Gestational long-term hypoxia induces metabolomic reprogramming and phenotypic transformations in fetal sheep pulmonary arteries.

Gestational long-term hypoxia increases the risk of myriad diseases in infants including persistent pulmonary hypertension. Similar to humans, fetal lamb lung development is susceptible to long-term intrauterine hypoxia, with structural and functional changes associated with the development of pulmonary hypertension including pulmonary arterial medial wall thickening and dysregulation of arterial reactivity, which culminates in decreased right ventricular output. To further explore the mechanisms associated with hypoxia-induced aberrations in the fetal sheep lung, we examined the premise that metabolomic changes and functional phenotypic transformations occur due to intrauterine, long-term hypoxia. To address this, we performed electron microscopy, Western immunoblotting, calcium imaging, and metabolomic analyses on pulmonary arteries isolated from near-term fetal lambs that had been exposed to low- or high-altitude (3,801 m) hypoxia for the latter 110+ days of gestation. Our results demonstrate that the sarcoplasmic reticulum was swollen with high luminal width and distances to the plasma membrane in the hypoxic group. Hypoxic animals were presented with higher endoplasmic reticulum stress and suppressed calcium storage. Metabolically, hypoxia was associated with lower levels of multiple omega-3 polyunsaturated fatty acids and derived lipid mediators (e.g., eicosapentaenoic acid, docosahexaenoic acid, α-linolenic acid, 5-hydroxyeicosapentaenoic acid (5-HEPE), 12-HEPE, 15-HEPE, prostaglandin E3, and 19(20)-epoxy docosapentaenoic acid) and higher levels of some omega-6 metabolites (P < 0.02) including 15-keto prostaglandin E2 and linoleoylglycerol. Collectively, the results reveal broad evidence for long-term hypoxia-induced metabolic reprogramming and phenotypic transformations in the pulmonary arteries of fetal sheep, conditions that likely contribute to the development of persistent pulmonary hypertension.

Heat acclimation causes a linear decrease in sweat sodium ion concentration.

The purpose of this study was to determine the time course for the previously reported reduction in sweat sodium ion concentration during heat acclimation. Four healthy volunteers completed 7 consecutive days of heat acclimation which included 2h of treadmill walking in a 40°C and 40% relative humidity environment. A modified constant hyperthermia protocol was used as workloads were increased each day to maintain a constant core temperature over the 7 days of heat acclimation. Forearm sweat was collected 3 times during each 2h exercise bout on days 1, 3, 5, and 7 of heat acclimation. Forearm sweat rate and sweat sodium ion concentration were determined from each sample. The results showed that there was a significant (p < 0.05) downward shift in the mean sweat rate vs. sweat sodium ion concentration relationship on days 3, 5, and 7 of heat acclimation, as compared to the pre-heat acclimation (day 1) data. Thus, at any given sweat rate, heat acclimation resulted in a significantly lower sweat sodium ion concentration. The response was very rapid and occurred following only 2 consecutive days of heat exposure (i.e., day 3 vs. day 1 data). Furthermore, the calculated sweat sodium ion concentration, at a sweat rate of 1µl/cm2/min, decreased linearly (r = - 0.50, p < 0.05) during the 7 days of heat acclimation. Such results suggest that heat acclimation rapidly improves sodium ion reabsorption from the eccrine sweat gland duct as evidenced by significant reductions in the sweat sodium ion concentration.

Heat stress and the velocity-duration relationship in amateur runners.

Tolerance to high-intensity constant power exercise can be characterized by the hyperbolic power-duration (or velocity-duration) relationship. The hyperbola is defined by the asymptote (critical power or velocity) and the curvature constant (W' or D'). The effects of thermoregulatory stress on middle-distance running performance are equivocal-possibly due to the complexities of the hyperbolic velocity-duration relationship for these relatively short duration events. We aimed to measure the effects of heat stress on the velocity-duration relationship in amateur runners. Fifteen participants (23 ± 6 years) completed a series of constant-velocity running bouts to intolerance in three heat indices (MILD: 20°C, VERY HOT: 38°C, EXTREME: 55°C). Critical velocity (CV) in MILD (3.52 ± 0.86 m/s) was higher than VERY HOT (3.39 ± 0.82 m/s) and EXTREME (3.29 ± 1.05 m/s; F[2.28] = 3.80, p < 0.035) with no effect of thermal stress on D' (F[2.28] = 2.48, p = 0.11). In amateur competitive/recreational runners, heat stress of ≥38°C heat index negatively affected CV. Thus, even during relatively short events, such as middle-distance running where fluid loss is not a primary concern, heat stress may negatively impact performance.

