Biomechanical Increase in Cervical Esophageal Wall Tension during Peristalsis.

During pharyngeal phase of swallowing circumferential tension of the cervical esophagus (CTE) increases caused by a biomechanical process of laryngeal elevation pulling the cervical esophagus orad. The esophagus contracts longitudinally during esophageal peristalsis, therefore, we hypothesized that CTE increases during esophageal peristalsis by a biomechanical process. METHODS: We investigated this hypothesis using 28 decerebrate cats instrumented with EMG electrodes on the pharynx and esophagus, and esophageal manometry. We recorded CTE, distal esophageal longitudinal tension (DET), and orad laryngeal tension (OLT) using strain gauges. Peristalsis was stimulated by injecting saline into esophagus or nasopharynx. We investigated the effects of transecting the pharyngo-esophageal nerve (PEN), hypoglossal nerve (HG), or administering (10 mg/kg, IV) hexamethonium (HEX). RESULTS: We found that the durations of CTE and DET increased and OLT decreased simultaneously during the total extent of esophageal peristalsis. CTE duration was highly correlated with DET, but not esophageal EMG or manometry. The peak magnitudes of the DET and CTE were highly correlated. After HEX administration, peristalsis in the distal esophagus did not occur, and the duration of the CTE response decreased. PEN transection blocked the occurrence of cricopharyngeal or cervical esophageal response during peristalsis, but had no significant effect on the CTE response. HG transection had no significant effect on CTE. CONCLUSION: We conclude that there is a significant CTE increase, independent of laryngeal elevation or esophageal muscle contraction, which occurs during esophageal peristalsis. This response is a biomechanical process caused by esophageal shortening that occurs during esophageal longitudinal contraction of esophageal peristalsis.

Effect of inter-swallow interval on striated esophagus peristalsis; a comparative study with smooth muscle esophagus.

BACKGROUND: Effect of inter-swallow interval on the contractility of smooth muscle esophagus is well-documented. However, the effects on peristalsis of the striated esophagus have not been systematically studied. A better understanding of striated esophagus motor function in health and disease may enhance the interpretation of manometric studies and inform clinical care. The aim of this study was to assess the effect of inter-swallow interval on striated esophagus compared to findings with that of the smooth muscle esophagus. METHODS: We performed two sets of studies to (1) determine the effect of various inter-swallow interval in 20 healthy volunteers and (2) assess the effect of ultra-short swallow intervals facilitated by straw drinking in 28 volunteers. We analyzed variables using ANOVA with Tukey's pairwise comparison and paired t-test. KEY RESULTS: Unlike smooth muscle esophagus, the striated esophagus contractile integral did not change significantly for swallow intervals ranging from 30 to 5 s. On the contrary, striated esophagus demonstrated absent or reduced peristalsis in response to ultra-short (<2 s) intervals during straw-facilitated multiple rapid swallows. CONCLUSIONS AND INFERENCES: Striated esophagus peristalsis is subject to manometrically observed inhibition during swallows with ultra-short intervals. Inter-swallow intervals as short as 5 s that inhibit smooth muscle esophagus peristalsis do not inhibit striated muscle peristalsis. The mechanisms of these observations are unknown but may relate to central or myenteric nervous system influences or the effects of pharyngeal biomechanics.

Team science criteria and processes for promotion and tenure of Health Science University Faculty.

Although team science has expanded with far-reaching benefits, universities generally have not established criteria to recognize its value in faculty promotion and tenure. This paper recommends how institutions might weigh a faculty member's engagement in team science in the promotion and tenure process. Seventeen team science promotion and tenure criteria are recommended based on four sources - an evaluation framework, effectiveness metrics, collaborative influences, and authorship criteria. Suggestions are made for adaptation of the 17 criteria to committee guidelines, faculty team science portfolios, and the roles of individuals and institutions participating in large, cross-disciplinary research projects. Future research recommendations are advanced.

Biomechanical effects of esophageal elongation on the circumferential tension of the cervical esophagus in vivo.

