Meta-Analysis of Duplex Surveillance Following Lower Limb Endovascular Intervention.

INTRODUCTION: The aim of this systematic review was to identify the evidence in the literature for limb salvage with the introduction of duplex surveillance. METHODS: A systematic review and meta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA) methodology for all studies which compared a group undergoing clinical surveillance with a group undergoing combined clinical and duplex surveillance after endovascular therapy for peripheral arterial disease. MEDLINE, EMBASE, the Cochrane Database for Systematic Reviews, and ClinicalTrials.gov were searched for relevant studies by 2 reviewers. Studies were quality assessed using the ROBINS-I tool. An individual patient data survival analysis and meta-analysis for 1- and 2-year amputation outcomes using a random-effects model were performed. RESULTS: Two low-quality nonrandomized studies met the inclusion criteria. There was a statistically and clinically significant reduction in major amputation in patients undergoing combined clinical and duplex surveillance (log-rank p<0.001). The number needed to treat to prevent 1 amputation at 2 years was 5 patients. At 1 year, the odds ratio (OR) for amputation was 0.22, 95% confidence interval (CI)=0.10-0.48, with no statistical heterogeneity. At 2 years, the numbers of patients were low and the effect on amputation was less certain OR=0.25, 95% CI=0.04-1.58. CONCLUSIONS: Preliminary, low-quality data suggests that there may be a clinically significant reduction in major amputation with the introduction of duplex surveillance. It is recommended that a randomized controlled trial is performed to confirm these findings and identify the anatomical subgroups that benefit the most from surveillance. CLINICAL IMPACT: "Two low-quality studies reveal a significant clinical impact: combined clinical and duplex surveillance markedly reduces major amputations (log-rank p<0.001). At 1-year, the odds ratio for amputation is 0.22 (95% CI=0.10-0.48), emphasizing limb salvage benefits. Despite less certainty at 2-years, a notable absolute risk reduction of 19% is seen, with a number needed to treat of 5. This underscores the urgent need for a randomized controlled trial to validate findings and identify key subgroups. The meta-analysis strongly advocates implementing duplex surveillance for a year post-endovascular interventions, especially in patients fit for reintervention, with important considerations for cost-effectiveness and focused clinical trials."

Ultradian corticosterone secretion is maintained in the absence of circadian cues.

Plasma levels of corticosterone exhibit both circadian and ultradian rhythms. The circadian component of these rhythms is regulated by the suprachiasmatic nucleus (SCN). Our studies investigate the importance of the SCN in regulating ultradian rhythmicity. Two approaches were used to dissociate the hypothalamic-pituitary-adrenal (HPA) axis from normal circadian input in rats: (i) exposure to a constant light (LL) environment and (ii) electrolytic lesioning of the SCN. Blood was sampled using an automated sampling system. As expected, both treatments resulted in a loss of the circadian pattern of corticosterone secretion. Ultradian pulsatile secretion of corticosterone however, was maintained across the 24 h in all animals. Furthermore, the loss of SCN input revealed an underlying relationship between locomotor and HPA activity. In control (LD) rats there was no clear correlation between ultradian locomotor activity and hormone secretion, whereas, in LL rats, episodes of ultradian activity were consistently followed by periods of increased pulsatile hormone secretion. These data clearly demonstrate that the ultradian rhythm of corticosterone secretion is generated through a mechanism independent of the SCN input, supporting recent evidence for a sub-hypothalamic pulse generator.

The significance of glucocorticoid pulsatility.

Glucocorticoids are secreted in discrete pulses resulting in an ultradian rhythm in all species that have been studied. In the rat there is an approximately hourly rhythm of corticosterone secretion, which appears to be regulated by alternating activation and inhibition of the HPA axis. At the level of signal transduction, the response to these pulses of corticosterone is determined by its dynamic interaction with the two transcription factors--the glucocorticoid and mineralocorticoid receptors. While the mineralocorticoid receptor remains activated throughout the ultradian cycle, the glucocorticoid receptor shows a phasic response to each individual pulse of corticosterone. This phasic response is regulated by an intranuclear proteasome-dependent rapid downregulation of the activated glucocorticoid receptor.

Levels of agreement in the measurements of carotid artery ultrasound across a regional vascular network.

INTRODUCTION: Duplex ultrasound is often the sole imaging modality used in diagnosing carotid artery disease. However, the reproducibility and repeatability of scientists in determining the peak systolic velocity and end diastolic velocity of the internal carotid artery and common carotid artery (CCA) is widely debated. STUDY AIM: To investigate intra- and inter-operator variability in diagnostic ultrasound of the carotid arteries across a centralised vascular network using a healthy test subject. To identify potential causes of variability and highlight areas for improvement. METHODS: Fifteen vascular scientists across four hospital Trusts in the Bristol, Bath and Weston vascular network measured the peak systolic velocity and end diastolic velocity of the internal carotid artery and common carotid artery in a subject using a single portable ultrasound machine. A double blind assessment of spectral Doppler images was performed by two vascular clinical scientists for optimal caliper placement, spectral gain and angle correction. Results were compared for intra- and inter-operator variability. RESULTS: Initial quality assessment of the Doppler images revealed that three out of 15 scientists produced suboptimal results. Box plot analysis of the common carotid artery and internal carotid artery for each scientist revealed significant variance (ANOVA p < 0.05). However, a Levene's test revealed no single operator who consistently produced highly variable results (p = 0.569). CONCLUSION: This study highlights the difficulty in obtaining consistent velocity measurements from a subject. Despite the variability in absolute peak systolic velocity and end diastolic velocity, scientists were generally consistent in obtaining an optimal spectral Doppler trace. Some issues with consistency were, however, identified which were subsequently addressed.

Proteasome-dependent down-regulation of activated nuclear hippocampal glucocorticoid receptors determines dynamic responses to corticosterone.

Timing is a critical factor in neuroendocrinology. Despite this, the temporal aspects of glucocorticoid signaling in the regulation of in vivo targets have been largely overlooked. Here, we present data showing that plasma glucocorticoid levels differ greatly from the constant signal predominantly used in cell culture experiments. Using an automated blood sampling system, we found that under basal conditions in nonstressed rats, corticosterone release occurs in discrete pulses of various amplitudes dependent on the circadian cycle. This basal pattern changes to a prolonged elevated nonpulsatile release in response to stressful stimuli. We have been able to recapitulate these different patterns of corticosterone presentation (short pulse vs. prolonged elevation) in adrenalectomized rats, and show that each pattern results in differential activation of hippocampal glucocorticoid and mineralocorticoid receptors. Finally, we provide evidence for a rapid proteasome-dependent clearance of activated glucocorticoid receptors, but not mineralocorticoid receptors, as a novel mechanism to allow dynamic interaction with rapidly changing physiological and environmental conditions.

Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription.

Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. As corticosteroids are released from adrenal glands in a circadian and high-frequency (ultradian) mode, such treatments may not provide an accurate assessment of physiological hormone action. Here we demonstrate that ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation, or gene pulsing, both in cultured cells and in animal models. Equilibrium receptor-occupancy of regulatory elements precisely tracks the ligand pulses. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta, demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery, which promotes GR activation and reactivation in response to the ultradian hormone release, thus coupling promoter activity to the naturally occurring fluctuations in hormone levels. The GR signalling pathway has been optimized for a prompt and timely response to fluctuations in hormone levels, indicating that biologically accurate regulation of gene targets by GR requires an ultradian mode of hormone stimulation.