Acinar cystic transformation in the pancreatic tail.

Pancreatic acinar cystic transformation (ACT) is a rare non-neoplastic cystic lesion that is predominantly located at the pancreatic head in females. Preoperative definitive diagnosis of ACT remains challenging despite advances in radiologic imaging methods. A 25-year-old male patient presented with abdominal discomfort and a 50-mm cystic lesion in the pancreatic tail. The patient underwent laparoscopic distal pancreatectomy, because branch duct intraductal papillary mucinous neoplasm cannot be ruled out and the presence of abdominal symptoms. The resected specimen revealed a collection of small and large cysts lined by a single cuboidal epithelium layer with scattered pancreatic tissue exhibiting fibrosis in the septal wall. The cystic lesion was epithelial, trypsin-positive, B cell lymphoma 10-positive, cytokeratin 19-positive, mucin 1-positive, and MUC6-negative with a differentiated lobular central conduit causing to an adeno-cystic cell, thereby supporting the ACT diagnosis. Distinguishing ACT from other pancreatic cystic tumors remains a diagnostic challenge despite improvements in radiologic imaging methods. Surgical resection may be justified when other cystic neoplasms cannot be excluded because of its heterogeneous nature, although the ACT is a non-neoplastic lesion, and cases of malignant transformation have never been reported to date.

Opioid-induced adrenal insufficiency in transdermal fentanyl treatment: a revisited diagnosis in clinical setting.

Opioids are widely used for treatment of acute and chronic pain. However, opioids have several well-known clinical adverse effects such as constipation, nausea, respiratory depression and drowsiness. Endocrine dysfunctions are also opioid-induced adverse effects but remain under-diagnosed in clinical settings, especially opioid-induced adrenal insufficiency (OIAI). A 46-year-old woman was treated with transdermal fentanyl at a dose of 90-120 mg daily morphine milligram equivalent for non-malignant chronic pain for four years. Fatigue, loss of appetite and decrease in vitality began about two years after starting fentanyl. Subsequently, constipation and abdominal pain appeared and became worse, which led to suspicion of adrenal insufficiency. Clinical diagnosis of OIAI was established based on laboratory findings of secondary adrenal insufficiency, including corticotropin-releasing hormone stimulation test, clinical history of long-term fentanyl use, and exclusion of other hypothalamic-pituitary diseases. Oral corticosteroid replacement therapy was unable to relieve her abdominal pain and constipation; opioid-rotation and dose-reduction of fentanyl were not feasible because of her persistent pain and severe anxiety. While her clinical course clearly suggested that long-term, relatively high-dose transdermal fentanyl treatment may have contributed to the development of secondary adrenal insufficiency, the symptoms associated with OIAI are generally non-specific and complex. Together with under-recognition of OIAI as a clinical entity, the non-specific, wide range of symptoms can impede prompt diagnosis. Thus, vigilance for early symptoms enabling treatments including corticosteroid replacement therapy is necessary for patients taking long-term and/or high dose opioid treatment.

Utility of B-Type Natriuretic Peptide for Detecting Cardiac Involvement in Immunoglobulin Amyloidosis.

A useful biomarker for detecting cardiac amyloidosis (CA) has not been fully established. We aimed to investigate the utility of several biomarkers to detect CA in patients with amyloid light-chain (AL) amyloidosis.We examined the plasma levels of B-type natriuretic peptide (BNP), N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), serum amyloid A, and the difference between kappa and lambda free light chain (dFLC) between CA patients (n = 30, 47.6%) and non-CA patients (n = 33, 52.4%). Levels of BNP were significantly higher in the CA group compared to the non-CA group (1200.0 versus 224.0 pg/mL, P = 0.001). From the ROC analysis, the sensitivity and specificity of BNP for detecting CA (with a cut-off value of 412 pg/mL) were 83% and 70%, respectively, and the area under the receiver operating curve was 0.75 (95% CI 0.61-0.90, P < 0.001) in all AL amyloidosis patients (n = 63). In contrast, other markers such as NT-proBNP, hs-cTnT, serum amyloid A, and dFLC were not useful for detecting CA in AL amyloidosis patients. Additionally, in the Cox proportional hazard analysis, BNP was a predictor of all-cause mortality (hazard ratio 3.266, 95% confidence interval 1.498-7.119, P = 0.003).BNP is a useful biomarker for detecting cardiac involvement and predicting prognosis in AL amyloidosis patients.

An Essential and Synergistic Role of Purinergic Signaling in Guided Migration of Corneal Epithelial Cells in Physiological Electric Fields.

BACKGROUND/AIMS: Directional migration of corneal epithelial cells is essential for healing of corneal wounds, which is a robust response mediated by biochemical and bioelectrical cues. Naturally occurring electric fields at corneal wounds provide a powerful guidance cue for directional cell migration, as does extracellular ATP. Our recent large-scale siRNA library screening identified a role for purinergic signaling in the electric field-guided migration (galvanotaxis/electrotaxis) of human corneal epithelial (hTCEpi) cells. METHODS: We examined the effect of extracellular ATP on galvanotaxis of hTCEpi cells. Galvanotactic cell migration was recorded by video microscopy, and directedness and migration speed was calculated. The role of purinergic receptors in galvanotaxis regulation was evaluated by pharmacological inhibition or knocking down of P2X and P2Y receptors. RESULTS: Addition of ATP enhanced galvanotaxis, and most remarkably sensitized galvanotaxis response to very low level of electric fields in the physiological range (10-30 mV/mm). The stimulatory effect of extracellular ATP was diminished by apyrase treatment. Importantly, cells stimulated with extracellular ATP migrated with significantly increased directedness and speed, which were diminished by knocking down or pharmacological inhibition of P2X and P2Y receptors. Inhibition of pannexin-1 (ATP permeable channel) significantly impaired galvanotaxis. Moreover, pharmacological inhibition of ectoATPase enhanced galvanotaxis. CONCLUSION: Extracellular ATP and physiological electric fields synergistically enhanced the galvanotaxis response of hTCEpi cells. hTCEpi cells are likely to secrete ATP actively, and purinergic signaling is down-regulated by ecto-ATPases. Both P2X and P2Y receptors coordinately play a role for galvanotaxis of hTCEpi cells.

Valvular heart disease as a possible predictor of trastuzumab-induced cardiotoxicity in patients with breast cancer.

Although the use of trastuzumab has been reported to improve overall survival in patients with HER2-positive breast cancer, there is increasing concern about the adverse effects of trastuzumab-induced cardiotoxicity (TIC). The aim of the present study was to investigate the predictor of TIC and to consider appropriate management for such patients. The present study breast cancer 119 patients with breast cancer who had been treated with trastuzumab. Patients were referred to our department for cardiac function screening. The patients' baseline characteristics, echocardiographic data, presence of trastuzumab-induced cardiotoxicity (TIC) and all-cause mortality were investigated. TIC was defined as a manifestation of overt heart failure or ≥10% reduction of left ventricular ejection fraction (LVEF) from baseline to an LVEF <55% in asymptomatic patients. During the follow-up period (mean, 1,410 days), symptomatic heart failure occurred in 2 out of 119 patients (1.6%), 11 patients (9.2%) had asymptomatic impairment of cardiac function that was ameliorated by discontinuing trastuzumab and 20 patients (16.8%) succumbed to cancer-associated fatality. In the logistic regression analysis, only the presence of valvular heart disease at the baseline was indicated to be a predictor of TIC. There was no other predictor for TIC, including baseline characteristics, other therapies and echocardiographic parameters. In addition, impairment of cardiac function was ameliorated by discontinuing trastuzumab. TIC occurred in ~10% of the patients treated with trastuzumab. Only the presence of valvular heart disease seems to be associated with occurrence of TIC, with no other specific predictor of TIC demonstrated in the present study. The present data suggests the importance of regular monitoring of cardiac function, and that presence of valvular heart disease may be a possible predictor of TIC.

Glucocorticoid receptor suppresses gene expression of Rev-erbα (Nr1d1) through interaction with the CLOCK complex.

Glucocorticoids have various medical uses but are accompanied by side effects. The glucocorticoid receptor (GR) has been reported to regulate the clock genes, but the underlying mechanisms are incompletely understood. In this study, we focused on the suppressive effect of the GR on the expression of Rev-erbα (Nr1d1), an important component of the clock regulatory circuits. Here we show that the GR suppresses Rev-erbα expression via the formation of a complex with CLOCK and BMAL1, which binds to the E-boxes in the Nr1d1 promoter. In this GR-CLOCK-BMAL1 complex, the GR does not directly bind to DNA, which is referred to as tethering. These findings provide new insights into the role of the GR in the control of circadian rhythm.

