bluuebunny/crossref_metadata_2025 huggingface dataset:
FPR2/ALX is a therapeutic target for the resolution of thrombo‐inflammation
Authors: Gavins Felicity Nicola Emma
Published: June 2021

Patients with Sickle Cell Disease (SCD) are more susceptible to thrombotic events, in which leukocytes, platelets and erythrocytes have all been implicated in the pathogenesis. However, the underlying mechanisms promoting a pro‐coagulant and pro‐thrombotic phenotype in SCD (especially in the brain) are still unknown. The causes for the SCD phenotype may relate to a well‐established link between thrombosis and inflammation i.e. inflammation can beget local thrombosis, and thrombosis can amplify inflammation. Accumulating data linking inflammation and thrombosis supports the hypothesis that anti‐inflammatory therapies may limit thrombosis and that anti‐thrombotic therapies may reduce vascular inflammation. One such target is the anti‐inflammatory and pro‐resolving endogenous mediator Annexin A1 (AnxA1) and its interaction with the Formyl Peptide Receptor (FPR) family. In humans three FPRs (FPR1, FPR2, and FPR3) regulate innate inflammatory responses. Their function has been most extensively investigated in the context of leukocyte recruitment and activation, where FPRs promote cell motility (chemotaxis) and microbicidal respiratory burst. Here we have tested the effect of targeting the AnxA1‐Fpr2/ALX pathway as a therapeutic strategy for SCD with a special focus on thrombo‐inflammation. In conclusion, our novel results demonstrate the importance of the AnxaA1/FPR2 system in effecting the resolution of SCD associated cerebral thrombo‐inflammation and may therefore provide a novel anti‐thrombo‐inflammatory therapeutic target.

Support or Funding Information

NIH/NHLBI (HL125572‐01A1)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Are lymphatic contractions initiated and/or coordinated by ICC‐like cells in the lymphatic vessel wall?
Authors: Davis Michael J. , Castorena‐Gonzale Jorge , Li Min , Gui Peichun , Domeier Timothy L. , Zawieja Scott
Published: June 2021

Lymph propulsion relies critically on the spontaneous contractions of collecting lymphatic vessels, which are surrounded by smooth muscle cells (LMCs). Twitch‐like contractions are generated by an intrinsic ionic pacemaker that is assumed to originate in the LMC; however there are reasons to consider that pacemaking might be initiated and/or coordinated by a network of specialized cells. Precedents include interstitial cells of Cajal (ICC) in the GI tract and ICC‐like cells (ICC‐LC) in other smooth muscle‐invested organs, which are known to initiate pacemaking. ICCs express the receptor tyrosine kinase c‐Kit, and c‐Kit(+) cells have been identified in the lymphatic wall, although their function is unknown. We used existing and newly‐generated mouse models to test the hypothesis that ICC‐LCs control lymphatic pacemaking. In addition to c‐Kit, we considered PDGFRa, a receptor expressed by some ICC‐LCs. Our strategy was to use Cre lines specific for four cell types (c‐Kit‐ or PDGFRa‐expressing cells, pericytes, LMCs) and: 1) cross them with reporter mice to identify the recombined cell populations in the lymphatic wall; 2) use them to express the endogenous Ca2+ indicator GCaMP6f in the respective cell types and correlate Ca2+ signals with the lymphatic contraction cycle; 3) express the photo‐activated cation channel ChR2 in the respective cell types and test the consequences of triggering ChR2 activation. Rounded c‐Kit(+) cells were associated with the outer adventitia and co‐stained for mast cell markers. GCaMP expression revealed Ca2+ signals that did not oscillate with the contraction cycle, but responded robustly to a mast cell degranulator. PDGFRa cells formed a partial sheath of oak‐leaf shaped cells outside of the medial layer—characteristics of adventitial fibroblasts; they did not exhibit spontaneous Ca2+ oscillations, but occasional cells responded to ACh. A reputed pericyte‐specific Cre, Ng2CreERT2, produced recombination in about 50% of LMCs, some neurons, some spindle‐shaped cells in the wall, and a subpopulation of PDGFRa(+) cells. Expression of GCaMP under this Cre revealed Ca2+ oscillations in LMCs and spindle‐shaped cells at the same frequency as spontaneous contractions. Expression of GCaMP only in LMCs using SmmhcCreERT2 revealed synchronized Ca2+ signals in synchrony with and preceding spontaneous lymphatic contractions. Expression of ChR2 using the same Cre, followed by photo‐stimulation of single LMCs, triggered contractions that were consistently entrained over the entire vessel. Although we cannot exclude a role for pericytes due to the promiscuous recombination by Ng2CreERT2, our results suggest that LMCs are the only cell type responsible for lymphatic pacemaking in the mouse.

Support or Funding Information

NIH HL‐122578

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Decline in conduit artery function across the healthy human adult lifespan: influence of successful aging
Authors: Shields Katherine , Broxterman Ryan , Kwon Oh Sung , Park Sounghun , Jarrett Catherine , Smith Ken , Wray D Walter , Richardson Russell
Published: June 2021

