Image J as the quantification tool in endosonography strain elastography may be reflected in the disturbance of endocrine pancreatic dysfunction.

Objectives: Pancreatic fibrosis is one of the main pathological features of chronic pancreatitis (CP), suggesting a strong relationship between CP and pancreatic ductal cancer. There was no available data about pancreatic fibrosis and pancreatic dysfunction in the early CP (ECP) using endosonography (EUS). Methods: Asymptomatic patients with pancreatic enzyme abnormalities (AP-P; n = 56) and patients with ECP (n = 21) were determined by the absence of abnormal findings on upper gastrointestinal endoscopy, abdominal ultrasonography, and abdominal computed tomography. An Olympus EUS (GF-UCT 260; Olympus) was used to perform EUS. Open software "Image J", developed by NIH, was used to measure the surface area fraction of the designated elastic blue region. The maximum value among the pancreatic head, pancreatic body, and pancreatic tail was defined as the ELST-blue score. The exocrine and endocrine pancreatic functions were evaluated using the N-benzoyl-l-tyrosyl-p-aminobenzoic acid (BT-PABA) test and homeostasis model assessment of ß-cell function (HOMA-ß) value, respectively. Results: EUS score, lobularity, and hyperechoic foci/strands in patients with ECP were significantly (p < 0.001) higher than those in patients with AP-P. In addition, there were no significant differences in the BT-PABA test (73.1 ± 25.5, 68.5 ± 15.6) and HOMA-ß (93.1 ± 67.4, 73.5 ± 139.7) between patients with ECP and AP-P. The ELST-blue score measured by image J as the quantification tool in EUS strain elastography in patients with ECP was significantly higher (p = 0.002) than that in patients with AP-P. Interestingly, the ELST-blue score was significantly associated with HOMA-ß in patients with ECP. Conclusions: The ELST-blue score may be a useful tool for the evaluation of endocrine pancreatic dysfunction in the ECP.

CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism.

Mutations in the mitochondrial cristae protein CHCHD2 lead to a late-onset autosomal dominant form of Parkinson's disease (PD) which closely resembles idiopathic PD, providing the opportunity to gain new insights into the mechanisms of mitochondrial dysfunction contributing to PD. To begin to address this, we used CRISPR genome-editing to generate CHCHD2 T61I point mutant mice. CHCHD2 T61I mice had normal viability, and had only subtle motor deficits with no signs of premature dopaminergic (DA) neuron degeneration. Nonetheless, CHCHD2 T61I mice exhibited robust molecular changes in the brain including increased CHCHD2 insolubility, accumulation of CHCHD2 protein preferentially in the substantia nigra (SN), and elevated levels of α-synuclein. Metabolic analyses revealed an increase in glucose metabolism through glycolysis relative to the TCA cycle with increased respiratory exchange ratio, and immune-electron microscopy revelated disrupted mitochondria in DA neurons. Moreover, spatial genomics revealed decreased expression of mitochondrial complex I and III respiratory chain proteins, while proteomics revealed increased respiratory chain and other mitochondrial protein-protein interactions. As such, the CHCHD2 T61I point-mutation mice exhibit robust mitochondrial disruption and a consequent metabolic shift towards glycolysis. These findings thus establish CHCHD2 T61I mice as a new model for mitochondrial-based PD, and implicate disrupted respiratory chain function as a likely causative driver.

Salvage robotic-assisted radical prostatectomy in a patient with recurrence after two sessions of heavy ion radiotherapy.

Salvage radical prostatectomy is a postradiation treatment for patients with localized prostate cancer. In 2016, Ozu et al. (Ozu C, Aoki K, Nakamura K, Yagi Y, Muro Y, Nishiyama T, et al. The initial case report: salvage robotic assisted radical prostatectomy after heavy ion radiotherapy. Urol Case Rep 2016;7:45-7) first reported salvage robotic-assisted radical prostatectomy (sRARP) after heavy-ion radiotherapy (HIRT). Thereafter, sRARP has been performed in >100 cases. However, it is currently avoided owing to some difficulties. Herein, we report about sRARP in a 67-year-old man who received two sessions of HIRT despite some expected challenges. He was initially treated with HIRT for prostate cancer in 2009 and received the second HIRT as salvage treatment for local recurrence in 2016. In 2019, he had biochemical recurrence and underwent sRARP. There were no significant peri- or postoperative complications. Subsequently, 12 months after sRARP, hormonal therapy was introduced after the diagnosis of biochemical recurrence. The patient's prostate-specific antigen level is currently undetectable.

