bluuebunny/crossref_metadata_2025_split huggingface dataset:
Muscle Progenitor Cells for the Restoration of Irreversibly Damaged Sphincter Function: A Pre‐Clinical Study
Authors: Eberli Daniel , Yoo James , Soker Shay , Atala Anthony 
Published: June 2021

Background:We explored the possibility of achieving functional recovery of the urinary sphincter muscle using cell‐based therapy. We investigated whether irreversibly damaged urinary sphincter function could be fully restored using autologous muscle progenitor cells (MPC).Methods:A model of urinary sphincter insufficiency was created by excising approximately 80% of the sphincter muscle in 26 dogs. Sphincter function was assessed by urodynamic studies on normal and damaged sphincters. Autologous MPC were injected into the damaged sphincter muscle and the animals were followed for up to 6 months after injection.Results:Animals with MPC injection were able to recover the sphincter pressure to approximately 80% of normal, while the pressures in the control animals dropped and remained at 20%. Histologically, the implanted cells that were labeled with the fluorescent dye tracer survived and formed new innervated muscle fibers.Conclusion:Autologous muscle progenitor cells are able to restore otherwise irreversibly damaged sphincter function in dogs. The injected cells are able to survive and form mature tissue within the damaged sphincter. This study demonstrates the feasibility of using autologous muscle precursor cells for the functional restoration of urinary sphincter muscle in patients with sphincter insufficiency.
Notch pathway activation in lentiviral encephalitis
Authors: Kofler Julia Konstanze , Wang Guoji , Bonneh‐Barkay Dafna , Murphey‐Corb Michael , Wiley Clayton Alexander 
Published: June 2021

HIV encephalitis is characterized by infiltration of the brain by infected macrophages, formation of microglial nodules, multinucleated giant cells, and subsequent synaptic and neuronal loss. The Notch signaling pathway plays an important role in cell fate decision during development, but more recently has also been shown to be activated under various pathologic conditions of the adult brain. We performed immunohistochemical studies to investigate activation of the Notch pathway in lentiviral encephalitis and found strong upregulation of Notch‐4 in HIVE and SIVE brains, but not in infected but non‐encephalitic cases. Notch‐4 reactivity was restricted to perivascular macrophages and microglial nodules. Variable Notch 4 expression was also seen in vessels. No upregulation of Notch‐4 in microglia/macrophages was observed in non‐infected control brains from patients with Alzheimer‘s disease, subacute stroke, and HSV encephalitis. Our results suggest that Notch‐4 activation in microglia/macrophages may be a process specific to lentiviral infection, and further studies are warranted to evaluate the contribution of Notch activation to neuronal degeneration in HIVE.NIH funding: MH01717, MH64921 and MH071151
Role of Annexin A2 in Glutamate‐induced Extracellular matrix (ECM) Changes and Retinal Ganglion Cell Death
Authors: Valapala Mallika , Vishwanatha Jamboor K 
Published: June 2021

Glutamate excitotoxicity mediated increase in intracellular Ca2+ levels has been implicated in the pathogenesis of glaucoma. The downstream events leading to RGC damage after excitotoxic injury are poorly understood. It is suggested that retinal ganglion cells (RGCs) respond to excitotoxic injury by activating protease‐mediated remodeling of the extracellular matrix (ECM) through the plasminogen activator (PA)‐plasminogen (PG) system which results in detachment induced apoptosis of RGCs. Annexin A2 is a Ca2+ and phospholipid binding protein, it serves as a proteolytic center at the cell surface by recruiting matrix remodeling proteases and their substrates. Our goal is to determine the role of the annexin A2 and its associated proteases in glutamate excitotoxicity. Here we characterize the expression of annexin A2 in rat retinal sections, primary RGCs and in a transformed cell line; RGC‐5. Live cell Ca2+ imaging and time lapse confocal microscopy demonstrate glutamate‐mediated Ca2+ influx in RGC‐5 cells. A23187, a Ca2+ ionophore increases the phospholipid binding affinity of annexin A2. We demonstrate that annexin A2 translocates to the membrane of RGC‐5 cells upon glutamate treatment in a process that is independent of new protein synthesis and regulated by Ca2+.These results suggest that annexin A2 acts as a facilitator in glutamate induced changes in the ECM and subsequent RGC death.(Supported in part by grants from the National Center for Minority Health and Health Disparities, NIH (P20 MD001633), and Alcon Research, Inc.)
APRIL (TNFSF13) Promotes Collagen Induced Arthritis and IL‐17 Production and Inhibits IFN‐gamma and IL‐4 Production
Authors: Xiao Yanping , Motomura Seiichi , Podack Eckhard R. 
Published: June 2021

