bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxic pulmonary hypertension is not affected by neonatally induced diabetes in rats
Authors: Chalupsky Karel , Vajnerova Olga , Kratzerova Tereza , Durisova Jana , Mikova Dana , Rachacova Pavla , Sedlacek Radislav , Herget Jan , Hampl Vaclav 
Published: November 2023

Chronic hypoxia elicits pulmonary hypertension, in part through oxidative alterations of the vascular wall. Since diabetes is also characterized by oxidative stress, we hypothesized that diabetes would amplify hypoxic pulmonary hypertension. We measured lung hemodymamic parameters, heart morphology and serum malonyldialdehyde (MDA, marker of oxidative burden) at the end of a 2‐week exposure of 11 weeks old diabetic rats to hypoxia (12% O2). Diabetes (glycemia >8 mM) was induced in the neonatal period by streptozotocine (100 mg/kg s.c.). Chronic hypoxia elevated pulmonary artery pressure (PAP) and right ventricle weight/left ventricle weight ratio (RV/LV+S), and this was not affected by diabetes. Diabetes alone increased PAP to a similar extent as chronic hypoxia, but this was solely due to elevated cardiac output. Serum MDA was elevated by diabetes and not significantly altered by hypoxia. We conclude that the oxidative insults of chronic hypoxia and diabetes to the pulmonary vascular bed are not additive.Support or Funding InformationThis material is based upon work supported by the project COST LD 14068, IGA NT 13358, GACR 13‐01710S and by the project „BIOCEV ‐ Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University” (CZ.1.05/1.1.00/02.0109) from the European Regional Development Fund.
The Geometry of the Progression of Occlusive Lesions in Severe Pulmonary Arterial Hypertension
Authors: Francis Christopher Michael , Oshima Kaori , Stevens Troy , Oka Masahiko 
Published: November 2023

The vasculopathy of pulmonary arterial hypertension (PAH) includes the hallmark of occlusive, plexogenic lesions in pulmonary microvessels. Traditional studies of vascular lesions in PAH have relied on two‐dimensional histological preparations to grade and characterize lesion incidence and severity. However, this approach fails to acknowledge the physiological structure of vascular lesions in situ, and may systematically misidentify key anatomical features of the lung vasculature such as supernumerary arteries and vessel branching patterns. Therefore, we employed a three‐dimensional approach to composite serial histological lung sections to examine the geometry of vascular lesions in PAH. In light of recent three‐dimensional studies of vascular morphology in PAH which demonstrate that the progression of occlusive lesions has both temporal and spatial components, we tested the hypothesis that occlusive lesions within pulmonary microvessels in PAH exhibit patterns of severity along the length of vessel segments. Using Sugen/hypoxia treated hypertensive rats, we found that the incidence of occlusive lesions was undercounted with a conventional histological approach, due to the inability of cross‐sectional analysis to identify vascular trees linked in three‐dimensional space. Furthermore, we found that lesion severity was a complex function of vessel diameter, where disorganized lesions increased with decreased vessel diameter but were surrounded by a continuum of lesion grades. These results suggest that the contribution of occlusive lesions to the pathophysiology of PAH may be under represented, and underscore the necessity of three‐dimensional anatomical characterization of PAH vasculopathy.Support or Funding InformationThis work was funded by NIH grants HL60024 and HL66299
Ventilatory and Cerebrovascular Responses to Hypercapnia in Pulmonary Arterial Hypertension
Authors: Malenfant Simon , Brassard Patrice , Paquette Myriam , Le Blanc Olivier , Chouinard Audrey , Bonnet Sébastien , Provencher Steeve 
Published: November 2023

