A Case of Pancreaticobiliary Maljunction with Repeated Pancreatitis Due to Protein Plugs in a Short Period.

A 70-year-old woman was admitted to the hospital 1 month prior to presentation with acute pancreatitis due to pancreaticobiliary maljunction. After discharge, she was referred for elevated hepatobiliary enzyme levels. She was diagnosed with an acute pancreatitis flare-up. Computed tomography revealed dilation of the common duct compared to the previous admission. Considering the protein plug formation as the cause, endoscopic retrograde cholangiopancreatography (ERCP) was performed after improvement. ERCP revealed a defect in the duct, suspected to be caused by protein plugs, which were removed using a balloon after endoscopic papillary balloon dilatation. An analysis revealed that this component was a protein. No recurrence of pancreatitis was observed after the treatment.

Takayasu's arteritis associated with Crohn's disease treated with infliximab.

A 23-year-old woman presented with fever, diarrhea, bloody stools, and arthralgia that did not improve despite previous treatments and was diagnosed with Crohn's disease. Remission was achieved after the introduction of infliximab, nutritional therapy, and 5-aminosalicylic acid treatment. However, the patient's blood sedimentation rate remained elevated without symptom recurrence, except for abdominal pain in the following year. Aortic wall thickening in the thoracic descending aorta was also observed on computed tomography. Accumulation in the thoracic descending aorta and abdominal aorta was confirmed using positron emission tomography-computed tomography. The patient was diagnosed with Takayasu's arteritis. The patient's abdominal symptoms resolved, and her blood sedimentation rate normalized after steroid administration.

Association of plasminogen activator inhibitor-1 and fibroblastic growth factor 21 in 3 groups of type 2 diabetes: Without overweight/obesity, free of insulin resistance, and without hepatosteatosis.

The physiological effects of fibroblast growth factor 21 (FGF21), leading to beneficial metabolic outcomes, have been extensively revealed in recent decades. Significantly elevated serum levels of FGF21 in obesity and type 2 diabetes mellitus (T2DM) are referred to as FGF21 resistance. However, Asian population tend to develop metabolic disorders at a lesser degree of obesity than those of Western. This study aimed to explore factors potentially related to serum FGF21 according to the severity of metabolic disorders in patients with T2DM. This cross-sectional study included 176 T2DM patients. The patients were categorized according to whether they had hepatic steatosis (fatty liver index [FLI] ≥ 60), insulin resistance (homeostasis model assessment of insulin resistance [HOMA-R] ≥ median), and/or overweight/obesity (body mass index [BMI] ≥ 25.0 kg/m2). Independent predictors of serum FGF21 were determined using multiple linear regression analysis in these 3 groups of T2DM patients. Circulating FGF21 levels were correlated positively with BMI, abdominal fat areas, leptin, and plasminogen activator inhibitor-1 (PAI-1). After adjustment for potential confounders, multiple linear regression analysis identified leptin as a factor strongly associated with serum FGF21 levels in all patients. Moreover, PAI-1 was a significant predictor of FGF21 in those with FLI < 60, BMI < 25.0 kg/m2, and HOMA-R < median, while leptin was the only independent factor in each of their counterparts. The factors related to serum FGF21 differ according to the severity of metabolic disorders. FGF21 appears to be independently associated with PAI-1 in T2DM patients: without overweight/obesity, those free of insulin resistance, and those without hepatic steatosis.

A Novel Missense MEN1 Mutation in a Sporadic Case of Multiple Endocrine Neoplasia Type 1 Complicated with Papillary Thyroid Carcinoma.

Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disorder, resulting from MEN1 gene abnormalities, which causes tumors mainly in the endocrine glands. We experienced a sporadic case of MEN1 complicated with papillary thyroid carcinoma (PTC) and found a novel missense mutation in the patient's MEN1 gene. Her older sister, who showed no typical symptom of MEN1, had a history of PTC, suggesting the presence of another genetic factor involved in PTC development. This case suggests the importance of an individual's genetic background in the development of MEN1 complications.

A case of vasoactive intestinal peptide-secreting tumor (VIPoma) arising from MEN1 inactivation which recurred 15 years after the initial resection.

