bluuebunny/crossref_metadata_2025_split huggingface dataset:
Collaboration Between Basic Scientists and Clinicians: An Opportunity to Develop a Microanatomy Curriculum to Integrate Curricular Content and Encourage Student Interaction
Authors: McBride Jennifer M 
Published: November 2023

Many microanatomy courses still maintain a traditional approach to student instruction. This consists of a didactic presentation followed by a laboratory session, which uses specimens either on glass slides, specimens viewed virtually or a combination of the two. Maintaining the time required to conduct these two separate sessions within an educational climate that promotes independent student study time and integration of course information, is problematic.In an effort to encourage student interaction, basic scientists and clinicians at the Cleveland Clinic collaborated to create a case‐based microanatomy curriculum facilitated with the aid of a virtual microscopy system. They then identified time points, in each of the organ system courses, where microanatomy seminars would appropriately integrate with other course content and problem based learning cases. Student preparation for these seminars requires that they review the cases and examine virtual microscopy images. To encourage student participation during the seminar, the faculty member facilitates discussion of these cases with guiding questions and image review.Evaluation of students in this program occurs through a competency based portfolio system rather than graded quizzes or exams, thus numerical course data over time are not available. Other metrics that are available include; end of course reports, graduation questionnaire ratings and USMLE Step 1 scores. Overall student feedback regarding the end of course reports indicate that they feel there is “Appropriate Coverage” of histology content. In addition, graduation questionnaires indicate that the majority of students felt their study of microanatomy/histology was “Good” or “Excellent”, which helped them prepare for clinical clerkships and electives. Finally, students have consistently performed above or significantly above the national average for Histology/Cell Biology on USMLE Step 1.This approach to microanatomy instruction successfully addresses the desire to shorten student class time, integrate curricular content and encourage student interaction.
Sex dependent effects of prenatal infection on adult cardiovascular health: are females at greater risk for cardiovascular disease?
Authors: Hayward Linda , Watkins Jaqueline , Von Chamier Maria , Reyes Leticia , Brown Mary 
Published: November 2023

Prenatal infection (INF) has been linked to an increased risk for psychiatric disorders such as schizophrenia. Emerging evidence suggests that a common cause of death among schizophrenics is cardiovascular disease. This study's aim was to investigate the link between INF and the risk for cardiovascular disease later in life. A rodent model of INF was used where Mycoplasma pulmonis or vehicle (SHAM) was given intravenously on gestational day 14. Following birth, litters were culled to 8, cross‐fostered, weaned and pair housed until adulthood. At 12 weeks of age (n=4–6/group), sex dependent differences in weight were identified: INF females weighed 17.8% more than SHAMs (P<0.05) while INF males weighed only 4.2% more than SHAMs (P>0.05). Resting mean arterial pressure (MAP) was not significantly different between groups, however in response to angiotensin II (10 μg/kg, subcutaneous) both INF males and females had a significantly greater rise in MAP (+31 and +19 mmHg, respectively; P<0.05) when compared to the sex‐matched SHAMs. In response to acute nicotine (0.37 mg/kg, subcutaneous) however only INF females demonstrated a greater increase in MAP (+ 5mmHg; P<0.02) when compared to sex‐matched SHAMs. These results suggest that offspring exposed to infection in utero are likely to have a greater risk for development of cardiovascular disease in adulthood, with females potentially having the greatest risk.Support or Funding InformationFlorida Department of Health‐James and Esther King 4KB11
Inhibition of Glial Metabolism Decreases Intestinal Afferent Nerve Activity
Authors: Miranda‐Morales Marcela , Ochoa‐Cortes Fernando , Christofi Fievos L , Villalobos‐Hernandez Egina C , Barajas‐Lopez Carlos 
Published: November 2023

