bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of bias of underlying literature in guidelines on its recommendations: assessment of the German fluoride guideline
Authors: Al Masri A. , Schiffner U. , Mourad M. S. , Schmoeckel J. , Joseph P. , Splieth C. H.
Published: November 2023

Purpose

The significance of the underlying literature in clinical guidelines can be weakened by the risk of bias, which could negatively affect the recommendations. Especially in controversial matters, such as fluoride use for caries prevention in children, biased results may be not reliable and lead to incorrect conclusions. This study was performed to detect bias in underlying literature of the German guideline for caries prevention using fluoride in children, where no consensus was reached between paediatricians and paediatric dentists.

Methods

Three tools used for risk of bias assessments of different study designs were RoB 2 for RCTs, ROBINS-I for non-randomized studies, and ROBIS for systematic reviews. For each study cited in the guideline two independent risk of bias assessments were performed. Disagreements were resolved by consensus.

Results

Out of 58 papers, 48.3% (n = 28) showed high risk of bias, with the majority in sections regarding fluoride tablets, fluoridated toothpaste, and paediatricians’ recommendations. 9 out of 20 recommendations and statements were based on studies with high risk of bias, all of which were in these three controversial sections. 13 out of 29 RCTs showed high risk of bias (44.8%), as all 13 non-randomized trials did, while only 2 of 16 (12.5%) systematic reviews had high risk of bias.

Conclusion

Considering risk of bias of cited studies in clinical guidelines may result in substantial changes in its recommendations and aid in reaching consensus. Efforts should be made to assess risk of bias of underlying literature in future clinical guidelines.
The role of loneliness and negative schemas in the moment-to-moment dynamics between social anxiety and paranoia
Authors: Chau Anson Kai Chun , So Suzanne Ho-wai , Barkus Emma
Published: November 2023

Social anxiety and paranoia often co-occur and exacerbate each other. While loneliness and negative schemas contribute to the development of social anxiety and paranoia separately, their role in the development of the two symptoms co-occurring is rarely considered longitudinally. This study examined the moment-to-moment relationship between social anxiety and paranoia, as well as the effects of loneliness and negative schemas on both experiences individually and coincidingly. A total of 134 non-clinical young adults completed experience sampling assessments of momentary social anxiety, paranoia, and loneliness ten times per day for six consecutive days. Participants’ negative-self and -other schemas were assessed with the Brief Core Schema Scale. Dynamic structural equation modelling revealed a bidirectional relationship between social anxiety and paranoia across moments. Loneliness preceded increases in both symptoms in the next moment. Higher negative-self schema was associated with a stronger link from paranoia to social anxiety; whereas higher negative-other schema was associated with a stronger link from social anxiety to paranoia. Our findings support the reciprocal relationship between social anxiety and paranoia. While loneliness contributes to the development of social anxiety and paranoia, negative self and other schemas appear to modify the relationships between the two symptoms.
SSR molecular marker developments and genetic diversity analysis of Zanthoxylum nitidum (Roxb.) DC
Authors: Zhu Yanxia , Ma Tao , Lin Yang , Peng Yude , Huang Yuan , Jiang Jianping
Published: November 2023

Zanthoxylum nitidum (Roxb.) is a commonly used traditional Chinese medicine. However, the collection and protection of wild germplasm resources of Z. nitidum are still insufficient, and there is limited research on its genetic diversity and fingerprint. In the present study, 15 simple sequence repeat (SSR) markers were developed by genotyping based on multiplexed shotgun sequencing. The genetic diversity of 51 populations (142 individuals) of Z. nitidum was evaluated using these 15 SSRs. A total of 245 alleles (Na) were detected, with an average value of 16.333, and the average polymorphism information content was 0.756. The genetic distance among 51 populations was 0.164~1.000, with an average of 0.659. Analysis of molecular variance showed low genetic differentiation (40%) and high genetic differentiation (60%) between populations and individuals, respectively. The genetic differentiation coefficient (Fst) of the population was 0.338, indicating that 66.2% of the genetic variation occurred within the population, and the gene flow (Nm) was 0.636, demonstrating that the gene exchange between populations was low. Clustering analysis revealed that the genetic similarity coefficient was 0.30, dividing the 51 populations into 4 groups of 2, 17, 3, and 29 populations. There was no specific relationship between geographical location differences and genetic distance. The genetic diversity level of Z. nitidum is relatively high, and our results provide a theoretical basis for the rapid identification of Z. nitidum germplasm resources and variety selection.
Unveiling human origins of replication using deep learning: accurate prediction and comprehensive analysis
Authors: Yin Zhen-Ning , Lai Fei-Liao , Gao Feng
Published: November 2023

Accurate identification of replication origins (ORIs) is crucial for a comprehensive investigation into the progression of human cell growth and cancer therapy. Here, we proposed a computational approach Ori-FinderH, which can efficiently and precisely predict the human ORIs of various lengths by combining the Z-curve method with deep learning approach. Compared with existing methods, Ori-FinderH exhibits superior performance, achieving an area under the receiver operating characteristic curve (AUC) of 0.9616 for K562 cell line in 10-fold cross-validation. In addition, we also established a cross-cell-line predictive model, which yielded a further improved AUC of 0.9706. The model was subsequently employed as a fitness function to support genetic algorithm for generating artificial ORIs. Sequence analysis through iORI-Euk revealed that a vast majority of the created sequences, specifically 98% or more, incorporate at least one ORI for three cell lines (Hela, MCF7 and K562). This innovative approach could provide more efficient, accurate and comprehensive information for experimental investigation, thereby further advancing the development of this field.
Alfalfa weevils (Coleoptera: Curculionidae) in the western United States are resistant to multiple type II pyrethroid insecticides
Authors: Rodbell Erika A , Caron Christopher G , Rondon Silvia I , Masood M Umer , Wanner Kevin W
Published: November 2023

