Transient Relaxation Research Articles

A Patient with Uncontrollable Belching: What to Do?

Aim.In this paper, we discuss the clinical significance of belching and present a clinical case with the description of the belching differential diagnosis.Main findings.Belching may be either a physiological or a pathological phenomenon. Pathological belching requires an adequate diagnostic approach in order to clarify the nature of its occurrence. Gastric belching occurs reflexively at the moment of stomach stretching by excess air trapped during swallowing, which initiates the transient relaxation of the lower esophageal sphincter. As a consequence, the swallowed air escapes from the stomach first into the esophagus and then into the throat. Supragastric belching is a phenomenon, in which the air entering the esophagus does not reach the stomach, but rapidly returns to the throat. In this case, unlike aerophagia, the air entering the esophagus is not accompanied by the act of swallowing. Supragastric belching is not a reflex process; rather, it is considered to be a manifestation of behavioural disorders. 24-hour pH-impedancemetry and high-resolution esophageal manometry are highly informative methods for detecting various types of belching (gastric and supragastric), as well as their mechanisms. We present a clinical observation of a 47-year-old patient suffering from supragastric belching and treated by speech therapy under the supervision of a speech therapist.Conclusion.24-hour pH-impedancemetry and high-resolution esophageal manometry (also in combination with impedancemetry) provide a complete differential diagnosis of belching and allow the most effective patient management strategy to be selected.

Excitation and control of spin waves in FeBO3 by a strong-field THz pulse

The dynamically resolved response of the canted-antiferromagnet FeBO3 excited near a magnon resonance shows fast oscillations after THz-excitation’ followed by the magnons’ intrinsic relaxation’ enabling to probe transient magnetic relaxation dynamics over large frequency range.

Erythromycin and Reflux Events in Premature Neonates: A Randomized Clinical Trial.

Gastroesophageal reflux disease (GERD) in premature neonates may manifest as apnea, bradycardia, growth failure, aspiration, or feeding intolerance. Erythromycin ethylsuccinate (EES), is often used as a pro-kinetic in the management of GERD, despite lack of evidence or safety from randomized controlled trials. We sought to study the efficacy of enteral EES at a dose of 50 mg · kg · day in decreasing the frequency of gastroesophageal reflux events as determined by pH-multichannel intraluminal impedance (pH-MII) monitoring. In a randomized, double-blind, placebo-controlled trial, eligible premature neonates with clinical signs of GERD underwent 24-hour pH-MII monitoring. If >5 reflux events were identified on pH-MII, then subjects were randomized to receive either EES or placebo. Repeat 24-hour pH-MII was performed on day 7 of study treatment and compared to initial pH-MII. Forty-three premature neonates were enrolled. Of those, 31 neonates were randomized, 15 to EES and 16 to placebo with a median (IQR) pretreatment total reflux events per 24 hours of 23 (16-40) and 29 (12-40), respectively. Day 7 total events per 24 hours decreased by 4 events in the EES group to 19 (15-33) and by 10 events in the placebo group to 19 (11-26) (P = 0.09). There were no differences in pretreatment and day 7 acidic and nonacidic reflux, proximal reflux, total or percent reflux time, median or longest bolus clearance time, or nurse-reported apnea events between groups. Enteral EES did not decrease reflux events on 24-hour pH-MII at the dose studied. Therefore, it may be ineffective in the treatment of GERD in premature neonates.

Winter counter-wind current in western Taiwan Strait: characteristics and mechanisms

A new dataset based on in-situ observations and a numerical model are employed to reveal the spatio-temporal variation and driving mechanism of counter-wind current (CWC) in the western Taiwan Strait (TWS) during the winter monsoon. Our results confirm the existence of the CWC in the western TWS during the months of strong northeasterly wind, which is well supported by a rarely observed through-flow pattern recorded by a Lagrangian drifter, during which the average wind speed was 11 m/s. Moreover, both the synchronous ADCP observations and model results demonstrate that the CWC acted as an episodic local event when the winter monsoon went into transient relaxation. By examining the model results, the momentum budget and the time-dependent dynamics, we further revealed that the wind relaxation mechanism is crucial in explaining the existence of the CWC, which acted as a short-lived local event in the form of a return current that lied in the downstream of a significant along-strait sea-level set-up in the northern Taiwan Bank when the prevailing strong wind experienced a short transient relaxation. Last but not least, the large-scale pressure gradient related to the open-ocean forcing was found to play a predominant role in driving a stable CWC in the frame of geostrophy when the winter-monsoon wind gradually relaxed.

