bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood Flow Heterogeneity and Oxygenation in the Lung: Effect of the Hypoxic Pulmonary Vasoconstriction Response Curve
Authors: Roy Tuhin K. , Secomb Timothy W.
Published: May 2022

The ability of the lung to take up oxygen can be characterized by its effective diffusing capacity, which is determined by the transport characteristics of the alveolar‐capillary membrane as well as heterogeneity of pulmonary blood flow. At rest, the healthy lung has a high degree of tolerance for pulmonary flow heterogeneity, but under conditions of physiological stress such as exercise, oxygen uptake may be inadequate to satisfy tissue demand if flow is very heterogeneous. We previously used a mathematical model of pulmonary oxygen uptake to examine the ability of hypoxic pulmonary vasoconstriction (HPV) to mitigate flow heterogeneity. In the model, flow heterogeneity is characterized by the coefficient of variation (CV) of pulmonary capillary blood flow. Assuming an initial lognormal distribution of blood flow with a normal level of heterogeneity (CV = 1.66), we simulate flow regulation over a range of oxygen consumption from rest to maximal exercise by adjusting pulmonary flow resistance in each vessel in accordance with an HPV response curve obtained from previously published experimental data. The effect of HPV on vessel flow resistance is assumed to be characterized by a sigmoidal response dependent on the capillary oxygen tension, which is approximated as the mean of the venous and arterial values in each pulmonary capillary; its maximal sensitivity occurs at a stimulus oxygen tension of approximately 30 torr. The purpose of the present study was to determine whether altering the shape of the HPV response curve would result in an improvement in CV reduction. Altering the HPV by shifting the sigmoidal curve to the right by 10 or 20 torr worsened CV, extraction and total pulmonary vascular resistance (PVR). Similar detrimental results were obtained when the range of oxygen tensions over which HPV varied was expanded by a factor of two, increasing the oxygen tension at which the sensitivity of HPV to oxygen tension was maximal. On the other hand, shrinking the range of variation of the HPV curve by a factor of two neither improved nor significantly worsened the CV or extraction, and resulted in a PVR distribution similar to the case of the normal HPV curve. These results demonstrate that the observed shape of the HPV response tends to minimize heterogeneity of pulmonary flow under conditions of exercise.
Next generation personalized blood vessel‐on‐chip: Mimicking patient‐specific pathophysiology in sickle cell disease through blood‐derived endothelial progenitors
Authors: Mathur Tanmay , Tronolone James , Jain Abhishek
Published: May 2022

Advances in tissue engineering and organ‐chip technology have accelerated in vitro research of the vascular system. Incorporating patient‐derived endothelial cells either through direct tissue biopsies or stem cell differentiation techniques further enhance the impact of organ‐chips on precision medicine. However, these methods pose certain challenges and might be difficult to adopt in lab, thereby limiting the predictive power of organ‐chips. Here we report the use of Blood Outgrowth Endothelial Cells (BOECs) directly isolated from patient blood as an alternative to primary and iPSC‐derived endothelial cells for organ‐chip applications. BOECs exhibit the gold‐standard endothelial hallmarks of the “cobblestone” morphology in vitro. When compared to primary HUVECs and iPSC‐derived endothelial cells, healthy BOECs reveal similar levels of growth rates, migration capabilities, de novo vessel formation, response to fluid shear stress and exogenous cytokine inflammation in vitro. To study patient‐specificity, we derive BOECs from two sickle cell disease (SCD) patients with known differences in clinical severity of the disease. Through next generation RNA sequencing, differential gene expression (DGE) analysis and qRT‐PCR, we reveal that SCD patient‐derived BOECs are indeed activated and that the more severe SCD patient exhibited a greater magnitude of activation. This is further confirmed by real‐time recalcified whole blood perfusion through endothelialized vessel‐chips. Blood‐derived endothelial cells may be employed in preclinical research for developing more robust and personalized next‐generation disease models that can ultimately enable clinicians in identifying individuals at high risk of stroke or cardiovascular complications.
Providing effective feedback with soaring class sizes: It’s still possible
Authors: Hart Orla M.
Published: May 2022

“Do more with less”, is a message that many of us are likely used to hearing, whether explicitly, or implicitly. We consolidate resources, streamline processes etc, in the name of economy. Sometimes streamlining grading and feedback means grading with minimal or no feedback, and/or eliminating intensive writing assignments that take a lot of time to grade. However, in upper‐level, discipline‐specific classes, automated grading and feedback do not always do what we need it to do for formative assessment. Writing assignments are a critical component of students demonstrating learning outcomes, and thoughtful, specific feedback accompanying the grading, is just as important. But how we do this in a class of 20 students just isn’t scalable. Does that mean the feedback component is lost? Not necessarily. My hypothesis is that the feedback that students require on higher Bloom’s level assignments can be consolidated by topic/question, and effectively delivered to large classes via video feedback.

Results

In studying the errors made in different types of questions/topics of a particular assignment over multiple semesters, it appeared that between 3‐5 specific errors accounted for more than 95% of the errors in each question on the assignment. When the protocol was implemented, grading was completed expeditiously, without any direct written feedback other than number grades. Subsequently, a feedback video was released to the class discussing the assignment and going through each question/topic. Common errors, and how to avoid them, were covered in the video feedback. In a class of 68 students, 186 video plays were recorded for a single remediation assignment. And although some of the engagement durations were highly variable, that is the engagement model that was suggested to students by encouraging them to only watch those parts of the video feedback they felt was necessary.