BACKGROUNDPatients with pulmonary arterial hypertension (PAH) exhibit excessive ventilation at rest and during exercise. This is generally attributed to an increased physiological dead space related to extensive vascular remodeling and ventilation‐perfusion mismatch as well as hyperventilation resulting in low arterial carbon dioxide partial pressure (PCO2). However, mechanisms accounting for this hyperventilation remain elusive. We hypothesized that PAH patients exhibit enhanced central chemoreflex sensitivity, resulting in increased ventilator drive, hyperventilation and reduced cerebral blood flow.METHODSCentral chemoreflex sensitivity was evaluated in 11 PAH patients and 11 healthy controls matched for age, sex and body mass index, using the modified hyperoxic hypercapnic rebreathing method. Participants underwent a 5‐minute period breathing room air. Then, they were asked to hyperventilate for one minute to an end‐tidal PCO2 (PETCO2) of 20–25 mmHg, before they started to breathe in a rebreathing bag (air mixture containing 7% CO2 and 93% O2) until PETCO2 reached 60 mmHg. During this protocol, left middle cerebral artery mean flow velocity (MCAvmean; transcranial Doppler), mean arterial pressure (MAP; finger photoplethysmography), PETCO2 and minute ventilation (VE,) were continuously monitored. The linear regression slope of VE‐PETCO2 characterized central chemoreflex sensitivity during the rebreathing period. Associations between central chemoreflex sensitivity, resting VE and MCAvmean were explored (Pearson's correlations).RESULTSCentral chemoreflex sensitivity was significantly higher in PAH patients compared to controls (2.1 (0.3) vs 0.9 (0.2) L/min/mmHg; p=0.003). PAH patients also displayed lower PETCO2 (37 (5) vs 43 (5) mmHg; p=0.01) and increased VE (14 (2) vs 10 (2) L/min; p=0.0003) at baseline compared to controls. Central chemoreflex sensitivity correlated with resting VE (r=0.68; p=0.0005) and also inversely correlated with MCAvmean (r=−0.48; p=0.02), which was lower in PAH patients (59.3 (10.6) vs 74.2 (15.8) cm/s; p=0.01).CONCLUSIONThese results suggest that PAH patients exhibit reduced cerebral blood flow as a result of higher chemoreflex sensitivity and secondary hyperventilation. Alternatively, the reduction in cerebral blood flow induced by hypocapnia might decrease brain tissue carbon dioxide wash‐out, acidifying the cerebrospinal fluid and leading to a higher chemoreceptor stimulus and increased ventilation.Support or Funding InformationDoctoral scholarship from Fond de Recherche du Québec ‐ Santé (FRQ‐S) to Simon Malenfant
Metabolic syndrome and heart failure with preserved ejection fraction: a new model of pulmonary hypertension associated with left heart disease
Authors: Potus Francois , Ranchoux Benoit , Tremblay Eve , Provencher Steeve , Bonnet Sébastien 
Published: November 2023

RationaleHeart failure (HF) with preserved ejection fraction (HFpEF) is the more common cause of HF and affecting over 50% of all patients with HF. Interestingly 50% of HFpEF culminates to pulmonary hypertension (PH), which confers poor prognosis. On the other hand, metabolic syndrome (MS), which affects more than 34% of adults in the world, is strongly associated with PH (pulmonary venous hypertension (94.1%); pulmonary arterial hypertension (34.3%)) and HFpEF (prevalence of 35%). Taken together, these results suggest that MS and HFpEF, which are two major healthcare challenges in the occidental society, may predispose to PH. Unfortunately; studies supporting this hypothesis remain limited by the lack of good pre‐clinical models that preclude extensive investigation. We developed a new animal model for WHO2 pulmonary hypertension associating HFpEF and metabolic syndrome.Methods/ResultsUsing supra‐coronary aortic banding, we first induced HFpEF in wistar male rats characterized by left ventricular (LV) hypertrophy, raise in LV systolic pressure, LV end‐diastolic pressure and no significant modification of LV end‐diastolic area and LV ejection fraction, 5 weeks post‐surgery (n=5; p<0,05). We then induced MS with high fat diet and daily injection of olanzapine (4mg/kg for 21 days) initiated two weeks after surgery. Establishment of MS was confirmed by significant increase in the fat/lean body mass (minispec Brucker lf90) and insulin resistance (high blood insulin level) compared to vehicle‐treated rats (n=5 per group; P<0.05). As expected, compared to healthy and sham surgery, HFpEF rats (n=5) displayed PH characterized by a significant decreased pulmonary acceleration time and tricuspid annular plane excursion (PAAT; TAPSE; echocardiography; P <0.05) and increased mean pulmonary arterial pressure and right ventricular systolic pressure (PAP, RVSP; P<0.05) (right heart catheterizations in closed chest). Interestingly, MS‐HFpEF displayed significant worsening in hemodynamic parameters (PAAT, TAPSE, PAP, RVSP) compared to HFpEF rats without MS (P<0.05, n=5 per group). Interestingly, remodelling of the distal pulmonary arteries, strongly correlates with fat/lean body mass and was significantly increased in MS‐HFpEF rats compared to the other conditions (p<0.05, n=5 per group).ConclusionIn the present study we demonstrated that metabolic syndrome worsens PH associated with HFpEF. Therefore, the MS and HFpEF combination represents a novel and attractive animal model to study WHO2 PH.
Aquaporin 1 (AQP1) Elevates cMyc and Cyclin D1 via β‐Catenin in Pulmonary Arterial Smooth Muscle Cells (PASMCs)
Authors: Yun Xin , Jiang Haiyang , Lai Ning , Shimoda Larissa 
Published: November 2023

