bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary functions in different phases of menstrual cycle
Authors: Saperova Elena , Dimitriev Dmitry
Published: June 2021

The purpose of the present study was to evaluate the influence of the normal menstrual cycle on respiratory parameters.

Material and methods

Nineteen healthy regularly cycling woman (age 20–25 years) kept daily records of lung function parameters during the follicular phase (FP) and luteal phase (LP) over three menstrual cycles.

Results

Tidal volume was significantly higher during the LP (0.583±0.017) compared to the FP (0.530±0.015; Mann‐Whitney test (U)=5181.00; p=0.008). Minute ventilation showed the same pattern, being significantly higher during the LP compared with the FP (11.47±0.42 vs 9.82±0.32; U=4801.00; p=0.0007). Peak expiratory flow was significantly higher in LP (6.70±0.08) than in the FP (6.43±0.09; U=5381.50; p=0.026). Breath rate also vas higher during the LP than that during the FP (19.58±0.39 vs 18.42±0.33; U=5342.00; p=0.043). Forced vital capacity, forced expiratory volume in one s, forced expired flow from 25–75% of FVC, forced expired flow at 25%, 50%, 75% of FVC and maximal voluntary ventilation were not different between the cycle phases. In conclusion, lung function changes were found during menstrual cycles in healthy women.

Conclusion

The luteal increase in lung function parameters suggests a possible role for progesterone or other endogenous sex hormones in stimulating the respiratory drive, either centrally or through the peripheral chemoreceptors or by both.
The Role of Hyaluronic Acid in SEB‐Induced Acute Lung Inflammation
Authors: Castillejo Clara Miluska , Uchakina Olga , Bridges Christy , McKallip Robert
Published: June 2021

It is becoming increasingly clear that the extracellular matrix can play a major role in the regulation of the inflammatory response. Recent evidence from our laboratory suggests that extracellular matrix component, hyaluronic acid (HA), is important in the development of lung injury/acute respiratory distress syndrome (ALI/ARDS) following staphylococcal enterotoxin B (SEB) exposure. In this study, we tested the hypothesis that SEB exposure leads to increased expression of HA which when released into the lungs plays an important role in the development of SEB‐induced ALI/ARDS. Using both an in vitro spleen cell culture model as well as an in vivo mouse model, we tested the effect of HA on SEB‐induced ALI/ARDS. Intranasal exposure of mice to SEB led to a significant increase in the level of soluble HA in the lungs. The in vitro model mirrored these results demonstrating that SEB exposure led to a significant increase in soluble levels of hyaluronic acid, increased proliferation, and increased cytokine production. We also showed that targeting hyaluronic acid with blocking peptide, Pep‐1, led to a decrease of SEB‐induced cytokine production and proliferation in vitro. These results were further confirmed in vivo by treating SEB‐exposed mice with Pep‐ 1 which significantly reduced SEB‐induced ALI/ARDS by reducing inflammatory cytokine production and the number of lung inflammatory cells. Together, these results demonstrate an important role of the extracellular matrix component HA in regulating lung inflammation and suggest the possibility of targeting hyaluronic acid for the treatment of SEB‐induced ALI/ARDS.
Exercise pulmonary gas exchange differentiates type and severity of pulmonary hypertension in heart failure
Authors: Smetana Michael Robert , Taylor Bryan , Frantz Robert , O'Malley Kathy , Johnson Bruce
Published: June 2021

Background

Heart failure (HF) is associated with impaired exercise pulmonary gas exchange (PGX) that is likely related to the development and severity of pulmonary hypertension (PH).

Purpose

To determine whether PGX measures differentiate HF patients with reactive PH from patients with passive PH or no PH.

Methods/Results

Pulmonary arterial pressure (PAP), pulmonary wedge pressure (PWP), transpulmonary pressure gradient (TPG) and PGX indices [end‐tidal CO2 (PETCO2), ventilatory efficiency (VE/VCO2), O2pulse, estimated pulmonary arterial capacitance (GXCAP)] were assessed simultaneously at rest and during cycle exercise in 38 HF patients undergoing right heart catheterization. Post hemodynamic evaluation, patients were classified as having no PH (n = 12), passive PH (n = 10) or reactive PH (n = 16). TPG increased during exercise in all groups but was greater at end exercise in the reactive PH vs. the passive PH and no PH patients (21±9 vs. 14±7 vs. 12±7 mmHg). At an equivalent VO2, PETCO2, O2pulse and GXCAP were higher and VE/VCO2 ratio lower in the no PH and, to a lesser extent, in the passive PH vs. the reactive PH subjects (Figure 1).

Conclusion

Noninvasive measures of PGX during exercise appear to differentiate HF patients with reactive PH from patients with passive PH or no PH and may be a useful adjunct to invasive catheterization in assessing PH type and severity. HL71478, AHA12POST12070084, Gilead Science
Aging diminishes cerebral blood volume and vasodilation in rats: non‐invasive absolute measurements by Near Infrared Spectroscopy
Authors: Shaul Merav Esther , Hallacoglu Bertan , Fantini Sergio , Rosenberg Irwin , Troen Aron
Published: June 2021

Brain microvasculature pathology is common in all forms of dementia, but it is unclear whether it precedes or follows neurodegeneration. Since aging is the strongest risk factor for dementia, we hypothesized that it would be accompanied by pathologic microvascular changes that would be discernible by non‐invasive absolute Near Infrared Spectroscopy (NIRS). We measured longitudinal changes in cerebral blood volume (CBV), at rest and in response to hypercapnia, in Wistar‐Kyoto rats, aged 4 months and one year later in middle‐age. Mean absolute CBV dropped with age from 4.42±0.25 to 2.71±0.17 ml/100gr tissue, reflecting a highly significant 37.7±4.3% age‐related decrease. Vasodilation also decreased with age: In middle‐aged rats, hypercapnia caused CBV to increase by only 0.121±0.044ml above resting values, compared to 0.175±0.027ml in young rats. These findings indicate that such microvascular changes may occur as early as middle age. The ability to detect and measure physiological evidence of structural and functional microvascular pathology during life can help to understand the role of microvascular pathology in dementia.
The influence of combined lower body negative pressure and mental stress on cerebral blood flow in men and women
Authors: Young Angelea H. , Strong Chelsea R. , Cooke William H. , Carter Jason R. , Durocher John J.
Published: June 2021