Conclusions

In concert with other types of feedback including peer feedback, and immediate in‐class feedback, video feedback for common misconceptions/errors provides an efficient way to engage students in formative learning. Despite this, it is clear that alternative (or traditional) access to feedback must be provided for those students who fall outside these so‐called normal thresholds. However, streamlining the feedback process for >90% of students will allow more time to be spent with non‐typical learners, or other students who require alternate resources. In this way, it is hoped that learners from marginalized communities and neuroatypical learners, who may benefit from increased guidance, can still get what they need, while the greater majority have opportunities to refine and tailor the feedback they most need.
Structural studies of regulatory elements in the RNA transcript for streptolysin S associated gene A (sagA) in group A Streptococcus
Authors: Lee Brian M. , Carroll Cameron R. , Nibar Sara G. , Brown Alexis S. , Angello Lauren R. , Calderon Kayla J. , Finn Regan A. , Pérez‐Alvarado Gabriela C.
Published: May 2022

Group A Streptococcus releases a cytotoxic peptide, streptolysin S, that targets sensory neurons and induces an inhibition of the immune response to the invasive disease, necrotizing fasciitis (flesh‐eating disease). The sagA gene for streptolysin S also produces a small regulatory RNA (sRNA) known as the pleiotropic effector locus (Pel), which regulates the expression of multiple mRNA transcripts associated with virulence. Potential mRNA interactions have been mapped to the 5′ and 3′ untranslated regions (UTRs) of sagA, which contain conserved, predicted secondary structures that may be regulatory elements. These results suggest that the 5′ UTR of sagA plays a key role in the trans‐acting regulatory activity of Pel with other virulence factor mRNA transcripts. Differential scanning fluorimetry and RNase T1 digest assays provided experimental evidence for the predicted secondary structures of these elements. Three dimensional models of the Pel/sagA regulatory elements were built using the FARFAR algorithm in the Rosetta molecular modelling suite. The 3′ UTR of sagA contains a complex structural element that combines a branched stem‐loop structure with a weak rho‐independent terminator, which may be regulated by other factors that dictate expression of the entire sag operon required for the maturation and secretion of streptolysin S. Current studies are focused on experimental determination of the Pel/sagA RNA structure and identification of functional interactions with other virulence factors. The development of therapeutic strategies that target regulatory RNA structural elements may be an effective strategy to mitigate the invasive forms of streptococcal infections.
Biocompatible and biodegradable nanoparticles for enhancing solubility and bioavailability of trans‐resveratrol
Authors: Hu Qiaobin , Zhou Fang , Wang Shu
Published: May 2022

Objectives

Trans‐resveratrol (R) is a natural polyphenolic compound found in red grapes, mulberries, and other berries. Cell and animal studies indicate that it can improve metabolic health through its anti‐inflammation, anti‐obesity, anti‐oxidant properties. However, the evidence is inconclusive in human studies regarding its effectiveness in improving metabolic health, most likely due to its low aqueous solubility, and trivial bioavailability. The objectives of this study are to encapsulate R into biocompatible and biodegradable nanoparticles (R‐NPs), and measure their characteristics and oral bioavailability in C57BL/6J mice.

Methods

The R‐NPs were made of soy phosphatidylcholine, vitamin E, Tween 80, and R. Their size, polydispersity index and zeta potential were measured using Zetasizer Pro. R‐NPs were stored in dark at 4°C, 22°C and 37°C, and their physical and chemical stability was measured every day. The physical stability was determined using Zetasizer Pro. The encapsulation efficiency and chemical stability were determined using an Agilent 1290 Infinity II UHPLC system. After oral administration of R‐NPs and free R at R concentration 50 mg/kg body weight in C57BL/6J mice, their oral bioavailability was determined by measuring blood R concentrations using the UHPLC system.

Results

Nanoencapsulation significantly increased aqueous solubility of R by more than 140 times. The mean particle size of freshly made R‐NPs was around 70 nm. The polydispersity index was less than 0.3. The zeta potential of R‐NPs was around −13 mV. R’s encapsulation efficiency was more than 95%. The size, polydispersity index, zeta potential, and R concentrations of R‐NPs did not change significantly at 4°C, 22°C and 37°C for 3 days. The encapsulation efficiency of R‐NPs remained above 94% after storage for 3 days at three tested temperatures. These data indicated good chemical and physical stability of R‐NPs. As compared to free R, R‐NPs had higher oral bioavailability in C57BL/6J mice.

Conclusions

Nanoencapsulation increased the aqueous solubility and stability of R, and improved R’s oral bioavailability in mice.
Potential Drug Therapy For Fragile X Tremor/Ataxia Syndrome
Authors: Brown Collis , Sobrian Sonya , Hudson Tamaro
Published: May 2022

Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a late‐onset neurological disorder that affects carriers of the alleles for the Fragile X gene, Fragile X Mental Retardation (FMR1) due to the CGG triplet repeat expansion within the 5’UTR of FMR1. Clinical symptoms that are likely to occur are progressive ataxia, intention tremor, intranuclear inclusions, and Parkinsonian‐like motor symptoms. The goal of this research is to assess the biological efficacy of Curcumin, Muscadine Grape Seed Extract (MSKE) on the neuroprotective capacity with respect to mitochondrial damage, and their ability to restore mitochondrial health in patient with FXTAS. To establish mitochondrial dysfunction, normal human cell lines and human‐induced pluripotent cells were treated with multiple concentrations of glucose/ glucose oxidase (GluOx) at 2,12,and 24 hour time points to induce varying intensities of oxidative stress. The degrees of oxidative stress were measured by apoptosis and mitochondrial reactive oxygen species (ROS) production. Curcumin and MSKE, compounds effective against oxidative damage in mitochondria, were used to rescue glucose oxidase induced oxidative damage in both cell lines. To test the ability of these drugs to restore mitochondrial health, cell viability and cellular superoxide production were assessed by propidium iodide and the MitoSox fluorescence assay, respectively. We anticipated that GluOx at varying concentrations and time points would proportionally increase levels of apoptosis and mitochondrial ROS, reflective of mitochondrial damage, with the most severe dysfunction occurring at a dose of 25 nM and the longest duration of 24‐hr exposure. Administration of MSKE in concentrations ranging from 10‐8 to 10‐5 M in half log increments, did not reverse the oxidative defects induced in the cell lines. However, curcumin concentrations increased cell viability at the 2, 12, and 24 hour time period. Results indicate that the research design should be modified by increasing concentration of both glucose and MSKE to provide a reliable test of the hypothesis. Although, the research design will be modified to better assessed the hypothesis, the overall research is translational in that it lends flexibility to testing therapeutics in neuronal FXTAS models and expands the discovery of mitochondrial markers for the syndrome.
Loss of SR‐PM Contact Sites May Contribute to The Development of Hypertension in Spontaneously Hypertensive Rats
Authors: Niloy Sayeman Islam , Jarajapu Yagna , O'Rourke Stephen , Sun Chengwen
Published: May 2022

Sarcoplasmic reticulum (SR)‐plasma membrane (PM) contact sites in vascular smooth muscle (VSM) cells bring the SR Ca2+ release channels into proximity of plasma membrane large‐conductance Ca2+‐activated K+ (BKca) channels and regulate intracellular Ca2+ through BKca‐mediated membrane hyperpolarization. Loss of BKca channel activity leads to increased intracellular Ca2+ concentration, vascular hypercontractility, and activation of hypertrophic genes. We hypothesized that the loss of close contact between the SR and the PM contributes to the development of vascular hypercontractility and hypertrophy in the Spontaneously Hypertensive Rat (SHR). To evaluate this hypothesis, we compared BKca channel activity in response to the activation of inositol 1,4,5‐trisphosphate receptor (IP3R), an SR Ca2+ channel between SHR and normotensive Sprague Dawley (SD) rats. We found that in endothelium‐denuded pressurized mesenteric arteries, paxilline (1μM), a selective BKca channel blocker, significantly increased norepinephrine (NE, 0.5μM)‐induced vasoconstriction in SD arteries (n=5) by ~15% (% initial diameter from 78.58±3.93 to 66.77±3.07). However, paxilline failed to increase NE‐induced vasoconstriction in SHR arteries (Figure 1). Paxilline treatment significantly augmented the hypertrophic effect of angiotensin II (ANG II) in SD, where the total cell area of paxilline treated ANG II group was ~11% (from 3471.48±121.35 to 3854.86±129.99μm2) greater compared to the non‐paxilline‐treated ANG II group. In contrast, the paxilline‐induced increase in hypertrophic response was absent in SHR. Similarly, in WST‐1 cell proliferation assay, paxilline treatment significantly increased ANG II‐induced proliferation in SD by ~15% (Absorbance(A440nm‐A630nm) from 0.15±0.01 to 0.17±0.01) while having no effect on cell proliferation in SHR. Next, we compared the effect of 5‐HT on BKca channel activity between SHR and SD rat mesenteric VSM cells using patch‐clamp whole‐cell mode. 5‐HT activates IP3Rs by stimulating the production of IP3 in VSM cells. At +60mV, 5‐HT (0.3μM) significantly increased BKca current density at +60mV in SD VSM cells from 50.78±2.19 to 69.40±5.50 pA/pF (n=6 cells, P<0.05) but the increase in current density was non‐significant in SHR (from 36.77±3.11 to 47.45±8.83 pA/pF, n=6 cells, Figure 2). We also examined the Ca2+‐ and voltage‐sensitivity of BKca channels using inside‐out patch‐clamp. BKca channels in VSM cells isolated from mesenteric arteries of SHR and SD rats displayed identical Ca2+‐ and voltage‐sensitivity. In conclusion, our data suggest a lack of BKca activation in response to IP3R activation in VSM cells ofSHR, which may be due to the loss of close contact between the SR and the PM.
The minor groove topology of nucleic acid ligands plays a key role in nuclease resistance and targeting of HMGB1
Authors: Bose Emma , O'Murphy Fiona , Tumusiime Shamillah , Fairweather Samantha , Rogers Miles , Troisi Maria , Alvarado Alice , Smith Andrew , Moorhead Gaston , Kebede Yonatan , Herrada Hector , Wlodychak Kelly , Bell Anthony J.
Published: May 2022

