Mathematical modelling of the pathogenesis of multiple myeloma-induced bone disease

Multiple myeloma (MM) is the second most common haematological malignancy and results in destructive bone lesions. The interaction between MM cells and the bone microenvironment plays an important role in the development of the tumour cells and MM-induced bone disease and forms a 'vicious cycle' of tumour development and bone destruction, intensified by suppression of osteoblast activity and promotion of osteoclast activity. In this paper, a mathematical model is proposed to simulate how the interaction between MM cells and the bone microenvironment facilitates the development of the tumour cells and the resultant bone destruction. It includes both the roles of inhibited osteoblast activity and stimulated osteoclast activity. The model is able to mimic the temporal variation of bone cell concentrations and resultant bone volume after the invasion and then removal of the tumour cells and explains why MM-induced bone lesions rarely heal even after the complete removal of MM cells. The behaviour of the model compares well with published experimental data. The model serves as a first step to understand the development of MM-induced bone disease and could be applied further to evaluate the current therapies against MM-induced bone disease and even suggests new potential therapeutic targets

Naturally Occurring Stable Calcium Isotope Ratios in Body Compartments Provide a Novel Biomarker of Bone Mineral Balance in Children and Young Adults

Serum calcium (Ca), bone biomarkers, and radiological imaging do not allow accurate evaluation of bone mineral balance (BMB), a key determinant of bone mineral density (BMD) and fracture risk. We studied naturally occurring stable (non‐radioactive) Ca isotopes in different body pools as a potential biomarker of BMB. {42}^Ca and {44}^Ca are absorbed from our diet and sequestered into different body compartments following kinetic principles of isotope fractionation; isotopically light {42}^Ca is preferentially incorporated into bone, whereas heavier {44}^Ca preferentially remains in blood and is excreted in urine and feces. Their ratio (δ^{44/42}Ca) n serum and urine increases during bone formation and decreases with bone resorption. In 117 healthy participants, we measured Ca isotopes, biomarkers, and BMD by dual‐energy X‐ray absorptiometry (DXA) and tibial peripheral quantitative CT (pQCT). {44}^Ca and 42Ca were measured by multi‐collector ionization‐coupled plasma mass‐spectrometry in serum, urine, and feces. The relationship between bone Ca gain and loss was calculated using a compartment model. δ^{44/42}Ca_{serum} and δ^{44/42}Ca_{urine} were higher in children (n = 66, median age 13 years) compared with adults (n = 51, median age 28 years; p < 0.0001 and p = 0.008, respectively). δ^{44/42}Ca_{serum} increased with height in boys (p < 0.001, R^{2} = 0.65) and was greatest at Tanner stage 4. δ^{44/42}Ca_{serum} correlated positively with biomarkers of bone formation (25‐hydroxyvitaminD [p < 0.0001, R^{2} = 0.37] and alkaline phosphatase [p = 0.009, R^{2} = 0.18]) and negatively with bone resorption marker parathyroid hormone (PTH; p = 0.03, R^{2} = 0.13). δ^{44/42}Ca_{serum} strongly positively correlated with tibial cortical BMD Z‐score (n = 62; p < 0.001, R^{2} = 0.39) but not DXA. Independent predictors of tibial cortical BMD Z‐score were δ^{44/42}Ca_{serum} (p = 0.004, β = 0.37), 25‐hydroxyvitaminD (p = 0.04, β = 0.19) and PTH (p = 0.03, β = −0.13), together predicting 76% of variability. In conclusion, naturally occurring Ca isotope ratios in different body compartments may provide a novel, non‐invasive method of assessing bone mineralization. Defining an accurate biomarker of BMB could form the basis of future studies investigating Ca dynamics in disease states and the impact of treatments that affect bone homeostasis

miR-21 Promotes Fibrogenesis in Peritoneal Dialysis.

Peritoneal dialysis (PD) is a life-saving form of renal replacement therapy for those with end-stage kidney disease. Mesothelial cells (MCs) line the peritoneal cavity and help define peritoneal response to treatment-associated injury, a major reason for treatment failure. miRNAs are important regulators, but their roles in peritoneal fibrosis are largely unknown. In this study, miR-21 was one of the most abundant miRNAs in primary MCs, and was up-regulated by the profibrotic cytokine transforming growth factor-β1 and in PD effluent-derived MCs exhibiting mesenchymal phenotypic change. Increased miR-21 was found in peritoneal membrane biopsy specimens from PD patients compared to healthy controls (PD biocompatible, 5.86×, P = 0.0001; PD conventional, 7.09×, P < 0.0001, n = 11 per group). In PD effluent from a cohort of 230 patients, miR-21 was higher in those receiving the therapy long-term compared to new starters (n = 230, miR-21 3.26×, P = 0.001) and associated with icodextrin use (R = 0.52; 95% CI, 0.20-0.84), peritonitis count (R = 0.16; 95% CI, 0.03-0.29), and dialysate cytokines. miR-21 down-regulated programmed cell death 4 and programmed cell death 4 protein was decreased in peritoneal membrane biopsy specimens from PD patients compared to healthy controls. New miR-21 targets were identified that may be important during PD fibrogenesis. These data identify miR-21 as an important effector of fibrosis in the peritoneal membrane, and a promising biomarker in the dialysis effluent for membrane change in patients receiving PD