Lower body negative pressure (LBNP) decreases mean middle cerebral blood velocity (MCAv) and mental stress (MS) typically increases MCAv, but the MCAv response to these combined autonomic stressors is unknown. We hypothesized that performing MS during LBNP would result in an additive MCAv interaction. Eighteen participants (9 men, 9 women) completed three randomized trials: 1) 3 min LBNP (−40 mmHg), 2) 3 min MS (serial subtraction), and 3) combined LBNP and MS. Mean arterial pressure (MAP), heart rate (HR) and MCAv were continuously measured. Baseline MAP (81±2 vs. 80±1 vs. 80±1 mmHg) and HR (65±2 vs. 64±2 vs. 65±2 beats/min) were similar preceding each trial. LBNP significantly (p<0.05) decreased MCAv (Δ−3±1 cm/s), but did not alter MAP or HR. MS significantly (p<0.05) increased MAP (Δ10±1 mmHg), HR (Δ17±2 beats/min) and MCAv (Δ3±1 cm/s; p=0.05). Combined LBNP and MS significantly (P<0.05) increased MAP (Δ7±3 mmHg) and HR (Δ18±4 beats/min) and significantly decreased MCAv (Δ−5±2 cm/s). Increases in MAP and HR were similar during the combination trial when compared to the calculated sum of the individual trials. However, the MCAv (Δ−5±2 vs. Δ0±2 cm/s) response was blunted during the combination trial vs. the sum of individual trials. In conclusion, our findings are contrary to our hypothesis and suggest there is not an additive MCAv interaction during combined cognitive and orthostatic stress.

Supported by NASA.
Perinatal inflammation and oxidative stress induce fetal cardiac dysfunction
Authors: Velten Markus , Gorr Matthew W , Youtz Dane Y , Velten Christina , Rogers Lynette K , Wold Loren E
Published: June 2021

Background

Epidemiological data suggest that maternal inflammation contributes to intrauterine growth restriction, preterm birth, and adult‐onset cardiovascular diseases.

Objective

We hypothesize that perinatal inflammation and oxidative stress may induce discernible alterations in cardiomyocyte contractility and calcium signaling, causing cardiac dysfunction in the absence of subsequent risk factors.

Methods

Pregnant C3H/HeN mice were LPS or saline injected on embryonic day 16. Offspring were placed in room air or 85% O2 for 14 days. In vivo echocardiography, in vitro cardiomyocyte function, protein, and RNA analyses were performed.

Main Results

LPS/O2 exposed mice exhibited a compromised LV function and decrease in myocyte peak shortening and time‐to‐90% peak shortening. β‐MHC protein levels were increased and calcium transient amplitude was greatest in LPS/O2 mice, a pattern observed in humans and animal models of heart failure. SERCA2a RNA and protein levels were increased and phospholamban mRNA levels were decreased in LPS/O2 mice, a pattern observed during fetal development. Phosphorylation of phospholamban was increased, along with Sorcin mRNA levels.

Conclusions

Maternal inflammation and neonatal oxidative stress resulted in impaired cardiac contractility consistent with heart failure, with the fetal cardiac phenotype persistent during the postnatal stage.
Study of Zebrafish Cardiac Morphogenesis Using Computational Fluid Dynamics
Authors: Lee Juhyun , Cao Hung , Hsiai Tzung Keith
Published: June 2021

Hemodynamics is intimately linked to cardiac structural morphogenesis. Intracardiac blood flow creates shear stresses and pressure forces on the endoluminal surface of developing heart tubes. Zebrafish is a genetically tractable model to investigate the cardiac morphogenesis owing to their transparency and fast cardiac development in embryo stages. However, in vivo and real‐time measurement of intracardiac shears stress and pressure in zebrafish is challenging due to size limitation. Computational Fluid Dynamics (CFD) model with specific boundary conditions [may provide an entry point to establish the indirect measurement of intracardiac parameters over time. Here, we quantified intracardiac shear stress and pressure starting from 30 hours post fertilization (hpf) to 120 hpf. To reconstruct 2‐D dynamic boundary conditions, CFD simulation was used to demonstrate incremental increase in shear stress along the atrioventricular (AV) valve region. The decrease in the diameter of AV valve was consistent with the increase in blood velocity. At 120 hpf, AV valve was fully developed to allow for comparing changes in intracardiac shear stress. Our dynamic CFD modeling provides a basis to elucidate the molecular mechanisms whereby biomechanical forces modulate the AV valvular morphogenesis.
Effects of Chronic Green Tea (GT) or Green Tea Extract (GTE) treatment in cardiovascular function in Hypertensive Rats.
Authors: Garcia Michelle Louvaes , Nishi Erika E , Lincevicius Gisele S , Veiga Glaucia R L , Pontes Roberto B , Campos Ruy R , Oyama Lila , Bergamaschi Cassia T
Published: June 2021

To evaluate the effects of GT and purified GTE treatment in hypertension, male Wistar rats were treated orally for 2 weeks with L‐Name, 20 mg/Kg/day). By the end of the first week of treatment, the animals were divided in: L‐Name treated; L‐Name + GT (9,6g/L) and L‐Name + GTE (20 mg/Kg/day). The same treatment was performed in control normotensive animals. By the end of treatment period blood pressure (BP) and heart rate (HR) were directly measured. Baroreflex sensitivity was evaluated by changes in BP elicited by IV infusion of phenylephrine or sodium nitroprusside and reflex HR responses. Water/tea ingestion and urinary volume were also evaluated for 24h. L‐Name treated rats (188±11 mmHg) had a significant increase in BP compared to control group (103±5 mmHg) and treatment with GT (123±6 mmHg) or GTE (132±2 mmHg) promoted a significant reduction in this parameter. It was also observed an improvement in baroreflex sensitivity in treated rats. There was no statistically difference among groups in urinary or intake volume. Treatment with GT and GTE presented an important antihypertensive effect associated with improvement in baroreflex control, and independently of a diuretic effect.

