Development of the Physiology Professional Skills Curriculum Mapping Tool (PS-MAP).

During the course of undergraduate studies, physiology (and related STEM) majors should acquire a both broad and in-depth foundation in physiological knowledge along with a distinct range of transferable (professional) skills (e.g., critical thinking, communication skills, data analysis). Previously, through a consultative and iterative process with physiology educators, the Professional Skills Committee of the Physiology Majors Interest Group (PMIG) defined and refined a consensus list of professional skills that physiology majors should acquire during their program of study. Here we describe the development and beta testing of a convenient tool to enable physiology and physiology-related program educators to map these professional skills across their curricula. The tool, referred to as PS-MAP, uses the Qualtrics platform and allows programs to collect and organize data about whether students are provided the opportunity to learn and develop the defined professional skills during their undergraduate experience. The authors have made the PS-MAP tool freely available to educators and provide practical tips for its implementation. Use of the PS-MAP tool and the data collected can help programs identify curricular strengths and gaps as well as facilitate curricular discussions among educators within the program.NEW & NOTEWORTHY In addition to foundational physiology knowledge, undergraduate physiology and related STEM majors should develop a range of transferable professional skills. However, evidence of this curricular goal has been lacking. Therefore, the Professional Skills Committee of the Physiology Majors Interest Group (PMIG) developed the freely available and convenient Physiology Professional Skills Curriculum Mapping Tool (PS-MAP) to assist educators in mapping these professional skills throughout their programs.

Effects of long-term inhaled corticosteroid treatment on fragility fractures in older women: the Manitoba BMD registry study.

The effects of inhaled corticosteroids (ICS) on fracture risk in older women with chronic respiratory diseases are not well established. Our results indicate long-term ICS use in this population does not increase the risk of major osteoporotic fracture. This finding further elucidates the long-term safety of ICS in older women. INTRODUCTION: Inhaled corticosteroids (ICS) are frequently used in older women with chronic respiratory diseases. There is insufficient evidence regarding the association between long-term ICS use and the risk of fragility fractures in this population. METHODS: We used linked Manitoba health administrative databases and the provincial bone mineral density (BMD) registry (1996-2013) to identify women ≥ 40 years of age with asthma and/or chronic obstructive pulmonary disease (COPD) within 3 years preceding the baseline BMD test. We followed them until the first major osteoporotic fracture or end of study, whichever came first. ICS use, stratified by exposure tertiles, was measured within the 12-month period following the baseline BMD test (by total days and quantity, primary outcome), and over the entire follow-up period (by medication possession ratio (MPR) and average annual dose, secondary outcome). The hazard ratio of fracture with ICS use was estimated using a Cox proportional hazards model, controlling for baseline determinants of fracture. RESULTS: Of 6880 older women with asthma (38%) or COPD (62%), 810 (12%) experienced a major osteoporotic fracture over a mean follow-up of 7.7 years (SD = 3.9). ICS use at any tertile was not associated with an increased risk of fracture (dispensed days, p = 0.90; dispensed quantity, p = 0.67). Similarly, ICS use at any tertile during the entire follow-up period was not associated with an increased risk of fracture (MPR, p = 0.62; average annual dose, p = 0.58). CONCLUSION: Our findings do not support an increased risk of major osteoporotic fracture in older women with chronic respiratory diseases due to long-term ICS use.

Decreased rotational flow and circumferential wall shear stress as early markers of descending aorta dilation in Marfan syndrome: a 4D flow CMR study.