The enteric nervous system is embedded in the walls of the gastrointestinal tract and regulates among other functions: digestion, secretion and motility in synchrony with the central nervous system. The enteric ganglia consist of neurons and glial cells; these outnumber neurons and appear to participate in maintaining their homeostasis.A lot is ignored about the physiological role of glial cells in the enteric nervous system. Recent experimental data indicates that inhibition of the functions of glial cells, decrease the gastrointestinal transit and contraction in response to field stimulation in mice. However, there are not reports on their role in the mesenteric afferent nerve functions.The objective of this work was to investigate the role of enteric glia in the multiunit afferent activity in mesenteric nerves, both spontaneous and induced by increasing intraluminal intestinal pressure.Multiunit afferent nerve activity from a segment of jejunum from C57BL/6 mice were recorded, a nerve was dissected from the mesenteric border. We recorded the spontaneous action potentials in response to the application of intraluminal pressure. Extraluminal application fluoroacetate (5 mM during 10 min) decreases afferent response to intraluminal pressure progressively. The maximum effect is observed around 50 minutes, time in which the response of the high threshold fibers is almost inhibited and the low threshold fibers decrease to one third of the control value. In addition multiunit basal activity remains unchanged.Our results suggest a relevant role of enteric glia in mesenteric afferent nerve activity. The fact that the spontaneous activity is unchanged suggests that participation would be on sensory mechanisms that detect the tension of the intestinal wall.Support or Funding InformationThis work was supported by Fiscal Funds. Scholarships of EC‐VH was supported by CONACYT.
Organophosphorus Pesticides Stimulate Macrophages to Release Factors That Modulate M2 Muscarinic Receptors
Authors: Proskocil Becky , Lein Pamela , Jacoby David , Fryer Allison 
Published: November 2023

BACKGROUNDThe organophosphorus pesticides (OP) parathion, chlorpyrifos, and diazinon are widely used agricultural pesticides. We found that OPs cause airway hyperreactivity via dysfunction of autoinhibitory M2 muscarinic receptor expressed by parasympathetic nerves in the airways of guinea pigs. OP‐induced airway hyperreactivity occurs at concentrations below currently recommended exposure limits. OP‐induced effects are prevented by depleting alveolar macrophages or blocking tumor necrosis factor α (TNFα).OBJECTIVETo determine if OPs and/or their oxon metabolites directly stimulate human macrophages to increase the expression of cytokines and growth factors known to modulate M2 receptors. Since OPs interact with nicotinic and muscarinic receptors, which are expressed on macrophages, and since OPs are a potent acetylcholinesterase (AChE) inhibitor, we also evaluated whether OP stimulation of macrophages is mediated by AChE inhibition and/or modulation of nicotinic or muscarinic receptor activity.METHODSTHP1 cells, a human monocyte cell line differentiated into macrophages, were treated with 1–100 μM parathion, chlorpyrifos, or diazinon or 1 nM – 100 μM paraoxon, chlorpyrifos oxon, or diazoxon for 24 hr. Some THP1 cells were pretreated with 100 μM mecamylamine (nicotinic antagonist) or 100 μM atropine (muscarinic antagonist) 1 hr prior to addition of the OPs. Other cells were treated with 100 μM eserine (AChE inhibitor). Cells were harvested for RT‐PCR and supernatants were collected for ELISA.RESULTSParathion, chlorpyrifos, and diazinon increased mRNA expression of TNFα, IL‐1β, platelet derived growth factor (PDGF), and transforming growth factor β (TGFβ) in a concentration‐dependent manner. TNFα protein was significantly increased at 100 μM, however IL‐1β and PDGF proteins were not increased and fibroblast growth factor (FGF) and TGFβ proteins were undetectable. No oxon metabolite increased mRNA or protein levels of these factors. Inhibiting nicotinic or muscarinic receptors did not prevent OP‐induced increase in IL‐1β, TNFα, PDGF, and TGFβ mRNA or secreted TNFα protein. Blocking AChE with eserine did not increase cytokine or growth factor expression.CONCLUSIONSParent OP compounds, but not their metabolites, stimulate macrophages to express cytokines and growth factors that have previously been shown to modulate parasympathetic M2 muscarinic receptor function. Macrophage stimulation occurs via a non‐muscarinic, non‐nicotinic pathway and independent of AChE inhibition. Characterizing this pathway is important for determining biological effects of OPs and treatment following OP exposure.Support or Funding InformationThis work was supported by NIH grants ES017592, ES014521, ES014601, HL124165, HL113023, and AR061567.
Exaggerated blood pressure and sympathetic reactivity in patients with Type 2 Diabetes
Authors: Vranish Jennifer R , Holwerda Seth W , Keller David M , Fadel Paul J 
Published: November 2023

