Results of vascular resections during pancreatectomy from two European centres: an analysis of survival and disease-free survival explicative factors

AbstractObjectives. The object of our study was to report on the experience with vascular resections at pancreatectomy in two European specialist hepatopancreatobiliary centres and evaluate outcome and prognostic factors. Patients and methods. From 1989 to 2002, 45 patients (21 men, 24 women) underwent pancreatectomy for a pancreatic mass: Whipple's procedure (n= 33), total pancreatectomy (n= 10) or left splenopancreatectomy (n= 2), along with a vascular resection, i.e. venous (n= 39), arterial (n= 1) or venous + arterial (n= 5). Results. Operative mortality was nil, postoperative mortality was 2.2% (n= 1); 34 patients had an uneventful postoperative course. Reoperations were performed for portal vein thromobosis (n= 1), pancreatic leak (n= 1), gastric outlet syndrome (n= 1) and gastrointestinal bleeding (n= 1). In all, 43 patients had cancer on pathology examination, with retropancreatic invasion in 72% and lymph node extension in 62.8%. Resection was R0 in 21 cases. Vessel wall invasion was present in 13 cases and 19 had perivascular invasion. Disease-free survival (DFS) at 1, 2 and 3 years was 36.0%, 15.0% and 12.0%, respectively. Median DFS length was 8.7 months (95% CI: 7.2; 10.2). Overall survival rates were 56.6%, 28.9% and 19.2%, respectively. Median survival length was 14.2 months (95% CI: 9.8; 18.6). A multivariate analysis of prognostic variables identified tumour location (other than head of pancreas), neoadjuvant chemotherapy and advanced disease stage as adverse factors for DFS. Conclusion. Survival and DFS rates of these patients are comparable to those without vascular resection. Tumour localization, tumour stage, neoadjuvant treatment and tumour recurrence are explanatory variables of survival. Tumour localization, tumour stage and neoadjuvant treatment were explanatory variables for DFS. However, the type and extent of vascular resections as well as vessel wall invasion does not affect survival and DFS

Application of Portsmouth modification of physiological and operative severity scoring system for enumeration of morbidity and mortality (P-POSSUM) in pancreatic surgery

<p>Abstract</p> <p>Background</p> <p>Pancreatoduodenectomy (PD) is associated with high incidence of morbidity and mortality. We have applied P-POSSUM in predicting the incidence of outcome after PD to identify those who are at the highest risk of developing complications.</p> <p>Method</p> <p>A prospective database of 241 consecutive patients who had PD from January 2002 to September 2005 was retrospectively updated and analysed. P-POSSUM score was calculated for each patient and correlated with observed morbidity and mortality.</p> <p>Results</p> <p>30 days mortality was 7.8% and morbidity was 44.8%. Mean physiological score was 16.07 ± 3.30. Mean operative score was 13.67 ± 3.42. Mean operative score rose to 20.28 ± 2.52 for the complex major operation (p < 0.001) with 2 fold increase in morbidity and 3.5 fold increase in mortality. For groups of patients with a physiological score of (less than or equal to) 18, the O:P (observed to Predicted) morbidity ratio was 1.3–1.4 and, with a physiological score of >18, the O:P ratio was nearer to 1. Physiological score and white cell count were significant in a multivariate model.</p> <p>Conclusion</p> <p>P-POSSUM underestimated the mortality rate. While P-POSSUM analysis gave a truer prediction of morbidity, underestimation of morbidity and potential for systematic inaccuracy in prediction of complications at lower risk levels is a significant issue for pancreatic surgery</p

Co-populated Conformational Ensembles of β(2)-Microglobulin Uncovered Quantitatively by Electrospray Ionization Mass Spectrometry

