Liver cell therapy: is this the end of the beginning?

The prevalence of liver diseases is increasing globally. Orthotopic liver transplantation is widely used to treat liver disease upon organ failure. The complexity of this procedure and finite numbers of healthy organ donors have prompted research into alternative therapeutic options to treat liver disease. This includes the transplantation of liver cells to promote regeneration. While successful, the routine supply of good quality human liver cells is limited. Therefore, renewable and scalable sources of these cells are sought. Liver progenitor and pluripotent stem cells offer potential cell sources that could be used clinically. This review discusses recent approaches in liver cell transplantation and requirements to improve the process, with the ultimate goal being efficient organ regeneration. We also discuss the potential off-target effects of cell-based therapies, and the advantages and drawbacks of current pre-clinical animal models used to study organ senescence, repopulation and regeneration

2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field

Transcutaneous carbon dioxide and oxygen tension in newborn infants: reliability of a combined monitor of oxygen tension and carbon dioxide tension.

We evaluated a new combined sensor for monitoring transcutaneous carbon dioxide tension (PtcCO2) and oxygen tension (PtcO2) in 20 critically ill newborn infants. Arterial oxygen tension (PaO2) ranged from 16 to 126 torr and arterial carbon dioxide tension (PaCO2) from 14 to 72 torr. Linear correlation analysis (100 paired values) of PtcO2 versus PaO2 showed an r value of 0.75 with a regression equation of PtcO2 = 8.59 + 0.905 (PaO2), while PtcCO2 versus PaCO2 revealed a correlation coefficient of r = 0.89 with an equation of PtcCO2 = 2.53 + 1.06 (PaCO2). The bias between PaO2 and PtcO2 was -2.8 with a precision of +/- 16.0 torr (range, -87 to +48 torr). The bias between PaCO2 and PtcCO2 was -5.1 with a precision of +/- 7.3 torr (range, -34 to +8 torr). The transcutaneous sensor detected 83% of hypoxia (PaO2 less than 45 torr), 75% of hyperoxia (PaO2 greater than 90 torr), 45% of hypocapnia (PaCO2 less than 35 torr), and 96% of hypercapnia (PaCO2 greater than 45 torr). We conclude that the reliability of the combined transcutaneous PO2 and PCO2 monitor in sick neonates is good for detecting hypercapnia, fair for hypoxia and hyperoxia, but poor for hypocapnia. It is an improvement in that it spares available skin surface and requires less handling, but it appears to be slightly less accurate than the single electrodes

Association of incident obstructive sleep apnoea with outcomes in a large cohort of US veterans

Rationale There is a paucity of large cohort studies examining the association of obstructive sleep apnoea (OSA) with clinical outcomes including all-cause mortality, coronary heart disease (CHD), strokes and chronic kidney disease (CKD). Objectives We hypothesised that a diagnosis of incident OSA is associated with higher risks of these adverse clinical outcomes. Methods, measurements In a nationally representative cohort of over 3 million (n=3 079 514) US veterans (93% male) with baseline estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2, we examined the association between the diagnosis of incident OSA, treated and untreated with CPAP, and: (1) all-cause mortality, (2) incident CHD, (3) incident strokes, (4) incident CKD defined as eGFR<60 mL/min/1.73 m2, and (5) slopes of eGFR. Main results Compared with OSA-negative patients, untreated and treated OSA was associated with 86% higher mortality risk, (adjusted HR and 95% CI 1.86 (1.81 to 1.91) and 35% (1.35 (1.21 to 1.51)), respectively. Similarly, untreated and treated OSA was associated with 3.5 times (3.54 (3.40 to 3.69)) and 3 times (3.06 (2.62 to 3.56)) higher risk of incident CHD; 3.5 times higher risk of incident strokes (3.48 (3.28 to 3.64) and 3.50 (2.92 to 4.19)) for untreated and treated OSA, respectively. The risk of incident CKD was also significantly higher in untreated (2.27 (2.19 to 2.36)) and treated (2.79 (2.48 to 3.13)) patients with OSA. The median (IQR) of the eGFR slope was -0.41 (-2.01 to 0.99), -0.61 (-2.69 to 0.93) and -0.87 (-3.00 to 0.70) mL/min/1.73 m2 in OSA-negative patients, untreated OSA-positive patients and treated OSA-positive patients, respectively. Conclusions In this large and contemporary cohort of more than 3 million US veterans, a diagnosis of incident OSA was associated with higher mortality, incident CHD, stroke and CKD and with faster kidney function decline