Foreign Body Granuloma After Embolization of Internal Iliac Artery Aneurysm Using N-Butyl-2-Cyanoacrylate: A Case Report.

Foreign body granulomas following endovascular treatment are rare complications and are mostly reported in the brain or cutaneous vascular tissues. To the best of our knowledge, no study to date has reported on foreign body granulomas in the abdomen after injection of N-butyl-2-cyanoacrylate (NBCA)-lipiodol mixture into the abdominal arteries. This study reports a case of foreign body granuloma that appeared 12 months after the embolization of a right internal iliac artery aneurysm using an NBCA-lipiodol mixture, which posed challenges in differentiation from malignant tumors. We present a 77-year-old man who underwent embolization of a right internal iliac artery aneurysm and open surgical repair of an abdominal aortic aneurysm. A contrast-enhanced CT performed 12 months postoperatively revealed a right-sided retroperitoneal mass surrounding the iliopsoas muscle. The mass contained multiple, small, hyperdense areas, suggesting the migration of the NBCA-lipiodol mixture casts from the embolized right internal iliac artery aneurysm. The differential diagnosis included foreign body granuloma, lymphoma, and sarcoma. A biopsy of the lesion revealed a granuloma with various stages of inflammation, no hemosiderin deposition, multinucleated giant cells, and foam cells containing fat, and was diagnosed with a foreign body granuloma. Special staining for microorganisms revealed no findings suggestive of infection. Because the patient was asymptomatic, no treatment was administered. Contrast-enhanced CT at 24 months postoperatively showed shrinkage of the mass, with no change in size noted at 48 months postoperatively. This report highlights a foreign body granuloma that mimicked malignant tumors. Extravascular migration of the NBCA-lipiodol mixture casts likely contributed to granuloma formation. Radiologists should consider foreign body granulomas after embolization using NBCA into the abdominal arteries.

Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration.

Parkinson's disease (PD) is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but the pathophysiological mechanisms that precede and drive their death remain unknown. The activity of DA neurons is likely altered in PD, but we understand little about if or how chronic changes in activity may contribute to degeneration. To address this question, we developed a chemogenetic (DREADD) mouse model to chronically increase DA neuron activity, and confirmed this increase using ex vivo electrophysiology. Chronic hyperactivation of DA neurons resulted in prolonged increases in locomotor activity during the light cycle and decreases during the dark cycle, consistent with chronic changes in DA release and circadian disturbances. We also observed early, preferential degeneration of SNc projections, recapitulating the PD hallmarks of selective vulnerability of SNc axons and the comparative resilience of ventral tegmental area axons. This was followed by eventual loss of midbrain DA neurons. Continuous DREADD activation resulted in a sustained increase in baseline calcium levels, supporting an important role for increased calcium in the neurodegeneration process. Finally, spatial transcriptomics from DREADD mice examining midbrain DA neurons and striatal targets, and cross-validation with human patient samples, provided insights into potential mechanisms of hyperactivity-induced toxicity and PD. Our results thus reveal the preferential vulnerability of SNc DA neurons to increased neural activity, and support a potential role for increased neural activity in driving degeneration in PD.

Penetrating cardiac injury caused by multiple rib fractures following high-energy trauma: Usefulness of the exploratory video-assisted thoracoscopic surgery.

Background: Penetrating cardiac injuries are usually fatal and associated with poor survival rates. Case Presentation: A 69-year-old man was injured in a motor vehicle accident and suffered from left hemothorax and multiple rib fractures near the heart. A comprehensive assessment raised suspicions of lacerated pericardium and myocardial injury. Consequently, a thoracoscopy was performed 9 h after injury. A penetrating cardiac injury was detected and surgically treated via video-assisted thoracoscopic surgery. The patient recovered uneventfully and was discharged on postoperative day 16. Conclusion: Exploratory video-assisted thoracoscopic surgery may play a key role in the primary diagnosis of patients with high-energy chest traumas with cardiac injury and simultaneously allow for the appropriate surgical interventions.