Vasoactive intestinal peptide-secreting tumors (VIPomas) are extremely rare functional pancreatic neuroendocrine neoplasms (p-NENs) characterized by watery diarrhea, hypokalemia, and achlorhydria. Here, we report the case of a 51-year-old female patient with VIPoma that recurred after a long-term disease-free interval. This patient had been asymptomatic for approximately 15 years after the initial curative surgery for pancreatic VIPoma, with no metastasis. The patient underwent a second curative surgery for the locally recurrent VIPoma. Whole-exome sequencing of the resected tumor revealed a somatic mutation in MEN1, which is reportedly responsible not only for multiple endocrine neoplasia type 1 (MEN1) syndrome but also sporadic p-NENs. Symptoms were controlled with lanreotide before and after surgery. The patient is alive with no relapse following 14 months after surgery. This case demonstrates the importance of long-term observation of patients with VIPoma.

Serum 25-hydroxycholesterol levels are increased in patients with coronavirus disease 2019.

BACKGROUND: 25-hydroxycholesterol (25HC), produced by cholesterol 25-hydroxylase (CH25H) in macrophages, has been reported to inhibit the replication of viral pathogens such as severe acute respiratory syndrome coronavirus-2. Also, CH25H expression in macrophages is robustly induced by interferons (IFNs). OBJECTIVE: To better understand the serum level increase of 25HC in coronavirus disease 2019 (COVID-19) and how it relates to the clinical picture. METHODS: We measured the serum levels of 25HC and five other oxysterols in 17 hospitalized COVID-19 patients. RESULTS: On admission, 25HC and 27-hydroxycholesterol (27HC) serum levels were elevated; however, 7-ketocholesterol (7KC) levels were lower in patients with COVID-19 than in the healthy controls. There was no significant correlation between 25HC serum levels and disease severity markers, such as interferon-gamma (IFN-γ) and interleukin 6. Dexamethasone effectively suppressed cholesterol 25-hydroxylase (CH25H) mRNA expression in RAW 264.7 cells, a murine leukemia macrophage cell line, with or without lipopolysaccharide or IFNs; therefore, it might mitigate the increasing effects of COVID-19 on the serum levels of 25HC. CONCLUSIONS: Our results highlighted that 25HC could be used as a unique biomarker in severe COVID-19 and a potential therapeutic candidate for detecting the severity of COVID-19 and other infectious diseases.

Mesalazine-Induced Diffuse Lung Injury in a Patient Without Respiratory Signs and Symptoms.

Mesalazine is a drug used to treat ulcerative colitis and Crohn's disease, and is known to rarely cause lung injury. We show herein a unique case who developed this drug-induced injury. A 17-year-old boy presented with fever and anorexia after administration of mesalazine. Computed tomography showed extensive ground-glass opacities with peripheral distribution in both lungs. He had general weakness, but had no respiratory symptoms such as cough and dyspnea. With prednisolone, which is primarily aimed at controlling ulcerative colitis, the extensive opacity in both lungs were improved. All patients with this drug-induced lung injury reported to date have had respiratory symptoms, but this patient had no subjective respiratory symptoms and had no abnormalities in respiratory rate and oxyhaemoglobin saturation. Although very rare, we do believe that this clinical course will provide some suggestive information on treatment for patients with similar course in the future.

Dietitian-supported dietary intervention leads to favorable dietary changes in patients with type 2 diabetes: A randomized controlled trial.

AIMS/INTRODUCTION: It remains to be fully elucidated whether nutrition education by dietitians can lead to specific positive changes in the food choices of patients with diabetes. MATERIALS AND METHODS: A total of 96 patients with type 2 diabetes and diabetic kidney disease were randomly assigned to the intensive intervention group that received nutritional education at every outpatient visit and the control group that received nutritional education once a year. The total energy intake, energy-providing nutrients and 18 food groups were analyzed at baseline, and 1 and 2 years after the intervention in 87 patients. Furthermore, the relationship between the changes in hemoglobin A1c, body composition and changes in the total energy or energy-producing nutrient intake was analyzed in 48 patients who did not use or change hypoglycemic agents during the study period. RESULTS: The total energy intake, carbohydrates, cereals, confections, nuts and seeds, and seasonings significantly decreased, and fish and shellfish intake significantly increased during the study period in the intensive intervention group, whereas these changes were not observed in the control group. The decrease in the total energy intake and carbohydrates after 2 years was significantly greater in the intensive intervention group than in the control group. The change in the total energy and carbohydrate intake showed a significant positive correlation with that in muscle mass. The multivariate analysis showed that the decrease in total energy intake was independently associated with that in muscle mass. CONCLUSION: Dietitian-supported intensive dietary intervention helps improve the diet of patients with type 2 diabetes.