The alfalfa weevil (Hypera postica Gyllenhal (Coleoptera: Curculionidae)), a key pest of alfalfa (Medicago sativa L. (Fabales: Fabacae)) across the US, has developed resistance to pyrethroids lambda-cyhalothrin and zeta-cypermethrin in at least 6 western US states. Unfortunately, 6 pyrethroid active ingredients represent most commercial insecticides registered for alfalfa weevil control in forage alfalfa systems. Thus, the loss of efficacy of this mode of action group due to multiple resistance represents a significant agricultural challenge because of a limited registered alternative mode of actions. To evaluate the extent and severity of resistance among pyrethroids around the United States, laboratory bioassays using larvae from Arizona, California, Montana, Oregon, Washington, and Wyoming, including both the Egyptian and western strains, were conducted. Results indicated that similar degrees of resistance among type II pyrethroids as determined by both laboratory bioassays and field trials exist. The LC50 values of alpha-cypermethrin, beta-cyfluthrin and zeta-cypermethrin produced significant correlations with the LC50 values of lambda-cyhalothrin. In contrast, resistance did not include type I pyrethroid, bifenthrin (registered for seed alfalfa production), whose LC50 values yielded a slope not significantly different from zero when correlated with lambda-cyhalothrin. Field trials conducted in Arizona, Montana, and Washington corroborated laboratory results, as commercial formulations with type II pyrethroid active ingredients failed to adequately control alfalfa weevils resistant to lambda-cyhalothrin. Integrated resistance management recommendations are discussed.
Large mandibular mass with several floating teeth: granular cell ameloblastoma
Authors: Razmi Samuel E , Hayden Richard E , Chang Brent A
Published: November 2023

Ameloblastomas are benign, locally aggressive, odontogenic epithelial neoplasms. We present a patient with a rare granular cell ameloblastoma. This is a case report and literature review conducted from July 2022 to the present. Our 52-year-old male patient presented to the clinic with a several month history of right lower lateral lip swelling and dental complaints. On imaging and physical exam, we noticed a large heterogenous, multiloculated, expansile lesion of the right mandible with several floating teeth. After incisional biopsy confirmed multicystic granular cell ameloblastoma, the patient underwent successful surgical resection and osteocutaneous fibula free-flap reconstruction. At the time of writing this report, 7 years after resection, the patient is alive with no evidence of recurrence. The recognition and treatment of mandibular lesions can represent significant clinical challenges, especially for rarely seen subtypes such as the granular cell ameloblastoma. Special consideration must be given for the identification and treatment of these neoplasms.
The role of the right to life in respect of deaths caused by negligence in the healthcare context
Authors: Wicks Elizabeth
Published: November 2023

This article investigates the question of whether a death caused by negligence in the healthcare context is capable of violating the right to life under Article 2 of the European Convention on Human Rights. This provision imposes extensive positive obligations upon Contracting States, including an operational duty to take reasonable steps to save a life that they know, or ought to know, is at risk. This article addresses the question of exactly when such an operational duty arises, with particular focus on the healthcare context in which deaths caused by medical negligence have not traditionally been regarded as amounting to violations of the right to life. This article argues that two key factors in determining the existence of an operational duty to save life are the assumption of responsibility and nature of risk. It also argues for the need to take surrounding circumstances into account and for an increased use of the right to life in holding public bodies to account for deaths caused by negligence in the healthcare context.
Fiber intake and fiber intervention in depression and anxiety: a systematic review and meta-analysis of observational studies and randomized controlled trials
Authors: Aslam Hajara , Lotfaliany Mojtaba , So Daniel , Berding Kirsten , Berk Michael , Rocks Tetyana , Hockey Meghan , Jacka Felice N , Marx Wolfgang , Cryan John F , Staudacher Heidi M
Published: November 2023

Context

Dietary fibers hold potential to influence depressive and anxiety outcomes by modulating the microbiota–gut–brain axis, which is increasingly recognized as an underlying factor in mental health maintenance.

Objective

Evidence for the effects of fibers on depressive and anxiety outcomes remains unclear. To this end, a systematic literature review and a meta-analysis were conducted that included observational studies and randomized controlled trials (RCTs).

Data sources

The PubMed, Embase, CENTRAL, CINAHL, and PsychINFO databases were searched for eligible studies.

Data extraction

Study screening and risk-of-bias assessment were conducted by 2 independent reviewers.

Data analysis

Meta-analyses via random effects models were performed to examine the (1) association between fiber intake and depressive and anxiety outcomes in observational studies, and (2) effect of fiber intervention on depressive and anxiety outcomes compared with placebo in RCTs. A total of 181 405 participants were included in 23 observational studies. In cross-sectional studies, an inverse association was observed between fiber intake and depressive (Cohen’s d effect size [d]: −0.11; 95% confidence interval [CI]: −0.16, −0.05) and anxiety (d = −0.25; 95%CI, −0.38, −0.12) outcomes. In longitudinal studies, there was an inverse association between fiber intake and depressive outcomes (d = −0.07; 95%CI, −0.11, −0.04). In total, 740 participants were included in 10 RCTs, all of whom used fiber supplements. Of note, only 1 RCT included individuals with a clinical diagnosis of depression. No difference was found between fiber supplementation and placebo for depressive (d = −0.47; 95%CI, −1.26, 0.31) or anxiety (d = −0.30; 95%CI, −0.67, 0.07) outcomes.

