The interaction between general or abdominal obesity and hypertension on the risk of type 2 diabetes mellitus: a cross-sectional analysis in Iranian adults from the RaNCD cohort study.

BACKGROUND: Interactions between risk factors may influence disease severity. Knowing this relationship is important for preventive interventions and disease control. The purpose of this study was to determine the interactions effects of obesity and hypertension on the risk of type 2 diabetes mellitus (T2DM). METHODS: The data of 9,283 adults 35 to 65 years were examined from the cohort study of Ravansar Non-Communicable Disease (RaNCD). Waist circumference (WC) was used to identify both general and abdominal obesity based on body mass index (BMI). To assess the interaction between hypertension and obesity (general/abdominal) and the risk of T2DM, the additive interaction was calculated. RESULTS: The adjusted odds ratios for T2DM were 2.38 (1.67, 3.41) in men and 4.02 (2.47, 6.47) in women for the combinations of hypertension and abdominal obesity. The adjusted odds ratios for T2DM were 2.53 (1.63, 3.82) in men and 2.66 (1.92, 3.70) in women for the combinations of hypertension and general obesity. The results of the additive interaction indicators were inconsistent with gender. The relative excess risk due to interaction (interaction between hypertension and central obesity) (RERI), attributable proportion due to interaction (AP) and synergy index (SI) were0.27 (-1.01, 1.54), 0.11 (-0.41, 0.63) and 1.23 (0.41, 3.68) in male and were 0.61 (-1.12, 2.33), 0.23 (0.08, 0.37) and 1.26 (0.60, 2.61) in female, respectively. CONCLUSION: General/abdominal obesity and hypertension have a synergistic effect on the risk of T2DM. The recommendation for preventing T2DM is lifestyle modification. Large longitudinal studies are necessary to investigate causal relationships.

Antinociceptive Effects of an Anti-CGRP Antibody in Rat Models of Colon-Bladder Cross-Organ Sensitization.

Irritable bowel syndrome (IBS) and bladder pain syndrome/interstitial cystitis (BPS/IC) are comorbid visceral pain disorders seen commonly in women with unknown etiology and limited treatment options and can involve visceral organ cross-sensitization. Calcitonin gene-related peptide (CGRP) is a mediator of nociceptive processing and may serve as a target for therapy. In three rodent models, we employed a monoclonal anti-CGRP F(ab')2 to investigate the hypothesis that visceral organ cross-sensitization is mediated by abnormal CGRP signaling. Visceral organ cross-sensitization was induced in adult female rats via transurethral infusion of protamine sulfate (PS) into the urinary bladder or infusion into the colon of trinitrobenzene sulfonic acid (TNBS). Colonic sensitivity was assessed via the visceromotor response to colorectal distension (CRD). Bladder sensitivity was assessed as the frequency of abdominal withdrawal reflexes to von Frey filaments applied to the suprapubic region. PS- or TNBS-induced changes in colonic and bladder permeability were investigated in vitro via quantification of transepithelial electrical resistance (TEER). Peripheral administration of an anti-CGRP F(ab')2 inhibited PS-induced visceral pain behaviors and colon hyperpermeability. Similarly, TNBS-induced pain behaviors and colon and bladder hyperpermeability were attenuated by anti-CGRP F(ab')2 treatment. PS into the bladder or TNBS into the colon significantly increased the visceromotor response to CRD and abdominal withdrawal reflexes to suprapubic stimulation and decreased bladder and colon TEER. These findings suggest an important role of peripheral CGRP in visceral nociception and organ cross-sensitization and support the evaluation of CGRP as a therapeutic target for visceral pain in patients with IBS and/or BPS/IC. SIGNIFICANCE STATEMENT: A monoclonal antibody against calcitonin gene-related peptide (CGRP) was found to reduce concomitant colonic and bladder hypersensitivity and hyperpermeability. The results of this study suggest that CGRP-targeting antibodies, in addition to migraine prevention, may provide a novel treatment strategy for multiorgan abdominopelvic pain following injury or inflammation.

Effects of chemically EGFR targeting on non-targeted physical cell behaviors in 2D and 3D microfluidic cultures of invasive and non-invasive breast cancer cell lines.