Ordered assembly of monomeric human β(2)-microglobulin (β(2)m) into amyloid fibrils is associated with the disorder hemodialysis-related amyloidosis. Previously, we have shown that under acidic conditions (pH <5.0 at 37 °C), wild-type β(2)m assembles spontaneously into fibrils with different morphologies. Under these conditions, β(2)m populates a number of different conformational states in vitro. However, this equilibrium mixture of conformationally different species is difficult to resolve using ensemble techniques such as nuclear magnetic resonance or circular dichroism. Here we use electrospray ionization mass spectrometry to resolve different species of β(2)m populated between pH 6.0 and 2.0. We show that by linear deconvolution of the charge state distributions, the extent to which each conformational ensemble is populated throughout the pH range can be determined and quantified. Thus, at pH 3.6, conditions under which short fibrils are produced, the conformational ensemble is dominated by a charge state distribution centered on the 9+ ions. By contrast, under more acidic conditions (pH 2.6), where long straight fibrils are formed, the charge state distribution is dominated by the 10+ and 11+ ions. The data are reinforced by investigations on two variants of β(2)m (V9A and F30A) that have reduced stability to pH denaturation and show changes in the pH dependence of the charge state distribution that correlate with the decrease in stability measured by tryptophan fluorescence. The data highlight the potential of electrospray ionization mass spectrometry to resolve and quantify complex mixtures of different conformational species, one or more of which may be important in the formation of amyloid

Pre-operative stenting is associated with a higher prevalence of post-operative complications following pancreatoduodenectomy

AbstractObjectivesWhilst there are theoretical benefits from pre-operatively draining the biliary tree prior to pancreatoduodenectomy (PD), the current literature does not support this intervention. The aim of this study was to explore the relationship between pre-operative stenting, bactibilia and outcome in a large United Kingdom tertiary referral practice.MethodsPatients undergoing PD were identified from a prospectively maintained database. The presence or absence of a stent prior to PD, and the results of bile cultures taken at PD were related to the subsequent post-operative course and the development of complications.Results280 patients underwent PD for periampullary malignancies, all of whom presented with jaundice. 118 patients were stented prior to referral (98 ERCP, 20 PTC). Bile cultures were positive more frequently in the stent group (83% vs. 55%; p = 0.000002) and bactibilia was more common after ERCP than PTC (83% vs. 56%; p = 0.006). The overall prevalence of complications was 54% in the stented and 41% in the non-stented group (p = 0.03) with statistical significance achieved for pancreatic leak (p = 0.013) and haemorrhagic complications (p = 0.03). Comparing stent with no stent, there as no difference in the 30-day mortalities (8.5% vs. 6.8%; p = 0.6) or the 1-year mortality rates (35% vs. 28%; p = 0.21). Mortality rates in the infection versus no infection groups were comparable at 30 days (8.5% vs. 5.5%; p = 0.21), and at 1 year (30.7% vs. 26.4%; p = 0.25).ConclusionsPre-operative stent insertion prior to PD is associated with increased morbidity but not mortality and this is greatest for stents placed at ERCP

Cocaine Disrupts Pup-Induced Maternal Behavior in Juvenile and Adult Rats

Impaired onset of maternal behavior in first generation rat dams was previously correlated with rearing by cocaine-treated dams and prenatal cocaine exposure. Pup-induced maternal behavior in non-lactating rats has not been examined with regard to cocaine exposure and rearing conditions. First generation male and female juveniles and young adult males reared by cocaine-treated or control dams and prenatally exposed to either cocaine or control conditions were tested for pup-induced maternal behavior at postnatal days 28 and 60. We now report disruptions in pup-induced maternal behavior in both 28 and 60 day old first generation offspring attributable to rearing condition and prenatal cocaine exposure. Originally published Neurotoxicology and Teratology, Vol. 29, No. 6, Nov 200

Influence of preoperative nucleus pulposus status and radiculopathy on outcomes in mono-segmental lumbar total disc replacement: results from a nationwide registry