BACKGROUND: Diseases of the descending aorta have emerged as a clinical issue in Marfan syndrome following improvements in proximal aorta surgical treatment and the consequent increase in life expectancy. Although a role for hemodynamic alterations in the etiology of descending aorta disease in Marfan patients has been suggested, whether flow characteristics may be useful as early markers remains to be determined. METHODS: Seventy-five Marfan patients and 48 healthy subjects were prospectively enrolled. In- and through-plane vortexes were computed by 4D flow cardiovascular magnetic resonance (CMR) in the thoracic aorta through the quantification of in-plane rotational flow and systolic flow reversal ratio, respectively. Regional pulse wave velocity and axial and circumferential wall shear stress maps were also computed. RESULTS: In-plane rotational flow and circumferential wall shear stress were reduced in Marfan patients in the distal ascending aorta and in proximal descending aorta, even in the 20 patients free of aortic dilation. Multivariate analysis showed reduced in-plane rotational flow to be independently related to descending aorta pulse wave velocity. Conversely, systolic flow reversal ratio and axial wall shear stress were altered in unselected Marfan patients but not in the subgroup without dilation. In multivariate regression analysis proximal descending aorta axial (p = 0.014) and circumferential (p = 0.034) wall shear stress were independently related to local diameter. CONCLUSIONS: Reduced rotational flow is present in the aorta of Marfan patients even in the absence of dilation, is related to aortic stiffness and drives abnormal circumferential wall shear stress. Axial and circumferential wall shear stress are independently related to proximal descending aorta dilation beyond clinical factors. In-plane rotational flow and circumferential wall shear stress may be considered as an early marker of descending aorta dilation in Marfan patients.

Demographic consequences of invasion by a native, controphic competitor to an insular bird population.

Species invasions and range shifts can lead to novel competitive interactions between historically resident and colonizing species, but the demographic consequences of such interactions remain controversial. We present results from field experiments and 45 years of demographic monitoring to test the hypothesis that the colonization of Mandarte Is., BC, Canada, by fox sparrows (Passerella iliaca) caused the long-term decline of the resident population of song sparrows (Melospiza melodia). Several lines of evidence indicate that competition with fox sparrows for winter food reduced over-winter survival in juvenile song sparrows by 48% from 1960 to 2015, enforcing population decline despite an increase in annual reproductive rate in song sparrows over the same period. Preference for locally abundant seeds presented at experimental arenas suggested complete overlap in diet in song and fox sparrows, and observations at arenas baited with commercial seed showed that fox sparrows displaced song sparrows in 91-100% of interactions in two periods during winter. In contrast, we found no evidence of interspecific competition for resources during the breeding season. Our results indicate that in the absence of marked shifts in niche dimension, range expansions by dominant competitors have the potential to cause the extirpation of historically resident species when competitive interactions between them are strong and resources not equitably partitioned.

Comparison of radial 4D Flow-MRI with perivascular ultrasound to quantify blood flow in the abdomen and introduction of a porcine model of pre-hepatic portal hypertension.

OBJECTIVES: Objectives of this study were to compare radial time-resolved phase contrast magnetic resonance imaging (4D Flow-MRI) with perivascular ultrasound (pvUS) and to explore a porcine model of acute pre-hepatic portal hypertension (PHTN). METHODS: Abdominal 4D Flow-MRI and pvUS in portal and splenic vein, hepatic and both renal arteries were performed in 13 pigs of approximately 60 kg. In six pigs, measurements were repeated after partial portal vein (PV) ligature. Inter- and intra-reader comparisons and statistical analysis including Bland-Altman (BA) comparison, paired Student's t tests and linear regression were performed. RESULTS: PvUS and 4D Flow-MRI measurements agreed well; flow before partial PV ligature was 322 ± 30 ml/min in pvUS and 297 ± 27 ml/min in MRI (p = 0.294), and average BA difference was 25 ml/min [-322; 372]. Inter- and intra-reader results differed very little, revealed excellent correlation (R 2 = 0.98 and 0.99, respectively) and resulted in BA differences of -5 ml/min [-161; 150] and -2 ml/min [-28; 25], respectively. After PV ligature, PV flow decreased from 356 ± 50 to 298 ± 61 ml/min (p = 0.02), and hepatic arterial flow increased from 277 ± 36 to 331 ± 65 ml/min (p = n.s.). CONCLUSION: The successful in vivo comparison of radial 4D Flow-MRI to perivascular ultrasound revealed good agreement of abdominal blood flow although with considerable spread of results. A model of pre-hepatic PHTN was successfully introduced and acute responses monitored. KEY POINTS: • Radial 4D Flow-MRI in the abdomen was successfully compared to perivascular ultrasound. • Inter- and intra-reader testing demonstrated excellent reproducibility of upper abdominal 4D Flow-MRI. • A porcine model of acute pre-hepatic portal hypertension was successfully introduced. • 4D Flow-MRI successfully monitored acute changes in a model of portal hypertension.

Inflammatory cytokine receptor blockade in a rodent model of mild traumatic brain injury.

