A Primer: Peer Review Process for Advances in Physiology Education.

The dissemination of discipline-focused educational scholarship advances theory and stimulates pedagogical application. The aim of Advances in Physiology Education is to publish manuscripts that advance knowledge and inform educators in the field. This primer is tailored for individuals new to manuscript reviewing, early in their careers, or experienced in reviewing research but not educational manuscripts. Peer reviewing for basic and applied science is akin to evaluating research questions and rigor in teaching and learning studies, with differences in approach and analysis similar to those between biophysics and molecular physiology or cell and integrated physiology. Our purpose is to provide an overview of the review process and expectations. The submission and peer review process involves several steps: authors submit a manuscript, the Editor assigns an Associate Editor, who then assigns peer Reviewers. Reviewers are contacted via email and can accept or decline the invitation. Reviewers evaluate the work's strengths and weaknesses, then independently submit comments and recommendations to the Associate Editor. After review, the Associate Editor collects and weighs Reviewers' comments, sometimes garners additional reviews and input, to make a recommendation to the Editor. The Editor reviews the process, comments, and recommendations to render a final decision. Both authors and Reviewers receive an email with the decision. The editorial staff assist with communication and help track the overall process. Peer review is integral to scientific publishing, ensuring quality and rigor, and reviewing is both a privilege and a responsibility of all in the scientific community.

Perspectives Against Racism: educational and socialization efforts at the departmental level.

The current heightened social awareness and anxiety triggered by escalating violence against Black Americans in the United States demands a safe space for reflection, education, and civil discourse within the academic setting. Too often there is an unmet need paired with a collective urgent desire to better understand the chronic existing structural, social, educational, and health inequities affecting disadvantaged populations, particularly Black Americans. In this perspective, the authors provide insight into a shared learning approach that provided a forum to discuss Perspectives Against Racism (PAR). Unlike existing top-down approaches, faculty, trainees, and staff were engaged in leading a series of focused discussions to examine unconscious bias, promote awareness of implicit biases, and reflect on individual and collective roles and responsibilities in working toward becoming antiracist. An existing 1-h graduate elective seminar course was dedicated to creating a space for learning, discussion, and exchange of ideas related to the experience and existence of racism (personal and institutional/systemic). A goal of each session was to go beyond didactics and identify mechanisms to implement change, at the level of the individual, department, and institution. This perspective of the shared experience may provide an adaptable framework that can be implemented in an academic setting at the departmental, center, or institutional level.

Knowledge gains in a professional development workshop on diversity, equity, inclusion, and implicit bias in academia.

As literature indicates, historic racism and implicit bias throughout academia have been profound metrics leading to a lack of diversity, as related to people from underrepresented groups according to race and ethnicity, among biomedical sciences graduate students in U.S. universities. Recognizing such challenges, a team of biomedical scientists and inclusivity educators developed and implemented a pilot training program within an academic health sciences center as an initial step to educate faculty and staff regarding their roles in the promotion of an inclusive academic environment, receptive to all students, including underrepresented students. The 3-h workshop included didactic modules, videos, teaching modules, and active attendee participation. Faculty and staff were presented common terminology and ways to promote the development of an inclusive and diverse academic workforce. Compared with pre-workshop, post-workshop survey results indicated a statistically significant improvement in attendee knowledge of correctly identifying definitions of "implicit bias," "status leveling," "color-blind racial attitudes," "tokenism," and "failure to differentiate." Additionally, by the end of the workshop, participants had a statistically significant increase in self-perceptions regarding the importance of improving diversity and recognizing biases and stereotypes in graduate education, knowing what to say when interacting with people from different cultures, and the ability to acknowledge bias when mentoring students from groups underrepresented in the biomedical field. This preliminary initiative was successful in the introduction of faculty and staff to the importance of fostering an inclusive academic environment and thereby developing a diverse workforce.

Longitudinal interprofessional education in a graduate physiology course.