Background: Currently, herniated nucleus pulposus (HNP) with radiculopathy and other preconditions are regarded as relative or absolute contraindications for lumbar total disc replacement (TDR). In Switzerland it is left to the surgeon's discretion when to operate. The present study is based on the dataset of SWISSspine, a governmentally mandated health technology assessment registry. We hypothesized that preoperative nucleus pulposus status and presence or absence of radiculopathy has an influence on clinical outcomes in patients treated with mono-segmental lumbar TDR. Methods. Between March 2005 and April 2009, 416 patients underwent mono-segmental lumbar TDR, which was documented in a prospective observational multicenter mode. The data collection consisted of perioperative and follow-up data (physician based) and clinical outcomes (NASS, EQ-5D). Patients were divided into four groups according to their preoperative status: 1) group degenerative disc disease ("DDD"): 160 patients without HNP and no radiculopathy, classic precondition for TDR; 2) group "HNP-No radiculopathy": 68 patients with HNP but without radiculopathy; 3) group "Stenosis": 73 patients without HNP but with radiculopathy, and 4) group "HNP-Radiculopathy": 132 patients with HNP and radiculopathy. The groups were compared regarding preoperative patient characteristics and pre- and postoperative VAS and EQ-5D scores using general linear modeling. Results: Demographics in all four groups were comparable. Regarding the improvement of quality of life (EQ-5D) there were no differences across the four groups. For the two main groups DDD and HNP-Radiculopathy no differences were found in the adjusted postoperative back- and leg pain alleviation levels, in the stenosis group back- and leg pain relief were lower. Conclusions: Despite higher preoperative leg pain levels, outcomes in lumbar TDR patients with HNP and radiculopathy were similar to outcomes in patients with the classic indication; this because patients with higher preoperative leg pain levels benefit from a relatively greater leg pain alleviation. The group with absence of HNP but presence of radiculopathy showed considerably less benefits from the operation, which is probably related to ongoing degenerative processes of the posterior segmental structures. This observational multicenter study suggests that the diagnoses HNP and radiculopathy, combined or alone, may not have to be considered as absolute or relative contraindications for mono-segmental lumbar TDR anymore, whereas patients without HNP but with radiculopathy seem to be suboptimal candidates for the procedure. © 2011 Zweig et al; licensee BioMed Central Ltd

Thermodynamic stability, unfolding kinetics, and aggregation of the N-terminal actin-binding domains of utrophin and dystrophin.

Muscular dystrophy (MD) is the most common genetic lethal disorder in children. Mutations in dystrophin trigger the most common form of MD, Duchenne, and its allelic variant Becker MD. Utrophin is the closest homologue and has been shown to compensate for the loss of dystrophin in human disease animal models. However, the structural and functional similarities and differences between utrophin and dystrophin are less understood. Both proteins interact with actin through their N-terminal actin-binding domain (N-ABD). In this study, we examined the thermodynamic stability and aggregation of utrophin N-ABD and compared with that of dystrophin. Our results show that utrophin N-ABD has spectroscopic properties similar to dystrophin N-ABD. However, utrophin N-ABD has decreased denaturant and thermal stability, unfolds faster, and is correspondingly more susceptible to proteolysis, which might account for its decreased in vivo half-life compared to dystrophin. In addition, utrophin N-ABD aggregates to a lesser extent compared with dystrophin N-ABD, contrary to the general behavior of proteins in which decreased stability enhances protein aggregation. Despite these differences in stability and aggregation, both proteins exhibit deleterious effects of mutations. When utrophin N-ABD mutations analogous in position to the dystrophin disease-causing mutations were generated, they behaved similarly to dystrophin mutants in terms of decreased stability and the formation of cross-β aggregates, indicating a possible role for utrophin mutations in disease mechanisms

The Substrate-Bound Crystal Structure of a Baeyer–Villiger Monooxygenase Exhibits a Criegee-like Conformation

The Baeyer\u2013Villiger monooxygenases (BVMOs) are a family of bacterial flavoproteins that catalyze the synthetically useful Baeyer\u2013Villiger oxidation reaction. This involves the conversion of ketones into esters or cyclic ketones into lactones by introducing an oxygen atom adjacent to the carbonyl group. The BVMOs offer exquisite regio- and enantiospecificity while acting on a wide range of substrates. They use only NADPH and oxygen as cosubstrates, and produce only NADP+ and water as byproducts, making them environmentally attractive for industrial purposes. Here, we report the first crystal structure of a BVMO, cyclohexanone monooxygenase (CHMO) from Rhodococcus sp. HI-31 in complex with its substrate, cyclohexanone, as well as NADP+ and FAD, to 2.4 \uc5 resolution. This structure shows a drastic rotation of the NADP+ cofactor in comparison to previously reported NADP+-bound structures, as the nicotinamide moiety is no longer positioned above the flavin ring. Instead, the substrate, cyclohexanone, is found at this location, in an appropriate position for the formation of the Criegee intermediate. The rotation of NADP+ permits the substrate to gain access to the reactive flavin peroxyanion intermediate while preventing it from diffusing out of the active site. The structure thus reveals the conformation of the enzyme during the key catalytic step. CHMO is proposed to undergo a series of conformational changes to gradually move the substrate from the solvent, via binding in a solvent excluded pocket that dictates the enzyme\u2019s chemospecificity, to a location above the flavin\u2013peroxide adduct where catalysis occurs.Peer reviewed: YesNRC publication: Ye

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology