The circadian pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus maintains phase coherence in peripheral cells through metabolic, neuronal, and humoral signaling pathways. Here, we ...investigated the role of daily body temperature fluctuations as possible systemic cues in the resetting of peripheral oscillators. Using precise temperature devices in conjunction with real-time monitoring of the bioluminescence produced by circadian luciferase reporter genes, we showed that simulated body temperature cycles of mice and even humans, with daily temperature differences of only 3°C and 1°C, respectively, could gradually synchronize circadian gene expression in cultured fibroblasts. The time required for establishing the new steady-state phase depended on the reporter gene, but after a few days, the expression of each gene oscillated with a precise phase relative to that of the temperature cycles. Smooth temperature oscillations with a very small amplitude could synchronize fibroblast clocks over a wide temperature range, and such temperature rhythms were also capable of entraining gene expression cycles to periods significantly longer or shorter than 24 h. As revealed by genetic loss-of-function experiments, heat-shock factor 1 (HSF1), but not HSF2, was required for the efficient synchronization of fibroblast oscillators to simulated body temperature cycles.
In mammals, including humans, nearly all physiological processes are subject to daily oscillations that are governed by a circadian timing system with a complex hierarchical structure. The central ...pacemaker, residing in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus, is synchronized daily by photic cues transmitted from the retina to SCN neurons via the retinohypothalamic tract. In turn, the SCN must establish phase coherence between self-sustained and cell-autonomous oscillators present in most peripheral cell types. The synchronization signals (Zeitgebers) can be controlled more or less directly by the SCN. In mice and rats, feeding-fasting rhythms, which are driven by the SCN through rest-activity cycles, are the most potent Zeitgebers for the circadian oscillators of peripheral organs. Signaling through the glucocorticoid receptor and the serum response factor also participate in the phase entrainment of peripheral clocks, and these two pathways are controlled by the SCN independently of feeding-fasting rhythms. Body temperature rhythms, governed by the SCN directly and indirectly through rest-activity cycles, are perhaps the most surprising cues for peripheral oscillators. Although the molecular makeup of circadian oscillators is nearly identical in all cells, these oscillators are used for different purposes in the SCN and in peripheral organs.
The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) in the hypothalamus, which is thought to set the phase of slave oscillators in virtually all ...body cells. However, due to the lack of appropriate in vivo recording technologies, it has been difficult to study how the SCN synchronizes oscillators in peripheral tissues. Here we describe the real-time recording of bioluminescence emitted by hepatocytes expressing circadian luciferase reporter genes in freely moving mice. The technology employs a device dubbed RT-Biolumicorder, which consists of a cylindrical cage with reflecting conical walls that channel photons toward a photomultiplier tube. The monitoring of circadian liver gene expression revealed that hepatocyte oscillators of SCN-lesioned mice synchronized more rapidly to feeding cycles than hepatocyte clocks of intact mice. Hence, the SCN uses signaling pathways that counteract those of feeding rhythms when their phase is in conflict with its own phase.
The circadian clock enables the anticipation of daily recurring environmental changes by presetting an organism's physiology and behavior. Driven and synchronized by a central pacemaker in the brain, ...circadian output genes fine-tune a wide variety of physiological parameters in peripheral organs. However, only a subset of circadianly transcribed genes seems to be directly regulated by core clock proteins. Assuming that yet unidentified transcription factors may exist in the circadian transcriptional network, we set out to develop a novel technique, differential display of DNA-binding proteins (DDDP), which we used to screen mouse liver nuclear extracts. In addition to several established circadian transcription factors, we found DNA binding of heat-shock factor 1 (HSF1) to be highly rhythmic. HSF1 drives the expression of heat-shock proteins at the onset of the dark phase, when the animals start to be behaviorally active. Furthermore, Hsf1-deficient mice have a longer free-running period than wild-type littermates, suggesting a combined role for HSF1 in the mammalian timekeeping and cytoprotection systems. Our results also suggest that the new screening method DDDP is not limited to the identification of circadian transcription factors but can be applied to discover novel transcriptional regulators in various biological systems.
There are several methods of treating hard-to-heal (chronic) wounds, each differing in terms of efficiency, selectivity, speed, cost and pain. The objective is to activate a wound to initiate the ...healing cascade. For this pilot study we assessed the feasibility of a new microjet wound therapy technology compared to standard sharp debridement in wound outcomes.
A randomised, controlled, open-label pilot study was conducted in one outpatient wound clinic in Western Switzerland from March 2022 to May 2023.
A total of 13 consecutive patients were randomly assigned to receive either microjet wound therapy (n=5) or standard mechanical debridement with instruments (n=8). As a feasibility study, there was insufficient power to detect significant differences between the groups. However, in the intervention group, our analysis may indicate a modestly faster reduction in wound area. Microjet wound therapy appears to alleviate patient anxiety and offer cost savings due to the potential for reduced time, as well as the number of required treatments. This meant fewer overall consultations.