PGAP3 regulates human bronchial epithelial cell mRNAs present in asthma and respiratory virus reference data sets.

PGAP3 is a glycosylphosphatidylinositol (GPI) phospholipase gene localized within chromosome 17q12-21, a region highly linked to asthma. Although much is known about the function of other chromosome 17q12-21 genes expressed at increased levels in bronchial epithelium such as ORMDL3 and GSDMB, little is known about the function of increased PGAP3 expression in bronchial epithelium in the context of asthma. The aim of this study was therefore to determine whether increased PGAP3 expression in human bronchial epithelial cells regulated expression of mRNA pathways important to the pathogenesis of asthma by utilizing RNA-sequencing and bioinformatic analysis. We performed RNA-sequencing on normal human bronchial epithelial cells transfected with PGAP3 for 24 and 48 hours. PGAP3 regulated genes were compared to asthma and respiratory virus (influenza A, rhinovirus, respiratory syncytial virus) reference data sets to identify PGAP3 target genes and pathways. Approximately 9% of the upregulated PGAP3-induced genes were found in an asthma reference data set, 41% in a rhinovirus reference data set, 33% in an influenza A reference data set, and 3% in a respiratory syncytial virus reference data set. PGAP3 significantly upregulated the expression of several genes associated with the innate immune response and viral signatures of respiratory viruses associated with asthma exacerbations. Two of the highest expressed genes induced by PGAP3 are RSAD2, OASL, and IFN-λ, which are anti-viral genes associated with asthma. PGAP3 also upregulated the antiviral gene BST2, which like PGAP3 is a GPI-anchored protein. We conclude that PGAP3 expression in human bronchial epithelial cells regulates expression of genes known to be linked to asthma, and also regulates the bronchial epithelial expression of genes pertinent to the pathogenesis of respiratory viral triggered asthma exacerbations.

Descriptive Analysis of Dexmedetomidine's Utility in a Palliative Care Unit at the End of Life.

Context: Pain and symptom management at the end of life (EoL) can pose unique challenges, particularly when symptoms are refractory to conventional methods. Dexmedetomidine, originally approved for sedation in ventilated patients, has been demonstrated to be beneficial in pain management and palliative care settings by functioning as an alpha-2 agonist. Methods: A retrospective review of inpatient palliative care unit (IPU) records from January 2020 to December 2023 was conducted. Twenty-five adult patients receiving continuous dexmedetomidine for refractory pain at the EoL were identified. These patients were further evaluated for concurrent opioid, benzodiazepine, and chlorpromazine usage. Results: Patients experienced predominantly cancer-related pain, and had a median infusion duration of 5 days. Dexmedetomidine's initial dosing differed between the intensive care unit (ICU) and IPU settings. There was a trend toward a decreased opioid requirement 24 hours after initiation. Patients transferred from the ICU showed a progressive increase in opioid use. Conclusion: This study contributes to understanding dexmedetomidine's role in managing refractory symptoms at the EoL in the palliative care setting.

Impact of Maternal Exercise on Mice Offspring Development, Pulmonary Hypertension, and Vascular Remodeling in Chronic Hypoxia.

PURPOSE: Chronic, high-altitude hypoxic exposure increases the risk of high-altitude pulmonary hypertension (PH). Emerging evidence shows maternal exercise may improve offspring resistance to disease throughout life. The purpose of this study is to determine if maternal exercise mitigates chronic hypoxic-induced changes in the offspring indicative of high-altitude PH development. METHODS: Female adult C57BL/6J mice were randomly allocated to nonexercise or exercise conditions. Exercise consisted of voluntary running wheel exercise for 4 wk during the perinatal period. Three days after birth, the pups remained at low altitude (normoxia) or were exposed to hypobaric hypoxia of 450 mm Hg to simulate ~4500 m of altitude exposure until 8 wk of age. The study consisted of four groups: hypoxia + nonexercise pregnancy, hypoxia + exercise, or the respective normoxia conditions (normoxia + nonexercise or normoxia + exercise). Offspring body size, motor function, right ventricular systolic pressure (RVSP), and cardiopulmonary morphology were assessed after 8 wk in normoxia or hypoxia. RESULTS: Both hypoxic groups had smaller body sizes, reduced motor function, increased hematocrit, RVSP, muscularization in medium-sized pulmonary arteries, as well as right ventricular hypertrophy and contractility compared with the normoxic groups ( P < 0.05). CONCLUSIONS: Chronic hypoxia simulating 4500 m attenuated growth, lowered motor function, and elicited PH development. Voluntary maternal exercise did not significantly decrease RVSP in the offspring, which aligned with a lack of effect to attenuate abnormal body size and cardiopulmonary development due to chronic hypoxia. These findings are preliminary in nature, and more powered studies through larger group sizes are required to generalize the results to the population.

