Paradoxical Response Research Articles

Radiation Induced Lung Injury (RILI) and COVID-19 Pneumonia: Are There Similarities by The Radiation Oncologist’s Point of View?

Coronavirus disease 2019 (COVID-19), is a novel infectious disease responsible for a severe acute respiratory syndrome due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, which was firstly reported in January 2020 in Wuhan, Hubei Province, China, and then rapidly spread to other countries beyond China with a pandemic proportion in these last two years. In its severe lung expression, disease onset may result in death due to massive alveolar damage and progressive respiratory failure due to acute lung injury (ALI) which predisposes to fatal acute respiratory distress syndrome (ARDS). Autopsies reports describe a diffuse alveolar damage with vascular congestion, inflammatory cell population entrapped, thrombosis with hyaline membrane formation in the alveolar walls allowing to an irreversible lung destruction. Altogether these findings remind the radiation oncologists many similarities with radiation induced lung injury which is a well-known side effect of radiotherapy for lung cancer. A fascinating hypothesis is that a common inflammatory paradoxical response of lung could be underlying the injury whatever the causes may be, virus, drugs or ionizing radiation. In this paper we will review the similarities between these two illnesses just going through the mechanisms of ALI-ARDS and the role of the most important immune cells and cytokines involved.

Analgesia and Sedation in Critically Ill Patients With Burns.

Analgesia and Sedation in Critically Ill Patients With Burns.

Intercostal muscle oxygenation and expiratory loaded breathing at rest: Respiratory pattern effect

In patients with airway obstruction, an increase in breathing frequency at rest is commonly associated with a dynamic hyperinflation (DH). In such a situation, intercostal muscle oxygenation may be disturbed. This hypothesis was examined in a context of simulated airway obstruction in healthy subjects.After a control period of 5 min, twelve participants (20 ± 2 years) breathed at rest through a 20-cmH2O expiratory threshold load, either by increasing or reducing their respiratory rate (ETLF+ or ETLF). Tissue saturation index (TSI) and concentration changes in oxyhaemoglobin (oxy[Hb+Mb]) were measured as well as cardiorespiratory variables.Inspiratory capacity was decreased in ETLF+ (p < 0.001) and correlated with dyspnea. An increase in oxy[Hb+Mb] occurred in ETLF+ that was higher than in ETLF (p < 0.01). TSI was not different between conditions.In healthy subjects at rest, an increase in respiratory rate during a simulated obstruction with an expiratory threshold load resulted in paradoxical response with DH emergence while intercostal muscle oxygenation was preserved.

Ambivalence toward bureaucracy: responses from Korean school principals

PurposeGiven the context of accountability-driven policy environments, research has shown that school leaders perceive bureaucratic rules and protocols in negative ways, but they also utilize organizational structures and routines to lead changes. To better understand both enabling and hindering mechanisms of bureaucracy in schools, this study explores how Korean school principals understand and perceive bureaucratic structures using a lens of ambivalence. The authors draw on Weber's theory of bureaucracy, with a particular focus on the paradoxical aspect of bureaucracy that might be experienced by individuals within the system.Design/methodology/approachThis study analyzed qualitative data collected from 26 in-depth interviews with 10 Korean school principals between 2013 and 2015. The authors used the multiple cycles of coding to explore patterns and themes that emerged from the participants' responses.FindingsThe analysis of this study showed that the participants' ambivalent responses toward bureaucracy were particularly salient in three areas where formal organizational structures were changing through policy initiatives: teacher evaluation, electronic approval system and school-based management promoting decentralized decision making. The study participants reflected on how such changes can enable and/or hinder schools to achieve organizational goals and collective values, from the viewpoints of multiple aspects, which led to their ambivalent responses to bureacratic structures in school settings.Originality/valueThis study contributes to the understanding of school organizations by revisiting Weber's theory of bureaucracy in school settings. Using the lens of ambivalence enabled us to reconcile school principals' contradictory perceptions toward bureaucracy, which complicates analyses of tensions and paradoxical responses found in leadership practices within school systems.

Paradoxical immune response in leishmaniasis: The role of toll-like receptors in disease progression.

