Combination of high-density cholesterol level, elastic score, and severity of exocrine pancreatic dysfunction may be useful for a predictive factor for patients with early chronic pancreatitis.

BACKGROUND: This study aimed to clarify whether any risk factors including clinical characteristics, endosonographic features, and exocrine pancreatic dysfunction may be useful for a predictive factor for patients with early chronic pancreatitis. METHODS: A total of 163 consecutive patients that presented with functional dyspepsia with pancreatic enzyme abnormalities (FD-P) (n = 46), early chronic pancreatitis (ECP) (n = 47), and asymptomatic patients with pancreatic enzyme abnormalities (AP-P) (n = 70) based on the Rome III classification and the Japan Pancreatic Association were included in this study. The enrolled patients were evaluated using endosonography (EUS) and EUS elastography. The levels of the five pancreatic enzymes were measured. Pancreatic exocrine function was analyzed using N-benzoyl-l-tyrosyl-p-aminobenzoic acid (BT-PABA). 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 ratio of BT-PABA test less than 35% in patients with ECP was significantly (P = 0.043) higher than in AP-P patients. Elastic score was a useful tool to differentiate the FD-P group from the ECP group. The high-density cholesterol levels in patients with ECP were significantly lower than those in AP-P. In addition, the combination of total and high-density cholesterol levels, BT-PABA test, and elastic score has a higher area under the curve value (0.708) of patients with ECP than in the other groups. CONCLUSIONS: The combination of high-density cholesterol levels, elastic score, and severity of exocrine pancreatic dysfunction may be useful for a predictive factor for patients with ECP.

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.

Comparison of clinical characteristics, eating behaviors, and clinical symptoms following fat intake in functional dyspepsia with functional dyspepsia with pancreatic enzyme abnormalities between Singapore and Japan.

BACKGROUND AND AIM: To clarify whether there were any significant differences in clinical symptoms and eating patterns between functional dyspepsia (FD) patients and FD with pancreatic enzyme abnormalities (FD-P) patients as refractory FD, we compared these factors in multicenter studies in Singapore and Japan. METHODS: One hundred ninety-eight consecutive patients presenting with FD (n = 88), FD-P patients (n = 81) based on Rome III classification and controlled group (n = 39) recruited from six institutions in Singapore and Japan. Clinical characteristics, clinical symptoms for dietary fat intake, and eating behaviors were estimated using questionnaires. Anxiety and health-related quality of life were determined by STAI-state/-trait and SF-8, respectively. RESULTS: There were no significant differences in age, sex, BMI, smoking, alcohol intake, past medical history, and history of allergy in FD and FD-P patients between Singapore and Japan. There were no significant differences in FD subtypes, gastrointestinal symptom rating scale score, severity of FD symptoms, and eating pattern in Singapore and Japan. Moreover, there were significant differences in certain eating behaviors between FD and FD-P patients in Singapore and Japan. Interestingly, epigastric pain and early satiety following fat meals in FD-P patients were significantly (P = 0.003 and P = 0.008, respectively) higher compared with those in FD patients in Japan. Physical component score in FD-P patients was significantly (P = 0.019) disturbed compared with those in FD patients in Japan. CONCLUSIONS: Epigastric pain and early satiety following fat meals in FD-P patients may be useful tools to differentiate FD-P patients from FD patients in Japan.

State of anxiety may be associated with exocrine pancreatic insufficiency in functional dyspepsia patients with pancreatic enzyme abnormalities.