Conclusion

Although observational data suggest a potential benefit for higher fiber intake for depressive and anxiety outcomes, evidence from current RCTs does not support fiber supplementation for improving depressive or anxiety outcomes. More research, including RCTs in clinical populations and using a broad range of fibers, is needed.

Systematic Review Registration

PROSPERO registration no. CRD42021274898.
897. Patients with Mpox, Minnesota, 2022
Authors: Lehnertz Nicholas , Babcock Marcie , Ruprecht Ali , Griffith Jayne , Lynfield Ruth
Published: November 2023

Background

A global outbreak of mpox occurred in 2022; we evaluated characteristics of mpox patients in Minnesota.

Methods

Cases of mpox are reportable to the MN Department of Health (MDH). Cases are interviewed to collect demographic, exposure and clinical information; medical records from hospitalized patients (HP) are reviewed to collect data on clinical course, testing and treatment.

Results

Between June 25 and November 5, 2022, 234 lab-confirmed cases of mpox, including 10 HP and 0 deaths were reported; 85% cases were interviewed. Overall median age was 34 years (IQR 29-43), 59% White, 92.3% male and 34% persons living with HIV (PWH). One outpatient received JYNNEOS vaccine > 14 days prior to symptoms; no HP received vaccine. Unstable housing and substance use were reported in 5 and 7 HP respectively. HP, if PWH were 4.1 times more likely to have CD4< 200 or detectable virus (p=0.035). Reasons for hospitalization included oropharyngeal pain/airway compromise (4), painful proctitis (1), isolation (2), epididymitis/orchitis (1), and preseptal cellulitis (1). The median length of initial stay was 4.5 days (range 1-10). A case with concomitant GAS pharyngitis (not PWH) required intubation and prolonged stay. Other longer length of stay occurred for isolation (2 PWH) and for PWH who had non-suppressed HIV and severe mpox disease.

Among HP, mean orthopox testing occurred 6.1 days (range 0-14) and mean tecovirimat initiation 8.6 days (range 3-18), following symptom onset; similar to outpatient cases. Three HP received no mpox therapies (including 1 PWH). Of 5 HP and PWH, 3 had CD4 < 100; all received tecovirimat. One PWH (with CD4 36) required 3 hospitalizations totaling 69 days and multiple courses of po (108 days) and IV (26 days) tecovirimat, VIGIV (6), brincidofivir (4), cidofovir (7), and topical and intralesional cidofovir.

Conclusion

Approximately 4% of reported mpox were HP; reasons varied including unstable housing and need for isolation. Very severe courses occurred in a patient with GAS superinfection and 1 of 3 PWH with low CD4. Attention to potential superinfection, HIV infection and suppression are important. Efforts must be strengthened to reach at risk populations, including those with less access to care, for education and mpox vaccination.

Disclosures

All Authors: No reported disclosures
Patient Priorities Concerning Treatment Decisions for Advanced Neuroendocrine Tumors Identified by Discrete Choice Experiments
Authors: Anaka Matthew , Chan David , Pattison Sharon , Thawer Alia , Franco Bryan , Moody Lesley , Jackson Christopher , Segelov Eva , Singh Simron
Published: November 2023

Background

Patients with advanced neuroendocrine tumors (NETs) have multiple treatment options. Ideally, treatment decisions are shared between physician and patient; however, previous studies suggest that oncologists and patients place different value on treatment attributes such as adverse event (AE) rates. High-quality information on NET patient treatment preferences may facilitate patient-centered decision making by helping clinicians understand patient priorities.

Methods

This study used 2 discrete choice experiments (DCE) to elicit preferences of NET patients regarding advanced midgut and pancreatic NET (pNET) treatments. The DCEs used the “potentially all pairwise rankings of all possible alternatives” (PAPRIKA) method. The primary objective was to determine relative utility rankings for treatment attributes, including progression-free survival (PFS), treatment modality, and AE rates. Ranking of attribute profiles matching specific treatments was also determined. Levels for treatment attributes were obtained from randomized clinical trial data of NET treatments.

Results

One hundred and 10 participants completed the midgut NET DCE, and 132 completed the pNET DCE. Longer PFS was the highest ranked treatment attribute in 64.5% of participants in the midgut NET DCE, and in 59% in the pNET DCE. Approximately, 40% of participants in both scenarios prioritized lower AE rates or less invasive treatment modalities over PFS. Ranking of treatment profiles in the midgut NET scenario identified 60.9% of participants favoring peptide receptor radionuclide therapy (PRRT), and 30.0% somatostatin analogue dose escalation.

Conclusion

NET patients have heterogeneous priorities when choosing between treatment options based on the results of 2 independent DCEs. These results highlight the importance of shared decision making for NET patients.
The Interrupted Learner – How Students’ Choices to Attend Lectures or Watch Lecture Video Recordings Influence Learning Outcomes in a Medical Histology Course
Authors: Hortsch Michael , Burk‐Rafel Jesse , Zureick Andrew H. , Purkiss Joel
Published: November 2023