A Multiple Biomarker Approach in Patients with Cardiac Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease including heart (cardiac sarcoidosis, CS). It has recently been reported that isolated CS, which presenting primarily cardiac symptoms without clinical evidence of sarcoid involvement in other organs. Diagnostic and prognostic biomarkers of CS, especially in isolated CS, have not yet been established.We studied plasma levels of angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), B-type natriuretic peptide (BNP) and cardiac troponin I (cTnI) in consecutive 172 patients with diagnosed sarcoidosis. We compared these markers between non-cardiac sarcoidosis (non-CS, n = 123, 71.5%) and CS patients (n = 49, 28.5%), including non-isolated CS (n = 30, 17.4%) and isolated CS (n = 19, 11.1%). ROC analysis revealed that BNP identified CS with AUC of 0.85 (P < 0.01) in sarcoidosis patients. In addition, ACE and sIL-2R levels were significantly higher in non-isolated CS than in isolated CS (P < 0.05). Furthermore, in the Cox proportional hazard analysis, cTnI, but not ACE, IL2R or BNP, was a predictor of fatal arrhythmia in sarcoidosis patients (HR 2.418, P = 0.003).Higher ACE and sIL2-R are associated with systemic lesions, whereas BNP is a useful marker for detecting cardiac involvement in sarcoidosis patients. cTnI is a predictor of fatal arrhythmia in CS patients. A multiple biomarker approach supports comprehensive management of sarcoidosis.

Hypoglycemia Unawareness in Insulinoma Revealed with Flash Glucose Monitoring Systems.

The delayed diagnosis of insulinoma remains a clinical issue. One of the main causes of such a delay is hypoglycemia unawareness. A 53-year-old woman fell unconscious during postprandial exercises. Flash glucose monitoring (FGM) systems revealed glucose profiles with fasting hypoglycemia, which facilitated the clinical diagnosis of insulinoma even though she was unaware of her hypoglycemia. The preoperative comparison of the blood glucose values provided by FGM with those obtained from capillary blood were consistent. Thus, FGM may have potential utility in revealing the presence of insulinoma-induced hypoglycemia.

Association of Serum Zinc Level With Prognosis in Patients With Heart Failure.

BACKGROUND: Zinc is an essential cofactor for energy transfer and physiological heart function, has antioxidant properties, and is involved in multiple signaling pathways. We aimed to investigate the associations between serum zinc levels with prognosis, as well as underlying cardiac function and exercise capacity, in patients with heart failure (HF). METHODS AND RESULTS: We measured serum zinc levels in 968 consecutive hospitalized patients with decompensated HF, who were divided into 3 groups based on serum zinc levels (µg/dL): first (zinc ≥75, n = 323), second (62≤ zinc <75, n = 322), and third (zinc <62, n = 323) tertiles. We examined cardiac function and exercise capacity and followed up on all patients. Although cardiac function did not differ among the 3 groups, peak oxygen consumption was significantly lower in the third tertile than in the first and second tertiles (peak oxygen consumption, 14.2 vs 15.9 and 15.2 mL/kg/min, P = .010). In the Kaplan-Meier analysis (mean duration of follow-up 1103 days), cardiac and all-cause mortality was highest in the third tertile compared with the first and second tertiles. In the Cox proportional hazard analysis, serum zinc level was a predictor of cardiac and all-cause mortality. In the subgroup analysis, there were no interactions concerning associations between serum zinc levels with prognosis and other important variables, including age, gender, comorbidities, medications, other micronutrient levels, B-type natriuretic peptide, and left ventricular ejection fraction. The associations between zinc levels with mortality were consistent in all subgroups. CONCLUSION: Decreased serum zinc levels are associated with high mortality, accompanied by impaired exercise capacity.