Evidence obtained ex vivo suggests that physical elongation of the esophagus increases esophageal circumferential stress-strain ratio, but it is unknown whether this biomechanical effect alters esophageal function in vivo. We investigated the effects of physical or physiological elongation of the cervical esophagus on basal and active circumferential tension in vivo. The esophagus was elongated, using 29 decerebrate cats, either physically by distal physical extension of the esophagus or physiologically by stimulating the hypoglossal nerve, which activates laryngeal elevating muscles that elongate the esophagus. Hyoid, pharyngeal, and esophageal muscles were instrumented with electromyogram (EMG) electrodes and/or strain gauge force transducers. Esophageal intraluminal manometry was also recorded. We found that physical or physiological elongation of the cervical esophagus increased esophageal circumferential basal as well as active tension initiated by electrical stimulation of the pharyngo-esophageal nerve or the esophageal muscle directly, but did not increase esophageal intraluminal pressure or EMG activity. The esophageal circumferential response to the esophago-esophageal contractile reflex was increased by distal physical elongation, but not orad physiological elongation. We conclude that physical or physiological elongation of the esophagus significantly increases esophageal circumferential basal and active tension without muscle activation. We hypothesize that this effect is caused by an increase in esophageal stress-strain ratio by a biomechanical process, which increases circumferential wall stiffness. The increase in esophageal circumferential stiffness increases passive tension and the effectiveness of active tension. This increase in cervical esophageal circumferential stiffness may alter esophageal function.NEW & NOTEWORTHY Physical or physiological esophageal elongation increases esophageal circumferential active or passive tension by a biomechanical process, which causes a decrease in esophageal circumferential elasticity. This increased stiffness of the esophageal wall likely promotes esophageal bolus flow during various esophageal functions.

A biomechanical response of the esophagus participates in swallowing.

Evidence suggests that a biomechanical process participates in esophageal function, but no such function has yet been identified. We investigated the role of a biomechanical process during swallowing in 30 decerebrate cats instrumented using electromyogram (EMG) electrodes, strain gauge force transducers, and manometry. We found that the cervical esophagus has a short-lasting circumferential tension response during the pharyngeal phase of swallowing (CTPP), and a concomitant EMG response. The CTPP magnitude was correlated with magnitudes of contraction of the geniohyoideus, laryngeal elevation force, and esophageal orad elongation force. The magnitude of the CTPP was not correlated with the peak or area under the curve of the concomitant esophageal EMG response. Restricting laryngeal elevation by physical force or transecting the hypoglossal nerves decreased or eliminated the CTPP during swallowing. Elongation of the distal cervical esophagus increased basal circumferential cervical esophageal tension as well as the CTPP. Transecting the vagus or pharyngoesophageal nerves, or administering hexosamine intravenously, had no significant effect on CTPP. We conclude that CTPP is a response to esophageal elongation during laryngeal elevation during the pharyngeal phase of swallowing, which is not caused by muscle contraction or mediated by the nervous system. The CTPP may assist in the distal movement of boluses before activation of the esophageal phase of swallowing, and may serve to prevent esophagopharyngeal reflux. We hypothesize that the CTPP is a biomechanical decrease in elasticity of the circumferential connective tissue of the cervical esophagus caused by the stress of cervical esophageal elongation.NEW & NOTEWORTHY The pharyngeal phase of swallowing includes increased circumferential tension of the cervical esophagus during the pharyngeal phase of swallowing (CTPP). The CTPP is a biomechanical response caused by elongation of the esophagus during laryngeal elevation, and is not caused by muscle contraction or mediated by the nervous system. The CTPP may assist in the distal movement of boluses before activation of the esophageal phase of swallowing, and may serve to prevent esophagopharyngeal reflux.

Variables influencing manometric parameters of deglutitive and non-deglutitive upper esophageal sphincter: A study of 89 asymptomatic participants.

