Minimally invasive and endoscopic versus open necrosectomy for necrotising pancreatitis: a pooled analysis of individual data for 1980 patients.

OBJECTIVE: Minimally invasive surgical necrosectomy and endoscopic necrosectomy, compared with open necrosectomy, might improve outcomes in necrotising pancreatitis, especially in critically ill patients. Evidence from large comparative studies is lacking. DESIGN: We combined original and newly collected data from 15 published and unpublished patient cohorts (51 hospitals; 8 countries) on pancreatic necrosectomy for necrotising pancreatitis. Death rates were compared in patients undergoing open necrosectomy versus minimally invasive surgical or endoscopic necrosectomy. To adjust for confounding and to study effect modification by clinical severity, we performed two types of analyses: logistic multivariable regression and propensity score matching with stratification according to predicted risk of death at baseline (low: <5%; intermediate: ≥5% to <15%; high: ≥15% to <35%; and very high: ≥35%). RESULTS: Among 1980 patients with necrotising pancreatitis, 1167 underwent open necrosectomy and 813 underwent minimally invasive surgical (n=467) or endoscopic (n=346) necrosectomy. There was a lower risk of death for minimally invasive surgical necrosectomy (OR, 0.53; 95% CI 0.34 to 0.84; p=0.006) and endoscopic necrosectomy (OR, 0.20; 95% CI 0.06 to 0.63; p=0.006). After propensity score matching with risk stratification, minimally invasive surgical necrosectomy remained associated with a lower risk of death than open necrosectomy in the very high-risk group (42/111 vs 59/111; risk ratio, 0.70; 95% CI 0.52 to 0.95; p=0.02). Endoscopic necrosectomy was associated with a lower risk of death than open necrosectomy in the high-risk group (3/40 vs 12/40; risk ratio, 0.27; 95% CI 0.08 to 0.88; p=0.03) and in the very high-risk group (12/57 vs 28/57; risk ratio, 0.43; 95% CI 0.24 to 0.77; p=0.005). CONCLUSION: In high-risk patients with necrotising pancreatitis, minimally invasive surgical and endoscopic necrosectomy are associated with reduced death rates compared with open necrosectomy.

Internal fit of three-unit fixed dental prostheses produced by computer-aided design/computer-aided manufacturing and the lost-wax metal casting technique assessed using the triple-scan protocol.

Suboptimal adaptation of fixed dental prostheses (FDPs) can lead to technical and biological complications. It is unclear if the computer-aided design/computer-aided manufacturing (CAD/CAM) technique improves adaptation of FDPs compared with FDPs made using the lost-wax and metal casting technique. Three-unit FDPs were manufactured by CAD/CAM based on digital impression of a typodont model. The FDPs were made from one of five materials: pre-sintered zirconium dioxide; hot isostatic pressed zirconium dioxide; lithium disilicate glass-ceramic; milled cobalt-chromium; and laser-sintered cobalt-chromium. The FDPs made using the lost-wax and metal casting technique were used as reference. The fit of the FDPs was analysed using the triple-scan method. The fit was evaluated for both single abutments and three-unit FDPs. The average cement space varied between 50 µm and 300 µm. Insignificant differences in internal fit were observed between the CAD/CAM-manufactured FDPs, and none of the FPDs had cement spaces that were statistically significantly different from those of the reference FDP. For all FDPs, the cement space at a marginal band 0.5-1.0 mm from the preparation margin was less than 100 µm. The milled cobalt-chromium FDP had the closest fit. The cement space of FDPs produced using the CAD/CAM technique was similar to that of FDPs produced using the conventional lost-wax and metal casting technique.

Digital evaluation of marginal and internal fit of single-crown fixed dental prostheses.

The present study used a new, digitized version of the impression replica technique, namely the dual-scan technique, to evaluate the adaptation of single-crown fixed dental prostheses (FDPs). Scans of the bare master model and of the master model with a silicone layer representing the cement layer were superimposed and analyzed using designated software. Single crowns produced using the lost-wax metal casting technique were included. The cement space of the band width, 0.5-1.0 mm from the preparation margin (marginal fit), was smallest for crowns made from laser-sintered cobalt-chromium. The internal fit in both mesial-distal and buccal-palatal directions was statistically significantly better for crowns made using the conventional lost-wax metal casting technique than for crowns produced using computer-aided design/computer-aided manufacturing (CAD/CAM). Fixed dental prostheses produced by milled cobalt-chromium had the loosest internal fit. The results agree with those of our previous study of the same test specimens, in which the triple-scan method was used, and imply that the dual-scan method is well suited for adaptation studies.

Internal fit of single crowns produced by CAD-CAM and lost-wax metal casting technique assessed by the triple-scan protocol.

STATEMENT OF PROBLEM: Whether single crowns produced by computer-aided design and computer-aided manufacturing (CAD-CAM) have an internal fit comparable to crowns made by lost-wax metal casting technique is unknown. PURPOSE: The purpose of this in vitro study was to compare the internal fit of single crowns produced with the lost-wax and metal casting technique with that of single crowns produced with the CAD-CAM technique. MATERIAL AND METHODS: The internal fit of 5 groups of single crowns produced with the CAD-CAM technique was compared with that of single crowns produced in cobalt-chromium with the conventional lost-wax and metal casting technique. Comparison was performed using the triple-scan protocol; scans of the master model, the crown on the master model, and the intaglio of the crown were superimposed and analyzed with computer software. The 5 groups were milled presintered zirconia, milled hot isostatic pressed zirconia, milled lithium disilicate, milled cobalt-chromium, and laser-sintered cobalt-chromium. RESULTS: The cement space in both the mesiodistal and buccopalatal directions was statistically smaller (P<.05) for crowns made by the conventional lost-wax and metal casting technique compared with that of crowns produced by the CAD-CAM technique. CONCLUSIONS: Single crowns made using the conventional lost-wax and metal casting technique have better internal fit than crowns produced using the CAD-CAM technique.