Saxagliptin but Not Sitagliptin Inhibits CaMKII and PKC via DPP9 Inhibition in Cardiomyocytes.

Some oral anti-hyperglycemic drugs, including gliptins that inhibit dipeptidyl peptidase 4 (DPP4), have been linked to the increased risk of heart failure (HF) in type-2 diabetic patients. While the cardiovascular safety trial, TECOS, revealed no link between sitagliptin and the risk of HF, a substantial 27% increase in the hospitalization for HF was observed in type-2 diabetic patients treated with saxagliptin within the SAVOR-TIMI 53 trial. A previous in vitro study revealed that saxagliptin impairs the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-phospholamban (PLB)-sarcoplasmic reticulum Ca2+-ATPase 2a axis and protein kinase C (PKC) activity in cardiomyocytes leading to impaired cardiac contractility and electrophysiological function. However, the link between saxagliptin and its target proteins (CaMKII and PKC) remains to be explored. Since DPP8 and DPP9 (but not DPP4) are expressed by cardiomyocytes and saxagliptin is internalized by cardiomyocytes, we investigated whether DPP8/9 contribute to saxagliptin-mediated inhibition of CaMKII and PKC activity. Structural analysis revealed that the DPP4-saxagliptin interaction motif (S630, Y547) for the cyanopyrrolidine group is conserved in DPP8 (S755, Y669) and DPP9 (S730, Y644). Conversely, F357 that facilitates binding of the anchor lock domain of sitagliptin in the S2 extensive subsite of DPP4 is not conserved in DPP8/9. In parallel, unlike saxagliptin, sitagliptin did not affect phosphorylation of CaMKII/PLB or activity of PKC in HL-1 cardiomyocytes. These findings were recapitulated by pharmacological inhibition (TC-E-5007, a DPP8/9 antagonist) and knock-down of DPP9 (but not DPP8). In primary mouse ventricular cardiomyocytes, saxagliptin (but not sitagliptin) impaired Ca2+ transient relaxation and prolonged action potential duration (APD). These results suggest that saxagliptin-DPP9 interaction impairs the CaMKII-PLB and PKC signaling in cardiomyocytes. We reveal a novel and potential role of DPP9 in cardiac signaling. The interaction of saxagliptin with DPP9 may represent an underlying mechanism for the link between saxagliptin and HF. Elucidation of saxagliptin-DPP9 interaction and downstream events may foster a better understanding of the role of gliptins as modulators of cardiac signaling.

Phonon branch-resolved electron-phonon coupling and the multitemperature model

Electron-phonon $(e\text{\ensuremath{-}}p)$ interaction and transport are important for laser-matter interactions, hot-electron relaxation, and metal-nonmetal interfacial thermal transport. A widely used approach is the two-temperature model (TTM), where $e\text{\ensuremath{-}}p$ coupling is treated with a gray approach with a lumped coupling factor ${G}_{ep}$ and the assumption that all phonons are in local thermal equilibrium. However, in many applications, different phonon branches can be driven into strong nonequilibrium due to selective $e\text{\ensuremath{-}}p$ coupling, and a TTM analysis can lead to misleading or wrong results. Here, we extend the original TTM into a general multitemperature model (MTM), by using phonon branch-resolved $e\text{\ensuremath{-}}p$ coupling factors and assigning a separate temperature for each phonon branch. The steady-state thermal transport and transient hot electron relaxation processes in constant and pulse laser-irradiated single-layer graphene (SLG) are investigated using our MTM respectively. Results show that different phonon branches are in strong nonequilibrium, with the largest temperature rise being more than six times larger than the smallest one. A comparison with TTM reveals that under steady state, MTM predicts 50% and 80% higher temperature rises for electrons and phonons respectively, due to the ``hot phonon bottleneck'' effect. Further analysis shows that MTM will increase the predicted thermal conductivity of SLG by 67% and its hot electron relaxation time by 60 times. We expect that our MTM will prove advantageous over TTM and gain use among experimentalists and engineers to predict or explain a wide ranges of processes involving laser-matter interactions.