Toll‐like receptors (TLRs), members of pattern recognition receptors, are expressed on many cells of the innate immune system, and their engagements with antigens regulate specific immune responses. TLRs signalling influences species‐specific immune responses during Leishmania infection; thus, TLRs play a decisive role towards elimination or exacerbation of Leishmania infection. To date, there is no single therapeutic or prophylactic approach that is fully effective against leishmaniasis. An in‐depth understanding of the mechanisms by which Leishmania species evade, or exploit host immune machinery could lead to the development of novel therapeutic approaches for the prevention and management of leishmaniasis. In this review, the role of TLRs in the induction of a paradoxical immune response in leishmaniasis was discussed. This review focuses on highlighting the novel interplay of TLR2‐ /TLR9‐driven resistance or susceptibility to 5 clinically important Leishmania species in human. The activation of TLR2/TLR9 can induce diverse anti‐Leishmania activities depending on the species of infecting Leishmania parasite. Infection with L. infantum and L. mexicana initiates TLR2/9 activation leading to host protective immune response, while infection with L. major, L. donovani and L. amazonensis trigger either a TLR2‐ /9‐related protective or non‐protective immune responses. These findings suggest that TLR2 and TLR9 are targets worth pursuing either for modulation or blockage to trigger host protective immune response towards leishmaniasis.

Innate lymphoid cells and cancer.

The innate lymphoid cell (ILC) family is composed of natural killer (NK) cells, ILC1, ILC2 and ILC3, which participate in immune responses to virus, bacteria, parasites and transformed cells. ILC1, ILC2 and ILC3 subsets are mostly tissue-resident, and are profoundly imprinted by their organ of residence. They exhibit pleiotropic effects, driving seemingly paradoxical responses such as tissue repair and, alternatively, immunopathology toward allergens and promotion of tumorigenesis. Despite this, a trickle of studies now suggests that non-NK ILCs may not be overwhelmingly tumorigenic and could potentially be harnessed to drive anti-tumor responses. Here, we examine the pleiotropic behavior of ILCs in cancer and begin to unravel the gap in our knowledge that exposes a new horizon for thinking about modifying ILCs and targeting them for immunotherapy.

Electrocardiographic features of paradoxical ventriculophasic response

BackgroundParadoxical ventriculophasic response (P-VR), a rare entity, has not been fully investigated. This study sought to compare the electrocardiographic features of P-VR and typical ventriculophasic response (T-VR). MethodsThe 12‑lead electrocardiogram (ECG) data recorded before implantation of a cardiac implantable electronic device were analyzed in patients with greater than second-degree atrioventricular block (AVB). P-VR or T-VR was defined as present if the PP interval interposing a QRS complex was prolonged or shortened, respectively, by >3% compared with the preceding PP interval without a QRS complex when a QRS complex occurred within a span of 60% of the preceding PP interval. ResultsOf 95 patients (age 80 ± 9 years; 49 men) with heart block, 1868 instances (an instance was defined as a set of PP intervals without a QRS complex and the subsequent PP interval interposing a QRS complex) from 214 ECGs were analyzed: 894 instances from 122 ECGs in 64 patients with complete AVB (cAVB) and 974 instances from 92 ECGs in 43 patients with 2:1 AVB (12 showed both cAVB and 2:1 AVB). P-VR was observed in 48 patients (51%). The position of the interposed QRS complex relative to the preceding PP interval was earlier in P-VR than in T-VR. The PP interval was shorter in P-VR than in T-VR. ConclusionP-VR was present in >50% of patients and was affected by the position of the interposed QRS complex and the PP interval.

Advancing high-resolution manometry: evaluating the use of multiple rapid swallows versus apple viscous swallows in clinical practice.

