bluuebunny/crossref_metadata_2025 huggingface dataset:
A Molecular Update and Review of Current Trials in Paediatric Low-Grade Gliomas
Authors: Al-Jilaihawi Sarah , Lowis Stephen
Published: October 2023

Background: Paediatric low-grade gliomas (pLGGs) are the most common primary brain tumour in children. Though considered benign, slow-growing lesions with excellent overall survival, their long-term morbidity can be significant, both from the tumour and secondary to treatment. Vast progress has been made in recent years to better understand the molecular biology underlying pLGGs, with promising implications for new targeted therapeutic strategies. Summary: A multi-layered classification system of biologic subgroups, integrating distinct molecular and histological features has evolved to further our clinical understanding of these heterogeneous tumours. Though surgery and chemotherapy are the mainstays of treatment for pLGGs, many tumours are not amenable to surgery and/or progress after conventional chemotherapy. Therapies targeting common genetic aberrations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway have been the focus of many recent studies and offer new therapeutic possibilities. Here, we summarise the updated molecular classification of pLGGs and provide a review of current treatment strategies, novel agents, and open trials. Key Messages: (1) There is a need for treatment strategies in pLGG that provide lasting tumour control and better quality of survival through minimising toxicity and protecting against neurological, cognitive, and endocrine deficits. (2) The latest World Health Organisation classification of pLGG incorporates a growing wealth of molecular genetic information by grouping tumours into more biologically and molecularly defined entities that may enable better risk stratification of patients, and consideration for targeted therapies in the future. (3) Novel agents and molecular-targeted therapies offer new therapeutic possibilities in pLGG and have been the subject of many recent and currently open clinical studies. (4) Adequate molecular characterisation of pLGG is therefore imperative in today’s clinical trials, and treatment responses should not only be evaluated radiologically but also using neurological, visual, and quality of life outcomes to truly understand treatment benefits.
Application of Multiple Omics to Understand Postoperative Delirium Pathophysiology in Humans
Authors: Vasunilashorn Sarinnapha M. , Dillon Simon T. , Marcantonio Edward R. , Libermann Towia A.
Published: October 2023

Delirium, an acute change in cognition, is common, morbid, and costly, particularly among hospitalized older adults. Despite growing knowledge of its epidemiology, far less is known about delirium pathophysiology. Initial work understanding delirium pathogenesis has focused on assaying single or a limited subset of molecules or genetic loci. Recent technological advances at the forefront of biomarker and drug target discovery have facilitated application of multiple “omics” approaches aimed to provide a more complete understanding of complex disease processes such as delirium. At its basic level, “omics” involves comparison of genes (genomics, epigenomics), transcripts (transcriptomics), proteins (proteomics), metabolites (metabolomics), or lipids (lipidomics) in biological fluids or tissues obtained from patients who have a certain condition (i.e., delirium) and those who do not. Multi-omics analyses of these various types of molecules combined with machine learning and systems biology enable the discovery of biomarkers, biological pathways, and predictors of delirium, thus elucidating its pathophysiology. This review provides an overview of the most recent omics techniques, their current impact on identifying delirium biomarkers, and future potential in enhancing our understanding of delirium pathogenesis. We summarize challenges in identification of specific biomarkers of delirium and, more importantly, in discovering the mechanisms underlying delirium pathophysiology. Based on mounting evidence, we highlight a heightened inflammatory response as one common pathway in delirium risk and progression, and we suggest other promising biological mechanisms that have recently emerged. Advanced multiple omics approaches coupled with bioinformatics methodologies have great promise to yield important discoveries that will advance delirium research.
Zinc Oxide Patches Are a Highly Effective Treatment for Chronic Prurigo: A Randomized Split-Body Study
Authors: Schuermann Manuel , Richter Clara , Tanadini Matteo , Steigmiller Klaus , Burri Elias , Guillet Carole , Luchsinger Isabelle , Meier-Schiesser Barbara , Boesch Andrea , Nägeli Mirjam , Hafner Jürg
Published: October 2023

Background: Chronic prurigo (CPG) presents with pruriginous lesions and reduced quality of life (QoL). Established treatment options are often unsatisfying. Little is known about the efficacy of topical occlusive treatments. Patients often report rapid relief of symptoms when using topical occlusive zinc oxide patches (ZOP). We, therefore, aimed to assess the efficacy of ZOP. Methods: In this randomized controlled split-body crossover study, 22 participants were analyzed, receiving three treatments sequentially: ZOP, topical betamethasone 17-valerate (topical glucocorticosteroids [TGCs]), and both ZOP and TGC combined (ZOP + TGC). Each intervention was applied to either the right or left side of the body for seven consecutive days. Outcomes were a count of active excoriated pruriginous lesions (APLs), itch, recurrence of APL, QoL, and treatment comfort. They were assessed through photographs and questionnaires: modified Prurigo Activity and Severity Score, modified Itchy Quality of Life Questionnaire, and Therapy Comfort Score. Results: We observed a significant reduction of 46% in APL count for ZOP (95% CI from 30% to 58%, p value: <0.0001). Similar reduction was seen for ZOP + TGC, and a lower reduction was seen for TGC alone (48% [95% CI from 33% to 60%, p value: <0.0001] vs. 26% [95% CI from 4% to 43%, p value: 0.02]). APL counts on the non-treated side remained stable. Significant reduction in itch was observed after all treatments, with the largest improvement for ZOP + TGC, followed by TGC and, lastly, ZOP alone (−2.3 units [95% CI from −3.5 to −1.1, p value: 0.00015] vs. −1.5 units [95% CI from −2.8 to −0.3, p value: 0.01 vs. −1.4 units [95% CI from −2.6 to −0.2, p value: 0.02]). QoL increased significantly after ZOP + TGC as well as after TGC (−8.3 units [95% CI from −13.6 to −3.1, p value: 0.0018] vs. −5.7 units [95% CI from −10.9 to −0.5, p value: 0.03]). A good subjective response concerning treatment comfort was observed. Conclusion: ZOP are effective in reducing APL after 1 week of treatment. Adding TGC to ZOP did not add considerable benefit in reducing APL. All three treatments reduced itch and improved QoL, with the largest improvement shown by ZOP combined with TGC. Patients tolerated ZOP well and reported no adverse events. We therefore suggest ZOP combined with TGC as an effective, fast-acting, low-cost treatment for reducing APL and itch in patients with CPG.
tRNA-Derived Small RNAs: A Novel Regulatory Small Noncoding RNA in Renal Diseases
Authors: Li Dan , Xie Xian , Yin Ni , Wu Xueqin , Yi Bin , Zhang Hao , Zhang Wei
Published: October 2023