Safe and promising outcomes of in-hospital preoperative rehabilitation for coronary artery bypass grafting after an acute coronary syndrome.

OBJECTIVE: In patients with stable hemodynamic status after an acute coronary syndrome (ACS), coronary artery bypass grafting (CABG) after preoperative investigations can provide outcomes comparable to those of emergency surgery. However, no established guidelines exist regarding the preparation period before surgery. We report the results of the use of an inpatient cardiac rehabilitation program followed by CABG after an ACS to improve post-operative outcomes and prognosis after discharge. METHODS: From 2005 to 2017, 471 patients underwent either isolated or combined CABG at our institution, and of those, the 393 who received isolated CABG were included in the analysis. Twenty-seven patients (6.9%) were admitted with ACS and underwent preoperative rehabilitation before undergoing CABG, with a subsequent review of surgical morbidity and mortality rates. Propensity score matching yielded a cohort of 26 patients who underwent preoperative rehabilitation (group A) and 26 controls (group B). Preoperative characteristics were similar between groups. RESULTS: The completion rate of the rehabilitation program was 96.3%. All programs were conducted with inpatients, with an average length of stay of 23 ± 12 days. All patients completed in-bed exercises, and 85% completed out-of-bed exercises. The 30-day postoperative mortality was 0% in both groups A and B, and the rate of postoperative major adverse cardiac or cerebrovascular events at 12 months did not differ significantly between groups (7.7% vs 3.9%, respectively; p = 1.0). The duration of mechanical ventilation (1.3 ± 0.3 vs 1.5 ± 0.3 days, respectively; p = 0.633), length of intensive care unit stay (4.4 ± 2.1 vs 4.8 ± 2.3 days, respectively; p = 0.584) and length of hospital stay (25 ± 13 vs 22 ± 9 days, respectively; p = 0.378) did not differ significantly between groups. CONCLUSIONS: No complications of preoperative rehabilitation were observed, suggesting that it is an acceptable option for patients who experience ACS and undergo CABG. These results are promising in offering more robust designs of future trials.

Fewer systematic prostate core biopsies in clinical stage T1c prostate cancer leads to biochemical recurrence after brachytherapy as monotherapy.

BACKGROUND: After brachytherapy, fewer prostate biopsy cores at diagnosis can underestimate the pathological characteristics of prostate cancer (PCa) with lower concordance, resulting in improper treatment, particularly in patients with low-risk nonpalpable cT1c PCa. The aim of this study was to assess the relationship between the number of biopsy cores at diagnosis and long-term clinical outcomes after brachytherapy for cT1c PCa. METHODS: We reviewed 516 patients with localized cT1c PCa with Gleason scores of 3 + 3 = 6 or 3 + 4 = 7 who underwent brachytherapy as monotherapy without hormonal therapy between January 2005 and September 2014 at our institution. Clinical staging was based on the American Joint Committee on Cancer manual for staging. Thus, the cT1c category is based solely on digital rectal examination. The primary outcome was biochemical recurrence (BCR). Based on the optimized cutoff value for biopsy core number obtained from receiver operating characteristic analysis, patients were divided into the biopsy cores ≤8 (N = 123) and ≥9 (N = 393) groups. The BCR-free survival rate was compared between the groups. Prognostic factors for BCR were evaluated, including age, initial prostate-specific antigen (PSA) level, Gleason score, positive core rate, PSA density, prostate magnetic resonance imaging findings, and biopsy core number. RESULTS: The median patient age was 66.0 years (interquartile range [IQR]: 61.0-71.0 years), and the median follow-up time was 11.1 years (IQR: 9.5-13.3 years). The median number of core biopsies was 12 (IQR: 9-12). The area under the curve was 0.637 (95% confidence interval [CI]: 0.53-0.75), and the optimal biopsy core cutoff value for BCR prediction was 8.5 (sensitivity = 43.5%, specificity = 77.1%). Although fewer patients had Gleason scores of 3 + 4 = 7 (19/123 [15%] vs. 125/393 [32%], p < 0.02) in the biopsy cores ≤8 group, the 10-year BCR-free survival rate was significantly lower in the biopsy cores ≤8 group than in the biopsy cores ≥9 group (93.8% vs. 96.3%, p < 0.05). Multivariate analysis revealed that a lower biopsy core number (hazard ratio: 0.828, 95% CI: 0.71-0.97, p < 0.03) and a Gleason score of 3 + 4 = 7 (hazard ratio: 3.26, 95% CI: 1.37-7.73, p < 0.01) significantly predicted BCR. CONCLUSIONS: A low number of prostate core biopsies results in worse BCR-free survival after brachytherapy as monotherapy in patients with cT1c PCa.

Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.

Respiratory chain dysfunction can decrease ATP and increase reactive oxygen species (ROS) levels. Despite the importance of these metabolic parameters to a wide range of cellular functions and disease, we lack an integrated understanding of how they are differentially regulated. To address this question, we adapted a CRISPRi- and FACS-based platform to compare the effects of respiratory gene knockdown on ROS to their effects on ATP. Focusing on genes whose knockdown is known to decrease mitochondria-derived ATP, we showed that knockdown of genes in specific respiratory chain complexes (I, III, and CoQ10 biosynthesis) increased ROS, whereas knockdown of other low ATP hits either had no impact (mitochondrial ribosomal proteins) or actually decreased ROS (complex IV). Moreover, although shifting metabolic conditions profoundly altered mitochondria-derived ATP levels, it had little impact on mitochondrial or cytosolic ROS. In addition, knockdown of a subset of complex I subunits-including NDUFA8, NDUFB4, and NDUFS8-decreased complex I activity, mitochondria-derived ATP, and supercomplex level, but knockdown of these genes had differential effects on ROS. Conversely, we found an essential role for ether lipids in the dynamic regulation of mitochondrial ROS levels independent of ATP. Thus, our results identify specific metabolic regulators of cellular ATP and ROS balance that may help dissect the roles of these processes in disease and identify therapeutic strategies to independently target energy failure and oxidative stress.

Role of dopamine neuron activity in Parkinson's disease pathophysiology.

Neural activity is finely tuned to produce normal behaviors, and disruptions in activity likely occur early in the course of many neurodegenerative diseases. However, how neural activity is altered, and how these changes influence neurodegeneration is poorly understood. Here, we focus on evidence that the activity of dopamine neurons is altered in Parkinson's disease (PD), either as a compensatory response to degeneration or as a result of circuit dynamics or pathologic proteins, based on available human data and studies in animal models of PD. We then discuss how this abnormal activity may augment other neurotoxic phenomena in PD, including mitochondrial deficits, protein aggregation and spread, dopamine toxicity, and excitotoxicity. A more complete picture of how activity is altered and the resulting effects on dopaminergic neuron health and function may inform future therapeutic interventions to target and protect dopamine neurons from degeneration.

Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Mice Consuming Alcohol Attenuates Glycolysis.

mTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use and abuse. We report that activation of mTORC1 in the nucleus accumbens (NAc) of mice consuming alcohol promotes the translation of microRNA (miR) machinery components and the upregulation of microRNAs (miRs) expression including miR34a-5p. In parallel, we detected a paradoxical mTORC1-dependent repression of translation of transcripts including Aldolase A, an essential glycolytic enzyme. We found that miR34a-5p in the NAc targets Aldolase A for translation repression and promotes alcohol intake. Our data further suggest that glycolysis is inhibited in the NAc manifesting in an mTORC1-dependent attenuation of L-lactate, the end product of glycolysis. Finally, we show that systemic administration of L-lactate attenuates mouse excessive alcohol intake. Our data suggest that alcohol promotes paradoxical actions of mTORC1 on translation and glycolysis which in turn drive excessive alcohol use.

NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62.

NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding IKBKG gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62.

Iatrogenic aortic dissection during aortic root replacement in an older Loeys-Dietz syndrome type III patient with no family history of aortic disease: a case report.