While it is well‐established that vascular function decreases with age, potential differences in this decay between typical aging (≈ 70 yrs, many unlikely to become centenarians) and highly successful aging (>90 yrs, with preserved physical and cognitive health) remain unknown. Therefore, this study measured brachial artery flow‐mediated dilation (FMD) in 42 young (YA, 25 ± 7 yrs), 45 old (OA, 71 ± 7 yrs), and 16 oldest old (OOA, 96 ± 4 yrs) healthy adults. FMD was significantly lower in OA (5.4 ± 2.7 %) and OOA (4.5 ± 2.3%) than YA (7.7 ± 4.0 %), with no difference between OA and OOA, despite the ≈25 yr age difference. Across all age groups, a significant relationship between age and FMD was detected with a two‐segment linear model, identifying a significant change in the rate of FMD decline with age at 97 yrs (slope 1 = −0.040, slope 2 = −0.528 %/yr; r = 0.38). Utilizing this break point of 97 yrs, the OOA were further refined into OOA (93 ± 2 yrs, n = 10) and centenarians (CA, 99 ± 1 yrs, n = 6), with FMD significantly lower in CA (3.2 ± 1.4 %) than OOA (5.3 ± 2.4 %). These findings reveal a steady decline in conduit artery function across the human adult lifespan. However, of importance, successful aging serves to diminish the rate of decline in conduit artery function across the majority of the lifespan until >97 yrs of age, when this decline is greatly exacerbated.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Angiogenesis is Not Impaired in Cultured Rat Mesenteric Microvascular Networks
Authors: Hodges Nicholas A. , Murfee Walter
Published: June 2021

Angiogenesis is commonly assumed to be impaired in aged tissues. However, this preconception is challenged by evidence of increased angiogenesis during cancer and other pathological scenarios prevalent in aged models. In addition, the cumulative evidence from the literature remains non‐definitive. Hence, fundamental questions remain regarding the mechanisms by which angiogenesis is affected in aged tissues. The objective of this study was to compare the angiogenic responses in aged versus adult rat mesenteric cultured tissues. Adult (9 month) and Aged (24 month) male Wistar rat mesenteric tissue were harvested and cultured for 3 days per media group: 1) minimum essential media (MEM), 2) MEM with 10% fetal bovine serum (FBS), and 3) MEM with basic fibroblast growth factor (bFGF) (minimum of n = 8 tissues from 4 rats per group). After culture tissue microvessels were identified by PECAM labeling. FBS and bFGF stimulation induced an increase in the number of capillary sprouts per vascular area in the Adult (MEM = 2.14 ± 0.374 sprouts/mm2; FBS = 4.44 ± 0.595 sprouts/mm2; bFGF = 4.80 ± 0.447 sprouts/mm2; p < 0.05) and Aged (MEM = 3.12 ± 0.520 sprouts/mm2; FBS = 5.48 ± 0.609 sprouts/mm2; bFGF 5.98 ± 0.563 sprouts/mm2; p < 0.05) tissues compared to age group matched MEM only tissues. Capillary sprouting was not significantly different between the FBS stimulated aged and adult tissues (p = 0.216). Similarly, sprouting in the bFGF stimulated aged and adult tissues were not significantly different (p = 0.125). These results suggest that angiogenesis in aged tissues can be stimulated comparable to adult levels and that angiogenesis is not necessarily impaired.

Support or Funding Information

Funded by NIH R01AG049821.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Echocardiographic assessment of G‐protein coupled estrogen receptor (GPER) activation on coronary blood flow and cardiac function in mice
Authors: Yu Xuan , Guo Shaodong , Han Guichun
Published: June 2021

G protein coupled estrogen receptor (GPER) has been reported to have cardiovascular protective effects in animal models and human tissues. Our previous work also showed that activation of GPER induced porcine coronary artery relaxation. In this study, we used non‐invasive high resolution echocardiography to evaluate the in vivo effects of GPER on coronary blood flow (CBF) of left coronary artery and cardiac functions in C57BL/6 male mice. Animals were anesthetized with 3% isoflurane in 100% oxygen and anesthesia was maintained with 1% isoflurane. In this echocardiographic studies, pulse wave Doppler imaging and M mode Doppler imaging were performed to measure CBF, left anterior descending coronary artery diameter and cardiac function parameters. CBF was calculated by measuring coronary artery diameter and velocity time integral in pulse wave Doppler. Cardiac function parameters including heart rate (HR), stroke volume (SV), cardiac output (CO), ejection fraction (EF), end diastolic volume (EDV) and end systolic volume (ESV) were calculated by tracing the left ventricle long axis in M mode Doppler. Intraperitoneal injection of G‐1 (3 mg/kg) significantly increased CBF from 1.68 ± 0.1 mL/min to 2.37 ± 0.2 mL/min. G‐1 injection on the cardiac function parameters showed biphasic responses. Within the first two minutes of G‐1 injection, HR (from 423 ± 15 bpm to 563 ± 12 bpm) and EF (55% % to 77 %) were increased; while EDV (from 34 ± 3.5 μl to 18 ± 1.2 μl), ESV (from 15 ± 1.9 μl to 4 ± 1.1 μl) and SV (from 19 ± 1.8 μl to 14 ± 1.5 μl) were decreased. After two minutes of G‐1 injection, cardiac responses reversed. HR (from 563 ± 12 bpm to 399 ± 8 bpm) and EF (from 77 % to 56 %) were decreased; while EDV (from 18 ± 1.2 μl to 38 ± 2.2 μl), ESV (from 4 ± 1.1 μl to 10 ± 1.2 μl) and SV (from 14 ± 1.5 μl to 20 ± 2.6 μl) were increased. These findings demonstrated that activation of GPER showed biphasic responses that initial activation of GPER exerted a positive chronotropic effects, and then the chronotropic effect became negative, with a positive inotropic effects on both systolic and diastolic functions in mice. In conclusion, we revealed that GPER activation increases coronary blood flow and induces biphasic responses on cardiac functions.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Kvβ2 Subunit Regulates Cardiac Levels of SLC41a3 a Sodium‐Magnesium Transporter.
Authors: Tur Jared , Chapalamadugu Kalyan C. , Tipparaju Srinivas M.
Published: June 2021

