying degrees of cardiac vagal and sympathetic dysfunction. Compared with the age-matched healthy control group, the MSA patients showed significantly decreased HRV, most probably reflecting impaired vagal heart rate control, but the PD patients did not show such reduced variability. In both MSA and PD patients, the low-to-high frequency (LF/HF) ratio and the short-term fractal exponent α1, suggested to reflect the sympathovagal balance, were significantly decreased, as observed in congestive heart failure (CHF) patients with sympathetic overdrive. In contrast, the analysis of the non-Gaussianity index λ showed that a marked increase in intermittent and non-Gaussian HRV observed in the CHF patients was not observed in the MSA and PD patients with sympathetic dysfunction. These findings provide additional evidence for the relation between the non-Gaussian intermittency of HRV and increased sympathetic activity

MultiScale Wavelet p-Leader based Heart Rate Variability Analysis for Survival Probability Assessment in CHF Patients

International audienceA priori discrimination of high mortality risk amongst congestive heart failure patients constitutes an important clinical stake in cardiology and involves challenging analyses of the temporal dynamics of heart rate variability (HRV). The present contribution investigates the potential of a new multifractal formalism, constructed on wavelet p-leader coefficients, to help discrimination between survivor and non survivor patients. The formalism, applied to a high quality database of 108 patients collected in a Japanese hospital, enables to assess the existence of multifractal properties amongst congestive heart failure patients and to reveal significant differences in the multiscale properties of HRV between survivor and non survivor patients, for scales ranging from approximately 60 to 250 beats

Pathological Role of Tonsillar B Cells in IgA Nephropathy

Although impaired immune regulation along the mucosa-bone marrow axis has been postulated to play an important role, the pathogenesis of IgA nephropathy (IgAN) is unknown; thus, no disease-specific therapy for this disease exists. The therapeutic efficacy of tonsillectomy or tonsillectomy in combination with steroid pulse therapy for IgAN has been discussed. Although randomized control trials for these therapies are ongoing in Japan, the scientific rationale for these therapies remains obscure. It is now widely accepted that abnormally glycosylated IgA1 and its related immune complex (IC) are probably key molecules for the pathogenesis, and are thus considered possible noninvasive biomarkers for this disease. Emerging evidence indicates that B cells in mucosal infections, particularly in tonsillitis, may produce the nephritogenic IgA. In this paper, we briefly summarize characteristics of the nephritogenic IgA/IgA IC, responsible B cells, and underlying mechanisms. This clinical and experimental information may provide important clues for a therapeutic rationale

Neurovascular Compression in Atypical Odontalgia Patients

Background. Persistent idiopathic facial pain (PIFP) is the unexplained pain along the territory of the trigeminal nerve, including nonorganic tooth pain called atypical odontalgia (AO). Though PIFP is debilitating to patients’ livelihood and well-being, its pathophysiology remains poorly understood. Although neurovascular compression (NVC) of the trigeminal nerve is known to be associated with trigeminal neuralgia (TN), the relationship between NVC and other orofacial pains has not been fully elucidated. Methods. In this study, we investigated the differences in the characteristics of PIFP (primarily AO) patients in the presence or absence of NVC. A retrospective analysis was performed on data from 121 consecutive patients who had been diagnosed with unilateral PIFP according to the criteria of the International Classification of Headache Disorders (ICHD)–3 and underwent magnetic resonance imaging scans of the head. Results. In the group without NVC, characteristic findings were significant for psychiatric morbidity, somatization, and pain disability, when compared with the group with NVC. Furthermore, the group without NVC exhibited significant headache, noncardiac chest pain, shortness of breath, and pain catastrophizing. Conclusions. These results suggest that PIFP patients can be divided into two groups: one consistent with a neuropathic pain phenotype when NVC is present and a functional somatic symptom phenotype when presenting without NVC. Our findings may enable a more precise understanding of pathophysiology of PIFP and lead to better treatment strategies

Increased Non-Gaussianity of Heart Rate Variability Predicts Cardiac Mortality after an Acute Myocardial Infarction

