新機能性物質設計の基礎的研究 : 熱力学量と構造の関係について

博士（理学）神戸大

Intraoperative Ultrasound: A Tool to Support Tissue-Sparing Curative Pancreatic Resection in Focal Congenital Hyperinsulinism

Background: Focal congenital hyperinsulinism (CHI) may be cured by resection of the focal, but often non-palpable, pancreatic lesion. The surgical challenge is to minimize removal of normal pancreatic tissue.Aim: To evaluate the results of intraoperative ultrasound-guided, tissue-sparing pancreatic resection in CHI patients at an international expert center.Methods: Retrospective study of CHI patients treated at Odense University Hospital, Denmark, between January 2010 and March 2017.Results: Of 62 consecutive patients with persistent CHI, 24 (39%) had focal CHI by histology after surgery. All patients had a paternal ABCC8 or KCNJ11 mutation and a focal lesion by 18F-DOPA-PET/CT. Intraoperative ultrasound localized the focal lesion in 16/20 patients (sensitivity 0.80), including one ectopic lesion in the duodenal wall. Intraoperative ultrasound showed no focal lesion in 11/11 patients with diffuse CH (specificity 1.0). The positive predictive value for focal histology was 1.0, negative predictive value 0.73.Tissue-sparing pancreatic resection (focal lesion enucleation, local resection of tail or uncinate process) was performed in 67% (n = 16). In 11/12 having tissue-sparing resection and intraoperative ultrasound, the location of the focal lesion was exactly identified. Eight patients had resection of the pancreatic head or head/body, four with Roux-en-Y, three with pancreatico-gastrostomy and one without reconstruction. None had severe complications to surgery. Cure of hypoglycaemia was seen in all patients after one (n = 21) or two (n = 3) pancreatic resections.Conclusion: In focal CHI, tissue-sparing pancreatic resection was possible in 67%. Intraoperative ultrasound was a helpful supplement to the mandatory use of genetics, preoperative 18F-DOPA-PET/CT and intraoperative frozen sections

Using core genome multilocus sequence typing (cgMLST) for vancomycin-resistant Enterococcus faecium isolates to guide infection control interventions and end an outbreak

Objectives: Until July 2016, vancomycin-resistantEnterococcus faecium (VREfm) was sporadically detected in Odense University Hospital, Denmark. After July 2016, the number of VREfm cases increased. This study aimed to apply a core genome multilocus sequence typing (cgMLST) scheme for E. faecium to type and analyse VREfm isolates collected at a single Danish hospital and to compare the results with cgMLST data from other regions of Denmark to trace transmission. Methods: A total of 38 VREfm clinical isolates from inpatients at the hospital in the period January 2014 through June 2017 were included in the study and analysed using whole-genome sequencing. Use of SeqSphere + software was initiated from the beginning of June 2017 to obtain MLST, cgMLST and epi curves. Admission histories were incorporated and national surveillance data on cgMLST were used to identify transmission routes. Results: Six different sequence types (STs) were identified, the most frequent being ST80, ST117 and ST203. cgMLST subdivided the 38 isolates into 18 different complex types (CTs) with 13 isolates (34%) belonging to ST80-CT993. Epi curves indicated transmission of ST80-CT993 in several departments. Transmission from patients transferred from other hospitals was not identifiable. Infection control interventions launched in one department ended the outbreak. Conclusion: The high resolution of cgMLST allowed for detailed interpretation with evidence of nosocomial transmission of specific CTs. cgMLST made it easy to compare our local isolates with national findings, thereby clarifying transmission routes. Supplemented with admission histories, cgMLST targeted the epidemiological investigation and delineated the expensive and time-consuming infection control interventions

Progressive alcohol-related liver fibrosis is characterised by imbalanced collagen formation and degradation

BACKGROUND: Liver fibrosis accumulation is considered a turnover disease, with formation exceeding degradation, although this hypothesis has never been tested in humans. AIMS: To investigate extracellular matrix (ECM) remodelling in a biopsy‐controlled study of alcohol‐related liver disease (ALD) patients. METHODS: We evaluated the relationship between formation and degradation of four collagens as a function of histological fibrosis, inflammation and steatosis in 281 patients with ALD and 50 matched healthy controls. Post hoc, we tested the findings in a cohort of patients with alcohol‐related cirrhosis and assessed the collagens' prognostic accuracy. We assessed the fibrillar collagens type III (PRO‐C3/C3M) and V (PRO‐C5/C5M), the basement membrane collagen IV (PRO‐C4/C4M), and the microfilament interface collagen VI (PRO‐C6/C6M). RESULTS: Mean age was 54 ± 6 years, 74% male, fibrosis stage F0/1/2/3/4 = 33/98/84/18/48. Compared to controls, patients with ALD had higher levels of type III collagen formation and degradation, with the highest concentrations in those with cirrhosis (PRO‐C3 = 8.2 ± 1.7 ng/mL in controls, 14.6 ± 13.5 in ALD, 34.8 ± 23.1 in cirrhosis; C3M 7.4 ± 1.9 in controls, 9.3 ± 4.4 in ALD, 14.0 ± 5 in cirrhosis). ECM remodelling became increasingly imbalanced in higher stages of liver fibrosis, with formation progressively superseding degradation. This was particularly pronounced for type III collagen. We observed similar imbalance for inflammatory severity, but not steatosis. CONCLUSIONS: ALD is characterised by both elevated collagen formation and degradation, which becomes increasingly imbalanced with more severe disease. Net increase in fibrillar collagens contributes to fibrosis progression. This has important implications for monitoring and very early identification of patients at highest risk of progressing to cirrhosis

The effect of postoperative gemcitabine on overall survival in patients with resected pancreatic cancer:A nationwide population-based Danish register study

Background: Adjuvant chemotherapy following curative resection is the standard treatment for pancreatic adenocarcinoma (PC). Randomized clinical trials using gemcitabine have shown a median overall survival (mOS) of 2 years and a 5-year survival rate of 15-20%. However, the effect of gemcitabine outside these trials is less clear. We examined the effect of postoperative gemcitabine on survival in an unselected cohort of patients receiving curative resection for PC in Denmark during a five-year period. Material and methods: From 1 May 2011 to 30 April 2016, 731 patients treated with curative resection were identified in the Danish Pancreatic Cancer Database (DPCD). Thirty patients died within 10 weeks postoperatively; 78 received other regimens or preoperative chemotherapy and were excluded. Of the remaining 623 patients, the chemotherapy (CT) group (n = 409, 66%) received gemcitabine within 10 weeks after resection, whereas the non-chemotherapy (NCT) group (n = 214, 34%) did not receive CT within 10 weeks. Results: CT patients were slightly younger than NCT patients but did not otherwise differ in baseline characteristics. The CT group showed a mOS of 24 months (95% CI; 21–27) and a 5-year survival rate of 22% (95% CI; 17–27); the NCT group had a mOS of 22 months (95% CI; 16–26, p = .27) and a 5-year survival rate of 26% (95% CI; 19–34, p = .66). Most patients (415/623) had lymph node metastases. Of these patients, those in the CT group (n = 280) had significantly longer mOS [20 months (95% CI; 18–24)] than those in the NCT group (n = 135) [14 months (95% CI; 11–17)]. Conclusions: In this national Danish cohort of PC patients undergoing resection between 2011 and 2016, the survival after postoperative gemcitabine was similar to that reported in previous clinical trials. However, the survival advantage of postoperative gemcitabine was limited to patients with lymph node metastases.</p