Concept: Ibn al-Nafis
A new wave of portable biosensors allows frequent measurement of health-related physiology. We investigated the use of these devices to monitor human physiological changes during various activities and their role in managing health and diagnosing and analyzing disease. By recording over 250,000 daily measurements for up to 43 individuals, we found personalized circadian differences in physiological parameters, replicating previous physiological findings. Interestingly, we found striking changes in particular environments, such as airline flights (decreased peripheral capillary oxygen saturation [SpO2] and increased radiation exposure). These events are associated with physiological macro-phenotypes such as fatigue, providing a strong association between reduced pressure/oxygen and fatigue on high-altitude flights. Importantly, we combined biosensor information with frequent medical measurements and made two important observations: First, wearable devices were useful in identification of early signs of Lyme disease and inflammatory responses; we used this information to develop a personalized, activity-based normalization framework to identify abnormal physiological signals from longitudinal data for facile disease detection. Second, wearables distinguish physiological differences between insulin-sensitive and -resistant individuals. Overall, these results indicate that portable biosensors provide useful information for monitoring personal activities and physiology and are likely to play an important role in managing health and enabling affordable health care access to groups traditionally limited by socioeconomic class or remote geography.
During development, endothelial cells (EC) display tissue-specific attributes that are unique to each vascular bed, as well as generic signaling mechanisms that are broadly applied to create a patent circulatory system. We have previously utilized human embryonic stem cells (hESC) to generate tissue-specific EC sub-types (Rafii et al., 2013) and identify pathways that govern growth and trans-differentiation potential of hESC-derived ECs (James et al., 2010). Here, we elucidate a novel Notch-dependent mechanism that induces endothelial to mesenchymal transition (EndMT) in confluent monolayer cultures of hESC-derived ECs. We demonstrate density-dependent induction of EndMT that can be rescued by the Notch signaling inhibitor DAPT and identify a positive feedback signaling mechanism in hESC-ECs whereby trans-activation of Notch by DLL4 ligand induces elevated expression and surface presentation of DLL4. Increased Notch activation in confluent hESC-EC monolayer cultures induces areas of EndMT containing transitional cells that are marked by increased Jagged1 expression and reduced Notch signal integration. Jagged1 loss of function in monolayer hESC-ECs induces accelerated feedback stimulation of Notch signaling, increased expression of cell-autonomous, cis-inhibitory DLL4, and EndMT. These data elucidate a novel interplay of Notch ligands in modulating pathway activation during both expansion and EndMT of hESC-derived ECs.
Systemic vascular pressure in vertebrates is regulated by a range of factors: one key element of control is peripheral resistance in tissue capillary beds. Many aspects of the relationship between central control of vascular flow and peripheral resistance are unclear. An important example of this is the relationship between hypoxic response in individual tissues, and the effect that response has on systemic cardiovascular adaptation to oxygen deprivation. We show here how hypoxic response via the HIF transcription factors in one large vascular bed, that underlying the skin, influences cardiovascular response to hypoxia in mice. We show that the response of the skin to hypoxia feeds back on a wide range of cardiovascular parameters, including heart rate, arterial pressures, and body temperature. These data represent the first demonstration of a dynamic role for oxygen sensing in a peripheral tissue directly modifying cardiovascular response to the challenge of hypoxia.
High-intensity interval training (HIT), in a variety of forms, is today one of the most effective means of improving cardiorespiratory and metabolic function and, in turn, the physical performance of athletes. HIT involves repeated short-to-long bouts of rather high-intensity exercise interspersed with recovery periods. For team and racquet sport players, the inclusion of sprints and all-out efforts into HIT programmes has also been shown to be an effective practice. It is believed that an optimal stimulus to elicit both maximal cardiovascular and peripheral adaptations is one where athletes spend at least several minutes per session in their ‘red zone,’ which generally means reaching at least 90 % of their maximal oxygen uptake ([Formula: see text]O2max). While use of HIT is not the only approach to improve physiological parameters and performance, there has been a growth in interest by the sport science community for characterizing training protocols that allow athletes to maintain long periods of time above 90 % of [Formula: see text]O2max (T@[Formula: see text]O2max). In addition to T@[Formula: see text]O2max, other physiological variables should also be considered to fully characterize the training stimulus when programming HIT, including cardiovascular work, anaerobic glycolytic energy contribution and acute neuromuscular load and musculoskeletal strain. Prescription for HIT consists of the manipulation of up to nine variables, which include the work interval intensity and duration, relief interval intensity and duration, exercise modality, number of repetitions, number of series, as well as the between-series recovery duration and intensity. The manipulation of any of these variables can affect the acute physiological responses to HIT. This article is Part I of a subsequent II-part review and will discuss the different aspects of HIT programming, from work/relief interval manipulation to the selection of exercise mode, using different examples of training cycles from different sports, with continued reference to T@[Formula: see text]O2max and cardiovascular responses. Additional programming and periodization considerations will also be discussed with respect to other variables such as anaerobic glycolytic system contribution (as inferred from blood lactate accumulation), neuromuscular load and musculoskeletal strain (Part II).
