Splenic Stiffness Measurement Combined With Liver Stiffness Measurement Compared With Baveno VII Criteria in Predicting the Presence of Oesophageal and Gastric Varices in Patients With Compensated Advanced Liver Cell Disease (cALCD).

Introduction: Liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE) is being increasingly used as a screening tool to predict varices. Our aim was to test the utility of Baveno VII criteria and other combinations of LSM, platelet count (PC), and splenic stiffness measurement (SSM) to predict the presence of varices in a cohort of Sri Lankan patients with compensated advanced liver cell disease (cALCD).

Methods: Consecutive patients with newly diagnosed Child-Pugh class A cALCD (non-viral, BMI<30) were recruited prospectively.

Chronic kidney disease-associated pruritus (CKD-aP) is associated with worse quality of life and increased healthcare utilization among dialysis patients.

Purpose: Chronic pruritus significantly impairs hemodialysis patients' health status and quality of life (QOL) and it is associated with higher mortality rate, more frequent hospitalizations, poorer dialysis and medication adherence, and deteriorated mental status. However, pruritus is still underestimated, underdiagnosed, and undertreated in the real-life clinical scenario. We investigated prevalence, clinical characteristics, clinical correlates, severity as well as physical and psychological burden of chronic pruritus among adult hemodialysis patients in a large international real-world cohort.

Dynamic Regulation of Mitochondrial [Ca] in Hippocampal Neurons.

While neuronal mitochondria have been studied extensively in their role in health and disease, the rules that govern calcium regulation in mitochondria remain somewhat vague. In the present study using cultured rat hippocampal neurons transfected with the mtRCaMP mitochondrial calcium sensor, we investigated the effects of cytosolic calcium surges on the dynamics of mitochondrial calcium ([Ca]m). Cytosolic calcium ([Ca]c) was measured using the high affinity sensor Fluo-2.

Correction: Fast calcium transients in dendritic spines driven by extreme statistics.

[This corrects the article DOI: 10.1371/journal.pbio.

Impact of COVID-19 on the mental health of frontline and non-frontline healthcare workers in Sri Lanka.

Introduction: Healthcare workers (HCWs) are at risk of mental health problems during a pandemic. Being stationed at the frontline or not may have implications on their mental health.

Objectives: The aims of this study were to assess depression, anxiety and stress among HCWs, to explore differences between frontline and non-frontline workers, and to investigate associated factors.

Nanoscale molecular architecture controls calcium diffusion and ER replenishment in dendritic spines.

Dendritic spines are critical components of neuronal synapses as they receive and transform synaptic inputs into a succession of calcium-regulated biochemical events. The spine apparatus (SA), an extension of smooth endoplasmic reticulum, regulates slow and fast calcium dynamics in spines. Calcium release events deplete SA calcium ion reservoir rapidly, yet the next cycle of signaling requires its replenishment.

Extreme escape from a cusp: When does geometry matter for the fastest Brownian particles moving in crowded cellular environments?

We study here the extreme statistics of Brownian particles escaping from a cusp funnel: the fastest Brownian particles among n follow an ensemble of optimal trajectories located near the shortest path from the source to the target. For the time of such first arrivers, we derive an asymptotic formula that differs from the mean first passage times obtained for classical narrow escape and dire strait. When particles are initially distributed at a given distance from a cusp, the time of the fastest particles depends on the cusp geometry.

Fast calcium transients in dendritic spines driven by extreme statistics.

Fast calcium transients (<10 ms) remain difficult to analyse in cellular microdomains, yet they can modulate key cellular events such as trafficking, local ATP production by endoplasmic reticulum-mitochondria complex (ER-mitochondria complex), or spontaneous activity in astrocytes. In dendritic spines receiving synaptic inputs, we show here that in the presence of a spine apparatus (SA), which is an extension of the smooth ER, a calcium-induced calcium release (CICR) is triggered at the base of the spine by the fastest calcium ions arriving at a Ryanodyne receptor (RyR). The mechanism relies on the asymmetric distributions of RyRs and sarco/ER calcium-ATPase (SERCA) pumps that we predict using a computational model and further confirm experimentally in culture and slice hippocampal neurons.

Secretion of IL-1β From Monocytes in Gout Is Redox Independent.

The pro-inflammatory cytokine interleukin-1β (IL-1β) plays important roles in immunity but is also implicated in autoimmune disease. The most well-established mechanism of IL-1β secretion is via activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome which requires an initial priming signal followed by an activating signal. However, the precise mechanism by which the inflammasome is activated remains unclear.

Redundancy principle and the role of extreme statistics in molecular and cellular biology.

The paradigm of chemical activation rates in cellular biology has been shifted from the mean arrival time of a single particle to the mean of the first among many particles to arrive at a small activation site. The activation rate is set by extremely rare events, which have drastically different time scales from the mean times between activations, and depends on different structural parameters. This shift calls for reconsideration of physical processes used in deterministic and stochastic modeling of chemical reactions that are based on the traditional forward rate, especially for fast activation processes in living cells.

A haemocompatible and scalable nanoporous adsorbent monolith synthesised using a novel lignin binder route to augment the adsorption of poorly removed uraemic toxins in haemodialysis.

Nanoporous adsorbents are promising materials to augment the efficacy of haemodialysis for the treatment of end stage renal disease where mortality rates remain unacceptably high despite improvements in membrane technology. Complications are linked in part to inefficient removal of protein bound and high molecular weight uraemic toxins including key marker molecules albumin bound indoxyl sulphate (IS) and p-cresyl sulphate (PCS) and large inflammatory cytokines such as IL-6. The following study describes the assessment of a nanoporous activated carbon monolith produced using a novel binder synthesis route for scale up as an in line device to augment haemodialysis through adsorption of these toxins.

