Fatigue, reduced sleep quality and restless legs syndrome in Charcot-Marie-Tooth disease: a web-based survey

To investigate the prevalence of fatigue, daytime sleepiness, reduced sleep quality, and restless legs syndrome (RLS) in a large cohort of patients with Charcot-Marie-Tooth disease (CMT) and their impact on health-related quality of life (HRQoL). Participants of a web-based survey answered the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the Multidimensional Fatigue Inventory, and, if the diagnostic criteria of RLS were met, the International RLS Severity Scale. Diagnosis of RLS was affirmed in screen-positive patients by means of a standardized telephone interview. HRQoL was assessed by using the SF-36 questionnaire. Age- and sex-matched control subjects were recruited from waiting relatives of surgical outpatients. 227 adult self-reported CMT patients answered the above questionnaires, 42.9% were male, and 57.1% were female. Age ranged from 18 to 78 years. Compared to controls (n = 234), CMT patients reported significantly higher fatigue, a higher extent and prevalence of daytime sleepiness and worse sleep quality. Prevalence of RLS was 18.1% in CMT patients and 5.6% in controls (p = 0.001). RLS severity was correlated with worse sleep quality and reduced HRQoL. Women with CMT were affected more often and more severely by RLS than male patients. With regard to fatigue, sleep quality, daytime sleepiness, RLS prevalence, RLS severity, and HRQoL, we did not find significant differences between genetically distinct subtypes of CMT. HRQoL is reduced in CMT patients which may be due to fatigue, sleep-related symptoms, and RLS in particular. Since causative treatment for CMT is not available, sleep-related symptoms should be recognized and treated in order to improve quality of life

Applying Benford’s law to detect accounting data manipulation in the banking industry

We utilise Benford’s Law to test if balance sheet and income statement data broadly used to assess bank soundness were manipulated prior to and also during the global financial crisis. We find that all banks resort to loan loss provisions to manipulate earnings and income upwards. Distressed institutions that have stronger incentives to conceal their financial difficulties resort additionally to manipulating loan loss allowances and non-performing loans downwards. Moreover, manipulation is magnified during the crisis and expands to encompass regulatory capital

Emerging role of the calcium-activated, small conductance, SK3 K ⁺ channel in distal tubule function: Regulation by TRPV4

The Ca2+-activated, maxi-K (BK) K+ channel, with low Ca2+-binding affinity, is expressed in the distal tubule of the nephron and contributes to flow-dependent K+ secretion. In the present study we demonstrate that the Ca2+-activated, SK3 (KCa2.3) K + channel, with high Ca2+-binding affinity, is also expressed in the mouse kidney (RT-PCR, immunoblots). Immunohistochemical evaluations using tubule specific markers demonstrate significant expression of SK3 in the distal tubule and the entire collecting duct system, including the connecting tubule (CNT) and cortical collecting duct (CCD). In CNT and CCD, main sites for K+ secretion, the highest levels of expression were along the apical (luminal) cell membranes, including for both principal cells (PCs) and intercalated cells (ICs), posturing the channel for Ca2+- dependent K+ secretion. Fluorescent assessment of cell membrane potential in native, split-opened CCD, demonstrated that selective activation of the Ca2+-permeable TRPV4 channel, thereby inducing Ca2+ influx and elevating intracellular Ca2+ levels, activated both the SK3 channel and the BK channel leading to hyperpolarization of the cell membrane. The hyperpolarization response was decreased to a similar extent by either inhibition of SK3 channel with the selective SK antagonist, apamin, or by inhibition of the BK channel with the selective antagonist, iberiotoxin (IbTX). Addition of both inhibitors produced a further depolarization, indicating cooperative effects of the two channels on Vm. It is concluded that SK3 is functionally expressed in the distal nephron and collecting ducts where induction of TRPV4-mediated Ca2+ influx, leading to elevated intracellular Ca2+ levels, activates this high Ca2+- affinity K+ channel. Further, with sites of expression localized to the apical cell membrane, especially in the CNT and CCD, SK3 is poised to be a key pathway for Ca2+-dependent regulation of membrane potential and K+ secretion. © 2014 Berrout et al

Opposing Roles of Dendritic Cell Subsets in Experimental GN

Dendritic cells (DCs) are thought to form a dendritic network across barrier surfaces and throughout organs, including the kidney, to perform an important sentinel function. However, previous studies of DC function used markers, such as CD11c or CX3CR1, that are not unique to DCs. Here, we evaluated the role of DCs in renal inflammation using a CD11c reporter mouse line and two mouse lines with DC-specific reporters, Zbtb46-GFP and Snx22-GFP. Multiphoton microscopy of kidney sections confirmed that most of the dendritically shaped CD11c(+) cells forming a network throughout the renal interstitium expressed macrophage-specific markers. In contrast, DCs marked by Zbtb46-GFP or Snx22-GFP were less abundant, concentrated around blood vessels, and round in shape. We confirmed this pattern of localization using imaging mass cytometry. Motility measurements showed that resident macrophages were sessile, whereas DCs were motile before and after inflammation. Although uninflamed glomeruli rarely contained DCs, injury with nephrotoxic antibodies resulted in accumulation of ZBTB46(+) cells in the periglomerular region. ZBTB46 identifies all classic DCs, which can be categorized into two functional subsets that express either CD103 or CD11b. Depletion of ZBTB46(+) cells attenuated the antibody-induced kidney injury, whereas deficiency of the CD103(+) subset accelerated injury through a mechanism that involved increased neutrophil infiltration. RNA sequencing 7 days after nephrotoxic antibody injection showed that CD11b(+) DCs expressed the neutrophil-attracting cytokine CXCL2, whereas CD103(+) DCs expressed high levels of several anti-inflammatory genes. These results provide new insights into the distinct functions of the two major DC subsets in glomerular inflammation