ARE THE PERSISTENT SYMPTOMS TO PROTON PUMP INHIBITOR THERAPY DUE TO REFRACTORY GASTROESOPHAGEAL REFLUX DISEASE OR TO OTHER DISORDERS?

Gastroesophageal reflux disease (GERD) is a clinical condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Transient lower esophageal sphincter relaxation is the main pathophysiological mechanism of GERD. Symptoms and complications can be related to the reflux of gastric contents into the esophagus, oral cavity, larynx and/or the lung. Symptoms and other possible manifestations of GERD are heartburn, regurgitation, dysphagia, non-cardiac chest pain, chronic cough, chronic laryngitis, asthma and dental erosions. The proton pump inhibitor (PPI) is the first-choice drug and the most commonly medication used for the treatment of GERD. The most widespread definition of Refractory GERD is the clinical condition that presents symptoms with partial or absent response to twice-daily PPI therapy. Persistence of symptoms occurs in 25% to 42% of patients who use PPI once-daily and in 10% to 20% who use PPI twice-daily. The objective is to describe a review of the current literature, highlighting the causes, diagnostic aspects and therapeutic approach of the cases with suspected reflux symptoms and unresponsive to PPI. Initially, the management of PPI refractoriness consists in correcting low adherence to PPI therapy, adjusting the PPI dosage and emphasizing the recommendations on lifestyle modification change, avoiding food and activities that trigger symptoms. PPI decreases the number of episodes of acid reflux; however, the number of "non-acid" reflux increases and the patient continues to have reflux despite PPI. In this way, it is possible to greatly reduce greatly the occurrence of symptoms, especially those dependent on the acidity of the refluxed material. Response to PPI therapy can be evaluated through clinical, endoscopic, and reflux monitoring parameters. In the persistence of the symptoms and/or complications, other causes of Refractory GERD should be suspected. Then, diagnostic investigation must be initiated, which is supported by clinical parameters and complementary exams such as upper digestive endoscopy, esophageal manometry and ambulatory reflux monitoring (esophageal pH monitoring or esophageal impedance-pH monitoring). Causes of refractoriness to PPI therapy may be due to the true Refractory GERD, or even to other non-reflux diseases, which can generate symptoms similar to GERD. There are several causes contributing to PPI refractoriness, such as inappropriate use of the drug (lack of patient adherence to PPI therapy, inadequate dosage of PPI), residual acid reflux due to inadequate acid suppression, nocturnal acid escape, "non-acid" reflux, rapid metabolism of PPI, slow gastric emptying, and misdiagnosis of GERD. This is a common cause of failure of the clinical treatment and, in this case, the problem is not the treatment but the diagnosis. Causes of misdiagnosis of GERD are functional heartburn, achalasia, megaesophagus, eosinophilic esophagitis, other types of esophagitis, and other causes. The diagnosis and treatment are specific to each of these causes of refractoriness to clinical therapy with PPI.

The Hard Burn - Phosphodiesterase 5 Inhibitors (PDE5 Inhibitors): A Possible Cause/ Exacerbator of Gastro Esophageal Reflux Disease