Pulmonary hypertension is a severe pulmonary vascular disease characterized by functional and structural changes in the vessels. During development of hypoxic pulmonary hypertension, primary features of remodeling in distal small pulmonary arteries include PASMC proliferation and migration. Formerly, we showed that hypoxia increased the expression of a water channel, AQP1, which mediates PASMC proliferation and migration by increasing β‐catenin protein levels. β‐catenin is a dual function protein that may interact with AQP1 in certain cell types and activates the transcription of crucial target genes related to cell migration and proliferation. Thus, we determined whether the AQP1 C‐terminal tail was required for AQP1 to increase β‐catenin levels in PASMCs and, if so, whether known β‐catenin target genes, such as c‐myc and cyclin D1, were also elevated. Primary cultured rat distal PASMCs were harvested and infected with adenoviral constructs expressing wild‐type AQP1 (AdWT), AQP1 lacking the C‐terminal tail (AdCT), or green fluorescent protein (AdGFP), as a control for infection. Compared to AdGFP cells, infection with AdWT, but not AdCT, increased β‐catenin protein and the mRNA and protein expression of c‐myc and cyclin D1. Moreover, knockdown of β‐catenin in PASMCs infected with AdWT prevented the AQP1‐induced increase in proliferation and migration.ConclusionsIncreased AQP1 enhances PASMC proliferation and migration through a mechanism involving modulation of β‐catenin protein levels and its targets via the C‐terminal tail of AQP1.
Sympathetic Nerve Activity and Baroreflex Dysfunction Paralleled the Progression of Pulmonary Arterial Hypertension in Monocrotaline Induced Rat Model
Authors: Shinoda Masako , Oga Yasuhiro , Saku Keita , Abe Kohtaro , Tohyama Takeshi , Kuwabara Yukimitsu , Yoshida Keimei , Takehara Takako , Fujii Kana , Nishizaki Akiko , Kishi Takuya , Ide Tomomi , Sunagawa Kenji 
Published: November 2023

BackgroundPulmonary arterial hypertension (PAH) is a fatal disease characterized by progressive pulmonary vascular remodeling and extremely high pulmonary artery (PA) resistance. Although patients with advanced PAH are known to have excessive sympathoexcitation and baroreflex dysfunction, the relationship between autonomic dysfunction and the progression of PAH remains unknown. Thus, we investigated how the progression of PAH alters sympathetic nerve activity (SNA) and baroreflex function in monocrotaline (MCT) induced PAH rats.MethodsIn 7 weeks‐old Sprague‐Dawley rats (220–260g), we subcutaneously injected MCT (60 mg/kg) or saline for control (CTL). One, 3 and 3.5 weeks after MCT injection (MCT1W, MCT3W and MCT3.5W, respectively), we assessed right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) (,‐the weight ratio of right to left ventricular) to evaluate the severity of PAH. We estimated SNA by 24 hours urine norepinephrine (U‐NE) and plasma norepinephrine (P‐NE). To measure open loop baroreflex function, we isolated bilateral carotid sinus regions and changed carotid sinus pressure (CSP) while measuring splanchnic SNA and arterial pressure (AP).ResultsRVSP significantly increased 3 and 3.5 week after MCT injection (CTL: 39±6, MCT3W: 73±6, MCT3.5W: 96±9 mmHg, p<0.05). RVH markedly increased in MCT3.5W (CTL: 0.29±0.04, MCT3.5W: 0.49±0.08, p<0.05). Both U‐NE and P‐NE paralleled RVSP (Fig. 1). In the baroreflex open loop analysis, increasing in CSP sigmoidally decreased SNA (neural arc), whereas SNA lineally increased AP (peripheral arc). The relationship between CSP and AP (i.e., baroreflex total loop function) was sigmoidal in both CTL and MCT3W, while the baroreflex induced maximum AP was lower in MCT3W than in CTL (Fig. 2). PAH lowered the baroreflex total loop gain at the operating point (CTL: −1.22±0.22, MCT3W:−0.35±0.14, p<0.05) (Fig. 3).ConclusionSympathetic activation paralleled the progression of PAH. RVH and excessive SNA may deteriorate the baroreflex function in rats with advanced PAH.
BK channel differences in near‐term fetal and adult ovine small pulmonary arteries
Authors: Hessinger David A , Thorington Glyne U , Sokolova Irina , Fletcher William H , Pretorius Miles R , Morris Daniel P , Longo Lawrence D 
Published: November 2023