BACKGROUND: Iatrogenic aortic dissection during cardiac surgery is a rare but critical complication. At present, no strategies have been developed to prevent it. We herein report a case of intraoperative aortic dissection during aortic root replacement in an older patient with Loeys-Dietz syndrome type III who had no family history of aortic disease. CASE PRESENTATION: A 60-year-old man was admitted to the hospital for Stanford type B acute aortic dissection and given conservative treatment. He was found to have aortic root dilatation and severe aortic regurgitation. Thus, elective Bentall procedure was performed. Postoperative computed tomography showed new Stanford type A aortic dissection that may have developed due to aortic cannulation during surgery. The patient was given conservative treatment and successfully discharged to home at postoperative day 34. Although he had no family history of aortic disease, a genetic test revealed an unreported SMAD3 frameshift mutation (c.742_749dup, p. Gln252ThrfsTer7), and the patient was diagnosed with Loeys-Dietz syndrome type III. CONCLUSION: In patients with connective tissue disorder, aortic manipulations may become the cause of critical complications. Avoiding the use of invasive techniques, such as cannulation and cross-clamping, and implementing treatment strategies, such as perfusion from other sites than the aorta and open distal anastomosis, can prevent these complications, and may be useful treatment modalities. The possibility of connective tissue disease should be considered even if the patient is older and has no family history of aortic disease.

Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.

Respiratory chain dysfunction can decrease ATP and increase reactive oxygen species (ROS) levels. Despite the importance of these metabolic parameters to a wide range of cellular functions and disease, we lack an integrated understanding of how they are differentially regulated. To address this question, we adapted a CRISPRi- and FACS- based platform to compare the effects of respiratory gene knockdown on ROS to their effects on ATP. Focusing on genes whose knockdown is known to decrease mitochondria-derived ATP, we showed that knockdown of genes in specific respiratory chain complexes (I, III and CoQ10 biosynthesis) increased ROS, whereas knockdown of other low ATP hits either had no impact (mitochondrial ribosomal proteins) or actually decreased ROS (complex IV). Moreover, although shifting metabolic conditions profoundly altered mitochondria-derived ATP levels, it had little impact on mitochondrial or cytosolic ROS. In addition, knockdown of a subset of complex I subunits-including NDUFA8, NDUFB4, and NDUFS8-decreased complex I activity, mitochondria-derived ATP and supercomplex level, but knockdown of these genes had differential effects on ROS. Conversely, we found an essential role for ether lipids in the dynamic regulation of mitochondrial ROS levels independent of ATP. Thus, our results identify specific metabolic regulators of cellular ATP and ROS balance that may help dissect the roles of these processes in disease and identify therapeutic strategies to independently target energy failure and oxidative stress.

Protocol to combine brain sections from multiple mice into a single block for spatial transcriptomic analyses.

Spatial transcriptomics couples visual spatial markers with gene expression levels, but slide space and cost limit the number of samples that can be processed. Here, we present a protocol for mounting brains from multiple mice onto a single capture area of a spatial transcriptomics slide. We describe steps for conjoining frozen hippocampal sections from different brains into a single cryostat block, reducing the quantity of reagents required. This protocol is applicable to a range of existing spatial genomics platforms. For complete details on the use and execution of this protocol, please refer to Li et al. (2023).1.

On the reaction-diffusion type modelling of the self-propelled object motion.

In this study, we propose a mathematical model of self-propelled objects based on the Allen-Cahn type phase-field equation. We combine it with the equation for the concentration of surfactant used in previous studies to construct a model that can handle self-propelled object motion with shape change. A distinctive feature of our mathematical model is that it can represent both deformable self-propelled objects, such as droplets, and solid objects, such as camphor disks, by controlling a single parameter. Furthermore, we demonstrate that, by taking the singular limit, this phase-field based model can be reduced to a free boundary model, which is equivalent to the [Formula: see text]-gradient flow model of self-propelled objects derived by the variational principle from the interfacial energy, which gives a physical interpretation to the phase-field model.

Early clinical outcomes and molecular smooth muscle cell phenotyping using a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome.