Cancer development comprehends changes in cell structural and physical states. Cancer cells are softer than normal cells, produce higher contractile forces, and migrate more easily. While chemotherapy, targets proteins involved in biological behaviors, it may affect cell physicomechanical state due to the interconnections among signaling pathways. Here we treated non-invasive and invasive breast cancer cell lines by targeting EGRF which modulates major biological behaviors. We quantified migration potential of cancer cells in a microfluidic device, and evaluated expression of proteins associated with physical behaviors. Results indicated significant alterations in physical behaviors, with a higher impact on invasive cells. The anti-cancer synergy between biological and physical behaviors was shown by decreasing actin, vinculin, and myosin II content and altered distribution, limiting cell invasion in 3D collagen structure, accompanied by decreasing cell viability and vimentin expression as the EMT biomarker. The center point of changes in physical behaviors was in cytoskeletal remodeling by chemical treatment, potentially through lower contractile force generation and less development of focal adhesions and stress fibers. The synergy between physical and chemical pathways can be used in enhancing anti-cancer drug efficacy.

Healthy eating index 2015 and major dietary patterns in relation to incident hypertension; a prospective cohort study.

BACKGROUND: Since hypertension (HTN) is responsible for more than half of all deaths from cardiovascular disease, it is vital to understand the nutritional factors that reduce its risk. Little information, however, is known about it in the Kurdish population. This study was aimed to evaluate the healthy eating index (HEI) 2015 and major dietary patterns concerning incident HTN. METHODS: This case-cohort study was designed using Ravansar non-communicable diseases (RaNCD) cohort study data (294 participants with incident HTN and 1295 participants as representative random sub-cohort). HEI 2015 and major dietary patterns were extracted using data from their dietary intake, and three major dietary patterns were identified, including plant-based, high protein, and unhealthy dietary patterns. To analyses the association between HEI 2015 and major dietary patterns with incident HTN Cox proportional hazards regression models were applied. RESULTS: There was a significant positive correlation between HEI 2015 and plant-based diet (r = 0.492). The participants in the highest quartile of HEI-2015 had a 39% and 30% lower risk of incident HTN, compared to participants in the first quartile in both crude and adjusted model (HR: 0.61; 95% CI: 0.46-0.82) and (HR: 0.70; 95% CI: 0.51-0.97), respectively. Furthermore, participants with the highest tertile of the plant-based dietary pattern were at lower risk of incident HTN in both crude and adjusted models (HR: 0.69; 95% CI: 0.54-0.9) and (HR: 0.70; 95% CI: 0.53-0.94), respectively. However, the other two identified dietary patterns showed no significant association with incident HTN. CONCLUSIONS: We found evidence indicating higher adherence to HEI 2015 and plant- based diet had protective effects on incident HTN. The HEI 2015 emphasizes limited sodium intake and adequate intake of vegetables and fruits.

The Mutual Influence of the World Health Organization (WHO) and Twitter Users During COVID-19: Network Agenda-Setting Analysis.

BACKGROUND: Little is known about the role of the World Health Organization (WHO) in communicating with the public on social media during a global health emergency. More specifically, there is no study about the relationship between the agendas of the WHO and Twitter users during the COVID-19 pandemic. OBJECTIVE: This study utilizes the network agenda-setting model to investigate the mutual relationship between the agenda of the WHO's official Twitter account and the agenda of 7.5 million of its Twitter followers regarding COVID-19. METHODS: Content analysis was applied to 7090 tweets posted by the WHO on Twitter from January 1, 2020, to July 31, 2020, to identify the topics of tweets. The quadratic assignment procedure (QAP) was used to investigate the relationship between the WHO agenda network and the agenda network of the 6 Twitter user categories, including "health care professionals," "academics," "politicians," "print and electronic media," "legal professionals," and the "private sector." Additionally, 98 Granger causality statistical tests were performed to determine which topic in the WHO agenda had an effect on the corresponding topic in each Twitter user category and vice versa. RESULTS: Content analysis revealed 7 topics that reflect the WHO agenda related to the COVID-19 pandemic, including "prevention," "solidarity," "charity," "teamwork," "ill-effect," "surveillance," and "credibility." Results of the QAP showed significant and strong correlations between the WHO agenda network and the agenda network of each Twitter user category. These results provide evidence that WHO had an overall effect on different types of Twitter users on the identified topics. For instance, the Granger causality tests indicated that the WHO tweets influenced politicians and print and electronic media about "surveillance." The WHO tweets also influenced academics and the private sector about "credibility" and print and electronic media about "ill-effect." Additionally, Twitter users affected some topics in the WHO. For instance, WHO followers affected "charity" and "prevention" in the WHO. CONCLUSIONS: This paper extends theorizing on agenda setting by providing empirical evidence that agenda-setting effects vary by topic and types of Twitter users. Although prior studies showed that network agenda setting is a "one-way" model, the novel findings of this research confirm a "2-way" or "multiway" effect of agenda setting on social media due to the interactions between the content creators and audiences. The WHO can determine which topics should be promoted on social media during different phases of a pandemic and collaborate with other public health gatekeepers to collectively make them salient in the public.