Patients with multiple myeloma have excellent long-term outcomes after recovery from dialysis-dependent acute kidney injury.

Objectives: The aim of this study was to report the long-term outcomes in patients with multiple myeloma (MM) who receive dialysis treatment for acute kidney injury (AKI) due to myeloma cast nephropathy and subsequently recover renal function.

Methods: Patients presenting with dialysis-dependent AKI secondary to myeloma cast nephropathy and subsequently recovering independent renal function between January 2005 and December 2012 were included in this study. Both renal and haematological parameters were collected at multiple time points as part of routine clinic practice.

The importance of screening for serum free light chains in suspected cases of multiple myeloma and their impact on the kidney.

Multiple myeloma (MM) is the second most common haematological malignancy in the UK. We present a case series of three patients with light chain only myeloma who had normal serum protein electrophoretic studies at screening and were diagnosed using serum and urine free light chain assessment. This series reiterates the importance of thorough and robust screening for MM in patients presenting with renal disease.

Serum polyclonal immunoglobulin free light chain levels predict mortality in people with chronic kidney disease.

Objective: To determine whether elevated serum polyclonal free light chain (FLC) levels predict mortality in a population of individuals with chronic kidney disease (CKD).

Patients And Methods: From January 2, 2006, through July 31, 2007, we recruited a cohort of 848 people with CKD who were not receiving renal replacement therapy and did not have monoclonal gammopathy. We measured serum kappa FLC and lambda FLC isotype levels to determine combined FLC (cFLC) levels.

An adsorbent monolith device to augment the removal of uraemic toxins during haemodialysis.

Adsorbents designed with porosity which allows the removal of protein bound and high molecular weight uraemic toxins may improve the effectiveness of haemodialysis treatment of chronic kidney disease (CKD). A nanoporous activated carbon monolith prototype designed for direct blood contact was first assessed for its capacity to remove albumin bound marker toxins indoxyl sulphate (IS), p-cresyl sulphate (p-CS) and high molecular weight cytokine interleukin-6 in spiked healthy donor studies. Haemodialysis patient blood samples were then used to measure the presence of these markers in pre- and post-dialysis blood and their removal by adsorbent recirculation of post-dialysis blood samples.

Recent advances in the pathogenesis and management of cast nephropathy (myeloma kidney).

Multiple myeloma is an incurable plasma cell malignancy that is often accompanied by renal failure; there are a number of potential causes of this, of which cast nephropathy is the most important. Renal failure is highly significant in myeloma, as patient survival can be stratified by the severity of the renal impairment. Consequently, there is an ongoing focus on the pathological basis of cast nephropathy and the optimal treatment regimens in this setting, including effective chemotherapy regimens to reduce light chain production and emerging extracorporeal techniques to remove circulating light chains.

The biology of immunoglobulin free light chains and kidney injury.

Kidney injury caused by immunoglobulin free light chains (FLCs) in the setting of plasma cell dyscrasias is common and associated with increased morbidity and mortality. All compartments of the kidney may be affected, from the glomerulus to the tubulointerstitium, in a wide variety of disease patterns. Here, we review our current knowledge of the biological effects of FLCs and the mechanisms that lead to kidney injury.

Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism.

One of the major attendant complications of multiple myeloma is renal injury, which contributes significantly to morbidity and mortality in this disease. Monoclonal immunoglobulin free light chains (FLCs) are usually directly involved, and tubulointerstitial renal injury and fibrosis are prominent histologic features observed in myeloma. The present study examined the role of monoclonal FLCs in altering the nuclear factor κ light chain enhancer of activated B cells (NF-κB) activity of renal epithelial cells.

Differential progression of renal scarring and determinants of late renal recovery in sustained dialysis dependent acute kidney injury secondary to myeloma kidney.

Background: Most cases of dialysis-dependent acute kidney injury due to myeloma cast nephropathy do not recover renal function. Renal biopsy typically shows cast formation, direct tubular injury and interstitial inflammation caused by nephrotoxic monoclonal free light chains (FLC). Established scarring at presentation is rarely severe.

Immunoglobulin light chains activate tubular epithelial cells through redox signaling.

The renal proximal tubule metabolizes circulating low-molecular-weight proteins such as Ig free light chains. In the setting of plasma cell dyscrasias, the burden of filtered protein can be very high. Endocytosis of certain nephrotoxic light chains induces H(2)O(2) production and monocyte chemoattractant protein-1 (MCP-1) release, leading to recruitment of inflammatory cells and interstitial fibrosis, but how these processes are linked mechanistically is not well understood.

Serum free light chain assessment in monoclonal gammopathy and kidney disease.

Abnormalities of immunoglobulin free light chains (FLCs) are frequently present in patients with monoclonal gammopathies and can cause kidney disease. The recent introduction of highly sensitive immunoassays that measure FLCs to levels below those present in normal individuals has provided a new tool for diagnosis and management in this setting. Here, we review the biology of FLC production in health and disease, and the utility of FLC immunoassays in the assessment of monoclonal gammopathies in kidney disease.

Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis.

Background And Objectives: Extended hemodialysis using a high cut-off dialyzer (HCO-HD) removes large quantities of free light chains in patients with multiple myeloma. However, the clinical utility of this method is uncertain. This study assessed the combination of chemotherapy and HCO-HD on serum free light chain concentrations and renal recovery in patients with myeloma kidney (cast nephropathy) and dialysis-dependent acute renal failure.