New instructional technologies are increasingly used in today's quickly changing learning environment. The classical lecture format is often supplanted by recordings of lectures that can be streamed by students at a time of their choosing. The published literature presents varying conclusions regarding how students accept this alternative learning experience and how it impacts their learning and academic success. A multi‐year study of the first‐year (M1) histology component at the University of Michigan Medical School revealed that students strongly prefer the use of electronic learning resources (Holaday et al., Med. Sci. Educ., 23: 607–19, 2013). In addition, performance on M1 histology examinations is positively correlated with attendance at live lectures and is negatively correlated with the use of video recordings of the same lecture (Selvig et al., Anat. Sci. Educ., 8: 1–11; 2015). Two recent classes of University of Michigan M1 students (n=304; 90.2% participation rate) were surveyed in greater depth regarding their lecture attendance and lecture video usage. This analysis was aimed to identify factors that modulate the relationship between learning outcomes and the use of live lectures versus lecture videos. Students’ resource choices and usage patterns were analyzed and correlated with examination results in histology, anatomy, biochemistry, and physiology. We identified several usage behaviors that were negatively correlated with histology examination results. Students who attended live lectures while engaging in non‐lecture activities (e.g., social media, reading emails, Internet browsing) performed poorly on histology examinations compared to attendees who did not engage in these activities. Similarly, students who watch lecture videos and report being interrupted, feeling sleepy, or engaging in non‐lecture activities score lower on histology assessments than their non‐distracted counterparts. Similar correlations and patterns between subject test scores and lecture attendance versus lecture video usage were also observed for gross anatomy and biochemistry, but not for physiology. Students, who reported always attending live lectures, had the highest average subject test scores for all four subjects. These results indicate that the effectiveness of either learning modality (e.g., a live lecture or lecture video) is modulated by a number of factors, including the didactic context in which the lecture is offered and how it is used by learners.
The Ying And Yang Of Antibiotic Discovery And Resistance
Authors: Wright Gerry
Published: November 2023

Resistance to antibiotics is ancient and pervasive in the microbial world. The presence of resistance elements in the genomes of virtually all bacteria and their ability to circulate across genera presents a daunting challenge to the drug discovery sector. The tension between antibiotic discovery and resistance must be managed in order to maintain an ability to produce new drugs and antimicrobial regimens needed by medicine. By harnessing our understanding of the natural history of antibiotic biosynthesis and resistance we can direct efforts to identify candidates for new drugs. One such approach is through applying resistance as a filter to identify microbes that produce known classes of antibiotics. Another is to target resistance itself to find potential co‐drugs that can be used in combination with antibiotics. We have develop a cell‐based platform that can be applied in both strategies. Using this approach, we have identified new inhibitors of resistance and producers of new and rare antibiotics.

Support or Funding Information

This work is supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.
Greater β‐Adrenergic Receptor Mediated Vasodilation in Women Using Oral Contraceptives
Authors: Peltonen Garrett L , Limberg Jacqueline K , Johansson Rebecca E , Harrell John W , Kellawan J. Mikhail , Crain Meghan K , Eldridge Marlowe W , Sebranek Joshua J , Walker Benjamin J , Schrage William G
Published: November 2023

Premenopausal women exhibit greater peripheral β‐adrenergic receptor (β‐AR) mediated vasodilation when compared to postmenopausal women, suggesting changes in female sex hormones may alter neurovascular control. Oral contraceptive use modulates cyclic hormonal profiles and therefore may influence β‐AR mediated vasodilation. We hypothesized β‐AR mediated vasodilation is greater in young (24±1 yrs), healthy women using oral contraceptives (OC+, n=13) compared to those not using oral contraceptives (OC−, n=12). Forearm blood flow (FBF) was measured by Doppler ultrasound during graded brachial artery infusion of the β‐AR agonist, isoproterenol (ISO: 1, 3, 6, and 12 ng/100g lean tissue/min). Forearm vascular conductance was calculated (FVC = FBF/MAP, ml/min/100mmHg), and the rise in FVC during ISO infusion (DFVC; FVCinfusion − FVCbaseline) was used to quantify β‐AR mediated vasodilation. Women were studied during the early follicular phase of the menstrual cycle (days 1–5) or low hormone phase of oral contraceptive use. ISO increased FVC in both groups (p<0.001). In support of our hypothesis, ISO mediated ΔFVC was greater in OC+ compared to OC− (main effect of group, p=0.020). Expressing data as FVC, FBF, and ΔFBF resulted in similar conclusions. These data are the first to demonstrate greater β‐AR mediated vasodilation in OC+ compared to OC−, and suggest altered hormonal profiles associated with oral contraceptive use may influence neurovascular control.

Support or Funding Information

NIH R01 HL105820
Renal Afferent Neurons are altered by Lipopolysaccharides (LPS)
Authors: Rodionova Kristina , Ditting Tilmann , Loosen Sonja , Ziemer Martin , Linz Peter , Ott Christian , Schmieder Roland E , Amann Kerstin , Veelken Roland
Published: November 2023

Sympathetic renal nerve activity (RSNA) is dramatically increased in lipopolycaccharide (LPS)‐incduced SIRS. This might be due to altered properties of renal afferent nerves (RANs), which exert complex neurogenic sympatho‐modulatory and paracrine effects. Hence, we wanted to test the hypotheses that LPS alters the TRPV1 receptor induced CGRP release from RANs in kidney tissue slices and/or the firing patterns and acid induced inward currents in cultured neurons. 1.) Anethetized male Sprague‐Dawley rats were treated with (E.coli O127/B8,20mg/kg IV) while blood pressure (BP), heart rate (HR), RSNA was measured. 2.)Dorsal root ganglion neurons (Th11‐L2) of rats were incubated with LPS (E.coli O127/B8,20mg/l) 12h before patch clamp recordings. Inward currents were assessed during stimulation of TRPV1 and ASICs with protons (pH6,9 and 5,0). Current clamp mode was performed at physiological conditions and after 12h of LPS‐incubation. Neurons were characterized as tonic, i.e. sustained AP firing or phasic, i.e.<5 APs in response to current injections. In an organ bath of kidney slices – incubated with or without LPS ‐ we stimulated TRPV1 receptors with Capsaicin and subsequently measured CGRP content in the organ bath supernatant (ELISA).

