bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating leptin and risk of pancreatic cancer: a pooled analysis of three cohorts (LB369)
Authors: Stolzenberg‐Solomon Rachael , Newton Christina , Silverman Debra , Pollak Michael , Nogueira Leticia , Albanes Demetrius , Männistö Satu , Tao Yuzhen , Jacobs Eric
Published: June 2021

Background: Diabetes, overweight and obesity are consistently associated with increased pancreatic cancer risk; however the underlying mechanism(s) is uncertain. Leptin is an adipokine important in metabolic regulation.

Methods: We conducted a pooled nested case‐control study of participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Trial (PLCO), Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study (ATBC), and Cancer Prevention Study II Nutrition (CPS‐II) cohorts to investigate whether pre‐diagnostic circulating leptin concentrations were associated with pancreatic cancer. In total, 759 incident pancreatic adenocarcinoma cases were included in this analysis (average follow‐up 8.3 years, up to 20 years). Incidence density selected controls (n=1069) were matched to cases by cohort, age, sex, race, and date of blood draw. We used conditional logistic regression analysis to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) and sex‐specific quintiles (Q) based on the distribution of the controls. Results: Overall, we did not observe an association between leptin and pancreatic cancer (compared to Q1, Q5 OR=1.13, 95% CI 0.75‐1.70, p‐trend=0.39). There was a statistically significant interaction by follow‐up time (p‐interaction=0.003) such that significantly elevated risk was apparent only among cases occurring 10 or more years after blood draw (compared to Q1, Q4 OR=2.21, 95% CI 1.18‐4.13, Q5 OR=2.55, 95% CI 1.23‐5.27, p‐trend=0.004). There were no significant interactions by cohort, sex, smoking, age, baseline BMI or diabetes.

Conclusion: The lack of association during early follow‐up might be explained by subclinical disease. Our results support the hypothesis that leptin plays a role in pancreatic carcinogenesis, however long follow‐up is necessary to observe the association.
Appetite sensation scores and dietary intake of pregnant and lactating women in western Kenya (LB473)
Authors: McDermid Joann , Spraggon Vicky , Oyier Beryl , Otticha Sophie , Onono Maricianah , Young Sera
Published: June 2021

Complex biological, behavioral, socioeconomic and psychological factors influence appetite and subsequent dietary intake; as such, focusing only on a single factor can lead to inappropriate dietary recommendations. This is especially true when poverty‐associated malnutrition and infectious diseases coexist; although both negatively impact dietary intake, very different solutions are needed. Therefore, our objective was to evaluate an adapted scale of appetite sensations and compare these scores to dietary intake among 20 pregnant and 18 lactating women in Nyanza province. A research dietitian implemented the adapted appetite and dietary intake questionnaires. The appetite questionnaire consisted of a 5‐point visual analog scale for each of 4 questions to assess degree of hunger, desire to eat, satiety or food aversions. Dietary intake was assessed by a 24‐hour dietary recall with macronutrient intake, dietary quality and diversity estimated. The majority (60%) consumed a sufficiently diverse diet (蠅6 food groups), with caloric intake distributed adequately between macronutrients (11%=protein; 64%=carbohydrate; 24%=lipid). Despite this, 2/3 consumed insufficient calories [mean(SD) pregnant=2000(717) kcal/d; lactating=2172(720)] and 40% consumed insufficient protein [pregnant=61(29)g/d; lactating=69(32)]. Higher caloric intake was moderately correlated with less hunger and weakly correlated with a greater desire to eat and fewer food aversions but not satiety. These data provide proof of concept that appetite sensations are correlated with dietary intake in this context, and future research is needed to evaluate how appetite scores differ according to poverty and/or infection causes of maternal malnutrition.
Thoracic Ultra Sound (TUS) integrated approach for FNAB‐US guided diagnosis and for monitoring environmental exposed subjects at risk of malignant pleural mesothelioma (MPM) and lung cancer (LC). Overview and preliminary report of TUS monitoring and screening approach. (LB498)
Authors: Sperandeo Marco , Dimitri Lucia , Trovato Francesca M. , Simeone Anna , Catalano Daniela , Pirri Clara , Trovato Guglielmo
Published: June 2021

Thoracic Ultrasound (TUS) Image‐guided sampling of thickened pleura and of lung nodules is a valuable approach in patients with lung cancer (LC) and malignant pleural mesothelioma (MPM); moreover, we monitor by TUS imaging patients with occupational or environmental risk of MPM and LC addressing them more selectively to high resolution computerized tomography (HRCT), also with contrast CT for a further definition. A retrospective analysis of TUS imaging and of the diagnostic yield and complications of TUS‐guided fine needle aspirate biopsies (FNAB) was done. Results: the records of 133 patients with MPM and 801 patients with LC were analyzed. In 55/133 MPM and in 801/801 patients with LC (2008‐2013)TUS‐guided FNAB was performed using 20 G needles and a US transducer with a central passage. The specimens were of satisfactory size (length 1.0‐2.5 cm); in 20/801 LC patients a second FNAB was needed for further immunohistochemistry specimens. No significant complication was observed; 5 patient had partial pneumothorax following biopsies. The TUS signs observed in histologically confirmed MPM were irregular thickening of pleural line (above 5.0 mm) with associated micro‐nodules (5‐10 mm); a lower percentage showed plaque nodulations (5‐10 mm), all with slight or relevant pleural effusion. Patients at risk, without MPM/LG, under TUS monitoring, have irregular thickening of pleural line (above 3.0 mm), with associated micro‐nodules (2‐4 mm); a lower percentage have plaque nodulations (4‐7 mm). These early signs of lung involvement in subjects exposed to asbestos were observed in the absence of CXR findings, and with subsequent HRCT evidence without need of FNAB. Conclusion: TUS guided FNAB is a safe, affordable and reliable tool for the diagnosis of MPM and LC patients, provided that an adequate expertise of the operator and of the pathologist is available.TUS is currently used in our Institution as a complementary tool for screening patients with environmental or occupational risk for MPM and LC. They are preliminarily assessed by HRCT and TUS; this last is scheduled every six months thereafter. Diagnosing patients with pleural thickenings and/or subpleural nodes suspect for MPM is used to address to HRCT and/or contrast CT with the prospect of further focused indications to ultrasound‐guided FNAB.