Esophageal reflux is an asymptomatic physiological defense mechanism aimed to protect mucosal integrity by clearing the esophagus of secreted acid post prandially. Pathologic reflux, which can lead to gastroesophageal reflux disease (GERD), is symptomatic and triggered by decreased lower esophageal sphincter (LES) pressure, prolonged esophageal clearance, and by transient lower esophageal sphincter relaxation. Sildenafil is a drug commonly used in the treatment of erectile dysfunction, but has also been proven to decrease LES pressure. By blocking the action of type 5 phosphodiesterase (5PD), Sildenafil amplifies concentrations of 3’,5’-cyclic monophosphate (cGMP) and consequently increases nitric oxide (NO) induced smooth muscle relaxation in various organs, including the LES. As mentioned earlier, reduced LES pressure is a known risk factor for GERD and thus, it is theoretically possible that Sildenafil use can cause or exacerbate GERD as an adverse effect. We present 3 cases of patients with ED (erectile dysfunction) who had symptoms of reflux after the initiation of 5PD inhibitors. The first patient was a 23 year old male who had begun taking 5PD inhibitors who presented to the clinic with symptoms consistent with reflux, post prandial burning and water-brash for 12 hours post coitus. The second patient was a 37 year old male who after taking a dose of 100mg of Viagra noted to have burning eructation and a metallic tasting regurgitation in his mouth for 12 hours after coitus. He noted it was relieved by drinking milk or taking dairy products. He additionally noted that his symptoms of reflux were not present when he took 50mg of Viagra, but this dose did not achieve his goals for coitus. A 67 year old male who was taking tadalafil noted to have burning chest pain for 24 hours after ingestion of his medications and switched to sildenafil at a lower dose which seemed to help his reflux but also maintained his ability to complete coitus. In conclusion, it can be extrapolated from these cases that a relationship between type 5 phosphodiesterase inhibitors and reflux may exist. In addition there may be a dose dependent component as well as more impactful symptoms with long acting 5PD inhibitors. Though 3 cases is not enough to make a clear distinction, our institution plans to conduct a prospective survey of patients taking ED medications to further delineate if a true relationship exists.

Anisotropy Characteristics of Stress Relaxation in Coal: An Improved Fractional Derivative Constitutive Model

To study the anisotropy characteristics of coal during stress relaxation, a series of uniaxial compressive stress relaxation experiments are conducted on samples cut perpendicular and parallel to bedding. Some conclusions are as follows: (1) the stress of the specimens undergoes rapid relaxation, transient relaxation and steady relaxation, approximately represented with a negative exponential law, before reaching the final strain. The stress decreases discontinuously at the final strain. (2) Anisotropy is observable from stress relaxation tests. The failure strengths and elastic moduli of the bedding-perpendicular samples are generally greater than those of the bedding-parallel samples due to the hardening effect. At the same strain and before the final strain, the relaxation stress of the bedding-perpendicular samples is also greater than that of the bedding-parallel samples. At the final strain, for the bedding-parallel samples, the relaxation stress increases more evidently with higher initial stress relaxation rate, and the residual stress ratio decrease more remarkably. (3) An improved nonlinear fractional derivative generalized Kelvin model is proposed by replacing the Newton dashpot by the Abel dashpot, and the parameters in the model reflect the sample anisotropy well. This new model is used to fit the stress relaxation data, and the results show an improved accuracy in depicting the nonlinear stress relaxation characteristics of raw lean coal in relation to anisotropy over that of other models.

Synchronized mechanical oscillations at the cell–matrix interface in the formation of tensile tissue

The formation of uniaxial fibrous tissues with defined viscoelastic properties implies the existence of an orchestrated mechanical interaction between the cytoskeleton and the extracellular matrix. This study addresses the nature of this interaction. The hypothesis is that this mechanical interplay underpins the mechanical development of the tissue. In embryonic tendon tissue, an early event in the development of a mechanically robust tissue is the interaction of the pointed tips of extracellular collagen fibrils with the fibroblast plasma membrane to form stable interface structures (fibripositors). Here, we used a fibroblast-generated tissue that is structurally and mechanically matched to embryonic tendon to demonstrate homeostasis of cell-derived and external strain-derived tension over repeated cycles of strain and relaxation. A cell-derived oscillatory tension component is evident in this matrix construct. This oscillatory tension involves synchronization of individual cell forces across the construct and is induced in each strain cycle by transient relaxation and transient tensioning of the tissue. The cell-derived tension along with the oscillatory component is absent in the presence of blebbistatin, which disrupts actinomyosin force generation of the cell. The time period of this oscillation (60-90 s) is well-defined in each tissue sample and matches a primary viscoelastic relaxation time. We hypothesize that this mechanical oscillation of fibroblasts with plasma membrane anchored collagen fibrils is a key factor in mechanical sensing and feedback regulation in the formation of tensile tissues.