1.) In vivo measurements showed a strong increase of RSNA (+250%, p<0.05) and HR (+25%, p<0.05) while BP did not change significantly. 2.) Firing patterns and currents induced by acidic superfusion were studied in 246 neurons. Renal neurons (RNs) exhibited in 59% tonic firing pattern under control conditions. The number of neurons with tonic response was significantly reduced by exposure to LPS (59% vs.42%, p<0,05). Under control conditions 70,8% of RNs exhibited both sustained and transient inward currents, whereas 29,2% showed sustained current only. LPS exposure significantly increased sustained, i.e. TRPV1 induced current (−793,18+/−66pA vs.−1224+/−200pA,p<0,05) and transient, i.e. ASICs induced inward current even under subthreshold proton stimulation (pH6,9) which could not be enhanced further by pH5,0. 3. Neurogenic CGRP release from kidney due to TRPV1 stimulation was also significantly increased after LPS incubation (LPS: 58□20 pg/ml, control: 14□2, *p<0.05).

LPS altered the properties of neurons with renal axons in a complex way: while the ease of AP production was significantly decreased, the responsiveness to acidic milieu was increased. The TRPV1 induced CGRP release (likely from renal afferent nerves) was also increased.

In how far these findings subserve neurogenic alterations in the kidney due to increased sympathetic drive and neural peptide release during experimental sepsis needs further research.
Functional changes of rostral ventrolateral medulla by nitric oxide from iNOS in conscious obese rats
Authors: Martins‐Pinge Marli Cardoso , Lopes Fernanda Novi Cortegoso , Zanluqui Nagela Ghabdan , Pinge‐Filho Phileno
Published: November 2023

The literature shows that obese animals present changes in the production of nitric oxide (NO). NO plays an important role in cardiovascular function, and the production via the inducible NO‐synthase (iNOS) is linked to inflammatory processes. In the rostral ventrolateral medulla (RVLM), glutamate is an important neurotransmitter and is modulated by NO. We aimed to evaluate the effects of L‐glutamate microinjection in RVLM on mean arterial pressure (MAP) and heart rate (HR) before and after microinjection of iNOS inhibitors and to asses NO (nitrite) in punchs of RVLM. The protocols were approved by our institutional ethic committee (process number: 33645/2010‐29). Neonatal Wistar rats received subcutaneous administration of 4 mg/g body weight of monosodium glutamate (MSG) or saline in the first 5 days of life. At 90 days were implanted cannulas guide to RVLM and after after 5 days, we performed catheterization of the femoral artery. After 24 hours the MAP and HR were recorded. The cardiovascular effects of glutamate (5nmol/100 ml) were evaluated before and after microinjection of aminoguanidine (AG) (250pmol/100NL) or S‐methylisothiourea (SMT) (250 pmol/100 ml) or physiological saline (100 ml) at RVLM. The increased MAP by L‐glutamate was higher in the obese group after AG (before: 40 mmHg ± 8; after: 61 ± 4 mmHg, n = 5) and SMT (before: 45± 8 mmHg; after: 65 ± 2 mmHg, n = 5). NO contend in the RVLM, showed a trend of MSG group is increased compared to the CTR (CTR 1.24 ± 0.33 uM/mg, n = 6; MSG 2.7 ± 1 uM/mg, n = 5). The data suggest that NO, probable derived from iNOS seems to be increased in RVLM of obese rats, and may have a role in the RVLM‐mediated cardiovascular responses.

Support or Funding Information

CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior)
Renal Denervation in male rats attenuates changes in cardiac sympathetic innervation in post‐infarction heart failure
Authors: Pinkham Maximilian I , Loftus Michael , Amirapu Satya , Barrett Carolyn J
Published: November 2023

Following myocardial infarction (MI) a decrease in the expression of sympathetic nerves in the myocardium remote from the infarct has been observed. Reduced sympathetic innervation of the cardiac ventricles is implicated in attenuated contractility and arrhythmia development, contributing to the development and progression of heart failure. Renal denervation is currently being investigated both clinically and experimentally as a treatment for heart failure, yet the precise mechanisms by which renal denervation may be beneficial are not completely understood. In the current study we set out to determine the effects of renal denervation on the expression of sympathetic nerves in the cardiac ventricles of rats with post‐infarction heart failure. MI or sham MI was performed in male Wistar rats and 4 weeks later renal denervation or sham surgery was performed. 7 weeks post‐MI, left ventricle function was assessed and then the hearts were removed and post‐fixed overnight in paraformaldehyde (4%). The hearts were then embedded in paraffin wax and stored until processing. Tyrosine‐hydroxylase (TH) immunoreactivity (IR) was used to visualize the sympathetic nerves and PGP 9.5 IR was used to visualize total nerves. The area density of the target nerves was quantitatively assessed using threshold discrimination. In sham MI animals, renal denervation did not alter the density or distribution of sympathetic and total nerves in the left and right ventricles. In the MI groups, the myocardium directly adjacent to the infarct border zone (peri‐infarct) displayed significantly reduced nerve density, almost complete denervation, when compared to areas remote from the infarct and this effect was unaltered by renal denervation. In both MI groups, particular areas within the infarct were observed to have a high density of sympathetic innervation. In animals with intact renal nerves, post‐infarction heart failure resulted in reduced expression of sympathetic and total nerves in the left and right ventricles, remote from the infarct. Renal denervation in animals with post‐infarction heart failure increased the sympathetic and total nerve density in the left and right ventricles remote from the infarct thereby abolishing the statistically significant difference in nerve density when compared to sham MI group. The current findings suggest that renal denervation may be beneficial in heart failure via attenuating adverse changes in cardiac innervation. In particular, renal denervation resulted in the conservation of sympathetic nerves in the ventricles consistent with improved contractility and reduced arrythmogenisis.