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An adult osseous head in the hippopotamus: seriated, frontal CT‐scan and reconstructions (LB5)
Authors: LE FLOCH‐PRIGENT Patrice , Verdeille Stéphane , Gillot Jean‐Bernard
Published: June 2021

The cranium and the mandible of an hippopotamus were separately CT‐scanned every 1 mm in the frontal plane. The CT‐scan was a Siemens Somatom definition AS one with 64 bars. The acquisition was performed by an helicoidal mode. 628 cross‐sections were obtained for the cranium and 669 for the mandible. About 20 reconstructions were realized. They brougth several external views under numerous incidences some of which would had been difficult to get from the dry bones as they were very large and heavy. The morphological data were very numerous especially for the study of the dental apparatus and of the intra‐cranial cavity. We acknowledge Mr Alain Piffault and Mrs Domenica Scalisi.
Losartan protects the lung from chronic cellular damage induced by fat embolism (LB512)
Authors: Poisner Alan , Herndon Betty , Bass Devin , Jain Ashwin , Fletcher Amanda , Molteni Agostino
Published: June 2021

In a model of triolein‐induced fat embolism (FE) in the rat, we have reported that the acute pulmonary histopathological changes were ameliorated by losartan (Los). The chronic pulmonary changes of FE persisted at 6 weeks and symptoms were exacerbated by a “second hit” at that time using LPS. The present experiment extended FE study to 10 weeks and examined whether the FE effects plus LPS would continue to be blocked by Los. Groups of rats were given FE (triolein i.v. or i.v. saline controls) followed 6 weeks later by LPS (3 mg/kg i.p). One‐hour after LPS rats were treated with saline or Los (2 mg/kg i.p. and then 0.1 mg/ml Los in the drinking water for 4 more weeks). In confirmation of our previous results, the FE group showed normal weight gain both at 6 and 10 weeks and appeared to be in no distress. However the lungs showed reduced lumen patency at 10 weeks, accompanied by inflammatory and fibrotic changes that were greater than what had been found previously at 6 weeks whether or not LPS was added. These changes were reduced or blocked by Los. In addition pulmonary arteries of all Los‐treated animals had increased lumen patency compared to their respective controls. The data suggest that the effect of FE continues to progress at 10 weeks. The involvement of the renin‐angiotensin system in the pathology of FE is supported by the action of the type 1 receptor blocker, Los. In addition, the enhanced effect of LPS on FE (second hit) was also blocked by Los. These results support the possibility of using angiotensin blockade in clinical situations where fat embolism is suspected .

Grant Funding Source: Supported by Geldmacher Foundation
Lung ultrasound imaging usefulness for assessing the severity of pulmonary fibrosis in systemic sclerosis. Relationship with high‐resolution computed tomography and nailfold videocapillaroscopy (LB514)
Authors: Sperandeo Marco , De Cata Angelo , Molinaro Francesca , Trovato Francesca M. , Dimitri Lucia , Catalano Daniela , Simeone Anna , Trovato Guglielmo
Published: June 2021

Thoracic UltraSound (TUS) assesses 70% of the subpleural areas. Systemic sclerosis (SSc) is characterized by collagen thickening of the skin and by early and progressive microcirculatory impairment. SSc microangiopathy, assessed in vivo by x200 magnification nailfold videocapillaroscopy (NVC), evolves from early enlargement of capillaries (giant capillaries) to capillary loss and hemorrhage (active pattern), and finally, to reactive neoangiogenesis, with capillary ramifications (late pattern). We aimed to assess concordance, if any, between TUS abnormalities, in any phase of disease, and High‐Resolution Computed Tomography (HRCT) findings in SSc, concurrently with the association of the NVC with TUS and HRCT patterns. Methods. 175 SSc patients (M 9, F 166), 46.46 ±15.33 years, were studied by chest x‐rays, TUS, HRCT, echocardiography, pulmonary function tests and NVC. Results. Among 38 patients with limited SSc, without respiratory symptoms, normal spirometry, normal diffusing capacity of the lung and 6‐min O2 desaturation walk test, 17/38 show TUS pleural line thickening 蠅3.0 <5 mm with slight posterior‐basal reticular pattern at HRCT, 21/38 have normal pleural thickness (<3 mm) and normal HRCT. In diffuse SSc: 97/137 patients have minor pleural line thickening (蠅3.0 <5 mm), 32/97 with subpleural nodules; 35/137 have major pleural line thickening (蠅5.0 mm), all with traction cysts and nodules; 5/137 with pleural thickness <3.0 mm have a normal HRCT. By HRCT 65/97 with minor pleural thickening have diffuse reticular pattern fibrosis and 32/97 a reticular‐nodular pattern; no honeycombing. Among the 35 patients with major pleural thickening 蠅 5.0 mm, 2/35 patients show a reticular‐nodular pattern and 33/35, show a frank honeycombing pattern; accuracy of TUS at the reliability analysis is high. There is also an incremental severity of NVC patterns associated with greater pulmonary fibrosis severity at HRCT and TUS; nonetheless, NVC is not discriminating among the different HRCT severity of pulmonary fibrosis,being actually a comprehensive clue of disease activity. Conclusion. TUS imaging with its reproducible measures is a promising complementary tool for early detection of structural lung abnormalities allowing to refer patients selectively to HRCT or to delay referral.
Small molecule Gβγ inhibition reduces pathologic activation of cardiac fibroblasts (LB563)
Authors: Travers Joshua , Kamal Fadia , Blaxall Burns
Published: June 2021