Sex-specific Association of Primary Aldosteronism With Visceral Adiposity.

Context: The association between primary aldosteronism and obesity, especially its sex difference, remains unknown. Objective: To assess the association for each subtype of primary aldosteronism with obesity parameters including visceral adipose tissue and differences between sexes. Methods: In this case-control study, 4 normotensive controls were selected for each case with primary aldosteronism. Multivariable conditional logistic regression models were used to estimate the association between each type of primary aldosteronism and obesity indicators. We used a random forest to identify which visceral or subcutaneous tissue areas had a closer association with disease status. Results: The study subjects included 42 aldosterone-producing adenoma cases (22 women) and 68 idiopathic hyperaldosteronism cases (42 women). In multivariable conditional logistic regressions, aldosterone-producing adenoma was significantly associated with body mass index only in men (odds ratio [OR] [95% CI)], 4.62 [1.98-10.80] per 2.89 kg/m2) but not in women (OR [95% CI], 1.09 [0.69-1.72] per 3.93 kg/m2) compared with the matched controls, whereas idiopathic hyperaldosteronism was associated with body mass index in both men (OR [95% CI], 3.96 [2.03-7.73] per 3.75 kg/m2) and women (OR [95% CI], 2.65 [1.77-3.96] per 3.85 kg/m2) compared with the matched controls. In random forests, visceral adipose tissue areas were the better predictor of both aldosterone-producing adenoma and idiopathic hyperaldosteronism than subcutaneous adipose tissue. Conclusions: Aldosterone-producing adenoma cases were obese among men, but not among women. Idiopathic hyperaldosteronism cases were obese among both men and women. Visceral adipose tissue may contribute to the pathophysiology of primary aldosteronism.

Serotonin-positive neuroendocrine neoplasm with pancreatic ductal dilation in which cytological immunostaining contributed to the diagnosis.

A 52-year-old man was transported via an ambulance because of syncope and the passage of tarry stools, which had been noted the previous day. He was diagnosed with upper gastrointestinal bleeding from a gastric ulcer and underwent endoscopic hemostasis. Prior to endoscopy, abdominal computerized tomography performed for gastrointestinal bleeding revealed pancreatic duct dilation. After discharge, abdominal imaging revealed a strongly enhancing tumor (5 mm) with caudal pancreatic duct dilation. Endoscopic retrograde pancreatography revealed that the main pancreatic duct was interrupted at the body. Pancreatic juice cytology was class III, and additional immunostaining were positive for chromogranin A, synaptophysin, and serotonin, suggesting a pancreatic neuroendocrine neoplasm (NEN). Distal pancreatectomy was performed and a yellowish-white solid lesion was found in the pancreatic duct. Pathological examination revealed narrowing of the pancreatic duct, extensive stromal fibrosis, and proliferation of tumor cells with small round nuclei and eosinophilic vesicles. Furthermore, the immunostaining findings of the resected specimen corresponded with those of the cytology. A diagnosis of NEN G1 (WHO classification) with Ki-67 index < 1% was made. Imaging of the pancreatic duct tend to be normal or show no involvement of the duct in pancreatic neuroendocrine neoplasms; however, there have been a few reports of stenosis due to fibrosis around the pancreatic duct. Serotonin positivity was previously documented to be significantly higher in patients with fibrosis. In lesions with pancreatic ductal stenosis, the addition of immunostaining to pancreatic juice cytology was thought to be useful in differentiating pancreatic cancer from pNEN.

Comparison of the effects of frequent versus conventional nutritional interventions in patients with type 2 diabetes mellitus: A randomized, controlled trial.