Pulmonary vasodilatation at birth underlies the fetal transition to lung breathing. Failure to vasodilate causes persistent pulmonary hypertension of newborn, persistent patency of the ductus arteriosus and foramen ovale, and bronchopulmonary dysplasia‐related hypoxia, often with dire consequences. The mechanism of pulmonary vasodilatation at birth is poorly understood. Pulmonary artery smooth muscle cells (PASMCs) isolated from 4th and 5th order resistance vessels of ovine near‐term fetus exhibited resting membrane potentials 8 mV more depolarized than adult (P<0.05), consistent with vasoconstriction. Whole‐cell Kv current densities for voltage‐clamped fetal and adult PASMCs were similar. In contrast, large‐conductance, calcium‐activated K+ (BK) channel current densities for fetal cells were significantly lower than adult at +20 to +60 mV, but equal to adult at higher potentials. By Western immunoblots, fetal PASMCs expressed twice the pore‐forming BKα subunit protein as adult, but only half as much accessary BKβ□ subunit. By flow cytometry, cell surface βl expression was also significantly lower in fetal PASMCs. Since optimal BK channel activity occurs at 1:1 β‐to‐α stoichiometry, our results suggested the near‐term fetus expressed BK β:α ratios about ¼ that of adult. These findings suggest near‐term fetal PASMCs are more depolarized than adult due to lower BK activity and lower BKβ□ subunit expression. In agreement with BKα protein levels, BKα mRNA levels were two‐fold higher in near‐term fetus than in adult by qRT‐PCR. However, in contrast to BKβ□ protein levels, BKβ□ mRNA levels were two‐fold higher in near‐term fetus than adult. These findings suggest that BKβ□ mRNA levels may be poised to express higher levels of BKβ□ protein at birth in order to enhance BK channel activity and promote pulmonary vasodilatation upon transition to lung breathing.Support or Funding InformationNational Institutes of Health Grants HD‐003807‐41 and HD031226‐20 (to LDL)
Developing Online Guided Self‐assessments in Cardiovascular Physiology for Medical School
Authors: Pressley Thomas A. , Fowler John C. 
Published: November 2023

Preclinical medical students have access to numerous question banks and books that provide examples of NBME‐style questions for use in USMLE Step 1 preparation. However, many of these questions are beyond the scope of first‐year medical physiology and are of limited utility when preparing for exams. Accordingly, many course directors and faculty members develop their own questions that are used by students for self‐assessment. In this study, we developed self‐assessment questions about cardiovascular physiology that could be delivered online and provided specific feedback to students in response to both correct and incorrect responses. We used Microsoft PowerPoint to create a series of multiple choice questions. Incorrect responses were linked to subsequent slides that attempted to correct misunderstandings or errors that might have contributed to the wrong choice. Correct responses were linked to slides that provided encouragement and reinforced the critical concept. The slides for both incorrect and correct responses offered links to slides containing short reviews of the relevant concepts. Once the PowerPoints were reviewed by colleagues and revised, iSpring Presenter was used to create online learning “packages” that could be posted on our course management system. These packages offered two advantages. First, they could be created in multiple formats that were compatible with most computers and tablets. Second, they prevented a student from circumventing the question‐response sequence via download of the original PowerPoint file. After developing four 10‐question self‐assessments covering various cardiovascular concepts, we compared students’ utilization statistics with those for four traditional sets of example questions on renal physiology. In the first year of their introduction, the online self‐assessment packages were used nearly twice as often. Our data suggest that such online guided self‐assessments are a popular mechanism for student learning that should be explored further.Support or Funding InformationSupported by departmental and institutional funds.
The Prevalence of Exercise Prescription‐related Course Offerings in U.S. Pharmacy School Curricula: Exercise is Medicine®
Authors: Dirks‐Naylor Amie J , Griffiths Carrie L. , Gibson Jacob L. , Luu Jacqueline A. 
Published: November 2023