In rodent models of traumatic brain injury (TBI), both Interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNFα) levels increase early after injury to return later to basal levels. We have developed and characterized a rat mild fluid percussion model of TBI (mLFP injury) that results in righting reflex response times (RRRTs) that are less than those characteristic of moderate to severe LFP injury and yet increase IL-1α/ß and TNFα levels. Here we report that blockade of IL-1α/ß and TNFα binding to IL-1R and TNFR1, respectively, reduced neuropathology in parietal cortex, hippocampus, and thalamus and improved outcome. IL-1ß binding to the type I IL-1 receptor (IL-1R1) can be blocked by a recombinant form of the endogenous IL-1R antagonist IL-1Ra (Kineret). TNFα binding to the TNF receptor (TNFR) can be blocked by the recombinant fusion protein etanercept, made up of a TNFR2 peptide fused to an Fc portion of human IgG1. There was no benefit from the combined blockades compared with individual blockades or after repeated treatments for 11 days after injury compared with one treatment at 1 hr after injury, when measured at 6 hr or 18 days, based on changes in neuropathology. There was also no further enhancement of blockade benefits after 18 days. Given that both Kineret and etanercept given singly or in combination showed similar beneficial effects and that TNFα also has a gliotransmitter role regulating AMPA receptor traffic, thus confounding effects of a TNFα blockade, we chose to focus on a single treatment with Kineret.

A rodent model of mild traumatic brain blast injury.

One of the criteria defining mild traumatic brain injury (mTBI) in humans is a loss of consciousness lasting for less than 30 min. mTBI can result in long-term impairment of cognition and behavior. In rats, the length of time it takes a rat to right itself after injury is considered to be an analog for human return to consciousness. This study characterized a rat mild brain blast injury (mBBI) model defined by a righting response reflex time (RRRT) of more than 4 min but less than 10 min. Assessments of motor coordination relying on beam-balance and foot-fault assays and reference memory showed significant impairment in animals exposed to mBBI. This study's hypothesis is that there are inflammatory outcomes to mTBI over time that cause its deleterious effects. For example, mBBI significantly increased brain levels of interleukin (IL)-1ß and tumor necrosis factor-α (TNFα) protein. There were significant inflammatory responses in the cortex, hippocampus, thalamus, and amygdala 6 hr after mBBI, as evidenced by increased levels of the inflammatory markers associated with activation of microglia and macrophages, ionized calcium binding adaptor 1 (IBA1), impairment of the blood-brain barrier, and significant neuronal losses. There were significant increases in phosphorylated Tau (p-Tau) levels, a putative precursor to the development of neuroencephalopathy, as early as 6 hr after mBBI in the cortex and the hippocampus but not in the thalamus or the amygdala. There was an apparent correlation between RRRTs and p-Tau protein levels but not IBA1. These results suggest potential therapies for mild blast injuries via blockade of the IL-1ß and TNFα receptors.

Four-dimensional velocity mapping of the hepatic and splanchnic vasculature with radial sampling at 3 tesla: a feasibility study in portal hypertension.

PURPOSE: To demonstrate the feasibility of PC-VIPR (Phase Contrast Vastly undersampled Imaging with Projection Reconstruction) for the depiction and hemodynamic analysis of hepatic and splanchnic vessels in patients with portal hypertension. MATERIALS AND METHODS: Twenty-four cirrhotic patients (55.9 ± 10.4 years) were scanned using 5-point PC-VIPR for high spatial resolution imaging with large volume coverage at 3 Tesla (T) using a 32-channel body coil. Vessel segmentation and hemodynamic visualization included color-coded three-dimensional (3D) streamlines and particle traces. Segmentation quality was compared with contrast-enhanced multi-phase liver imaging. Flow pattern analysis was performed in consensus of three readers. The MELD score was calculated to estimate disease severity and was correlated to image quality. RESULTS: Good to excellent visualization quality was achieved in 23/24 cases. All arterial vessels and 144/168 vessels of the portal venous (PV) circulation were unambiguously identified. No correlation with the MELD score was found. Eight of 148 vessels of the PV circulation demonstrated reverse (hepatofugal) flow. Hepatofugal flow in small tributaries to PV flow were present in three cases despite hepatopetal flow in the PV. CONCLUSION: This feasibility study demonstrates the feasibility of PC-VIPR for simultaneous morphological and hemodynamic assessment of the hepatic and splanchnic vasculature in cirrhosis and portal hypertension. Future studies with quantitative analyses are warranted.