Optimizing the Use of Medications and Other Therapies in Infant Gastroesophageal Reflux.

Gastroesophageal reflux (GER) is the retrograde movement of gastric (and sometimes duodenal) contents into the esophagus. While the majority of GER is physiologic, for patients, it can be associated with symptoms. While some symptoms are merely bothersome (crying), others can be life threatening (cough, gagging, choking). The main driver of GER in infants is the frequent feedings that produce increased intra-abdominal pressure, which is known to trigger transient relaxations of the lower esophageal sphincter. The recent 2018 clinical practice guidelines reported by the North American and European Societies for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN/ESPGHAN) have recommended non-pharmacologic management initially with subsequent consideration of brief trials with acid suppressants. The main target for these acid suppressants is the gastric parietal cells. Our review of the literature has revealed a paucity of data regarding the use of histamine-2 receptor antagonists and proton pump inhibitors in infants. Despite the absence of well-controlled clinical studies, the prescription rate of these medications has increased internationally. Risks to patients of all ages have become increasingly recognized, with new associations being reported all too often. Here we report our review of all pharmacologic modalities as well as some non-surgical options.

Spatiotemporal Variation of Mantle Viscosity and the Presence of Cratonic Mantle Inferred From 8 Years of Postseismic Deformation Following the 2010 Maule, Chile, Earthquake

AbstractPostseismic displacements following great subduction earthquakes show significant long‐wavelength and time‐dependent patterns caused primarily by transient viscoelastic relaxation processes occurring broadly at depth. However, the Earth's viscosity structure and time‐dependent variations are still poorly understood, especially in the years immediately following a great earthquake. Here we investigate the spatiotemporal variation of mantle viscosity proximal and distal to the southern Andes using 8 years of continuous high‐resolution GPS observations following the 2010 Mw 8.8 Maule earthquake in south Central Chile. We remove the potential influences of relocking and afterslip on far‐field GPS displacements and estimate viscosities that can explain the 3‐D displacements. The optimal viscosity structure exhibits a low‐viscosity (~1018Pa s) mantle beneath the Andean volcanic arc and high‐viscosity (>1022Pa s) cratonic mantle, indicating a dependence of transient viscosity on temperature. Comparisons of the viscosity distributions at different times show that mantle viscosities increase with time throughout the study region. Viscosity increase is generally fastest in the mantle wedge beneath the Andes and slows down with increasing distance from the source region of the Maule earthquake. Such temporal viscosity evolution may indicate a stress dependence of the viscosity proximal to the rupture zone, while regions east of the Andes act as a relatively rigid body (i.e., cratonic mantle) with much higher viscosity. Our results thus suggest that both temperature structure and stress state contribute to spatiotemporal variations of the mantle viscosity. Heterogeneous spatiotemporal variations of viscosity seem to control the expansion and duration of the postseismic deformation and therefore the postseismic stress evolution.

Risk factors for gastroesophageal reflux disease and analysis of genetic contributors.

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder with an increasing prevalence. GERD develops when the reflux of stomach contents causes troublesome typical and atypical symptoms and/or complications. Several risk factors of GERD have been identified and evaluated over the years, including a considerable amount of genetic factors. Multiple mechanisms are involved in the pathogenesis of GERD including: (1) motor abnormalities, such as impaired lower esophageal sphincter (LES) resting tone, transient LES relaxations, impaired esophageal acid clearance and delayed gastric emptying; and (2) anatomical factors, such as hiatal hernia and obesity. Genetic contribution seems to play a major role in GERD and GERD- related disorders development such Barrett’s esophagus and esophageal adenocarcinoma. Twin and family studies have revealed an about 31% heritability of the disease. Numerous single-nucleotide polymorphisms in various genes like FOXF1, MHC, CCND1, anti-inflammatory cytokine and DNA repair genes have been strongly associated with increased GERD risk. GERD, Barrett’s esophagus and esophageal adenocarcinoma share several genetic loci. Despite GERD polygenic basis, specific genetic loci such as rs10419226 on chromosome 19, rs2687201 on chromosome 3, rs10852151 on chromosome 15 and rs520525 on the paired related homeobox 1 gene have been mentioned as potential risk factors. Further investigation on the risk genes may elucidate their exact function and role and demonstrate new therapeutic approaches to this increasingly common disease.