Heart failure (HF) is a devastating disease characterized by cardiac hypertrophy, fibrosis and inflammation. Excess signaling through Gβγ subunits leads to chronic β‐adrenergic receptor (β‐AR) downregulation, mediated predominantly by β‐AR kinase 1 (GRK2) in complex with phosphoinositide 3 kinase γ (PI3Kγ). Our recent work has demonstrated the therapeutic potential of the small molecule Gβγ‐GRK2 inhibitor Gallein in limiting HF progression. Chronic activation of cardiac fibroblasts (CF), critical yet underappreciated myocardial cells, is a key contributor to pathologic cardiac remodeling. We hypothesized that Gβγ‐GRK2 inhibition may limit pathologic CF activation. CFs were stimulated with Isoproterenol (Iso, β‐AR agonist) or Angiotensin II +/‐ Gallein for 24hr. Gallein treatment attenuated the induction in the expression of α smooth muscle actin (αSMA), a marker of pathologic CF activation, several inflammatory cytokines and collagen, as assessed by qRT‐PCR. Gβγ inhibition also mitigated the induction in the phosphorylation of Akt, a kinase downstream of PI3Kγ, in both rodent and failing human CFs. We have recently demonstrated that the protease‐activated receptor 1 (PAR1), a GPCR we have implicated in cardiac hypertrophy, is pathologically transactivated via chronic β‐AR stimulation by induction of MMP‐13, a protease we have found to be elevated in HF. Interestingly, Gβγ inhibition reduced PAR1 cleavage in response to chronic Iso. In summary, small molecule Gβγ inhibition appears to reduce pathologic CF activation, and the reduction in β‐AR‐mediated PAR1 cleavage reveals an alternative mechanism for Gβγ inhibition. These data suggest a potential therapeutic role for small molecule Gβγ inhibition in limiting pathologic CF activation and HF progression.

Grant Funding Source: Supported by the Pharmaceutical Research and Manufacturers of America Foundation
Functional angiotensin and endothelin, but not thromboxane, pathways are necessary for the hypertension and ‎baroreflex dysfunction caused by cyclosporine in rats (LB565)
Authors: Nasser Suzanne , Elmallah Ahmed , Mohy El‐Din Mahmoud , Khedr Mohamed , El‐Mas Mahmoud
Published: June 2021

We investigated the effects of pharmacologic interventions that selectively interrupt angiotensin II (Ang II), endothelin (ET), or ‎thromboxane (TXA2) signaling on CSA‐evoked hypertension and arterial baroreflex impairment in conscious rats. Baroreflex ‎curves relating changes in heart rate (HR) to increases (phenylephrine, PE) or decreases (sodium nitroprusside, SNP) in blood ‎pressure (BP) were constructed and slopes of the curves were taken as a measure of baroreflex sensitivity (BRSPE and BRSSNP). ‎CSA (25 mg/kg/day i.p., 7 days) significantly increased BP and HR and attenuated reflex HR responses and slopes of the ‎baroreflex curves generated by PE and SNP. Concurrent blockade of ETA (atrasentan) or AT1 receptors (losartan), or inhibition of ‎angiotensin converting enzyme (captopril) reduced the hypertensive, but not the tachycardic, effect of CSA. Further, atrasentan ‎reversed the CSA‐evoked impairment in both BRSPE and BRSSNP whereas losartan or captopril selectively improved BRSPE. The ‎blockade of TXA2 receptors by terutroban failed to alter the detrimental effects of CSA on BP or baroreflex gain. It is concluded ‎that the facilitation of Ang II and ETA, but not TXA2, signaling contributes, at least partly, to the rise in BP caused by CSA ‎possibly via the inhibition of reflex HR control. The study highlights some potential therapeutic modalities for the control of the ‎adverse effects of CSA on hemodynamics.‎
Sildenafil citrate attenuates acute renal injury in an animal model of contrast‐induced nephropathy (LB573)
Authors: Lauver D. , Lucchesi Benedict , Gurm Hitinder
Published: June 2021

Contrast‐induced nephropathy (CIN) is defined as acute renal failure occurring within 48 hr of exposure to intravascular contrast agents. Although the exact etiology of CIN remains unclear, one hypothesis involves vasoconstriction of afferent arterioles resulting in renal ischemia. Increased renal blood flow, therefore, might represent an attractive target for the treatment of CIN. In this study we evaluated the effect of inhibition of cGMP‐specific phosphodiesterase type 5 (PDE5), a process resulting in renal vasodilation, in an animal model of CIN.

New Zealand white rabbits were used due to their susceptibility to CIN. Contrast agent (ioxilan, 2.5‐10.0 g I/kg) was infused intravenously over 30 m. Another group of animals received an equiosmolar NaCl solution and served as the control. To evaluate the effects of PDE5 inhibition, a final group was treated with sildenafil citrate before contrast infusion and repeatedly throughout the remainder of the experiment (6 mg/kg, p.o., t.i.d.). The animals were sacrificed after 48 hr and the kidneys were prepared for histological evaluation.

Intravenous administration of ioxilan produced marked kidney injury. Serum creatinine concentrations were elevated within two hr of the infusion and remained elevated for the duration of the experiment. Histological evaluation of the kidneys revealed significant tubular necrosis. The effects of the contrast agent were dose dependent, but absent in the animals that were administered NaCl solution. Notably, the effects of contrast infusion were attenuated by simultaneous treatment with sildenafil citrate.

The conclusions of this study are two fold. First, the absence of deleterious effects in animals treated with equiosmolar NaCl solution suggests that the mechanism by which the contrast agent induced kidney injury was independent of osmolality. Second, selective PDE5 inhibition protected the kidney from CIN. The results suggest a possible role for PDE5 inhibitors in the treatment of CIN and warrant further evaluation to determine the exact mechanism of protection.
Vanillins relax isolated porcine coronary arterial smooth muscle by inhibiting L‐type Ca2+ channels (LB574)
Authors: Raffai Gábor , Kim Jihye , Khang Gilson , Lee Dongwon , Vanhoutte Paul
Published: June 2021

Vanillin (VA) and vanillyl alcohol (VAA) are major components of natural vanilla, while ethyl vanillin (EtVA) is a synthetic vanillin analog with antioxidant and anti‐inflammatory properties. This study compared the relaxing effect of vanillins (VA, VAA, EtVA) and poly(vanillin) oxalate (PVO) nanoparticles (Ø 260nm) containing VA in porcine coronary artery rings by measuring isometric tension. Vanillins but not PVO caused concentration‐dependent, endothelium‐independent and complete relaxations during contractions to U46619, KCl or endothelin‐1 with an order of potency of VAA<VA<EtVA. The relaxations of U46619 contracted preparations were unaffected by inhibitors of NOS (L‐NAME), cyclooxygenases (indomethacin), soluble guanylyl cyclase (ODQ), KCa (TRAM‐34, UCL‐1684, iberiotoxin), KATP (glibenclamide), Kir (BaCl2), and TRPV3 channels (camphor) or by antioxidants (catalase, apocynin, tempol, N‐acetylcysteine, tiron). Vanillins inhibited contractions induced by both Ca2+ reintroduction in 40mM KCl solution and BayK8644. Both VA and PVOs caused partial relaxation of XO/XOD contracted rings. In conclusion, relaxation to vanillin(s) is solely due to the inhibition of L‐type Ca2+ channels in porcine coronary arteries. Both VA and PVO can prevent contractions induced by superoxide anions, and thus could be used to relieve coronary vasospasm associated with elevated oxidative stress.

Grant Funding Source: Supported by Brain Korea 21 PLUS Project, NRF and NRF‐2012M3A9C6050204
Enteric‐coated capsule intestinal delivery of human immunoglobulin G in cynomolgus macaques (LB603)
Authors: Mabus John , Muzammil Salman , Cooper Philip , Brezski Randall , Kunta Jeevan , Huebert Norman , Kliwinski Connie , Bradley Dino , Giles‐Komar Jill , Hornby Pamela
Published: June 2021

In adult primates, immunoglobulin G (IgG) is not detectable in the serum when taken orally due to enzymatic degradation and low intestinal permeation. Direct IgG infusion (2 mg/kg) into the ileum/proximal colon of cynomolgus macaques (n=3), where FcRn is expressed in enterocytes, resulted in ~ 0.3% fractional uptake at 90 min (124±104 ng/mL; mean±SD; Hornby et al., 2013). Here we tested whether a protease‐resistant, high FcRn binding monoclonal antibody (mAb), loaded in enteric‐coated capsules for release in the ileum, would achieve higher circulating levels. An IgG2 isotype, or IgG1 with complete IgG2 hinge insertion, had increased survival over IgG1 in fluid extracted from cynomolgus ileum. Thus, an IgG2 isotype was formulated (10 mM histidine, pH 5.7, 8.5% sucrose, 0.04% PS80), lyophilized, and milled. This isotype (50 mg/mL) was stable in PBS at 40°C and retained molecular integrity in simulated fasted small intestinal fluid (37°C; 48 hr). The pH of cynomolgus ileum was determined by operator‐assisted IntelliCap® technology (Medimetrics) to be > 7.5 (n = 3); thus, size 3 hard gel capsules (0.3 mL) were loaded with either ~ 3 mg/kg mAb or titanium oxide, and coated with hydroxypropyl methylcellulose acetate succinate for dissolution at pH 7.5. Three hours after oral dosing, passage of intact titanium capsules through the pyloric sphincter and subsequent dissolution was confirmed by x‐ray (n = 6). Single capsule mAb dosing achieved serum levels of 0.2±0.1 ng/mL at 24 hours (n = 5). Once weekly dosing for 5 weeks achieved serum levels of 0.4±0.2 ng/mL. Increasing the dose to one capsule biweekly, or two capsules biweekly, did increase serum levels above 1 ng/mL. Intestinal delivery of mAb in cynomolgus macaques resulted in very low oral bioavailability, consistent with a minimal epithelial FcRn contribution in ileum/colon to IgG transcytosis in adults. Engineering protease resistant IgGs increases their survival in the intestinal lumen and may be useful in the oral treatment of intestinal diseases.
Alternating light/dark cycle affects autonomic modulation in spontaneously hypertensive rats (LB660)
Authors: Al‐Siyabi Sultan , Albarwani Sulayma , Al‐Husseini Isehaq , Tanira Musbah
Published: June 2021

Effect of light‐dark cycle shift on autonomic nervous system modulation hasn’t been previously investigated. We studied the effect of alternating light‐dark cycle on autonomic biomarkers in spontaneously hypertensive rats (12mold). ECG and blood pressure (BP) were recorded telemetrically. Rats were subjected to a 12:12h light:dark cycle followed by 12:12h dark:light cycle each for five days, this design was repeated three times. Autoregressive model was used to extract rhythmic oscillations of beat‐beat interval composed of very low frequency (VLF; 0‐0.2Hz), low frequency (LF; 0.2‐0.7Hz) and high‐frequency (HF; 0.7‐4.0Hz). The alternation showed that during light period, alternating light:dark cycle reduced total variance (16.3±5.5 vs 9.65±2.6ms2/Hz) and VLF (5.6±2.3 vs 2.8±0.6) and increased sympathetic modulation (LFnu; 7.34±2.3 to 8.4±0.99), symothovagal tone (LF/HF; 0.08±0.03 vs 0.11±0.01) and systolic BP (179.7±4.9 to 189.3±1.20 mmHg); whereas, during dark period, shifting light cycle increased total variance (5.6±2.2 vs 18.7±4.4ms2/Hz) and VLF (2.7±1.6 vs 5.7±0.8) and decreased HR (314.7±19.9 vs 257.67±7.6) and the dominance of the sympathetic modulation (13.5±2.9 vs 10.7±4.4). Our findings demonstrate that alternating light:dark cycle was associated autonomic function modulation that is more apparent during dark period.
The role of cardiac O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) transferase (OGT) on endurance capacity and physical activity (LB681)
Authors: Duenwald Elizabeth , Miller Lindsey , Medford Heidi , Cox Emily , Marsh Susan
Published: June 2021