Background

Clinical evidence has demonstrated that administration of magnesium can provide cardioprotective benefits during acute MI as well as suppression of cardiac arrhythmias. Further, meta‐analysis data has uncovered an inverse relation to circulatory levels of magnesium and risk for cardiac injury. Magnesium influx/efflux behaviors have been recorded in isolated cardiomyocytes; further the addition of magnesium during and prior to cardiac injury such as ischemia reperfusion was demonstrated to significantly reduce ischemic injury. While clinical evidence highlights magnesium's cardiovascular benefits, identification and subsequent regulation remain largely unknown of the magnesium channels responsible. Recent research has identified one of the key magnesium/sodium exchange channels as SLC41a1‐3 family. Murine cardiac expression levels demonstrate significant mRNA levels of SLC41a3 in particular.

Methods and Results

A recent microarray study performed in hearts from Kvβ2 knockout mice demonstrated a significant decrease in SLC41a3 mRNA expression compared with control. Protein expression validated the decrease in expression levels of SLC41a3. These findings may indicate the Kvβ2 subunit acts as a novel regulator to SLC41a3, previous research identified Kvβ2 having protein‐protein interactions with SLC39a1 another member of the solute carrier family (SLC). Cardiac function measured by monophasic action potential (AP) recordings presented with a significant reduction in AP duration values in control hearts perfused with magnesium (MgSO4) while Kvβ2 KO hearts demonstrate little to no alterations in AP duration post magnesium exposure. Further functionality will be assessed in isolated cardiomyocytes testing the influx and efflux of magnesium to understand Kvβ2's role in channel activity.

Hypothesis

Based upon our preliminary data we hypothesis that the Kvβ2 subunit plays significant roles in SLC41a3 expression as well as function within the heart.

Conclusion

These novel roles of Kvβ2 may shed new light on the molecular understanding of how administration of magnesium can benefit both cardiac injury and arrhythmias.

Support or Funding Information

Research Supported: This Research work was funded by National Institutes of Health (NIH) Grant R01‐HL‐102171 (S. M. Tipparaju).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Study of Vascular and Endothelial Function in Type II Diabetes with Newly Diagnosed
Authors: Srivastava Prachi , Chandran Dinu S. , Jaryal Ashok Kumar S. , Jyotsna Viveka P. , Deepak Kishore Kumar S.
Published: June 2021

Background

High risk of cardiovascular and cerebrovascular diseases are associated with diabetes and this risk is augmented with coexistent hypertension. Increased arterial stiffness and endothelial dysfunction are independent risk factors and predictor of adverse cardiovascular outcome. Angiotensin converting enzyme inhibitors (ACE inhibitors) have been prescribed for the hypertension treatment and are known to reduce cardiovascular mortality and morbidity.

Objective

To study the effect of ACE inhibitor on vascular and endothelial function in type 2 diabetes with newly diagnosed hypertension.

Methods

Sixty‐five diabetic patients with newly diagnosed hypertension with the mean age of 48 ± 6.5 years were enrolled in the study. The mean duration of diabetes and BMI was 6.01 ± 5.03 years and 28.18 ± 4.23 kg/m2, respectively. Arterial stiffness was assessed using Augmentation index (AIx@75) and Pulse Wave Velocity (PWV) [carotid‐radial (cr), and carotid‐femoral (cf)] by applanation tonometry using SphygmocorR. Endothelial function was assessed by flow mediated dilatation (FMD) using B‐mode vascular ultrasound. All the recordings were done at baseline, after 1 week and after 3 Months of ACE inhibition.

Results

Both Peripheral and central blood pressures (systolic, diastolic and pulse pressure) were reduced significantly after ACE inhibition (p <0.0001). There was significant reduction in AIx@75 after 1 week of ACE inhibitor treatment as compared to baseline (25.86 ± 10.01 vs 20.85 ± 10.06 %, p<0.0001). cr and cf PWV were significantly decreased from baseline to after 1 week of treatment [9.15 ± 1.64 Vs 8.32 ± 1.52 m/s (p<0.0001) and 11.3 ± 2.84 Vs 10.38 ± 3.08 m/s (p<0.05) respectively] and from baseline to after 3 months of ACE inhibitor treatment [9.15 ± 1.64 Vs 8.16 ± 1.53 m/s, (p<0.0001) and 11.3 ± 2.84 Vs 9.78 ± 2.98 m/s (p=0.0002), respectively]. Similarly, FMD was significantly increased after 1 week and 3 months of ACE inhibition as compared to baseline [6.1 ± 3.2 Vs 8 ± 3.11%, and 6.29 ± 3.27 Vs 9.99 ± 3.17% (p<0.0001)]. There was further improvement in FMD from 1 week to 3 months of ACE inhibition [8 ± 3.11 Vs 9.99 ± 3.17% (p<0.0001)].

Conclusion

Both arterial stiffness, including central pressures and endothelial function improved within 1 week of ACE inhibition. Endothelial function further improved after 3 months of ACE inhibition in type II diabetic patients with newly diagnosed hypertension. This could be because of ACE inhibitor mitigates the effect of angiotensin II on endothelium and vascular smooth muscles.