Information Geometry of Nonlinear Stochastic Systems.

We elucidate the effect of different deterministic nonlinear forces on geometric structure of stochastic processes by investigating the transient relaxation of initial PDFs of a stochastic variable x under forces proportional to () and different strength D of -correlated stochastic noise. We identify the three main stages consisting of nondiffusive evolution, quasi-linear Gaussian evolution and settling into stationary PDFs. The strength of stochastic noise is shown to play a crucial role in determining these timescales as well as the peak amplitude and width of PDFs. From time-evolution of PDFs, we compute the rate of information change for a given initial PDF and uniquely determine the information length as a function of time that represents the number of different statistical states that a system evolves through in time. We identify a robust geodesic (where the information changes at a constant rate) in the initial stage, and map out geometric structure of an attractor as , where is the position of an initial Gaussian PDF. The scaling exponent m increases with n, and also varies with D (although to a lesser extent). Our results highlight ubiquitous power-laws and multi-scalings of information geometry due to nonlinear interaction.

Gastroesophageal Reflux Disease in Obese Patients

Gastroesophageal reflux disease (GERD) and obesity coexist in many patients in the Western population. The association is not coincidental, since GERD pathophysiology is, in part, linked to obesity. Visceral adipose tissue secretes hormones, which increase the risk of GERD. Obesity increases esophageal motor disorders and higher number of transient lower esophageal sphincter relaxations. Central obesity increases abdominal-thoracic pressure gradient and disrupts the gastroesophageal junction by inducing hiatal hernia formation. Obese patients benefit from weight loss by diet to decrease GERD symptoms; however, Roux-en-Y gastric bypass surgery is associated with a higher weight loss and a decrease in GERD symptoms, and is considered the best way to treat both diseases at the same time.

Intra-bolus pressure and esophagogastric gradient, assessed with high-resolution manometry, are associated with acid exposure and proximal migration of refluxate.

Trans-sphincteric pressure gradient (TSPG) seems to play a relevant role in eliciting refluxes during transient lower esophageal sphincter relaxations (TLESRs). Intra-bolus pressure (IBP) is considered to be correlated to esophageal wall tone. We aimed to evaluate the relationship between IBP, TSPG during TLESRs and the dynamic properties of refluxate in gastroesophageal reflux disease. Sixteen non-erosive reflux disease (NERD), 10 erosive disease (ERD) patients and 12 healthy volunteers (HVs), underwent 24-hour impedance-pH monitoring and combined high-resolution manometry-impedance before and 60 minutes. After a meal, ERD patients presented a significantly lower mean IBP (4.7 ± 1.6 mmHg) respect to NERD patients (8.9 ± 2.8 mmHg) and HVs (9.2 ± 3.2 mmHg). NERD patients with physiological abnormal acid exposure time showed a mean IBP (10.4 ± 3.1 mmHg) significantly higher than that in NERD with pathological abnormal acid exposure time (5.1 ± 1.5 mmHg). The TSPG value was significantly higher during TLESRs accompanied by reflux than during TLESRs not associated with reflux, both in patients and in HVs. A significant direct correlation was found between IBP, TSPG and proximal spread of refluxes in patients and in HVs. Gastroesophageal reflux disease patients display different degrees of esophageal distension. An increased compliance of the distal esophagus may accommodate larger volumes of refluxate and likely facilitates the injuries development. Higher TSPG values appear to facilitate the occurrence of refluxes during TLESRs. In patients with NERD, higher TSPG and IBP values favor proximal spread of refluxate and hence may play a relevant role in symptom generation.