BACKGROUND: High-resolution manometry overcomes limitations imposed by axial and radial asymmetry as well as swallow and respiration-induced movement of the upper esophageal sphincter (UES), allowing for its reliable use in evaluation of dysphagic and reflux patients. The aim of this study was to determine normative values and their variability across position, sex, age, height, weight, BMI, and volume for clinically relevant deglutitive and non-deglutitive UES parameters. METHODS: We studied 89 asymptomatic volunteers age 19-90 years, (45 female) during 3-10 repetitions of dry, 5 and 10 ml water swallows at 30-s intervals using high-resolution manometry. KEY RESULTS: Upper esophageal sphincter high-pressure zone was longer in men than women and in supine than upright position. UES basal contractile integral and mean basal pressure were higher in supine compared to upright; higher in men than women, inversely correlated with age, correlated positively with height and with weight in the supine position only. UES relaxation duration was longer in upright than in supine position but not affected by age, sex, height, weight, or BMI. It was longer with 5 and 10 ml compared with dry swallows. UES minimum/nadir relaxation and mean relaxation pressures were lower in upright than supine position, increased with increase in age and were higher in men than women. CONCLUSIONS AND INFERENCES: Position, sex, age, height, weight, and volume affect some deglutitive and non-deglutitve UES manometric parameters. BMI does not affect the studied manometric parameters. These effects should be taken into consideration in clinical evaluation of UES.

Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial.

Importance: There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19. Objective: To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen. Design, Setting, and Participants: CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation. Interventions: A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline). Main Outcomes and Measures: The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8. Results: Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06). Conclusions and Relevance: In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use. Trial Registration: ClinicalTrials.gov Identifier: NCT04364737.

Characteristics of high-resolution esophageal manometry in children without dysphagia.

BACKGROUND: The absence of high-resolution esophageal manometry (HREM) norms in pediatrics limits the assessment of children with dysphagia. This study aimed to describe HREM parameters in a cohort of children without dysphagia. METHODS: Children ages 9-16 years with a negative Mayo Dysphagia Questionnaire screen and normal histologic findings underwent HREM after completion of esophagogastroduodenoscopy. Ten swallows of 5 ml 0.45% saline boluses per subject were captured in supine position. Analyzed data included resting and integrated relaxation pressures (IRP) of lower (LES) and upper (UES) esophageal sphincters, peristaltic contractile integrals, transition zone (TZ) breaks, velocities, and lengths associated with proximal and distal esophagus. KEY RESULTS: 33 subjects (15 female) with mean (range) age 12.9 (9-16) years completed the study. Two of 330 analyzed swallows failed. The UES mean resting pressure, and its 0.2 s and 0.8 s IRPs were 48.3 (95% CI 12.9) mmHg, 2.9 (95% CI 1.9) mmHg, and 12.1 (95% CI 2.5) mmHg, respectively. The LES mean resting pressure and its 4 s IRP were 29.0 (95% CI 4.0) mmHg and 9.2 (95% CI 1.3) mmHg. The mean proximal (PCI) and distal (DCI) esophageal contractile integrals were 231 (95% CI 54.8) mmHg-s-cm and 1789.3 (95% CI 323.5) mmHg-s-cm, with mean TZ break 0.5 (95% CI 0.3) cm. CONCLUSIONS & INFERENCES: This is the first study to describe HREM parameters in children without dysphagia. Most of the reported measurements were significantly different and less variable from reported adult norms. This emphasizes the need for child-specific catheters, norms, and protocols to define pediatric esophageal motility disorders.

Identification and characterization of rostral ventromedial medulla neurons synaptically connected to the urinary bladder afferents in female rats with or without neonatal cystitis.

The neurons in the rostral ventromedial medulla (RVM) play a major role in pain modulation. We have previously shown that early-life noxious bladder stimuli in rats resulted in an overall spinal GABAergic disinhibition and a long-lasting bladder/colon sensitization when tested in adulthood. However, the neuromolecular alterations within RVM neurons in the pathophysiology of early life bladder inflammation have not been elucidated. In this study, we have identified and characterized RVM neurons that are synaptically linked to the bladder and colon and examined the effect of neonatal bladder inflammation on molecular expressions of these neurons. A transient bladder inflammation was induced by intravesicular instillation of protamine sulfate and zymosan during postnatal days 14 through 16 (P14-16) followed by pseudorabies virus PRV-152 and PRV-614 injections into the bladder and colon, respectively, on postnatal day P60. Tissues were examined 96 h postinoculation for serotonergic, GABAergic, and enkephalinergic expressions using in situ hybridization and/or immunohistochemistry techniques. The results revealed that > 50% of RVM neurons that are synaptically connected to the bladder (i.e., PRV-152+) were GABAergic, 40% enkephalinergic, and about 14% expressing serotonergic marker tryptophan hydroxylase 2 (TpH2). Neonatal cystitis resulted in a significant increase in converging neurons in RVM receiving dual synaptic inputs from the bladder and colon. In addition, neonatal cystitis significantly downregulated vesicular GABA transporter (VGAT) with a concomitant increase in TpH2 expression in bladder-linked RVM neurons, suggesting an alteration in supraspinal signaling. These alterations of synaptic connectivity and GABAergic/serotonergic expressions in RVM neurons may contribute to bladder pain modulation and cross-organ visceral sensitivity.