Support or Funding Information

All India Institute of Medical Sciences, New Delhi, India.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Endothelin‐Related Gene Polymorphisms on Age‐Related Arterial Stiffening: A 10‐Year Longitudinal Study
Authors: Sugawara Jun , Tomoto Tsubasa , Noda Naohiro , Matsukura Satoko , Tsukagoshi Kazuya , Maeda Seiji
Published: June 2021

Increased arterial stiffness has emerged as a strong predictor of future cardiovascular events and all‐cause mortality. The aim of this study was to elucidate influences of endothelin (ET)‐related genetic polymorphisms on age‐related arterial stiffening through a 10‐year longitudinal study. A decadal change in brachial‐ankle pulse wave velocity (baPWV), an index of arterial stiffness, was evaluated retrospectively among 92 volunteers (63 ± 14yrs, 51 men). The targeted single‐nucleotide polymorphisms were ET‐A receptor SNP rs5333 (ET‐A) and ET‐B receptor SNP rs5351 (ET‐B). Subjects with either ET‐A TC or CC genotypes exhibited significantly greater increases in baPWV (+15.3 ± 11.7 and +16.6 ± 15.7%/dec, respectively) than ET‐A TT genotype holders (+9.2 ± 9.0%/dec), while subjects with the ET‐B GG genotype showed a significantly greater increase in baPWV (+17.7 ± 14.1%/dec) than other ET‐B genotype holders (AA: +9.5 ± 10.0%/dec; AG: +11.2 ± 9.6%/dec). The combination of these ET‐related genetic risks was associated with a 2.4 times greater decadal increase in baPWV compared with no genetic risk (+8.1 ± 8.4 vs. 19.5 ± 16.0%/dec). These differences remained significant after adjusting for confounding factors, including baseline baPWV. Our current longitudinal study found that ET‐related gene polymorphisms contribute to diverse age‐related changes in arterial stiffness.

Support or Funding Information

This study was supported by special coordination funds of the Japanese Ministry of Education, Culture, Sports, Science, and Technology (KAKENHI JP25702045 and JP26670116, to JS).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Changes in CRP and TNF‐a after Runs at Different Intensities in Smokers Following Two Hour Cessation
Authors: Dao Vivian , Nickerson Brett Stephen , Park Kyung‐Shin
Published: June 2021

The purpose of this study was to examine changes in C‐reactive protein (CRP) and TNF‐α from blood samples before and after exercise at different intensities in smokers (SM) and non‐smokers (NS) after a 2 hour smoking cessation. Our laboratory previously reported large differences in CRP and TNF‐α at Pre between SM and NS. Furthermore, there were more profound disturbances in SM following three runs at different intensities approximately 30 minutes after smoking cessation before each run (EB 2015, Boston). The previous findings indicated that SM responded more sensitively to relatively equal intensity of exercise, which suggested that high intensity aerobic exercise should be avoided in SM in the beginning phase of exercise training.

Methods

A total of eighteen physically inactive subjects (eight SM and ten NS) aged 20 to 27 were recruited. Smokers were accepted if their level of exhaled carbon monoxide (eCO) was greater than 16 ppm. Each subject completed three treadmill runs at different intensities in a random order (55%, 65%, and 75% of VO2max). Running distance for all three runs was equivalent to 35‐min run at 65% VO2max. Smokers had a 2 hour smoking cessation before each run. Blood samples were collected before (Pre), immediately post (IP), and an hour following each run (1h Post).

Results

Pre‐exercise CRP levels were higher in SM as compared to the NS. (2.291±.27 mg/L Vs. 2.082±.25, mean±SE, P = 0.042). As compared to Pre, no significant changes were found in CRP at IP and 1h Post following runs at three different intensities in both SM and NS. TNF‐α showed higher pre‐exercise levels in SM compared to NS (32.565±4.28 mg/L vs. 27.732±3.34, P=0.027). TNF‐α was significantly increased at IP following 75% of VO2max run in both SM and NS (SM: 32.657±4.36 → 38.797±6.33, P=0.013; NS: 27.694±3.26 → 33.466±4.35, P=0.019), but not significantly changed at IP following 55% and 65% of VO2max runs.

Conclusion

Findings of the current study revealed a dose‐response relationship for CRP and TNF‐a in SM and NS. The patterns of changes corresponded with previous presentation (EB, 2015) with a 30 minute smoking cessation; however, the differences between SM and NS were much smaller in this study suggesting that smokers may need to avoid cigarette smoking before exercise to minimize immune disturbance caused by combined stress from exercise and chronic smoking.

Support or Funding Information

This study was supported by Texas A&M International University Research Grant.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of acute loaded wheel running on BDNF expression in the rat hippocampus
Authors: Lee Min Chul , Cha Joo Eu , Yoo Tae Woo
Published: June 2021

Voluntary wheel running has beneficial effects on hippocampal cognitive functions if done abundantly. However it is still uncertain whether resistance wheel running would be the same. Voluntary resistance wheel running with a load is a suitable model, since it allows increased work levels and resultant fast‐twitch muscular adaptation. Here we examined whether acute voluntary wheel running with an additional load on BDNF expression in the rat hippocampus. We used 10‐week‐old male Wistar rats and divided randomly into sedentary (Sed), voluntary exercised with No‐load 3) voluntary exercised with additional Load group for acute 1 week. The load for the Load group was increased to reach ~30% of body weight during training. The expression of BDNF genes was quantified by realtime PCR. The relative soleus weights were greater in the No‐Load group. Further, loaded wheel running up‐regulated gene expressions in BDNFmRNA level compared with the Control group. Interestingly, BDNFmRNA levels showed a positive correlation with work load levels(r=0.75), supporting the idea that work levels availability contributes to the BDNF benefits of loaded wheel running revealed in this study. Overall, this novel approach assessing the first time that voluntary loaded wheel running which causes a muscular adaptation, resulted in enhanced gene expression of BDNF, suggesting a possible role of high‐intense short term exercise on hippocampal BDNF actions.