The primary purpose of conducting two interprofessional education (IPE) experiences during a multidisciplinary physiology graduate-level course was to provide basic science, physical therapy, and physician assistant graduate students opportunities to work as a team in the diagnosis, treatment, and collaborative care when presented with a patient case focused on acute kidney injury (first case) and female athlete triad (second case). The secondary purpose was to apply basic physiology principles to patient case presentations of pathophysiology. The overall purpose was to assess the longitudinal effects and the value of IPE integrated within a basic science course. The following Interprofessional Education Collaborative subcompetencies were targeted: roles/responsibilities (RR1, RR4). Students were given a pre- and postsurvey to assess their IPE perceptions and knowledge of professional roles. There were statistically significant increases from the presurvey renal IPE experience to the presurvey endocrine IPE experience for two perception questions regarding the ability to explain the roles and responsibilities of a physical therapist (PT) and physician assistant using a Likert scale. In addition, student knowledge of the role of a PT increased significantly when comparing the renal IPE presurvey to the endocrine IPE presurvey results to open-ended questions. Students' perceptions of their knowledge as well as their ability to express, in writing, their newly learned knowledge of the role of a PT was sustained over time. Incorporating multiple IPE experiences into multidisciplinary health science courses represents an appropriate venue to have students learn and apply interprofessional competencies.

Lack of contribution of nitric oxide synthase to cholinergic vasodilation in murine renal afferent arterioles.

We have previously reported significant increases in neuronal nitric oxide synthase (NOS) immunostaining in renal arterioles of angiotensin type 1A receptor (AT1A) knockout mice, and in arterioles and macula densa cells of AT1A/AT1B knockout mice. The contribution of nitric oxide derived from endothelial and macula densa cells in the maintenance of afferent arteriolar tone and acetylcholine-induced vasodilation was functionally determined in kidneys of wild-type, AT1A, and AT1A/AT1B knockout mice. Acetylcholine-induced changes in arteriolar diameters of in vitro blood-perfused juxtamedullary nephrons were measured during control conditions, in the presence of the nonspecific NOS inhibitor, Nω-nitro-l-arginine methyl ester (NLA), or the highly selective neuronal NOS inhibitor, N5-(1-imino-3-butenyl)-l-ornithine (VNIO). Acetylcholine (0.1 mM) produced a significant vasoconstriction in afferent arterioles of AT1A/AT1B mice (-10.9 ± 5.1%) and no changes in afferent arteriolar diameters of AT1A knockout mice. NLA (0.01-1 mM) or VNIO (0.01-1 µM) induced significant dose-dependent vasoconstrictions (-19.8 ± 4.0% 1 mM NLA; -7.8 ± 3.5% 1 µM VNIO) in afferent arterioles of kidneys of wild-type mice. VNIO had no effect on afferent arteriole diameters of AT1A knockout or AT1A/AT1B knockout mice, suggesting nonfunctional neuronal nitric oxide synthase. These data indicate that acetylcholine produces a significant renal afferent arteriole vasodilation independently of nitric oxide synthases in wild-type mice. AT1A receptors are essential for the manifestation of renal afferent arteriole responses to neuronal nitric oxide synthase-mediated nitric oxide release.

Effectiveness of interprofessional education in renal physiology curricula for health sciences graduate students.

The primary purpose of conducting an interprofessional education (IPE) experience during the renal physiology block of a graduate-level course was to provide basic science, physical therapy, and physician assistant graduate students with an opportunity to work as a team in the diagnosis, treatment, and collaborative care of a patient with acute kidney injury. The secondary purpose was to enhance the understanding of basic renal physiology principles with a patient case presentation of renal pathophysiology. The overall purpose was to assess the value of IPE integration within a basic science course by examining student perceptions and program evaluation. Graduate-level students operated in interprofessional teams while working through an acute kidney injury patient case. The following Interprofessional Education Collaborative subcompetencies were targeted: Roles/Responsibilities (RR) Behavioral Expectations (RR1, RR4) and Interprofessional Communication (CC) Behavioral Expectations (CC4). Clinical and IPE stimulus questions were discussed both within and between teams with assistance provided by faculty facilitators. Students were given a pre- and postsurvey to determine their knowledge of IPE. There were statistically significant increases from pre- to postsurvey scores for all six IPE questions for all students. Physical therapy and physician assistant students had a statistically significant increase in pre- to postsurvey scores, indicating a more favorable perception of their interprofessional competence for RR1, RR4, and CC4. No changes were noted in pre- to postsurvey scores for basic science graduate students. Incorporating planned IPE experiences into multidisciplinary health science courses represents an appropriate venue to have students learn and apply interprofessional competencies.