The architectural DNA‐binding protein High Mobility Group B1 (HMGB1) binds distorted double stranded DNA (e.g. kinked, cruciform) in the nucleus with extremely high affinity to modulate nuclear homeostasis. HMGB1 is a multifunctional protein that also plays a pivotal role outside of the nucleus. It is now clear that HMGB1 can also function as a Damage Molecular Pattern Molecule. In this capacity, HMGB1 can act as a friend or foe to: i)bolster innate immunity to ward off pathogens or ii)exacerbate unwanted immune responses that worsen disease states (e.g. lupus, rheumatoid arthritis). Research shows that cruciform DNA [four‐way junctions (4WJs)] and single strand DNA (ssDNA) can effectively bind/sequester HMGB1. The 4WJs and ssDNA investigated contain natural and phosphorothioate (PS) bonds. PS bonds are introduced to enhance nuclease resistance. Our prior study shows that intramolecular 4WJs composed of natural and PS bonds possess enhanced resistance against the endo‐ and exonucleases. We hypothesize that the increase in nuclease resistance is due to a combination of three factors: i)restricting access to the helical termini (end‐capping), ii)the presence of PS bonds and iii)altered minor groove topology. The objective of this study is to more stringently investigate the potential connection between minor groove topology and nuclease binding. Here, three nucleases are used that cleave double and ssDNA: DNase I, Exonuclease III (Exo III) and bacteriophage T5 Exonuclease (T5 Exo). The nucleases bind within the minor groove to initiate hydrolysis via a non‐specific (DNase I) or specific manner (Exo III and T5 Exo). We hypothesize that nucleases do not bind strongly to nucleic acid substrates with altered (likely wider) minor groove dimensions. As a result, nucleic acids with wider minor grooves tend to have enhanced nuclease resistance. Circular dichroism (CD) studies are used to investigate the minor groove topology of intramolecular 4WJs and ssDNA. The minor groove binder 4’,6‐diamidino‐2‐phenylindole (DAPI) is used to estimate the gross minor groove topology of each nucleic acid ligand. The data clearly shows the DNA substrates with altered minor groove dimensions, as reflected by weakened DAPI binding interactions, possess enhanced nuclease resistance. DNA substrates with enhanced nuclease resistance will be investigated further to target the DNA‐binding cytokine, HMGB1.
Regulation of LIM homeodomain 2 (Lhx2) in the distal limb bud during patterning and development
Authors: Britton Jessica C. , Cooper Allen M. , Pira Charmaine U. , Oberg Kerby C.
Published: May 2022

During limb morphogenesis, fibroblast growth factors (Fgfs) secreted from the apical ectodermal ridge (AER) direct proximodistal outgrowth of the limb, while sonic hedgehog (Shh) released from the zone of polarizing activity modulate anteroposterior expansion of the limb. Fgfs and Shh maintain each other’s expression through an autoregulatory loop. The transcription factor LIM homeodomain 2 (Lhx2) is expressed in the distal sub‐AER mesoderm and is important for Shh expression. We have identified a chicken enhancer upstream of the LHX2 promoter that is active in the distal sub‐AER LHX2 expression domain that contains putative transcription factor binding sites for known downstream targets of FGF signaling that are critical for activity. Therefore, we hypothesized that LASARM1 interacts with the LHX2 promoter and that FGF works through LASARM1 to regulate LHX2 expression. To determine this, we performed chromosome conformation capture (3C) on cells isolated from distal chicken limb buds and compared them to non‐LHX2 expressing tail cells. Promoter and enhancer specific primers were used to isolate ligated promoter‐enhancer fragments by end‐point PCR. Amplified sequences were then sequence validated. A 3C ligation product library was used as a control. We also evaluated the role of FGF to regulate LASARM1 activity in subAER mesoderm by analyzing LASARM1 activity following inhibition of FGF signaling by an FGF‐receptor inhibitor. End‐point PCR revealed promoter‐enhancer ligated amplicons in distal limb bud cells, but not in tail cells. DNA sequencing of enhancer‐ligated fragments confirmed LHX2‐LASARM1 fusion fragments for distal limb bud cells. Interestingly, disruption of FGF signaling via a specific FGF receptor inhibitor did not alter LASARM1 activity, although LHX2 expression was markedly reduced. These findings suggest that LASARM1 interacts with the LHX2 promoter during limb patterning, but additional enhancers are required to mediate the FGF‐mediated up‐regulation of LHX2. Evaluation of additional LHX2 enhancers is underway. Investigations regarding the relationship between FGF and LHX2 will provide important insights into the mechanisms underlying LHX2 regulation and the FGF‐to‐SHH reciprocal loop.
A Theoretical Model of the Mechanism by which Dietary Lipid Variance and Increased Oxysterols Allow Increased Formation of Soluble Endoglin in Preeclampsia
Authors: Hart Nancy R.
Published: May 2022

Endoglin (TGF‐β receptor III), an accessory receptor necessary for transforming growth factor‐β (TGF‐β) signaling, is essential during angiogenesis. Cleavage of endoglin by matrix metalloproteinase‐14 (MMP‐14) creates a soluble receptor (sEng) which is elevated in the sera of people with preeclampsia. Similarly to sflts which bind VEGF, sEng binds TGF‐β and impairs functions ranging from endothelial nitric oxide synthesis, vasodilation, and modulation of vascular permeability, to regulation of immune homeostasis, trophoblastic invasion and differentiation.

Cleavage of endoglin to form sEng is upregulated in the presence of oxysterols. Initially, oxysterols were believed to upregulate MMP‐14 and down regulate its inhibiter TIMP3. However, in placental explants, expression MMP14 and TIMP3 mRNA were not altered by oxysterols and pravastatin did not decrease oxysterol‐induced upregulation of sEng. Membrane raft domains negatively regulate TGF‐β signaling, and aspirin, which disperses membrane rafts, induces TGF‐β signaling.