High-Resolution Manometry (HRM) with provocative maneuvers, such as Multiple Rapid Swallows (MRS) and Apple Viscous Swallows (AVS), is commonly utilized to diagnose esophageal disorders. Increasing standardization in HRM protocol can help save time and reduce patient discomfort. This study assesses AVS and MRS to determine their respective benefits and limitations. Retrospective reviews were performed on 100 patients to analyze their AVS and/or MRS results. Parameters included abnormal motility patterns, tolerance, and DCI. Diagnostic benefits from MRS and AVS were assessed. Based on the previous studies, additional benefit from MRS was defined as detection of good peristaltic reserve, weak peristaltic reserve, or an abnormal motility/pressurization pattern. Additional benefit from AVS was defined as detection of IEM features or abnormal motility/pressurization pattern. When patients completed both MRS and AVS (n = 70), MRS provided additional benefit in assessing 36% of patients, while AVS provided additional benefit in 19% of patients (p < 0.0001). Furthermore, MRS detected significantly more abnormal motility/pressurization patterns than AVS (27% MRS; 8% AVS; p = 0.0005). Two unique strengths of AVS were higher tolerance for test completion (p = 0.009) and better detection of severe hypokinetic disorders in 4% of patients, which were missed by MRS. MRS may uniquely identify abnormal motility/pressurization patterns, such as paradoxical LES response, distal pressurization, hypercontractile, and spasm patterns. These findings argue for a tailored approach when selecting provocative testing. MRS may be more useful for patients with abnormal pathophysiology, while AVS may help to supplement MRS in detecting severe hypokinetic disorders in preoperative management.

Electromodulation of cellular innate immune response

Pulsed electric fields are widely used to permeabilize cell membranes in a variety of applications, from cancer therapy to food processing, although the mechanisms underlying this phenomenon are not yet fully understood. While for long-duration pulses (in the millisecond and microsecond range) the bioeffect of successive positive and negative cycles is additive, the electric field reversal of shorter nanosecond pulses was shown to reduce their efficiency. This paradoxical response has been called bipolar cancellation.

Flexibility-based stress-driven nonlocal frame element: formulation and applications

In the present work, a novel flexibility-based nonlocal frame element for size-dependent analyses of nano-sized frame-like structures is proposed. The material small-scale effect is consistently represented by the stress-driven nonlocal integral model and the element equation is constructed within the framework of flexibility-based finite element formulation. The merits of both stress-driven nonlocal integral model and flexibility-based finite element formulation render the proposed nonlocal frame element “consistent” and “exact”. Therefore, the “one-element-per-member” modeling approach is applicable. The modified Tonti’s diagram is utilized to show the overview of the element formulation and to summarize the formulation step. The element state determination process as well as the displacement recovery procedure are also discussed. Three numerical examples are employed to show accuracy, characteristics, and applications of the proposed nonlocal frame element. The first example shows the model capability to eliminate the “constant-force” paradoxical responses inherent to the Eringen’s nonlocal frame model and the simplified strain-gradient frame model; the second presents and characterizes the essence of the material small-scale effect on global and local responses of a propped-cantilever nanobeam; the third investigates the material small-scale effect on the tensile response of an auxetic metamaterial. All analysis results demonstrate that the material nonlocality associated with the stress-driven nonlocal integral model consistently yields a stiffer system response.

A Vasopressin-Induced Change in Prostaglandin Receptor Subtype Expression Explains the Differential Effect of PGE2 on AQP2 Expression.

Arginine vasopressin (AVP) stimulates the concentration of renal urine by increasing the principal cell expression of aquaporin-2 (AQP2) water channels. Prostaglandin E2 (PGE2) and prostaglandin2α (PGF2α) increase the water absorption of the principal cell without AVP, but PGE2 decreases it in the presence of AVP. The underlying mechanism of this paradoxical response was investigated here. Mouse cortical collecting duct (mkpCCDc14) cells mimic principal cells as they endogenously express AQP2 in response to AVP. PGE2 increased AQP2 abundance without desmopressin (dDAVP), while in the presence of dDAVP, PGE2, and PGF2α reduced AQP2 abundance. dDAVP increased the cellular PGD2 and PGE2 release and decreased the PGF2α release. MpkCCD cells expressed mRNAs for the receptors of PGE2 (EP1/EP4), PGF2 (FP), and TxB2 (TP). Incubation with dDAVP increased the expression of EP1 and FP but decreased the expression of EP4. In the absence of dDAVP, incubation of mpkCCD cells with an EP4, but not EP1/3, agonist increased AQP2 abundance, and the PGE2-induced increase in AQP2 was blocked with an EP4 antagonist. Moreover, in the presence of dDAVP, an EP1/3, but not EP4, agonist decreased the AQP2 abundance, and the addition of EP1 antagonists prevented the PGE2-mediated downregulation of AQP2. Our study shows that in mpkCCDc14 cells, reduced EP4 receptor and increased EP1/FP receptor expression by dDAVP explains the differential effects of PGE2 and PGF2α on AQP2 abundance with or without dDAVP. As the V2R and EP4 receptor, but not the EP1 and FP receptor, can couple to Gs and stimulate the cyclic adenosine monophosphate (cAMP) pathway, our data support a view that cells can desensitize themselves for receptors activating the same pathway and sensitize themselves for receptors of alternative pathways.