APRIL or TNFSF13 is a member of TNF super family. Analysis of APRIL knock out (APRIL−/−) mice gave conflicting results regarding B and T cell immunity. Therefore, we generated and characterized APRIL−/− mice and studied collagen induced arthritis (CIA). We confirmed that APRIL−/− mice have low basal IgA levels in serum. Splenic T cell proliferation was found increased in APRIL−/− mice. In the CIA model, the incidence of arthritis was decreased in APRIL−/− mice by about 35%, while disease severity and onset were unaffected. In mice with arthritis, chick and mouse anti‐collagen II specific IgG2a isotype antibody titers were significantly lower in APRIL−/− mice than in w.t. mice. Restimulated lymph node cells of w.t. CIA mice had elevated IL‐17 production which was diminished in APRIL−/− mice. The difference in IL‐17 production was disease specific and not observed upon restimulation of CD4 cells or in other disease models. However, APRIL−/− CD4 cells produced increased levels of IL‐4 and IFN‐? upon restimulation. Our data indicate that APRIL deficiency is responsible for diminished IgG2a levels and for diminished IL‐17 production which may be causally related to the pathogenesis of CIA. The combined effects of APRIL on antibody and IL‐17 may explain the decreased incidence of clinical arthritis in APRIL−/− mice. Our studies reveal an important role for APRIL in the regulation of Th1, Th2 and Th17 cytokines.This study is supported by AI 061807 and AI 068515.
The effect of almonds on plasma lipids in persons with prediabetes
Authors: Wien Michelle Ann , Sabate Joan , Monahan‐Couch Lynn , Oda Keiji 
Published: June 2021

Background: Persons with prediabetes are at increased risk of developing cardiovascular disease, yet there is scant research on effective meal planning approaches in this population.Aim and Methods: To evaluate the effect of daily almond consumption on blood lipids of adults with prediabetes, we performed a 16‐week trial in 66 free‐living adults (48 women and 18 men; mean±SE age 53±10 years; BMI 30±5 kg/m2) instructed to consume a background meal pattern yielding 35% fat, 50% CHO and 15% protein. Participants were randomized to consume 20% of energy from almonds (almond‐enriched) or a meal pattern without nuts (nut‐free). Fasting total cholesterol (TC), LDL‐cholesterol (LDL‐C), HDL‐cholesterol (HDL‐C) and triglycerides (TG) were measured at baseline and weeks 8 and 16. Mixed model analysis was performed adjusting for baseline values with all time points included in the model.Results: Daily supplementation with almonds was associated with a greater reduction in LDL‐C [−9% vs. −1% (P=0.03)] and LDL‐C:HDL‐C [−13% vs. −1% (P=0.04) over the 16‐week trial. Almond participants had a significant reduction in LDL‐C [−10% (P = 0.01)] and a significant increase in HDL‐C [+5% (P=0.04)] at week 16 compared to baseline levels, resulting in a significant reduction in LDL‐C:HDL‐C (P=0.001).Conclusion: Daily almond consumption within a defined meal pattern is effective in improving blood lipids in adults with prediabetes.
Incidence and severity of hypoglycemia
Authors: Sutton Leslie , Chapman‐Novakofski Karen 
Published: June 2021

Hypoglycemia or fear of hypoglycemia may inhibit achievement of optimal blood glucose goals. A needs assessment was conducted to determine if education pertaining to hypoglycemia treatment/prevention was indicated. Twelve questions pertained to experience with low blood glucose; 5 determined the participant's locus of control [LOC]; and 10 identified the participant's stages of change. The survey was evaluated by an “expert panel” of four and then administered to participants of the Illinois Extension's Dining with Diabetes program [n=64]. Most had been diagnosed with diabetes by a physician [n=47], with the remaining taking care of someone with diabetes [n=17]. Most take oral agents [n=42]; few insulin [n=6]. Thirty‐five have had hypoglycemia, with 23 having values < 70 mg/dl. Most have been advised by their doctor (n=50) about hypoglycemia, but many still experience episodes (16 have episodes a few times/year; 13 have episodes several to many times/year). Almost all (92%) have an internal LOC regarding their health, but only about half (55%) do so regarding sickness prevention, indicating an interpretation difference between control over health and over sickness. Preliminary data support the need for additional education concerning the prevention and treatment of hypoglycemia.This research is supported by Illinois AMVETS Diabetes Education Research Program and Illinois Extension.
Effect of Almonds on Insulin Secretion and Insulin Resistance: A Randomized Controlled Cross‐over Trial
Authors: Kendall Cyril WC , Josse Andrea R. , Marchie Augustine , Nguyen Tri H. , Lapsley Karen G. , Jenkins David JA 
Published: June 2021