Support or Funding Information

This research was supported by a grant from The National Heart Foundation of New Zealand
High fat diet induced hypertension and impaired glucose tolerance in the Obesity‐Prone Sprague Dawley rat: Effect of increased salt intake and renal denervation
Authors: Han Ruijun , Banek Christopher T , Asirvatham‐Jeyaraj Ninitha , Wang Xinying , Osborn John
Published: November 2023

Cardiovascular disease, including hypertension (HTN), remains a leading cause of morbidity and mortality worldwide. Indeed, high fat (HFD) and high salt (HSD) diets are closely linked to HTN development, but the mechanisms remain undefined. Moreover, HTN in these models is widely attributed to an increase in sympathetic nerve activity, particularly to the kidney, which is attenuated renal denervation (RDNX). This study was designed to elucidate the combined effects HFD and HSD in the development of HTN. Further, we hypothesized that HTN and impaired glucose tolerance commonly induced by a HFD would be exacerbated by increased salt intake. In addition, we predicted these effects would be attenuated or reversed by RDNX. To test this hypothesis, obesity prone Sprague Dawley male rats were fed with either a low fat diet (LFD; 10 KCal% fat, n=12) or a high fat diet (HFD; 45 KCal% fat, n=12) for 8 weeks, then switched to either a low (0.26% sodium chloride, LSD, n=5) or high sodium (4% sodium chloride, HSD, n=7) diet for an additional 6 weeks. Mean arterial pressure (MAP) was measured by radiotelemetry, and bodyweight and glucose clearance were also measured. At study termination, tissues and plasma were collected for further analysis. HFD rats exhibited increased body weight, and impaired glucose tolerance compared to LFD rats. Addition of HSD feeding had no additional effect on bodyweight or glucose tolerance. MAP in HFD rats was higher (123±2 mmHg) compared to LFD rats (114±2mmHg). HSD had no further hypertensive effect in HFD‐treated animals. RDNX normalized MAP in HFD fed rats and HFD+HSD fed rats, but had no effect on the bodyweight or glucose tolerance. Assessment of renal and peripheral inflammation is currently underway. Together, these findings indicate that addition of a HSD to obese hypertensive rats does not exacerbate HTN and or impaired glucose tolerance. Further study of these intriguing effects in experimental and clinical models is necessary to accurately assess the dietary contribution to cardiovascular and metabolic disease.

Support or Funding Information

Supported by RO1HL116476
The Role of G Protein‐Coupled Estrogen Receptor (GPER) in the PVN of Renovascular Hypertensive Rats
Authors: Maruyama Nadia Oliveira , Estrela Heder Frank , Lucas Thais F. , Porto Catarina Segreti , Bergamaschi Cassia Toledo , de Campos Ruy Ribeiro
Published: November 2023

It is well stablished that 17β‐estradiol acting on classic estrogen receptors is a cardiovascular protector in part via reduction of sympathetic vasomotor activity. However, there is no information regarding the G protein‐coupled estrogen receptor (GPER) actions in the paraventricular nucleus of hypothalamus (PVN) in the 2kidney‐1clip (2K‐1C) Goldblatt hypertension model. Thus, we investigated the role of GPER within the PVN on sympathetic vasomotor activity in 2K‐1C male Wistar rats. Protein expression of GPER within the PVN was evaluated by Western blot assay. Bilateral microinjection of G1 (GPER agonist) into the PVN was performed in control (C) and 2K‐1C rats, six weeks after renal clipping. Renal sympathetic nerve activity (rSNA) and mean arterial blood pressure (MAP) were recorded in urethane anesthetized rats (1,4 g/Kg, IV). A significant increase in GPER (563 ± 71% n=6) expression was found in 2K‐1C rats. G1 into the PVN induced significantly larger increase in rSNA in 2K‐1C rats (C,Δ 15.60 ± 4.885 n=5 and 2K1C,Δ 40.17 ± 4.199 n=6). However, there was no significant effect on MAP in both groups. Chronic 2K‐1C Losartan‐treated rats (30 mg/Kg/day for 7 consecutive days) significantly reduced GPER expression in the PVN (70%, n=4). The increase in GPER activity seems to contribute for the renal sympathoexcitation in renovascular hypertension. Apparently, Angiotensin II AT1 receptor is important for the PVN GPER upregulation in Goldblatt rats.

Support or Funding Information

Suported by: FAPESP, CAPES and CNPq
Roles Of Central α2 And AT1 Signal Transduction Via Gαi2 Proteins In Blood Pressure Regulation In Response To An Acute Sodium Challenge
Authors: Shim Joon W , Wainford Richard David , Carmichael Casey Yumi
Published: November 2023

Aim

We have previously reported that central Gαi2 proteins are required to suppress sympathetic outflow and restore blood pressure to baseline levels following an acute 3M NaCl challenge in conscious rats. The objective of this study was to establish the roles of central α2 Adrenergic and Angiotensin II type I (AT1) receptors in the activation of brain Gαi2 pathways in response to an acute sodium challenge to restore normotension.