Differences in fatigability of muscles involved in fecal continence: Potential clinical ramifications.

INTRODUCTION: Fatigue of the anal sphincter complex has been demonstrated using high-resolution anorectal manometry (HRAM). However, the fatigability of individual muscles such as the external anal sphincter (EAS) and puborectalis muscles (PRM) has not been described. Vaginal manometry has been used to study contractile activity of the PRM. By applying both modalities, we attempted to differentiate the fatigability between the PRM and the EAS under different exercise conditions. METHODS: We studied two groups: group 1, 12 healthy women (21 ± 2.7 years) with HRAM and group 2, 10 healthy (20 ± 3 years) women with vaginal manometry. All subjects performed 40 repetitive contractions with and without an intra-anal resistive load. In group 1, areas under the curve (AUC) of the anal canal high-pressure zone (HPZ) including the caudal and rostral halves were compared. In group 2, the maximum and mean pressures of the vaginal HPZ were compared. RESULTS: The AUC decreased significantly only after repetitive contractions against a resistive load (462 ± 129 vs. 390 ± 131 mmHg-cm, p = 0.02), indicating fatigue. The caudal half (EAS) decreased significantly after contractions against a load (288 ± 75 vs. 239 ± 82 mmHg-cm, p = 0.02), while the rostral half (PRM) did not. The vaginal pressures (PRM) also decreased only after repetitive contractions against a load (maximum pressures, 358 ± 171 vs. 239 ± 109 mmHg, p = 0.02). CONCLUSIONS: The EAS and PRM both exhibit fatigue with contractions only against a resistive load. These findings may guide the development of appropriate exercise regimens to target specific muscles involved in fecal continence.

The rights (and responsibilities) of the public to advance health through research.

In this commentary we assert that the rights and responsibilities of the community at large as an important key stakeholder in the effort of advancing health through research and discovery have not been carefully examined and delineated. The time has come to investigate the nature of the rights and responsibilities of the public in advancing health through research and discovery. We argue that the public has the right not merely to participate in research and have their rights protected, but that they have a right to engage in and take ownership in research.

Prioritizing studies of COVID-19 and lessons learned.

INTRODUCTION: COVID-19 altered research in Clinical and Translational Science Award (CTSA) hubs in an unprecedented manner, leading to adjustments for COVID-19 research. METHODS: CTSA members volunteered to conduct a review on the impact of CTSA network on COVID-19 pandemic with the assistance from NIH survey team in October 2020. The survey questions included the involvement of CTSAs in decision-making concerning the prioritization of COVID-19 studies. Descriptive and statistical analyses were conducted to analyze the survey data. RESULTS: 60 of the 64 CTSAs completed the survey. Most CTSAs lacked preparedness but promptly responded to the pandemic. Early disruption of research triggered, enhanced CTSA engagement, creation of dedicated research areas and triage for prioritization of COVID-19 studies. CTSAs involvement in decision-making were 16.75 times more likely to create dedicated diagnostic laboratories (95% confidence interval [CI] = 2.17-129.39; P < 0.01). Likewise, institutions with internal funding were 3.88 times more likely to establish COVID-19 dedicated research (95% CI = 1.12-13.40; P < 0.05). CTSAs were instrumental in securing funds and facilitating establishment of laboratory/clinical spaces for COVID-19 research. Workflow was modified to support contracting and IRB review at most institutions with CTSAs. To mitigate chaos generated by competing clinical trials, central feasibility committees were often formed for orderly review/prioritization. CONCLUSIONS: The lessons learned from the COVID-19 pandemic emphasize the pivotal role of CTSAs in prioritizing studies and establishing the necessary research infrastructure, and the importance of prompt and flexible research leadership with decision-making capacity to manage future pandemics.