Targeting Glomerular Hemodynamics for Kidney Protection.

The kidney microcirculation is a unique structure as it is composed to 2 capillary beds in series: the glomerular and peritubular capillaries. The glomerular capillary bed is a high-pressure capillary bed, having a 60 mm Hg to 40 mm Hg pressure gradient, capable of producing an ultrafiltrate of plasma quantified as the glomerular filtration rate (GFR), thereby allowing for waste products to be removed and establishing sodium/volume homeostasis. Entering the glomerulus is the afferent arteriole, and the exiting one is the efferent arteriole. The concerted resistance of each of these arterioles is what is known as glomerular hemodynamics and is responsible for increasing or decreasing GFR and renal blood flow. Glomerular hemodynamics play an important role in how homeostasis is achieved. Minute-to-minute fluctuations in the GFR are achieved by constant sensing of distal delivery of sodium and chloride in the specialized cells called macula densa leading to upstream alternation in afferent arteriole resistance altering the pressure gradient for filtration. Specifically, 2 classes of medications (sodium glucose cotransporter-2 inhibitors and renin-angiotensin system blockers) have shown to be effective in long-term kidney health by altering glomerular hemodynamics. This review will discuss how tubuloglomerular feedback is achieved, and how different disease states and pharmacologic agents alter glomerular hemodynamics.

Glomerular filtration rate determinations in conscious type II diabetic mice.

Diabetic nephropathy is a major cause of end-stage renal disease worldwide. The current studies were performed to determine the later stages of the progression of renal disease in type II diabetic mice (BKS; db/db). Methodology was developed for determining glomerular filtration rate (GFR) in conscious, chronically instrumented mice using continuous intravenous infusion of FITC-labeled inulin to achieve a steady-state plasma inulin concentration. Obese diabetic mice exhibited increased GFR compared with control mice. GFR averaged 0.313 ± 0.018 and 0.278 ± 0.007 ml/min in 18-wk-old obese diabetic (n = 11) and control (n = 13) mice, respectively (P < 0.05). In 28-wk-old obese diabetic (n = 10) and control (n = 15) mice, GFR averaged 0.348 ± 0.030 and 0.279 ± 0.009 ml/min, respectively (P < 0.05). GFR expressed per gram BW was significantly reduced in 18- and 28-wk-old obese diabetic compared with control mice (5.9 ± 0.3 vs. 9.0 ± 0.3; 6.6 ± 0.6 vs. 7.8 ± 0.3 µl·min(-1)·g body wt(-1)), respectively (P < 0.05). However, older nonobese type II diabetic mice had significantly reduced GFR (0.179 ± 0.023 ml/min; n = 6) and elevated urinary albumin excretion (811 ± 127 µg/day) compared with obese diabetic and control mice (514 ± 54, 171 ± 18 µg/day), which are consistent with the advanced stages of renal disease. These studies suggest that hyperfiltration contributes to the progression of renal disease in type II diabetic mice.

Major role for ACE-independent intrarenal ANG II formation in type II diabetes.