Lower cardiorespiratory fitness contributes to increased insulin resistance and fasting glycaemia in middle-aged South Asian compared with European men living in the UK

AIMS/HYPOTHESIS: This study aimed to determine the extent to which increased insulin resistance and fasting glycaemia in South Asian men, compared with white European men, living in the UK, was due to lower cardiorespiratory fitness (maximal oxygen uptake [[Formula: see text]]) and physical activity. METHODS: One hundred South Asian and 100 age- and BMI-matched European men without diagnosed diabetes, aged 40–70 years, had fasted blood taken for measurement of glucose concentration, HOMA-estimated insulin resistance (HOMA(IR)), plus other risk factors, and underwent assessment of physical activity (using accelerometry), [Formula: see text], body size and composition, and demographic and other lifestyle factors. For 13 South Asian and one European man, HbA(1c) levels were >6.5% (>48 mmol/mol), indicating potential undiagnosed diabetes; these men were excluded from the analyses. Linear regression models were used to determine the extent to which body size and composition, fitness and physical activity variables explained differences in HOMA(IR) and fasting glucose between South Asian and European men. RESULTS: HOMA(IR) and fasting glucose were 67% (p < 0.001) and 3% (p < 0.018) higher, respectively, in South Asians than Europeans. Lower [Formula: see text], lower physical activity and greater total adiposity in South Asians individually explained 68% (95% CI 45%, 91%), 29% (11%, 46%) and 52% (30%, 80%), respectively, and together explained 83% (50%, 119%) (all p < 0.001) of the ethnic difference in HOMA(IR). Lower [Formula: see text] and greater total adiposity, respectively, explained 61% (9%, 111%) and 39% (9%, 76%) (combined effect 63% [8%, 115%]; all p < 0.05) of the ethnic difference in fasting glucose. CONCLUSIONS/INTERPRETATION: Lower cardiorespiratory fitness is a key factor associated with the excess insulin resistance and fasting glycaemia in middle-aged South Asian, compared with European, men living in the UK. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-013-2969-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users

Introducing the international home dialysis consortium

The use of home dialysis, peritoneal dialysis (PD) and home hemodialysis (HHD), remains low despite the well-known benefits to the person on dialysis in terms of lifestyle and treatment satisfaction, and to the health care system because of lower financial costs and lesser dependence on trained professionals.1 With projections of doubling of the population of people receiving dialysis from 2010 to 2030,2 health care systems delivering dialysis therapy have the responsibility to ensure cost-effectiveness. Resources are limited, including qualified staff and finances to cover treatment costs. Remote patient monitoring holds promise of high quality follow up and improved clinical outcomes for home dialysis patients.3 Furthermore, shared decision making enables patients to choose and therefore benefit from the dialysis modality most suitable for the individual to improve their quality of life. Furthermore, by avoiding multiple journeys to a dialysis center, home dialysis is less disruptive for the environment and for those living in remote geographic areas, prevents individuals from having to relocate from their communities to urban areas for dialysis treatment. In addition, PD avoids use of large quantities of water for each treatment, which is critically important in regions with water scarcity. During the height of the COVID-19 pandemic, when even “home dialysis sceptics” perceived the advantage of dialysis at home rather than in-center, an International Home Dialysis Roundtable was convened by industry leaders to consider practical steps for increasing access to home dialysis.4 Around the same time, Kidney Disease Improving Global Outcomes held a controversies conference on home dialysis, looking at multiple facets of improving the adoption and propagation of home dialysis globally.5 Building on this work, and in the light of the global importance and interests in home dialysis, the leadership of the International Society of Nephrology and the International Society for Peritoneal Dialysis have joined forces to form the International Home Dialysis Consortium. This consortium aims to bring regional stakeholder forces together to drive home dialysis uptake globally, in a scientifically advised, structured, and accountable manner

BIOKID: Randomized controlled trial comparing bicarbonate and lactate buffer in biocompatible peritoneal dialysis solutions in children [ISRCTN81137991]