Liver fibrosis marker, 7S domain of collagen type IV, in patients with pre-capillary pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) causes right ventricular dysfunction and central venous congestion, and may lead to congestive hepatopathy. The serum 7S domain of collagen type IV (P4NP 7S) is an established marker of liver fibrosis in chronic liver disease. We aimed to determine whether P4NP 7S is related to hemodynamic parameters, and assessed the potential values of P4NP 7S to predict mortality. METHODS: Consecutive 76 pre-capillary PH patients were divided into tertiles based on their serum P4NP 7S levels. We compared right-heart catheterization, echocardiographic findings, and mortality among the tertiles, and compared P4NP 7S with other known biomarkers of mortality. RESULTS: Cardiac index, mean pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular fractional area change did not differ among the three groups. In contrast, compared to 1st and 2nd tertiles, the 3rd tertile had higher levels of right atrial pressure, right atrial area, and right ventricular area (P<0.05, respectively). In the Kaplan-Meier analysis, mortality progressively increased from the 1st to 2nd and 3rd tertiles (log-rank, P=0.002). In the Cox proportional hazard analysis, P4NP 7S was a predictor of mortality. ROC analysis demonstrated that a P4NP 7S concentration of 4.75ng/ml predicted mortality (AUC 0.85, 95% CI 0.75-0.94; P<0.001), and that the prognostic value of P4NP 7S was comparable or superior to that of other biomarkers (total bilirubin, creatinine, uric acid, C-reactive protein, B-type natriuretic peptide, and troponin I). CONCLUSIONS: Serum P4NP 7S is associated with higher central venous pressure, right-sided volume overload, and mortality in PH patients.

A candidate functional SNP rs7074440 in TCF7L2 alters gene expression through C-FOS in hepatocytes.

The SNP rs7903146 at the transcription factor 7-like 2 (TCF7L2) locus is established as the strongest known genetic marker for type 2 diabetes via genome-wide association studies. However, the functional SNPs regulating TCF7L2 expression remain unclear. Here, we show that the SNP rs7074440 is a candidate functional SNP highly linked with rs7903146. A reporter plasmid with rs7074440 normal allele sequence exhibited 15-fold higher luciferase activity compared with risk allele sequence in hepatocytes, demonstrating a strong enhancer activity at rs7074440. Additionally, we identified C-FOS as an activator binding to the rs7074440 enhancer using a TFEL genome-wide screen method. Consistently, knockdown of C-FOS significantly reduced TCF7L2 expression in hepatocytes. Collectively, a novel enhancer regulating TCF7L2 expression was revealed through searching for functional SNPs.

Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have both anti-diabetic and anti-obesity effects. However, the precise mechanism of the anti-obesity effect remains unclear. We previously demonstrated that the glycogen depletion signal triggers lipolysis in adipose tissue via liver-brain-adipose neurocircuitry. In this study, therefore, we investigated whether the anti-obesity mechanism of SGLT2 inhibitor is mediated by this mechanism. Diet-induced obese mice were subjected to hepatic vagotomy (HVx) or sham operation and loaded with high fat diet containing 0.015% tofogliflozin (TOFO), a highly selective SGLT2 inhibitor, for 3 weeks. TOFO-treated mice showed a decrease in fat mass and the effect of TOFO was attenuated in HVx group. Although both HVx and sham mice showed a similar level of reduction in hepatic glycogen by TOFO treatment, HVx mice exhibited an attenuated response in protein phosphorylation by protein kinase A (PKA) in white adipose tissue compared with the sham group. As PKA pathway is known to act as an effector of the liver-brain-adipose axis and activate triglyceride lipases in adipocytes, these results indicated that SGLT2 inhibition triggered glycogen depletion signal and actuated liver-brain-adipose axis, resulting in PKA activation in adipocytes. Taken together, it was concluded that the effect of SGLT2 inhibition on weight loss is in part mediated via the liver-brain-adipose neurocircuitry.

A key role of nuclear factor Y in the refeeding response of fatty acid synthase in adipocytes.

Fatty acid synthase (Fasn) is a key component of energy metabolism that is dynamically induced by food intake. Although extensive studies have revealed a number of transcription factors involved in the fasting/refeeding transition of Fasn expression in hepatocytes, much less evidence is available for adipocytes. Using the in vivo Ad-luc analytical system, we identified the inverted CCAAT element (ICE) around -100 nucleotides in the Fasn promoter as a critical cis-element for the refeeding response in adipocytes. Electrophoretic mobility shift assays and chromatin immunoprecipitation show that nuclear factor Y (NF-Y) binds to ICE specifically in refeeding states. Notably, the NF-Y binding to ICE is differently regulated between adipocytes and hepatocytes. These findings provide insights into the specific mechanisms controlling energy metabolism in adipocytes.