Implementation of boundary conditions in modeling the femur is critical for the evaluation of distal intramedullary nailing

In previous numerical and experimental studies of the intramedullary nail implanted human femur several simplifications to model the boundary and loading conditions during pre-clinical testing have been proposed. The distal end of the femur was fixed in the majority of studies dealing with the biomechanics of the lower extremity, be it numerical or experimental, which resulted in obviously non-physiological deflections. Per contra, Speirs et al. (2007) proclaimed physiological deflections as a result of constraining the femur in a novel statically determinate fashion in combination with using a complex set of muscle forces. In tandem with this, we have shown that not only the deflections but also the stress and strain predictions turn out to be much lower in magnitude, as a result of using the latter approach. To illustrate the dramatic change in results, we compared these results with those of two other models employing commonly used boundary and loading conditions in retrograde stabilization of a distal diaphyseal fracture. The model used herewith resulted in more realistic femoral cortical strains, lower stresses on both the nail and the screws, as well as such deflections in the overall structure

Dosing-time makes the poison : circadian regulation and pharmacotherapy

Daily rhythms in physiology significantly modulate drug pharmacokinetics and pharmacodynamics according to the time-of-day, a finding that has led to the concept of chronopharmacology. The importance of biological clocks for xenobiotic metabolism has gained increased attention with the discovery of the molecular circadian clockwork. Mechanistic understanding of the cell-autonomous molecular circadian oscillator and the circadian timing system as a whole has opened new conceptual and methodological lines of investigation to understand first, the clock's impact on a specific drug's daily variations or the effects/side effects of environmental substances, and second, how clock-controlled pathways are coordinated within a given tissue or organism. Today, there is an increased understanding of the circadian modulation of drug effects. Moreover, several molecular strategies are being developed to treat disease-dependent and drug-induced clock disruptions in humans

Clock gene Per2 as a controller of liver carcinogenesis

Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2m/m liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2m/m mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2m/m mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2m/m further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-α as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression

Immunohistochemical studies on the effect of Aloe vera on the pancreatic â-cells in neonatal streptozotocin-induced type-II diabetic rats

Aloe vera is used worldwide for several medical purposes as alternative medicine. There are positive and negative reports on the hypoglycaemic effects of this plant. From previous acute studies, Aloe leaf gel and pulp extracts lead to significant decreases in blood glucose in neonatal streptozotocin (n0-STZ)-treated type-II diabetic rats, whereas lowering of blood glucose during chronic treatment with the same extracts was statistically insignificant. Here we try to detect whether Aloe leaf gel and pulp extracts affect pancreatic â-cells. Using n0-STZ type-IIdiabetic rats, the immunoreactivity of â-cells of the islets of Langerhans did not differ among treatments of control, glibenclamide-, Aloe vera leaf pulp- and gel extract-treated rats. These results suggest that treatment of diabetic rats with Aloe vera gel or pulp or glibenclamide has no beneficial influence on the pancreatic â-cells in type II diabetes

A combined experimental and mathematical approach for molecular-based optimization of irinotecan circadian delivery

Circadian timing largely modifies efficacy and toxicity of many anticancer drugs. Recent findings suggest that optimal circadian delivery patterns depend on the patient genetic background. We present here a combined experimental and mathematical approach for the design of chronomodulated administration schedules tailored to the patient molecular profile. As a proof of concept we optimized exposure of Caco-2 colon cancer cells to irinotecan (CPT11), a cytotoxic drug approved for the treatment of colorectal cancer. CPT11 was bioactivated into SN38 and its efflux was mediated by ATP-Binding-Cassette (ABC) transporters in Caco-2 cells. After cell synchronization with a serum shock defining Circadian Time (CT) 0, circadian rhythms with a period of 26 h 50 (SD 63 min) were observed in the mRNA expression of clock genes REV-ERBα, PER2, BMAL1, the drug target topoisomerase 1 (TOP1), the activation enzyme carboxylesterase 2 (CES2), the deactivation enzyme UDP-glucuronosyltransferase 1, polypeptide A1 (UGT1A1), and efflux transporters ABCB1, ABCC1, ABCC2 and ABCG2. DNA-bound TOP1 protein amount in presence of CPT11, a marker of the drug PD, also displayed circadian variations. A mathematical model of CPT11 molecular pharmacokinetics-pharmacodynamics (PK-PD) was designed and fitted to experimental data. It predicted that CPT11 bioactivation was the main determinant of CPT11 PD circadian rhythm. We then adopted the therapeutics strategy of maximizing efficacy in non-synchronized cells, considered as cancer cells, under a constraint of maximum toxicity in synchronized cells, representing healthy ones. We considered exposure schemes in the form of an initial concentration of CPT11 given at a particular CT, over a duration ranging from 1 to 27 h. For any dose of CPT11, optimal exposure durations varied from 3h40 to 7h10. Optimal schemes started between CT2h10 and CT2h30, a time interval corresponding to 1h30 to 1h50 before the nadir of CPT11 bioactivation rhythm in healthy cells

