Liver regeneration by small hepatocyte-like progenitor cells after hepatotoxic and necrotic injury in Fischer 344 rats

Liver regeneration after surgical partial hepatectomy (PH) in animals exposed to the mito-inhibitory agent retrorsine is completed through the outgrowth and expansion of small hepatocyte-like progenitor cells (SHPCs). Although the SHPC-mediated regenerative response has been well characterized in the retrorsine/PH model of liver injury, the role that these cells play in other forms of liver injury has not been investigated. The experimental objectives of the current studies were: (i) to characterize SHPC responses in hepatotoxic and necrotic models of liver injury, (ii) to determine the progenitor cell of origin of SHPCs, and (iii) to identify factors involved in the activation of SHPCs after liver injury. SHPCs are not observed after PH in retrorsine-exposed rats treated with the mito-inhibitory agent 2- acetamidofluorene, but are observed after PH in retrorsine-exposed rats treated with the biliary toxin 4,4'-diaminodiphenylmethane. Together, these observations suggest strongly that oval cells do not represent progenitor cells of SHPCs, but that SHPCs represent another liver progenitor cell population that resides in the hepatic parenchyma and responds to certain forms of liver injury. In addition, these investigations found that SHPCs respond to restore liver mass and structure when retrorsine-exposed rats are treated with the pericentral necrotizing agent carbon tetrachloride. This observation shows that SHPCs are capable of regenerating liver damaged by surgical resection as well as chemically-induced necrotic injury. Finally, these studies establish that treatment of retrorsine-exposed rats with the cytokine inhibitor dexamethasone blocks SHPC proliferation after PH and that this blockade can be overcome by administration of recombinant IL6 protein. These observations suggest that SHPCs are activated for proliferation in a cytokine-dependent manner similar to other regenerative cell populations in liver (mature hepatocytes, oval cells), and that IL6 may function as the master regulatory molecule for activation of progenitor cell responses after liver injury. Together, these investigations provide evidence that a hierarchy of cellular responses exists in the mammalian liver in which the form of regenerative response occurring after liver injury reflects (i) the type of liver injury, and (ii) the progenitor cell populations that are capable of proliferating

The effectiveness of weight‐loss lifestyle interventions for improving fertility in women and men with overweight or obesity and infertility: a systematic review update of evidence from randomized controlled trials.

Being overweight or obese can have a negative impact on fertility outcomes. This systematic review updates randomized controlled trial (RCT) findings on the effectiveness of weight loss interventions in reducing weight and improving reproductive outcomes of women and men with overweight or obesity and infertility. Eligible studies, published since the last review, were identified by searching databases from March 20, 2016 until March 31, 2020. RCTs involving any type of lifestyle intervention were considered. Eight RCTs were identified and aggregated with seven RCTs included in our previous review. Meta-analyses revealed that women randomized to a combined diet and exercise intervention were more likely to become pregnant, risk ratio (RR) = 1.87 (95% CI 1.20, 2.93) and achieve a live birth RR = 2.20 (95% CI 1.23, 3.94), compared to women in control groups who received no or minimal intervention. This pattern was not replicated in trials where control groups received immediate access to assisted reproductive technology (ART). No eligible randomized trials involving men were identified. Data were largely obtained from small scale studies. Better designed, adequately powered, robust randomized trials are needed to better understand the effect of weight loss interventions on reproductive outcomes in both women and men

Time to 're-think' physical activity promotion for young people? Results from a repeated cross-sectional study