Support or Funding Information

This work supported by the National Research Foundation of Korea Grant funded by the Korean Government (NRF‐201700310001).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cessation of Nightly Voluntary Wheel Running Activity Following Exposure to a Mouse Model of Posttraumatic Stress
Authors: Stroh Courtney M. , Kinney Erin M. , Coste Sarah C.
Published: June 2021

Regular physical activity (PA) is well known to positively impact physical and mental health outcomes. In our work to examine cardiovascular benefits of PA in a mouse model of post‐traumatic stress, we stumbled upon the reciprocal relationship between PA and stress exposure, wherein stress significantly reduced healthy levels of routine PA. The aim of the present studies was to define the parameters of our paradigm as first steps for its future use in examining mechanisms that underlie stress‐induced declines in PA. Five week old, C67BL/6J male mice were divided into four groups (n=8/group); sedentary/control, voluntary running/control, sedentary/stress and voluntary running/stress. Voluntary running groups were given 24 hr unlimited access to a running wheel in the home cage for 9 weeks. Mice ran a nightly average of 4.75 ± 1 km. During the 9th week, stress groups were exposed to a 5 day resident‐intruder social stress that models human post traumatic stress outcomes. Running behavior essentially ceased following stress. Running distance dropped to 0.31 km following the 1st stress day. Some habituation to stress occurred, as running distance increased to 1.12 km by the 5th day of stress but remained significantly lower then pre‐stress running distances and distances recorded in non‐stressed mice. A separate study examined a single exposure to resident‐intruder social stress and found plasma corticosterone significantly increased (16.66 ± 4 ng/ml basal to 496 ± 155 ng/ml immediately post stress) while nightly running dropped significantly from 5.58 ± 1.7 km to 1.22 ± 1.1 km, and returned to near normal levels (4.35 ±1.7 km) by the 3rd night post stress. Food intake was moderately increased in the first 2 nights post stress, but also returned to normal by the 3rd night. These studies show the sensitivity of habitual running behavior to stress exposure and suggest the utility of this mouse model in exploring the means by which stress negatively impacts routine PA.

Support or Funding Information

Linfield College Student‐Faculty Collaborative Research Grant

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Biomarker Time Course Recovery Profile in Military Exertional Heat Stroke Populations
Authors: Ward Matthew , King Michelle , Leon Lisa
Published: June 2021

Current return‐to‐duty and training decisions following Exertional Heat Stroke (EHS) are based on ‘best‐guess' criteria. A time‐resolved progression of biomarker changes following EHS has previously not been determined to describe ‘normal’ recovery. In order to characterize EHS injury severity and recovery progression in military populations and identify objective measures of medical readiness, we performed a retrospective clinical records review focusing on available clinical laboratory values assessed on the day of injury, and all follow‐up visits. This dataset was limited to US active duty service members (ADSM) who had at least one EHS during the years 2008–2014. Incidence was identified using the International Classification of Disease 9th (ICD‐9) Revision code for Heat Stroke (992.0). We collated and analyzed daily clinical laboratory values of circulating biomarkers from de‐identified electronic medical records contained in the Medical Health System Data Repository (MDR). Lacking consensus laboratory reference ranges between treatment facilities, the most prevalent reported reference ranges were used as consensus values to orient the analysis. Over the prescribed period, 2,529 ADSM experienced at least one episode of EHS. A total of 181,918 daily clinical laboratory results for 50 laboratory analytes were used for this analysis including a range of blood counts, and serum/plasma or urine assays from 0–340 days following the initial injury. As expected, the median daily value for 11 analytes (ALT, AST, Cl, CK, hematocrit, creatinine, hemoglobin, LDH, myoglobin, WBC, RBC) exceeded the upper limit of the normal reference range, indicating multi‐organ damage or dysfunction. Notably, creatine kinase (CK; consensus reference range 22–269 unit/L) exhibited the highest deviation 3‐days following the initial injury, the median value topped at 4.65‐fold elevation above the upper reference limit; median = 1,251 units/L (interquartile range, 321.25–5,256.75) units/L. Median CK values persisted above the reference range for 8‐days. Each biomarker showed a distinct pattern of peaks (ranging from 0–3 days). In conclusion, this work exploited population‐based EHS responses to characterize injury severity and recovery progression that has not previously been defined. However, due to the high degree of inter‐individual variability in the magnitude and duration of biomarker fluctuations, it remains difficult to set a generalizable criterion for diagnosis, recovery and medical readiness following EHS. The opinions or assertions contained herein are the private views of the authors and should not be construed as official or reflecting the views of the Army or the Department of Defense.

Support or Funding Information

Supported, in part, by Defense Health Program grant, award #W81XWH‐13‐MOMJPC5‐IPPEHA.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Critical Environmental Limits for Prolonged Work in the Heat Using a Simulated Burn Injury Model
Authors: Cramer Matthew N. , Moralez Gilbert , Huang Mu , Crandall Craig G.
Published: June 2021