BACKGROUND: Peritoneal dialysis (PD) is the preferred dialysis modality in children. Its major drawback is the limited technique survival due to infections and progressive ultrafiltration failure. Conventional PD solutions exert marked acute and chronic toxicity to local tissues. Prolonged exposure is associated with severe histopathological alterations including vasculopathy, neoangiogenesis, submesothelial fibrosis and a gradual loss of the mesothelial cell layer. Recently, more biocompatible PD solutions containing reduced amounts of toxic glucose degradation products (GDPs) and buffered at neutral pH have been introduced into clinical practice. These solutions contain lactate, bicarbonate or a combination of both as buffer substance. Increasing evidence from clinical trials in adults and children suggests that the new PD fluids may allow for better long-term preservation of peritoneal morphology and function. However, the relative importance of the buffer in neutral-pH, low-GDP fluids is still unclear. In vitro, lactate is cytotoxic and vasoactive at the concentrations used in PD fluids. The BIOKID trial is designed to clarify the clinical significance of the buffer choice in biocompatible PD fluids. METHODS/DESIGN: The objective of the study is to test the hypothesis that bicarbonate based PD solutions may allow for a better preservation of peritoneal transport characteristics in children than solutions containing lactate buffer. Secondary objectives are to assess any impact of the buffer system on acid-base status, peritoneal tissue integrity and the incidence and severity of peritonitis. After a run-in period of 2 months during which a targeted cohort of 60 patients is treated with a conventional, lactate buffered, acidic, GDP containing PD fluid, patients will be stratified according to residual renal function and type of phosphate binding medication and randomized to receive either the lactate-containing Balance solution or the bicarbonate-buffered Bicavera(® )solution for a period of 10 months. Patients will be monitored by monthly physical and laboratory examinations. Peritoneal equilibration tests, 24-h dialysate and urine collections will be performed 4 times. Peritoneal biopsies will be obtained on occasion of intraabdominal surgery. Changes in small solute transport rates, markers of peritoneal tissue turnover in the effluent, acid-base status and peritonitis rates and severity will be analyzed

Quantitative Histomorphometry of the Healthy Peritoneum

The peritoneum plays an essential role in preventing abdominal frictions and adhesions and can be utilized as a dialysis membrane. Its physiological ultrastructure, however, has not yet been studied systematically. 106 standardized peritoneal and 69 omental specimens were obtained from 107 patients (0.1-60 years) undergoing surgery for disease not affecting the peritoneum for automated quantitative histomorphometry and immunohistochemistry. The mesothelial cell layer morphology and protein expression pattern is similar across all age groups. Infants below one year have a thinner submesothelium; inflammation, profibrotic activity and mesothelial cell translocation is largely absent in all age groups. Peritoneal blood capillaries, lymphatics and nerve fibers locate in three distinct submesothelial layers. Blood vessel density and endothelial surface area follow a U-shaped curve with highest values in infants below one year and lowest values in children aged 7-12 years. Lymphatic vessel density is much lower, and again highest in infants. Omental blood capillary density correlates with parietal peritoneal findings, whereas only few lymphatic vessels are present. The healthy peritoneum exhibits major thus far unknown particularities, pertaining to functionally relevant structures, and subject to substantial changes with age. The reference ranges established here provide a framework for future histomorphometric analyses and peritoneal transport modeling approaches. © 2016, EDP Science. All rights reserved

Survival Rate, Fracture Strength and Failure Mode of Ceramic Implant Abutments After Chewing Simulation

The aim of this study was to compare titanium-reinforced ZrO2 and pure Al2O3 abutments regarding their outcome after chewing simulation and static loading. Forty-eight standard diameter implants with an external hexagon were divided into three groups of 16 implants each and restored with three different types of abutments (group A: ZrO2 abutments with titanium inserts; group B: densely sintered high-purity Al2O3 abutments; group C: titanium abutments). All abutments were fixated on the implants with gold-alloy screws at 32 Ncm torque, and metal crowns were adhesively cemented onto the abutments. The specimens were exposed to 1.2 million cycles in a chewing simulator. Surviving specimens were subsequently loaded until fracture in a static testing device. Fracture loads (N) and fracture modes were recorded. A Wilcoxon Rank test to compare fracture loads among the 3 groups and a Fisher exact test to detect group differences in fracture modes were used for statistical evaluation (

Conifers in cold environments synchronize maximum growth rate of tree-ring formation with day length

Intra-annual radial growth rates and durations in trees are reported to differ greatly in relation to species, site and environmental conditions. However, very similar dynamics of cambial activity and wood formation are observed in temperate and boreal zones. Here, we compared weekly xylem cell production and variation in stem circumference in the main northern hemisphere conifer species (genera Picea, Pinus, Abies and Larix) from 1996 to 2003. Dynamics of radial growth were modeled with a Gompertz function, defining the upper asymptote (A), x-axis placement (β) and rate of change (κ). A strong linear relationship was found between the constants β and κ for both types of analysis. The slope of the linear regression, which corresponds to the time at which maximum growth rate occurred, appeared to converge towards the summer solstice. The maximum growth rate occurred around the time of maximum day length, and not during the warmest period of the year as previously suggested. The achievements of photoperiod could act as a growth constraint or a limit after which the rate of tree-ring formation tends to decrease, thus allowing plants to safely complete secondary cell wall lignification before winter