We have reported that refractory functional dyspepsia patients with pancreatic enzyme abnormalities (FD-P). We tried to analyze the prevalence of exocrine pancreatic insufficiency (EPI) in FD-P patients to clarify whether the pathophysiology of FD patients including clinical symptoms and quality of life were associated with EPI. We enrolled forty-nine patients presenting with typical symptoms of FD-P patients (n = 20) and asymptomatic patients with pancreatic enzyme abnormalities (AP-P) (n = 29). Five pancreatic enzymes (p-amylase, lipase, elastase-1, trypsin, and PLA2) were measured and STAI-state/-trait and SF-8 were evaluated. Pancreatic exocrine function was analyzed using N-benzoyl-l-tyrosyl-p-aminobenzoic acid (BT-PABA). There were no significant differences in patient background between FD-P and AP-P patients. BT-PABA test scores for FD-P patients (61.67 ±â€…5.55) were significantly (p = 0.01) lower than in AP-P patients (95.38 ±â€…2.36). Physical component scale (PCS) in FD-P patients was significantly (p = 0.002) lower than that in AP-P patients. STAI-state was relatively (p = 0.054) associated with BT-PABA test in FD-P and AP-P patients by multiple logistic regression analysis. The prevalence of EPI in FD-P patients was significantly higher than that in AP-P patients and was relatively associated with state of anxiety. Further studies will be needed to clarify how EPI or pancreatic enzyme abnormalities are associated with the pathophysiology of FD-P patients.

Long-Term Vonoprazan and Acotiamide-Refractory Patients With Functional Dyspepsia Partly Exhibit Pancreatic Enzyme Abnormalities.

BACKGROUND: Although a new potassium-competitive acid blocker (P-CAB) vonoprazan has been developed in Japan, no data are available regarding long-term vonoprazan or vonoprazan and acotiamide combination treatment in patients with functional dyspepsia (FD). METHODOLOGY: A total of 73 consecutive patients with FD diagnosed according to the Rome III classification were enrolled. Forty-two patients with FD were treated with vonoprazan monotherapy and thirty-one patients with FD were treated with vonoprazan and acotiamide combination therapy for 24 weeks. The levels of five pancreatic enzymes were measured, and the overall treatment efficacy (OTE) was defined as the ratio of FD patients with improved or unchanged in all items of GSRS and FD symptom scores after the treatment. RESULTS: Treatment with vonoprazan monotherapy and vonoprazan and acotiamide combination therapy significantly improved FD symptoms. There were no significant differences in OTE between patients treated with vonoprazan monotherapy (42.9%) and those treated with vonoprazan and acotiamide combination therapy (52%). There were no significant differences in duodenal eosinophilic infiltration between the improved and unimproved groups treated with vonoprazan alone and vonoprazan and acotiamide combination therapy, respectively. In contrast, there was a significant difference (P = 0.004) in the ratio of pancreatic enzyme abnormalities between the improved and unimproved patients treated with vonoprazan monotherapy and those treated with vonoprazan and acotiamide combination therapy. CONCLUSIONS: Long-term vonoprazan alone or vonoprazan and acotiamide combination therapy significantly improved each FD symptom. The OTE in patients treated with vonoprazan alone or vonoprazan and acotiamide combination therapy was only 50%. Long-term vonoprazan and acotiamide combination therapy may differentiate patients with pancreatic enzyme abnormalities from those with FD.

Genotypes of carboxypeptidase A1 and gamma-glutamyltransferase 1 may be useful tools for the diagnosis and the predictor of worrisome features of intraductal papillary mucinous neoplasm in Japan.

