Short-term oxygen administration restores blunted baroreflex sensitivity in patients with type 1 diabetes.

AIMS/HYPOTHESIS: We hypothesised that the blunted baroreflex sensitivity (BRS) typical of type 1 diabetes is caused by a higher degree of tissue hypoxia in diabetes, and tested whether oxygen increased BRS and ventilation less, equally or more than in healthy control participants (the latter suggesting higher tissue hypoxia). In addition, we also considered the possible interference between oxygen and breathing pattern. METHODS: In 96 participants with type 1 diabetes and 40 age-matched healthy controls, we measured BRS (average of six different standard methods), oxygen saturation, end-tidal carbon dioxide and ventilation changes during spontaneous and controlled breathing at 15 and six breaths/min, in normoxia and during 5 l/min oxygen administration. RESULTS: BRS was blunted and blood pressure higher in diabetic participants during spontaneous breathing (p < 0.05). BRS increased with oxygen during spontaneous breathing in diabetic (p < 0.001) but not in control participants, and with oxygen the difference in BRS was no longer significant. Slow breathing in normoxia restored BRS to a similar extent to giving oxygen. Oxygen increased systolic and diastolic blood pressure, RR interval, heart rate variability, minute ventilation and tidal volume to a greater extent in diabetic patients than in controls, and decreased carbon dioxide similarly to controls. CONCLUSIONS/INTERPRETATION: The increased response to hyperoxia suggests a pre-existing condition of tissue hypoxia that functionally restrains parasympathetic activity in patients with type 1 diabetes. Autonomic abnormalities can be partially and temporarily reversed by functional manoeuvres such as slow breathing or oxygen administration through enhancement of parasympathetic activity and/or correction of tissue hypoxia.

A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia.

Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges as a consequence of the t(15;17) translocation, acts as a transcriptional repressor that blocks neutrophil differentiation at the promyelocyte (PM) stage. In this study, we used publicly available microarray data sets and identified signatures of genes dysregulated in APL by comparison of gene expression profiles of APL cells and normal PMs representing the same stage of differentiation. We next subjected our identified APL signatures of dysregulated genes to a series of computational analyses leading to (i) the finding that APL cells show stem cell properties with respect to gene expression and transcriptional regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost. In a broader perspective, our study provides strong evidence that genomic strategies might be used in a clinical setting to prospectively identify candidate drugs that subsequently are validated in vitro to define the most effective drug combination for individual cancer patients on a rational basis.

Antisense transcription in the mammalian transcriptome.

Antisense transcription (transcription from the opposite strand to a protein-coding or sense strand) has been ascribed roles in gene regulation involving degradation of the corresponding sense transcripts (RNA interference), as well as gene silencing at the chromatin level. Global transcriptome analysis provides evidence that a large proportion of the genome can produce transcripts from both strands, and that antisense transcripts commonly link neighboring "genes" in complex loci into chains of linked transcriptional units. Expression profiling reveals frequent concordant regulation of sense/antisense pairs. We present experimental evidence that perturbation of an antisense RNA can alter the expression of sense messenger RNAs, suggesting that antisense transcription contributes to control of transcriptional outputs in mammals.