The effect of plasma osmolality and baroreceptor loading status on postexercise heat loss responses.

We examined the separate and combined effects of plasma osmolality and baroreceptor loading status on postexercise heat loss responses. Nine young males completed a 45-min treadmill exercise protocol at 58 ± 2% V̇o2 peak, followed by a 60-min recovery. On separate days, participants received 0.9% NaCl (ISO), 3.0% NaCl (HYP), or no infusion (natural recovery) throughout exercise. In two additional sessions (no infusion), lower-body negative (LBNP) or positive (LBPP) pressure was applied throughout the final 45 min of recovery. Local sweat rate (LSR; ventilated capsule: chest, forearm, upper back, forehead) and skin blood flow (SkBF; laser-Doppler flowmetry: forearm, upper back) were continuously measured. During HYP, upper back LSR was attenuated from end-exercise to 10 min of recovery by ∼0.35 ± 0.10 mg·min(-1)·cm(-2) and during the last 20 min of recovery by ∼0.13 ± 0.03 mg·min(-1)·cm(-2), while chest LSR was lower by 0.18 ± 0.06 mg·min(-1)·cm(-2) at 50 min of recovery compared with natural recovery (all P < 0.05). Forearm and forehead LSRs were not affected by plasma hyperosmolality during HYP (all P > 0.28), which suggests regional differences in the osmotic modulation of postexercise LSR. Furthermore, LBPP application attenuated LSR by ∼0.07-0.28 mg·min(-1)·cm(-2) during the last 30 min of recovery at all sites except the forehead compared with natural recovery (all P < 0.05). Relative to natural recovery, forearm and upper back SkBF were elevated during LBPP, ISO, and HYP by ∼6-10% by the end of recovery (all P < 0.05). We conclude that 1) hyperosmolality attenuates postexercise sweating heterogeneously among skin regions, and 2) baroreceptor loading modulates postexercise SkBF independently of changes in plasma osmolality without regional differences.

Micro-RNA Profiling of Exosomes from Marrow-Derived Mesenchymal Stromal Cells in Patients with Acute Myeloid Leukemia: Implications in Leukemogenesis.

Gene regulatory networks in AML may be influenced by microRNAs (miRs) contained in exosomes derived from bone marrow mesenchymal stromal cells (MSCs). We sequenced miRs from exosomes isolated from marrow-derived MSCs from patients with AML (n = 3) and from healthy controls (n = 3; not age-matched). Known targets of mIRs that were significantly different in AML-derived MSC exosomes compared to controls were identified. Of the five candidate miRs identified by differential packaging in exosomes, only miR-26a-5p and miR-101-3p were significantly increased in AML-derived samples while miR-23b-5p, miR-339-3p and miR-425-5p were significantly decreased. Validation of the predicted change in gene expression of the potential targets was investigated by interrogating gene expression levels from public datasets of marrow-derived CD34-selected cells from patients with AML (n = 69) and healthy donors (n = 40). Two molecules with decreased gene expression in AML (EZH2 and GSK3ß) were predicted by the miR profiling and have been previously implicated in AML while three molecules were increased in AML-derived cells and have not been previously associated with leukemogenesis (KRBA2, RRBP1 and HIST2H 2BE). In summary, profiling miRs in exosomes from AML-derived MSCs allowed us to identify candidate miRs with potential relevance in AML that could yield new insights regarding leukemogenesis or new treatment strategies.

Use of Statins to Augment Progenitor Cell Function in Preclinical and Clinical Studies of Regenerative Therapy: a Systematic Review.

BACKGROUND: Mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) are used in cell-based regenerative therapy. HMG CoA reductase inhibitors (statins) appear promising in blocking apoptosis, prolonging progenitor cell survival and improving their capacity to repair organ function. METHODS: We performed a systematic review of preclinical and clinical studies to clarify whether statins can improve cell-based repair of organ injury. MEDLINE, EMBASE, and PUBMED databases were searched (1947 to June 25, 2013). Controlled clinical and pre-clinical studies were included that evaluated statin therapy used alone or in combination with MSCs or EPCs in patients or animals with organ injury. RESULTS: After screening 771 citations, 100 records underwent full eligibility screening of which 38 studies met eligibility and were included in the review: Studies were grouped into pre-clinical studies that involved statin treatment in combination with cell therapy (18 studies), preclinical studies of statin therapy alone (13 studies) and clinical studies of statin therapy (7 studies). Studies addressed cardiac injury (14 studies), vascular disorders (15 studies), neurologic conditions (8 studies) and bone fractures (1 study). Pre-clinical studies of statins in combination with MSC infusion (15 studies) or EPC therapy (3 studies) were described and despite marked heterogeneity in reporting outcomes of cellular analysis and organ function, all of these cell-based pre-clinical studies reported improved organ recovery with the addition of statin therapy. Moreover, 13 pre-clinical studies involved the administration of a statin drug alone to animals. An increase in EPC number and/or function (no studies of MSCs) was reported in 11 of these studies (85 %) and improved organ function in 12 studies (92 %). We also identified 7 clinical studies and none involved the administration of cells but described an increased number and/or function of EPCs (no studies of MSCs) and improved organ function with statin therapy (1.2-fold to 35-fold improvement over controls) in all 7 studies. CONCLUSION: Our systematic review provides a foundation of encouraging results that support further study of statins in regenerative therapy to augment the number and/or function of MSCs used in cell-based repair and to augment the number and function of EPCs in vivo to repair damaged tissues. Larger studies are needed to ensure safety and confirm clinical benefits.