Background and Aim: This study aimed to clarify whether several single-nucleotide polymorphisms (SNPs)-related chronic pancreatitis such as carboxypeptidase A1 (CPA1), carboxypeptidase B1 (CPB1), Gamma-glutamyltransferase 1 (GGT1), G-protein-coupled receptor Class C Group 6 Member A (GPRC6A), and serine protease inhibitor, Kazal type 1 (SPINK-1) genotypes were associated with clinical characteristics of patients with intraductal papillary mucinous neoplasm (IPMN) and worrisome features of IPMN. Methods: We enrolled 100 patients with IPMN and 116 patients as a control. Serum p-amylase, lipase, trypsin, phospholipase A2 (PLA2), and elastase-1 levels were measured. An Olympus EUS (GF-UCT 260) was used to perform endosonography in 100 patients with IPMN. Total EUS score was evaluated using endosonography. DNA was isolated from the duodenal tissue using a commercial system and polymerase chain reaction (PCR) was performed on 7500 Fast PCR System. Results: There were no associations between glucose tolerances, lipid levels and genotypes of CPA1, GGT1, GPRC6A, and SPINK-1 in patients with IPMN. CPA1 genotype was significantly associated with the pathophysiology of IPMN. Then, GGT1 genotype was also significantly associated with EUS total score and the size of cyst more than 20 mm and more than 30 mm as one of worrisome features of IPMN. Conclusion: Genotypes of carboxypeptidase A1 and gamma-glutamyltransferase 1 may be useful tools for the diagnosis and the predictor of worrisome features of IPMN.

Trypsin may be associated with duodenal eosinophils through the expression of PAR2 in early chronic pancreatitis and functional dyspepsia with pancreatic enzyme abnormalities.

BACKGROUND: Early chronic pancreatitis (ECP) has been reported to advance into chronic pancreatitis, it may be critical to differentiate the pathophysiology of ECP and functional dyspepsia (FD) in patients with pancreatic enzyme abnormalities (FD-P). This study aimed to clarify differences in the pathophysiology of ECP and FD-P and to determine whether duodenal inflammatory responses in the two diseases were associated with protease-activated receptor (PAR) 2, as the trypsin receptor. METHODS: Eighty patients who presented with FD-P and ECP were enrolled. In duodenal specimens, PAR2 mRNA levels were determined using real-time PCR. Using immunostaining, CD68-, GLP-1-, PRG2-, and CCR2-positive cells, tight junction proteins, and PAR 2 were evaluated. RESULTS: There were no significant differences in clinical symptoms and gastric motility between ECP and FD-P patients. The CD68-positive cells infiltrations and occludin expression levels in the duodenal mucosa of patients with FD-P were significantly (p<0.001 and p = 0.048, respectively) lower than those in patients with ECP. Although serum trypsin levels in ECP and FD-P patents were significantly (p<0.05 and p<0.001, respectively) associated with duodenal eosinophils counts, elevated trypsin levels were not significantly associated with degranulated eosinophils, occludin, claudin-1 and ZO-1 expression levels in the duodenum of either group. PAR2 mRNA levels were increased in the duodenum of patients with ECP and FD-P. PAR2 was localized in the epithelial cells of the duodenal mucosa and the surface of degranulated eosinophils in ECP and FD-P patients. CONCLUSIONS: Elevated trypsin levels might be partly associated with duodenal inflammatory responses through PAR2-related degranulated eosinophils and the reduction of occludin in patients with ECP and FD-P.

Cerebromalacia with epilepsy and cortical blindness in a laboratory Japanese macaque (Macaca fuscata).

The authors performed a pathological examination of a 5-year-old female laboratory Japanese monkey who developed cortical blindness and epileptic seizures. Generalized, tonic-clonic seizures started to occur during behavioral training to get the animal to enter a carrying cage for future psychological experiments. Blindness was suspected because of a lack of approaching behavior toward foods such as fruits. Although the monkey was extensively treated with anticonvulsants, the clinical signs did not improve. An increased serum creatine phosphokinase (CPK) level and bilateral occipital brain atrophy were detected. Histopathologically, a severe degree of cerebromalacia was detected bilaterally in the occipital lobe, and necrosis and gliosis were seen mainly in the temporal lobe. Focal inflammation was found in the meninges. No other changes were observed in other nervous tissues or organs, and no signs of a parasitic or viral infection were found in the systemic organs. Spontaneously occurring lesions in the central nervous system have been rarely reported in laboratory monkeys. In the present case, the cause of cerebromalacia could not be confirmed, but the relationship between symptoms such as abnormal vision and the presence of brain lesions was distinct. The authors believe that this case is a valuable historical control case for the laboratory Japanese macaque.

iNOS inhibitor, L-NIL, reverses burn-induced glycogen synthase kinase-3ß activation in skeletal muscle of rats.