Critical cholangiocarcinogenesis control by cryptochrome clock genes

A coordinated network of molecular circadian clocks in individual cells generates 24-hour rhythms in liver metabolism and proliferation. Circadian disruption through chronic jet lag or Per2 clock gene mutation was shown to accelerate hepatocarcinoma development in mice. Since divergent effects were reported for clock genes Per and Cry regarding xenobiotic toxicity, we questioned the role of Cry1 and Cry2 in liver carcinogenesis. Male WT and Cry1-/-Cry2-/- mice (C57Bl/6 background) were chronically exposed to diethylnitrosamine (DEN) at ZT11. Rest-activity and body temperature rhythms were monitored using an implanted radiotransmitter. Serum aspartate and alanine aminotransferases (AST, ALT) were determined on four occasions during the progression stage. After 7 months, serum alkaline phosphatases (ALP) were determined, and livers were sampled for microscopic tumor nodule counting and histopathology. Five months after initiation of DEN treatment, we found that Cry1-/-Cry2-/- mice developed severe liver dysplasia, as evident from the increased AST, ALT and ALP levels, as compared to WT mice. DEN exposure induced primary liver cancers in nearly fivefold as many Cry1-/-Cry2-/- mice as compared to WT mice (p= 0.01). Microscopic study revealed no difference in the average number of hepatocarcinomas and a nearly 8-fold increase in the average number of cholangiocarcinomas in Cry1-/-Cry2-/- mice, as compared to WT mice. The study validated the hypothesis that molecular circadian clock disruption dramatically increased chemically-induced liver carcinogenesis. In addition, the pronounced shift towards cholangiocarcinoma in DEN exposed Cry1-/-Cry2-/- mice revealed a critical role of the Cry clock genes in bile duct carcinogenesis. This article is protected by copyright. All rights reserved

Ocean current connectivity propelling the secondary spread of a marine invasive comb jelly across western Eurasia

Aim: Invasive species are of increasing global concern. Nevertheless, the mechanisms driving furtherdistribution after the initial establishment of non-native species remain largely unresolved, especiallyin marine systems. Ocean currents can be a major driver governing range occupancy, but this hasnot been accounted for in most invasion ecology studies so far. We investigate how well initialestablishment areas are interconnected to later occupancy regions to test for the potential role ofocean currents driving secondary spread dynamics in order to infer invasion corridors and thesource–sink dynamics of a non-native holoplanktonic biological probe species on a continental scale.Location: Western Eurasia.Time period: 1980s–2016.Major taxa studied: ‘Comb jelly’ Mnemiopsis leidyi.Methods: Based on 12,400 geo-referenced occurrence data, we reconstruct the invasion historyof M. leidyi in western Eurasia. We model ocean currents and calculate their stability to match thetemporal and spatial spread dynamics with large-scale connectivity patterns via ocean currents.Additionally, genetic markers are used to test the predicted connectivity between subpopulations.Results: Ocean currents can explain secondary spread dynamics, matching observed range expansionsand the timing of first occurrence of our holoplanktonic non-native biological probe species,leading to invasion corridors in western Eurasia. In northern Europe, regional extinctions after coldwinters were followed by rapid recolonizations at a speed of up to 2,000 km per season. SourceJASPERS ET AL. | 815areas hosting year-round populations in highly interconnected regions can re-seed genotypes overlarge distances after local extinctions.Main conclusions: Although the release of ballast water from container ships may contribute tothe dispersal of non-native species, our results highlight the importance of ocean currents drivingsecondary spread dynamics. Highly interconnected areas hosting invasive species are crucial forsecondary spread dynamics on a continental scale. Invasion risk assessments should considerlarge-scale connectivity patterns and the potential source regions of non-native marine species