Long-term health-related quality of life after pancreatic resection for malignancy in patients with and without severe postoperative complications

Background

Surgery for pancreatic cancer yields significant morbidity and mortality risks and survival is limited. Therefore, the influence of complications on quality of life (QoL) after pancreatic surgery is important. This study compares QoL in patients with and without severe complications after surgery for pancreatic (pre-)malignancy.

Detection of chymase activity using a specific peptide probe conjugated onto gold nanoparticles

Gold nanoparticles (AuNPs) can be applied in biosensors using fluorescence resonance energy transfer (FRET) technique. Based on this technique, we have established a sensitive and efficient biosensing method by modifying a peptide-probe onto AuNPs to detect proteinase enzyme activity in this study. This biosensing method was designed for chymase activity detection and applied in kidney disease diagnosis. In this study, 16 nm-AuNPs were used to construct the AuNPs-based fluorescence peptide probe (named AuNPs-peptide probe) for chymase activity determination. The peptide sequence is FITC-Acp-DRVYIHPFHLDDDDDC, which comprises a fluorophore at the N-terminal end, an enzyme (chymase) substrate (DRVYIHPFHL), a spacer (DDDDD) and cysteine (C) to conjugate to AuNPs surface. When the enzyme catalyzes the substrate sequence, the fluorophore drifts away from AuNPs and the fluorescence emitting signal can be excited at 495 nm and detected at 515 nm. The results indicate that the time required for the AuNPs-peptide probe for activity detection of chymase was only 15 min, and a linear correlation from 10 to 100 ng mL⁻¹ of chymase was acquired. The chymase reaction would be significantly inhibited by addition of specific chymase inhibitor chymostatin. The AuNPs-peptide probe was tested for the detection of high concentrations of trypsin and chymotrypsin, but only minor emitted fluorescence intensity was detected. According to these results, sensitivity and specificity of the AuNPs-peptide probe for chymase detection have been confirmed. AuNPs-peptide probe was successfully used for the detection of renal chymase activity; and the results indicate the pathogenically increased chymase activity in kidney tissue of nephropathic mice from aristolochic acid I treatment.

The gold nanoparticles (AuNPs) peptide probe functionalized with specific peptide sequences was developed for the sensitive and efficient detection of chymase activity.     

Over-the-wire US catheter probe as an adjunct to ERCP in the detection of choledocholithiasis

BACKGROUND: Intraductal ultrasound (IDUS) as an adjunct to ERCP for detection of extrahepatic bile duct stones is technically easy, accurate, and safe. This prospective study evaluated IDUS with an "over-the-wire" catheter US probe as an adjunct to ERCP. METHODS: Sixty-five patients, highly suspected to have choledocholithiasis, underwent IDUS during ERCP. The IDUS probe was inserted by means of the duodenoscope into the bile duct without performing a sphincterotomy. All stones identified by IDUS or retrograde cholangiography were removed with either a basket or retrieval balloon after endoscopic sphincterotomy. RESULTS: The final diagnosis was choledocholithiasis in 59 patients. Bile duct diameter ranged from 0.6 to 2.3 cm and stone size from 2 mm to 2 cm. IDUS successfully identified all stones in these patients. IDUS resulted in 2 false-positive diagnoses in the remaining 6 patients without stones (overall accuracy 97%, sensitivity 100%, specificity 67%). Cholangiography detected stones in 55 of the patients with stones (accuracy 94%, sensitivity 93%, specificity 100%). CONCLUSION: IDUS, a safe, technically easy procedure, is highly accurate in the detection of extrahepatic bile duct stones regardless of the diameter of the bile ducts. The "over-the-wire" technique preserves access to the cannulated duct. IDUS is an excellent adjunct to ERCP for the diagnosis of choledocholithiasis. IDUS differentiates stones from air bubbles and prevents unnecessary sphincterotomy.     

GPCR dimerization in brainstem nuclei contributes to the development of hypertension

Background and Purpose

μ-Opioid receptors, pro-opiomelanocortin and pro-enkephalin are highly expressed in the nucleus tractus solitarii (NTS) and μ receptor agonists given to the NTS dose-dependently increased BP. However, the molecular mechanisms of this process remain unclear. In vitro, μ receptors heterodimerize with α_2A-adrenoceptors. We hypothesized that α_2A-adrenoceptor agonists would lose their depressor effects when their receptors heterodimerize in the NTS with μ receptors.