Although greater blood pressure (BP) responses to exercise have been observed in Type 2 Diabetes (T2D) patients, our understanding of the time course and mechanisms involved remains limited. Herein, we focused on the immediate onset of isometric handgrip (i.e., first 30 seconds) and tested the hypothesis that T2D patients would exhibit an augmented increase in BP and muscle sympathetic nerve activity (MSNA) relative to age and bodyweight‐matched, healthy controls. T2D patients (n=14) and controls (n=8) performed isometric handgrip at 40% of maximal voluntary contraction while BP, MSNA, and heart rate (HR) were continuously recorded. A cold pressor test (CPT) was also performed as a generalized, central sympatho‐excitatory stimulus. Data were averaged over 10s intervals for the initial 30s of handgrip and CPT. HR increased at exercise onset (first 10s; P < 0.001) with no differences between groups (8±1.9 vs. 11±1.7; P = 0.655). However, mean BP (9±1.2 vs. 4±1.9 mmHg; P = 0.019) and systolic BP (12±1.7 vs. 3±2.5 mmHg; P = 0.003) were significantly greater for the first 10s of handgrip in T2D patients than controls. These differences were maintained over the entire 30s onset of exercise. Likewise, MSNA was also greater for T2D patients (10±2.1 vs. 1±2.6 bursts per minute; P = 0.031) at the onset of exercise. Interestingly, T2D patients also exhibited a greater mean BP (11±2.4 vs. 3±1.4 mmHg; P = 0.013) and MSNA (17±3.6 vs. 7±2.4 bursts per minute; P = 0.042) response to the first 30s of CPT. Collectively, these data suggest that T2D patients exhibit heightened pressor and sympathetic responsiveness at the onset of isometric handgrip that may be mediated by greater central reactivity, although a role for the muscle mechanoreflex also warrants consideration.Support or Funding InformationSupported by AHA‐20160072 (P.J.F.).
The Effect of Stimulation of β2 Adrenergic Receptor on Glucose Uptake in Skeletal Muscles
Authors: Gao Hongbo 
Published: November 2023

Background and HypothesisSkeletal muscles are innervated with sympathetic nervous systems. β2 adrenergic receptor (β2AR) is predominantly expressed in skeletal muscles. Activation of β2AR has been shown to improve glucose uptake in skeletal muscles. However, the underlying mechanisms remain to be fully understood.Methods and ResultsIn this study, adult healthy female mice were pretreated with β2AR selective agonist formoterol (Fm) for 15min prior to insulin tolerance test (ITT), or glucose tolerance test (GTT). The ITT displayed that the blood glucose level, while was restored at 60 min in controls, remained a continual low level throughout the 120 min test period in Fm treated group. In GTT, the magnitude of blood glucose in mice pretreated with Fm was significantly blunted at 15 and 30 min compared to the control group. We further assessed the effect of Fm on insulin receptor β (IRβ)/AKT2/AS160 pathway in extensor digitorum longus (EDL) and soleus dissected from mice at 90 min of insulin stimulation with or without Fm pretreatment. Results showed that phosphorylation of AS160 was comparably increased among groups treated with Fm only, insulin only, and Fm and insulin combined in EDL. Interestingly, the phosphorylation of AKT2, the upstream kinase of AS160, was unfailingly enhanced in EDL and soleus from the group co‐treated with Fm and insulin as compared with those from other groups. Consistently, phosphorylation of IRβ, the onset of insulin signal transduction remained at a significantly higher level in the groups co‐treated with Fm and insulin compared to other groups in EDL.Conclusionβ2AR might be involved in the enhancement of insulin‐induced glucose uptake in skeletal muscles via prolonging insulin signal transduction.Support or Funding InformationThis work was partially supported by NIH grant No. 1R15HL118696 and SSOM BBS bridge grant.
Role of renal nerves in cardiovascular nuclei and kidneys in renovascular hypertensive rats
Authors: Nishi Erika E , Gomes Guiomar N , Perry Juliana C , Simões Alex Y , Bergamaschi Cassia T , Campos Ruy R 
Published: November 2023