Supported by CAPES and Cnpq.
The relationship between peripheral endothelial function and cerebrovascular reactivity to CO2 in older adults
Authors: Brar Ikdip , Robertson Andrew , Hughson Richard L
Published: June 2021

Reduced cerebrovascular reactivity to CO2 contributes to a higher risk of cerebrovascular events. Studies on healthy and hypertensive middle‐aged adults have suggested the involvement of nitric oxide in CO2 reactivity based on the relationship observed with peripheral reactive hyperemia. We tested the hypothesis that hyper‐and hypocapnic reactivity is correlated with peripheral vascular endothelial function assessed by flow‐mediated dilation (FMD) in healthy older adults.

Methods

Blood pressure, heart rate, end‐tidal PCO2, middle cerebral artery blood flow velocity (CBFV), as well as brachial artery diameter and shear rate, were monitored in 31 individuals (18 women; 72 ± 5 yrs). CO2 reactivity was assessed by the relative change in CBFV during hypercapnia (5% CO2, 21% O2) and hypocapnia (mild hyperventilation). Peripheral vascular function was measured by the relative brachial artery dilation after 5 min of forearm ischemia.

Results

Non‐parametric analyses suggested a possible relationship between cerebral and peripheral vascular function, such that a trend was observed between cerebrovascular reactivity and FMD in the hypocapnic range (rs=0.284, p=0.1), but not the hypercapnic range (rs=−0.22, p>;0.1).

Conclusion

Our study suggests only a weak relationship between peripheral endothelial function and reactivity to hypocapnia in older adults free of cardiovascular disease. Funded by CIHR.
A novel method to detect in vivo oxidant production reveals microvascular endothelial dysfunction linked to NADPH oxidase in obese human skeletal muscle
Authors: La Favor Justin D , Anderson Ethan J , Hickner Robert C
Published: June 2021

Excessive production of reactive oxygen species (ROS) contributes to the development of endothelial dysfunction and progression of vascular diseases that are observed in obesity. Three microdialysis probes were inserted into the vastus lateralis of young, sedentary lean (LN; n=7), overweight (OW; n=8) and obese (OB; n=7) individuals, allowing sampling of extracellular fluid. To measure extracellular ROS, probes were perfused with saline containing 5 mM ethanol, 100 μM Amplex Ultrared, 1 U/ml horseradish peroxidase, and 10 U/ml superoxide dismutase, with or without 300 μM apocynin (Apo; an NADPH oxidase inhibitor). Dialysate fluorescence was measured at the outlet. Endothelial function was assessed with addition of acetylcholine (ACh) to the perfusate, with local blood flow calculated from the ethanol outflow:inflow ratio. Extracellular ROS was elevated in OB 3.2‐fold over OW, and 5.6‐fold over LN (p < 0.05), which was prevented by Apo (p < 0.01). ACh‐stimulated blood flow was depressed 60% in OB vs. OW, and 68% vs. LN (p = 0.01). Apo augmented ACh‐stimulated blood flow only in OB (p = 0.02). Microvascular endothelial dysfunction was evident in OB, which was largely reversed by NADPH oxidase inhibition. It can be concluded that the substantial elevation in ROS in OB was predominantly driven by NADPH oxidase.

Supported by a doctoral student grant from the American College of Sports Medicine.
Assessment of protein synthesis and cellular proliferation in long‐lived crowded litter mice
Authors: Drake Joshua C. , Peelor Fredrick F. , Biela Laurie M. , Miller Richard A. , Hamilton Karyn L. , Miller Benjamin F.
Published: June 2021

Increasing the number of pups prior to weaning (“crowded litter” or CL) increases the lifespan of mice. In previous studies with caloric restriction, rapamycin feeding, and Snell dwarf mice, we have described the general phenomenon that DNA synthesis is decreased and mitochondrial (mito) protein synthesis is maintained, though this varies by tissue and model. Therefore, we hypothesized that CL mice would also have decreased DNA synthesis and maintained mito protein synthesis. UM‐HET3 mice were housed as litters of 8 (CON) or 12 (CL) prior to weaning. At 20 days of age pups were weaned onto a normal chow diet. At 4 months of age 4 CON and 4 CL animals had their drinking water supplemented with 8% deuterium oxide for 2 weeks to determine fraction of new total, cytosolic, and mito proteins, and fraction of new DNA. Protein synthesis was not statistically different in any tissue or fraction assessed. DNA synthesis was significantly greater in CL skeletal muscle (Con = 0.024±0.003, CL = 0.037±0.004), tended to be greater in heart (p=0.08; Con = 0.047±0.003, CL = 0.066±0.018), but did not differ in liver. CL mice were studied at a younger age than our previous investigations, and thus we conclude that either: 1) long‐lived models have a previously unrecognized increase in proliferation at young ages, or 2) CL mice are long‐lived through different mechanisms than our previously studied models.
Association between Cerebral tissue Structural Integrity and Dynamic Cerebral Autoregulation in Elderly Individuals
Authors: Purkayastha Sushmita , Fadar Otite , Mehregan Aujan , Lipsitz Lewis A , Sorond Farzaneh A
Published: June 2021

Objective

Cerebral white matter hyperintensity (WMH) is prevalent in the elderly population and is associated with hypoperfusion and ischemia presumably due to altered cerebral autoregulation (CA). Our study sought to examine the association between cerebral white matter structural integrity and dynamic CA in elderly individuals.