Experimental Approach

We microinjected μ-opioid agonists and antagonists into the NTS of rats and measured changes in BP. Formation of μ receptor/α_2A-adrenoceptor heterodimers was assessed with immunofluorescence and co-immunoprecipitation methods, along with proximity ligation assays.

Key Results

Immunofluorescence staining revealed colocalization of α_2A-adrenoceptors and μ receptors in NTS neurons. Co-immunoprecipitation revealed interactions between α_2A-adrenoceptors and μ receptors. In situ proximity ligation assays confirmed the presence of μ receptor/α_2A-adrenoceptor heterodimers in the NTS. Higher levels of endogenous endomorphin-1 and μ receptor/α_2A-adrenoceptor heterodimers were found in the NTS of hypertensive rats, than in normotensive rats. Microinjection of the μ receptor agonist [D-Ala², MePhe⁴, Gly⁵-ol]-enkephalin (DAMGO), but not that of the α_2A-adrenoceptor agonist guanfacine, into the NTS of normotensive rats increased μ receptor/α_2A-adrenoceptor heterodimer formation and BP elevation. The NO-dependent BP-lowering effect of α_2A-adrenoceptor agonists was blunted following increased formation of μ receptor/α_2A-adrenoceptor heterodimers in the NTS of hypertensive rats and DAMGO-treated normotensive rats.

Conclusions and Implications

Increases in endogenous μ receptor agonists in the NTS induced μ receptor/α_2A-adrenoceptor heterodimer formation and reduced the NO-dependent depressor effect of α_2A-adrenoceptor agonists. This process could contribute to the pathogenesis of hypertension.     

Activating mitochondrial function and haemoglobin expression with EH-201, an inducer of erythropoietin in neuronal cells,reverses memory impairment

Background and Purpose

Memory impairment can be progressive in neurodegenerative diseases, and physiological ageing or brain injury, mitochondrial dysfunction and oxidative stress are critical components of these issues. An early clinical study has demonstrated cognitive improvement during erythropoietin treatment in patients with chronic renal failure. As erythropoietin cannot freely cross the blood–brain barrier, we tested EH-201 (2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside, also known as TSG), a low MW inducer of erythropoietin, for its therapeutic effects on memory impairment in models of neurodegenerative diseases, physiological ageing or brain injury.

Experimental Approach

The effects of EH-201 were investigated in astrocytes and PC12 neuronal-like cells. In vivo, we used sleep-deprived (SD) mice as a stress model, amyloid-β (Aβ)-injected mice as a physiological ageing model and kainic acid (KA)-injected mice as a brain damage model to assess the therapeutic effects of EH-201.

Key Results

EH-201 induced expression of erythropoietin, PPAR-γ coactivator 1α (PGC-1α) and haemoglobin in astrocytes and PC12 neuronal-like cells. In vivo, EH-201 treatment restored memory impairment, as assessed by the passive avoidance test, in SD, Aβ and KA mouse models. In the hippocampus of mice given EH-201 in their diet, levels of erythropoietin, PGC-1α and haemoglobin were increased

Conclusions and Implications

The induction of endogenous erythropoietin in neuronal cells by inducers such as EH-201 might be a therapeutic strategy for memory impairment in neurodegenerative disease, physiological ageing or traumatic brain injury.     

Betulinic acid exerts anti-hepatitis C virus activity via the suppression of NF-κB- and MAPK-ERK1/2-mediated COX-2 expression

Background and Purpose

This study was designed to evaluate the effect of betulinic acid (BA), extracted from Avicennia marina, on the replication of hepatitis C virus (HCV) and to investigate the mechanism of this BA-mediated anti-HCV activity.

Experimental Approach

HCV replicon and infectious systems were used to evaluate the anti-HCV activity of BA. Exogenous COX-2 or knock-down of COX-2 expression was used to investigate the role of COX-2 in the anti-HCV activity of BA. The effects of BA on the phosphorylation of NF-κB and on kinases in the MAPK signalling pathway were determined. The anti-HCV activity of BA in combination with other HCV inhibitors was also determined to assess its use as an anti-HCV supplement.