Vesicular stomatitis virus (Indiana serotype): transovarial transmission by phlebotomine sandlies.

Transovarial transmission of vesicular stomatitis virus (Indiana serotype) by experimentally infected Lutzomyia trapidoi and Lutzomyia ylephiletrix to their progeny was demonstrated. Virus was recovered from all developmental stages; mean virus titers from egg to first generation adult showed a four-log increase, indicating that virus multiplication occurred during development of the sandflies. Virus titers in first generation adult females were comparable to those found in their parents. These infected female sandflies transmitted vesicular stomatitus virus Indiana by bite to susceptible animals and transmitted the virus transovarially to their offspring (second generation). Results demonstrate a possible mechanism for transmission and maintenance of this virus in nature without a vertebrate (heat) host reservoir.

Dissolved organic matter and heterotrophic microneuston in the surface microlayers of the north atlantic.

Dissolved organic carbon, carbohydrates, and adenosine triphosphate in the size fractions 0.2 to 3 micrometers and 3 to 1000 micrometers are significantly enriched in the upper 150-micrometer surface layer compared to subsurface water, mean enrichment factors being 1.6, 2.0, 2.5, and 3.1, respectively. When calculated as a 0.1-micrometer microlayer of wet surfactants, the mean concentration of organic matter was 2.9 grams per liter, of which carbohydrates accounted for 28 percent. The data for plant pigments and particulate adenosine triphosphate indicated that bacterioneuston was enriched at seven of nine stations while phagotrophic protists were enriched at five stations. Instances of enrichment and inhibition were verified by cultural data for bacteria and amoebas. The observations indicate that the surface microlayers are largely heterotrophic microcosms, which can be as rich as laboratory cultures, and that an appreciable part of the dissolved organic carbon is carbohydrate of phytoplankton origin, released and brought to the surface by migrating and excreting phagotrophic protists.

Guidelines for the development of social marketing programmes for sun protection among adolescents and young adults.

OBJECTIVES: To formulate 'best practice' guidelines for social marketing programmes for adolescents' and young adults' sun protection. STUDY DESIGN: A Delphi consensus process. METHODS: Eleven experts in sun protection and social marketing participated in a Delphi consensus process, where they were asked to provide up to 10 key points, based on their knowledge and practical experience, which they felt were most important in developing social marketing interventions for the primary prevention of skin cancer among adolescents and young adults. After reaching consensus, the evidence base for each guideline was determined and graded via the Scottish Intercollegiate Guideline Network grading system. Participants were then asked to indicate how strongly they rated the finalized 15 recommendations based on all aspects relating to their knowledge and practical opinion, as well as the research evidence, on a visual analogue scale. RESULTS: The resultant 15 guidelines offer general principles for sun protection interventions utilizing a social marketing approach. CONCLUSIONS: This method of guideline development brought the expertise of practitioners to the forefront of guideline development, whilst still utilizing established methods of evidence confirmation. It thus offers a useful method for guideline development in a public health context.

Synergistic Effects of Temperature and Salinity on the Gene Expression and Physiology of Crassostrea virginica.