Enhancement of bradykinin-induced relaxation by focal brain ischemia in the rat middle cerebral artery: Receptor expression upregulation and activation of multiple pathways.

Focal brain ischemia markedly affects cerebrovascular reactivity. So far, these changes have mainly been related to alterations in the level of smooth muscle cell function while alterations of the endothelial lining have not yet been studied in detail. We have, therefore, investigated the effects of ischemia/reperfusion injury on bradykinin (BK)-induced relaxation since BK is an important mediator of tissue inflammation and affects vascular function in an endothelium-dependent manner. Focal brain ischemia was induced in rats by endovascular filament occlusion (2h) of the middle cerebral artery (MCA). After 22h reperfusion, both MCAs were harvested and the response to BK studied in organ bath experiments. Expression of the BK receptor subtypes 1 and 2 (B1, B2) was determined by real-time semi-quantitative RT-qPCR methodology, and whole mount immunofluorescence staining was performed to show the B2 receptor protein expression. In control animals, BK did not induce significant vasomotor effects despite a functionally intact endothelium and robust expression of B2 mRNA. After ischemia/reperfusion injury, BK induced a concentration-related sustained relaxation in all arteries studied, more pronounced in the ipsilateral than in the contralateral MCA. The B2 mRNA was significantly upregulated and the B1 mRNA displayed de novo expression, again more pronounced ipsi- than contralaterally. Endothelial cells displaying B2 receptor immunofluorescence were observed scattered or clustered in previously occluded MCAs. Relaxation to BK was mediated by B2 receptor activation, abolished after endothelium denudation, and largely diminished by blocking nitric oxide (NO) release or soluble guanylyl cyclase activity. Relaxation to BK was partially inhibited by charybdotoxin (ChTx), but not apamin or iberiotoxin suggesting activation of an endothelium-dependent hyperpolarization pathway. When the NO-cGMP pathway was blocked, BK induced a transient relaxation which was suppressed by ChTx. After ischemia/reperfusion injury BK elicits endothelium-dependent relaxation which was not detectable in control MCAs. This gain of function is mediated by B2 receptor activation and involves the release of NO and activation of an endothelium-dependent hyperpolarization. It goes along with increased B2 mRNA and protein expression, leaving the functional role of the de novo B1 receptor expression still open.

Cholecystokinin induces esophageal longitudinal muscle contraction and transient lower esophageal sphincter relaxation in healthy humans.

Cholecystokinin (CCK) is known to cause lower esophageal sphincter (LES) relaxation through the activation of inhibitory motor neurons. CCK receptor agonists increase the frequency of transient LES relaxation through a peripheral mechanism. Recent studies show that the longitudinal muscle contraction (LMC)-related axial stretch might play a role in the LES relaxation by activating the mechanosensitive inhibitory motor neurons. The aim of our study was to determine whether the CCK-induced LES relaxation and the characteristics of LMC resemble those seen with spontaneous transient LES relaxation in humans. Nine healthy volunteers (5 Fr, 40 ± 12 yr) received escalating doses of CCK-octapeptide (CCK-8) (5, 10, 20, and 40 ng/kg). All subjects demonstrated a monophasic response to 5 ng/kg of CCK-8. In the majority of subjects, this response consisted of partial LES relaxation. All subjects showed a biphasic response to 40 ng/kg of CCK-8. The latter in most subjects consisted of 1) a period of partial relaxation followed by 2) complete LES relaxation along with crural diaphragm inhibition. The length of the esophagus decreased by 0.9 ± 0.4 cm, and muscle thickness increased by 40 ± 14% to 1.4 ± 0.2 mm ( P < 0.05) during initial partial LES relaxation. During complete LES relaxation there was greater LMC, as demonstrated by an esophageal shortening of 1.9 ± 0.5 cm and an increase in muscle thickness of 100 ± 16% ( P < 0.01). The complete phase 2 LES relaxation typically terminated with a robust after-contraction. Atropine significantly attenuated the CCK-induced esophageal LMC, prevented crural diaphragm inhibition, and abolished the phase 2 complete LES relaxation. NEW & NOTEWORTHY The phenotypic features of CCK-induced longitudinal muscle contraction (LMC), complete lower esophageal sphincter (LES) relaxation, and crural diaphragm inhibition, followed by a robust after-contraction, resemble those seen during spontaneous transient LES relaxation. A strong temporal relationship between the LMC and complete transient LES relaxation supports our hypothesis that the LMC plays an important role in the LES relaxation and crural diaphragmatic inhibition.