Following a deep burn injury, excision of devitalized skin and subsequent grafting impair sweat production within grafted sites. Since the capacity for whole‐body evaporative heat dissipation is dependent on sweat production and the total non‐injured skin area available for heat dissipation, burn injuries likely reduce the capacity for whole‐body heat dissipation in proportion to the size of the burn injury during heat stress. To test this possibility, four healthy subjects (1 female; 28 ± 7 years, 71.1 ± 9.0 kg, 1.87 ± 0.12 m2) visited the laboratory on separate days to complete an incremental humidity protocol while cycling at a fixed metabolic heat production (5 W/kg, equivalent to ~35% maximum oxygen uptake) in 40°C with and without simulated burn injuries of 20%, 40%, or 60% of total body surface area. During each trial, exercise was performed at an initial relative humidity (RH) of 25% for 30 min to achieve thermal equilibrium, after which exercise continued as RH was increased by 3% every 5 min up to 90 min. A ‘critical’ RH was identified as the RH value above which a steady‐state esophageal temperature could no longer be maintained, thus providing an indication of maximum evaporative heat dissipation. Burn injuries were simulated by covering skin on the torso, arms, and legs with highly absorbent, vapor‐impermeable material that prevents sweat evaporation. The results show that the average critical RH declined with the size of the simulated burn injury up to 40% (0%: 44.1 ± 2.4%; 20%: 41.8 ± 2.3%; 40%: 31.4 ± 5.1%), with significant reductions in the critical RH at 40% vs. 0% and 20% simulated burn injuries (P=0.009). However, a critical RH value could not be discerned in one subject with a 40% simulated burn injury or in any subject with a 60% simulated burn injury, indicating physiologically uncompensable conditions throughout the experimental protocol. These preliminary data suggest that under the current environmental conditions, burn survivors with injuries of ≥40% have a substantially attenuated capacity for heat dissipation, placing them at greater risk of heat‐related illness during prolonged work and heat stress. Such information may be incorporated into exposure guidelines for burn survivors working under severe occupational heat stress such as military personnel.

Support or Funding Information

Funding: Department of Defense – US Army, W81XWH‐15‐1‐0647

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Does electrodermal activity track capacitance hygrometry derived sweat rate during steady‐state and transient cholinergic‐induced sweating?
Authors: Jordan Alys S. , Narra Seetharam C. , White Briana N. , Wilson Thad E.
Published: June 2021

The classification of hyperhidrosis and hypohidrosis requires a precise quantification of sweat secretion. Recent studies have asserted a non‐invasive electrical conductance could be used to quantify precursor sweat formation. Precursor sweat is the isotonic fluid formed in the bulbous coil and the cell type most likely responsible for sweat gland pathology, rather than the modified fluid that reaches the skin surface. This study was designed to compare electrodermal activity (EDA), capacitance hygrometry, and skin blood flow (SkBF) during steady‐state and dose‐response sweating induced by cholinergic agonists to determine measurement congruence. 3 intradermal microdialysis fibers were placed in the dorsal forearm skin of 4 women and 3 men (age 22±2 years, BMI 25±6 k/m2) to perfuse pilocarpine nitrate (1.66 mg/ml for 60 min), 5 doses of acetylcholine (1•10−5 to 1M via 1•10−1 increments per dose for 5 min each), or the vehicle (lactated Ringer's). Perfusate flow rates were standardized at 5 μL/min. Forearm SkBF (laser‐Doppler flowmetry), EDA (constant voltage of 0.5 V and gain of 5 μS/V), and sweat rate (capacitance hygrometry) were measured directly over the microdialysis membrane. Cholinergic dose‐response relations increased sweat rate (0.0 to 0.56 mg/ml/min), SkBF (16 to 279 units), and EDA (0.61 to 0.91 μS). ACh dose dependent increases in sweat rate and SkBF were similarly correlated to EDA (r = 0.52 and 0.48), although SkBF increased from the first dose and sweat rate and EDA increased from the 3rd dose of ACh. EDA was correlated to SkBF (r = 0.52) but not sweat rate (r = −0.17) during the initial climb to steady‐state sweating, while during state‐steady sweating induced by pilocarpine EDA correlated to sweat rate (r = 0.59) but less so to SkBF (r = 0.21). The lactated Ringer's site did not induce changes in sweat rate, SkBF, or EDA; suggesting that the intradermal microdialysis technique does not affect EDA values. Combined, these data indicate EDA does not track capacitance hygrometry derived sweat rate or laser‐Doppler indexed SkBF consistently in either steady state or transient cholinergic‐induced sweating conditions.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of decreasing peripheral skin blood flow via local axon reflexes, decreases in perfusion pressure, and ischemia during systemic thermal‐induced eccrine sweating in humans
Authors: Wilson Thad E. , Daggett James W. , Alibegovic Kenan , Fang Milie M. , Metzler‐Wilson Kristen
Published: June 2021

In humans, skin blood flow (SkBF) and sweating are tightly coupled, suggesting common neural control and regulation and possible interactive effects of extracellular fluid delivery and sweat secretion. This study was designed to separate these two sympathetic nervous system end‐organ responses via SkBF‐decreasing mechanical perturbations in the presence of a strong sudomotor drive. Two women and 4 men (age 26±1 yrs and BMI 24±4 kg/m2) were tested in normothermia and heat stress conditions, by pumping neutral (34°C) and hot (46–50°C) water through a high‐density tube‐lined suit to either maintain internal temperature (pill telemetry) or increase it by ~1.0°C. Arm and leg SkBF (laser‐Doppler flowmetry) was decreased for 3 min by engaging the venoarteriolar response (limb lowered ~30 cm from heart level; CVAR), venoarteriolar response plus a decrease in perfusion pressure (venous occlusion by proximal cuff inflation; CVAR with ΔPP), and ischemia (arterial occlusion by proximal cuff inflation). Decreased SkBF was observed with CVAR (30±7 and 60±15%), CVAR with ΔPP (44±12 and 86±11%), and ischemia (96±1 and 99±1% for the arm and leg, respectively) during normothermia. Despite these significant decreases in SkBF, there were no significant effects on transepidermal water loss (TEWL). Heat stress increased intestinal temperature from 37.1±0.1 to 38.0±0.1°C, heart rate (ECG) from 65±5 to 93±4 bpm, arm cutaneous vascular conductance (SkBF/mean arterial pressure*100) from 52±12 to 473±85 units, and forearm sweat rate (capacitance hygrometry) from 0.0 to 0.6±0.1 mg/ml/min. During heat stress, decreased SkBF was also observed during CVAR (20±7 and 17±6%), CVAR with ΔPP (39±9 and 52±13%), and ischemia (99±1 and 100±1% for the arm and leg, respectively). Despite these significant decreases in SkBF, eccrine sweat rate was not significantly affected. These data indicate that a wide range of acute changes in SkBF do not appear to affect TEWL or eccrine sweating in peripheral skin.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exertional Heat Stroke: Discovering Specific and Sensitive Diagnostic Criteria
Authors: King Michelle , Ward Matthew , Plamper Mark , Leon Lisa
Published: June 2021