Methods

Fifty‐three subjects (75±7 years, Mean ± SD) were enrolled in the study and WMH was assessed using magnetic resonance imaging and microstructural integrity of the white matter (WM) was estimated from fractional anisotropy (FA) and mean diffusivity (MD) using diffusion tensor imaging. Arterial blood pressure and middle cerebral artery blood velocity (MCAV) was obtained using finger plethysmography and Transcranial Doppler ultrasound while subjects were seated upright for 5 minutes. Transfer function analysis was used to evaluate dynamic CA.

Results

Higher phase (better CA) in the low‐frequency range (0.03–0.15Hz) was associated with smaller WMH volume (P = 0.02), higher FA (better microstructural integrity) in normal WM (P <0.001) and WMH (P= 0.001) and lower MD (better microstructural integrity) in normal WM (P= 0.006) and WMH (P= 0.012).

Conclusion

Our results suggest that higher WMH burden and loss of cerebral microstructure integrity are associated with impaired dynamic CA in elderly individuals.

Research supported by NIH T32 grant (5 T32 AG 23480–7).
Acute hypoxia in neonatal rats: a novel ACTH‐and cAMP‐independent control of adrenal function
Authors: Johnson Karl , Bruder Eric D , Engeland William C , Raff Hershel
Published: June 2021

The hypothalamic‐pituitary‐adrenal (HPA) axis plays a critical role in the adaptation to neonatal hypoxia. The classic adrenocortical response involves ACTH‐stimulated corticosterone (Cort) synthesis mediated by increased cAMP. We previously demonstrated that, in the neonatal rat, the Cort response to acute hypoxia shifts from ACTH‐independence to ACTH‐dependence between postnatal day (PD) 2 and 8. We now correlate plasma ACTH and Cort responses with adrenal cAMP content from PD2 and PD8 rats exposed to acute hypoxia. In PD2 rats, hypoxia elicited a minimal increase in plasma ACTH, no change in adrenal cAMP content, but a robust increase in plasma Cort. In PD8 rats, hypoxia elicited large increases in plasma ACTH, adrenal cAMP content, and plasma Cort, consistent with the classic mechanism of adrenocortical control. Preliminary results using adrenocortical cells in vitro to bioassay plasma corticotropic activity showed a hypoxia‐induced 3.5‐fold increase in PD2 plasma and a 1.7 fold increase in PD8 plasma, suggesting a humoral mechanism of stimulation of Cort in PD2 rats. The data indicate that the robust plasma Cort response to hypoxia in the PD2 rat does not require ACTH‐mediated increases in cAMP production in the adrenal. This ACTH‐and cAMP‐independent control of adrenocortical function, exhibited only in the newborn rat, may be due to a novel hormonal mechanism of zona fasciculata control. NSF IOS1025199
Lifestyle Intervention Reduces Skeletal Muscle Dynamin‐Related Protein‐1 (Drp1) Activation in Obese Insulin Resistant Humans
Authors: Fealy Ciaran Eoin , Mulya Anny , Kirwan John P
Published: June 2021

Mitochondria play a central role in cellular bioenergetics and metabolic homeostasis. Defects in mitochondrial dynamics, the processes of fission, fusion and mitochondrial autophagy, may contribute to metabolic disease including type 2 diabetes. Drp1 is a key regulator of mitochondrial fission. We hypothesized that an exercise/diet lifestyle intervention would decrease Drp1 mediated mitochondrial fission, increase fat oxidation, and contribute to increased insulin sensitivity in older (66±1 years) obese (BMI: 34.6±0.8 kg/m2) adults. Seventeen subjects performed supervised exercise for 60 min/d, 5 days/week at 80–85% of max heart rate, and were provided a eucaloric diet for 12 weeks. Insulin sensitivity was measured by hyperinsulinemic‐euglycemic clamp and fat oxidation was determined by indirect calorimetry. Skeletal muscle biopsies were obtained from the vastus lateralis muscle prior to each clamp. The lifestyle intervention increased insulin sensitivity 2.1±0.2 fold (P<0.01) and fat oxidation 1.3±0.3 fold (P<0.01). Phosphorylation of Drp1 at Ser616 was reduced (pDrp1:tDrp1: 0.58±0.14 vs 0.81±0.15, P<0.05) following the intervention. Furthermore, reductions in the pDrp1:tDrp1 ratio were negatively correlated with increases in fat oxidation (r=−0.58, P<0.05) and insulin sensitivity (rho=−0.52, P<0.05). These are the first data to suggest that lifestyle‐mediated improvements in substrate metabolism and insulin sensitivity in obese insulin resistant adults may be regulated through decreased activation of the mitochondrial fission protein Drp1.
Activation of intestinal NHE3 by insulin depends on the coordination of IRBIT, NHERF1, and Ezrin
Authors: He Peijian , Srinivasan Shanthi , Yun Chris
Published: June 2021