Abstract Background The aim of this study was to investigate the relationship between knowledge of the current UK physical activity (PA) guidelines and amount of daily PA using a sample population of 11–16 year olds in Northern Ireland. Methods Cross-sectional survey data from the 2010 and 2013 Young Persons’ Behaviour and Attitudes Survey of 10,790 young people provided information on PA, knowledge of guidelines and socio-demographic characteristics. Multinomial logistic regression was used to investigate the associations between knowledge and amount of daily PA. Results Results from 2013 showed 67.0% of respondents were aware of PA guidelines with 15.4% reporting meeting them. Males were more likely to meet PA guidelines than females (OR 3.36, 95% CI 2.47, 4.59). Males who were active for 60 min or more, 7 days per week were less likely to be aware of guidelines (OR = 1.51, 95% CI 1.02, 2.24). For females, knowledge of PA guidelines had no significant association with amount of daily PA (OR = 1.74, 95% CI 0.99, 3.07). Those who did not enjoy being active were less likely to meet the guidelines (OR = 0.05, 95% CI 0.02, 0.12). Conclusions Knowledge did not appear to be an important predictor of PA in young people. Consequently, threshold based messaging containing recommended minimum PA guideline information may not be appropriate for this age group. Re-branding PA promotion to include the use of humour may offer a new direction for public health messaging based around fun and enjoyment

Patient-specific independent 3D GammaPlan quality assurance for Gamma Knife Perfexion radiosurgery

One of the most important aspects of quality assurance (QA) in radiation therapy is redundancy of patient treatment dose calculation. This work is focused on the patient-specific time and 3D dose treatment plan verification for stereotactic radiosurgery using Leksell Gamma Knife Perfexion (LGK PFX). The virtual model of LGK PFX was developed in MATLAB, based on the physical dimensions provided by the manufacturer. The ring-specific linear attenuation coefficients (LAC) and output factors (OFs) reported by the manufacturer were replaced by the measurement-based collimator size-specific OFs and a single LAC = 0.0065 mm-1. Calculation depths for each LGK PFX shot were obtained by ray-tracing technique, and the dose calculation formalism was similar to the one used by GammaPlan treatment planning software versions 8 and 9. The architecture of the QA process was based on the in-house online database search of the LGK PFX database search for plan-specific information. A series of QA phantom plans was examined to verify geometric and dosimetric accuracy of the software. The accuracy of the QA process was further evaluated through evaluation of a series of patient plans. The shot time/focus point dose verification for each shot took less than 1 sec/shot with full 3D isodose verification taking about 30 sec/shot on a desktop PC. GammaPlan database access time took less than 0.05 sec. The geometric accuracy (location of the point of maximum dose) of the phantom and patient plan was dependent on the resolution of the original dose matrix and was of the order of 1 dose element. Dosimetric accuracy of the independently calculated phantom and patient point (focus) doses was within 3.5% from the GammaPlan, with the mean = 2.3% and SD= 1.1%. The process for independent pretreatment patient-specific Gamma Knife Perfexion time and dose verification was created and validated

Treatment with 2-AAF blocks the small hepatocyte-like progenitor cell response in retrorsine-exposed rats

Liver regeneration after partial hepatectomy (PH) in retrorsine-exposed rats is accomplished through proliferation and differentiation of small hepatocyte-like progenitor cells (SHPCs). The cells of origin of SHPCs are not known. We investigated the possibility that SHPCs are directly derived from oval cells, a known liver progenitor cell, by combining the retrorsine/PH (RP) model with 2-acetamidofluorene (2-AAF), an anti-mitotic agent that elicits an oval cell reaction in response to liver deficit

Mobilising knowledge in complex health systems: A call to action

Worldwide, policymakers, health system managers, practitioners and researchers struggle to use evidence to improve policy and practice. There is growing recognition that this challenge relates to the complex systems in which we work. The corresponding increase in complexity-related discourse remains primarily at a theoretical level. This paper moves the discussion to a practical level, proposing actions that can be taken to implement evidence successfully in complex systems. Key to success is working with, rather than trying to simplify or control, complexity. The integrated actions relate to co-producing knowledge, establishing shared goals and measures, enabling leadership, ensuring adequate resourcing, contributing to the science of knowledge-to-action, and communicating strategically. This is the final version of the article. It first appeared from Policy Press via http://dx.doi.org/10.1332/174426416X1471255375031