Fatigability of the external anal sphincter muscles using a novel strength training resistance exercise device.

Exercises involving pelvic floor muscles including repetitive voluntary contractions of external anal sphincter (EAS) musculature have been used to improve fecal incontinence. Muscle fatigue is a prerequisite for successful strength training. However, muscle fatigue induced by these exercises has not been systematically studied. We aimed to assess the fatigability of EAS muscles during various exercise methods. Twelve nulliparous (21 ± 2.7 yr) women were studied. We evaluated fatigue during 40 repetitive 3-s contractions and 30-s long squeeze contractions both with and without an intra-anal compressible resistant load. The sequence of exercises was randomized. This load was provided by the continence muscles Resistance Exerciser Device. Anal canal pressures were recorded by high-resolution manometry. Exercise against a resistive load showed significant decrease in anal contractile integral (CI) and maximum squeeze pressure during repetitive short squeeze contractions compared with exercise without a load. Linear regression analysis showed a significant negative correlation between anal CI and successive contraction against load, suggesting "fatigue." Similar findings were observed for maximum squeeze pressure (slope with load = -4.2, P = 0.0003, vs. without load = -0.9, P = 0.3). Long squeeze contraction against a load was also more susceptible to fatigue than without a load (P < 0.0001). In conclusion, repetitive contractions against a compressible load induce fatigue and thus have the potential to strengthen the anal sphincter contractile function than contractions without a load. Fatigue rate in long squeeze contraction exercises with a load is significantly faster than that without a load, also indicating greater effectiveness in inducing muscle fatigue.NEW & NOTEWORTHY Fecal incontinence is a distressing disorder with a mainstay of treatment being pelvic floor muscle exercises. However, none of these exercises has proven occurrence of fatigability, which is an important prerequisite for successful muscle strengthening in rehabilitative exercises. In this study, we proved that we can fatigue the external anal sphincter muscles more efficiently by providing a resistive load during anal repetitive short squeeze contractions and long squeeze contraction exercise.

Managing the risks and benefits of clinical research in response to a pandemic.

Introduction: The coronavirus disease 2019 (COVID-19) created major disruptions at academic centers and healthcare systems globally. Clinical and Translational Science Awards (CTSA) fund hubs supported by the National Center for Advancing Translational Sciences provideinfrastructure and leadership for clinical and translational research at manysuch institutions. Methods: We surveyed CTSA hubs and received responses from 94% of them regarding the impact of the pandemic and the processes employed for the protection of research personnel and participants with respect to the conduct of research, specifically for studies unrelated to COVID-19. Results: In this report, we describe the results of the survey findings in the context of the current understanding of disease transmission and mitigation techniques. Conclusions: We reflect on common practices and provide recommendations regarding lessons learned that will be relevant to future pandemics, particularly with regards to staging the cessation and resumption of research activities with an aim to keep the workforce, research participants, and our communities safe in future pandemics.

Mechanisms of bradycardia in premature infants: Aerodigestive-cardiac regulatory-rhythm interactions.

OBJECTIVE: Eating difficulties coupled with cardiorespiratory spells delay acquisition of feeding milestones in convalescing neonates, and the mechanisms are unclear. Aims were to examine and compare the pharyngoesophageal-cardiorespiratory (PECR) response characteristics: (a) in control neonates and those with recurrent bradycardia spells; and (b) during pharyngeal stimulation when bradycardia occurs versus when no bradycardia occurs. METHODS: Preterm infants (N = 40, 27 ± 3 weeks gestation), underwent concurrent pharyngoesophageal manometry, electrocardiography, respiratory inductance plethysmography, and nasal airflow thermistor to evaluate pharyngoesophageal motility, heart rate (HR), and respiration during graded abrupt pharyngeal sterile water stimuli. Infants with recurrent bradycardia (N = 28) and controls (N = 12) were evaluated at 38 (38-40) and 39 (38-40) weeks postmenstrual age, respectively. Comparisons were performed (a) between study and control groups; and (b) among HR responses of <80 BPM, 80-100 BPM, and >100 BPM. RESULTS: Overall, characteristics of PECR responses in infants with a history of recurrent bradycardia (vs. controls) did not differ (p > .05). However, when pharyngeal stimulus induced severe bradycardia (<80 BPM): prolonged respiratory rhythm change, increased pharyngeal activity, increased esophageal dysmotility (as evidenced by prolonged esophageal inhibition and motor activity), and prolonged lower esophageal sphincter relaxation were noted (all p < .05). CONCLUSIONS: In control infants and those with recurrent bradycardia, pharyngeal stimulation results in similar PECR response characteristics. However, when severe bradycardia occurs, PECR response characteristics are distinct. The mechanisms of severe bradycardia spells are related to abnormal prolongation of vagal inhibitory effects on cardiorespiratory rhythms in conjunction with prolonged esophageal inhibition and delays with terminal swallow.