Transmission of a detonation across a density interface

The present study investigates the transmission of a detonation wave across a density interface. The problem is first studied theoretically considering an incident Chapman–Jouguet (CJ) detonation wave, neglecting its detailed reaction-zone structure. It is found that, if there is a density decrease at the interface, a transmitted strong detonation wave and a reflected expansion wave would be formed; if there is a density increase, one would obtain a transmitted CJ detonation wave followed by an expansion wave and a reflected shock wave. Numerical simulations are then performed considering that the incident detonation has the Zel’dovich–von Neumann–Doring reaction-zone structure. The transient process that occurs subsequently to the detonation-interface interaction has been captured by the simulations. The effects of the magnitude of density change across the interface and different reaction kinetics (i.e., single-step Arrhenius kinetics vs. two-step induction–reaction kinetics) on the dynamics of the transmission process are explored. After the transient relaxation process, the transmitted wave reaches the final state in the new medium. For the cases with two-step induction–reaction kinetics, the transmitted wave fails to evolve to a steady detonation wave if the magnitude of density increase is greater than a critical value. For the cases wherein the transmitted wave can evolve to a steady detonation, the numerical results for both reaction models give final propagation states that agree with the theoretical solutions.

Implementation of higher-order vertical finite elements in ISSM v4.13 for improved ice sheet flow modeling over paleoclimate timescales

Abstract. Paleoclimate proxies are being used in conjunction with ice sheet modeling experiments to determine how the Greenland ice sheet responded to past changes, particularly during the last deglaciation. Although these comparisons have been a critical component in our understanding of the Greenland ice sheet sensitivity to past warming, they often rely on modeling experiments that favor minimizing computational expense over increased model physics. Over Paleoclimate timescales, simulating the thermal structure of the ice sheet has large implications on the modeled ice viscosity, which can feedback onto the basal sliding and ice flow. To accurately capture the thermal field, models often require a high number of vertical layers. This is not the case for the stress balance computation, however, where a high vertical resolution is not necessary. Consequently, since stress balance and thermal equations are generally performed on the same mesh, more time is spent on the stress balance computation than is otherwise necessary. For these reasons, running a higher-order ice sheet model (e.g., Blatter-Pattyn) over timescales equivalent to the paleoclimate record has not been possible without incurring a large computational expense. To mitigate this issue, we propose a method that can be implemented within ice sheet models, whereby the vertical interpolation along the z axis relies on higher-order polynomials, rather than the traditional linear interpolation. This method is tested within the Ice Sheet System Model (ISSM) using quadratic and cubic finite elements for the vertical interpolation on an idealized case and a realistic Greenland configuration. A transient experiment for the ice thickness evolution of a single-dome ice sheet demonstrates improved accuracy using the higher-order vertical interpolation compared to models using the linear vertical interpolation, despite having fewer degrees of freedom. This method is also shown to improve a model's ability to capture sharp thermal gradients in an ice sheet particularly close to the bed, when compared to models using a linear vertical interpolation. This is corroborated in a thermal steady-state simulation of the Greenland ice sheet using a higher-order model. In general, we find that using a higher-order vertical interpolation decreases the need for a high number of vertical layers, while dramatically reducing model runtime for transient simulations. Results indicate that when using a higher-order vertical interpolation, runtimes for a transient ice sheet relaxation are upwards of 5 to 7 times faster than using a model which has a linear vertical interpolation, and this thus requires a higher number of vertical layers to achieve a similar result in simulated ice volume, basal temperature, and ice divide thickness. The findings suggest that this method will allow higher-order models to be used in studies investigating ice sheet behavior over paleoclimate timescales at a fraction of the computational cost than would otherwise be needed for a model using a linear vertical interpolation.