Our aim was to investigate whether renal nerves play a role in the renal injury process and modulation of AngII receptors expression in the central nuclei and kidneys in renovascular hypertension. Denervation of clipped kidney (RD: visible bundles were dissected + 10% phenol) was performed in Wistar male rats (n=5/group) 4–5 weeks after clip implantation (gap width: 0.2mm). Ten days after RD, blood pressure (BP) was significantly reduced in the 2K‐1C rats. Gene expression of upregulated AT1R and AT2R within the rostral ventrolateral medulla (RVLM) and paraventricular nucleus of the hypothalamus (PVN) in the 2K‐1C group was normalized after RD. Following RD, there was no change in plasma renin activity in control and 2K‐1C rats. In order to distinguish the effects of RD from the reduction in BP, 2K‐1C rats were treated orally with hydralazine (25mg/kg/day for seven consecutive days). Hydralazine significantly reduced BP and AT1R and AT2R within the RVLM and PVN in the 2K‐1C rats. Renal injury was observed in both ischemic and contralateral kidneys of 2K‐1C rats. Following RD, renal injury was attenuated in both kidneys of hypertensive rats, however, hydralazine improved injury only in the contralateral kidney. These results demonstrate that the renal nerves contribute to AngII receptors changes within the cardiovascular nuclei and renal injury in the ischemic kidney independent of plasma renin activity in the 2K‐1C model of arterial hypertension.Support or Funding InformationSupported by FAPESP and CNPq.
Effect of B‐type natriuretic peptide and phosphodiesterase 2A is coupled to neurotransmitter release in pro‐hypertensive rats
Authors: LIU KUN , Woodward Lavinia , Ioannides Demetris , Lu Chieh‐Ju , Li Dan , Paterson David 
Published: November 2023

BackgroundB‐type natriuretic peptide (BNP) decreases cardiac sympathetic neurotransmission by attenuating activation of neuronal calcium channels and the intracellular calcium transient via a cGMP‐protein kinase G (PKG) pathway. Elevated levels of BNP are regarded as an early compensatory response to cardiac myocyte hypertrophy, although exogenously administered BNP shows poor clinical efficacy in heart failure and hypertension. Emerging evidence suggests that phosphodiesterase 2A (PDE2A) is upregulated in heart failure. Therefore we tested whether PDE2A was directly involved in modulating cardiac neurotransmitter release and Ca2+ handling from young (pre‐hypertensive) spontaneously hypertensive rats (SHRs) that show an enhanced Ca2+ phenotype.Methods and ResultsFour week old SHRs and the normotensive Wistar‐Kyoto (WKY) rats were humanely killed by an approved Home Office (UK) schedule 1 method. Intracellular free Ca2+ concentration ([Ca2+]i) was measured by ratiometric fluorescence imaging using fura‐2AM in cultured cardiac sympathetic neurons. The evoked [Ca2+]i transient was evaluated following 30 sec exposure to 50 mM KCL in the Tyrode solution. [3H] labelled noradrenaline (NE) release was measured from isolated spontaneously beating atrial in response to 5Hz field stimulation for 1 minute at the 16th (S1, control) and 40th (S2, with BNP) minutes. BNP significantly reduced the magnitude of the calcium transients in WKY rats, but not in SHR. PDE2A protein and activity levels from the stellate ganglia were greater in SHRs (n=8) compared with WKY rats (n=8). PDE2 inhibitor Bay60‐7550 restored the capacity of BNP to reduce [Ca2+]i in the SHR. Overexpression of dnPDE2A (a catalytically‐dead mutant of PDE2A) using a viral vector (Ad.CMVmCherry. dnPDE2A) also rescued the BNP inhibition of the calcium transients from the SHR. Functionally, BNP significantly reduced [3H]‐NE release in the WKY, whereas it failed in the SHR. Overexpression of dnPDE2A recovered the BNP inhibition of the NE release in the SHR.ConclusionThese data support the hypothesis that higher PDE2A expression in the SHR abolishes the capacity of BNP to reduce neurotransmitters release. They also suggest that inhibiting neuronal PDE2 may be important in restoring the efficacy of BNP to decrease sympathetic neurotransmission in cases of dysautonomia.Support or Funding InformationSupported by the British Heart Foundation
The Central Deacetylase Sirtuin1 Decreases Sympathetic Hyperactivity by Anti‐oxidative Stress in Hypertensive Rats
Authors: Wang Weizhong , Wu Zhaotang , Ren Changzhen , Wang Yangkai 
Published: November 2023