The Effect of Platelet-Rich Fibrin (PRF), Plasma Rich in Growth Factors (PRGF), and Enamel Matrix Proteins (Emdogain) on Migration of Human Gingival Fibroblasts.

STATEMENT OF THE PROBLEM: Platelet preparations such as plasma rich in growth factors (PRGF), platelet-rich fibrin (PRF), or enamel matrix proteins (Emdogain) are commonly used for soft and hard tissue regeneration. However, their comparative effectiveness has not been extensively studied, and a consensus has yet to be reached on their efficacy. PURPOSE: The aim of this in vitro study was to compare the effect of PRF, PRGF, and Emdogain on the proliferation of human gingival fibroblasts (HGF). MATERIALS AND METHOD: Artificial wounds were made in HGF cell culture after the fibroblasts reached nearly 100% of confluence. The study groups included leukocyte and platelet-rich fibrin (LPRF), pure platelet-rich fibrin (PPRF), PRGF and Emdogain. Stained cells were photographed at 48 h and one week and the percent of wound filling was measured. Statistical analysis was performed by one-way ANOVA and p values < 0.05 were considered statistically significant. RESULTS: The highest wound filling percentages at both time intervals were observed in the PPRF group, followed by the PRGF. The lowest percentage of wound healing among test groups was observed in the LPRF while Emdogain yielded modest results. However, statistical analysis showed similar wound healing values in PRGF, PPRF, and Emdogain groups. CONCLUSION: Within the limitations of this study, PRGF, PPRF, and Emdogain were similarly effective in enhancing the fibroblast proliferation and artificial wound closure.

Characterization and mechanism of the esophago-esophageal contractile reflex of the striated muscle esophagus.

An esophago-esophageal contractile reflex (EECR) of the cervical esophagus has been identified in humans. The aim of this study was to characterize and determine the mechanisms of the EECR. Cats (n = 35) were decerebrated, electrodes were placed on pharynx and cervical esophagus, and esophageal motility was recorded using manometry. All areas of esophagus were distended to locate and quantify the EECR. The effects of esophageal perfusion of NaCl or HCl, vagus nerve or pharyngoesophageal nerve (PEN) transection, or hexamethonium administration (5 mg/kg iv) were determined. We found that distension of the esophagus at all locations activated EECR rostral to stimulus only. EECR response was greatest when the esophagus 2.5-11.5 cm from cricopharyngeus (CP) was distended. HCl perfusion activated repetitively an EECR-like response of the proximal esophagus only within 2 min, and after ~20 min EECR was inhibited. Transection of PEN blocked or inhibited EECR 1-7 cm from CP, and vagotomy blocked EECR at all locations. Hexamethonium blocked EECR at 13 and 16 cm from CP but sensitized its activation at 1-7 cm from CP. EECR of the entire esophagus exists, which is directed in the orad direction only. EECR of striated muscle esophagus is mediated by vagus nerve and PEN and inhibited by mechanoreceptors of smooth muscle esophagus. EECR of smooth muscle esophagus is mediated by enteric nervous system and vagus nerve. Activation of EECR of the striated muscle esophagus is initially sensitized by HCl exposure, which may have a role in prevention of supraesophageal reflux.NEW & NOTEWORTHY An esophago-esophageal contractile reflex (EECR) exists, which is directed in the orad direction only. EECR of the proximal esophagus can appear similar to and be mistaken for secondary peristalsis. The EECR of the striated muscle is mediated by the vagus nerve and pharyngoesophageal nerve and inhibited by mechanoreceptor input from the smooth muscle esophagus. HCl perfusion initially sensitizes activation of the EECR of the striated muscle esophagus, which may participate in prevention of supraesophageal reflux.