Non-Gaussianity index (λ) is a new index of heart rate variability (HRV) that characterizes increased probability of the large heart rate deviations from its trend. A previous study has reported that increased λ is an independent mortality predictor among patients with chronic heart failure. The present study examined predictive value of λ in patients after acute myocardial infarction (AMI). Among 670 post-AMI patients, we performed 24-h Holter monitoring to assess λ and other HRV predictors, including SD of normal-to-normal interval, very-low frequency power, scaling exponent α1 of detrended fluctuation analysis, deceleration capacity, and heart rate turbulence (HRT). At baseline, λ was not correlated substantially with other HRV indices (|r| < 0.4 with either indices) and was decreased in patients taking β-blockers (P = 0.04). During a median follow-up period of 25 months, 45 (6.7%) patients died (32 cardiac and 13 non-cardiac) and 39 recurrent non-fatal AMI occurred among survivors. While all of these HRV indices but λ were significant predictors of both cardiac and non-cardiac deaths, increased λ predicted exclusively cardiac death (RR [95% CI], 1.6 [1.3–2.0] per 1 SD increment, P < 0.0001). The predictive power of increased λ was significant even after adjustments for clinical risk factors, such as age, diabetes, left ventricular function, renal function, prior AMI, heart failure, and stroke, Killip class, and treatment ([95% CI], 1.4 [1.1–2.0] per 1 SD increment, P = 0.01). The prognostic power of increased λfor cardiac death was also independent of all other HRV indices and the combination of increased λ and abnormal HRT provided the best predictive model for cardiac death. Neither λ nor other HRV indices was an independent predictor of AMI recurrence. Among post-AMI patients, increased λ is associated exclusively with increased cardiac mortality risk and its predictive power is independent of clinical risk factors and of other HRV predictors

Dkk3/REIC Deficiency Impairs Spermiation, Sperm Fibrous Sheath Integrity and the Sperm Motility of Mice

The role of Dickkopf-3 (Dkk3)/REIC (The Reduced Expression in Immortalized Cells), a Wnt-signaling inhibitor, in male reproductive physiology remains unknown thus far. To explore the functional details of Dkk3/REIC in the male reproductive process, we studied the Dkk3/REIC knock-out (KO) mouse model. By examining testicular sections and investigating the sperm characteristics (count, vitality and motility) and ultrastructure, we compared the reproductive features between Dkk3/REIC-KO and wild-type (WT) male mice. To further explore the underlying molecular mechanism, we performed RNA sequencing (RNA-seq) analysis of testicular tissues. Our results showed that spermiation failure existed in seminiferous tubules of Dkk3/REIC-KO mice, and sperm from Dkk3/REIC-KO mice exhibited inferior motility (44.09 +/- 8.12% vs. 23.26 +/- 10.02%, p 0.05) nor the difference in the sperm vitality rate (72.83 +/- 1.55% vs. 72.50 +/- 0.71%, p > 0.05) were statistically significant. The RNA-seq and GO (Gene Oncology) enrichment results indicated that the differential genes were significantly enriched in the GO terms of cytoskeleton function, cAMP signaling and calcium ion binding. Collectively, our research demonstrates that Dkk3/REIC is involved in the process of spermiation, fibrous sheath integrity maintenance and sperm motility of mice

Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells

The adenovirus-REIC/Dkk-3 expression vector (Ad-REIC) has been the focus of numerous clinical studies due to its potential for the quenching of cancers. The cancer-suppressing mechanisms of the REIC/DKK-3 gene depend on multiple pathways that exert both direct and indirect effects on cancers. The direct effect is triggered by REIC/Dkk-3-mediated ER stress that causes cancer-selective apoptosis, and the indirect effect can be classified in two ways: (i) induction, by Ad-REIC-mis-infected cancer-associated fibroblasts, of the production of IL-7, an important activator of T cells and NK cells, and (ii) promotion, by the secretory REIC/Dkk-3 protein, of dendritic cell polarization from monocytes. These unique features allow Ad-REIC to exert effective and selective cancer-preventative effects in the manner of an anticancer vaccine. However, the question of how the REIC/Dkk-3 protein leverages anticancer immunity has remained to be answered. We herein report a novel function of the extracellular REIC/Dkk-3—namely, regulation of an immune checkpoint via modulation of PD-L1 on the cancer-cell surface. First, we identified novel interactions of REIC/Dkk-3 with the membrane proteins C5aR, CXCR2, CXCR6, and CMTM6. These proteins all functioned to stabilize PD-L1 on the cell surface. Due to the dominant expression of CMTM6 among the proteins in cancer cells, we next focused on CMTM6 and observed that REIC/Dkk-3 competed with CMTM6 for PD-L1, thereby liberating PD-L1 from its complexation with CMTM6. The released PD-L1 immediately underwent endocytosis-mediated degradation. These results will enhance our understanding of not only the physiological nature of the extracellular REIC/Dkk-3 protein but also the Ad-REIC-mediated anticancer effects