High-intensity exercise is associated with mechanical and/or metabolic stresses that lead to reduced performance capacity of skeletal muscle, soreness and inflammation. Cold-water immersion and other forms of cryotherapy are commonly used following a high-intensity bout of exercise to speed recovery. Cryotherapy in its various forms has been used in this capacity for a number of years; however, the mechanisms underlying its recovery effects post-exercise remain elusive. The fundamental change induced by cold therapy is a reduction in tissue temperature, which subsequently exerts local effects on blood flow, cell swelling and metabolism and neural conductance velocity. Systemically, cold therapy causes core temperature reduction and cardiovascular and endocrine changes. A major hindrance to defining guidelines for best practice for the use of the various forms of cryotherapy is an incongruity between mechanistic studies investigating these physiological changes induced by cold and applied studies investigating the functional effects of cold for recovery from high-intensity exercise. When possible, studies investigating the functional recovery effects of cold therapy for recovery from exercise should concomitantly measure intramuscular temperature and relevant temperature-dependent physiological changes induced by this type of recovery strategy. This review will discuss the acute physiological changes induced by various cryotherapy modalities that may affect recovery in the hours to days (<5 days) that follow high-intensity exercise.
To demonstrate proof-of-principle measurement for physiologic change within an active myofascial trigger point (MTrP) undergoing trigger point release (ischemic compression).
The intrinsic advantages of microcapsules with regard to nanocapsules as intravenous drug carrier systems are still not fully exploited. Especially, in clinical situations where a long-term drug release within the vascular system is desired, if large amounts of drug have to be administered or if capillary leakage occurs, long-circulating microparticles may display a superior alternative to nanoparticles. Here, microcapsules were synthesised and parameters such as in vitro tendency of agglomeration, protein adsorption and in vivo performance were investigated. Biocompatible poly(ethylene glycol) (PEG)-coated poly(DL-lactide-co-glycolide) (PLGA) as wall material, solid and perfluorodecalin (PFD)-filled PEG-PLGA microcapsules (1.5 µm diameter) were manufactured by using a modified solvent evaporation method with either 1% poly(vinyl alcohol) (PVA) or 1.5% cholate as emulsifying agents. Compared to microcapsules manufactured with cholate, the protein adsorption (albumin and IgG) was clearly decreased and agglomeration of capsules was prevented, when PVA was used. The intravenous administration of these microcapsules, both solid and PFD-filled, in rats was successful and exhibited a circulatory half-life of about 1 h. Our data clearly demonstrate that PEG-PLGA microcapsules, manufactured by using PVA, are suitable biocompatible, long-circulating drug carriers, applicable for intravenous administration.
OBJECTIVE: Compromised perfusion of the capillary bed can lead to organ failure and mortality in sepsis. We have reported that intravenous injection of ascorbate inhibits platelet adhesion and plugging in septic capillaries. In the present study we hypothesized that ascorbate reduces aggregation of platelets and their surface expression of P-selectin (a key adhesion molecule) in mice. METHODS: Platelets were isolated from control mice and subjected to agents known to be released into the bloodstream during sepsis (thrombin, ADP or U46619, thromboxane A2 analog). Platelet aggregation was analysed by aggregometry and P-selectin expression by flow cytometry. RESULTS: Platelet-activating agents increased aggregation and P-selectin expression. Ascorbate inhibited these increases. This inhibitory effect was NOS-independent (LNAME had no effect). In contrast to the platelet-activating agents, direct stimuli lipopolysaccharide, TNFα or plasma from septic mice did not increase aggregation/expression, a finding consistent with the literature. The results suggest a complex mechanism of platelet aggregation and P-selectin expression in sepsis, where generation of platelet-activating stimuli is required first, before platelet aggregation and adhesion in capillaries occur. CONCLUSION: The ability of ascorbate to reduce platelet aggregation and P-selectin expression could be an important mechanism by which ascorbate inhibits capillary plugging in sepsis. © 2013 John Wiley & Sons Ltd.
Acetylcholinesterase (AChE) is the physiological target of organophosphorus nerve agent compounds. Currently, the development of a formulation for prophylactic administration of cholinesterases as bioscavengers in established risk situations of exposure to nerve agents is the incentive for many efforts. While cholinesterases bioscavengers were found to be highly effective in conferring protection against nerve agent exposure in animal models, their therapeutic use is complicated by short circulatory residence time. To create a bioscavenger with prolonged plasma half-life, compatible with biotechnological production and purification, a chimeric recombinant molecule of HuAChE coupled to the Fc region of human IgG1 was designed. The novel fusion protein, expressed in cultured cells under optimized conditions, maintains its full enzymatic activity, at levels similar to those of the native AChE enzyme. Thus, this novel fusion product retained its bioscavenging reactivity toward the organophosphate-AChE inhibitors BW284c5, propidium, soman and VX. Furthermore, when administered to mice, AChE-Fc exhibits exceptionally circulatory residence longevity (MRT of 6000 min), superior to any other known cholinesterase-based recombinant bioscavengers. Owing to its optimized pharmacokinetic performance, high reactivity toward nerve agents and ease of production, AChE-Fc emerges as a promising next-generation organophosphorus bioscavenger.
Necropsy (also known as autopsy) is the post-mortem dissection of bodies after euthanasia or death and is a scientific examination conducted to observe and dissect the organs, collect tissues, and determine the extent of grossly evident disease. Research necropsies are conducted to obtain specific samples tailored according to study objectives. Diagnostic necropsy may be undertaken when unexpected illness or death occurs. The systematic collection of samples at necropsy is the critical first step in generating morphologic data from animal models. The morphologic (anatomic and histologic) data generates information on changes in cells, tissues, organs, and organ systems providing context for phenotypes (functional and morphological) to the level of the whole organism. Optimal insight into phenotype or pathophysiologic mechanisms is obtained when morphologic data is coupled with laboratory, medical, and molecular findings. This protocol provides a standard for an efficient routine mouse necropsy with brief comments on advanced or alternative techniques. © 2015 by John Wiley & Sons, Inc.