AIMS/INTRODUCTION: This randomized controlled trial aimed to determine whether frequent nutritional education improves the clinical parameters associated with the onset and progression of diabetic kidney disease in type 2 diabetes mellitus patients. MATERIALS AND METHODS: A total of 96 patients with type 2 diabetes and diabetic kidney disease were randomly assigned to the intensive intervention group that received nutritional education at every outpatient visit, and the usual intervention group that received nutritional education once a year. The anthropometric parameters, blood pressure, blood chemistry, albuminuria, protein and salt intake, and prescribed medications of 87 patients who completed the 2-year follow up were analyzed. RESULTS: In the intensive intervention group, body mass index and salt intake significantly decreased over the study period. Hemoglobin A1c levels and body fat percentage were significantly lower in the intensive intervention group than in the usual intervention group. At the end of the 2-year intervention period, the intensive intervention group had significantly lower salt intake (8.1 vs 9.4 g/day) than the usual intervention group. A significant positive correlation was found between salt intake and albuminuria in the overall group and intensive intervention group (r = 0.26, P = 0.02, and r = 0.36, P = 0.02, respectively). The intensive intervention group had a significantly lower insulin use rate than the usual intervention group after the 2-year intervention period (18% vs 42%). No differences were found in estimated glomerular filtration rate and albuminuria. CONCLUSION: Intensive nutritional education is useful for alleviating the risk factors associated with the onset and progression of diabetic kidney disease.

A case of insulinoma with hypoglycemia that was better managed with lanreotide than octreotide.

Long-acting somatostatin analogs, including lanreotide slow release (LAN-SR) and octreotide long-acting release (OCT-LAR), can improve hypoglycemia in insulinoma. LAN-SR may be more beneficial in some patients with insulinoma than OCT-LAR.

Crack- and Shrinkage-Free Ethylene-Bridged Polysilsesquioxane Film Prepared by a Hydrosilylation Reaction.

With the aim of developing an improved strategy for the preparation of ethylene-bridged polysilsesquioxanes as thermal insulator materials, this paper describes the synthesis of a crack- and shrinkage-free ethylene-bridged polysilsesquioxane film by the hydrosilylation reaction of hydrodimethyl-silylated oligomethylsilsesquioxane (MSQ-SiH) and dimethylvinyl-silylated oligomethylsilsesquioxane (MSQ-SiVi) in the presence of Karstedt's catalyst. Polysilsesquioxane precursors were prepared by the sol-gel reaction of triethoxymethylsilane and the successive capping reaction with chlorodimethylsilane and chlorodimethylvinylsilane. The obtained ethylene-bridged polysilsesquioxane film showed lower density and thermal diffusivity (1.13 g/cm3 and 1.15 × 10-7 m2/s, respectively) than a polymethylsilsesquioxane film (1.34 g/cm3 and 1.36 × 10-7 m2/s, respectively). As a result of the introduction of the SiCCSi ethylene bridge, the thermal insulation property of the polysilsesquioxane film was enhanced.

A novel SOX10 nonsense mutation in a patient with Kallmann syndrome and Waardenburg syndrome.

SUMMARY: The underlying genetic drivers of Kallmann syndrome, a rare genetic disorder characterized by anosmia and hypogonadotropic hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GNRH)-producing neurons during embryonic development, remain largely unknown. SOX10, a key transcription factor involved in the development of neural crest cells and established as one of the causative genes of Waardenburg syndrome, has been shown to be a causative gene of Kallmann syndrome. A 17-year-old male patient, who was diagnosed with Waardenburg syndrome on the basis of a hearing impairment and hypopigmented iris at childhood, was referred to our department because of anosmia and delayed puberty. As clinical examination revealed an aplastic olfactory bulb and hypogonadotropic hypogonadism, we diagnosed him as having Kallmann syndrome. Incidentally, we elucidated that he also presented with subclinical hypothyroidism without evidence of autoimmune thyroiditis. Direct sequence analysis detected a nonsense SOX10 mutation (c.373C>T, p.Glu125X) in this patient. Since this nonsense mutation has never been published as a germline variant, the SOX10 substitution is a novel mutation that results in Kallmann syndrome and Waardenburg syndrome. This case substantiates the significance of SOX10 as a genetic cause of Kallmann syndrome and Waardenburg syndrome, which possibly share a common pathway in the development of neural crest cells. LEARNING POINTS: Kallmann syndrome and Waardenburg syndrome possibly share a common pathway during neural crest cell development. SOX10, a key transcription factor involved in the development of neural crest cells, is a common causative gene of Kallmann syndrome and Waardenburg syndrome. Careful evaluation about various phenotypic features may reveal the unknown genetic drivers of Kallmann syndrome.

