Mutational impact of culturing human pluripotent and adult stem cells

Genetic changes acquired during in vitro culture pose a potential risk for the successful application of stem cells in regenerative medicine. To assess mutation accumulation risks induced by culturing, we determined genetic aberrations in individual human induced pluripotent stem cells (iPS cells) and adult stem cells (ASCs) by whole genome sequencing analyses. Individual iPS cells, intestinal ASCs and liver ASCs accumulated 3.5±0.5, 7.2±1.0 and 8.4±3.6 base substitutions per population doubling, respectively. The annual in vitro mutation accumulation rate of ASCs adds up to ∼1600 base pair substitutions, which is ∼40-fold higher than the in vivo rate of ∼40 base pair substitutions per year. Mutational analysis revealed a distinct in vitro induced mutational signature that is irrespective of stem cell type and distinct from the in vivo mutational signature. This in vitro signature is characterized by C to A changes that have previously been linked to oxidative stress conditions. Additionally, we observed stem cell-specific mutational signatures and differences in transcriptional strand bias, indicating differential activity of DNA repair mechanisms between stem cell types in culture. We demonstrate that the empirically defined mutation rates, spectra, and genomic distribution enable risk assessment by modelling the accumulation of specific oncogenic mutations during typical in vitro expansion, manipulation or screening experiments using human stem cells. Taken together, we have here for the first time accurately quantified and characterized in vitro mutation accumulation in human iPS cells and ASCs in a direct comparison. These results provide insights for further optimization of culture conditions for safe in vivo utilization of these cell types for regenerative purposes

Global Variation of Nutritional Status in Children Undergoing Chronic Peritoneal Dialysis : A Longitudinal Study of the International Pediatric Peritoneal Dialysis Network

While children approaching end-stage kidney disease (ESKD) are considered at risk of uremic anorexia and underweight they are also exposed to the global obesity epidemic. We sought to investigate the variation of nutritional status in children undergoing chronic peritoneal dialysis (CPD) around the globe. The distribution and course of body mass index (BMI) standard deviation score over time was examined prospectively in 1001 children and adolescents from 35 countries starting CPD who were followed in the International Pediatric PD Network (IPPN) Registry. The overall prevalence of underweight, and overweight/obesity at start of CPD was 8.9% and 19.7%, respectively. Underweight was most prevalent in South and Southeast Asia (20%), Central Europe (16.7%) and Turkey (15.2%), whereas overweight and obesity were most common in the Middle East (40%) and the US (33%). BMI SDS at PD initiation was associated positively with current eGFR and gastrostomy feeding prior to PD start. Over the course of PD BMI SDS tended to increase on CPD in underweight and normal weight children, whereas it decreased in initially overweight patients. In infancy, mortality risk was amplified by obesity, whereas in older children mortality was markedly increased in association with underweight. Both underweight and overweight are prevalent in pediatric ESKD, with the prevalence varying across the globe. Late dialysis start is associated with underweight, while enteral feeding can lead to obesity. Nutritional abnormalities tend to attenuate with time on dialysis. Mortality risk appears increased with obesity in infants and with underweight in older children.Peer reviewe

Methodological and conceptual issues in studying effort-reward fit

Purpose Research on effort-reward "imbalance" (ERI) has gained popularity in the occupational health literature, and authors typically use effort-reward ratios (ERRs) to study this phenomenon. This article provides a methodological and theoretical critique of this literature and suggestions on how future research can better study joint effects of efforts and reward. Design/methodology/approach The authors conducted a simulation study, analyzed panel data and surveyed the literature on the theoretical and methodological basis of the "imbalance" concept. Findings The simulation study indicates that under many conditions the ERR captures main effects of effort and reward and that effects also depend on the scaling of the variables. The panel data showed that when main effects and the interactions of effort and reward are entered simultaneously in a regression predicting mental and physical health, the significant effect of the ERRs disappears. The literature review reveals that psychological theories include more elaborate theoretical ideas on joint effects of effort and reward. Research limitations/implications The results suggest that moderated multiple regression analyses are better suited to detect a misfit between effort and reward than ERRs. The authors also suggest to use the term effort-reward fit in future research. Originality/value Methodologically and conceptually the authors showed that the ERR is not an appropriate approach because it confuses main effects with interaction effects. Furthermore, the concept of ERI is better substituted by a broader conceptualization of effort-reward fit that can be integrated with the existing literature on person-environment fit. Recommendations for future research are provided