The eastern oyster, Crassostrea virginica, forms reefs that provide critical services to the surrounding ecosystem. These reefs are at risk from climate change, in part because altered rainfall patterns may amplify local fluctuations in salinity, impacting oyster recruitment, survival, and growth. As in other marine organisms, warming water temperatures might interact with these changes in salinity to synergistically influence oyster physiology. In this study, we used comparative transcriptomics, measurements of physiology, and a field assessment to investigate what phenotypic changes C. virginica uses to cope with combined temperature and salinity stress in the Gulf of Mexico. Oysters from a historically low salinity site (Sister Lake, LA) were exposed to fully crossed temperature (20°C and 30°C) and salinity (25, 15, and 7 PSU) treatments. Using comparative transcriptomics on oyster gill tissue, we identified a greater number of genes that were differentially expressed (DE) in response to low salinity at warmer temperatures. Functional enrichment analysis showed low overlap between genes DE in response to thermal stress compared with hypoosmotic stress and identified enrichment for gene ontologies associated with cell adhesion, transmembrane transport, and microtubule-based process. Experiments also showed that oysters changed their physiology at elevated temperatures and lowered salinity, with significantly increased respiration rates between 20°C and 30°C. However, despite the higher energetic demands, oysters did not increase their feeding rate. To investigate transcriptional differences between populations in situ, we collected gill tissue from three locations and two time points across the Louisiana Gulf coast and used quantitative PCR to measure the expression levels of seven target genes. We found an upregulation of genes that function in osmolyte transport, oxidative stress mediation, apoptosis, and protein synthesis at our low salinity site and sampling time point. In summary, oysters altered their phenotype more in response to low salinity at higher temperatures as evidenced by a higher number of DE genes during laboratory exposure, increased respiration (higher energetic demands), and in situ differential expression by season and location. These synergistic effects of hypoosmotic stress and increased temperature suggest that climate change will exacerbate the negative effects of low salinity exposure on eastern oysters.

Mechanism of action of rab3A in mossy fiber LTP.

In mossy fiber synapses of the hippocampal CA3 region, LTP is induced by cAMP and requires the synaptic vesicle protein rab3A. In contrast, CA1-region synapses do not exhibit this type of LTP. We now show that cAMP enhances glutamate release from CA3 but not CA1 synaptosomes by (1) increasing the readily releasable pool as tested by hypertonic sucrose; (2) potentiating release evoked by KCl depolarization, which opens voltage-gated Ca2+ channels; and (3) by enhancing Ca2+ action on the secretory apparatus as monitored by the Ca2+-ionophore ionomycin. In rab3A-deficient synaptosomes, forskolin still enhances KCl- and sucrose-induced glutamate release but not ionomycin-induced release. Our results show that cAMP has multiple actions in mossy fiber synapses, of which only the direct activation of the secretory apparatus requires rab3A and functions in mfLTP.

Pressure Mapping and Hemodynamic Assessment of Intracranial Dural Sinuses and Dural Arteriovenous Fistulas with 4D Flow MRI.

The feasibility of 4D flow MR imaging to visualize flow patterns and generate relative pressure maps in the dural venous sinus in healthy subjects (n = 60) and patients with dural arteriovenous fistulas (n = 7) was investigated. Dural venous drainage was classified based on torcular Herophili anatomy by using 4D flow MR imaging-derived angiograms and magnitude images. Subjects were scanned in a 3T clinical MR imaging system. 4D flow MR imaging enabled noninvasive characterization of dural sinus anatomy and mapping of relative pressure differences.

Eukaryotic transcription: the core of eukaryotic gene activation.

Gene expression is controlled by interactions between activators and coactivators. These interactions in turn are regulated by signaling pathways and by chromatin remodeling events. Recent studies indicate that the final arbiter of gene regulation is a coactivator scaffold at the promoter.

Physiologic and anatomic assessment of a canine carotid artery stenosis model utilizing phase contrast with vastly undersampled isotropic projection imaging.

BACKGROUND AND PURPOSE: Noninvasive assessment of the hemodynamic significance of carotid stenosis is often performed with MR angiography and supplemented with carotid Doppler sonography. Phase contrast with vastly undersampled isotropic projection reconstruction (PC-VIPR), a novel MR imaging technique, accelerates phase-contrast MR flow imaging and provides both images of the vessels and measurements of blood-flow velocities. For this study, we determined the accuracy of PC-VIPR blood-flow velocity measurements to determine pressure gradients across an experimental carotid stenosis. MATERIALS AND METHODS: A focal stenosis was surgically created in each common carotid artery of 6 canines. Digital subtraction angiography (DSA) was performed, and the degree of stenosis was determined using the North American Symptomatic Carotid Endarterectomy Trial methodology. A microcatheter was positioned in the carotid artery proximal and distal to the stenosis, and pressures were measured in the vessel through the catheter. PC-VIPR was then performed on a 1.5T MR imaging scanner with parameters producing 0.8-mm isotropic voxel resolution. From the velocity measurements, pressure gradients were calculated from the Navier-Stokes relationship to compare with the pressures measured by a catheter. RESULTS: Carotid stenoses in the 50%-85% range were produced in the 12 arteries. Pressure gradients across the stenoses ranged from 6 to 26 mm Hg. The pressure gradient calculated from the PC-VIPR data correlated (r = 0.91, P < .0001) with the actual pressure measurements. CONCLUSION: With PC-VIPR, a novel MR imaging technique, the hemodynamic effect of a stenosis on flow and pressure can be evaluated.

