The role of Wnt signaling in the development of the epiblast and axial progenitors.

Understanding how the body plan is established during embryogenesis remains a fundamental biological question. The Wnt/ß-catenin signaling pathway plays a crucial and highly conserved role in body plan formation, functioning to polarize the primary anterior-posterior (AP) or head-to-tail body axis in most metazoans. In this chapter, we focus on the roles that the mammalian Wnt/ß-catenin pathway plays to prepare the pluripotent epiblast for gastrulation, and to elicit the emergence of multipotent axial progenitors from the caudal epiblast. Interactions between Wnt and retinoic acid (RA), another powerful family of developmental signaling molecules, in axial progenitors will also be discussed. Gastrulation movements and somitogenesis result in the anterior displacement of the RA source (the rostral somites and lateral plate mesoderm (LPM)), from the posterior Wnt source (the primitive streak (PS)), leading to the establishment of antiparallel gradients of RA and Wnt that control the self-renewal and successive differentiation of neck, trunk and tail progenitors.

The incidence of mismatch repair gene defects in colorectal liver metastases.

Knowledge of the molecular biology of primary colorectal cancer (CRC) has improved in recent years, and one reason for this is the identification of microsatellite instability (MSI), which occurs in up to 15% of sporadic CRC. However, less is known regarding the processes involved in colorectal liver metastases (CRLM). Increasing numbers of patients with CRLM are suitable for curative resection, so the identification of molecular markers may improve patient selection. The aim of the present study was to characterise the incidence of MSI in resected CRLM. Fifty­one sequentially resected CRLM specimens were selected. Clinicopathologic data was collated and immunohistochemistry for MLH1 and MSH2 was performed on paraffin sections of the CRLM specimens. The association between abnormal staining and the clinicopathological data was examined. The median age of the subjects in the current study was 65 years, the average number of CRLM was 2 and the median overall survival time was 42.1 months post liver resection. None of the 50 resected specimens demonstrated abnormal staining for MLH1 or MSH2. Compared with the previously reported incidence of MSI in primary CRC, the low incidence of MSI in the current cohort of CRLM precludes its use as a marker for use in making clinical decisions regarding this condition.

Portal vein embolization prior to major liver resection.

BACKGROUND: Portal vein embolization (PVE) induces compensatory hypertrophy of the future liver remnant volume (FLRV) to improve the safety of major liver surgery by reducing the risk of post-operative liver failure. The aim was to describe our experience of PVE for patients with large or multifocal malignant liver tumours who initially were deemed unresectable. METHODS: Perioperative data were retrieved from a prospective database and computed tomographic scans were retrospectively reviewed to calculate volume changes and the degree of liver hypertrophy following PVE. RESULTS: PVE was successful in 23 out of 25 patients and resulted in a change in the mean estimated FLRV from 585 to 788 mL following PVE. This represented a 35% increase in the remnant liver parenchymal volume post-embolization (P < 0.01). The procedure was well tolerated and did not compromise the surgical resection in any patient. Nineteen patients went on to have a liver resection following PVE with an in-hospital mortality of 16% (3 out of 19) and a 42% morbidity rate. After a mean follow-up of 31 months (1-130 months), 32% (6 out of 19) of patients are alive and 4 of these (21%) are completely disease-free. CONCLUSIONS: PVE results in an increase in the FLRV prior to major hepatectomy. Failure to develop hypertrophy following PVE is a surrogate marker for underlying liver dysfunction. PVE is safe and may increase the pool of patients suitable for liver resection. Long-term survival is similar to those not requiring embolization prior to liver resection.

Applications of Hadamard transform-gas chromatography/mass spectrometry for the detection of hexamethyldisiloxane in a wafer cleanroom.