Background: tRNA-derived small RNAs (tsRNAs) are an emerging class of small noncoding RNAs derived from tRNA cleavage. Summary: With the development of high-throughput sequencing, various biological roles of tsRNAs have been gradually revealed, including regulation of mRNA stability, transcription, translation, direct interaction with proteins and as epigenetic factors, etc. Recent studies have shown that tsRNAs are also closely related to renal disease. In clinical acute kidney injury (AKI) patients and preclinical AKI models, the production and differential expression of tsRNAs in renal tissue and plasma were observed. Decreased expression of tsRNAs was also found in urine exosomes from chronic kidney disease patients. Dysregulation of tsRNAs also appears in models of nephrotic syndrome and patients with lupus nephritis. And specific tsRNAs were found in high glucose model in vitro and in serum of diabetic nephropathy patients. In addition, tsRNAs were also differentially expressed in patients with kidney cancer and transplantation. Key Messages: In the present review, we have summarized up-to-date works and reviewed the relationship and possible mechanisms between tsRNAs and kidney diseases.
Emerging Roles of cGAS-STING Signaling in Mediating Ocular Inflammation
Authors: Zhou Linbin , Ho Bo Man , Chan Hoi Ying Emily , Tong Yan , Du Lin , He Jing Na , Ng Danny Siu-Chun , Tham Clement C. , Pang Chi Pui , Chu Wai Kit
Published: October 2023

Cyclic GMP-AMP (cGAMP) synthase (cGAS), a sensor of cytosolic DNA, recognizes cytoplasmic nucleic acids to activate the innate immune responses via generation of the second messenger cGAMP and subsequent activation of the stimulator of interferon genes (STINGs). The cGAS-STING signaling has multiple immunologic and physiological functions in all human vital organs. It mediates protective innate immune defense against DNA-containing pathogen infection, confers intrinsic antitumor immunity via detecting tumor-derived DNA, and gives rise to autoimmune and inflammatory diseases upon aberrant activation by cytosolic leakage of self-genomic and mitochondrial DNA. Disruptions in these functions are associated with the pathophysiology of various immunologic and neurodegenerative diseases. Recent evidence indicates important roles of the cGAS-STING signaling in mediating inflammatory responses in ocular inflammatory and inflammation-associated diseases, such as keratitis, diabetic retinopathy, age-related macular degeneration, and uveitis. In this review, we summarize the recently emerging evidence of cGAS-STING signaling in mediating ocular inflammatory responses and affecting pathogenesis of these complex eye diseases. We attempt to provide insightful perspectives on future directions of investigating cGAS-STING signaling in ocular inflammation. Understanding how cGAS-STING signaling is modulated to mediate ocular inflammatory responses would allow future development of novel therapeutic strategies to treat ocular inflammation and autoimmunity.
Bortezomib and Vorinostat Therapy as Maintenance Therapy Post-Autologous Transplant for Non-Hodgkin’s Lymphoma Using R-BEAM or BEAM Transplant Conditioning Regimen
Authors: Holmberg Leona A. , Maloney David G. , Connelly-Smith Laura
Published: October 2023

Introduction: The success of autologous stem cell transplantation (ASCT) for treating non-Hodgkin’s lymphoma (NHL) is limited by its high relapse rates. To reduce the risk of relapse, additional maintenance therapy can be added post-transplant. In a non-transplant setting at the time of initiation of this study, both bortezomib and vorinostat had been studied alone or in combination for some NHL histology and showed some clinical activity. At our center, this combination therapy post-transplant for multiple myeloma showed acceptable toxicity. Therefore, it seemed reasonable to study this combination therapy post-ASCT for NHL. Methods: NHL patients underwent conditioning for ASCT with rituximab, carmustine, etoposide, cytarabine, melphalan/carmustine, etoposide, cytarabine, melphalan. After recovery from the acute transplant-related toxicity, combination therapy with IV bortezomib and oral vorinostat (BV) was started and was given for a total of 12 (28-day) cycles. Results: Nineteen patients received BV post-ASCT. The most common toxicities were hematologic, gastrointestinal, metabolic, fatigue, and peripheral neuropathy. With a median follow-up of 10.3 years, 11 patients (58%) are alive without disease progression and 12 patients (63%) are alive. Conclusions: BV can be given post-ASCT for NHL and produces excellent disease-free and overall survival rates.
The Microcirculation of Vaginal Tissue in Women with Obstetric Vesicovaginal Fistula and Short-Term Effects of Surgical Repair on Microvascular Parameters
Authors: Maljaars Lennart P. , Kastelein Arnoud W. , Latul Yani P. , Nakoma Gerald , Chipungu Ennet , Roovers Jan-Paul W.R. , Pope Rachel J.
Published: October 2023