Diarrhea is one of the troublesome disorders of diabetic intestine, but the cause is not clear. We have shown that NHE3 activity is reduced in streptozotocin (STZ)‐induced diabetic intestine, and insulin treatment restores NHE3 activity. The goal of this study is to determine the mechanisms by which insulin activates intestinal NHE3. We found that expression of NHE3 and IRBIT, but not NHERF1–3 and Ezrin, was significantly decreased in the bush border membrane (BBM) of STZ‐treated mice. Insulin treatment restored BBM expression of NHE3 and IRBIT. In addition, we found by using Proximity Ligation Assay that insulin increased NHE3‐IRBIT, NHERF1‐IRBIT, and NHE3‐NHERF1 interaction in the apical membrane. Importantly, knockdown of either IRBIT or NHERF1 abrogated NHE3 activation in intestinal epithelial SK‐CO15 cells. Insulin also increased Ezrin phosphorylation and its interaction with NHERF1, IRBIT, and NHE3. Moreover, Ezrin was found in the same macromolecular complex with IRBIT, NHERF1 and NHE3 by blue native PAGE analysis, suggesting a role of Ezrin. In conclusion, insulin activates NHE3 trafficking and activity that depends on the formation of a macroprotein complex with IRBIT, NHERF1, and Ezrin.
Identification of candidate susceptibility genes in a murine model of respiratory syncytial virus (RSV)‐induced bronchiolitis
Authors: Verhein Kirsten C , High Monica , Marzec Jacqui , McCaw Zachary , Wiltshire Tim , Chen Yu , Burkholder Adam , Klimczak Les , Fargo David , Kleeberger Steven R
Published: June 2021

RSV is the most common cause of serious lower respiratory illnesses in infants and children. While genetic association studies have been reported for candidate susceptibility genes for RSV disease, no biomarkers exist for predicting severe versus mild disease. Here we use a combined genetics and genomics approach to understand the genetic basis of RSV disease susceptibility. We screened 32 inbred mouse strains for response to RSV by measuring disease phenotypes, including bronchoalveolar lavage inflammatory cells. Quantitative trait loci (QTL) were found for all disease phenotypes using SNPster (Novartis), and expression QTLs were identified with the FastMap haplotype algorithm. To identify transcripts differentially expressed at baseline that predict response to RSV, baseline mouse lung gene transcript expression for 24 strains of mice (Novartis) was correlated to phenotype data from the RSV strain screen using linear regression. These studies identified a battery of baseline gene transcripts significantly correlated with RSV disease severity. Disease and gene correlations in the final model were validated using cross validation. Together, these approaches have identified genetic markers of susceptibility to RSV disease to predict severe responders and potentially provide more effective therapeutic targets.

Supported by the NIEHS Intramural Program.
Age‐dependent differential gene expression in exposureresponse of contraction‐induced muscle injury
Authors: Ensey James , Li Shengqiao , Kashon Michael L , Hollander Melinda S , Cutlip Robert G , Baker Brent A
Published: June 2021

A high volume of repetitions that results in contraction‐induced muscle injury in young rats has been shown to have a more robust genomic response to the physiological trauma than similar paradigms in old rats. Thus, the purpose was to identify if this age‐dependent genomic signature was present in skeletal muscle following lower number of muscular contractions. The left dorsiflexor muscles of young (3 mo) and old (30 mo) male Fischer 344 × BN rats were injured using 30, 80 and 150 stretch‐shortening contractions (SSCs) at a velocity of 500°/s in vivo. Seventy‐two hours following exposure the left tibialis anterior muscle was harvested and RNA was isolated. cRNA samples were prepared and loaded onto Sentrix Rat‐Ref12 Beadchips for gene array analyses. With respect to contraction number, there was a graded up‐regulation in response of genes related to the inflammatory response (i.e. SPP1, MMP12, CD68), cell death (CTSS, CTSB, CTSL1) and muscle regeneration (i.e. ANXA1,S100A11, RPS6) in young rats following injurious SSCs, yet the same genes have an attenuated, and even opposite, response in old rats regardless of contraction number. These data suggest desensitization in the old rats’ ability to mount a competent response to graded contraction‐induced injury stimuli, which, ultimately, may adversely affect recovery kinetics following injury with increased age.
The Calculation of LD50 Using Probit Analysis
Authors: Akçay Aytaç
Published: June 2021

Probit analysis is a type of regression used to analyze binomial response variables. The statistical theory and techniques using probit analysis for analyzing data from dose‐quantal response experiments were developed by D.J. Finney (1971) and details are discussed in Finney (1978) and Robertson et al (2007). Data obtained from the bioassays are generally in percent response (mortality or affected) at the corresponding doses (or concentrations). The response is always binomial (e.g. death/no death) and the relationship between the response and the various concentrations is always sigmoid. Probit analysis acts as a transformation from sigmoid to linear and then runs a regression on the relationship. Once a regression is run, the researcher can use the output of the probit analysis to compare the amount of chemical required to create the same response in each of the various chemicals. There are many endpoints used to compare the differences of doses response, but LD50 are the most widely used outcomes of the modern dose‐response experiments. LD50 represent dose at which 50 % of the population responds. The critical LD50 values may be estimated from probits and log doses in several ways. The simplest is by graphical methods. Another is by using standard computation using a calculator (Finney 1971, Heong 1998). Step by step calculations are also available in Busvine (1971). The faster and more accurate way is using computer program or software. Several statistical packages like SAS, SPSS, R, Statistica etc. have probit analyses options. Aim of this study, to introduce the application of software SPSS 14.01 in calculation of LD50. The parameter estimates, probit analysis and graphs in probit transformed responses were output automatically. As a result, the calculation of LD 50 using Probit Analysis with SPSS is simple, rapid, visual and convenient.
Acceptability of pumping breastmilk among working mothers in Vietnam, a rapidly industrializing country
Authors: Henry Megan E. , Christian Parul , Kim Sunny S. , Pham Van , Nguyen Nam , Nguyen Phuong , Menon Purnima , Rawat Rahul
Published: June 2021

Previous research identified returning to work as a major barrier to exclusive breastfeeding (EBF) in Vietnam. Pumping breastmilk (BM) is a potential solution to this constraint. In the context of a process evaluation (PE) of the Alive & Thrive program to promote EBF, an analysis of in‐depth interviews with 22 rural Vietnamese mothers identified cultural facilitators and barriers to pumping BM. Facilitators included an awareness of the benefits of BM, a culture of predominant breastfeeding, and support from grandparents. Hand‐expressing BM was also common, but mainly for discarding some foremilk after activities such as washing dishes or returning from the market, which exposed the mother to ngoai (outside) influences and “cold” milk, causing infant stomach illness. Scientific knowledge about bacterial contamination reinforced negative perceptions of BM stored at room temperature. Mothers expressed concern that cooling and reheating BM stored in a refrigerator degraded it. Most mothers responded unfavorably to pumping, emphasizing the importance of milk directly from the breast, and formula feeding as the best alternative. An understanding of traditional practices and current pressures helps to identify challenges to pumping as a solution to continued breastfeeding in this context.