Social Media Discussions on the FDA's Modified Risk Tobacco Product Authorization of IQOS.

Background: The U.S. Food and Drug Administration (FDA) authorized the marketing of the IQOS tobacco heating system as a modified risk tobacco product (MRTP) in July 2020, permitting its 'reduced exposure' marketing. This decision is accompanied by much controversy among the global health community. We provide a preliminary analysis of Twitter conversations regarding the MRTP authorization of IQOS by identifying the authors, valence towards the policy decision, source of cited link, and focused topic. Methods: We analyzed 548 tweets mentioning MRTP posted between July 2016 (when PMI submitted the proposal) and October 2020. Results: We found a higher proportion of pro-MRTP valence (25.4%) than anti-MRTP (16.2%). Nearly half of the tweets (47.2%) expressing personal opinions presented pro-MRTP valence (vs. anti-MRTP = 23.9%). The FDA website was more frequently cited in pro-MRTP tweets (30.8% vs. anti = 4.8%), while tobacco control advocates' websites were cited only in anti-MRTP tweets (77.4% vs. pro = 0). Pro-MRTP valence appeared more frequently in tweets mentioning health (53.1% vs. anti =38.5%) and cessation (100% vs. anti = 0). Nearly 42% of tweets showed a bot score greater than .43, indicating a possibility of automation. Conclusion: Continuous efforts are needed to surveil the industry's attempts to create a climate of false consensus and circulate misinformation regarding MRTP on social media, as well as to assist non-scientific audiences' understanding of MRTP.

Chemical inhibitor anticancer drugs regulate mechanical properties and cytoskeletal structure of non-invasive and invasive breast cancer cell lines: Study of effects of Letrozole, Exemestane, and Everolimus.

Regardless of their target and mechanism, anticancer drugs directly influence biological behavior of cancer cells by activating chemical signaling pathways. Due to the complex interaction between diverse signaling pathways, these drugs may profoundly impact the physical characteristics of cancer cells and regulate their mechanical properties. In this study, the effects of two Aromatase Inhibitor (Letrozole and Exemestane), and one mTOR Inhibitor (Everolimus) on cell mechanical properties, actin content/distribution, and nuclear areas of two invasive and non-invasive breast cancer cell line after 24 h treatment with concentrations previously reported were investigated. While metabolic activity of cell lines was highly affected by drug treatment, significant alterations in Young's modulus of cell bodies, nuclear areas, and actin content and distribution were reported with higher impact on invasive cells. It was concluded that regulation of mechanical behavior of cells by all three drugs emphasizes the cross talk between chemical and physical signaling cascades, and describes a correlation between biological and physical behaviors of cancer cells which might give an insight to a better understanding of mechanisms by which anti-cancer drugs function to enhance their performances.

A Monoclonal Anti-Calcitonin Gene-Related Peptide Antibody Decreases Stress-Induced Colonic Hypersensitivity.