Objectives: The objective of the study was to better understand the extent of the ischemic trauma and the effects of surgical repair on the vaginal microcirculation in patients with obstetric vesicovaginal fistula (VVF). Design: In this observational study, we evaluated the vaginal microvasculature surrounding VVF using handheld vital microscopy (HVM) before, during, and 2 weeks after surgical VVF repair. Participants: Seventeen women undergoing VVF repair were included in this study. Setting: The study was conducted in the Fistula Care Centre in Lilongwe, Malawi. Methods: We used HVM with incident dark-field imaging to non-invasively visualize the microvasculature of the vaginal tissue surrounding fistulas. The primary outcome was the presence of microvascular flow. Secondary outcomes included angioarchitecture, fistula closure (postoperative dye test), and urinary continence (pad weight test). Results: Microvascular flow was present before, during, and after surgical repair in, respectively, 83.8%, 83.9%, and 93.4% of obtained image sequences. The angioarchitecture was normal in 75.8% of the image sequences before surgery, 69.4% at fistula closure, and 89.1% two weeks after VVF repair. Fourteen (82.4%) patients had a closed fistula after surgical repair. Limitations: The study was limited by the lack of a control group and the relatively small sample size. Conclusion: Although the vaginal microcirculation in women with VVF is compromised, extensive ischemic damage is not observed in the tissue surrounding fistulas. This suggests significant regenerative capacity of the vaginal vasculature in young women, or less extensive ischemic damage than presumed. Following surgical repair, we observed improvement of microcirculatory flow and angioarchitecture, suggesting that surgery is a good option for patients with obstetric VVF.
Low Prognostic Nutritional Index Is Common and Associated with Poor Outcomes following Curative-Intent Resection for Gastro-Entero-Pancreatic Neuroendocrine Tumors
Authors: Xiang Jun-Xi , Qian Ye-Rong , He Jin , Lopez-Aguiar Alexandra G. , Poultsides George , Rocha Flavio , Weber Sharon , Fields Ryan , Idrees Kamran , Cho Cliff , Maithel Shishir K. , Lv Yi , Zhang Xu-Feng , Pawlik Timothy M.
Published: October 2023

Introduction: To investigate the impact of prognostic nutritional index (PNI) on short- and long-term outcomes of patients who underwent curative-intent resection for gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). Methods: Patients with GET-NETs who underwent curative-intent resection were identified from a multi-center database. The prognostic impact of clinicopathological factors including PNI on post-operative outcomes were evaluated. A novel nomogram was developed and externally validated. Results: A total of 2,099 patients with GEP-NETs were included in the training cohort; 255 patients were in the external validation cohort. Median PNI (n = 973) was 47.4 (IQR 43.1–52.4). At the time of presentation, 1,299 (61.9%) patients presented with some type of clinical symptom. Low-PNI (≤42.2) was associated with gastrointestinal symptoms, as well as nodal metastasis and distant metastasis (all p < 0.05). Patients with a low PNI had a higher incidence of severe (≥Clavien-Dindo grade IIIa: low PNI 24.9% vs. high PNI 15.4%, p = 0.001) and multiple (≥3 types of complications: low PNI 14.5% vs. high PNI 9.2%, p = 0.024) complications, as well as a worse overall survival (OS)(5-year OS, low PNI 73.7% vs. high PNI 88.5%, p < 0.001), and RFS (5-year RFS, low PNI 68.5% vs. high PNI 79.8%, p = 0.008) versus patients with high PNI (>42.2). A nomogram based on PNI, tumor grade and metastatic disease demonstrated excellent discrimination and calibration to predict OS in both the training (C-index 0.748) and two external validation (C-index 0.827, 0.745) cohorts. Conclusions: Low PNI was common and associated with worse short- and long-term outcomes among patients with GEP-NETs.
Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome
Authors: Yang Hao , Ma Xiuqi , Tian Hongjuan , Yuan Jinna , Wu Dehua , Dong Guanping , Liu Qian , Fu Junfen
Published: October 2023

Introduction: The pathogenic variants in DEAH-box RNA helicase DHX37 are one of the major causes of 46,XY gonadal dysgenesis and testicular regression syndrome (TRS). To date, only 13 different missense variants have been reported. We report two additional cases with different clinical presentations carrying two novel variants in the DHX37 gene. Case Presentation and Results: Case 1 (4.4-year-old boy) presented with significant micropenis and cryptorchidism and was diagnosed as TRS. Case 2 (13.5-year-old girl) had a 46,XY karyotype with female external genitalia and was diagnosed as GD. Two novel DHX37 variants affecting the RecA2 domain, p.G478R and p.L627F, were identified in these cases. Both variants identified in the probands were also present in their unaffected mother. Conclusion: Our findings broaden the variant spectrum of DHX37 in 46,XY differences of sex development (DSD) individuals.
Deep Learning Neural Network-Guided Detection of Asbestos Bodies in Bronchoalveolar Lavage Samples
Authors: Hakkarainen Antti J. , Randen-Brady Reija , Wolff Henrik , Mäyränpää Mikko I. , Sajantila Antti
Published: October 2023

Introduction: Asbestos is a global occupational health hazard, and exposure to it by inhalation predisposes to interstitial as well as malignant pulmonary morbidity. Over time, asbestos fibers embedded in lung tissue can become coated with iron-rich proteins and mucopolysaccharides, after which they are called asbestos bodies (ABs) and can be detected in light microscopy (LM). Bronchoalveolar lavage, a cytological sample from the lower airways, is one of the methods for diagnosing lung asbestosis and related morbidity. Search for ABs in these samples is generally laborious and time-consuming. We describe a novel diagnostic method, which implements deep learning neural network technology for the detection of ABs in bronchoalveolar lavage samples (BALs). Methods: BALs with suspicion of asbestos exposure were scanned as whole slide images (WSIs) and uploaded to a cloud-based virtual microscopy platform with a neural network training interface. The images were used for training and testing a neural network model capable of recognizing ABs. To prioritize the model’s sensitivity, we allowed it to also make false-positive suggestions. To test the model, we compared its performance to standard LM diagnostic data as well as the ground truth (GT) number of ABs, which we established by a thorough manual search of the WSIs. Results: We were able to reach overall sensitivity of 93.4% (95% CI: 90.3–95.7%) in the detection of ABs in comparison to their GT number. Compared to standard LM diagnostic data, our model showed equal to or higher sensitivity in most cases. Conclusion: Our results indicate that deep learning neural network technology offers promising diagnostic tools for routine assessment of BALs. However, at this stage, a human expert is required to confirm the findings.
Are Current Data Sufficient to Infer that Hearing Aids Contribute to Postural Control and Balance in Older Adults? A Systematic Review
Authors: Lavie Limor , Tobia Nawras , Slav-Zarfati Neta , Castel Shefi , Banai Karen
Published: October 2023