This perspective considers the known changes in dietary lipids over the last 100 years, the possible effects of these changes on membrane raft formation, oxidative stress, and oxysterol formation, as well as the known effects of oxysterols on membrane thickness and fluidity and proposes an alternate mechanism by which oxysterols might increase sEng formation.
Assessing Racial Consciousness in Anatomy Educators
Authors: Anand Shreya
Published: May 2022

Anatomy teaching faculty have the ability to affect how race is discussed and portrayed in the curriculum, such as choosing which images to use, which textbooks to assign and reference, and whether to include race or other social determinants of health in discussions of clinical correlates of anatomy. Inclusive learning materials can impact medical students’ self‐perception and either reinforce or dismantle implicit and explicit biases that may be held toward future patients and colleagues. Using a mixed methods approach, we surveyed faculty teaching anatomy at a variety of levels in order to assess the materials, resources, and concepts that are currently taught in anatomy classrooms, and the barriers that anatomy faculty face in creating diverse and inclusive teaching materials.

Survey results show that of 162 total respondents, only 17.86% of anatomy faculty are satisfied with the diversity represented in their anatomy textbook, while 50.89% are not satisfied. Overall, it appears that while race is at least sometimes discussed in the majority of curricula surveyed here (39.69 % “sometimes”, 17.46% “often,” 3.05% “always”), it appears to be less frequently discussed in the anatomy classroom (37.40% “sometimes,” 6.11% “often,” 0.0% “always”).

Qualitative data collected from survey participants suggests that some anatomy faculty (18) feel that race is outside of the scope of discussion in an anatomy course. However, 17 educators felt that discussion of race is within scope for an anatomy course. Interestingly, describing race as a social construct was used both to justify its exclusion in the anatomy curriculum (2 respondents) as well as its inclusion (4 respondents).

Our preliminary data that most educators desire to be more inclusive in their instructional materials, however, they feel restricted by the lack of diverse resources at their disposable. We hope the insights from this study will help us understand information gaps and create a more racially conscious anatomy curriculum.
ST segment elevation: the lost measure of early ischemic preconditioning in the landmark study of Murry et al. 1986
Authors: Sturek Michael , Byrd James , Alloosh Mouhamad
Published: May 2022

Background

In their landmark study Murry et al. (Circulation 74:1124, 1986) showed dramatic ST segment elevation of the ECG during the first occlusion of a dog coronary artery. They made the insightful observation that “… in subsequent occlusions, these changes were slower to develop and frequently did not reach the magnitude seen during the first occlusion.” This electrophysiological preconditioning has been almost completely dismissed as irrelevant to ischemic preconditioning in animal models. We found in the Ossabaw miniature swine model of metabolic syndrome that brief coronary occlusion often led to ST elevation that quickly progressed to ventricular tachycardia and fibrillation.

Hypothesis

An AMPKγ3 mutation in Ossabaw swine will explain the extreme ST elevation and provide evidence for the relevance of ST segment ischemic preconditioning.

Methods and Results

Lean mutants had impaired glucose tolerance compared to wild type Ossabaw swine. Myocardial ischemia induced by balloon occlusion of the circumflex artery elicited profound electrocardiographic ST elevation in lean mutant compared to wild type swine. Infusion of an AMPK agonist, AICAR (0.5 mM), prior to occlusion significantly reduced ST elevation in lean mutants, while completely preventing ST segment elevation in wild type. Ischemic preconditioning of the ST segment changes occurred in wild type pigs during the course of 5 occlusions, but only occurred in mutant pigs with AICAR infusion. Infusion of compound C (30 μM), an AMPK antagonist, prior to occlusion blocked the AICAR‐induced attenuation of ST elevation in lean mutants. The KATP channel agonist pinacidil increased ST elevation and the antagonist glibenclamide attenuated ST elevation during occlusion. While the degree of diet‐induced MetS (obesity, further impaired glucose tolerance, insulin resistance, and hypertension) was not different between mutant and wild type swine, except for greater plasma lipids in mutants, there was no difference in ST elevation during myocardial occlusion.

Conclusions

Lean Ossabaw swine with the V199l AMPK mutation have impaired glucose tolerance and exacerbated KATP channel‐mediated ST elevation during myocardial ischemia. Excess calorie diet induces MetS and abolishes cardioprotection in wild type AMPK swine. ST segment changes are an excellent measure of ischemic preconditioning in this model, thus showing the relevance of Murry’s landmark discovery.
Histopathology of Dermatologic Complications of Tattoos
Authors: Torre-Castro Juan , Nájera Laura , Suárez Dolores , García-Fresnadillo Diego , Freites-Martínez Azael , Briz Angel Santos , Rodríguez Peralto Jose Luis , Requena Luis
Published: May 2022

Tattoos are characterized by the introduction of exogenous pigments into the dermis. Tattoos usually serve cosmetic purposes, although they may have other causes, such as traumatic pigment implants in accidents or medical-related tattoos in the context of radiotherapy. Dermatologic adverse reactions are relatively uncommon, and they include infections, immune-mediated reactions, cutaneous lesions secondary to the Koebner phenomenon, exacerbation of preexisting dermatosis, benign and malignant neoplasms, and a miscellaneous group of dermatologic conditions that may appear in a preexisting tattoo. The aim of this study is to review the types of histopathologic reactions that may appear in a preexisting permanent tattoo.
Spindle Cell/Pleomorphic Lipoma With Trichodiscoma-like Epithelial Hyperplasia Mimicking Atypical Fibroxanthoma/Pleomorphic Dermal Sarcoma
Authors: Aghighi Maryam , Andea Aleodor A. , Patel Rajiv M. , Fullen Douglas R. , Bresler Scott C.
Published: May 2022