A retrospective analysis of contamination and periphyton PICT patterns for the antifoulant irgarol 1051, around a small marina on the Swedish west coast.

Irgarol is a triazine photosystem II (PSII) inhibitor that has been used in Sweden as an antifouling ingredient since the 1990s. Early microcosm studies indicated that periphyton was sensitive to irgarol at concentrations regularly found in harbours and marinas. However, field studies of irgarol effects on the Swedish west coast in 1994, using the pollution-induced community tolerance (PICT) approach, failed to detect any effects of the toxicant in the field. A PICT study involves sampling of replicate communities in a gradient of contamination, and a comparison of their community tolerance levels, with an increase being an indication that sensitive species have been eliminated and replaced by more tolerant ones. Typically, short-term assays are used to quantify the community tolerance levels. Later PICT studies in the same area over a 10 year period demonstrate that irgarol tolerance levels have increased, although the contamination pattern has been stable. Our results support the hypothesis that that the PICT potential was low initially, due to a small differential sensitivity between the community members, and that a persistent selection pressure was required to favour and enrich irgarol-tolerant species or genotypes.

Tesaglitazar, a PPARalpha/gamma agonist, induces interstitial mesenchymal cell DNA synthesis and fibrosarcomas in subcutaneous tissues in rats.

The development of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar as an oral antidiabetic was recently discontinued. Here we present tumor data from a 2-year carcinogenicity study in rats given 0.3, 1, 3, and 10 micromol/kg tesaglitazar is presented with focus on the findings of subcutaneous fibrosarcomas. To investigate the mechanism for induction of fibrosarcomas, replicative DNA synthesis (immunohistochemical detection of BrdU-labeled cells) and expression of PPARgamma (immunohistochemistry and reverse transcription-polymerase chain reaction) in subcutaneous adipose tissues was assessed in rats administered 1 or 10 micromol/kg for 2 weeks or 3 months. Poorly differentiated subcutaneous mesenchymal sarcomas with a predominant spindle cell appearance occurred at the highest dose level of 10 micromol/kg in both sexes, and these tumors were diagnosed as fibrosarcomas. The 10-micromol/kg dose was at or above the maximum tolerated dose and caused considerable cardiovascular mortality. Tesaglitazar stimulated DNA synthesis mainly in subcutaneous interstitial mesenchymal cells. The percentage of BrdU-labeled interstitial cells was increased at 1 and 10 micromol/kg after 2 weeks. The increase in DNA synthesis was still significant at the end of the 12-week treatment at 10 mumol/kg, the dose producing fibrosarcoma. However, at 1 micromol/kg, a dose below the no-observed-effect level for fibrosarcoma, the level of DNA synthesis was similar to control levels at 12 weeks. Immunohistochemical analyses showed no detectable PPARgamma protein in the majority of BrdU-labeled interstitial mesenchymal cells in white and brown fat. This indicates that stimulation of DNA synthesis is not mediated via direct activation of PPARgamma in these cells. The results suggest that the induction of rat fibrosarcoma by tesaglitazar, at exposures 100-fold above the human therapeutic exposure, may involve proliferation of undifferentiated mesenchymal cells in subcutaneous tissues.

The peroxisome proliferator-activated receptor α agonist, AZD4619, induces alanine aminotransferase-1 gene and protein expression in human, but not in rat hepatocytes: Correlation with serum ALT levels.

Alanine aminotransferase (ALT) in serum is the standard biomarker for liver injury. We have previously described a clinical trial with a novel selective peroxisome proliferator-activated receptor α (PPARα) agonist (AZD4619), which unexpectedly caused increased serum levels of ALT in treated individuals without any other evidence of liver injury. We pinpointed a plausible mechanism through which AZD4619 could increase serum ALT levels; namely through the PPARα-specific activation of the human ALT1 gene at the transcriptional level. In the present study, we present data from the preceding rat toxicity study, demonstrating that AZD4619 had no effect on rat serum ALT activity levels, and further experiments were performed to elucidate the mechanisms responsible for this species-related difference. Our results revealed that AZD4619 increased ALT1 protein expression in a dose-dependent manner in human, but not in rat primary hepatocytes. Cloning of the human and rat ALT1 promoters into luciferase vectors confirmed that AZD4619 induced only the human, but not the rat ALT1 gene promoter in a dose-dependent manner. In PPARα-GAL4 reporter gene assays, AZD4619 was >100-fold more potent on the human vs. rat PPARα levels, explaining the differences in induction of the ALT1 gene between the species at the concentration range tested. These data demonstrate the usefulness of the human and rat ALT1 reporter gene assays for testing future drug candidates at the preclinical stage. In drug discovery projects, these assays elucidate whether elevations in ALT levels observed in vivo or in the clinic are due to metabolic effects rather than a toxic event in the liver.