OBJECTIVES: Recent studies suggest that activation of glycogen synthase kinase (GSK)-3ß may be involved in burn injury-induced metabolic derangements and protein breakdown in skeletal muscle. However, the mechanism for GSK-3ß activation after burn injury is unknown. To investigate the role of inducible nitric oxide synthase (iNOS) in this scenario, a major mediator of inflammation, we examined the effects of a specific inhibitor for iNOS, L-NIL, on GSK-3ß activity in skeletal muscle of burned rats. MATERIALS/METHODS: Full-thickness third degree burn injury comprising 40% of total body surface area was produced under anesthesia in male Sprague-Dawley rats (160-190g) by immersing the back of the trunk for 15s and the abdomen for 8s in 80°C water. Burned and sham-burned rats were treated with L-NIL (60mg/kg BW, b.i.d., IP) or phosphate-buffered saline for three days. GSK-3ß activity in skeletal muscle was evaluated by immune complex kinase assay, and by phosphorylation status of GSK-3ß and its endogenous substrate, glycogen synthase. RESULTS: GSK-3ß activity was increased in a time-dependent manner in skeletal muscle after burn injury, concomitant with the induction of iNOS expression. iNOS inhibitor, L-NIL, reverted the elevated GSK-3ß activity in skeletal muscle of burned rats, although L-NIL did not alter GSK-3ß activity in sham-burned rats. CONCLUSIONS: Our results clearly indicate that iNOS plays an important role in burn injury-induced GSK-3ß activation in skeletal muscle. These findings suggest that iNOS may contribute to burn injury-induced metabolic derangements, in part, by activating GSK-3ß.

Inducible nitric oxide synthase deficiency ameliorates skeletal muscle insulin resistance but does not alter unexpected lower blood glucose levels after burn injury in C57BL/6 mice.

Burn injury is associated with inflammatory responses and metabolic alterations including insulin resistance. Impaired insulin receptor substrate-1 (IRS-1)-mediated insulin signal transduction is a major component of insulin resistance in skeletal muscle following burn injury. To further investigate molecular mechanisms that underlie burn injury-induced insulin resistance, we study a role of inducible nitric oxide synthase (iNOS), a major mediator of inflammation, on burn-induced muscle insulin resistance in iNOS-deficient mice. Full-thickness third-degree burn injury comprising 12% of total body surface area was produced in wild-type and iNOS-deficient C57BL/6 mice. Insulin-stimulated activation (phosphorylation) of IR, IRS-1, and Akt was assessed by immunoblotting and immunoprecipitation. Insulin-stimulated glucose uptake by skeletal muscle was evaluated ex vivo. Burn injury caused induction of iNOS in skeletal muscle of wild-type mice. The increase of iNOS expression paralleled the increase of insulin resistance, as evidenced by decreased tyrosine phosphorylation of IR and IRS-1, IRS-1 expression, insulin-stimulated activation of phosphatidylinositol 3-kinase and Akt/PKB, and insulin-stimulated glucose uptake in mouse skeletal muscle. The absence of iNOS in genetically engineered mice significantly lessened burn injury-induced insulin resistance in skeletal muscle. In wild-type mice, insulin tolerance test revealed whole-body insulin resistance in burned mice compared with sham-burned controls. This effect was reversed by iNOS deficiency. Unexpectedly, however, blood glucose levels were depressed in both wild-type and iNOS-deficient mice after burn injury. Gene disruption of iNOS ameliorated the effect of burn on IRS-1-mediated insulin signaling in skeletal muscle of mice. These findings indicate that iNOS plays a significant role in burn injury-induced skeletal muscle insulin resistance.

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.