Irritable bowel syndrome (IBS) is a brain-gut disorder characterized by abdominal pain and altered bowel habits. Although the etiology of IBS remains unclear, stress in adulthood or in early life has been shown to be a significant factor in the development of IBS symptomatology. Evidence suggests that aberrant calcitonin gene-related peptide (CGRP) signaling may be involved in afferent sensitization and visceral organ hypersensitivity. Here, we used a monoclonal anti-CGRP divalent antigen-binding fragment [F(ab')2] antibody to test the hypothesis that inhibition of peripheral CGRP signaling reverses colonic hypersensitivity induced by either chronic adult stress or early life stress. A cohort of adult male rats was exposed to repeated water avoidance stress. Additionally, a second cohort consisting of female rats was exposed to a female-specific neonatal odor-attachment learning paradigm of unpredictable early life stress. Colonic sensitivity was then assessed in adult animals via behavioral responses to colorectal distension (CRD). To analyze spinal nociceptive signaling in response to CRD, dorsal horn extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was measured via immunohistochemistry. Repeated psychologic stress in adulthood or unpredictable stress in early life induced colonic hypersensitivity and enhanced evoked ERK1/2 phosphorylation in the spinal cord after CRD in rats. These phenotypes were reversed by administration of a monoclonal anti-CGRP F(ab')2 fragment antibody. Stress-induced changes in visceral sensitivity and spinal nociceptive signaling were reversed by inhibition of peripheral CGRP signaling, which suggests a prominent role for CGRP in central sensitization and the development of stress-induced visceral hypersensitivity. SIGNIFICANCE STATEMENT: Targeting peripheral calcitonin gene-related peptide (CGRP) with a monoclonal anti-CGRP divalent antigen-binding fragment antibody reduced central sensitization and attenuated colonic hypersensitivity induced by either chronic adult stress or early life stress. CGRP-targeting antibodies are approved for migraine prevention, and the results of this study suggest that targeting CGRP may provide a novel treatment strategy for irritable bowel syndrome-related, stress-induced visceral pain.

Framing of and Attention to COVID-19 on Twitter: Thematic Analysis of Hashtags.

BACKGROUND: Although past research has focused on COVID-19-related frames in the news media, such research may not accurately capture and represent the perspectives of people from diverse backgrounds. Additionally, research on the public attention to COVID-19 as reflected through frames on social media is scarce. OBJECTIVE: This study identified the frames about the COVID-19 pandemic in the public discourse on Twitter, which voices diverse opinions. This study also investigated the amount of public attention to those frames on Twitter. METHODS: We collected 22 trending hashtags related to COVID-19 in the United States and 694,582 tweets written in English containing these hashtags in March 2020 and analyzed them via thematic analysis. Public attention to these frames was measured by evaluating the amount of public engagement with frames and public adoption of those frames. RESULTS: We identified 9 frames including "public health guidelines," "quarantine life," "solidarity," "evidence and facts," "call for action," "politics," "post-pandemic life," "shortage panic," and "conflict." Results showed that some frames such as "call for action" are more appealing than others during a global pandemic, receiving greater public adoption and engagement. The "call for action" frame had the highest engagement score, followed by "conflict" and "evidence and facts." Additionally, "post-pandemic life" had the highest adoption score, followed by "call for action" and "shortage panic." The findings indicated that the frequency of a frame on social media does not necessarily mean greater public adoption of or engagement with the frame. CONCLUSIONS: This study contributes to framing theory and research by demonstrating how trending hashtags can be used as new user-generated data to identify frames on social media. This study concludes that the identified frames such as "quarantine life" and "conflict" and themes such as "isolation" and "toilet paper panic" represent the consequences of the COVID-19 pandemic. The consequences could be (1) exclusively related to COVID-19, such as hand hygiene or isolation; (2) related to any health crisis such as social support of vulnerable groups; and (3) generic that are irrespective of COVID-19, such as homeschooling or remote working.

The effect of VDR gene polymorphisms and vitamin D level on blood pressure, risk of preeclampsia, gestational age, and body mass index.

We investigated the influence of vitamin D receptor (VDR) polymorphisms and vitamin D level on the blood pressure and the risk of preeclampsia. In a case-control study, 200 pregnant women, including 100 individuals with preeclampsia along with 100 healthy pregnant women, were studied for VDR FokI, TaqI, and BmsI polymorphisms and serum 25 (OH)-D level using polymerase chain reaction-restriction fragment length polymorphism method and commercial kit, respectively. The mean level of 25 (OH)-D in preeclamptic patients was significantly lower (16.6 ± 4.2 ng/mL, P < 0.001) compared with controls (19.6 ± 3.8 ng/mL). Among all women, a significantly higher systolic blood pressure and before-pregnancy body mass index and also lower gestational age were observed in the presence of 25 (OH)-D level < 20 ng/mL compared with the 20 to 30 ng/mL. A significantly higher frequency of VDR FokI C allele in preeclamptic patients (83%) than controls (74%) was associated with a 1.72-fold increased risk of preeclampsia. In all the studied individuals, the systolic and diastolic blood pressures were significantly higher in the presence of the FokI CC genotype compared with the TC and TT+TC genotypes. Neither VDR Taq1 nor VDR BmsI was associated with the risk of preeclampsia. The haplotype FokI C, TaqI C and BmsI A (CCA) compared with haplotype CTG increased the risk of preeclampsia by 1.4-fold (P = 0.33). Our study suggests an association between VDR FokI polymorphism and an insufficient serum level of 25 (OH)-D with the risk of preeclampsia and also the influence of insufficient 25 (OH)-D level and VDR FokI polymorphism on maternal factors, including blood pressure.