Eating disorder related research using Amazon Mechanical Turk (MTurk): Friend or foe?: Commentary on Burnette et al. (2021).

Burnette et al. reported a study that they sought to undertake to validate common eating disorder questionnaires in sexual and gender minorities. The researchers took advantage of the online recruitment platform Amazon Mechanical Turk (MTurk). Contrary to their expectations, the study proved not feasible due to invalid answering. Thus, Burnette et al. raise concerns against the trustworthiness of crowd-sourced data that may be undermined by financial interests and other kinds of motivations. Our commentary highlights the potential of the COVID-19 pandemic to inflate especially those intentions, which are monetary. Against the background of the COVID-19 pandemic, a further problem seems to be that the anonymity of online crowd sourcing platforms might tempt participants to provide inconsistent answers, possibly reflecting tendencies of reactance. The reported pattern of paradoxical responses in Burnette et al.'s work does not reflect malingering; rather we believe that the study might have served some participants as an outlet for negative emotions. We discuss mechanisms of quality control and highlight the lack of interpersonal interaction associated with online data collections.

Special issue introduction: what is the new state capitalism?

ABSTRACT This article introduces and lays the groundwork for this Contemporary Politics special issue on the ‘new’ state capitalism. We start by noting that the rubric state capitalism tends to elicit paradoxical responses, from uncritically embracing the term and overstretching its realms of application, to rejecting its validity altogether. We argue that the source of such ambivalence resides in issues of conceptual definition, which have led to a number of analytical impasses. We propose instead to construe state capitalism as a set of critical interrogations concerning the changing role of the state, thereby introducing a degree of plasticity in the use of the category. We call this the problématique of state capitalism. We subsequently identify three major themes that are explored in this dedicated issue, and that warrant further research in light of the COVID-19 pandemic, namely (1) its class underpinnings, (2) its global nature, and (3) its relational character.

Ratio-Dependence in Predator-Prey Systems as an Edge and Basic Minimal Model of Predator Interference

The functional response (trophic function or individual ration) quantifies the average amount of prey consumed per unit of time by a single predator. Since the seminal Lotka-Volterra model, it is a key element of the predation theory. Holling has enhanced the theory by classifying prey-dependent functional responses into three types that long remained a generally accepted basis of modeling predator-prey interactions. However, contradictions between the observed dynamics of natural ecosystems and the properties of predator-prey models with Holling-type trophic functions, such as the paradox of enrichment, the paradox of biological control, and the paradoxical enrichment response mediated by trophic cascades, required further improvement of the theory. This led to the idea of the inclusion of predator interference into the trophic function. Various functional responses depending on both prey and predator densities have been suggested and compared in their performance to fit observed data. At the end of the 1980s, Arditi and Ginzburg stimulated a lively debate having a strong impact on predation theory. They proposed the concept of a spectrum of predator-dependent trophic functions, with two opposite edges being the prey-dependent and the ratio-dependent cases, and they suggested revising the theory by using the ratio-dependent edge of the spectrum as a null model of predator interference. Ratio-dependence offers the simplest way of accounting for mutual interference in predator-prey models, resolving the abovementioned contradictions between theory and natural observations. Depending on the practical needs and the availability of observations, the more detailed models can be built on this theoretical basis.

Dorsal Push and Abdominal Binding Improve Respiratory Compliance and Driving Pressure in Proned Coronavirus Disease 2019 Acute Respiratory Distress Syndrome.