The Hadamard transform-gas chromatography/mass spectrometry (HT-GC/MS) technique was successfully employed for the detection of hexamethyldisiloxane (HMDSO, C(6)H(18)OSi(2)) at the sub-nL/L level in a semiconductor wafer cleanroom. Indoor air samples were collected from the room, according to EPA Method TO-17 using a Tedlar bag where the air samples were allowed to pass through an absorption tube for 24 h. The condensed components were then heated and simultaneously injected into a GC column through a Hadamard-injector, which was operated in accordance with the Hadamard codes. Compared to the single injection used in most GC/MS systems, the signal-to-noise (S/N) ratios were substantially improved after the inverse Hadamard transformation of the encoded chromatogram. Under optimized conditions, when cyclic S-matrix orders of 255, 1023 and 2047 were used, the S/N ratios of the HMDSO signals were substantially improved by 7.4-, 15.1- and 20.1-fold, respectively. These improvements are in good agreement with theoretically calculated values (8.0-, 16.0- and 22.6-fold, respectively). We found that when the HT-GC/MS technique was applied, HMDSO could be detected at the 0.1 nL/L level.

The role of peribiliary cysts in biliary obstruction.

Peribiliary cysts are cystic dilatations of the extramural glands of the intrahepatic biliary tree. This disorder is uncommon and is usually asymptomatic. However, it may cause extrinsic biliary compression and consequently, obstructive jaundice. This paper describes 2 such cases presenting with jaundice. The etiology, natural history, investigation findings and treatment of this disorder are also discussed.

Expression of S100A2 calcium-binding protein predicts response to pancreatectomy for pancreatic cancer.

BACKGROUND & AIMS: Current methods of preoperative staging and predicting outcome following pancreatectomy for pancreatic cancer (PC) are inadequate. We evaluated the utility of multiple biomarkers from distinct biologic pathways as potential predictive markers of response to pancreatectomy and patient survival. METHODS: We assessed the relationship of candidate biomarkers known, or suspected, to be aberrantly expressed in PC, with disease-specific survival and response to therapy in a cohort of 601 patients. RESULTS: Of the 17 candidate biomarkers examined, only elevated expression of S100A2 was an independent predictor of survival in both the training (n = 162) and validation sets (n = 439; hazard ratio [HR], 2.19; 95% confidence interval [CI]: 1.48-3.25; P < .0001) when assessed in a multivariate model with clinical variables. Patients with high S100A2 expressing tumors had no survival benefit with pancreatectomy compared with those with locally advanced disease, whereas those without high S100A2 expression had a survival advantage of 10.6 months (19.4 vs 8.8 months, respectively) and a HR of 3.23 (95% CI: 2.39-4.33; P < .0001). Of significance, patients with S100A2-negative tumors had a significant survival benefit from pancreatectomy even in the presence of involved surgical margins (median, 15.7 months; P = .0007) or lymph node metastases (median, 17.4 months; P = .0002). CONCLUSIONS: S100A2 expression is a good predictor of response to pancreatectomy for PC and suggests that high S100A2 expression may be a marker of a metastatic phenotype. Prospective measurement of S100A2 expression in diagnostic biopsy samples has potential clinical utility as a predictive marker of response to pancreatectomy and other therapies that target locoregional disease.

Sporadic pancreatic polypeptide secreting tumors (PPomas) of the pancreas.

BACKGROUND: Sporadic pancreatic neuroendocrine tumors, which predominantly secrete pancreatic polypeptide (PPoma), are rare and have not been associated with a clinical syndrome. A wider understanding of their pathological features and behavior is needed. METHODS: Four PPoma patients who presented with nonspecific abdominal pain are described. Their diagnosis was established by the presence of an enhancing solitary pancreatic tumor on computed tomography (CT) and elevated fasting pancreatic polypeptide hormone levels. Patient 1 was treated with a pancreatoduodenectomy because of elevation of serum CEA level. Two of the cases underwent enucleation because of prolonged stable CT appearance. Patient 4 underwent distal pancreatectomy for a pancreatic neck tumor causing ductal obstruction and distal parenchymal atrophy. RESULTS: All cases had benign histological features apart from patient 1 whose tumor demonstrated occasional mitotic activity. These tumors have not recurred after a median of 49 (range, 35-57) months. The protein expression in the tumor tissue was measured by SELDI-TOF MS and was different than the profile of pancreatic adenocarcinoma that was previously demonstrated in our laboratory. This may lead to future helpful diagnostic testing on fine needle aspirates. CONCLUSION: Resection of sporadic PPomas presenting as a solitary well-defined mass with benign histological features results in good long-term survival.