HCF-1 amino- and carboxy-terminal subunit association through two separate sets of interaction modules: involvement of fibronectin type 3 repeats.

When herpes simplex virus infects permissive cells, the viral regulatory protein VP16 forms a specific complex with HCF-1, a preexisting nuclear protein involved in cell proliferation. The majority of HCF-1 in the cell is a complex of associated amino (HCF-1(N))- and carboxy (HCF-1(C))-terminal subunits that result from an unusual proteolytic processing of a large precursor polypeptide. Here, we have characterized the structure and function of sequences required for HCF-1(N) and HCF-1(C) subunit association. HCF-1 contains two matched pairs of self-association sequences called SAS1 and SAS2. One of these matched association sequences, SAS1, consists of a short 43-amino-acid region of the HCF-1(N) subunit, which associates with a carboxy-terminal region of the HCF-1(C) subunit that is composed of a tandem pair of fibronectin type 3 repeats, a structural motif known to promote protein-protein interactions. Unexpectedly, the related protein HCF-2, which is not proteolyzed, also contains a functional SAS1 association element, suggesting that this element does not function solely to maintain HCF-1(N) and HCF-1(C) subunit association. HCF-1(N) subunits do not possess a nuclear localization signal. We show that, owing to a carboxy-terminal HCF-1 nuclear localization signal, HCF-1(C) subunits can recruit HCF-1(N) subunits to the nucleus.

Calcium ionophore enhances the electron spin resonance signal from isolated skeletal muscle.

Electron spin resonance studies of the free radical signal from isolated skeletal muscle during experimental damage have shown that elevation of muscle intracellular calcium with the calcium ionophore A23187 induced an average 61% increase in the amplitude of the signal of g value 2.0047 compared to paired, untreated control muscles, accompanied by a large efflux of intracellular creatine kinase to the external medium. Inhibitors of the calcium-induced loss of cell viability leading to enzyme efflux, i.e., chlorpromazine, phenidone and nordihydroguaiaretic acid had variable effects on the signal, suggesting that the free radical signal obtained from skeletal muscle by electron spin resonance techniques is stimulated by intracellular calcium overload, but is not directly related to the mechanisms by which calcium overload leads to a loss of cell viability leading to intracellular enzyme efflux.

Neurobiology of cocaine abuse.

The recent escalation of cocaine abuse has increased awareness of the need to understand the behavioral effects of cocaine and the determinants of those effects. Cocaine alters both conditioned and unconditioned behavior, and has prominent reinforcing and subjective effects that are particularly relevant to its abuse. An increase in CNS dopamine neurotransmission, resulting from a competitive blockade of high-affinity dopamine uptake mediated by both D1 and D2 dopamine receptors, is a primary determinant of the behavioral effects of cocaine. Either tolerance or sensitization may develop with repeated administration of cocaine. Dependence also develops, although the behavioral changes associated with cocaine withdrawal are subtle. Although numerous CNS changes have been associated with repeated administration of cocaine, the neuropharmacological mechanisms that underlie the behavioral changes that occur with repeated administration remain to be firmly established. Bill Woolverton and Ken Johnson stress that continued collaboration between behavioral pharmacologists and neuroscientists is critical for a complete understanding of the effects of cocaine.

Noncompetitive excitatory amino acid receptor antagonists.

In the first article in this series, Watkins, Krogsgaard-Larsen and Honoré outlined the structure-activity requirements at the receptor sites for excitatory amino acids in the mammalian CNS. The postsynaptic depolarizing actions of glutamate are thought to be mediated by NMDA, AMPA and kainate receptors. Here David Lodge and Kenneth M. Johnson review some of the recent developments in the pharmacology of other means by which the function of these receptors may be modulated. Divalent cations, phencyclidine-like drugs, glycine analogues and polyamines all modulate NMDA receptors whereas barbiturates and some arthropod toxins reduce channel responses to non-NMDA receptor agonists. Modes of action and implications for physiology and pathophysiology are discussed.