Introduction: Balance and postural control are related to hearing and hearing loss, but whether they can be improved with hearing aid use in older adults is not clear. We systematically reviewed controlled studies in which balance and hearing were tested in experienced older hearing aid users to determine the potential effects of hearing aid use on balance. Methods: The review was pre-registered in PROSPERO and performed in accordance with PRISMA. The question, inclusion, and exclusion criteria were defined using the Population, Intervention, Control, Outcomes and Study design (PICOS) framework. Older adults with hearing loss and no experience with hearing aids, or balance tests conducted without hearing aids in hearing aid users served as controls. Results: A total of 803 studies were screened, eight of which met the inclusion and exclusion criteria and were included in the final review. Five of the eight studies found a significant correlation between the use of hearing aids and the outcomes of the balance tests. The quality of the studies was limited or moderate. Key Discussion: The role of hearing aids in balance and postural control is unclear because of the quality of the papers and the sparse reporting of hearing status and hearing aids quality of fitting and use.
Clinical Outcomes after the Use of Antiadhesive Agents in Laparoscopic Reproductive Surgery
Authors: Esber Sabine , Etrusco Andrea , Laganà Antonio Simone , Chiantera Vito , Arsalan Hafiz Muhammad , Khazzaka Aline , Dellino Miriam , Sleiman Zaki
Published: October 2023

Introduction: Intra-abdominal adhesions are abnormal fibrous attachments between tissues and organs that can be congenital or acquired. Adhesion formation is a critical postoperative complication that may lead to bowel obstruction, chronic abdominal pain, and infertility. Physical barrier agents separate opposing peritoneal surfaces in the critical 5-day period of remesotheliazation. These agents are subdivided into solid or liquid/gel. Liquid agents seem easier to use in laparoscopic procedures than solid agents. Methods: The search for suitable articles published in English was carried out using the following databases: MEDLINE, Embase, Global Health, the Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), Health Technology Assessment Database, Web of Science, and search register (ClinicalTrial.gov). Only studies reporting data about the impact of the use of an antiadhesive agent on adhesion formation after a primary gynecologic laparoscopic surgery were considered eligible. Results: Twenty-two papers that met the inclusion criteria were included in this systematic review. Conclusions: Surgeons should consider applying antiadhesive agents after gynecologic surgery to help reduce adhesion formation and its adverse effects. However, further studies are still needed to confirm their impact on reproductive outcome and to implement clear guidelines on their per-operative application.
A Novel Acoustic Evaluation Method for the Diagnosis of Adductor Spasmodic Dysphonia
Authors: Liu Boquan , Ji Mingjun , Fang Jin , Ren Qingyi , Lan Jinwei , Zhu Zhixian , Ge Pingjiang , Kang Jing
Published: October 2023

Introduction: Adductor spasmodic dysphonia (ADSD) is characterized by involuntary laryngeal muscle spasms. Due to the lack of a quantitative evaluation method, most measurements have demonstrated difficulty in validity and reliability for diagnosing ADSD. This study aimed to establish a novel indicator for ADSD and determine its diagnostic effects. Methods: We investigated 98 voice samples from 49 patients with ADSD and 49 healthy participants. A sustained vowel was recorded by a high-definition audio recorder. Voice samples underwent regular acoustic evaluation and a novel global dimension (GD) method. GD, Jitter, Shimmer, HNR, Frequency shift, and CPPS were measured for both groups. Results: Statistical analysis revealed that the GD method effectively differentiated ADSD patients from healthy participants (p < 0.001, D′>0.8). Subsequent multiclass receiver operating characteristic analysis demonstrated that GD possessed the most significant classification accuracy (area under the curve = 0.988) compared with other acoustic parameters. Conclusion: GD was an effective metric for objective differentiation between ADSD patients and healthy participants. This metric could assist clinicians in the diagnosis of ADSD patients.
Cellular Therapy in Chronic Lymphocytic Leukemia: Have We Advanced in the Last Decade?
Authors: Katz Ofrat Beyar , Yehudai-Ofir Dana , Zuckerman Tsila
Published: October 2023

Background: Chronic lymphocytic leukemia (CLL) is a heterogeneous B-cell malignancy, affecting mainly older adults. Despite the recent introduction of multiple targeted agents, CLL remains an incurable disease. Cellular therapy is a promptly evolving area that has developed over the last decades from such standard of care as hematopoietic cell transplantation (HCT) to the novel treatment modalities employing genetically engineered immune cells. Summary: Tailoring the proper treatment for each patient is warranted and should take into account the disease biology, patient characteristics, and the available treatment modalities. Nowadays, the most broadly applied cellular therapies for CLL management are HCT and chimeric antigen receptor-T (CAR-T) cells. However, CAR-T cell therapy is currently not yet approved in CLL, and the appropriate sequencing for the administration of these agents remains to be clarified. Key Messages: The current review will discuss various available cellular treatment options, their advances and limitations, as well as the optimal timing for the employment of such therapies in CLL patients.
Prenatal Findings in Postnatal Cases of Disorders of Sex Development: Experience from a Tertiary-Specialized Center in Brazil
Authors: Cursino Kleber Andrade , Garcia Guilherme Mantelato , Barros Beatriz Amstalden , Mazzola Tais Nitsch , Fabbri-Scallet Helena , Guaragna Mara Sanches , Vieira Tarsis Antonio Paiva , Mello Maricilda Palandi de , Maciel-Guerra Andrea Trevas , Guerra-Junior Gil
Published: October 2023