Combination therapy of angiotensin-converting enzyme (ACE) inhibition and AT(1) receptor blockade has been shown to provide greater renoprotection than ACE inhibitor alone in human diabetic nephropathy, suggesting that ACE-independent pathways for ANG II formation are of major significance in disease progression. Studies were performed to determine the magnitude of intrarenal ACE-independent formation of ANG II in type II diabetes. Although renal cortical ACE protein activity [2.1 +/- 0.8 vs. 9.2 +/- 2.1 arbitrary fluorescence units (AFU) x mg(-1) x min(-1)] and intensity of immunohistochemical staining were significantly reduced and ACE2 protein activity (16.7 +/- 3.2 vs. 7.2 +/- 2.4 AFU x mg(-1) x min(-1)) and intensity elevated, kidney ANG I (113 +/- 24 vs. 110 +/- 45 fmol/g) and ANG II (1,017 +/- 165 vs. 788 +/- 99 fmol/g) levels were not different between diabetic and control mice. Afferent arteriole vasoconstriction due to conversion of ANG I to ANG II was similar in magnitude in kidneys of diabetic (-28 +/- 3% at 1 microM) and control (-23 +/- 3% at 1 microM) mice; a response completely inhibited by AT(1) receptor blockade. In control kidneys, afferent arteriole vasoconstriction produced by ANG I was significantly attenuated by ACE inhibition, but not by serine protease inhibition. In contrast, afferent arteriole vasoconstriction produced by intrarenal conversion of ANG I to ANG II was significantly attenuated by serine protease inhibition, but not by ACE inhibition in diabetic kidneys. In conclusion, there is a switch from ACE-dependent to serine protease-dependent ANG II formation in the type II diabetic kidney. Pharmacological targeting of these serine protease-dependent pathways may provide further protection from diabetic renal vascular disease.

The renal renin-angiotensin system.

The renin-angiotensin system (RAS) is a critical regulator of sodium balance, extracellular fluid volume, vascular resistance, and, ultimately, arterial blood pressure. In the kidney, angiotensin II exerts its effects to conserve salt and water through a combination of the hemodynamic control of renal blood flow and glomerular filtration rate and tubular epithelial cell sodium chloride and water transport mechanisms. Pharmacological inhibition of the actions of the RAS are widely used in the treatment of patients with hypertension, congestive heart failure, left ventricular dysfunction, pulmonary and systemic edema, diabetic nephropathy, cirrhosis of the liver, scleroderma, and migraines. Therefore, a thorough understanding of the influences of the RAS on normal renal physiology is of major importance for first-year medical students.

Chymase inhibition retards albuminuria in type 2 diabetes.

Chymase released from mast cells produces pro-fibrotic, inflammatory, and vasoconstrictor agents. Studies were performed to test the hypothesis that chronic chymase inhibition provides a renal protective effect in type 2 diabetes. Diabetic (db/db) and control mice (db/m) were chronically infused with a chymase-specific inhibitor or vehicle for 8 weeks. Baseline urinary albumin excretion (UalbV) averaged 42 ± 3 and 442 ± 32 microg/d in control (n = 22) and diabetic mice (n = 27), respectively (p < .05). After administration of chymase inhibitor to diabetic mice, the change in UalbV was significantly lower (459 ± 57 microg/d) than in vehicle-treated diabetic mice (645 ± 108 microg/d). UNGAL V was not different at baseline between diabetic mice that would receive the chymase inhibitor (349 ± 56 ng/d, n = 6) and vehicle (373 ± 99 ng/d, n = 6) infusions, but increased significantly only in the vehicle-treated diabetic mice (p < .05). Glomeruli of diabetic kidneys treated chronically with chymase inhibition demonstrated reduced mesangial matrix expansion compared to glomeruli from untreated diabetic mice. Plasma angiotensin II levels were not altered by chymase inhibitor treatment. In summary, chronic chymase inhibition slowed the progression of urinary albumin excretion in diabetic mice. In conclusion, renal chymase may contribute to the progression of albuminuria in type 2 diabetes renal disease.

Augmented renal vascular nNOS and renin protein expression in angiotensin type 1 receptor null mice.