A 58-year-old man presented with a lesion on the nose suspicious for basal cell carcinoma. An initial biopsy specimen reviewed at an outside institution showed a cytologically atypical spindle cell proliferation that lacked expression of cytokeratins or melanocytic markers. The resulting differential diagnosis included atypical fibroxanthoma and pleomorphic dermal sarcoma. Histopathologic examination of the excision specimen at our institution revealed an intradermal pleomorphic and spindle cell tumor which extended into underlying skeletal muscle. The tumor was associated with a fibromyxoid stroma, scattered adipocytes, and hyperplastic folliculosebaceous epithelium at the periphery. The pleomorphic tumor cells showed hyperchromatic nuclei with smudgy chromatin, and no mitotic activity was detected. Overall, the cellularity was less than would be expected for atypical fibroxanthoma/pleomorphic dermal sarcoma. Furthermore, the tumor cells were strongly positive for CD34 and showed diffuse loss of retinoblastoma protein by immunohistochemistry. Consequently, a diagnosis of benign CD34-positive pleomorphic spindle cell tumor was rendered, with features overlapping between spindle cell/pleomorphic lipoma and trichodiscoma. Subsequent single-nucleotide pleomorphism array testing revealed heterozygous loss of chromosome 13q in a region that spanned the RB1 locus and copy number loss at 16q, favoring that the proliferation in fact represents a spindle cell/pleomorphic lipoma with trichodiscoma-like epithelial induction. This case highlights an important diagnostic pitfall that may be avoided by recognizing characteristic architectural and cytologic features of this spectrum of lesions.
PRAME Expression Correlates With Genomic Aberration and Malignant Diagnosis of Spitzoid Melanocytic Neoplasms
Authors: Gerami Pedram , Benton Sarah , Zhao Jeffrey , Zhang Bin , Lampley Nathaniel , Roth Andrew , Boutko Anastasiya , Olivares Shantel , Busam Klaus J.
Published: May 2022

Spitzoid melanocytic neoplasms are a diagnostically challenging class of lesions in dermatopathology. Recently, molecular assays and immunohistochemical markers have been explored as ancillary methods to assist in the diagnostic workup. Specifically, preferentially expressed antigen in melanoma (PRAME) immunohistochemistry is a nuclear stain commonly positive in melanomas, but not in nevi. This study investigates PRAME immunoreactivity (≥75% positive nuclear staining in tumor cells) in a set of 59 spitzoid melanocytic neoplasms with known clinical outcomes. We compared PRAME status with (1) the clinical outcomes, (2) the morphologic diagnoses, and (3) the status of TERT promoter mutation. Regarding clinical outcomes, 3 cases developed metastatic disease, of which 2 expressed diffusely positive PRAME staining. Of the 56 cases that did not show evidence of metastasis, 6 expressed diffusely positive PRAME staining. Morphologically, diffusely positive PRAME staining was seen in 7 of 21 cases (33.3%) diagnosed as melanoma and only 1 benign tumor 1 of 38 (2.6%). There were 4 of 8 cases with a TERT promoter mutation which were diffusely PRAME-positive compared with 4 of 51 cases without TERT promoter mutation (P = 0.001). Our results show a statistically significant correlation between PRAME expression and the diagnosis, outcome, and TERT promoter mutation status of atypical spitzoid melanocytic neoplasms, suggesting immunohistochemistry for PRAME can help support a suspected diagnosis. However, because of occasional false-positive and negative test results, correlation with the clinical and histologic findings as well as results from other tests is needed for the interpretation of diagnostically challenging spitzoid melanocytic neoplasms.
Sex differences in the acute ethanol effects on object recognition memory: influence of estrous cycle
Authors: Paiva-Santos Murilo A. , Leão Anderson H.F.F. , Kurita João P.F. , Becegato Marcela S. , Lima Alvaro C. , Bioni Vinicius S. , Meurer Ywlliane S.R. , Cunha Débora M.G. , Medeiros André M. , Silva Regina H.
Published: May 2022

Effects of acute ethanol (EtOH) on memory depend on several factors, including type of behavioral task. Sex differences in EtOH effects have been reported in humans and animals, and recognition memory can be influenced by circulating sex hormones. The aim of this study was to investigate the influence of sex and estrous cycle in the acute effects of EtOH on novel object recognition memory in rats. Male and female Wistar rats were part of one of the groups: control, 0.6-g/kg EtOH and 1.8-g/kg EtOH (administered intraperitoneally before the training session). The estrous cycle was evaluated by vaginal smear. The task was conducted in an open field arena. During training, animals were exposed to two identical objects, and test sessions were performed 1 h (short-term) and 24 h (long-term) later. One of the objects was changed in each test. Increased novel object exploration was shown by male and female controls in the short- and long-term tests, respectively. In the short-term test, females did not show preference for the novel object, and EtOH 1.8 g/kg impaired performance in males. In the long-term test, both sexes showed object discrimination, and 1.8-g/kg EtOH reduced preference for the new object in male rats. The phase of the cycle, the performance on proestrus was worse compared with other phases, and EtOH failed to impair performance mainly on estrous. In conclusion, while male rats displayed ethanol-induced recognition memory deficit, female rats were unaffected by EtOH impairing effects. In addition, the performance of female rats was influenced by the estrous cycle phases.
Proposals for a standardized procedure of validation of DNA extraction and allelic discrimination assays in pharmacogenomics according to ISO15189 requirements
Authors: Imbert Laurent , Lagoutte-Renosi Jennifer , Wils Julien , Lamoureux Fabien
Published: May 2022