A Comparison of the Central versus Peripheral Gastrointestinal Prokinetic Activity of Two Novel Ghrelin Mimetics.

The gastrointestinal (GI) prokinetic effects of ghrelin occur through direct peripheral effects on ghrelin receptors within the enteric nervous system and via the ghrelin receptor on the vagus nerve, which activate a centrally mediated mechanism. However, the relative contribution of peripheral versus central effects to the overall prokinetic effect of ghrelin agonists requires further investigation. Here, we investigated the central versus peripheral prokinetic effect of ghrelin by using two novel ghrelin agonists: HM01 (N'-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-N-methyl-N-[1,3,3-trimethyl-(4R)-piperidyl]-urea HCL) with high brain penetration compared with HM02 (N'-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-N-hydroxy-N-(1-methyl-4-piperidinyl)-urea), a more peripherally acting ghrelin agonist. The pharmacokinetic profiles of both ghrelin agonists were evaluated after intravenous and oral administration in rats. The efficacy of HM01 and HM02 was assessed in a rat model of postoperative ileus (POI) induced by abdominal surgery and in a rodent defecation assay. Pharmacokinetic results in our models confirmed that HM01, but not HM02, was a brain-penetrant ghrelin agonist. Administration of either HM01 or HM02 reversed the delayed upper and lower gastrointestinal transit induced by abdominal surgery to levels resembling the non-POI controls. In the defecation test, HM01, but not HM02, significantly increased the weight of fecal pellets. Our findings suggest that, in a rodent model of POI, synthetic ghrelin agonists stimulate GI transit through a peripheral site of action. However, in the defecation assay, our data suggest that a ghrelin-mediated mechanism is located at a central site. Taken together, a ghrelin agonist with both central and peripheral prokinetic activity may show therapeutic potential to treat delayed GI transit disorders.

Exploring the Potential of RET Kinase Inhibition for Irritable Bowel Syndrome: A Preclinical Investigation in Rodent Models of Colonic Hypersensitivity.

Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal inflammation or psychologic stress is frequently associated with the development of symptoms. Inflammation or stress-induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here, we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor, rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae. In RET-cyan fluorescent protein [(CFP) RetCFP/+] mice, thoracic and lumbosacral dorsal root ganglia were shown to express RET, which colocalized with calcitonin gene-related peptide. To understand the role of RET in visceral nociception, we employed GSK3179106 as a potent, selective, and gut-restricted RET kinase inhibitor. Colonic hyperalgesia, quantified as exaggerated visceromotor response to graded pressures (0-60 mm Hg) of isobaric colorectal distension (CRD), was produced in multiple rat models induced 1) by colonic irritation, 2) following acute colonic inflammation, 3) by adulthood stress, and 4) by early life stress. In all the rat models, RET inhibition with GSK3179106 attenuated the number of abdominal contractions induced by CRD. Our findings identify a role for RET in visceral nociception. Inhibition of RET kinase with a potent, selective, and gut-restricted small molecule may represent a novel therapeutic strategy for the treatment of IBS through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity.

Linaclotide Attenuates Visceral Organ Crosstalk: Role of Guanylate Cyclase-C Activation in Reversing Bladder-Colon Cross-Sensitization.