The present study was performed to determine the influence of absence of angiotensin type 1A (AT(1A)) and/or AT(1B) receptor feedback regulation of kidney neuronal nitric oxide synthase (nNOS) and renin protein expression. Kidneys were harvested from wild-type (WT), AT(1A)(-/-), AT(1B)(-/-), and AT(1A)(-/-)AT(1B)(-/-) mice and immunostained for nNOS and renin protein localization. AT(1A)(-/-) and AT(1A)(-/-)AT(1B)(-/-) kidneys demonstrated an increase in the percentage of glomeruli with nNOS-positive afferent and interlobular arterioles compared with WT mice. Density of vascular nNOS immunostaining was 20-fold higher in kidneys of AT(1A)(-/-) and AT(1A)(-/-)AT(1B)(-/-) compared with WT mice. Density of macula densa nNOS immunostaining was 7-fold higher in AT(1A)(-/-)AT(1B)(-/-) than in WT mice. Percent of glomeruli positive for juxtaglomerular (JG) cell renin was 3-fold higher, whereas the density of JG cell renin immunostaining was 15-fold higher in kidneys of AT(1A)(-/-) and AT(1A)(-/-)AT(1B)(-/-) compared with WT mice. Kidneys of AT(1A)(-/-) and AT(1A)(-/-)AT(1B)(-/-) mice displayed recruitment of renin protein expression along afferent and interlobular arterioles. Absence of AT(1) receptor signaling resulted in enhanced nNOS protein expression in both microvascular and tubular structures. Enhanced NO generation may contribute to the reduced renal vascular tone and blood pressure observed with blockade of the renin-angiotensin system.

Knockout mice reveal that the angiotensin II type 1B receptor links to smooth muscle contraction.

BACKGROUND: Rodents express two isoforms of the angiotensin II type 1 (AT(1)) receptor: AT(1A) and AT(1B). It is unclear which receptor subtype mediates contraction in response to angiotensin II in various arteries. We tested the hypothesis that the AT(1B) receptor is the predominant receptor that mediates contraction in the abdominal aorta in response to angiotensin II. METHODS: Isometric tension responses to angiotensin II were determined in abdominal aortic rings obtained from male wild-type and AT(1B) receptor knockout mice. The rings were suspended in an organ bath of a wire myograph and contractions to angiotensin II and other vasoconstrictors were determined. RESULTS: Angiotensin II contracted aortic segments from wild-type mice; however, this response was virtually absent in rings obtained from AT(1B) receptor knockout mice. Contractions in response to K(+) and U46619 (thromboxane A(2) mimetic) were not different between rings obtained from wild-type and AT(1B) receptor knockout mice. CONCLUSIONS: Reduced angiotensin II contraction is not related to a generalized decrease in smooth muscle function, rather it is specifically due to genetic ablation of the AT(1B) receptor. Our data support the concept that AT(1B) receptors couple to contraction in the mouse abdominal aorta, a function that parallels the single known AT(1) receptor in human vascular smooth muscle.

High Frequency Spinal Cord Stimulation for Complex Regional Pain Syndrome: A Case Report.

Complex regional pain syndrome (CRPS) is a chronic, debilitating, neuropathic pain condition which is often misdiagnosed, difficult to manage, and lacks proven methods for remission. Most available methods provide some relief to a small percentage of patients. Recent FDA approval and superiority of the Nevro Senza 10-kHz high frequency (HF10) spinal cord stimulation (SCS) therapy over traditional low-frequency spinal cord stimulation for treatment of chronic back and leg pain may provide a new interventional therapeutic option for patients suffering from CRPS. We provide a case report of a 53-year-old Caucasian woman who suffered with CRPS in the right knee and thigh for over 7 years. Implantation of the HF10 device provided over 75% relief of pain, erythema, heat, swelling, and tissue necrosis to the entire region within 1 month of treatment. Because the HP10 therapy provides pain relief without paresthesia typical of traditional low-frequency, this system may provide relief for patients suffering from chronic pain.Key words: Complex regional pain syndrome, spinal cord stimulation, Nevro Senza HF10, erythema, knee, thigh.

Enhanced vascular chymase-dependent conversion of endothelin in the diabetic kidney.