Older Adult Aerobic Capacity, Muscular Strength, Fitness and Body Composition After 20+ Years of Exercise Training: A Systematic Review and Meta-Analysis.

Older adults (≥ 65 years) are recommended to participate in regular exercise to maintain health in late adulthood. The impact of long-term (20+ years) exercise training that align with the American College of Sports Medicine's (ACSM) recommended guidelines has not been evaluated for older adults. To address this, a systematic review and meta-analyses were performed regarding the effects of long-term exercise training on older adult aerobic capacity, muscular fitness, and body composition that meet the ACSM's recommendation for weekly training volume. Ten studies with individuals that performed cardiorespiratory or resistance exercise met the inclusion criteria for the systematic review. Data from five included studies were analyzed in meta-analyses to determine the relationship between the effects of cardiorespiratory training on fitness and body composition measured in the same subjects. Main findings include higher cardiorespiratory fitness (MD: +11.36 mL/kg/min, 95% CI: 5.63 to 17.09 mL/kg/min, p < 0.01) in older adults who performed long-term cardiorespiratory exercise that was found in conjunction with lower percent body fat (MD: -5.41%, 95% CI: -7.65 to -3.17%, p < 0.01). Higher volume of cardiorespiratory exercise beyond the minimum recommendations did not impact benefits. Additionally, resistance-trained older adults showed greater muscular strength and lower percent body fat with comparable cardiorespiratory fitness to sedentary older adults. These findings primarily highlight a preservation of cardiorespiratory fitness and lower risk of mortality and cardiometabolic disease risk for older adults who participate in long-term cardiorespiratory and exercise that meet the ACSM's recommended weekly training volume.

Can Maternal Exercise Prevent High-Altitude Pulmonary Hypertension in Children?

Leslie, Eric, Ann L. Gibson, Laura V. Gonzalez Bosc, Christine Mermier, Sean M. Wilson, and Michael R. Deyhle. Review: can maternal exercise prevent high-altitude pulmonary hypertension in children? High Alt Med Biol. 24:1-6, 2023.-Chronic high-altitude exposure reduces oxygen delivery to the fetus during pregnancy and causes pathologic pulmonary artery remodeling, This increases the risk of high-altitude pulmonary hypertension (PH), which is a particularly fatal disease that is difficult to treat. Therefore, finding ways to prevent high-altitude PH, including during the neonatal period, is preferable. Cardiorespiratory exercise can improve functional capacity and quality of life in patients with high-altitude PH. However, similar to other treatments and surgical procedures, the benefits are not enough to cure the disease after a diagnosis. Cardiorespiratory exercise by mothers during pregnancy (i.e., maternal exercise) has not been previously evaluated to prevent the development of high-altitude PH in children born and living at high altitude. This focused review describes the pathophysiology of high-altitude PH and the potential benefit of maternal exercise for preventing the disease caused by high-altitude pregnancies.

A novel pattern of longitudinal muscle contraction with subthreshold pharyngeal stimulus: a possible mechanism of lower esophageal sphincter relaxation.

A subthreshold pharyngeal stimulus induces lower esophageal sphincter (LES) relaxation and inhibits progression of ongoing peristaltic contraction in the esophagus. Recent studies show that longitudinal muscle contraction of the esophagus may play a role in LES relaxation. Our goal was to determine whether a subthreshold pharyngeal stimulus induces contraction of the longitudinal muscle of the esophagus and to determine the nature of this contraction. Studies were conducted in 16 healthy subjects. High resolution manometry (HRM) recorded pressures, and high frequency intraluminal ultrasound (HFIUS) images recorded longitudinal muscle contraction at various locations in the esophagus. Subthreshold pharyngeal stimulation was induced by injection of minute amounts of water in the pharynx. A subthreshold pharyngeal stimulus induced strong contraction and caudal descent of the upper esophageal sphincter (UES) along with relaxation of the LES. HFIUS identified longitudinal muscle contraction of the proximal (3-5 cm below the UES) but not the distal esophagus. Pharyngeal stimulus, following a dry swallow, blocked the progression of dry swallow-induced peristalsis; this was also associated with UES contraction and descent along with the contraction of longitudinal muscle of the proximal esophagus. We identify a unique pattern of longitudinal muscle contraction of the proximal esophagus in response to subthreshold pharyngeal stimulus, which we propose may be responsible for relaxation of the distal esophagus and LES through the stretch sensitive activation of myenteric inhibitory motor neurons.