This study highlights a trend that may indicate that microjet therapy holds value in promoting faster healing of hard-to-heal wounds, and it provides a feasibility basis for a sufficiently powered multicentre trial.
Background and aim The care of chronic wounds (CWs) is complex and their management is multifaceted. To manage the clinical manifestations, the performance of a multi-purpose dressing in the ...management of odour, exudate, pain and healing in patients with CWs attending a wound outpatient clinic was assessed.
Method A case series using descriptive statistics was conducted with 22 consecutive patients with an existing odorous CW attending a wound outpatient clinic. Participants were treated with a multi-purpose dressing.
Results All participants had a complete reduction of their wound odour between the first and the second dressing application (p<0.001). Maceration was reduced or completely eliminated in all exudative wounds (81.8%). All cases decreased in wound size during the study time (mean percentage 45.5%; SD 15.3). Pain was reduced in 55% and unchanged in 45% of wounds.
Conclusion and implication for practice Multi-purpose dressings provide a reduction of wound odour, wound area, as well as maceration area. In addition, the dressing has a more moderate impact on pain reduction.
The mammalian circadian timing system is composed of a central pacemaker in the suprachiasmatic nucleus (SCN) of the brain and subsidiary oscillators in most peripheral cell types. While oscillators ...in SCN neurons are known to function in a self-sustained fashion, peripheral oscillators have been thought to damp rapidly when disconnected from the control exerted by the SCN. Using two reporter systems, we monitored circadian gene expression in NIH3T3 mouse fibroblasts in real time and in individual cells. In conjunction with mathematical modeling and cell co-culture experiments, these data demonstrated that in vitro cultured fibroblasts harbor self-sustained and cell-autonomous circadian clocks similar to those operative in SCN neurons. Circadian gene expression in fibroblasts continues during cell division, and our experiments unveiled unexpected interactions between the circadian clock and the cell division clock. Specifically, the circadian oscillator gates cytokinesis to defined time windows, and mitosis elicits phase shifts in circadian cycles.
A critical role of circadian oscillators in orchestrating insulin secretion and islet gene transcription has been demonstrated recently. However, these studies focused on whole islets and did not ...explore the interplay between α-cell and β-cell clocks. We performed a parallel analysis of the molecular properties of α-cell and β-cell oscillators using a mouse model expressing three reporter genes: one labeling α cells, one specific for β cells, and a third monitoring circadian gene expression. Thus, phase entrainment properties, gene expression, and functional outputs of the α-cell and β-cell clockworks could be assessed in vivo and in vitro at the population and single-cell level. These experiments showed that α-cellular and β-cellular clocks are oscillating with distinct phases in vivo and in vitro
Diurnal transcriptome analysis in separated α and β cells revealed that a high number of genes with key roles in islet physiology, including regulators of glucose sensing and hormone secretion, are differentially expressed in these cell types. Moreover, temporal insulin and glucagon secretion exhibited distinct oscillatory profiles both in vivo and in vitro. Altogether, our data indicate that differential entrainment characteristics of circadian α-cell and β-cell clocks are an important feature in the temporal coordination of endocrine function and gene expression.
Aims
The aim of this study is to: (a) develop an evidence‐based multidisciplinary educational intervention for patients with a venous leg ulcer; and (b) conduct a pilot study to assess the ...feasibility of the intervention in the clinical setting.
Design
A two‐stage study design was used: (a) an multidisciplinary expert committee designed an educational intervention including support materials; and (b) a pilot randomized controlled trial was conducted to assess the feasibility of the intervention in one wound care outpatient clinic in Western Switzerland.
Methods
A multidisciplinary expert committee identified evidence for effective care interventions to improve venous leg ulcer patients’ wound healing and recurrences rates. They subsequently designed the educational intervention and support materials. In this pilot study venous leg ulcer patients were then randomly assigned to receive multidisciplinary education or standard care from March–July 2018. The objective was to evaluate the feasibility of the intervention in the clinical setting. Allocation to groups was achieved to concealed, simple randomization. Participants and study nurses were not blinded, data analyst was blinded.
Results
The intervention, including support material was developed. Twelve of 16 invited venous leg ulcer patients were recruited and randomized (control group N = 6; intervention group N = 6). Participation rate was 75%. The implementation of the intervention was feasible in the clinical setting. The performance of the Venous Leg Ulcer Self Efficacy Tool for measuring adherence to therapy and the Mini Nutritional Assessment and Frequent Food Questionnaire for the assessment of the nutritional intake was satisfactory. However, Fitbit smartwatch for measuring activity was not a suitable device in this study population.
Conclusion
The implementation of the designed multidisciplinary educational program was feasible. The pilot study identified weaknesses in the study protocol, which will be amended for the full‐size clinical trial.
Impact
Findings of the pilot study informed the improvement of the design of the main study.
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