Safety and efficacy of empagliflozin in elderly Japanese patients with type 2 diabetes mellitus: A post hoc analysis of data from the SACRA study.

Elderly diabetic patients are likely to have uncontrolled nocturnal hypertension, which confers higher risks of cardiovascular events and heart failure. To investigate the efficacy and safety of empagliflozin in elderly patients with type 2 diabetes (T2DM), a sub-analysis was performed of data from the SGLT2 inhibitor and Angiotensin receptor blocker Combination theRapy in pAtients with diabetes and uncontrolled nocturnal hypertension (SACRA) study, a multi-center, double-blind, randomized, parallel study of T2DM patients who were treated with empagliflozin for 12 weeks. In the present analysis, we compared efficacy and safety outcomes in participants aged <75 and ≥75 years. At baseline, 44 participants were ≥75 years and 87 were <75 years. Nighttime ambulatory systolic blood pressure (SBP) decreased by 4.2 mm Hg in the ≥75-year-old group and by 7.9 mm Hg in the <75-year-old group (p = .884 for the between-age group difference in the change between baseline and week 12) [primary endpoint]. Empagliflozin, but not placebo, significantly reduced mean 24-h SBP (-8.7 mm Hg in ≥75-year-olds vs. -11.0 mm Hg in <75-year-olds) and daytime SBP (-10.8 mm Hg in ≥ 75-year-olds vs. -12.3 mm Hg in <75-year-olds) between baseline and week 12, with no significant differences between the groups. In addition, there were significant reductions in glycated hemoglobin, body weight, and uric acid during 12 weeks of empagliflozin treatment in the two age groups. The incidences of hypoglycemic episodes, hypotension, and metabolic adverse events were similar in the two groups. Thus, empagliflozin was effective and well tolerated in elderly diabetic patients with uncontrolled nocturnal hypertension when administered for 12 weeks.

Ethylene-bridged polysilsesquioxane/hollow silica particle hybrid film for thermal insulation material.

Ethylene-bridged polysilsesquioxane (EBPSQ) was prepared by the sol-gel reaction of bis(triethoxysilyl)ethane. The whitish slurry was prepared by mixing EBPSQ and hollow silica particles (HSPs) with a median diameter of 18-65 µm at 80 °C, and it formed a hybrid film by heating at 80 and 120 °C for 1 h at each temperature, then at 200 °C for 20 min. The surface temperatures of EBPSQ films containing 10 wt% and 20 wt% of HSPs (90.2 °C-90.5 °C) were lower than those of EBPSQ films (93.6 °C), when the films on the duralumin plate were heated at 100 °C for 10 min from the bottom of the duralumin plate. The thermal conductivity/heat flux (k/q) obtained from the temperature difference between the surface temperature and bottom temperature of the films and the film thickness also decreased with adding the HSPs. EBPSQ film without HSPs exhibited T 5 d of 258 °C and T 10 d of 275 °C. However, EBPSQ film containing 20 wt% of HSPs exhibited high thermal stability, and T 5 d and T 10 d were 299 °C and 315 °C, respectively. Interestingly, T 5 d and T 10 d of the hybrid films increased with an increase in the number of HSPs. Overall, it was shown that HSPs could improve the thermal insulation properties and thermal stability.