OBJECTIVES:We describe seven proned patients with coronavirus disease 2019-related acute respiratory distress syndrome in whom a paradoxical decrease in driving pressure reversibly occurred during passive, volume-controlled ventilation when compressing the lower back by a sustained “dorsal push.” We offer a potential explanation for these unexpected observations and suggest the possible importance of eliciting this response for lung-protective ventilation of similar patients.DESIGN/SETTING:Case series at a single teaching hospital affiliated with the University of Minnesota. Measurements were recorded from continuously monitored airway pressure and flow data.PATIENTS:Nonconsecutive and nonrandomized sample of coronavirus disease 2019 acute respiratory distress syndrome patients who were already prone and paralyzed for optimized lung protective clinical management while inhaling pure oxygen.INTERVENTIONS:Sustained, firm manual pressure applied over the lower back in all patients, followed by abdominal binding in a subset of these.MEASUREMENTS AND MAIN RESULTS:Respiratory system driving pressure declined and respiratory system compliance improved in seven patients with the dorsal push maneuver. In a subset of four of these, abdominal binding sustained those improvements over >3 hours.CONCLUSIONS:Sustained compressive force applied to the dorsum of the passive and prone patient with severe respiratory failure due to coronavirus disease pneumonia may elicit a paradoxical response characterized by improved compliance and for a given tidal volume, lower plateau, and driving pressures. Such findings, which suggest end-tidal overinflation within the aerated part of the diseased lung despite the already compressed anterior chest wall of prone positioning, complement and extend those observations recently described for the supine position in coronavirus disease 2019 acute respiratory distress syndrome.

Abstract 14580: Methodological Challenges Conducting In Vitro Ischemia and Reperfusion: A Fundamental Problem in Cell Viability Determination

Background: Oxygen &amp; Glucose Deprivation (OGD) and Reperfusion (OGD-R) is considered one of the best models for studying ischemia and reperfusion injury (IRI) in vitro. Cell viability (CV) experimentation can aid in estimating cell survival after IRI insults and potential benefits from therapeutic attempts. However, the different metabolites used in various CV assays may compromise the usefulness and validity of various CV tools. We conducted two independent cell viability assays (WST-8 &amp; ATP) after OGD and OGD-R on neurons (NE) and astrocytes (AS). Methods: NE (HT-22) and AS (C8-D1A) were subjected to 6h OGD only and 6h OGD followed by 20h Reperfusion (OGD-R). OGD is based on the combination of chemical ischemia (standard culture media depleted of glucose and other energy sources) and severe hypoxia (O2 ~1.4 to 1.8%) for 6h, while 20h reperfusion consists of readdition of standard culture media and conditions (21% O2, 5% CO2, 37°C). CV was determined by WST-8 and ATP “CellTiter-Glo 2.0” assays. Results: By WST-8 assay, OGD decreased CV in NE (Fig. 1A, P value = 0.0121), but increased CV in AS (Fig. 1A, P value = 0.0079). OGD-R decreased CV in NE and AS (Fig. 2A, P value = 0.0010, 0.0146, respectively). By ATP assay, OGD decreased CV in NE (Fig. 1B, P value &lt;0.0001) and AS (Fig. 1C, P value &lt;0.0001). OGD-R also decreased CV in NE (Fig. 2B, P value &lt;0.0001) and AS (Fig. 2C, P value = 0.0001). Conclusions: The current data reveals opposite CV results after OGD in AS when comparing WST-8 and ATP assays; OGD caused CV decrease in NE but increased in AS, which constitutes a paradoxical response based on previous literature. However, OGD-R caused similar injury patterns in NE and AS from WST-8 and ATP assays. It is unknown why OGD increased CV in AS through WST-8 after OGD, however, it can potentially occur due to AS hypermetabolism leading to increased NADPH+ production, which is the main substrate in this CV estimation. We conclude that CV should be carefully assessed with multiple, independent CV assays.

Paradoxical Stimulatory Response of Remanent Sphincter of Oddi to Buscapina After Endoscopic Sphincterotomy.