BACKGROUND: Diabetic nephropathy (DN) is associated with enhanced renal, plasma, and urinary endothelin (ET)-1 levels. Chymase cleaves Big ET-1 (1-38) to ET-1 (1-31), which is further cleaved by neutral endopeptidase to ET-1 (1-21). The current study tested the hypothesis that afferent arterioles (AA) of diabetic kidneys exhibit enhanced vasoconstrictor responses to chymase-dependent intrarenal ET formation compared to control kidneys. METHODS: In situ juxtamedullary AA vasoconstrictor responses to the intrarenal conversion of Big ET-1 (1-38) to ET-1 (1-21) were performed in the absence and presence of chymase inhibition in type 2 diabetic db/db and control db/m mice studied under in vitro experimental conditions. RESULTS: AA vasoconstrictor responses to Big ET-1 (1-38) were significantly enhanced in diabetic compared to control kidneys. In the presence of chymase inhibition (JNJ-18054478), AA vasoconstrictor responses of diabetic kidneys to Big ET-1 (1-38) were significantly less than the responses of control kidneys. AA diameters decreased similarly to ET-1 (1-21) in diabetic and control kidneys. CONCLUSIONS: AA responses to the intrarenal conversion of Big ET-1 (1-38) to ET-1 in the absence of chymase enzymatic activity were significantly reduced in kidneys of diabetic compared to control mice, while the magnitude of the vasoconstriction to ET-1 (1-21) was not different. These data suggest that AA vasoconstriction produced by the chymase-dependent pathway is significantly greater in diabetic compared to control kidneys. We propose that intrarenal chymase-dependent ET-1 production contributes to the decline in function and progression to end-stage renal disease in patients with type 2 diabetes.

Cardinal role of the intrarenal renin-angiotensin system in the pathogenesis of diabetic nephropathy.

Diabetes mellitus is one of the most prevalent diseases and is associated with increased incidence of structural and functional derangements in the kidneys, eventually leading to end-stage renal disease in a significant fraction of afflicted individuals. The renoprotective effects of renin-angiotensin system (RAS) blockade have been established; however, the mechanistic pathways have not been fully elucidated. In this review article, the cardinal role of an activated RAS in the pathogenesis of diabetic nephropathy (DN) is discussed with a focus on 4 themes: (1) introduction to RAS cascade, (2) intrarenal RAS in diabetes, (3) clinical outcomes of RAS blockade in DN, and (4) potential of urinary angiotensinogen as an early biomarker of intrarenal RAS status in DN. This review article provides a mechanistic rational supporting the hypothesis that an activated intrarenal RAS contributes to the pathogenesis of DN and that urinary angiotensinogen levels provide an index of intrarenal RAS activity.

Assessment of renal function; clearance, the renal microcirculation, renal blood flow, and metabolic balance.

Historically, tools to assess renal function have been developed to investigate the physiology of the kidney in an experimental setting, and certain of these techniques have utility in evaluating renal function in the clinical setting. The following work will survey a spectrum of these tools, their applications and limitations in four general sections. The first is clearance, including evaluation of exogenous and endogenous markers for determining glomerular filtration rate, the adaptation of estimated glomerular filtration rate in the clinical arena, and additional clearance techniques to assess various other parameters of renal function. The second section deals with in vivo and in vitro approaches to the study of the renal microvasculature. This section surveys a number of experimental techniques including corticotomy, the hydronephrotic kidney, vascular casting, intravital charge coupled device videomicroscopy, multiphoton fluorescent microscopy, synchrotron-based angiography, laser speckle contrast imaging, isolated renal microvessels, and the perfused juxtamedullary nephron microvasculature. The third section addresses in vivo and in vitro approaches to the study of renal blood flow. These include ultrasonic flowmetry, laser-Doppler flowmetry, magnetic resonance imaging (MRI), phase contrast MRI, cine phase contrast MRI, dynamic contrast-enhanced MRI, blood oxygen level dependent MRI, arterial spin labeling MRI, x-ray computed tomography, and positron emission tomography. The final section addresses the methodologies of metabolic balance studies. These are described for humans, large experimental animals as well as for rodents. Overall, the various in vitro and in vivo topics and applications to evaluate renal function should provide a guide for the investigator or physician to understand and to implement the techniques in the laboratory or clinic setting.