Publisher Correction: The mutational impact of culturing human pluripotent and adult stem cells

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Condições de iluminação em ambiente de escritório : influência no conforto visual

Mestrado em Ergonomia na Segurança no TrabalhoCom o aumento da população laboral na actividade de escritório surge a necessidade de adequar estes espaços ao homem de forma a tornar o ambiente de trabalho motivante, e a melhorar o desempenho laboral. A adequada iluminação do posto de trabalho é um importante factor que contribui directamente para a segurança, saúde, bem-estar e conforto do trabalhador. As condições de iluminação condicionam a percepção do trabalhador face ao conforto visual, que se traduz em fadiga visual, stress e esforço físico. Este estudo pretendeu identificar condições anómalas e avaliar as condições de iluminação que influenciam o conforto visual dos trabalhadores em ambientes de escritório. A amostra do estudo é constituída por 143 indivíduos do sector administrativo, de 3 empresas. Os instrumentos usados para recolha de informação foram questionário, checklist, luxímetro e máquina fotográfica. Para tratar os dados foi usado o SPSS, versão 18. Efectuou-se análise descritiva, análise de inferência estatística sendo aplicados os testes de Kruskal-Wallis e de comparações múltiplas. Para a medição da iluminância e a uniformidade foram seguidas as normas europeias EN 12464 (2002), DIN 5035 (1990) e ISO 8995 (2002). Os resultados do estudo revelam desconforto visual (fadiga visual, irritabilidade ocular, dores de cabeça, dores musculares, dificuldade de concentração e de SVC) relacionado com o tempo de trabalho em computador sem pausas, com valores de iluminância inferiores aos valores recomendados e com a existência de brilhos e reflexos.With increasing population in the labor office activity comes the need to adapt these workplaces to man in order to make the work environment motivating, and improve task performance. Adequate lighting of the workplace is an important factor that directly contributes to the health, well-being and worker comfort. The lighting conditions affect the perception of the worker towards visual comfort, which results in eyestrain, stress and physical exertion. This study aims to identify anomalous conditions and evaluate the lighting conditions that influence the visual comfort of workers in office environments. The study sample is composed of 143 individuals from three companies, of the administrative sector. The data collection instruments were a questionnaire, a checklist, a light meter and a camera. To process the data SPSS software, version 18 was used. A descriptive analysis and a statistical inference analysis were carried and Kruskal-Wallis tests and multiple comparisons tests were applied. For measuring the illuminance and uniformity European standards EN 12464 (2002), DIN 5035 (1990) and ISO 8995 (2002) were followed. The study results revealed visual discomfort (eyestrain, irritated eyes, headaches, muscle aches and Computer Visual Syndrome) related to working time with computer without breaks, with illuminance below the recommended values and with the existence of glare and reflections

Risk factors for loss of residual renal function in children treated with chronic peritoneal dialysis