Introduction and Objective: Prenatal suspicion of disorders/differences of sex development (DSDs) is a relatively new phenomenon. The aim of this study was to review the prenatal findings of DSD cases postnatally diagnosed in our tertiary referral center. Methods: We evaluated 57 DSD cases with sex ambiguity who had undergone prenatal ultrasound with phenotypic sex assessment and/or cell-free fetal DNA (cffDNA) for genotypic sex assessment. Results: Prenatal cffDNA had been performed in 32 cases, being positive (suggestive of male genotypic sex) in 26 and negative (suggestive of female genotypic sex) in 6. Five with cffDNA negative had a prenatal ultrasound indicating female external genitalia, in turn, in those with cffDNA positive, only two had a prenatal ultrasound indicating male external genitalia. Our postnatal data showed that when external genitalia were female or poorly virilized, prenatal ultrasound indicated female sex, but in cases of higher degree of virilization, ultrasound showed similar rates of male, female, or undetermined sex. Regarding the karyotype, our data showed those with XY karyotype had positive cffDNA, those with XX karyotype had negative cffDNA, and all five with sex chromosome anomalies had positive cffDNA because they were 45,X/46,XY. We suggested an algorithm to investigate these cases during gestation, including evaluation of uterus, fetal growth, and malformations. Conclusion: We suggest that the parents should be counseled prenatally by a dedicated multidisciplinary team with experience in DSD management and evaluated as soon as possible after birth.
How Can Experimental Endotoxemia Contribute to Our Understanding of Pain? A Narrative Review
Authors: Benson Sven , Karshikoff Bianka
Published: October 2023

The immune system and the central nervous system exchange information continuously. This communication is a prerequisite for adaptive responses to physiological and psychological stressors. While the implicate relationship between inflammation and pain is increasingly recognized in clinical cohorts, the underlying mechanisms and the possibilities for pharmacological and psychological approaches aimed at neuro-immune communication in pain are not fully understood yet. This calls for preclinical models which build a bridge from clinical research to laboratory research. Experimental models of systemic inflammation (experimental endotoxemia) in humans have been increasingly recognized as an approach to study the direct and causal effects of inflammation on pain perception. This narrative review provides an overview of what experimental endotoxemia studies on pain have been able to clarify so far. We report that experimental endotoxemia results in a reproducible increase in pain sensitivity, particularly for pressure and visceral pain (deep pain), which is reflected in responses of brain areas involved in pain processing. Increased levels of blood inflammatory cytokines are required for this effect, but cytokine levels do not always predict pain intensity. We address sex-dependent differences in immunological responses to endotoxin and discuss why these differences do not necessarily translate to differences in behavioral measures. We summarize psychological and cognitive factors that may moderate pain sensitization driven by immune activation. Together, studying the immune-driven changes in pain during endotoxemia offers a deeper mechanistic understanding of the role of inflammation in chronic pain. Experimental endotoxemia models can specifically help to tease out inflammatory mechanisms underlying individual differences, vulnerabilities, and comorbid psychological problems in pain syndromes. The model offers the opportunity to test the efficacy of interventions, increasing their translational applicability for personalized medical approaches.
Abstract 002: PO
2
-guided Adrenal Vein Sampling In Primary Aldosteronism
Authors: Omata Kei , Tezuka Yuta , Ono Yoshikiyo , Satoh Fumitoshi
Published: October 2023

Background:
Accurate diagnosis of laterality of adrenal aldosterone over-secretion is crucial in determining specific treatment for primary aldosteronism (PA). Although adrenal vein sampling (AVS) is considered as the gold standard method for lateralization, successful canulation to right adrenal vein (RAV) has been reported to be challenging since RAV usually empties directly into inferior vena cava (IVC). In addition, the entrance of RAV is close to that of hepatic vein (HV) or opens to a common trunk with HV in up to 20% of the patients with PA. Cortisol step-up and other proposed indices are not always available during the procedure.

Method:
AVS was performed in confirmed PA patients between January 2021 and April 2022 at Tohoku University Hospital. During AVS, a small portion (0.3mL) of the sampled veins (RAV, IVC and HV) were analyzed with a blood gas analyzer for partial pressure of oxygen (pO
2
) measurement.

Result:
A total of 120 AVS was performed. After excluding inappropriate samples, further analyzed were 120 samples of IVC, 107 of RAV, 116 of HV before cosyntropin stimulation, and 120 samples of IVC, 117 of RAV, 115 of HV after cosyntropin stimulation. We observed an average of 22 mmHg increase of pO
2
in RAV than IPV, and 28 mmHg increase than HV before stimulation. The difference between RAV and IPV was 15 mmHg in average and that of RAV and HV was 22 mmHg after stimulation. Similar pO
2
step-up was also observed between left adrenal vein and left inferior phrenic vein. Discussion: Here we describe prominent pO
2
step-up in both adrenal veins compared to neighboring non-adrenal veins and peripheral blood. pO
2
measurement is easier, faster, less expensive, and requires a very small amount of sample, can be performed by routine equipments in angiography suite, compared to other selectivity indices for successful cannulation in AVS. This would also contribute to reducing unnecessary blood sampling, radiation exposure and repeat AVS. pO
2
step-up in adrenal vein suggests low oxygen consumption in adrenal glands, which potentially contributes to survival advantage in systemic hypoxic conditions. We propose novel pO
2
-guided AVS especially in patients with difficult RAV anatomy and in unexperienced centers.
Abstract 009: Age-related Clonal Hematopoiesis Predisposes To Hypertension In Mice Through An Inflammasome Mechanism
Authors: Polizio Ariel , Min Kyung-Duk , Yura Yoshimitsu , Marino Lucila , Rolauer Luca , Miura-Yura Emiri , Evans Megan A , Park Eunbee , Good Miranda , Wolpe Abigail , Grandoch Maria , Isakson Brant , Walsh Kenneth
Published: October 2023

Hypertension incidence increases with age and represents one of the most prevalent risk factors for cardiovascular disease (CVD). Clonal events in the hematopoietic system resulting from somatic mutations in “driver” genes such as Tet2 are prevalent in elderly individuals in the absence of overt hematologic disorders. This condition is referred to as age-related clonal hematopoiesis (ARCH), and it is a newly recognized risk factor for CVD. It is unknown whether ARCH and hypertension in the elderly are causally related and, if so, what are the mechanistic features.