The cardiovascular benefits obtained from endurance exercise are well established. Physiological cardiac hypertrophy occurs in response to the beneficial stress of exercise at both the cellular and transcriptional levels. The mechanisms triggering cardiac remodeling to induce a physiological or pathological hypertrophic phenotype remain largely unknown. The posttranslational attachment of O‐Linked β‐N‐acetylglucosamine (O‐GlcNAc) to serine or threonine residues of proteins is catalyzed by O‐GlcNAc transferase (OGT). O‐GlcNAcylation is an important mediator of signal transduction and protein‐protein interactions. However, the relevance of elevated O‐GlcNAc levels in the heart is complex as it is implicated in both cardiac dysfunction, and cardioprotection. Preliminary data and recent literature also suggests that inducible cardiomyocyte‐specific knockdown of OGT (OGT‐KD) alters gene transcription, which results in a heart failure phenotype. We investigated the impact of inducible, cardiomyocyte‐specific OGT‐KD on exercise capacity in a mouse model. Ten week old OGT‐KD mice were randomly assigned to a one‐time run to exhaustion treadmill (TM) cohort, or a 4 week voluntary wheel running (WR) cohort, or appropriate control groups. The TM cohort tolerated a decreased workload overall and exhibited increased ventricular heart weight with an increase in the ratio of heart weight (HW) to tibia length (TL). OGT‐KD mice in the WR cohort had decreased body weight, decreased overall activity, and increased HW:TL. These data suggest that inducible cardiac‐specific OGT‐KD in a mouse model significantly decreases endurance capacity and physical activity, while causing hypertrophy of the heart muscle as early as 11 weeks of age.

Grant Funding Source: NIH/NHLBI HL104549
Reduced carotid artery blood flow of spontaneously hypertensive rats is unaffected by aging from 20 weeks (young adulthood) to 65 weeks (upper middle age) (LB690)
Authors: Denniss Steven , Smith Christopher , Rush James
Published: June 2021

The objective of this study was to quantify blood flow (using a perivascular flowprobe) and pressure (using a catheter‐tip transducer) in the common carotid artery (CCA) of anesthetized young adult (~20 week old) and upper middle aged (~65 week old) Wistar Kyoto rats (WKY) and Spontaneously Hypertensive rats (SHR). In young adult SHR vs. WKY, mean (172±10 vs. 82±2 mmHg), systolic (198±13 vs. 92±4), diastolic (151±9 vs. 72±5), and pulse pressure (48±5 vs. 20±2), and heart rate (371±12 vs. 277±19 beats/min), were each elevated (p<0.01). In SHR, aging had no effect on these pressure parameters, or heart rate; whereas, in WKY, aging was associated with a significant increase in pulse pressure (31±1 mmHg; p=0.04) but no other pressure parameter. Mean (4.94±0.29 vs. 3.80±0.54 ml/min), maximum systolic (11.58±1.08 vs. 19.00±2.18), and minimum diastolic blood flow (0.62±0.73 vs. 1.90±0.34) were each reduced in young adult SHR vs. WKY (p<0.05), while flow pulsatility was no different (3.23±0.73 vs. 3.43±0.44). Aging had no effect on these flow parameters in either SHR or WKY. Together, these data demonstrate that CCA blood flow is >20% reduced in young adult SHR, and that this reduction is neither exacerbated nor attenuated at upper middle age. Given the important contribution of the internal branches of the CCAs to the total perfusion of the brain, these findings may be of pathophysiological and clinical relevance.

Grant Funding Source: Supported by NSERC Canada
Sex differences in the relation between 24h urine volume and osmolality (LB710)
Authors: Perrier Erica , Johnson Evan , McKenzie Amy , Ellis Lindsay , Klein Alexis , Armstrong Lawrence
Published: June 2021

Twenty‐four hour (24h) urinary hydration biomarkers have value in assessing hydration and disease risk. Specifically, highly concentrated urine and low urine volume increase relative risk for lithiasis and chronic kidney disease, respectively, and thus maintaining a high volume of dilute urine has been suggested as a simple preventive measure. Although there is a strong inverse relationship between 24h urine osmolality (UOsm) and volume (UVol), sex differences in urine concentration have been reported. This suggests the possibility of sex differences in the UOsm:UVol relationship which have not been fully explored. Our aim was to assess sex differences in the relationship between UOsm and UVol, and to determine whether body mass may explain any observed differences. METHODS: 24h urine samples from 238 healthy American and French adults (50% men; age 28±6 y; BMI 22.9 ± 2.6 kg∙m‐2) were analyzed for UOsm and UVol. Sex differences in the UVol:UOsm relationship were evaluated with linear regression. RESULTS: UOsm was higher in men at any given UVol (whole model R2=0.67; βwomen mean±SE; ‐127±11 mOsm∙kg‐1; p<.0001); however, the change in UOsm for a given change in UVol was not different between sexes. Adjusting for body mass reduced the UOsm gap between men and women (βwomen; ‐95±13 mOsm∙kg‐1), yet sex remained as a significant predictor of UOsm and the fit of the model was unchanged (whole model R2=0.68; p<.0001). Although the distributions of both UOsm and UVol show a slight positive skew; neither log‐ nor root‐ transformations substantially improved the fit of the model, nor the UOsm gap between men and women. CONCLUSIONS: At similar UVol, men have higher UOsm than women. Though differences in body mass explain part of this sex gap, other factors likely play a role in the differential relationship of UVol:UOsm in men and women.
Lubiprostone reduces murine colitis principally in a ClC‐2‐dependent manner. (LB750)
Authors: Jin Younggeon , Pridgeon Tiffany , Blikslager Anthony
Published: June 2021