Exercise training has proven to be beneficial in the prevention of disease. In addition, exercise can improve the pathogenesis and symptoms associated with a variety of chronic disease states and can attenuate drug‐induced adverse effects. Exercise is a drug‐free polypill. Because the benefits of exercise are clear and profound, Exercise is Medicine®, a joint initiative between the American Medical Association and the American College of Sports Medicine, was launched in 2007 to call on all health care providers to counsel patients and prescribe exercise in the prevention and treatment of chronic disease states. Pharmacists play an increasing role in direct patient care and are the most accessible health care providers in the community. Thus, pharmacists should be knowledgeable in counseling patients on the amount and type of exercise that is appropriate for various conditions and disease states. The aim of the study was to determine the prevalence of didactic course offerings in U.S. pharmacy school curricula regarding training in exercise prescription. School websites were accessed for information regarding course offerings in Pharm.D. programs. The majority of U.S. pharmacy schools do not offer courses with a focus on the role of exercise in disease prevention or exercise prescription in disease management. When offered, such courses are commonly titled with descriptors such as lifestyle/behavioral modifications, wellness, disease prevention, and health promotion which comprised of several modifiable behavior topics affecting health and disease. No institutions offer a course dedicated solely to exercise prescription.Support or Funding InformationNone
Students as the Unit and Instrument of Analysis for the Assessment of Advising
Authors: Johnson Kathryn M.S. , Greene Kathleen , Guttchen Emma , McLeod Ruth , Paquin Zachary W. , Young Megan K.M. 
Published: November 2023

Since the 1970's, advising has been one of four areas of faculty evaluation (with teaching, scholarship/professional activity, and service/campus citizenship) at Beloit College, a small residential liberal arts college in the Midwest. Advising can occur in many different ways, but can be considered a form of teaching, and faculty members’ approaches to teaching and advising are closely related. Assessment of faculty advising for the tenure process at the institution is limited, but includes a consensus within the department about the faculty member's ability to engage in conversations with students. Evaluation is primarily determined by the accessibility of the advisor to the students, with less acknowledgment of the content of the conversation or student gains. To understand what students are learning from advising interactions and the effectiveness of advising, four student facilitators were trained and actively participated in the development and implementation of student‐facilitated student and alumni focus groups (8 total groups, 6 student, 2 alumni). Participants (n=51, 40 current students, 11 alumni) assembled in small groups (4–12 participants/group) and student facilitators (2–4 facilitators/group) asked participants a series of questions pertaining to their experiences with advising. Student facilitators recorded and analyzed focus group responses. Comparing responses between current students and alumni provided evidence of similar experiences, with alumni responses providing the advantage of retrospection. Student facilitators identified six themes: 1) students are much more likely to have influential conversations and seek advice from family, friends, and peers, rather than from academic advisors; 2) a good advisor is honest and knows how to “be real”; 3) advisees should be open‐minded and come prepared; 4) pre‐major advising varies from horrible to wonderful; 5) peer mentoring works and students love it; and 6) according to alumni, advising happens everywhere. Based on their analysis, the student facilitators concluded that students recognize that positive, effective, and successful advising involves a two‐way relationship between the advisor and the advisee. Working closely with the student facilitators to analyze and interpret the focus group responses has helped us identify institutional advising strengths and avenues for evaluating and addressing weaknesses.Support or Funding InformationThis research was supported by the Beloit College Office of the Provost and Dean of the College.