Hypertension is characterized by sympathetic hyperactivity, which is associated with pathophysiological progressing of hypertension. The rostral ventral lateral medulla (RVLM) plays a vital role of the sympathetic activity and blood pressure regulation. The NAD‐dependent deacetylase Sirtuin1 (Sirt1) plays an organ protective role by regulating the transcription of its target genes. Sirt1 is reported to show a protective effect in circulation system such as heart and blood vessel. However, it is not clear if Sirt1 in the RVLM is involved in modulating the central control of cardiovascular activity in hypertension. In our research work, Sirt1 was detected to be expressed in the catecholaminergic neurons in the RVLM, and Sirt1 was downregulated in the RVLM of the spontaneous hypertensive rats (SHR) compared with normotensive WKY rats. Chronic central administration of resveratrol (a specific agonist of Sirt1, 4 weeks) or injection of lentivirus containing Sirt1 gene in the RVLM produced a significant decrease in blood pressure, heart rate and renal sympathetic nerve activity in SHR but not in WKY rats. Furthermore, high level of reactive oxygen species in the RVLM was significantly reduced in SHR treated with over‐expression of Sirt1 gene in the RVLM. In summary, the present data suggest that Sirt1 in the RVLM exerts an anti‐hypertensive effect, which is associated with anti‐oxidative stress.Support or Funding InformationThis work was supported by NSCF (81570385 and 31500933)
Maximum Blood Lactate Responses Acutely and After Two Weeks of Moderate Altitude Exposure in a Large Multi‐year Study
Authors: Davis John 
Published: November 2023

There has been a great deal of controversy associated with the Lactate Paradox since Edwards in 1936 proposed that maximum blood lactate responses are reduced after altitude acclimatization. Conversely, with acute ascent to altitude there are many reports that maximum blood lactate responses are unchanged. To our knowledge, no studies with a large subject pool have looked at maximum blood lactate after acute exposure, acclimatization and upon return to sea level in the same study.PurposeTherefore, the purpose of these studies was to determine the effect of moderate altitude exposure on maximum blood lactate acutely, after acclimatization, and upon return to sea level.MethodsOver the course of a 6‐year period, thirty nine, active subjects (age = 23.3 ± 3.5 yrs, weight = 80.1 ± 17.5 kg, VO2max = 44.9 ± ml/kg/min) completed a graded‐exercise test to exhaustion on a cycle ergometer at sea level (SL1), upon acute exposure to 3400 m (ALT1), two weeks following acclimatization at 3400 m (ALT2), and upon return to sea level (SL2). Workloads were increased every two minutes following a two‐minute warmup until volitional fatigue. A venous blood sample was taken via an in‐dwelling catheter without stasis for subsequent lactate determination. Lactate was measured every 2 minutes during the exercise and then every 2 minutes after for 10 minutes.ResultsMaximum blood lactate was unchanged from SL1 to ALT 1 (11.87 ±2.17 vs. 11.28 ±2.33 mmol/l). However, ALT2 (9.82±1.70 mmol/l ) was significantly lower than both SL1 and ALT1. Maximum blood lactate returned to SL1 values upon return to sea level (SL2 = 11.30±2.77mmol/l).ConclusionsThese data suggest that acute altitude exposure does not result in a reduction in maximum blood lactate. However, after two weeks of acclimatization maximum blood lactate is reduced and returns to pre‐sea level values upon return to sea level.