Bladder pain syndrome (BPS) is poorly understood; however, there is a female predominance and comorbidity with irritable bowel syndrome (IBS). Here we test the hypothesis that linaclotide, a guanylate cyclase-C (GC-C) agonist approved for the treatment of IBS with constipation (IBS-C), may represent a novel therapeutic for BPS acting through a mechanism involving an inhibition of visceral organ cross-sensitization. We showed previously that infusion of dilute protamine sulfate (PS) into the bladder increased sensitivity and permeability in the bladder and colon. PS was infused into the bladder of female rats; sensitivity was assessed via application of von Frey filaments applied to the suprapubic area and the frequency of withdrawal responses was recorded. Colonic sensitivity was measured via visceromotor behavioral response to graded pressures of colorectal distension (CRD). Permeability was measured in vitro via transepithelial electrical resistance (TEER) and conductance (G). Linaclotide (3 µg/kg, p.o.) or vehicle was administered daily for 7 days prior to experiments. Rats treated with PS bladder infusion exhibited visceral hyperalgesia, as shown by a significantly higher response frequency to individual von Frey filaments and increased behavioral responses to CRD. Linaclotide attenuated bladder and colonic hyperalgesia to control levels. PS infusion into the bladder increased bladder and colon permeability measured as a decrease in TEER and increased G. Linaclotide significantly inhibited PS-induced colonic hyperpermeability while having no effect on bladder hyperpermeability. Our findings suggest a novel treatment paradigm for GC-C agonism in IBS-C and BPS mediated through a mechanism involving visceral organ crosstalk.

Mechanisms of Visceral Organ Crosstalk: Importance of Alterations in Permeability in Rodent Models.

PURPOSE: The pathophysiology of painful bladder syndrome is poorly understood. However, there is evidence of female predominance and comorbidity with irritable bowel syndrome. Our hypothesis is that cross-sensitization between bladder and colon is due to altered permeability in 1 organ, which affects the other organ. MATERIALS AND METHODS: Experiments were performed in anesthetized, ovariectomized female rats. In separate groups protamine sulfate was infused in the bladder or trinitrobenzene sulfonic acid was infused in the colon. Untreated rats served as controls. Bladder and colonic tissue were harvested from all rats 1, 3 and 5 days after treatment. Permeability was assessed in vitro in Ussing chambers by measuring transepithelial electrical resistance and macromolecular flux of fluorescein isothiocyanate-dextran. RESULTS: Exposing the bladder to protamine sulfate induced a significant decrease in bladder transepithelial electrical resistance and an increase in the translocation of fluorescein isothiocyanate across the tissue compared to controls at 1 and 3 days (p <0.05). Colonic tissue from rats with enhanced bladder permeability showed a significant decrease in transepithelial electrical resistance and increase in fluorescein isothiocyanate compared to untreated controls at all time points (p <0.05). Conversely when colonic permeability was increased with trinitrobenzene sulfonic acid, we observed an increase in bladder permeability in the absence of any changes to the bladder urothelium. CONCLUSIONS: Changes in epithelial permeability may represent a novel mechanism for visceral organ crosstalk. It may explain the overlapping symptomology of painful bladder syndrome and irritable bowel syndrome.

Synergistic effect of 5-hydroxytryptamine 3 and neurokinin 1 receptor antagonism in rodent models of somatic and visceral pain.

Synergistic activity has been observed between serotonergic 5-hydroxytryptamine 3 (5-HT3) and tachykinergic neurokinin 1 (NK1) receptor-mediated responses. This study investigated the efficacy of a 5-HT3 antagonist, palonosetron, and a NK1 antagonist, netupitant, alone or in combination in rodent models of somatic and visceral colonic hypersensitivity. In a rat model of experimental neuropathic pain, somatic hypersensitivity was quantified by the number of ipsilateral paw withdrawals to a von Frey filament (6g). Electrophysiologic responses were recorded in the dorsal horn neurons after mechanical or thermal stimuli. Acute colonic hypersensitivity was induced experimentally in rats by infusing dilute acetic acid (0.6%) directly into the colon. Colonic sensitivity was assessed by a visceromotor behavioral response quantified as the number of abdominal contractions in response to graded isobaric pressures (0-60 mm Hg) of colorectal distension. Palonosetron or netupitant was administered alone or in combination via oral gavage. When dosed alone, both significantly reduced somatic sensitivity, decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation, and caused significant (P < 0.05) inhibition of colonic hypersensitivity in a dose-dependent manner. The combined administration of palonosetron and netupitant at doses that were ineffective alone significantly reduced both somatic and visceral sensitivity and decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation. In summary, the combination of palonosetron with a NK1 receptor antagonist showed synergistic analgesic activity in rodent models of somatic and visceral hypersensitivity, and may prove to be a useful therapeutic approach to treat pain associated with irritable bowel syndrome.