Background/AimsEndoscopic removal of bile duct stones has become the treatment of choice, which includes endoscopic sphincterotomy (EST) in the majority of cases, destroying at least partially the Oddi sphincter (OS). Loss of sphincter function in variable grade has been described, but changes in innervation are not known.MethodsEndoscopic manometry of OS was performed in 14 patients after EST with specialized perfused catheter. Pressure values were registered before and after 10 mg Buscapina injected intravenously.ResultsCholedocho-duodenal pressure gradient was absent in all of 14 patients. Basal OS pressure was zero in 7 and conserved in normal range in the remaining 7. Phasic motor activity was registered in 11 patients and was absent in 3 patients. After 10 mg Buscapina intravenous injection, instead of habitual inhibition, increase in basal OS pressure and in frequency of phasic contractions was observed in 9 patients. This response was not related to age of patients, neither with time elapsed between the EST and manometry, nor the estimated size of papillotomy orifice. Duodenal peristalsis was invariably inhibited in all patients.ConclusionsEST destroys not only the smooth muscle of OS, also alters the innervation interrupting the duodeno-sphincteric nerve circuit. This finding questions the use of Buscapina or other anticholinergic agent as spasmolytic in patients after EST.

MiR-19b-3p is associated with a diametric response to resistance exercise in older adults and regulates skeletal muscle anabolism via PTEN inhibition.

Understanding paradoxical responses to anabolic stimulation and identifying the mechanisms for this inconsistency in mobility-limited older adults may provide new targets for the treatment of sarcopenia. Our laboratory has discovered that dysregulation in microRNA (miRNA) that target anabolic pathways is a potential mechanism resulting in age-associated decreases in skeletal muscle mass and function (sarcopenia). The objective of the current study was to assess circulating miRNA expression profiles in diametric response of leg lean mass in mobility-limited older individuals after a 6-mo progressive resistance exercise training intervention (PRET) and determine the influence of differentially expressing miRNA on regulation of skeletal muscle mass. Participants were dichotomized by gain (Gainers; mean +561.4 g, n = 33) or loss (Losers; mean −589.8 g, n = 40) of leg lean mass after PRET. Gainers significantly increased fat-free mass 2.4% vs. −0.4% for Losers. Six miRNA (miR-1-3p, miR-19b-3p, miR-92a, miR-126, miR-133a-3p, and miR-133b) were significantly identified to be differentially expressed between Gainers and Losers, with miR-19b-3p being the miRNA most highly associated with increases in fat-free mass. Using an aging mouse model, we then assessed if miR-19b-3p expression was different in young mice with larger muscle mass compared with older mice. Circulating and skeletal muscle miR-19b-3p expression was higher in young compared with old mice and was positively associated with muscle mass and grip strength. We then used a novel integrative approach to determine if differences in circulating miR-19b-3p potentially translate to augmented anabolic response in human skeletal muscle cells in vitro. Results from this analysis identified that overexpression of miR-19b-3p targeted and downregulated PTEN by 64% to facilitate significant ∼50% increase in muscle protein synthetic rate as measured with SUnSET. The combine results of these three models identify miR-19b-3p as a potent regulator of muscle anabolism that may contribute to an inter-individual response to PRET in mobility-limited older adults.

Separating Fact from Fiction in the Diagnosis and Management of Food Allergy

Separating Fact from Fiction in the Diagnosis and Management of Food Allergy

Dual orexin receptor antagonists for insomnia in youth with neurodevelopmental disorders: a case series and review

Insomnia is a common, impairing, and difficult-to-treat comorbidity in children with neurodevelopmental disorders (NDDs). Behavioral interventions can be challenging because of developmental and behavioral features that interfere with treatment. Medication management also can be difficult due to a high burden of side effects, a high rate of paradoxical responses, and frequent treatment resistance. Therefore, new treatment options for insomnia in children with NDDs are needed. Dual orexin receptor antagonists (DORAs) are a relatively new class of pharmacotherapeutics that induce sleep by inhibiting the orexin signaling pathway. To date, there is little safety or efficacy data on the use of DORAs in children with NDDs. We present four patients with NDDs and insomnia that we treated with the DORA, suvorexant. We found that patients had a wide range of responses, with one patient displaying a robust improvement in sleep onset and maintenance, while another had significant improvement in insomnia symptoms on combination therapy with trazodone. Our final two patients had mild or no benefit from suvorexant therapy. Further research is necessary to establish the safety and efficacy of DORAs in this population and to identify predictive factors, such as specific neurogenetic diagnoses or clinical features, of a positive treatment response.