Exertional heat stroke (EHS) is currently defined as presenting with arectal core temperature (Tc) of ≥104°F accompanied by central nervous system (CNS)dysfunction. This definition often lacks in specificity and sensitivity for diagnostic purposes and does not distinguish EHS from exercise‐induced hyperthermia or less severe conditions of exertional heat illness. The purpose of this study was to analyze 179EHS clinical records from the U.S. Marine Corps Base Quantico, VA (2012–2015)to: 1) determine the specificity and sensitivity of the current EHS definition and, 2) identify a more sensitive and specific definition that accurately diagnoses EHS cases with a distinguishable biomarker profile. Specificity and sensitivity was determined through Receiver Operating Characteristic (ROC) curve analysis. The sensitivity of the traditional EHS clinical definition was 64.7% (95% CI 55.9%–72.8%) and specificity was 30.4% (95% CI 17.7%–45.8%). Positive predictive value (PPV) was 72.9% (95% CI 68.1%–77.2%), the negative predictive value (NPV) was 23.0%, (95% CI 15.4%–32.8%), and overall disease prevalence was 74.3% (95% CI 67.3%–80.5%) with an accuracy of 55.9% (95% CI48.3%–63.3%). Using this diagnostic criteria, blood biomarker profiles of EHS and non‐EHS cases were similar. In a secondary analysis, we re‐defined EHS as Tc ≥106°F with at least one form of CNS dysfunction. Sensitivity was lower(30.1%; 95%CI 22.4%–38.6%) whereas these criteria proved more specific (73.3%;95% CI 58.1%–85.4%). PPV and NPV were higher (76.9%; 95%CI 65.8%–85.4%, and 26.2%; 95% CI 22.4%–30.4% respectively)with this classification, while disease prevalence (74.7%; 95% CI 67.6%–80.9%)was indistinguishable and accuracy of diagnosis suffered (41.0%; 95%CI 33.71%–48.62%). Interestingly with this revised EHS definition, blood biomarker profiles (iStat hand held clinical analyzer)separated the most severe cases of EHS (Tc ≥106°F with CNS dysfunction vs. any case with Tc <106). Specifically, chloride (103.1 ± 0.7 vs. 105.2 ± 0.3 (mEq/L); p=0.0089), total carbon dioxide (13.4 ± 1 vs. 16.06 ±0.6 (mEq/L); p=0.0414), glucose (184.1 ± 13.7 vs. 148.2 ± 6.5 (mg/dL); p= 0.021), creatinine (6.5 ± 4.9 vs 1.5 ± 0 (mg/dL); p=0.0285), anion gap (27.8 ± 1.1 vs. 23.7 ± 0.6 (mEq/L); p=0.0016), hematocrit (44.3 ± 1.1 vs. 39.7 ± 0.6 (%); p=0.0377), and hemoglobin (15.0 ± 0.4 vs. 13.5 ± 0.2 (g/dL); p= 0.0390) were significantly different in EHS vs non‐EHS cases, respectively. These results demonstrate that a revised clinical definition of Tc of ≥106° F with CNS dysfunction does not improve sensitivity or accuracy of EHS diagnosis, but it does stratify EHS severity via blood biomarkers. Author view not official USARMY or DoD policy.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
NOVEL ROLE OF GLYCINE IN CONTROL OF SYMPATHETIC OUTFLOW
Authors: Hong Gao , Korim Willian S. , Yao Song T. , Heesch Cheryl M. , Derbenev Andrei V.
Published: June 2021

The arterial baroreflex is one of the essential negative‐feedback mechanisms that compensates rapid changes in blood pressure (BP) through inhibition of presympathetic neurons in the rostral ventrolateral medulla (RVLM). There is general consensus that GABAergic projections originating from the caudal VLM (CVLM) provide the primary inhibitory input that controls the excitability of presympathetic RVLM neurons and sympathetic output. However, glycine, another inhibitory neurotransmitter, is also present in the RVLM. In anesthetized rats, we found that RVLM glycine played a critical role in arterial baroreflex function by controlling the time course of baroreflex mediated inhibition of renal sympathetic nerve activity. Blockade of glycine receptors in the RVLM, following an increase in BP, increased recovery of renal sympathetic nerve activity to baseline levels (5.1 ± 1.0 vs 11.7 ± 1.3 min, N=6, P<0.01) in comparison to control. In addition, tonic glycinergic inhibition of the RVLM was unmasked following blockade of output from the nucleus tractus solitaries and/or during disinhibition of the CVLM. Our whole‐cell, patch‐clamp recordings were obtained from brainstem slices containing presympathetic neurons in the RVLM labeled with PRV‐152. We confirmed that in steady state conditions GABAergic inhibition of RVLM neurons predominated and glycine contributed less than 25% of overall inhibition. In contrast, activation of the network produced saturation of GABAergic inhibition and glycinergic inhibition became prominent. Our findings demonstrated that blockade of glycine receptors in the RVLM decreased duration of baroreflex sympathoinhibition; increase of BP and activation of the network unmasked glycinergic inhibition of the RVLM; and release of glycine in the RVLM depended on the activity of presynaptic inhibitory inputs.