Background: Cohort studies have shown that nut consumption is strongly associated with a reduced risk of coronary heart disease (CHD). Intervention studies demonstrate that almonds reduce serum LDL‐C. However, their documented reduction in LDL‐C can only explain a proportion of the reduced CHD risk.Methods: Whole almonds, taken as snacks, were compared to low‐saturated fat (<5% energy) whole‐wheat muffins (control) in the therapeutic diets of subjects with hyperlipidemia. Twenty seven hyperlipidemic men and women each consumed three iso‐energetic (mean 423kcal/d) supplements for 1 month. Supplements consisted of full‐dose almonds (73±3g/d), half‐dose almonds plus half‐dose muffins, and full‐dose muffins. In each phase, subjects were assessed at weeks 0, 2 and 4.Results: No baseline or treatment differences were seen in fasting serum glucose, insulin, C‐peptide or calculated insulin resistance (HOMA‐IR). However, creatinine corrected, 24‐hour urinary C‐peptide output, a marker of daily insulin secretion, was significantly reduced on both the half‐ and full‐almond doses compared to the control (P=0.002 and P=0.004, respectively).Conclusion: Almond consumption reduced 24‐hour insulin secretion. This may be a further metabolic advantage of nuts that in the long‐term may help to explain the strong association between nuts and CHD risk reduction.Funding support: Almond Board of California
Guinea pig hippocampal 5‐HT1E receptors: a tool for selective drug development
Authors: Klein Michael Thomas , Smith Carol , Toohey Nicole , Teitler Milt 
Published: June 2021

Recent studies have indicated that the 5‐HT1ER, discovered in human brain tissue (Leonhardt et al, 1989), is not expressed in mouse or rat brain, but is expressed in guinea pig brain (Bai et al, 2004). Thus there have been few reports on 5‐HT1ER drug development. In order to establish an animal model that will allow 5‐HT1ER drug development we identified regions of the guinea pig brain that when homogenized exhibit 5‐CT, mesulergine, and sumatriptan ‐insensitive 3H5‐HT binding (characteristic of the 5‐HT1ER). The hippocampus was determined to have a receptor density sufficiently high for further analysis. In hippocampal homogenates, 100nM 5‐CT, 30nM ritanserin, and 100nM LY344864 were used to block high‐affinity 3H5‐HT binding at non‐1E binding sites. The Kd value of 3H5‐HT was found to be 5.7±0.7nM which is indistinguishable from the cloned receptor Kd of 5.7±0.6nM. Drug affinities for the hippocampal and cloned 5‐HT1ER binding were identical. These findings indicate the 3H‐5‐HT binding is specific to the guinea pig 5‐HT1ER and levels of receptors can be determined in various brain tissues. Autoradiographical analysis and signal transduction studies of 5‐HT1ER in guinea pig brain can thus be determined. This should provide important insights into possible functions of the 5‐HT1ER receptor and may predict the possible therapeutic potential of selective h5‐HT1ER agonists and antagonists.(Supported by MH56650)
Renal ischemia‐reperfusion injury (I/R) is prevented by adrenal glands removal
Authors: Ramírez Victoria , Trujillo Joyce , Valdez Rafael , Cruz Cristino , Gamba Gerardo , Bobadilla Norma A. 
Published: June 2021