Osmoreceptors do not exhibit a sex-dependent modulation of forearm skin blood flow and sweating.

Studies show that increases in plasma osmolality result in a delayed onset threshold of thermoeffector responses. However, it remains unclear if there are sex-related differences in the osmotically induced changes in both sweating and cutaneous vascular conductance (CVC). Nine young men and nine young women were passively heated (water-perfused suit) to 1.5°C above baseline esophageal temperature while in an isosmotic (0.9% NaCl saline infusion) (ISO) and hyperosmotic (3% NaCl saline infusion) (HYP) state. Forearm sweat rate (ventilated capsule), skin blood flow (laser-Doppler), esophageal temperature and skin temperature were continuously recorded. Sweat gland output (SGO) on the forearm was calculated from the number of heat activated sweat glands (modified iodine-paper technique) at the end of heating. The onset threshold and thermosensitivity of sweating and CVC were determined using the linear portion of each response plotted against mean body temperature and analyzed using segmented regression analysis. We show that the osmotically induced delay in the onset threshold of sweating and CVC is similar between males and females. Although the thermosensitivity of CVC was similar between sexes (P = 0.601), the thermosensitivity of sweating was consistently lower in females compared to males (P = 0.018). The lower thermosensitivity in sudomotor response of females was accompanied by a lower SGO (P = 0.003), albeit similar sweat gland activation to males (P = 0.644). We conclude that sex-related differences in thermoeffector activity are independent of osmoreceptor activation. Therefore, osmoreceptors do not exhibit sex-related differences in the modulation of CVC and sweating responses during heat stress.

Impairments in local heat loss in type 1 diabetes during exercise in the heat.

UNLABELLED: Studies show that vasomotor and sudomotor activities are compromised in individuals with Type 1 diabetes mellitus (T1DM), which could lead to impaired skin blood flow (SkBF) and sweating during heat stress. However, recent work suggests the impairments may only be evidenced beyond a certain level of heat stress. PURPOSE: We examined T1DM-related differences in heat loss responses of SkBF and sweating during exercise performed at progressive increases in the requirement for heat loss. METHODS: Sixteen adults (10 males and six females) with (T1DM, n = 8) and without T1DM (control, n = 8) matched for age, sex, body surface area, and fitness cycled at fixed rates of metabolic heat production of 200, 250, and 300 W·m in the heat (35°C and 20% relative humidity). Each rate was performed sequentially for 30 min. Local sweat rate (LSR, ventilated capsule), sweat gland activation (modified iodine paper technique), and sweat gland output were measured on the forearm, upper back, and chest, whereas SkBF (laser Doppler) was measured on the forearm and upper back. RESULTS: Despite a similar requirement for heat loss, LSR was lower in T1DM on the forearm and chest relative to that in the control. Reductions were measured in the second (forearm: 0.68 ± 0.14 vs 0.85 ± 0.11 mg·min·cm, P = 0.004; chest: 0.58 ± 0.08 vs 0.82 ± 0.12 mg·min·cm, P = 0.046) and third exercise bouts (forearm: 0.75 ± 0.11 vs 0.98 ± 0.12 mg·min·cm, P = 0.005; chest: 0.66 ± 0.1 vs 1.02 ± 0.16 mg·min·cm, P = 0.032). Differences in forearm LSR were the result of a reduction in sweat gland output, whereas the decrease in chest LSR was due to lower sweat gland activation. SkBF did not differ between groups. CONCLUSIONS: We show that T1DM is associated with impairments in heat dissipation during exercise in the heat, as evidenced by attenuated LSR. However, these differences are only shown beyond a certain requirement for heat loss.

Comparison of heart and respiratory rate variability measures using an intermittent incremental submaximal exercise model.

To better understand the alterations in cardiorespiratory variability during exercise, the present study characterized the patterns of change in heart rate variability (HRV), respiratory rate variability (RRV), and combined cardiorespiratory variability (HRV-RRV) during an intermittent incremental submaximal exercise model. Six males and six females completed a submaximal exercise protocol consisting of an initial baseline resting period followed by three 10-min bouts of exercise at 20%, 40%, and 60% of maximal aerobic capacity (V̇O2max). The R-R interval and interbreath interval variability were measured at baseline rest and throughout the submaximal exercise. A group of 93 HRV, 83 RRV, and 28 HRV-RRV measures of variability were tracked over time through a windowed analysis using a 5-min window size and 30-s window step. A total of 91 HRV measures were able to detect the presence of exercise, whereas only 46 RRV and 3 HRV-RRV measures were able to detect the same stimulus. Moreover, there was a loss of overall HRV and RRV, loss of complexity of HRV and RRV, and loss of parasympathetic modulation of HRV (up to 40% V̇O2max) with exercise. Conflicting changes in scale-invariant structure of HRV and RRV with increases in exercise intensity were also observed. In summary, in this simultaneous evaluation of HRV and RRV, we found more consistent changes across HRV metrics compared with RRV and HRV-RRV.