In dialyzed patients, preservation of residual renal function is associated with better survival, lower morbidity, and greater quality of life. To analyze the evolution of residual diuresis over time, we prospectively monitored urine output in 401 pediatric patients in the global IPPN registry who commenced peritoneal dialysis (PD) with significant residual renal function. Associations of patient characteristics and time-variant covariates with daily urine output and the risk of developing oligoanuria (under 100 ml/m(2)/day) were analyzed by mixed linear modeling and Cox regression analysis including time-varying covariates. With an average loss of daily urine volume of 130 ml/m(2) per year, median time to oligoanuria was 48 months. Residual diuresis significantly subsided more rapidly in children with glomerulopathies, lower diuresis at start of PD, high ultrafiltration volume, and icodextrin use. Administration of diuretics significantly reduced oligoanuria risk, whereas the prescription of renin-angiotensin system antagonists significantly increased the risk oligoanuria. Urine output on PD was significantly associated in a negative manner with glomerulopathies (-584 ml/m(2)) and marginally with the use of icodextrin (-179 ml/m(2)) but positively associated with the use of biocompatible PD fluid (+111 ml/m(2)). Children in both Asia and North America had consistently lower urine output compared with those in Europe perhaps due to regional variances in therapy. Thus, in children undergoing PD, residual renal function depends strongly on the cause of underlying kidney disease and may be modifiable by diuretic therapy, peritoneal ultrafiltration, and choice of PD fluid

Risk factors for loss of residual renal function in children treated with chronic peritoneal dialysis

Artículo de publicación ISIIn dialyzed patients, preservation of residual renal function is associated with better survival, lower morbidity, and greater quality of life. To analyze the evolution of residual diuresis over time, we prospectively monitored urine output in 401 pediatric patients in the global IPPN registry who commenced peritoneal dialysis (PD) with significant residual renal function. Associations of patient characteristics and time-variant covariates with daily urine output and the risk of developing oligoanuria (under 100 ml/m(2)/day) were analyzed by mixed linear modeling and Cox regression analysis including time-varying covariates. With an average loss of daily urine volume of 130 ml/m(2) per year, median time to oligoanuria was 48 months. Residual diuresis significantly subsided more rapidly in children with glomerulopathies, lower diuresis at start of PD, high ultrafiltration volume, and icodextrin use. Administration of diuretics significantly reduced oligoanuria risk, whereas the prescription of renin-angiotensin system antagonists significantly increased the risk oligoanuria. Urine output on PD was significantly associated in a negative manner with glomerulopathies (-584 ml/m(2)) and marginally with the use of icodextrin (-179 ml/m(2)) but positively associated with the use of biocompatible PD fluid (+111 ml/m(2)). Children in both Asia and North America had consistently lower urine output compared with those in Europe perhaps due to regional variances in therapy. Thus, in children undergoing PD, residual renal function depends strongly on the cause of underlying kidney disease and may be modifiable by diuretic therapy, peritoneal ultrafiltration, and choice of PD fluid

Long-term expanding human airway organoids for disease modeling

Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non-structural viral NS2 protein, and preferentially recruits neutrophils upon co-culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease

Global Variation of Nutritional Status in Children Undergoing Chronic Peritoneal Dialysis: A Longitudinal Study of the International Pediatric Peritoneal Dialysis Network.

While children approaching end-stage kidney disease (ESKD) are considered at risk of uremic anorexia and underweight they are also exposed to the global obesity epidemic. We sought to investigate the variation of nutritional status in children undergoing chronic peritoneal dialysis (CPD) around the globe. The distribution and course of body mass index (BMI) standard deviation score over time was examined prospectively in 1001 children and adolescents from 35 countries starting CPD who were followed in the International Pediatric PD Network (IPPN) Registry. The overall prevalence of underweight, and overweight/obesity at start of CPD was 8.9% and 19.7%, respectively. Underweight was most prevalent in South and Southeast Asia (20%), Central Europe (16.7%) and Turkey (15.2%), whereas overweight and obesity were most common in the Middle East (40%) and the US (33%). BMI SDS at PD initiation was associated positively with current eGFR and gastrostomy feeding prior to PD start. Over the course of PD BMI SDS tended to increase on CPD in underweight and normal weight children, whereas it decreased in initially overweight patients. In infancy, mortality risk was amplified by obesity, whereas in older children mortality was markedly increased in association with underweight. Both underweight and overweight are prevalent in pediatric ESKD, with the prevalence varying across the globe. Late dialysis start is associated with underweight, while enteral feeding can lead to obesity. Nutritional abnormalities tend to attenuate with time on dialysis. Mortality risk appears increased with obesity in infants and with underweight in older children