We showed that spironolactone (Sp) prevented I/R injury by mechanisms that include preservation of renal blood flow (RBF), reestablishment of UNO2/NO3V, reduction of lipoperoxidation and cell apoptotic death, suggesting that aldosterone participates in promoting renal injury in this model. However, renal protection conferred by Sp could potentially due to unknown mechanisms. To evaluate if Sp renoprotection is mediated by blocking aldosterone actions, the effect of adrenalectomy (Adx) prior I/R injury was evaluated.Three groups of 7 rats were studied. Sham operated; rats underwent 20 min of bilateral ischemia and reperfusion (24h); Adx rats, 3 days before I/R. To prevent hypoglycemia in Adx rats, physiological doses of glucocorticoids were given. In collected urine samples, creatinine clearance (CrC), n‐acetil‐beta‐d‐glucosaminidasa (NAG) and protein excretion (Prot) were measured. After 24h, mean arterial pressure and renal blood flow (RBF) were recorded and one kidney was fixed for histopathological evaluation.As expected, I/R induced renal dysfunction as compared to sham group that was characterized by reduction of RBF (4±0.4 vs. 7±0.2) and CrC (0.4±0.1 vs. 1.5±±0.2). At histological level, I/R produced severe tubular necrosis and increased Prot (46.7±3.9 vs. 10.4±1.2) and NAG excretion (0.6±0.1 vs. 0.2±0.02). In contrast, in Adx group RBF and CrC were not affected by I/R (7.3±0.4 and 1.4±0.2 respectively). Moreover, histological signs of tubular injury were not observed, effect that was associated with NAG and Prot normalization.Our data show that aldosterone plays a central role in the pathogenesis of renal I/R injury and pointed out to Sp as a promising tool for renal protection against I/R.
Role of Angiotensin II internalization in the activation of Proximal Tubule Angiotensinogen
Authors: Gonzalez‐Villalobos Romer A , Satou Ryousuke , Kobori Hiroyuki , Navar L. Gabriel 
Published: June 2021

Angiotensin (Ang) II increases the expression of angiotensinogen (AGT) mRNA and protein by proximal tubules (PT) in the kidney; however the molecular mechanisms are unclear. Because Ang II internalization regulates several actions of this hormone in PT cells, studies were performed to determine if Ang II internalization is required for activation of AGT expression in these cells. Immortalized rat PT cells (IRPTCs) were exposed to Ang II (1 nM, 1 hour), with or without an AT1R blocker (candesartan, 10 μM), or an endocytosis inhibitor (PAO, 0.1 μM) before mRNA collection. AGT mRNA expression was determined by qRT‐PCR. Ang II internalization was determined by exposing cells to fluorescent‐Ang II (Alexa488‐Ang II, 100 nM, 15–240 min) and detecting intracellular fluorescent signal with an epifluorescence microscope. Ang II increased AGT expression by 20% (1.21 ± 0.19 vs. 1.00 in controls, p<0.05). This effect was both AT1R‐dependent and endocytosis‐dependent as it was prevented by candesartan (0.89 ± 0.24, NS) and by PAO respectively (0.93 ± 0.04, NS). Microscopy studies demonstrated that Ang II is internalized in a time‐dependent manner, with a signal shift from the cell membrane to the perinuclear area after 1 hour. In conclusion, Ang II internalization by PT cells is required for activation of the AGT gene, and this effect is concomitant with a signal shift that suggests Ang II translocation to perinuclear compartments.Work supported by NIH grants P20RR017659, HL26371 (LGN), (R01DK072408) (HK), and the COSEHC Warren Trust Fellowship award (RAGV).
CARDIOVASCULAR EFFECTS OF ACETYLCHOLINE MICROINJECTED INTO THE VENTROLATERAL PERIAQUEDUCTAL GRAY AREA OF RATS.
Authors: Deolindo Milena Vieira , Pelosi Gislaine Garcia , de aguiar Correa Fernando Morgan 
Published: June 2021

INTRODUCTIONThe periaqueductal gray area (PAG) is a mesencephalic region that is involved in the modulation of cardiovascular changes associated with behavioural responses. Among the neurotransmitters present in the PAG, acetylcholine (Ach) is also known to be involved in central cardiovascular control. In the present study, we attempted to study the cardiovascular effects of the microinjection of Ach into the ventrolateral portion of the PAG (vlPAG) of rats.METHODS: Male Wistar rats were used. Guide cannulas were implanted in the vlPAG for drug injection and a polyethylene catheter was implanted into the femoral artery for arterial pressure (AP) and heart rate (HR) recording using a computerized acquisition system. RESULTS: The injection of different doses of Ach (27 and 81nmol/50nL) into the vlPAG of unanaesthetized rats caused dose‐related depressor responses accompanied by bradycardia. However, the injection of different doses of Ach (27 and 81nmol/50nL) into the vlPAG of anaesthetized rats caused dose‐related depressor responses accompanied by tachycardia.CONCLUSION: The present results indicate that activation of cholinergic receptors within the vlPAG can evoke cardiovascular responses in rats.FINANCIAL SUPPORT: CNPq and Fapesp (05/57227‐0)
Scheduled sampling of cardiovascular parameters: how often should one collect data?
Authors: Guild Sarah‐Jane , Barrett Carolyn J , McBryde Fiona D , Van Vliet Bruce N , Malpas Simon C 
Published: June 2021

