Erythroid-Specific Expression of β-globin from Sleeping Beauty-Transduced Human Hematopoietic Progenitor Cells

Gene therapy for sickle cell disease will require efficient delivery of a tightly regulated and stably expressed gene product to provide an effective therapy. In this study we utilized the non-viral Sleeping Beauty (SB) transposon system using the SB100X hyperactive transposase to transduce human cord blood CD34+ cells with DsRed and a hybrid IHK–β-globin transgene. IHK transduced cells were successfully differentiated into multiple lineages which all showed transgene integration. The mature erythroid cells had an increased β-globin to γ-globin ratio from 0.66±0.08 to 1.05±0.12 (p = 0.05), indicating expression of β-globin from the integrated SB transgene. IHK–β-globin mRNA was found in non-erythroid cell types, similar to native β-globin mRNA that was also expressed at low levels. Additional studies in the hematopoietic K562 cell line confirmed the ability of cHS4 insulator elements to protect DsRed and IHK–β-globin transgenes from silencing in long-term culture studies. Insulated transgenes had statistically significant improvement in the maintenance of long term expression, while preserving transgene regulation. These results support the use of Sleeping Beauty vectors in carrying an insulated IHK–β-globin transgene for gene therapy of sickle cell disease

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

A simple protein-energy wasting score predicts survival in maintenance hemodialysis patients

International audienceOBJECTIVE: Nutritional status is a powerful predictor of survival in maintenance hemodialysis patients but remains challenging to assess. We defined a new Protein Energy Wasting (PEW) score based on the nomenclature proposed by the International Society of Renal Nutrition and Metabolism in 2008. DESIGN AND METHODS: This score, graded from 0 (worse) to 4 (best) was derived from 4 body nutrition compartments: serum albumin, body mass index, a normalized serum creatinine value, and protein intake as assessed by nPNA. SUBJECTS: We applied this score to 1443 patients from the ARNOS prospective dialysis cohort and provide survival data from 2005 until 2008. MAIN OUTCOME MEASURE: Patients survival at 3.5 year. RESULTS: Survival ranged from 84%-69% according to the protein-energy wasting score. There was a clear-cut reduction in survival (5%-7%; P \textless 0.01) for each unit decrement in the score grade. There was a 99% survival at 1 year for patients with the score of 4. In addition, the 6-month variation of this PEW score also strongly predicted patients' survival (P \textless 0.01). CONCLUSION: A new simple and easy-to-get PEW score predicts survival in maintenance hemodialysis patients. Furthermore, increase of this nutritional score over time also indicates survival improvement, and may help to better identify subgroups of patients with a high mortality rate, in which nutrition support should be enforced

Prognostic Value of Serum Albumin Changes Over Time in Elderly Adults Undergoing Hemodialysis

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Impact of BMI Variations on Survival in Elderly Hemodialysis Patients

International audienceOBJECTIVES: In elderly hemodialysis patients, protein-energy wasting is associated with poor outcome; however, the association between body mass index (BMI) changes over time, and survival has been seldom studied in this particularly frail population. DESIGN AND METHODS: This prospective study recruited 502 hemodialysis patients aged \textgreater/=75 years from the French cohort ARNOS and followed them from 2005 to 2009. BMI changes over time were modeled by individual linear regression models. Survival analyses used frailty Cox models. RESULTS: The population average age was 80.9 years. Forty-one percent of the patients died during follow-up. A 1 kg/m(2) lower baseline BMI was associated with a 4% increase in the risk of death over the study period (hazard ratio [HR] 1.04, 95% confidence interval [1.01-1.08], P = .02). A 5% BMI loss per year was associated with a 52% increase in the risk of death (HR 1.52, 95% confidence interval [1.32-1.75], P \textless .001). In patients who lost weight (\textgreater5% BMI loss per year), the lower was the baseline BMI, the higher was the HR for death. There was a similar trend in the patients with stable weight (5% BMI loss-5% BMI gain per year). In patients who gained weight, the HR was unexpectedly higher than in those with stable weight. CONCLUSIONS: In elderly hemodialysis patients, the impact of the BMI percent change on survival was stronger than that of the baseline BMI. Patients with stable weight had longer survivals than patients who lost or gained weight. Thus, in this population, BMI changes should be regularly assessed. Further studies should assess the safety of weight gain strategies

Kidney cachexia or protein-energy wasting in chronic kidney disease: facts and numbers

BACKGROUND: Weight loss and homeostatic disturbances of both energy and protein balances are characteristics of several illnesses including cancer, heart failure, and chronic kidney disease (CKD). Different definitions have been used to describe this deleterious process. The term protein-energy wasting (PEW) has been proposed for CKD patients by the International Society of Renal Nutrition and Metabolism. METHODS: We searched the publication in Medline from February 2008 to September 2018 using PEW or cachexia in their title. RESULTS: Since its inception, the term PEW has been exceptionally successful, highlighted by 327 original publications referenced in PubMed over 10 years. Using this classification, several studies have confirmed that PEW is among the strongest predictors of mortality in CKD patients [hazard ratio of 3.03; confidence interval of 1.69-5.26 in 1068 haemodialysis patients and 1.40 (1.04-1.89) in 1487 non-dialysed patients across PEW stages 0 to 4]. Based on this classification, prevalence of PEW is 28% to 54% among 16 434 adults undergoing maintenance dialysis. PEW prevalence increases when renal function declines, that is, from \textless2% in CKD stages 1-2 to 11-54% in CKD stages 3-5. A more general definition of cachexia for all chronic diseases proposed by the Society on Sarcopenia, Cachexia and Wasting Disorders was also published concurrently. In the CKD area, we found 180 publications using 'cachexia' underlining that some confusion or overlap may exist. The definitions of PEW and cachexia are somewhat similar, and the main difference is that a loss of body weight \textgreater5% is a mandatory criterion for cachexia but supportive for PEW. CONCLUSIONS: The recent understanding of cachexia physiopathology during CKD progression suggests that PEW and cachexia are closely related and that PEW corresponds the initial state of a continuous process that leads to cachexia, implicating the same metabolic pathways as in other chronic diseases. Despite the success of the definition of PEW, using a more uniform term such as 'kidney disease cachexia' could be more helpful to design future research through collaborative groups of researchers with focus on cachexia