Mobilising knowledge in complex health systems: a call to action

Worldwide, policymakers, health system managers, practitioners and researchers struggle to use evidence to improve policy and practice. There is growing recognition that this challenge relates to the complex systems in which we work. The corresponding increase in complexity-related discourse remains primarily at a theoretical level. This paper moves the discussion to a practical level, proposing actions that can be taken to implement evidence successfully in complex systems. Key to success is working with, rather than trying to simplify or control, complexity. The integrated actions relate to co-producing knowledge, establishing shared goals and measures, enabling leadership, ensuring adequate resourcing, contributing to the science of knowledge-to-action, and communicating strategically

The SPRED1 Variants Repository for Legius Syndrome

Legius syndrome (LS) is an autosomal dominant disorder caused by germline loss-of-function mutations in the sprouty-related, EVH1 domain containing 1 (SPRED1) gene. The phenotype of LS is multiple café au lait macules (CALM) with other commonly reported manifestations, including intertriginous freckling, lipomas, macrocephaly, and learning disabilities including ADHD and developmental delays. Since the earliest signs of LS and neurofibromatosis type 1 (NF1) syndrome are pigmentary findings, the two are indistinguishable and individuals with LS may meet the National Institutes of Health diagnostic criteria for NF1 syndrome. However, individuals are not known to have an increased risk for developing tumors (compared with NF1 patients). It is therefore important to fully characterize the phenotype differences between NF1 and LS because the prognoses of these two disorders differ greatly. We have developed a mutation database that characterizes the known variants in the SPRED1 gene in an effort to facilitate this process for testing and interpreting results. This database is free to the public and will be updated quarterly

Back-flow ripples in troughs downstream of unit bars: Formation, preservation and value for interpreting flow conditions

Back-flow ripples are bedforms created within the lee-side eddy of a larger bedform with migration directions opposed or oblique to that of the host bedform. In the flume experiments described in this article, back-flow ripples formed in the trough downstream of a unit bar and changed with mean flow velocity; varying from small incipient back-flow ripples at low velocities, to well-formed back-flow ripples with greater velocity, to rapidly migrating transient back-flow ripples formed at the greatest velocities tested. In these experiments back-flow ripples formed at much lower mean back-flow velocities than predicted from previously published descriptions. This lower threshold mean back-flow velocity is attributed to the pattern of velocity variation within the lee-side eddy of the host bedform. The back-flow velocity variations are attributed to vortex shedding from the separation zone, wake flapping and increases in the size of, and turbulent intensity within, the flow separation eddy controlled by the passage of superimposed bedforms approaching the crest of the bar. Short duration high velocity packets, whatever their cause, may form back-flow ripples if they exceed the minimum bed shear stress for ripple generation for long enough or, if much faster, may wash them out. Variation in back-flow ripple cross-lamination has been observed in the rock record and, by comparison with flume observations, the preserved back-flow ripple morphology may be useful for interpreting formative flow and sediment transport dynamics

Modulating hESC-derived cardiomyocyte and endothelial cell function with triple-helical peptides for heart tissue engineering.

In this study, we investigated the role of cardiomyocyte (CM) and endothelial cell (EC) specific interactions with collagen in the assembly of an operational myocardium in vitro. Engineered cardiac patches represent valuable tools for myocardial repair following infarction and are generally constituted of a suitable biomaterial populated by CMs and supportive cell types. Among those, ECs are required for tissue vascularization and positively modulate CM function. To direct the function of human embryonic stem cell (hESC)-derived CM and EC seeded on biomaterials, we replicated cell-collagen interactions, which regulate cellular behaviour in the native myocardium, using triple-helical peptides (THPs) that are ligands for collagen-binding proteins. THPs enhanced proliferation and activity of CMs and ECs separately and in co-culture, drove CM maturation and enabled coordinated cellular contraction on collagen films. These results highlight the importance of collagen interactions on cellular response and establish THP-functionalized biomaterials as novel tools to produce engineered cardiac tissues