Objective:
Given that the aging process increases the prevalence of hypertension and ARCH, the current experimental study was designed to test the effect of ARCH in hypertension incidence.

Methods and Results:
A murine model of adoptive bone marrow transplantation to nonconditioned mice was employed to examine the interplay between ARCH and hypertension. Mice carrying Tet2-deficiency in hematopoietic cells resulted in elevated systolic (SBP) and diastolic blood pressure (DBP) as early as one day after challenge with a sub-pressure dose of angiotensin II (Ang II) 200ng/kg/min; SBP (day 1 Tet2
-/-
: 148 mmHg± 4 vs. WT: 129±2 mmHg, P=0.002); day 9 Tet2
-/-
159±7 mmHg vs. WT: 139±5 mmHg, P<0.05), and DBP (day 1, Tet2
-/-
: 108 ±3 mmHg vs. WT: 100±1 mmHg, P<0.005; day 9, Tet2
-/-
: 111 ±4 mmHg vs. WT 107±3 mmHg). The ARCH Tet2 model of CH led to greater macrophage infiltration in the kidney, aorta and mesentery after Ang II compared with WT-treated mice. The Tet2-/- CH condition led to renal NLRP3 inflammasome activation and elevated renal levels of IL (interleukin)-1β (Tet2
-/-
1.4 vs. WT: 0.96, P<0.005) and IL-18 (Tet2
-/-
1.56 vs. WT: 1.18, P<0.005) after Ang II administration. Interestingly, administration of the inflammasome inhibitor MCC950 reversed hypertension seen in the mouse model of Tet2
-/-
CH.

Conclusion:
Our data show that a sub-pressor dose of Ang II promotes hypertension due to elevated renal immune cell infiltration in a Tet2-CH model, promoting IL1-β and IL-18. These data suggest that Tet2
-/-
CH carriers could be at elevated risk for the development of hypertension, and that NLRP3 inhibitors could be useful for treating hypertension in this population.
Abstract 016: GRN Gene Mutation Leads To Vascular Abnormalities Via Mitochondrial Dysfunction And Oxidative Stress
Authors: Singh Shubhnita , Bruder do Nascimento Ariane , Costa Rafael M , Bharathi Sivakama S , Goetzman Eric , Bruder Thiago
Published: October 2023

Background:
Cardiovascular disease (CVD) is the leading cause of death worldwide. Loss of contractility of vascular smooth muscle cells (VSMC) is a major factor of CVD. The GRN gene encodes the glycoprotein progranulin (PGRN). Ubiquitously expressed, PGRN is implicated in anti-inflammation and cell proliferation. However, the role of PGRN in CVD remains to be elucidated. Herein, we tested the hypothesis that PGRN influences VSMC contraction via regulating mitochondria quality.

Methods:
We used aortae from wildtype (PGRN
+/+
) and PGRN global knockout (PGRN
-/-
) mice to study vascular contraction via wire myograph and isolate primary aVSMCs to elucidate mechanisms.

Results:
We observed a significantly suppressed contractile profile in PGRN
-/-
aVSMC characterized by reduced α smooth muscle actin expression and impaired VSMC contractility, analyzed by collagen disc assay. PGRN
-/-
aortae demonstrated diminished vascular contractility to KCl (maximal response in mN, PGRN
+/+
5.3±0.3 vs PGRN
-/-
4.0±0.4*, *P<0.05) and thromboxane A2 analog, U46619 (maximal response in mN, PGRN
+/+
6.0±0.5 vs PGRN
-/-
4.7±0.3*, *P<0.05). RNA-sequencing in aortae revealed a suppression in oxidative phosphorylation in PGRN
-/-
. Furthermore, PGRN
-/-
VSMC and aortae displayed a suppressed mitochondrial oxygen consumption rate (OCR) analyzed by Seahorse and Oroboros followed by attenuated ATP levels and elevated mitochondrial oxidative stress. No difference was observed for mitochondria DNA number or biogenesis. To rescue the PGRN levels, we incubated aortae from PGRN
-/-
mice with lentivirus (LV) encoding PGRN for 48h, which elevated the vascular contractility to KCl (maximal response in mN, PGRN
-/-
4.8 ± 0.4 vs PGRN
-/-LV
7.1 ± 0.3*, *P<0.05) and U46619 (maximal response in mN, PGRN
-/-
8.0 ± 0.2 vs PGRN
-/-LV
16.0 ± 0.2*, *P<0.05), increased OCR, and controlled the oxidative stress, whereas inhibiting mitochondria with rotenone prevented the LV effects.