Experimental assessment of energy tower's performance: evaluation of the impacts of solar radiation, humidity, and chimney's height on the overall efficiency.

Solar energy is one of the most feasible options to produce energy in countries where unexploited desert areas or solar radiation are abundant. An energy tower is an effective system for electrical power generation that can perform more efficiently along with solar radiation. As the primary aim of the present study, effects of different environmental parameters on total efficacy of energy tower were investigated. In this study, the efficiency of the energy tower system is investigated experimentally by an indoor fully adjustable apparatus. In this regard, a comprehensive set of influencing parameters like air velocity, humidity, and temperature and the effects of tower height on the performance of the energy tower are individually assessed. It is demonstrated that there is a direct relationship between an increase in humidity percentage of the surrounding and performance of energy tower, meaning that a 274% increase in humidification rate led to 43% elevation in airflow velocity. The kinetic energy increases in the direction of airflow from top to bottom, and as the height of the tower lengthens, the kinetic energy enhances and subsequently increases the overall efficiency of the tower. An elevation about 2.7% in airflow velocity was seen due to an increase from 180 to 250 cm in chimney height. Although the energy tower performs efficiently in the nighttime, airflow velocity increases averagely about 8% during the daytime and at the peak of the solar radiation, the airflow velocity enhances by 58% compared to nighttime.

Assessment of Accuracy, User Engagement, and Themes of Eating Disorder Content in Social Media Short Videos.

Importance: Social media is simultaneously home to communities of users who promote eating disorders as a lifestyle and users who advocate for recovery. As studies have confirmed an association between exposure to pro-eating disorder content and engaging in disordered eating behaviors, an examination of the accuracy of and interactions with information shared in these complex and contradictory communities can provide insights into content available to users at risk. Objective: To determine the associations among themes, accuracy of information, and user engagement of eating disorder content on a short video-sharing social media platform. Design, Setting, and Participants: This qualitative study included a thematic analysis of a sample of 200 TikTok videos, as well as user engagement metrics and content creator characteristics, between February and June 2022. Data were analyzed from March to June 2022. Main Outcomes and Measures: Content themes, accuracy of information, user engagement, and the associations among these factors were identified in a sample of eating disorder videos on a social media platform. Data were analyzed with Pearson χ2, analysis of variance, linear regression, and random permutation tests. Results: Among the 200 videos assessed, 124 (62.0%) covered prorecovery content, 59 (29.5%) included pro-eating disorder content, and 17 (8.5%) contained anti-eating disorder content. Thematic analysis revealed 4 high-level themes: (1) encouraging the development or sustainment of eating disorders, (2) sharing physical or emotional experiences with eating disorders, (3) sharing narratives of recovery, and (4) social support. While the results of Pearson χ2 test indicated that videos in the prorecovery domain contained more accurate content than videos categorized in the pro-eating disorder and anti-eating disorder domains (χ24 = 157.92; P < .001), the results of analysis of variance demonstrated that there was no significant difference in user engagement between informative and misleading content (likes: F = 0.110; P = .95; comments: F = 2.031; P = .13; views: F = 0.534; P = .59; shares: F = 0.691; P = .50). Results of the 10 000 random permutation tests, in which all P values were between .40 and .60 regardless of the distances, suggested that there was no significant difference in user engagement among the 3 domains. Conclusions and Relevance: This mixed-methods qualitative analysis of misleading eating disorder information on social media found that pro-eating disorder and prorecovery communities were prevalent. However, social media users in the prorecovery community created more informative than misleading content. Furthermore, the study found no significant difference between users' engagement with accurate vs misleading videos, which may suggest that false information alone does not influence the virality of videos.

Analysis of EMT induction in a non-invasive breast cancer cell line by mesenchymal stem cell supernatant: Study of 2D and 3D microfluidic based aggregate formation and migration ability, and cytoskeleton remodeling.