Lubiprostone, a ClC‐2 chloride channel activator, induces intestinal secretion and is used in the management of idiopathic chronic constipation. Recent studies have suggested that lubiprostone has multiple targets and mechanisms of action in the intestine. However, we have previously reported that lubiprostone initiates intestinal barrier repair in ischemic‐injured intestine via its principal target, the chloride channel ClC‐2. Thus, we hypothesized that lubiprostone would have a protective or therapeutic effect in an in vivo colitis model. We administrated lubiprostone in a dextran sulfate sodium (DSS)‐induced colitis model in wild type and ClC‐2‐/‐ mice. We determined the severity of colitis based on body weight, disease activity index (DAI), histology scores, and levels of cytokine production. Additionally, intestinal permeability was measured in vivo to evaluate barrier function. Administration of DSS in the drinking water initiated symptoms of experimental IBD, including weight loos and elevation in DAI. Oral preventive or therapeutic administration of lubiprostone significantly reduced weight loss, DAI, histology scores, colon shortening, and intestinal permeability in a dose‐dependent manner as compared to DSS‐treated wild type mice that were not treated with lubiprostone. We also observed that the lubiprostone caused a significant elevation of the sealing tight junction protein expression for occludin and claudin‐1, while significant reduction of the pore‐forming tight junction protein claudin‐2. When administered to ClC‐2‐/‐ mice, the oral preventive lubiprostone treatment had a limited protective effect against DSS colitis. Specifically, loss of body weight, DAI, and intestinal permeability were significantly reduced in the high dose (100 μg/kg) lubiprostone treatment group of ClC‐2‐/‐ mice, but they showed no difference in colon length and histology score. In conclusion, lubiprostone might possess potential therapeutic interest for the treatment of IBD in a ClC‐2 dependent, but it also has some alternative mechanisms of action at high dosages. Additional investigation is required to determine the detailed mechanisms of action of lubiprostone in experimental colitis model.

Grant Funding Source: Supported by Sucampo Pharmaceuticals inc. and Takeda Pharmaceuticals inc
Role of IL‐4 and IL‐13 in Schistosoma‐induced pulmonary hypertension (LB780)
Authors: Kumar Rahul , Chabon Jacob , Gebreab Liya , Rodriguez Garcia Alexandra , Koyanangi Dan , Sanders Linda , Tuder Rubin , Graham Brian
Published: June 2021

Background: Schistosomiasis‐associated pulmonary arterial hypertension (PAH) occurs in the context of Th2 inflammation, which is induced by IL‐4 and IL‐13. We had previously observed that TGF‐β signaling is necessary for Schistosoma‐induced pulmonary hypertension (PH) in the mouse. We hypothesized that IL‐4 and IL‐13 were necessary for the TGF‐β‐induced pulmonary vascular disease induced by Schistosoma.

Methods: Wild type, IL‐13YFP, IL‐4GFP, IL‐4‐/‐, IL‐13‐/‐ and IL‐4‐/‐IL‐13‐/‐ mice (N=5‐17 per group) were intraperitoneally (IP) sensitized with 175 S. mansoni eggs/gram body weight, two weeks later intravenously (IV) challenged via tail vein with the same dose of eggs, and one week thereafter underwent right ventricular catheterization followed by quantitative histologic and protein analysis, or lung digestion and flow cytometry. Lung tissue from patients who died of schistosomiasis‐associated PAH was studied by immunostaining.

Results: The lungs of patients with schistosomiasis‐associated PAH and mice with experimental disease had an increase in IL‐13, IL‐4Rα, phospho‐STAT6 and periostin, a target of IL‐13 signaling. Flow cytometry with IL‐13YFP and IL‐4GFP mice identified both of these cytokines were produced by CD4+ T‐cells. IL‐4‐/‐IL‐13‐/‐ mice, but not IL‐4‐/‐IL13+/+ or IL4+/+IL‐13‐/‐ mice, were protected from Schistosoma‐induced vascular remodeling, although the elevated right ventricular pressure persisted. Immunostaining of Schistosoma‐exposed mice demonstrated decreased phospho‐STAT6, perivascular TGF‐β ligand, and intravascular nuclear phospho‐Smad2/3 in IL4/IL13 double‐deficient mice only.

Conclusions: Combined IL‐4 and IL‐13 deficiency are required for protection against Schistosoma‐induced pulmonary vascular remodeling.
Leukocyte subpopulation responses to resistance exercise are different in men and women and affected by protein supplementation (LB800)
Authors: Freidenreich Daniel , Hiester Kevin , Mastro Andrea , Volk Brittanie , Aristizabal Juan , Kraemer William , Volek Jeff
Published: June 2021

Immune cells are integral to the recovery from exercise, but little is known about the effects of supplementation and sex on the immune response. Untrained men (M) (N=88) and women (W) (N=54) performed a squat exercise protocol (6 sets, 10 repetitions, 2 minutes rest between sets at 65% of 1 RM) and randomly received a supplement immediately post exercise of carbohydrate (CHO) (M=27, W=16), whey (WHY) (M=25, W=18) or soy (SOY) (M=27, W=19). Immunophenotypic analysis of leukocytes was performed before (Pre) and 15 and 60 min post exercise (PE). Comparison of sexes disregarding supplementation indicated lower CD4 T cell counts at all time points in women. CD4 T cells continuously declined in men at 15 and 60 min PE while women only decreased below Pre at 60 min PE. Monocytes increased significantly at 15 min PE in women only (M=+11%, W=+17%) but decreased significantly in both sexes at 60 min PE (M=‐21%, W=‐11%). After division by sex and supplement, monocytes were not different from Pre to 60 min PE in women in all groups, but in men monocytes decreased below Pre at 60 min PE in both CHO and SOY. B cells decreased below Pre at 60 min PE in men in all groups, but only decreased below Pre at 60 min PE in women in SOY. Granulocytes continuously increased PE in men in WHY and CHO, and in women in CHO and SOY. Sex and supplementation differentially affect leukocyte compartmentalization with the most apparent effects on monocytes.