Methods

Male Sprague Dawley rats pre‐treated (24‐h) with an intracerebroventricular injection of a targeted Gαi2 oligodeoxynucleotide (ODN) (25 μg/5 μL) to downregulate brain Gαi2 protein expression or a scrambled (SCR) control ODN and were challenged with an acute sodium load (HS: intravenous bolus 3 M NaCl; 0.14 mL/100 g). In additional groups rats were pretreated 10‐min prior to an acute 3M bolus NaCl challenge with either yohimbine (α2 adrenergic receptor antagonist, 5.9 μg in 5 μl), or losartan (AT1 antagonist, 7.5 μg in 2 μl). In all treatment groups cardiovascular parameters (HR, MAP) were monitored for 120‐minutes (N=4–6 group).

Results

In response to an acute sodium load no difference was observed in peak change in mean arterial pressure (MAP) between Gαi2 and SCR ODN treated groups (peak ΔMAP [mmHg] SCR +17 ± 4 vs. Gαi2 +13 ± 3). However, MAP remained elevated 120‐min post sodium challenge in Gαi2 but not control SCR ODN treated rats (ΔMAP 100‐min post HS [mmHg] SCR +2 ± 3 vs. Gαi2 ODN: +13 ± 1, P<0.05). Central AT1 antagonism attenuated the peak pressor response to acute sodium challenge (peak ΔMAP [mmHg] SCR +17 ± 4 vs. losartan +11 ± 2, P<0.05) and decreased the time required to restore MAP to baseline from 100‐min to 50‐min (P<0.05). Central α2 adrenoceptor antagonism exacerbated the peak pressor response to acute sodium challenge (peak ΔMAP [mmHg] SCR +17 ± 4, Gαi2 +13 ± 3 vs. yohimbine +24 ± 3, P<0.05) and the magnitude of sodium evoked‐hypertension over the first 60‐min post sodium challenge.

Conclusion

These data highlight differential roles of central α2 and AT1 receptors in blood pressure regulation in response to an acute sodium challenge. The sympathoexcitatory pressor response to IV bolus sodium is mediated, in part, via central AT1 receptor activated Gai2‐independent signal transduction pathways. In contrast both α2 adrenoceptors contribute to the sympathoinhibitory hypotensive response to restore normotension following an acute sodium challenge, in part, via Gai2 signal transduction pathways. These data, and our prior studies, suggest that in response to acute challenges to sodium homeostasis α2 adrenoceptor activation evokes sympathoinhibition and hypotension via down stream pathways that involve Gai2 protein‐gated signal transduction.

Support or Funding Information

NHLBI R01HL107330, K02HL1127182
Increased Respiratory‐Sympathetic Coupling Via C1 Neurons Contributes to the Development of Hypertension in the Spontaneously Hypertensive Rat
Authors: Menuet Clement , Jancovski Nikola , Bassi Jaspreet K. , Connelly Angela A. , Allen Andrew M.
Published: November 2023

An interaction between neurons in the central respiratory and sympathetic vasomotor networks leads to the generation of bursts of sympathetic nerve activity in phase with the respiratory cycle (RespSNA), which produce respiratory phase‐locked oscillations in blood pressure (BP) called Traube‐Hering waves (TH waves). RespSNA and TH waves are increased in Spontaneously Hypertensive (SH) rats at pre‐hypertensive ages and are proposed to contribute to the development of hypertension. In normotensive rats, pre‐sympathetic adrenergic C1 neurons are inspiratory modulated, and their inhibition decreases RespSNA. In SH rats, the inspiratory modulation of pre‐sympathetic neurons is exaggerated. To examine the involvement of C1 neurons in the increased RespSNA and TH waves in SH rats and the development of hypertension, we lesioned C1 neurons in pre‐hypertensive (21 days old, P21) SH and control Wistar Kyoto (WKY) rats with the immunotoxin anti‐dopamine beta‐hydroxylase‐saporin (anti‐DBH‐SAP). Using radiotelemetry we observed reduced BP in anti‐DBH‐SAP injected SH rats compared to control SH rats at 3 months (134 ± 3 vs. 116 ± 2 mmHg, P<0.001). These injections did not significantly alter BP in WKY rats. TH wave amplitude was significantly reduced, to WKY level, in anti‐DBH‐SAP injected SH rats. Power spectral analysis of systolic BP revealed a decrease, to WKY level, in low and high frequency power in anti‐DBH‐SAP injected SH rats, suggesting decreased basal SNA and RespSNA respectively. To gain mechanistic understanding about these decreases in BP and TH waves, we used a recombinant virus to induce expression of the inhibitory allatostatin receptor in C1 neurons of P21 SH and WKY rats. The cardiorespiratory effects of acute C1 neurons inhibition were assessed using the Working Heart‐Brainstem Preparation. Pharmacogenetic inhibition of C1 neurons markedly attenuated RespSNA and TH waves in SH rats down to WKY rats level, by selective diminution of the exaggerated inspiratory component of RespSNA. The SNA response to peripheral chemoreflex stimulation, which is exacerbated in SH rats, was also reduced down to WKY level during C1 inhibition. Therefore, this proof of concept study demonstrates that increased RespSNA and TH waves contribute to the development of hypertension in SH rats, and that this is mediated by C1 neurons. These results are of critical importance for understanding the mechanisms driving the development of human hypertension.
PETCO2 In Women at Sea‐Level and Upon Acute Exposure to Normobaric Hypoxic Environments Simulating 3,500 m
Authors: Kambis Ken , Yasukawa Michio , Moran Thomas , Pleasant Austen , Hafner Gabriella , Barbour Veronique , Duckworth Courtney , Muza Stephen , Looft‐Wilson Robin
Published: November 2023