AIMS: The process of Epithelial-to-mesenchymal transition (EMT) as a phenotypic invasive shift and the factors affecting it, are under extensive research. Application of supernatants of human adipose-derived mesenchymal stem cells (hADMSCs) on non-invasive cancer cells is a well known method of in vitro induction of EMT like process. While previous researches have focused on the effects of hADMSCs supernatant on the biochemical signaling pathways of the cells through expression of different proteins and genes, we investigated pro-carcinogic alterations of physico-mechanical cues in terms of changes in cell motility and aggregated formation in 3D microenvironments, and cytoskeletal actin-myosin content and fiber arrangement. MAIN METHODS: MCF-7 cancer cells were treated by the supernatant from 48 hour-starved hADMSCs, and their vimentin/E-cadherin expressions were evaluated. The invasive potential of treated and non-treated cells was measured and compared through aggregate formation and migration capability. Furthermore, alterations in cell and nucleus morphologies were studied, and F-actin and myosin-II alterations in terms of content and arrangement were investigated. KEY FINDINGS: Results indicated that application of hADMSCs supernatant enhanced vimentin expression as the biomarker of EMT, and induced pro-carcinogenic effects on non-invasive cancer cells through increased invasive potential by higher cell motility and reduced aggregate formation, rearrangement of actin structure and generation of more stress fibers, together with increased myosin II that lead to enhanced cell motility and traction force. SIGNIFICANCE: Our results indicated that in vitro induction of EMT through mesenchymal supernatant influenced biophysical features of cancer cells through cytoskeletal remodeling that emphasizes the interconnection of chemical and physical signaling pathways during cancer progress and invasion. Results give a better insight to EMT as a biological process and the synergy between biochemical and biophysical parameters that contribute to this process, and eventually assist in improving cancer treatment strategies.

Epigenetic mechanisms underlying stress-induced visceral pain: Resilience versus vulnerability in a two-hit model of early life stress and chronic adult stress.

BACKGROUND: Women with a history of early life stress (ELS) have a higher risk of developing irritable bowel syndrome (IBS). In addition, chronic stress in adulthood can exacerbate IBS symptoms such as abdominal pain due to visceral hypersensitivity. We previously showed that sex and the predictability of ELS determine whether rats develop visceral hypersensitivity in adulthood. In female rats, unpredictable ELS confers vulnerability and results in visceral hypersensitivity, whereas predictable ELS induces resilience and does not induce visceral hypersensitivity in adulthood. However, this resilience is lost after exposure to chronic stress in adulthood leading to an exacerbation of visceral hypersensitivity. Evidence suggests that changes in histone acetylation at the promoter regions of glucocorticoid receptor (GR) and corticotrophin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) underlie stress-induced visceral hypersensitivity. Here, we aimed to investigate the role of histone acetylation in the CeA on visceral hypersensitivity in a two-hit model of ELS followed by chronic stress in adulthood. METHODS: Male and female neonatal rats were exposed to unpredictable, predictable ELS, or odor only (no stress control) from postnatal days 8 to 12. In adulthood, rats underwent stereotaxic implantation of indwelling cannulas. Rats were exposed to chronic water avoidance stress (WAS, 1 h/day for 7 days) or SHAM stress and received infusions of vehicle, the histone deacetylase inhibitor trichostatin A (TSA) or the histone acetyltransferase inhibitor garcinol (GAR) after each WAS session. 24 h after the final infusion, visceral sensitivity was assessed and the CeA was removed for molecular experiments. RESULTS: In the two-hit model (ELS + WAS), female rats previously exposed to predictable ELS, showed a significant reduction in histone 3 lysine 9 (H3K9) acetylation at the GR promoter and a significant increase in H3K9 acetylation at the CRF promoter. These epigenetic changes were associated with changes in GR and CRF mRNA expression in the CeA and an exacerbation of stress-induced visceral hypersensitivity in female animals. TSA infusions in the CeA attenuated the exacerbated stress-induced visceral hypersensitivity, whereas GAR infusions only partially ameliorated ELS+WAS induced visceral hypersensitivity. CONCLUSION: The two-hit model of ELS followed by WAS in adulthood revealed that epigenetic dysregulation occurs after exposure to stress in two important periods of life and contributes to the development of visceral hypersensitivity. These aberrant underlying epigenetic changes may explain the exacerbation of stress-induced abdominal pain in IBS patients.