Conclusion:
Collectively, we demonstrated that PGRN is essential to maintain vascular contractility via regulating mitochondrial function. Our results show that loss-of-function of PGRN is a risk factor for developing CVD and places PGRN as a potential alternative therapeutic target for high-risk CVD populations.
Abstract 035: Early Depletion Of Activated Neutrophils Ameliorates Ang Ii-induced Hypertension In
Gstm1
Deficient Mice
Authors: Chen Luojing , Beane Timothy , Wang Yves , alnuaimi ahmed , Liu Jing , Wu Jing , Le Thu H
Published: October 2023

Background:
Glutathione-S-transferase Mu1(
Gstm1
) gene encodes an enzyme that functions in the detoxification of electrophilic compounds. The common
GSTM1
deletion variant in humans is associated with increased risks of chronic kidney disease progression. We reported that deletion of
Gstm1
in mice increases oxidative stress, kidney inflammation and injury in angiotensin II induced hypertension (Ang II-HTN). Bone marrow cross-transplantation suggested a chemotaxis signal originating from the kidney. Moreover, we recently found that global deletion of
Gstm1
significantly increased neutrophil chemotaxis response to CXCL1 and CXCL2
in vitro
and kidney neutrophil populations early in Ang II-HTN by day 4. To test whether early activation of neutrophil mediates inflammation and kidney injury in
Gstm1
KO mice, we depleted neutrophils using Ly6G antibody.

Methods:
Gstm1
KO male mice (12 weeks old) on 129S6 background were used for the study. After a 2-week training period, baseline systolic blood pressure (SBP) was measured by tail cuff daily for 2 weeks. For neutrophil depletion, Ly6G antibody (1A8, BioXcell ) (n=3) or control IgG (2A3)(n=2) were injected IP (200 μg/mouse) at 48hr and 24hr before Ang II mini-osmotic pump was implanted (1000 ng/kg/minute). A third IP injection was performed at day 4 after the Ang II. SBP was measured for 8 days during Ang II-HTN. FACS analysis was performed at day 8 post Ang II to determine the efficiency of neutrophil depletion.

Results:
Compared to control IgG, Ly6G antibody significantly depleted neutrophil populations in the kidney, bone marrow, and spleen by 95%, 97%, and 93%, respectively. Baseline SBP was similar between the two groups (129.5 ± 6.7 vs 128.3 ± 0.8 mm Hg, p = 0.9). In Ang II-HTN, depletion of neutrophils with Ly6G antibody in
Gstm1
KO mice resulted in a trend in decrease in SBP compared to control antibody (154.7 ± 17.9 vs 182.6 ± 2.6 mm Hg; p = 0.13).

Conclusion:
Loss of
Gstm1
activates neutrophils early in Ang II-HTN. Successful depletion of neutrophils in
Gstm1
KO mice decreased blood pressure in response to Ang II. Further studies are underway to confirm the pressor response and to determine whether depletion of neutrophils early in Ang II-HTN can ameliorate kidney inflammation and injury in GSTM1 deficiency.
Abstract 037: Neuromodulation Of Adipocyte Activity In Perivascular Adipose Tissue In Healthy Mice
Authors: Hanscom Marie , Morales-Soto Wilmarie , Jackson William F , Gulbransen Brian D
Published: October 2023

Perivascular adipose tissue (PVAT) has emerged as a regulator of blood pressure by releasing anticontractile factors, which may be disrupted in disease. The production of adipocyte anticontractile factors is driven by norepinephrine (NE), a sympathetic neurotransmitter; however, the source of NE remains unknown. Here, we tested the hypothesis that neuronal innervation of PVAT stimulates adipocytes via NE. Mesenteric (mPVAT), aortic (aPVAT), and subcutaneous fat (sc) depots were studied in healthy male and female mice aged 8-12 weeks. Immunostaining with neuronal and vasculature markers was performed to assess anatomical evidence of neural innervation (n=3 region/sex). Adipocyte activity was studied in

Adiponectin
Cre;GCaMP
5g-tdT

mice, which express the calcium indicator GCaMP5g in adipocytes (125-350 cells/group). Adipocytes were challenged with NE, a parasympathomimetic (bethanechol, 10uM, bath application), and nerve fibers were activated by electrical field stimulation (EFS; +100V, 0.1ms, 10 Hz). Immunolabeling data show that nerve fibers run adjacent to the larger blood vessels within adipose tissue, rather than radiating throughout. Stimulation with NE induced large responses (female: 0.91±0.73, 1.15±0.73, 1.45±0.9 dF/F
0
; male: 0.75±0.57, 1.01±0.78, 0.73±0.53 dF/F
0
in aPVAT, mPVAT, sc, respectively). Both the parasympathomimetic and EFS induced minimal adipocyte responses compared to NE (% NE = [dF/F
0
bethanechol or EFS / dF/F
0
NE]*100%; bethanechol - female: 39.5%, 13.9%, 9.7%, male: 24.0%, 14.6%, 15.1% in aPVAT, mPVAT, sc, respectively; EFS - female: 31%, 12.2%, 9.7%, male: 28%, 13.9%, 13.7% in aPVAT, mPVAT, sc, respectively). These findings suggest that neural innervation within the PVAT, and functional regulation of adipocytes, is limited. Nerve fibers present within the PVAT are not the primary source of NE driving adipocyte production of anticontractile factors in the PVAT. Rather, this NE originates from other mechanisms including local production by non-neuronal cells or circulation of neurotransmitters.
Abstract 051: Racial Differences In Hypertension Self-care Behaviors Among Adults With Hypertension In The Baltimore And Washington, D.C. Area
Authors: Metlock Faith E , Ogungbe Oluwabunmi , Liu Xiaoyue , HINNEH THOMAS , Dennison Cheryl R , Greengold Judy , Han Haera , Commodore-Mensah Yvonne
Published: October 2023

Introduction:
Interventions utilizing comprehensive hypertension (HBP) self-care evaluation tools may reduce HBP disparities. However, studies examining racial differences in HBP self-care among people diagnosed with HBP are limited.