Objectives

In the era of quality management in clinical laboratories, method validation can be a challenge without appropriate guidelines, such as in the field of pharmacogenetics. The present work describes a method validation for DNA extraction and CYP3A5*3 genotyping, which would meet ISO15189:2012 requirements.

Methods

DNA extraction was performed using a QIAamp DSP DNA Blood kit, DNA purity and concentration were determined using a Nanodrop, and the genotyping assay was a real-rime PCR using TaqMan reagents. Validation criteria were similar to those usually verified when validating methods in the analytical field: specificity, sensitivity, cross-over contamination, stability of reagents, robustness, lower and upper limits of detection, and between-run and within-run precisions. A comparison to alternate or reference methods was also performed (i.e. QiAamp kit versus DNA extractor and TaqMan genotyping versus Sanger sequencing). Each validation step is described from the pharmacogenetic point of view, as well as acceptance criteria for both DNA extraction [i.e. concentration relative SD (RSD) below 25%, verified purity, and no DNA in blank samples] and genotyping assay (i.e. specificity and diagnostic sensitivity, RSD of mean threshold cycle below 15%, no amplification in blank samples).

Results

Concerning CYP3A5 genotyping following a DNA extraction described as an example, validation criteria were met, allowing routine use of this analytical process. Cost estimation of the overall validation procedure was approximately 290 euros, concerning reagents and consumables.

Conclusion

This work aims to provide a reference for method validation for pharmacogenetic analysis using real-time PCR to detect single nucleotide polymorphisms, in accordance with ISO15189:2012.
Submental Area Treatment with ATX-101: Relationship of Mechanism of Action, Tissue Response, and Efficacy
Authors: Humphrey Shannon , Munavalli Girish S. , Yoelin Steven G. , Friedmann Daniel P. , Kavali Carmen M. , Sangha Sara
Published: May 2022

Background:

ATX-101 is an injectable, synthetically derived formulation of deoxycholic acid used for submental fat reduction.

Methods:

A narrative review of references relevant to the mechanism of action of ATX-101 and its relationship to efficacy and inflammatory adverse events was conducted.

Results:

When injected into subcutaneous fat, deoxycholic acid physically disrupts adipocyte cell membranes, leading to local adipocytolysis, cell death, and a mild, local inflammatory reaction consisting of macrophage infiltration and fibroblast recruitment. At Day 28 postinjection, inflammation largely resolves, and key histologic features include fibrotic septal thickening, neovascularization, and atrophy of fat lobules. Based on the mechanism of action of ATX-101 and the demonstrated inflammatory response, localized inflammation and swelling are expected following treatment. Indeed, postinjection swelling and other local injection-site events, including pain, erythema, and bruising, are common during and after treatment. Because of inflammatory sequelae following injection, reduction in submental fat is gradual and may require months before the full response is apparent. Patients may also require multiple treatment sessions to achieve their treatment goals. Repeated treatments may result in less pain and swelling over time owing to a combination of factors, including less target tissue allowing for lower doses/injection volumes, persistent numbness, and greater tissue integrity from thickened fibrous septa.

Conclusions:

Physicians can manage expectations by counseling patients that, based on the mechanism of action of ATX-101 and data from pivotal clinical trials, ATX-101 treatment results in localized inflammation/swelling and gradual submental fat reduction. Patient education about common local adverse events is critical.
Health-related Quality of Life Measurement Tools for Lymphedema: A Review of the Literature
Authors: Lim Pelicia , Li Henry , Neoh Derek , Ng Sally Kiu-Huen
Published: May 2022

Background:

Lymphedema can significantly affect patients’ health-related quality of life (HRQoL). Various quality of life scales have been developed to assess the extent of the disease burden. The purpose of this study is to review various HRQoL instruments that have been used in lymphedema studies and compare their qualities against the COSMIN checklist.

Methods:

A systematic literature review search was conducted for clinical lymphedema studies published between January 1, 1984, and February 1, 2020, using Pubmed database. All clinical lymphedema studies which used HRQoL instruments as outcome measures were identified.

Results:

One thousand seventy-six studies were screened—of which, 288 studies were individually assessed. Thirty-nine HRQoL instruments were identified in these clinical lymphedema studies. Of these, there are eight lymphedema-specific questionnaires that cover all HRQoL domains, all of which have been validated for use in lymphedema. We contrasted the two most popular questionnaires [LYMQOL and Upper Limb Lymphedema (ULL)-27] and compared their features.