Grant Funding Source: Alive & Thrive, funded by the Bill & Melinda Gates Foundation and managed by FHI360
Transepithelial movement of intestinal pathogens is limited by γδ IEL occludin‐dependent migration
Authors: Edelblum Karen L , Singh Gurminder , McLeod Rima , Turner Jerrold R
Published: June 2021

Intraepithelial lymphocytes (IELs) expressing the γδ T cell receptor migrate extensively within the intestinal epithelium, which is primarily dependent on γδ IEL‐expressed occludin. Intravital microscopy was used to determine if enteric infection alters γδ IEL migration. Mucosal application of DsRed‐labeled Salmonella typhimurium (SL3201, 108 CFU) increased γδ IEL migration into the epithelial lateral intercellular space by 19%, particularly at sites of bacterial adhesion. Thus, we hypothesized that γδ IEL migration contributes to early innate immunity at mucosal surfaces. To assess the role of occludin‐dependent γδ IEL migration, mixed bone marrow chimeras were generated by engrafting irradiated hosts with γδ T cell‐deficient marrow (80%) with either wildtype GFPγδ or occludin knockout GFPγδ marrow (20%). Within 30 min, chimeras with occludin‐deficient γδ T cells displayed 3‐fold increases in S. typhimurium translocation relative to chimeras with occludin‐sufficient γδ T cells. Similarly, γδ IEL occludin‐deficiency increased Toxoplasma gondii (PRU, 10 cysts) translocation 1h after oral infection 3.5‐fold. In each case, pathogen invasion in chimeras with occludin‐deficient γδ T cells was similar to that in mice completely deficient in γδ T cells. These data show that occludin expression by γδ IELs is an important mediator of innate host defense, likely due to the role of occludin in γδ IEL migration.
Mechanisms for regulating splicing through signaling pathways
Authors: Lynch Kristen W
Published: June 2021

Recent insight into the human genome has revealed that most genes encode multiple distinct protein isoforms through the process of alternative pre‐mRNA splicing. Recently we have identified ~150 genes that exhibit an alteration in isoform expression in response to T cell stimulation. Through detailed studies of the regulated splicing of the protein tyrosine phosphatase CD45, we have identified the regulatory sequence and proteins that control activation‐induced isoform expression of CD45 as well as exons in several other genes essential for T cell function. Much of the regulation of CD45 exon inclusion is controlled by the multifunctional proteins hnRNP L and PSF (PTB‐associated splicing factor). Studies into how these proteins mediate exon repression has lead to new insight into mechanisms of alternative splicing. Moreover, we have gained extensive insight into how the activity of PSF, in particular, is regulated by the GSK3 signaling pathway. Progress in our understanding of the regulation of splicing of CD45 and other T cell related genes will be presented.
Daily almond consumption (1.5 oz.) decreases non‐HDL and remnant lipoproteins in mildly hypercholesterolemic individuals
Authors: Berryman Claire E , West Sheila G , Bordi Peter L , Fleming Jennifer A , Kris‐Etherton Penny M
Published: June 2021

Almonds independently improve total cholesterol, LDL‐C, HDL‐C, apo B, and apo A1, but their effects on emerging lipid risk factors are less well‐known. A randomized, 2‐period (6 wk/period), crossover, controlled‐feeding study was designed to investigate the effects of 1.5 oz./d almonds vs. a calorie‐matched, high CHO snack on CVD risk factors. Differences in nutrient profiles of the control (CON: 59% CHO, 15% PRO, 26% FAT, no almonds/d) and almond (ALD: 51% CHO, 16% PRO, 33% FAT, 1.5 oz. of almonds/d) diets were due to specific nutrients inherent to each snack and did not differ in saturated fat (~7%) or cholesterol (~110 mg/d). Subjects (n=53) were generally healthy adults (BMI 20–35 m/kg2) with elevated LDL‐C (50–95th percentile). Both diets decreased non‐HDL cholesterol (ALD: − 18.7 ± 2.5 and CON: −11.5 ± 2.6 mg/dl; P <0.01 for both); however, there was a greater decrease with ALD vs. CON (P <0.01). The diets had significantly different effects on remnant lipoproteins (ALD: −0.8 ± 1.1 vs. CON: 2.1 ± 1.1 mg/dl; P=0.02), but neither changed from baseline. Both diets reduced LDL1, LDL2, and LDL3 (ALD: −3.3 ± 0.7, −6.4 ± 1.4, −9.4 ± 1.6 and CON: −2.2 ± 0.7, −9.0 ± 1.4, −7.6 ± 1.7 mg/dl, respectively; P <0.01 for all), though there was a greater LDL2 reduction with CON vs. ALD (P=0.03). Almond consumption improves atherogenic lipoprotein subclasses, demonstrating cardiovascular risk reduction beyond established risk factors.