Support or Funding Information

National Institutes of Health R01 HL98602 (Cheryl M. Heesch) and HL122829 (Andrei V. Derbenev). Australian Research Council Future Fellowship FT170100363 and the National Health and Medical Research Council of Australia GNT 1079680 (Song T. Yao). High Blood Pressure Research Council of Australia, the Rebecca L Cooper Medical Foundation, and the Victorian Government through the Operational Infrastructure Scheme (Willian S. Korim).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Baroreflex Sensitivity and Mortality in Septic dysfunction
Authors: dos Santos Fernando , Nogueira Antonio Carlos , Biselli Paolo , Hoshino Wagner , Mostarda Cristiano Teixeira , De Angelis Katia , Soriano Francisco Garcia , Irigoyen Maria Claudia
Published: June 2021

Mortality in experimental septic shock has been attributed to systemic hypotension, hyporeactiveness to vasocostrictors, metabolic acidosis and organ damage but there is no clear information about the involvement of the baroreflex sensitivity (BRS) or autonomic dysfunction in the survival of these animals. In patients with multiple organ dysfunction syndrome autonomic function is impaired and this impairment seems to have prognostic implications. In this study we aimed to observe the role of the baroreflex sensitivity (BRS) in mortality of the patients who were admitted in the intensive care unit from the University of São Paulo Hospital (Univesitary Hospital) with sepsis or septic shock diagnosis (follow up of 28 days). The protocol was approved by Ethics Committee of Hospital and the written informed consent had been obtained from the closest family member. Thirty patients were included in this observational and prospective study in which the patients were analyzed in two groups: survivors and nonsurvivors.. The patients were instrumentalized with direct blood pressure and heart rate recordings, obtained in the first 24 hs in the Instensive Care Unit. The measurements of C reactive protein (Surv: 206.8±25.7, NonS: 204.4±43.6) and gravity APACHE score (Surv: 24.7±0.9, NonS: 24.8±1.0) were similar in the two groups. However, the nonsurvivor group presented reduced glycaemia (NonS: 133.7±10.7 vs Surv: 185.5±16.2 mg/dl) and elevated plasma levels of citokines, IL‐6 (NonS: 1654.1±420.4 vs Surv: 390.1±123.5) and IL‐10 (NonS: 532.3±180.3 vs Surv: 76.0±35.4) and of troponin I (NonS: 1.56±0.4 vs Surv: 0.63±0.2), indicating a myocardial agression. Heart rate variability and the relationship between Heart rate and Blood pressure variation (LF index of BRS) were reduced in septic patients and additionaly reduced in nonsurvivor group. BRS < or =6.5 ms/mmHg were found to be related to mortality in nonsurvivors group by The Kaplan Meyer analysis, suggesting that autonomic dysfunction could be indicative of mortality risk in these patients.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Re‐expression of REST Promotes Ventricular Arrhythmogenesis via Repressing N‐type Calcium Channel in Ventricular Vagal Neurons in Chronic Heart Failure
Authors: Zhang Dongze , Tu Huiyin , Wadman Michael C. , Li Yu‐Long
Published: June 2021

Ventricular arrhythmia is a common complication in chronic heart failure (CHF) and accounts for nearly 50–60% of mortality in patients with CHF. Decrease in cardiac vagal activity is considered to be an important trigger for ventricular arrhythmogenesis in CHF. Our previous study has demonstrated that expression of N‐type calcium channel α‐subunits (Cav2.2‐α) and N‐type Ca2+ currents were reduced in atrioventricular ganglion (AVG) neurons in CHF rats. We have also demonstrated that reduced expression of Cav2.2‐α in AVG neurons contributes to ventricular arrhythmogenesis. The repressor element 1‐silencing transcription factor (REST) is a key to block Cav2.2‐α expression. Normally REST is not expressed in neuronal cells. Here, we test the hypothesis that re‐expression of REST inhibits N‐type Ca2+ channel function in AVG neurons and further trigger ventricular arrhythmogenesis in coronary arterial ligation‐induced CHF rat. Using reverse‐phase protein array, we found that there was no expression of REST in the AVG from sham rats, while REST expression was significantly increased in the AVG from CHF rats. In vivo transfection of lentiviral REST shRNA (2 μl, 1×107 TU/ml) into the AVG markedly reduced REST expression in the AVG from CHF rats. REST shRNA also increased Cav2.2‐α expression in AVG neurons from CHF rats. The results from whole‐cell patch clamp recording showed that REST shRNA increased N‐type Ca2+ currents in AVG neurons from CHF rats (19.47±1.13 pA/pF in REST shRNA transfected CHF rats vs. 11.37±1.65 pA/pF in non‐transfected CHF rats). The data obtained from radiotelemetry ECG recording in conscious rat demonstrated that transfection of REST shRNA into AVG neurons reduced the cumulative duration of ventricular tachycardia/fibrillation in CHF rats (2.64 ±2.05 sec/hour in REST shRNA transfected CHF rats vs. 10.03±3.43 sec/hour in non‐transfected CHF rats). We conclude that re‐expression of REST decreases Cav2.2‐α expression and N‐type Ca2+ currents in AVG neurons and subsequently triggers ventricular arrhythmogenesis in the CHF state.

Support or Funding Information

This study was supported by AHA Grant‐in‐Aid (15GRANT24970002)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.