OBJECTIVES: Patients with Loeys-Dietz syndrome demonstrate a heightened risk of distal thoracic aortic events after valve-sparing aortic root replacement. This study assesses the clinical risks and hemodynamic consequences of a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome and characterizes smooth muscle cell phenotype in Loeys-Dietz syndrome aneurysmal and normal-sized downstream aorta. METHODS: Patients with genetically confirmed Loeys-Dietz syndrome (n = 8) underwent prophylactic aortic arch replacement during valve-sparing aortic root replacement. Four-dimensional flow magnetic resonance imaging studies were performed in 4 patients with Loeys-Dietz syndrome (valve-sparing aortic root replacement + arch) and compared with patients with contemporary Marfan syndrome (valve-sparing aortic root replacement only, n = 5) and control patients (without aortopathy, n = 5). Aortic tissues from 4 patients with Loeys-Dietz syndrome and 2 organ donors were processed for anatomically segmented single-cell RNA sequencing and histologic assessment. RESULTS: Patients with Loeys-Dietz syndrome valve-sparing aortic root replacement + arch had no deaths, major morbidity, or aortic events in a median of 2 years follow-up. Four-dimensional magnetic resonance imaging demonstrated altered flow parameters in patients with postoperative aortopathy relative to controls, but no clear deleterious changes due to arch replacement. Integrated analysis of aortic single-cell RNA sequencing data (>49,000 cells) identified a continuum of abnormal smooth muscle cell phenotypic modulation in Loeys-Dietz syndrome defined by reduced contractility and enriched extracellular matrix synthesis, adhesion receptors, and transforming growth factor-beta signaling. These modulated smooth muscle cells populated the Loeys-Dietz syndrome tunica media with gradually reduced density from the overtly aneurysmal root to the nondilated arch. CONCLUSIONS: Patients with Loeys-Dietz syndrome demonstrated excellent surgical outcomes without overt downstream flow or shear stress disturbances after concomitant valve-sparing aortic root replacement + arch operations. Abnormal smooth muscle cell-mediated aortic remodeling occurs within the normal diameter, clinically at-risk Loeys-Dietz syndrome arch segment. These initial clinical and pathophysiologic findings support concomitant arch replacement in Loeys-Dietz syndrome.

Apolipoprotein A2 isoforms associated with exocrine pancreatic insufficiency in early chronic pancreatitis.

BACKGROUND AND AIM: Apolipoprotein A2 (apoA2) isoforms have been reported to undergo the aberrant processing in pancreatic cancer and pancreatic risk populations compared with that in healthy subjects. This study aimed to clarify whether apoA2 isoforms were as useful as N-benzoyl-p-aminobenzoic acid (BT-PABA) test for exocrine pancreatic dysfunction markers in patients with early chronic pancreatitis (ECP). METHODS: Fifty consecutive patients with functional dyspepsia with pancreatic enzyme abnormalities (FD-P) (n = 18), with ECP (n = 20), and asymptomatic patients with pancreatic enzyme abnormalities (AP-P) (n = 12) based on the Rome IV classification and the Japan Pancreatic Association were enrolled in this study. The enrolled patients were evaluated using endoscopic ultrasonography and endoscopic ultrasonography elastography. Five pancreatic enzymes were estimated. Pancreatic exocrine function was analyzed using the BT-PABA test. Lighter and heavier apoA2 isoforms, AT and ATQ levels were measured by enzyme-linked immunosorbent assay methods. RESULTS: There were no significant differences in clinical characteristics such as age, gender, body mass index, alcohol consumption and smoking among patients with AP-P, FD-P, and ECP. The BT-PABA test and lighter apoA2 isoform, AT level in the enrolled patients had a significant correlation (P < 0.01). The BT-PABA test in patients with ECP was significantly lower (P = 0.04) than that in AP-P. ApoA2-AT level in patients with ECP was lower than that in AP-P, albeit, insignificantly. Interestingly, apo A2-AT level was significantly (P = 0.041) associated with exocrine pancreatic insufficiency by multiple logistic regression analysis. CONCLUSIONS: ApoA2-AT level is a useful tool to evaluate exocrine pancreatic insufficiency in the early stage of chronic pancreatitis.

Comparison of pancreatic enzyme abnormalities and protease-activated receptor-2-positive eosinophils in the duodenum of patients with functional dyspepsia-irritable bowel syndrome overlap with functional dyspepsia alone in Asian populations.