Key Results

BA inhibited HCV replication in both Ava5 replicon cells and in a cell culture-derived infectious HCV particle system. Treatment with a combination of BA and IFN-α, the protease inhibitor telaprevir or the NS5B polymerase inhibitor sofosbuvir resulted in the synergistic suppression of HCV RNA replication. Exogenous overexpression of COX-2 gradually attenuated the inhibitory effect of BA on HCV replication, suggesting that BA reduces HCV replication by suppressing the expression of COX-2. In particular, BA down-regulated HCV-induced COX-2 expression by reducing the phosphorylation of NF-κB and ERK1/2 of the MAPK signalling pathway.

Conclusions and Implications

BA inhibits HCV replication by suppressing the NF-κB- and ERK1/2-mediated COX-2 pathway and may serve as a promising compound for drug development or as a potential supplement for use in the treatment of HCV-infected patients.     

Emphysematous pyelonephritis: clinicoradiological classification, management, prognosis, and pathogenesis

BACKGROUND: Emphysematous pyelonephritis (EPN) is a rare, severe gas-forming infection of renal parenchyma and its surrounding areas. The radiological classification and adequate therapeutic regimen are controversial and the prognostic factors and pathogenesis remain uncertain. OBJECTIVES: To elucidate the clinical features, radiological classification, and prognostic factors of EPN; to compare the modalities of management (ie, antibiotic treatment alone, percutaneous catheter drainage combined with antibiotic treatment, or nephrectomy) and outcome among the various radiological classes of EPN; and to clarify the gas-forming mechanism and pathogenesis of EPN by gas analysis and pathological findings. PATIENTS AND METHODS: Forty-eight EPN cases from our institution were enrolled between August 1,1989, and November 30, 1997. According to the radiological findings on computed tomographic scan, they were classified into the following classes: (1) class 1: gas in the collecting system only; (2) class 2: gas in the renal parenchyma without extension to extrarenal space; (3) class 3A: extension of gas or abscess to perinephric space; class 3B: extension of gas or abscess to pararenal space; and (4) class 4: bilateral EPN or solitary kidney with EPN. The clinical manifestations, management, and outcome were compared. The gas contents of specimens from 6 patients were analyzed. The pathological findings from 8 patients who received nephrectomy were reviewed. The statistical methods consisted of the Fisher exact test (2 tailed) for categorical variables and Wilcoxon rank sum test for continuous variables to test the predictors of poor prognosis. RESULTS: Forty-six patients (96%) had diabetes mellitus, and 10 (22%) of the 46 also had urinary tract obstruction in the corresponding renoureteral unit. The other 2 nondiabetic patients (4%) had severe hydronephrosis. Twenty-one (72%) of the 29 patients with diabetes mellitus also had a glycosylated hemoglobin A(1c) level higher than 0.08. Escherichia coli (69%) and Klebsiella pneumoniae (29%) were the most common pathogens. The mortality rate in patients who received antibiotic treatment alone was 40% (2 of 5 patients). The success rate of management by percutaneous catheter drainage (PCD) combined with antibiotic treatment was 66% (27 of 41 patients). In classes 1 and 2 EPN, all the patients who were treated using a PCD or ureteral catheter combined with antibiotic treatment survived. In extensive EPN (classes 3 and 4), 17 (85%) of the 20 patients with fewer than 2 risk factors (ie, thrombocytopenia, acute renal function impairment, disturbance of consciousness, or shock) were successfully treated using PCD combined with antibiotic treatment; and the patients with 2 or more risk factors had a significantly higher failure rate than those with no or only 1 risk factors (92% vs 15%, P<.001). Eight of the 14 patients who had an unsuccessful treatment using a PCD underwent subsequent nephrectomy, 7 of whom survived. Only 2 patients were managed by direct nephrectomy and survived. The overall success rate of nephrectomy was 90% (9 of 10 patients). The total mortality was 18.8% (9 of 48 patients). Five of the 6 gas samples contained hydrogen (average, 12.8%), and all had carbon dioxide (average, 14.4%). The pathological findings from 8 of 10 who underwent nephrectomy revealed poor perfusion in most cases (ie, infarction, 5 patients; vascular thrombosis, 3 patients; and arteriosclerosis and/or glomerulosclerosis, 4 patients). CONCLUSION: Acute renal infection with E coli or K pneumoniae in patients with diabetes mellitus and/or urinary tract obstruction is the cornerstone for the development of EPN. Mixed acid fermentation of glucose by Enterobacteriaceae is the major pathway of gas formation. For localized EPN (classes 1 and 2), PCD combined with antibiotic treatment can provide a good outcome. (ABSTRACT TRUNCATED)