A 1-year randomized controlled study of everolimus versus mycophenolate mofetil with reduced-dose cyclosporine in maintenance heart transplant recipients.

BACKGROUND: The aim of this study was to demonstrate noninferiority of everolimus with reduced cyclosporine (CsA) vs mycophenolate mofetil (MMF) with reduced CsA in improving renal function. METHODS: In this 1-year randomized, open-label, noninferiority study in maintenance heart transplant recipients with impaired renal function 70 patients received everolimus (n = 36) or MMF (n = 34) in combination with reduced CsA. The planned sample size was not reached as the study was prematurely discontinued due to slow recruitment. RESULTS: Noninferiority of the everolimus regimen could not be shown: In the total population MMF seemed to be favorable on renal function assessed by serum creatinine and filtration rates, but not in the subset of patients who reached the intended reduced CsA level. Incidence rates of rejection episodes were significantly higher under MMF at month 6 (P = .0332). CONCLUSIONS: Overall, the results of this trial using reduced CsA in combination with either everolimus or MMF show that there is evidence to reduce the CsA level when everolimus is given concomitantly and that the benefit of MMF with reduced CsA levels is limited due to insufficient immunosuppression.

Neural stem cells: on where they hide, in which disguise, and how we may lure them out.

In contrast to the haematopoietic system in which each cell type is subject to constant turnover, thus endowing this system with the permanent ability to reconstitute itself, the nervous system has long been known as an organ devoid of spontaneous cellular reconstitution. Yet the discovery that certain regions of the mammalian central nervous system do sustain neurogenesis throughout life, together with the fact that cells can be isolated from the adult brain that generate neurons in vitro, has led to the idea that the nervous tissue harbours neural stem cells. The term "neural stem cell" has now become associated with enormous expectations for curing diseases of the nervous system. Yet many of the biological fundamentals of neural stem cells need to be revealed before these expectations can be properly judged or even fulfilled. This begins with the question of whether the neural stem cell corresponds to a real entity or rather represents an in vitro dedifferentiation phenomenon. In this chapter we attempt to give an overview of our current knowledge of the biology of the presumable adult neural stem cell. This is followed by a comparative assessment of the possibilities of using adult neural stem cells and embryonic stem cells for therapeutic approaches in the context of neurodegenerative diseases. Finally, we will look at the "evil side" of stemness by discussing the evidence that brain cancers may originate from cells with stem cell-like properties.

Regionalization and fate specification in neurospheres: the role of Olig2 and Pax6.

Neurosphere cultures are widely used to propagate multipotent CNS precursors, but their differentiation into neurons or oligodendrocytes is rather poor. To elucidate fate determination in this system, we examined the expression and function of candidate transcription factors in neurospheres derived from different CNS regions during development and adulthood. We observed prominent down-regulation of most transcription factors present in telencephalic precursors upon growth factor exposure in neurosphere cultures while Olig1 and Olig2 expression was strongly up-regulated. Interference with Olig2 in neurospheres revealed its role in self-renewal during expansion and for the generation of neurons and oligodendrocytes during differentiation. We further show that neurogenesis becomes fully Pax6-dependent in the neurosphere culture system, independent of the region of origin, and that Pax6 overexpression is sufficient to direct almost all neurosphere-derived cells towards neurogenesis. Thus, a pathway combining transcription factors of dorsal and ventral regions is activated in the neurosphere culture model.

Comparison of the effects of sleep deprivation, alcohol and obstructive sleep apnoea (OSA) on simulated steering performance.

Patients with obstructive sleep apnoea (OSA) are reported to have an increased risk of road traffic accidents. This study examines the nature of the impairment during simulated steering in patients with OSA, compared to normal subjects following either sleep deprivation or alcohol ingestion. Twenty-six patients with OSA and 12 normal subjects, either deprived of one night's sleep or following alcohol ingestion [mean (SD) alcohol blood level 71.6 mg dl(-1) (19.6)], performed a simulated steering task for a total of 90 min. Performance was measured using the tendency to wander (SD), deterioration across the task, number of 'off-road' events and the reaction time to peripheral events. Control data for OSA, sleep deprivation and alcohol were obtained following treatment with nasal continuous positive airway pressure (nCPAP), after a normal night of sleep, and following no alcohol, respectively. Patients with untreated OSA, and sleep-deprived or alcohol-intoxicated normal subjects performed significantly less well, compared to their respective controls (P<0.01 for all tests), with untreated OSA lying between that of alcohol intoxication and sleep deprivation. Alcohol impaired steering error equally throughout the whole drive, whilst sleep deprivation caused progressive deterioration through the drive, but not initially. Untreated OSA was more like sleep deprivation than alcohol, although there was a wide spread of data. This suggests that the driving impairment in patients with OSA is more compatible with sleep deprivation or fragmentation as the cause, rather than abnormal cognitive or motor skills.

Steering simulation performance in patients with obstructive sleep apnoea and matched control subjects.

Patients with obstructive pulmonary disease (OSA) have an increased rate of driving accidents, perhaps due to poor vigilance or impaired cognitive skills that influence their driving ability. The authors have assessed whether patients with OSA perform differently to control subjects on a steering simulator which allows the separate assessment of the two visual tasks required for steering a car, immediate positioning on road with reference to the road edges, and assessment of the curve of the oncoming road which allows faster driving. Twelve patients with OSA and 12 control subjects, matched for age, sex and driving experience, performed three 30-min drives with either all the oncoming road visible, only the near part of the road visible, or only the distant part of the road visible. Steering was assessed by measuring the SD around the theoretical perfect path (steering error) and the number of times the driver went "off road". Subjects identified the appearance of target numbers at the four corners of the screen as quickly as possible, thus making the test a divided attention task. Patients with OSA performed significantly less well on the three different road fields as measured by steering error (p<0.001), time to detect the target number (p<0.03), and off road events (p<0.03). The patients appeared to be particularly impaired on the two drives when only part of the road ahead was available to guide steering. This steering simulator, with its more realistic view of the road ahead, identifies impaired performance in patients with obstructive sleep apnoea. In addition it suggests that patients with obstructive sleep apnoea may be more disadvantaged compared to normal subjects when the view of the road ahead is limited (such as in fog).