Using continuous overnight pulse oximetry to guide home oxygen therapy in chronic neonatal lung disease.

AIM: The aims of this study are: (i) to survey the knowledge of paediatric clinicians using overnight continuous pulse oximetry data to guide management of infants with chronic neonatal lung disease (CNLD); (ii) to assess the ability of paediatric clinicians to interpret overnight continuous pulse oximetry data; and (iii) to describe the overnight oximetry interpretation practices of paediatric respiratory specialists. METHODS: Paediatric clinicians from three tertiary teaching hospitals completed an anonymous survey regarding overnight continuous pulse oximetry in chronic neonatal lung disease. Using a modified Delphi technique, paediatric respiratory specialists participated in a concordance exercise and discussions to establish consensus interpretations for 25 oximetry studies. Paediatric clinicians were invited to complete the same exercise as a comparison. RESULTS: Self-rated knowledge from 74 surveyed clinicians was proportional to clinical experience. Twenty paediatric clinicians and nine paediatric respiratory specialists completed the oximetry exercise with scores of 64% (κ = 0.25) and 80% (κ = 0.45), respectively. Individual parameters like a mean peripheral arterial haemoglobin saturation (SpO2 ) below 93% and percentage time spent below SpO2 93% correlated poorly with the consensus interpretations. Paediatric respiratory specialists instead relied on visual analysis of SpO2 waveforms, utilising the frequency and depth of desaturations to guide management. CONCLUSION: Interpretation of overnight oximetry data is variable amongst both paediatric clinicians and respiratory specialists. This likely reflects inadequate evidence defining clinically significant intermittent hypoxaemia, whether in terms of desaturation duration, frequency or nadir.

Cholinergic neuronal defect without cell loss in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (IT15) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium-sized spiny neurons. Traditionally, the large cholinergic striatal interneurons are believed to be spared. Recent studies demonstrate that neuronal dysfunction without cell death also plays an important role in early and mid-stages of the disease. Here, we report that cholinergic transmission is affected in a HD transgenic mouse model (R6/1) and in tissues from HD patients. Stereological analysis shows no loss of cholinergic neurons in the striatum or septum in R6/1 mice. In contrast, the levels of mRNA and protein for vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) are decreased in the striatum and cortex, and acetylcholine esterase activity is lowered in the striatum of R6/1 mice already at young ages. Accordingly, VAChT is also reduced in striatal tissue from patients with HD. The decrease of VAChT in the patient samples studied is restricted to the striatum and does not occur in the hippocampus or the spinal cord. The expression and localization of REST/NRSF, a transcriptional regulator for the VAChT and ChAT genes, are not altered in cholinergic neurons. We show that the R6/1 mice exhibit severe deficits in learning and reference memory. Taken together, our data show that the cholinergic system is dysfunctional in R6/1 and HD patients. Consequently, they provide a rationale for testing of pro-cholinergic drugs in this disease.

Dual action of oestrogens on the mouse constitutive androstane receptor.

mCAR (mouse constitutive androstane receptor; NR1I3) controls the expression of cytochrome P450 as well as other enzymes involved in drug and steroid metabolism. The high basal activity of mCAR can be modulated by inhibitory steroids related to androstenol and by activating xenobiotic chemicals such as 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene and chlorpromazine. The ability of oestrogens and some other xenobiotics to activate mCAR is not clear. In the present study, co-transfection assays in HEK-293 cells indicated that oestrogens varied in their efficacy to activate mCAR, depending on variation at the steroid D-ring and position of hydroxy groups. In general, oestrogens were weaker activators of mCAR than 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene and chlorpromazine. Also, the induction of CYP2B10 mRNA by oestrogens was less pronounced in mouse primary hepatocytes. Yeast two-hybrid assays indicated that, unlike androstenol and the established activators, oestrogens attracted both nuclear receptor co-repressors and co-activators to the mCAR ligand-binding domain, thus limiting the extent of mCAR activation. This novel dual action is not limited to oestrogens, but is shared by some xenobiotic CYP2B inducers such as clotrimazole and methoxychlor. These findings offer an alternative explanation for the recently suggested nuclear activation step of mCAR.