Grant Funding Source: Almond Board of California
Carbohydrate restriction reduces dyslipidemias associated with atherogenic lipoprotein profiles in Emirati men and women with metabolic syndrome
Authors: Al‐Sarraj Taif , Volek Jeff S , Saadi Hussein , Fernandez Maria Luz
Published: June 2021

We evaluated the effects of carbohydrate restricted diets (CRD) on atherogenic dyslipidemia by measuring lipoprotein subfractions and size and apolipoproteins in Emirati adults classified with metabolic syndrome (MetS). Participants (15 men/24 women) were randomly allocated to a CR diet [20–25% energy from carbohydrate (CHO)] (n = 20) or a combination treatment (n =19) consisting of CRD for 6 wk followed by a diet 50–55% CHO and < 30% fat diet for additional 6 wk. All subjects reduced body weight, LDL cholesterol and triglycerides (P < 0.01) post‐interventiion. After 12 wk, the large VLDL subfraction was decreased over time for subjects in the CRD group (P < 0.01) only. The number of medium and small LDL particles decreased for all subjects rendering a less atherogenic lipoprotein profile. In agreement with these results, a significant decrease in apolipoprotein (apo) B was observed (P < 0.01). The medium HDL subfraction and apo A‐II, which can be considered pro‐atherogenic, were also decreased over time in the CRD group only. These results suggest that weight loss favorably affects lipoprotein metabolism and that the CRD had a better effect on atherogenic VLDL and HDL than a diet containing 50–55% CHO
Using qualitative data to contrast the socio‐ecological conditions of low‐income pregnant and postpartum women
Authors: Graham Meredith , Olson Christine M , Paul Keriann , Niederdeppe Jeff
Published: June 2021

The socio‐ecological factors that affect the health of women of childbearing age are fairly well known, but the degree to which those factors become more debilitating after delivery is not well described. This qualitative study compares the challenges faced by low‐income women during pregnancy and postpartum. We conducted 5 pregnancy focus groups (n=15), 5 postpartum focus groups (n=23) and 7 interviews with WIC eligible women. All focus groups and interviews were recorded and detailed notes were taken. The constant comparative method was used to code notes and identify emergent themes. All of the women faced many challenges that affected their attitudes, beliefs and ability to maintain or improve healthy behaviors. Challenges included unemployment, relationship issues, minimal social support, lack of education, healthcare access, medical conditions and neighborhood disadvantage. Compared to pregnant women, postpartum women faced additional difficulties, such as child illnesses, custody issues and homelessness. While some women reported similar difficulties during pregnancy; the severity of those challenges was felt more deeply among postpartum women. A multitude of factors make women's lives increasingly difficult in the postpartum period, including challenges that are present prior to delivery, those present prior to but worse after delivery, and some new challenges that begin after delivery.
The interaction of tomato powder and soy germ on prostate carcinogenesis in the TRAMP model
Authors: Zuniga Krystle Erin , Smith Joshua W , Clinton Steven K , Erdman John W
Published: June 2021

Epidemiological and laboratory studies support the hypotheses that diets rich in soy or tomato products may reduce the risk of prostate cancer (PCa). The objective of this study was to examine the efficacy of dietary tomato and soy germ, alone and in combination, for prevention of PCa in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Four week old, male C57BL/6 × FVB TRAMP mice (n=119) were randomized to consume: AIN‐93G control, 10% tomato powder (TP), 2% soy germ (SG) or 10% tomato powder with 2% soy germ (TP+SG) for 14 weeks. Tomato lycopene and soy germ isoflavones were bioavailable and accumulated in the serum and prostate. 100% of mice fed the control diet had PCa, while incidence was significantly lower in mice consuming TP (61%, p<0.001), SG (66%, p<0.001) and TP+SG (45%, p<0.001). The protection offered by TP+SG was not synergistic, but it was quantitatively the most effective intervention. The ratio of proliferative index to apoptotic index in the prostate was over two times higher in the controls (161 ± 19) than mice consuming TP (75 ± 20, p=0.009), SG (62 ± 19, p=0.001) and TP+SG (70 ± 19, p =0.002), suggesting a greater stimulus for malignant progression in the control group. Maximally effective strategies for PCa prevention may result from optimizing combinations of nutrients and bioactives provided in scientifically designed novel food products targeting high risk populations.

Grant Funding Source: NIH (1 F31 CA153804‐01A1 and PHS‐1‐R01 CA125384)
Linking Inflammation to Tumorigenesis in a Mouse Model of High‐Fat‐Diet‐Enhanced Colon Cancer
Authors: Murphy E Angela , Day Stani D , Enos Reilly T , McClellan Jamie L , Steiner Jennifer L , Velazquez Kandy T
Published: June 2021

We examined the effect of a high‐fat‐diet (HFD) closely mimicking the standard American diet (12% and 40% of total caloric intake from saturated fat and total fat, respectively) on adiposity, polyp characteristics, macrophage markers, and inflammatory mediators in a mouse model of intestinal tumorigenesis. Male ApcMin/+ mice (7–8/group) were fed a control diet (Con) or high‐fat diet (HFD‐12%) from 4 to 12 weeks of age. Body weight and body composition were measured weekly and monthly, respectively. Intestinal tissue was analyzed for polyp burden (number and size). Macrophage markers and inflammatory mediators were examined in the adipose tissue and polyps. The HFD‐12% increased body weight, body fat percent, fat mass and blood glucose (P<0.05), which was associated with an increase in the number of large polyps (P<0.05), but not total polyps. This was linked to an elevation in macrophage markers and inflammatory mediators in the adipose tissue (F4/80, CD11c, TLR‐4 & MCP‐1) and tumor microenvironment (IL‐12, MCP‐1, IL‐6 & TNFa). In summary, a HFD diet similar to the standard American diet increased adiposity and promoted tumorigenesis in concert with alterations in macrophage phenotype and inflammation in adipose tissue and intestinal polyps.

This work was supported by an ASPIRE (Advanced Support Programs for Innovative Research Excellence) grant from the University of South Carolina to E.A.M.
Why children use dietary supplements
Authors: Bailey Regan L , Gahche Jaime J , Thomas Paul R , Dwyer Johanna T
Published: June 2021

Background

Dietary supplements are used by one‐third of children although the reasons motivating use remain uncertain.