Grant Funding Source: Supported by the Dairy Research Institute
Antioxidative effects of allopurinol and sodium ascorbate increase posfatigue tension in avian skeletal muscle (LB809)
Authors: Sánchez‐Duarte Elizabeth , Guzmán‐Ambriz Ana , Trujillo Xóchitl , Huerta Miguel , Cortés‐Rojo Christian , Saavedra‐Molina Alfredo , Meza‐Carmen Víctor , Montoya‐Pérez Rocío
Published: June 2021

Muscle fatigue is conceived as a decrease in force development after periods of intense activity, and is considered a multifactorial process. Reactive oxygen species (ROS) could play an important role in the regulation of the signaling pathways involved in the proper functioning of muscles, particularly during fatigue. It has previously been reported that the use of antioxidants can reduce the development of fatigue and reverse the decline of force induced by ROS. Moreover, it has been reported that low concentrations of antioxidants are beneficial to the cells, while high concentrations may become detrimental. Although several studies indicate that mitochondria are the predominant site for ROS generation during activity, there has been considerable speculation concerning the role of xanthine oxidase in generation of ROS by skeletal muscle. The aim of this study was to determine the effect of Allopurinol (inhibitor of xanthine oxidase) and sodium ascorbate (ageneral antioxidant) during the muscle fatigue.

Anterior Latissimus Dorsi (ALD) muscle of chicken was dissected and mounted on an experimental recording chamber by placing the proximal end to the bottom of the chamber and the distal end to the hook of a mechanic‐electric transducer (Grass FT03), which through an amplifier and a 320 CyberAmp analog‐digital interface (Digidata 1322A) allowed to acquire the muscle tension generated in a computer (Pentium 4) and a “software” of data acquisition (AXOTAPE, pCLAMP 9.2). We performed a fatigue protocol by twitches (pulses of 100 V, 300 ms duration, 0.5 Hz). The bundle was stimulated until the force decreased by 60 %, then was applied the study drug for 6 min to observe its effect. We used concentrations of Allopurinol (1uM, 10uM and 100 µM) and sodium ascorbate (10, 30 and 100 uM).

In dose response curves the mayor effect for Allopurinol was 100 uM and 10 uM by sodium ascorbate. In combination of Allopurinol and sodium ascorbate the tension post‐fatigue increased to 27.24% ± 8.47% in peak tension, while in total tension was an increase by 53.38% ± 18.60% compared with fatigue. The post‐fatigue increase was similar in combination of both drugs that separately, this suggested us the necessity of certain amount of ROS for the normal behavior of the muscle, since both Allopurinol and sodium ascorbate might act as antioxidants.

Grant Funding Source: Supported by CIC2014‐RMP
Nucleoprotein supplementation combined with intermittent loading prevents capillary regression induced by hindlimb unloading in rat soleus muscle (LB810)
Authors: Hirayama Yusuke , Nakanishi Ryosuke , Maeshige Noriaki , Fujino Hidemi
Published: June 2021

Amino acids supplementation and exercise have been shown to promote physical activity‐induced angiogenesis. Therefore, the aim of this study was to determine the effects of nucleoprotein, which was composed of wide variety of amino acids, supplementation combined with intermittent loading on the capillary regression. Hindlimb unloading resulted in decrease of capillary‐to‐fiber (C/F) ratio and citrate synthase (CS) activity in the soleus muscle. Intermittent loading could not prevent the decrease in C/F ratio and CS activity, whereas nucleoprotein supplementation combined with intermittent loading could prevent the decrease in C/F ratio and CS activity in the soleus muscle. In addition, disuse‐associated changes in kinase insert domain receptor (KDR), a pro‐angiogenesis factor, and thrombospondin‐1 (TSP‐1), an anti‐angiogenesis factor, were prevented by nucleoprotein supplementation combined with intermittent loading. These results indicate that nucleoprotein supplementation combined with intermittent loading is effective to prevent capillary regression, maintaining oxidative enzyme activity and the balance between pro‐ and anti‐angiogenesis factors. Supported by Grants‐in‐Aid for Science Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and the internal funds of Nissan Chemical Industries, Ltd.
Melatonin combined with treadmill exercise suppresses aberrant chondrocyte behavior in osteoarthritic cartilage via TGF‐β1 upregulation (LB834)
Authors: Choi Jeonghyun , Hong Yunkyung , Hong Yonggeun
Published: June 2021

There is no curative treatment that modifies the structure of the damaged articular cartilage. This study examined the effect of melatonin (MT) with or without treadmill exercise (Ex) on aberrant chondrocyte behavior. MT was injected twice/day subcutaneously and Ex was conducted for 1 h/day. The interventions were initiated 4 weeks after an intra‐articular collagenase injection, and were maintained for 4 weeks. Vehicle treatment (Veh) elevated the joint parameters, while MT with or without Ex restored them to the control levels. Intervention reduced the levels of both serum TNF‐α and its downstream molecules Hif‐2a and Runx2. COL2A1 was over‐expressed and cleaved in the Veh and MT alone groups, while active MMP‐13 was the same in all groups. Intervention decreased the cleaved caspase‐3 level regardless of the type, whereas LC3 II expression was abolished in MT+Ex only. Combined intervention induced the upregulation of TGF‐β1 gene expression, with lower ALP levels. Consistent with this, histological repair was stimulated in the MT+Ex group. These findings suggest that melatonin combined with exercise blocks the TNF‐α‐mediated death signal via TGF‐β1 upregulation, leading to cartilage recovery in the osteoarthritic rats.