BACKGROUND AND AIM: Some patients with functional gastrointestinal disorders exhibit pancreatic dysfunctions and pancreatic enzyme abnormalities. Thus, we aimed to clarify whether significant differences in clinical characteristics, prevalence of pancreatic enzyme abnormalities, duodenal inflammation, and protease-activated receptor 2 (PAR2) expression levels related to hypersensitivity exist between functional dyspepsia (FD) alone and FD-irritable bowel syndrome (IBS) overlap group. METHODS: Ninety-three patients based on the Rome IV criteria, FD alone (n = 44) and FD overlapped with IBS (n = 49) group were enrolled. The patients scored their own clinical symptoms after consuming high-fat meals. Serum trypsin, PLA2, lipase, p-amylase, and elastase-1 levels were measured. PAR2, eotaxin-3, and TRPV4 mRNA levels in duodenum were determined using real-time polymerase chain reaction methods. PRG2- and PAR2 in the duodenum were evaluated using immunostaining. RESULTS: FD score and global GSRS in patients with FD-IBS overlap were significantly higher than FD alone. Although the prevalence of pancreatic enzyme abnormalities in patients with FD alone was significantly (P < 0.01) higher than that in FD-IBS overlap, the ratio of aggravation of clinical symptoms following high-fat intake in patients with FD-IBS overlap was significantly higher (P = 0.007) than that in patients with FD alone. PAR2- and PRG2-double positive cells were localized in the degranulated eosinophils in the duodenum of patients with FD-IBS overlap. The number of PAR2- and PRG2-double positive cells in FD-IBS overlap was significantly (P < 0.01) higher than FD alone. CONCLUSIONS: Pancreatic enzyme abnormalities and PAR2 expression on degranulated eosinophils infiltrations in the duodenum may be associated with the pathophysiology of patients with FD-IBS overlap in Asian populations.

Smooth Muscle Cell Klf4 Expression Is Not Required for Phenotype Modulation or Aneurysm Formation in Marfan Syndrome Mice-Brief Report.

BACKGROUND: Smooth muscle cell (SMC) phenotypic reprogramming toward a mixed synthetic-proteolytic state is a central feature of aortic root aneurysm in Marfan syndrome (MFS). Previous work identified Klf4 as a potential mediator of SMC plasticity in MFS. METHODS: MFS (Fbn1C1041G/+) mouse strains with an inducible vascular SMC fluorescent reporter (MFSSMC) with or without SMC-specific deletion of Klf4 exons 2 to 3 (MFSSMC-Klf4Δ) were generated. Simultaneous SMC tracing and Klf4 loss-of-function (Klf4Δ mice) was induced at 6 weeks of age. Aneurysm growth was assessed via serial echocardiography (4-24 weeks). Twenty-four-week-old mice were assessed via histology, RNA in situ hybridization, and aortic single-cell RNA sequencing. RESULTS: MFS mice demonstrated progressive aortic root dilatation compared with control (WTSMC) mice regardless of Klf4 genotype (P<0.001), but there was no difference in aneurysm growth in MFSSMC-Klf4Δ versus MFSSMC (P=0.884). Efficient SMC Klf4 deletion was confirmed via lineage-stratified genotyping, RNA in situ hybridization, and immunohistochemistry. Single-cell RNA sequencing of traced SMCs revealed a highly similar pattern of phenotype modulation marked by loss of contractile markers (eg, Myh11, Cnn1) and heightened expression of matrix genes (eg, Col1a1, Fn1) between Klf4 genotypes. Pseudotemporal quantitation of SMC dedifferentiation confirmed that Klf4 deletion did not alter the global extent of phenotype modulation, but reduced expression of 23 genes during this phenotype transition in MFSSMC-Klf4Δmice, including multiple chondrogenic genes expressed by only the most severely dedifferentiated SMCs (eg, Cytl1, Tnfrsf11b). CONCLUSIONS: Klf4 is not required to initiate SMC phenotype modulation in MFS aneurysm but may exert regulatory control over chondrogenic genes expressed in highly dedifferentiated SMCs.