Methods:
We analyzed cross-sectional data from adults with HBP that receive care in the Baltimore and Washington D.C. area. Twenty self-care behaviors were examined via the Hypertension Self-Care Profile (HBP-SCP) tool and scored as 4-point Likert with total scores ranging between 20-80. Multinomial logistic regression models were used to assess the association between race categories (White, Black/African American, Asian, American Indian/Alaskan Native, Native Hawaiian/Pacific Islander, Other/Multi-racial) and HBP-SCP behaviors, adjusting for covariates.

Results:
The study included 4,391 adults diagnosed with HBP (mean age 62 ± 12 years; 55% female). The median HBP-SCP score was 47 and scores ≥ 47 or <47 were rated as good and poor, HBP self-care behavior, respectively. Compared to White adults, Asian and Black/African American adults were 29% less likely and 21% more likely, respectively, to have good HBP self-care behavior in the unadjusted model. Asian and Other/Multi-racial adults were 38% and 35%, respectively, less likely to have good HBP self-care behavior after adjusting for covariates compared to White adults (Table 1).

Conclusion:
Racial differences exist in HBP self-care behaviors among adults with HBP. These findings highlight the importance of practitioners assessing patients’ understanding of and adherence to self-care behaviors and developing culturally tailored approaches for improving adherence.
Abstract 053: Enhanced Endothelial Cd36 Signaling Promotes Vascular Stiffening
Authors: Chen Dongqing , Wattanasirakul Peeradol , Chishti Aman F , Morrison Katherine A , Jia Guanghong
Published: October 2023

The overweight and obesity epidemic has led to an increase in the metabolic syndrome and associated cardiovascular disease, which include insulin resistance, type 2 diabetes mellitus, vascular stiffness, and hypertension. We recently found that consumption of a high-fat/high-fructose Western diet (WD) increases expression of CD36, which is associated with increased arterial ectopic lipid accumulation, systemic and vascular insulin resistance, and arterial stiffening. However, the precise mechanisms by which enhanced activation of endothelial specific CD36 (ECCD36) induces insulin resistance and vascular stiffening remains to be elucidated. We hypothesized that ECCD36 would participate in WD-induced aortic insulin resistance, lipid accumulation, fibrosis, remodeling, and associated aortic stiffening. Six-week-old female ECCD36
-/-
and wild type (ECCD36
+/+
) mice were fed either a WD or a standard chow diet (CD) for 16 weeks. Aortic stiffness and vascular activity were determined by pulse wave velocity and wire myograph, respectively. Gene expression was examined by western blot. Lipid contents were determined by Oil red O staining. 16 weeks of WD increased aortic stiffening that was related to vascular insulin resistance and reduced insulin metabolic signaling in PI3K/Akt pathways. These metabolic disorders were associated with increased lipid disorders and aortic remodeling. However, ECCD36
-/-
mice attenuated WD-induced increases in pulse pressure and reduced vascular activity, aortic free fatty acid and lipid content, vascular insulin resistance, as well as aortic remodeling. These findings indicate that enhanced ECCD36 signaling mediates aortic insulin resistance, increased lipid accumulation, fibrosis, remodeling, and associated aortic stiffening in diet-induced obesity.
Abstract 060: Conditional Deletion Of Renin In The Mouse Brain Results In Cardiovascular And Respiratory Abnormalities In Response To Hypoxia Or Autonomic Blockade
Authors: Fekete Eva M , Muskus Veitia Patricia , Mathieu Natalia , Brozoski Daniel , Golosova Daria , Gomez Javier , Mouradian Gary , Hodges Matthew , Grobe Justin L , Sigmund Curt D , Nakagawa Pablo
Published: October 2023

Previously, we reported the existence of renin-expressing neurons in the nucleus ambiguus (NuAm), a major autonomic and respiratory center in the brainstem. Within the NuAm, renin is expressed in choline acetyltransferase (ChAT)-positive cardioinhibitory vagal neurons projecting to the cardiac ganglion. Based on this, we hypothesized that ablation of renin specifically in ChAT-positive neurons disrupts normal cardiorespiratory function. Cardiorespiratory function in control (WT) vs. mice lacking renin in cholinergic neurons (Ren-a
ChAT-null
) was compared using an integrated radiotelemetry/whole-body plethysmography system. We measured parameters at baseline and upon acute respiratory or pharmacological challenge in males. Using in situ mRNA hybridization, we confirmed that Ren-a
ChAT-null
exhibit lower expression of renin in the NuAm compared to the WT (Ren-a
ChAT-null
: 0.7±0.3 vs. WT: 3.9±0.9 arbitrary units, p<0.05, n=4-5). At baseline, there were no major differences in cardiorespiratory function between groups. Therefore, mice were subjected to acute cardiorespiratory challenges. During acute hypoxia (12% O
2
for 10 minutes), Ren-a
ChAT-null
displayed lower hypoxic ventilatory response compared to WT (1.53±0.04 vs. 1.94±0.10 fold change compared to baseline, p<0.05, n=4). Additionally, Ren-a
ChAT-null
exhibited exacerbated tachycardia (640±19 vs. 564±11 bpm, p<0.05, n=3-4). Subsequently, when subjected to sympathetic blockade with propranolol (5 mg/kg, ip), Ren-a
ChAT-null
exhibited an exacerbated bradycardic and hypotensive effect compared to WT (14427±293 vs 15722±498 AUC bpm*min, p<0.05, n=7-9 and 3661±90 vs 3988±78 AUC mmHg*min, p<0.05, n=7-9, respectively). In response to parasympathetic blockade with methyl atropine (2 mg/kg, ip), Ren-a
ChAT-null
exhibited a lower systolic blood pressure elevation compared to WT (4001±112 vs. 4324±84 AUC mmHg*min, p<0.05; n=7-9). These data suggest that renin in cholinergic neurons exerts a functional physiological role and contributes to maintaining an appropriate cardiorespiratory response to acute stressors. Ongoing studies are currently underway to investigate 1) sex differences and 2) the phenotype of Ren-a
ChAT-null
mice in chronic conditions such as hypertension.