Long‐term measurement of variables such as heart rate (HR), blood pressure (BP) and sympathetic nerve activity (SNA) via telemetry in laboratory animals has become indispensable in cardiovascular physiology. Due to the significant amount of data recorded and battery life limitations many researchers use acquisition software to intermittently collect data over short time periods at scheduled time points. The question is how much data does one need to collect to accurately reflect the underlying average value?Three separate days (0000–2400) of HR, BP and integrated renal SNA data were used from each of 6 rabbits. Each day's data (collected as 2s averages) were resampled according to 60 sampling protocols to investigate both the quantity of data collected and the number of sampling periods, e.g. 4 hours sampling per day could be two 2 hour or twenty–four 10 minute periods.The error in estimating the actual mean was calculated for each sampling protocol by comparing each day's estimated mean with that calculated using the complete data set for that day. The results show that the error in estimating the daily mean of SNA using a given protocol is approximately double that of BP and HR and good estimations (<2% error) can be achieved by scheduled sampling, particularly if short sampling periods are spread throughout the day. Supported by the Health Research Council of New Zealand and University of Auckland Research Committee.
Assessment of potential hypertensive risk during circuit training in normotensive and hypertensive subjects.
Authors: Margonato Vittoria 
Published: June 2021

Combined aerobic‐anaerobic exercise seem to be a valid not pharmacological way to reduce hypertension. Circuit training (CT) is often used to train normotensive (N) and hypertensive (H) subjects, but not all the circuits are equal and some exercises could be dangerous for H.Objective of the study, conducted in accordance with Basic Principles of the Declaration of Helsinki, was: assessing the trend of blood pressure response of N and H during a CT session; defining which exercises in a CT are most safe for H; verifying the possible risks of a CT session to rise excessively blood pressure in H. Methods. 10 N and 10 H moderately trained males were enrolled. Arterial blood pressure was measured at rest and at the end of each exercise. Heart rate was recorded by a heart rate monitor. Subjects performed a 7 CT stations: bike 65–70–75% of HRmax,, leg press, leg extention, leg curl and squat. Results. Mean arterial blood pressure was significantly higher in H respect N. No difference was detected for leg‐extension and for bike 75% HRmax diastolic pressure. Leg curl, leg‐extension, leg press and bike at 65%HRmax resulted clinically safe. Bike at 70–75% HRmax and isometric squat overcame the upper limit of clinically safe exercise. Conclusions: It is necessary to monitor blood pressure during a CT programme as bike (70–75% of HRmax) and isometric squat evidenced a potential risk for H subjects.
Acid‐Sensing Ion Channel‐1a Differentially Contributes to Blood Pressure and Heart Rate Responses to Hypoxia and Hypercapnia
Authors: Sabharwal Rasna , Wemmie John A , Abboud Francois M , Chapleau Mark W 
Published: June 2021

Hypoxia and hypercapnia influence blood pressure (BP) and heart rate (HR) through multiple mechanisms including chemoreflex activation, central neural actions, and peripheral effects on heart and vasculature. Acid‐Sensing Ion Channel‐1 (ASIC1) is expressed in tissues implicated in hypoxia‐ and/or acid‐sensing including carotid body glomus cells, and sensory and central neurons. We hypothesized that ASIC1a contributes to BP and HR responses to hypoxia and hypercapnia. BP and HR were recorded by telemetry in ASIC1a−/− (n=5) and wild‐type (WT) mice (n=9) before and during 10‐min exposures to hypoxia (10% O2) and hypercapnia (5 and 10% CO2). Mean BP and HR during normoxia did not differ in ASIC1a−/− and WT mice (127±3 vs. 117±4 mmHg, 707±18 vs. 712±34 bpm). HR increased transiently during hypoxia in WT and ASIC1a−/− mice (+35±14 and +48±11 bpm), and then decreased over time as did BP. The hypoxia‐induced bradycardia and hypotension were significantly enhanced in ASIC1a−/− mice vs. WT (see Table, *P<0.05). Sustained hypercapnia also decreased HR and BP in WT mice. Notably, CO2‐hypotension did not occur in ASIC1a−/− mice despite an enhanced bradycardia (Table).We conclude that ASIC1a mediates hypercapnia‐induced hypotension but opposes the CO2‐bradycardia. In contrast, ASIC1a‐dependent mechanisms oppose hypoxia‐induced hypotension and bradycardia. The results suggest that ASIC1a may contribute to autonomic responses and to the direct cardiac and vascular effects of hypoxia and hypercapnia in a differential manner. (AHA 0725771Z, HL14388)