Key words : Osteoarthritic cartilage, Melatonin, Treadmill exercise, Cell death, TGF‐β1
Dopamine Reuptake Inhibition as the Means of Antidepressant Mechanism of Function (LB92)
Authors: Deng Helend , Luo Thomas , Vorperian Sevahn , Petzold Christine , Nelson David
Published: June 2021

Maintaining the equilibrium of neurotransmitters (NT) at neural synapses is essential for normal brain functioning. Lack of regulation of NT levels is associated with disorders including depression, Parkinson’s disease, ADHD, and epilepsy. The dopamine transporter (DAT) is the primary removal mechanism of the NT, dopamine, from the synaptic cleft. The regulation of NT reuptake is critical for preventing chemical imbalance and the inhibition of reuptake has become the primary target for antidepressants. The Drosophila melanogaster DAT was crystallized in complex with a tricyclic antidepressant (TCA) and found induced in an outward‐open conformation towards the synaptic cleft. Three factors contribute to inhibiting the inward‐facing conformation required for DAT activity: the antidepressant nortriptyline bound at the substrate‐binding site blocks important helix movement, a cholesterol molecule stabilizes the outward conformation, and lastly the C‐terminus caps the cytoplasmic gate. The Madison West SMART (Students Modeling a Research Topic) modeled the DAT structure using 3D printing technology. The structure of TCA‐bound DAT provides new knowledge of eukaryotic transporters and enables a better understanding of the critical factors and conformational changes associated with NT transport inhibition to allow for targeted drug research.

Grant Funding Source: Supported by grants from the NIH‐SEPA and NIH‐CTSA.
A Review of the Role of Type 2 Diabetes Mellitus and Sodium-Glucose Cotransporter-1 Inhibitors in Heart Failure With Preserved Ejection Fraction
Authors: Palaguachi Gladys I. , Frishman William
Published: June 2021

Previous research has demonstrated that patients with type 2 diabetes (T2DM) are at an increased risk for cardiovascular events, including heart failure (HF). Moreover, there is a higher risk of mortality in individuals who have both T2DM and HF with preserved ejection fraction (HFpEF). Although there are antidiabetic agents that have shown both cardiovascular safety and improved cardiovascular outcomes, only certain agents have been associated with HF benefits, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors. This study aims to review the pathophysiology of HFpEF in the setting of T2DM and, more specifically, the role of SGLT2 inhibitors in HFpEF outcomes.
Trigger Site Deactivation Surgery for Headaches is Associated with Decreased Postoperative Medication Use
Authors: Amador Ricardo O. , Gfrerer Lisa , Panzenbeck Paul , Hansdorfer Marek A. , Austen William G.
Published: June 2021

Background:

Patients with chronic headaches suffer debilitating pain, which often leads to the use of numerous medications. Trigger site deactivation surgery has emerged as an effective treatment for select headache patients. This study aims to describe the preoperative and postoperative medication use among patients undergoing trigger site deactivation.

Methods:

One-hundred sixty patients undergoing trigger site deactivation surgery between September 2012 and November 2017 were prospectively enrolled. Information on medication use, including type, dose, and frequency of use, was collected. Follow-up surveys were sent to all patients 12 months postoperatively.

Results:

One-hundred twenty-nine patients met the inclusion criteria. At the time of screening, 96% of patients described taking prescription medication for their headache pain. The type of medication varied among patients but included preventative in 55%, abortive in 52%, rescue in 54%, and antiemetic in 18%. Thirty-one percent of patients reported using opioid medication for their headache pain. At 12 months postoperatively, 68% of patients reported decreased prescription medication use. Patients reported a 67% decrease in the number of days they took medication. Twenty-three percent stopped medications altogether. Fifty percent of patients reported that their migraine medication helped them more compared with preoperatively.

Conclusions:

Trigger site deactivation surgery has been associated with improvements in headache symptoms. We now show that it is also associated with a significant decrease in medication use.
Comparison of 30-day Clinical Outcomes with SimpliDerm and AlloDerm RTU in Immediate Breast Reconstruction
Authors: Tierney Brian P.
Published: June 2021

Background:

Acellular dermal matrix (ADM) is widely used in breast reconstruction, and outcomes of these procedures may be improved through optimized product design. SimpliDerm is a new human ADM designed to closely preserve the architecture of native dermis, with the goal of improving surgical outcomes. This study reports the initial (30-day) clinical experience with SimpliDerm compared with AlloDerm Ready-To-Use (RTU) in ADM-assisted breast reconstruction.

Methods:

Clinical characteristics and outcomes of 59 consecutive patients who underwent immediate 2-stage reconstruction with SimpliDerm (n = 28) or AlloDerm RTU (n = 31) following mastectomy are reported.

Results:

Fifty-nine women (108 breasts) underwent posmastectomy breast reconstruction with SimpliDerm or AlloDerm RTU. Mean patient age was 51.1 years, and mean body mass index was 28.2 kg/m2. Reconstructions were predominantly prepectoral (95.4%), used tissue expanders (100%), and followed a skin-sparing (64%) approach to mastectomy. Mean time to final drain removal did not differ between groups (17.0 days, SimpliDerm versus 17.7 days, AlloDerm RTU). Adverse events occurred in 13 (22%) patients; none considered serious—all were mild or moderate in intensity. Adverse event rates did not differ between groups. The observed adverse event profiles and rates are similar to those published for other ADMs in immediate breast reconstruction.

Conclusions:

There remains a clinical need for ADMs with more optimal characteristics. This case series describes comparable outcomes with SimpliDerm and AlloDerm RTU over 30 days after immediate 2-stage breast reconstruction.