Action potential morphology heterogeneity in the atrium and its effect on atrial reentry: a two-dimensional and quasi-three-dimensional study.

Atrial fibrillation (AF) is believed to be perpetuated by recirculating spiral waves. Atrial structures are often characterized with action potentials of varying morphologies; however, the role of the structure-dependent atrial electrophysiological heterogeneity in spiral wave behaviour is not well understood. The purpose of this study is to determine the effect of action potential morphology heterogeneity associated with the major atrial structures in spiral wave maintenance. The present study also focuses on how this effect is further modulated by the presence of the inherent periodicity in atrial structure. The goals of the study are achieved through the simulation of electrical behaviour in a two-dimensional atrial tissue model that incorporates the representation of action potentials in various structurally distinct regions in the right atrium. Periodic boundary conditions are then imposed to form a cylinder (quasi three-dimensional), thus allowing exploration of the additional effect of structure periodicity on spiral wave behaviour. Transmembrane potential maps and phase singularity traces are analysed to determine effects on spiral wave behaviour. Results demonstrate that the prolonged refractoriness of the crista terminalis (CT) affects the pattern of spiral wave reentry, while the variation in action potential morphology of the other structures does not. The CT anchors the spiral waves, preventing them from drifting away. Spiral wave dynamics is altered when the ends of the sheet are spliced together to form a cylinder. The main effect of the continuous surface is the generation of secondary spiral waves which influences the primary rotors. The interaction of the primary and secondary spiral waves decreased as cylinder diameter increased.

The effect of vagally induced dispersion of action potential duration on atrial arrhythmogenesis.

OBJECTIVE: The purpose of this study is to ascertain the effects of spatially variable ACh distributions on arrhythmogenesis in a morphologically realistic computer model of canine atria. BACKGROUND: Vagal stimulation releases acetylcholine (ACh), which causes a dose-dependent reduction in action potential duration (APD) in the atria. Due to the nonuniform distribution of nerve endings, APD dispersion may result, which has been shown to play a role in the breakup of activity. METHODS: Reentry was initiated in a computationally efficient, morphologically realistic computer model of the atria. Discrete regions corresponding to ACh release sites, referred to as islands, were assigned shortened APDs in an ACh-dependent fashion. Island APD was varied as well as the basal APD. The window of vulnerability for ectopic beat-induction of sustained reentry was determined for both left atrial(LA) and right atrial (RA) stimulation. The resulting reentries were categorized based on type and location. RESULTS: 1) Atrial geometry severely restricts the formation of reentrant circuits. 2) Wave fractionation only occurred for large differences between island and basal APD. 3) Small ACh concentration differences produced stable figure-of-8 reentrant patterns. 4) Large islands displayed more wave breakup but could sometimes anchor reentries. CONCLUSIONS: Large APD gradients produced by ACh heterogeneity can lead to a breakdown of organized activity.

The role of the promontory stimulation test in cochlear implantation.

To date, 290 adults have been implanted in the cochlear implant programme in Sydney (Australia), where the promontory stimulation test (PST) is routinely used to assess implant candidacy. There has been much controversy over the exact role and value of this test. Pre- and postoperative speech comprehension tests of 150 implantees were analysed, and scores were compared with preoperative PST performances. Eighty-nine per cent of the patients perceived sound when the promontory was stimulated electrically. This group of implantees scored 81% on CID speech tests at 12 months postoperatively, compared to the minority who lacked preoperative promontory stimulability, who scored 42%. The PST is therefore predictive of greater speech benefits after implantation. It also provides an important psychophysical experience of hearing electrical sound.