Interplay of spinal and vagal pathways on esophageal acid-related anterior cingulate cortex functional networks in rats.

Esophageal acid sensory signals are transmitted by both vagal and spinal pathways to the cerebral cortex. The influence and interplay of these pathways on esophageal acid-related functional connectivity has been elusive. Our aim was to evaluate the esophageal acid exposure-related effect on the anterior cingulate cortex (ACC) functional connectivity networks using functional MRI-guided functional connectivity MRI (fcMRI) analysis. We studied six Sprague-Dawley rats for fcMRI experiments under dexmedetomidine hydrochloride anesthesia. Each rat was scanned for 6 min before and after esophageal hydrochloric acid infusion (0.1 N, 0.2 ml/min). The protocol was repeated before and after bilateral cervical vagotomy on the same rat. Seed-based fcMRI analysis was used to examine ACC networks and acid-induced network alterations. Three-factor repeated-measures ANOVA analysis among all four subgroups revealed that the interaction of acid infusion and bilateral vagotomy was mainly detected in the hypothalamus, insula, left secondary somatosensory cortex, left parietal cortex, and right thalamus in the left ACC network. In the right ACC network, this interaction effect was detected in the caudate putamen, insula, motor, primary somatosensory cortex, secondary somatosensory cortex, and thalamic regions. These regions in the ACC networks showed decreased intranetwork connectivity due to acid infusion. However, after bilateral vagotomy, intranetwork connectivity strength inversed and became stronger following postvagotomy acid infusion. Signals transmitted through both the vagal nerve and spinal nerves play a role in esophageal acid-related functional connectivity of the ACC. The vagal signals appear to dampen the acid sensation-related functional connectivity of the ACC networks. NEW & NOTEWORTHY These studies show that esophageal acid-induced brain functional connectivity changes are vagally mediated and suggest that signals transmitted through both the vagal nerve and spinal nerves play a role in esophageal acid-related functional connectivity of the anterior cingulate cortex. This paper focuses on the development of a novel rat functional MRI model fostering improved understanding of acid-related esophageal disorders.

Dickkopf-1 (DKK1) promotes tumor growth via Akt-phosphorylation and independently of Wnt-axis in Barrett's associated esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is still associated with poor prognosis, despite modern multi-modal therapies. New molecular markers, which control cell cycle and promote lymph node metastases or tumor growth, may introduce novel target therapies. Dickkopf-1 (DKK1) is a secreted glycoprotein that blocks the oncogenic Wnt/ß-catenin signaling and its aberrant expression has been observed in many malignancies, including EAC. In this study, we investigated the biological role of DKK1 in EAC. Analysis of DKK1 and active ß-catenin expression in human esophageal tissues confirmed a simultaneous DKK1-overexpression together with aberrant activation of ß-catenin signaling in EAC in comparison with Barrett's and healthy mucosa. To elucidate the molecular role of DKK1, the OE33 adenocarcinoma cells, which were found to overexpress DKK1, were subjected to functional and molecular assays following siRNA-mediated DKK1-knockdown. At the functional level, OE33 cell viability, proliferation, migration and invasion were significantly attenuated by the absence of DKK1. At the molecular level, neither DKK1-knockdown nor application of exogenous recombinant DKK1 were found to alter the baseline ß-catenin signaling in OE33 cells. However, DKK1-knockdown significantly abrogated downstream Akt-phosphorylation. On the other hand, the Wnt-agonist, Wnt3a, restored the Akt-phorphorylation in the absence of DKK1, without, however, being able to further stimulate ß-catenin transcription. These findings suggest that the ß-catenin transcriptional activity in EAC is independent of Wnt3a/DKK1 site-of-action and define an oncogenic function for DKK1 in this type of malignancy via distinct activation of Akt-mediated intracellular pathways and independently of Wnt-axis inhibition. Taken together, DKK1 may present a novel therapeutic target in EAC.