Effects of luseogliflozin on arterial properties in patients with type 2 diabetes mellitus: The multicenter, exploratory LUSCAR study.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the occurrence of cardiovascular and renal complications in patients with type 2 diabetes mellitus (T2DM) and represent guideline-recommended therapy in this indication. However, precise mechanisms underlying the beneficial cardiovascular effects of SGLT2 inhibitors are not fully understood. This study investigated the effects of the SGLT2 inhibitor, luseogliflozin, on arterial properties and home blood pressure (BP) in patients with T2DM. This multicenter, single-arm study enrolled adults with T2DM, glycosylated hemoglobin (HbA1c) 6.5%-8.9% in the previous 4 weeks, and an indication for new/additional antidiabetic therapy. Luseogliflozin 2.5 mg/d was given for 12 weeks. Primary outcome was change in cardio-ankle vascular index (CAVI) from baseline to Week 4 and Week 12. Home and office BP, BP variability, and metabolic parameters were secondary endpoints. Forty-seven patients (mean age 63.5 ± 10.7 years) treated with luseogliflozin were included in the full analysis set. CAVI did not change significantly from baseline (mean [95% confidence interval] 8.67 [8.37-8.97]) to Week 12 (8.64 [8.38-8.91]; P = .750), but there were significant reductions from baseline in morning home BP, HbA1c, body weight, body mass index, and serum uric acid levels during luseogliflozin therapy. The reduction in morning home systolic BP was ≥ 5 mm Hg and was independent of baseline BP and BP control status. In conclusion, there was no change in arterial stiffness (based on CAVI) during treatment with luseogliflozin, but changes in BP and metabolic parameters were consistent with the known beneficial effects of SGLT2 inhibitors in T2DM.

Esterification of 4ß-hydroxycholesterol and other oxysterols in human plasma occurs independently of LCAT.

The acyltransferase LCAT mediates FA esterification of plasma cholesterol. In vitro studies have shown that LCAT also FA-esterifies several oxysterols, but in vivo evidence is lacking. Here, we measured both free and FA-esterified forms of sterols in 206 healthy volunteers and 8 individuals with genetic LCAT deficiency, including familial LCAT deficiency (FLD) and fish-eye disease (FED). In the healthy volunteers, the mean values of the ester-to-total molar ratios of the following sterols varied: 4ß-hydroxycholesterol (4ßHC), 0.38; 5,6α-epoxycholesterol (5,6αEC), 0.46; 5,6ß-epoxycholesterol (5,6ßEC), 0.51; cholesterol, 0.70; cholestane-3ß,5α,6ß-triol (CT), 0.70; 7-ketocholesterol (7KC), 0.75; 24S-hydroxycholesterol (24SHC), 0.80; 25-hydroxycholesterol (25HC), 0.81; 27-hydroxycholesterol (27HC), 0.86; and 7α-hydroxycholesterol (7αHC), 0.89. In the individuals with LCAT deficiency, the plasma levels of the FA-esterified forms of cholesterol, 5,6αEC, 5,6ßEC, CT, 7αHC, 7KC, 24SHC, 25HC, and 27HC, were significantly lower than those in the healthy volunteers. The individuals with FLD had significantly lower FA-esterified forms of 7αHC, 24SHC, and 27HC than those with FED. It is of note that, even in the three FLD individuals with negligible plasma cholesteryl ester, substantial amounts of the FA-esterified forms of 4ßHC, 5,6αEC, 7αHC, 7KC, and 27HC were present. We conclude that LCAT has a major role in the FA esterification of many plasma oxysterols but contributes little to the FA esterification of 4ßHC. Substantial FA esterification of 4ßHC, 5,6αEC, 7αHC, 7KC, and 27HC is independent of LCAT.

Long-term efficacy of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, in a case of type A insulin resistance syndrome.

Type A insulin resistance (IR) syndrome is a severe IR form caused by insulin receptor (INSR) gene defects. Antidiabetic drugs, including high-dose insulin and insulin-sensitizing agents, often fail to control associated hyperglycemia. Therapy with recombinant human insulin-like growth factor 1 can be more effective, but it is expensive. We report a case of type A IR syndrome with an in-frame INSR heterozygous deletion (ΔLeu999) that was treated with a combination of conventional therapy and ipragliflozin, a sodium-glucose cotransporter 2 inhibitor. Treatment reduced hemoglobin A1c levels (10.0-7.5%) and induced weight loss (54.4-52.0 kg) within 2 months, and the effects were sustained for >3 years. Sodium-glucose cotransporter 2 inhibitors might be useful to normalize blood glucose in type A IR syndrome by reducing bodyweight and ameliorating glucotoxicity.