Conclusion:

There is currently no ideal lymphedema HRQoL measurement tool available based on the COSMIN criteria. However, our review suggested that LYMQOL and ULL-27 are the most used and most validated instruments at present, but each has their own limitations. We recommend the use of LYMQOL and ULL-27 for future studies to allow direct HRQoL comparison to current literature. Further research is required to develop an optimal HRQoL questionnaire that can ultimately become the gold standard HRQoL instrument for lymphedema.
Utility of magnesium sulfate in the treatment of rapid atrial fibrillation in the emergency department: a systematic review and meta-analysis
Authors: Hoffer Megan , Tran Quincy K. , Hodgson Ryan , Atwater Matthew , Pourmand Ali
Published: May 2022

Atrial fibrillation with rapid ventricular response (Afib/RVR) is a frequent reason for emergency department (ED) visits and can be treated with a variety of pharmacological agents. Magnesium sulfate has been used to prevent and treat postoperative Afib/RVR. We performed a systematic review and meta-analysis to assess the effectiveness of magnesium for treatment of Afib/RVR in the ED. PubMed and Scopus databases were searched up to June 2021 to identify any relevant randomized trials or observational studies. We used Cochrane’s Risk-of-Bias tools to assess study qualities and random-effects meta-analysis for the difference of heart rate (HR) before and after treatment. Our search identified 395 studies; after reviewing 11 full texts, we included five randomized trials in our analysis. There were 815 patients with Afib/RVR; 487 patients (60%) received magnesium treatment, whereas 328 (40%) patients received control treatment. Magnesium treatment was associated with significant reduction in HR [standardized mean difference (SMD), 0.34; 95% CI, 0.21–0.47; P < 0.001; I
2 = 4%), but not associated with higher rates of sinus conversion (OR, 1.46; 95% CI, 0.726–2.94; P = 0.29), nor higher rates of hypotension and bradycardia (OR, 2.2; 95% CI, 0.62–8.09; P = 0.22). Meta-regressions demonstrated that higher maintenance dose (corr. coeff, 0.17; P = 0.01) was positively correlated with HR reductions, respectively. We observed that magnesium infusion can be an effective rate control treatment for patients who presented to the ED with Afib/RVR. Further studies with more standardized forms of control and magnesium dosages are necessary to assess the benefit/risk ratio of magnesium treatment, besides to confirm our observations.
Out of the labor force due to health reasons? An analysis of the Survey of Income and Program Participation regarding persons with visual impairments
Authors: Crudden Adele L. , McKnight Zhen S.
Published: May 2022

Persons with visual impairments (VI) have a high nonparticipation rate in the labor force. Information about factors influencing their labor force participation could provide insight into how to increase employment rates. We selected persons with VI from the Survey of Income and Program Participation to investigate factors that differentiate persons out of the labor force (OLF) for chronic health or disability reasons from those employed and those OLF due to other reasons. Persons with VI and OLF for chronic health or disability reasons were more likely to have additional disabilities; have physical, mental, or other health limitations to work; and receive Supplemental Security Income or Social Security Disability Insurance. Compared with those employed, people with VI and OLF for chronic health or disability reasons appear to have multiple characteristics indicating poorer health, lower education attainment, and greater financial insecurity. Compared with those OLF due to other reasons, people with VI and OLF for chronic health or disability reasons were less likely to be female but more likely to receive food assistance and to indicate disadvantaged health status. These results suggest that skills to accommodate vision disability or health conditions are essential to employment or further education, and additional education may expand vocational options. Benefits counseling, encouragement, and careful career planning may assist persons with VI in moving toward financial independence.
Use of Private, Parochial, and Public Schools in Baccalaureate Nursing Programs for Pediatric Practicum
Authors: Schultz Celeste M. , Krassa Teresa J.
Published: May 2022

Background:

Clinical sites are increasingly difficult to secure due to shorter hospital stays, increased clinical site competition, and limited practicum sites. Little is known about the use of schools for pediatric clinical practicum.

Purpose:

To explore utilization of private, parochial, and public primary and secondary schools for pediatric clinical practicum sites.

Methods:

Faculty (n = 108) completed a 38-item online survey.

Results:

Twenty-seven faculty members (25%) reported using schools for pediatric practicum. Most nursing students (85.1%) spent 23 total hours or less in schools obtaining anthropometric measurements, reviewing immunizations, and providing health education to children, parents, and teachers.

Conclusion:

Using schools for the pediatric practicum is thought to be a common practice; our findings suggest otherwise. School-based practicums provide students with skills beyond acute care competencies. Nursing faculty need to seriously consider which pediatric clinical settings provide the best experience to prepare future nurses.
An Interprofessional Yearlong Geriatrics Fellowship Program for Advanced Practice Nursing and Social Work Students
Authors: Glassburn Susan , Frank Kathryn , Fulton Jan , Westmoreland Glenda , Garrison Emilie , Roth Sarah , Litzelman Debra K.
Published: May 2022

Background:

The care of older adults with complex medical conditions requires effective team-based care.

Problem:

Nursing and social work students need a curriculum that provides them with immersive experiences in geriatrics to prepare them for competent practice.

Approach:

This Geriatric Workforce Enhancement Program supported 5 advanced practice nursing (APN) and 5 master of social work (MSW) student fellows in a 2-semester program, with 3 cohorts completing the fellowship over 3 years (N = 30).

Outcomes:

By the completion of the fellowship, students had (1) demonstrated increased knowledge of age-related changes and health problems experienced by older adults, (2) developed clinical competencies in providing patient-centered health care for older adults, and (3) assessed the fellowship as helpful in preparing for interprofessional team care.

Conclusions:

An interprofessional gerontology fellowship for APN and MSW students can develop knowledge and skills in team-based care for older adults. Recommendations for creating a fellowship curriculum are provided.