A prior study in men (Reeves, J. Appl. Physiol. 75: 1993) demonstrated that the ventilatory response to high altitude is highly variable among sea level residents, but the sea level end‐tidal PCO2 (PETCO2, a measurement of effective alveolar ventilation) is highly predictive of subsequent ventilation at high altitude. While prior work suggests that women and men have similar ventilatory responses to high altitude (Muza, J. Appl. Physiol. 91: 2001), no studies have determined if women's sea level PETCO2 is predictive of subsequent ventilation at high altitude. As part of a larger study examining individual variability upon acute exposure to normobaric hypoxia, PETCO2 was measured while subjects rested for >30 minutes at sea level (SL) and, no sooner than two days later, for >30 minutes in a normobaric hypoxia chamber at 13.55% FiO2 approximating oxygen partial pressures equivalent to those found at 3,500 m, or at a FiO2 of 20.93% in the case of control subjects.

METHODS

Informed volunteer female subjects participated in this IRB approved study. 47 (20.6±1.5 yr.; 165.6±6.9 cm; 62.9±10.4 kg; 22.9±3.4 kg/m2; VO2peak 42.6±7.4 ml/kg−1/min−1) subjects were assigned to the treatment group who were tested at SL then entered the normobaric chamber where the FiO2=13.55% (HYPO) and 9 subjects (21.8±4.3 yr.; 166.5±6.1 cm; 57.9 ±7.0 kg; 20.9 ±2.1 kg/m2; VO2peak 40.9 ±6.5 ml/kg−1/min−1) acted as controls (SHAM) who were in the normobaric chamber at a FiO2 = 20.93%. At both SL and chamber conditions, subjects rested for >30 minutes. PETCO2 was measured during the final 14 minutes of each rest period as was percent hemoglobin O2 saturation (SpO2), respiratory rate (RR), and heart rate (HR).

RESULTS

Two‐way RM ANOVA revealed that there was no difference (P>0.5) in PETCO2 between the HYPO vs SHAM groups at SL (37.9±2.7 vs 36.0±2.9) but, as expected, there was a difference (P<0.001) between the SL and chamber conditions (PETCO2 = 37.9±2.7 vs 36.0±2.2) in the HYPO group. A significant (P < 0.001) Pearson correlation (r = 0.759) was also observed between SL PETCO2 and HYPO PETCO2 while no difference was observed between the SHAM conditions. A multiple regression model [Y = 79.617 – 0.452 X1 – 0.207 X2 – 0.016 X3 (Where Y= PETCO2_HYPO, X1 = SpO2_HYPO, X2 = RR_HYPO, X3 = HR_HYPO; R2 = 0.500, F = 19.15, P < 0.001)] was used to plot the actual and predictive values for PETCO2 at 3,500 m (Fig. 1).

CONCLUSIONS

Women's SL PETCO2 is predictive of their ventilatory response to acute normobaric hypoxia and may be useful in predicting an individual's ventilation during travel to moderately high altitudes.

Support or Funding Information

The Doug Morton/Marilyn Brown Endowment for Biomedical Research, The Foundation for Aging Studies and Exercise Science Research, and The Borgenicht Program
Handgrip Training with Chronic Concomitant Exposure to Moderate Altitude Improves Blood Pressure Responses and Delays the Onset of Fatigue
Authors: Jarvis Sara Sun
Published: November 2023

Exposure to moderate altitude (~2500 m) elicits a sympathoexcitatory response. There may also be long term changes such as a reduction in muscular strength and a quicker onset of muscular fatigue. The purpose of this study was to determine whether a training program with concomitant hypoxic exposure could blunt cardiovascular and neural responses, as well as delay the onset of fatigue. Twelve healthy males had heart rate (HR) and blood pressure (systolic, SBP; diastolic, DBP) measured during baseline (BL), static handgrip to fatigue, and post‐exercise circulatory arrest (PECA). A subset of subjects (n=5) had measurements of muscle sympathetic nerve activity (MSNA). Assessments were done before (PRE) and after (POST) a 6‐week rhythmic handgrip training program (5 days/week, 30% of maximal voluntary contraction, 2 sets of 30 repetitions/min until fatigue). HR was higher at fatigue compared to BL (PRE BL: 65±8 vs 96±20 beats/min, p<0.01) but was not different PRE vs POST (POST BL: 61±7 beats/min). SBP was higher at fatigue and during PECA than during BL (PRE BL: 126±11 vs 168±13 vs 154±12 mmHg, both p<0.01) and was lower POST (main effect, p<0.05). DBP was also higher at fatigue and during PECA (PRE BL: 64±5 vs 90±17 vs 78±8 mmHg, both p<0.05) and tended to be lower POST (main effect, p=0.075). Indices of MSNA were higher during fatigue compared to BL (burst frequency, PRE BL: 11±9 vs 42±29 bursts/min, p<0.01; burst incidence, PRE BL: 17±13 vs 45±23 bursts/100 heart beats, p<0.05) but were no different from PRE to POST (burst frequency, POST BL: 12±10 bursts/min; burst incidence, POST BL: 18±15 bursts/100 heart beats). Maximal voluntary contraction was unchanged after training (52±6 vs 50±5 kg, p=NS); however, time to fatigue was delayed POST training (141.4±32.6 vs 176.4±42.3 sec, p<0.05). After 6 weeks of rhythmic handgrip training we found improvements in cardiovascular parameters and a delay in the onset of fatigue but no change in MSNA indices or strength.

Support or Funding Information

Supported by the Faculty Grant Program at Northern Arizona University