Objective

To examine motivations for dietary supplement use, to characterize the types of products used for the most commonly reported motivations, and to relate supplement use to health and demographic factors.

Design

Motivations for use of dietary supplements reported for children (< 20; n = 8,245) in NHANES 2007–10, a nationally representative, cross‐sectional population‐based survey.

Results

Dietary supplements were used by 31% of children; many different reasons were given: to “improve overall health” (41%), to “maintain health” (37%), for “supplementing the diet” (23%), to “prevent health problems” (20%), and to “boost immunity” (14%). Most children (~90%) who use dietary supplements use a multivitamin‐mineral (MVM) or multi‐vitamin product. Only a small group of supplements used by children (15%) were based on the recommendation of a physician or other healthcare provider.

Conclusions

Nearly one‐third of children in the US use dietary supplements, most often 1 product and most frequently a MVM. Children most often report using dietary supplements to improve or to maintain overall health. Patterns of use of supplements have been consistent across time in the US: users tend to be non‐Hispanic white, have higher incomes, report more physical activity, and have health insurance.
Benzyl isothiocyanate enhances chemosensitivity and inhibits migration and invasion of head and neck squamous cell carcinoma
Authors: Wolf M. Allison , Bailiff Oksana , Hardman W. Elaine , Claudio Pier Paolo
Published: June 2021

Approximately 500,000 cases of head and neck squamous cell carcinoma (HNSCC) are reported worldwide each year. Despite recent improvements in cancer treatment, the increase in overall survival of advanced HNSCC has not improved in the past 3 decades. Consequently, our objective is to find new therapeutic options to enhance survival of patients with aggressive HNSCC. Benzyl isothiocyanate (BITC), a natural compound found in cruciferous vegetables, is showing promising results in targeting chemoresistant and metastatic HNSCC cell lines. Our current data suggests that BITC enhances sensitivity of HNSCC cell lines to cisplatin after 24, 48, and 72 hours. A migration assay indicated that the wound healing of metastatic HNSCC cell lines are inhibited by BITC in a dose dependent manner. Additionally, an invasion assay showed that BITC significantly inhibits HNSCC cell invasion towards the chemoattractant EGF after 20 hrs, in a dose dependent manner. Immunofluorescence and Western blot analysis suggest that treatment with BITC inhibits the expression of epithelial‐mesenchymal transition marker, vimentin, in the HN12 cell line. Therefore, the present results suggest that BITC may be able to enhance the effect of chemotherapy, while also reducing migration and invasion of HNSCC cells. Thus suggesting that BITC may be a novel adjuvant therapy for patients with aggressive HNSCC.

Grant Funding Source: American Society for Nutrition
Food intake modulation by hop phytoestrogen (PE) in overweight neutered cats
Authors: Backus Robert Christian , Rottinghaus George E. , Shaw Daniel P. , Jeusette Isabelle
Published: June 2021

Estrogen inhibition of food intake diminishes with neutering, often resulting in unhealthy weight gain. A potent hop PE, 8‐prenylnaringinen (8PN), may be a suitable source of estrogen‐replacement to stem excessive post‐neutering food intake. Ad libitum‐fed, adult (3.9–4.3 y), neutered males (n=6) of 105–148% of pre‐neuter weight (4.7–7.0 kg) received daily for 5 d subcutaneous (SQ) injections (20 μL/kg) of 8PN at 10, 50, 100, & 200 μg/kg, 17β‐estradiol (E2) at 0.1 μg/kg, and vehicle of sesame oil:ethanol (9:1). Using a Latin‐square design with 2‐week blocks and 9 washout days between injection treatments, food intake was found decreased (P<0.05) with injections of E2 (−41±7%) and 8PN at 100 (−17±3%) and 200 (−29±5%) μg/kg. Effectiveness of oral daily dosage for 5 d was subsequently evaluated. Vehicle (ethanol) and 8PN at 10‐fold the minimally effective SQ dose (1 mg/kg) were air‐dried on voluntarily ingested kibbles. Food intakes during 8PN and vehicle ingestions were not significantly different, indicating low oral 8PN bioavailability relative to E2. Potency for food intake modulation by 8PN appears much greater than that reported for genistein, a soybean PE, but much less than that found for E2.
Folate status in relation to cognitive function and decline in a population with high folic acid intake
Authors: Morris Martha Savaria , Beiser Alexa , Jacques Paul F , Seshadri Sudha , Selhub Jacob
Published: June 2021

Strong evidence links low folate status to cognitive impairment and decline, but conflicting results weaken the case for boosting folate status to preserve cognition in older age. Study results depend on the population's folate status and the cognitive domains tested. We investigated this association in a sample with a >;50% prevalence of supplement use, exposure to food folic acid fortification, and mean plasma folate in the supraphysiologic range (i.e., >;45 nmol/L). The subjects were 835 Framingham Offspring Cohort members aged ≥65 y who underwent comprehensive neuropsychological testing. We assessed cross‐sectional and longitudinal relationships between folate status and standardized test scores. Covariates were age, sex, education, ApoE4 status, diabetes, hypertension, CHD history, and the plasma vitamin B‐12 concentration (<270 pmol/L, n=259; ≥270 pmol/L, n=576). We failed to link higher folate status in this population to cognitive benefits. In fact, higher log‐transformed plasma total folate (continuous) was related to somewhat lower verbal recall scores (β=−0.07±0.04, P=0.055) overall, and the inverse association was statistically significant among subjects with lower vitamin B‐12 status (β=−0.16±0.07, P=0.024, Pinteraction=0.034). Higher folate status also predicted decline in visual recall (β=−0.09, P=0.045) and executive function (β= −0.11, P=0.042), regardless of vitamin B‐12 status (Pinteraction>;0.1). Folate status well above the replete range may worsen the effect of low vitamin B‐12 status on memory and generally hasten cognitive decline.