Ketamine Use in Operation Enduring Freedom.

INTRODUCTION: Ketamine is a dissociative anesthetic increasingly used in the prehospital and battlefield environment. As an analgesic, it has been shown to have comparable effects to opioids. In 2012, the Defense Health Board advised the Joint Trauma System to update the Tactical Combat Casualty Care Guidelines to include ketamine as an acceptable first line agent for pain control on the battlefield. The goal of this study was to investigate trends in the use of ketamine during Operation Enduring Freedom (OEF) and Operation Freedom's Sentinel (OFS) during the years 2011-2016. MATERIALS AND METHODS: A retrospective review of Department of Defense Trauma Registry (DoDTR) data was performed for all patients receiving ketamine during OEF/OFS in 2011-2016. Prevalence of ketamine use, absolute use, mechanism of injury, demographics, injury severity score, provider type, and co-administration rates of various medications and blood products were evaluated. RESULTS: Total number of administrations during the study period was 866. Ketamine administration during OEF/OFS increased during the years 2011-2013 (28 patient administrations in 2011, 264 administrations in 2012, and 389 administrations in 2013). A decline in absolute use was noted from 2014 to 2016 (98 administrations in 2014, 41 administrations in 2015, and 46 administrations in 2016). The frequency of battlefield ketamine use increased from 0.4% to 11.3% for combat injuries sustained in OEF/OFS from 2011 to 2016. Explosives (51%) and penetrating trauma (39%) were the most common pattern of injury in which ketamine was administered. Ketamine was co-administered with fentanyl (34.4%), morphine (26.2%), midazolam (23.1%), tranexamic acid (12.3%), plasma (10.3%), and packed red blood cells (18.5%). CONCLUSIONS: This study demonstrates increasing use of ketamine by the U.S. Military on the battlefield and effectiveness of clinical practice guidelines in influencing practice patterns.

Unmasking Long QT Syndrome in the Emergency Department: A Case Report.

INTRODUCTION: Long QT syndrome (LQTS) is an uncommon disorder that can lead to potentially life-threatening dysrhythmias. LQTS can be genetic, acquired, or both. CASE REPORT: A 44-year-old female with well-controlled hypertension and asthma presented with chest tightness. An initial electrocardiogram yielded a normal corrected QT interval of 423 milliseconds (ms) (normal <480 ms in females). Albuterol was administered and induced agitation, tremulousness, and tachycardia. Follow-up electrocardiograms demonstrated extreme prolongation of the corrected QT interval to 633 ms and morphology change of the T wave. Lab values were later notable for hypokalemia and hypomagnesemia, attributable to a recently started thiazide diuretic. The patient was ultimately diagnosed with congenital LQTS after initial unmasking by albuterol in the emergency department. CONCLUSION: LQTS can be unmasked or exacerbated by electrolyte abnormalities and QT prolonging medications.

The Effects of Fast and Slow Yoga Breathing on Cerebral and Central Hemodynamics.

BACKGROUND: Yoga breathing has shown to impose significant cardiovascular and psychological health benefits. OBJECTIVE: The mechanism (s) responsible for these health benefits remain unclear. The aim of the present study was to assess the differences in cerebral and central hemodynamic responses following fast breathing (FB) and slow breathing (SB) protocols compared to breathing awareness (BA) as a control. METHODS: Twenty healthy participants (10 males and 10 females) volunteered to take part in the study. Participants were between ages 18-55 years (group mean: 24 ± 5 years), with a height of 168.7 ± 9.8 cm and a weight of 70.16 ± 10.9 kg. A familiarization trial including FB and SB protocols were performed by each participant at least 24 h before the testing day. The breathing protocols were designed to achieve 6 breath/min for SB and ~ 120 breaths/min for FB. RESULTS: FB resulted in an increase in both right prefrontal cortex (RPFC) and left prefrontal cortex (LPFC) hemoglobin difference (Hbdiff) (brain oxygenation) compared to BA (P < 0.05). FB resulted in an increased Hbdiff in LPFC compared to RPFC SB (P < 0.05). FB resulted in an increased Hbdiff in LPFC compared to SB (P < 0.05). CONCLUSION: FB may be an effective yoga breathing technique for eliciting cerebral brain oxygenation indicated by increased Hbdiff. These results may be applicable to both healthy and clinical populations.