Scalar activity induced phase separation and liquid-solid transition in a Lennard-Jones system.

We report scalar activity induced phase separation and crystallization in a system of 3-d Lennard-Jones particles taken at state points spanning from the gas to the liquid regime using molecular dynamics simulation (MD). Scalar activity was introduced by increasing the temperature of half of the particles (labeled 'hot') while keeping the temperature of the other half constant at a lower value (labeled 'cold'). The relative temperature difference between the two subsystems is considered as a measure of the activity. From our simulations we observe that the two species tend to phase separate at sufficiently high activity ratio. The extent of separation is quantified by the defined order parameter and the entropy production during this process is determined by employing the two-phase thermodynamic (2PT) model and the standard modified Benedict-Webb-Rubin (MBWR) equation of state for a LJ fluid. We observe that the extent of the phase separation and entropy production increases with the density of the system. From a cluster analysis, we obtain the mean number of clusters ncl, and the mean size of the largest cluster n0 in the system, complementing each other. Bond orientation order parameters reveal that the so formed largest cluster also develops solid-like order consisting of both FCC and HCP packing. The presence of such crystalline order is also supported by a common neighbor analysis.

Pancreatic cysts: Diagnostic accuracy and risk of inappropriate resections.

BACKGROUND: Pancreatic cystic neoplasms (PCN) frequently undergo surgery, given malignant potential. Pancreatic cyst surgery is associated with significant rates of morbidity and mortality. It is crucial to accurately characterize these lesions pre-operatively to avoid unnecessary surgery in patients with benign pancreatic cysts. AIM: We aimed to assess the correlation between pre-operative (pre-op) diagnosis based on imaging and clinical presentation, and post-operative (post-op) diagnosis based on histopathology in patients undergone pancreatic cyst surgery. METHODS: From January 2000 to January 2012, we randomly selected 2000 patients with ICD-9 code 211.6 and 577.2. Amongst these we identified 281 patients undergone pancreas surgery. Patients with no pre-op imaging or non-cyst indication for surgery were excluded (n = 107). Imaging details, demographics, pre-operative physician diagnosis and histopathologic details of pancreatic cysts were recorded in 174 patients. RESULTS: There was a discrepancy between the pre- and post-operative pancreatic cyst diagnosis in 54 (31%) patients. There was no difference in the proportion of various imaging studies (CT, EUS or MRI) between patients with a correct and patients with an incorrect pre-op diagnosis. The pre-op diagnosis was confirmed at pathology in 87.5% of the presumed SCNs, in 80% of the presumed pseudocysts, in 73.3% of the presumed BD-IPMNs, in 66.7% of the presumed MD/mixed-IPMNs and in 53.6% of the presumed MCNs. The accuracy of the pre-operative diagnosis of presumed MCN was significantly lower compared to the non-MCN cysts (53.6% vs. 75%; p = 0.037). Fourteen percent of resections were performed for asymptomatic benign cysts, preoperatively suspected to be potentially pre-malignant cysts. CONCLUSION: In nearly 1 out of 3 patients undergone pancreas cyst surgery, there is a discrepancy between pre- and post-op diagnosis. Pre-op diagnosis of presumed MCN is more likely to be incorrect, compared to the other cysts.

Combining clinicopathological predictors and molecular biomarkers in the oncogenic K-RAS/Ki67/HIF-1α pathway to predict survival in resectable pancreatic cancer.

BACKGROUND: The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS hyperactivation is virtually universal in pancreatic cancer, that confers drug resistance, drives aggressive tumorigenesis and rapid metastasis. Pancreatic tumours are often marked by hypovascularity, increased hypoxia and ineffective drug delivery. Thus, biomarker discovery and developing innovative means of countervailing oncogenic K-RAS activation are urgently needed. METHODS: Tumour specimens from 147 pancreatic cancer patients were analysed by immunohistochemical (IHC) staining and tissue microarray (TMA). Statistical correlations between selected biomarkers and clinicopathological predictors were examined to predict survival. RESULTS: We find that heightened hypoxia response predicts poor clinical outcome in resectable pancreatic cancer. SIAH is a tumour-specific biomarker. The combination of five biomarkers (EGFR, phospho-ERK, SIAH, Ki67 and HIF-1α) and four clinicopathological predictors (tumour size, pathological grade, margin and lymph node status) predict patient survival post surgery in pancreatic cancer. CONCLUSIONS: Combining five biomarkers in the K-RAS/Ki67/HIF-1α pathways with four clinicopathological predictors may assist to better predict survival in resectable pancreatic cancer.

Diabetes and pancreatic cancer.

The relationship between diabetes and pancreatic cancer is complex. Diabetes or impaired glucose tolerance is present in more than 2/3rd of pancreatic cancer patients. Epidemiological studies have consistently shown a modest increase in the risk of pancreatic cancer in type 2 diabetes, with an inverse relationship to duration of disease. Additionally, recent studies suggest that anti-diabetic medications may modulate the risk of pancreatic cancer in type 2 diabetes. Subjects >50 years of age with new onset diabetes are at higher risk of having pancreatic cancer. However, to screen new-onset diabetes for pancreatic cancer, additional markers are needed that can distinguish pancreatic cancer-associated diabetes from type 2 diabetes.

Recent advances in autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) is distinct from calcifying and obstructive forms of chronic pancreatitis. Clinically and histologically it has two distinct subsets: (i) lymphoplasmacytic sclerosing pancreatitis or type 1 AIP which appears to be a systemic disease characterised by abundant infiltration of affected organs with immunoglobulin G4 (IgG4)-positive plasma cells and (2) duct-centric or type 2 AIP characterised by granulocyte epithelial lesions in the pancreas without systemic involvement. In AIP a marked lymphoplasmacytic infiltrate that responds dramatically to steroid therapy suggests an autoimmune aetiology. However, the target autoantigen(s) and the effector cells in AIP remain speculative. Despite the consistent elevation in serum IgG4 levels and tissue infiltration with IgG4-positive plasma cells in type 1 AIP, the role of IgG4 in its pathogenesis remains unknown. Recent development of animal models of AIP will help improve our understanding of the pathogenesis of these newly described forms of chronic pancreatitis.

Microarray technologies for gene transcript analysis in pancreatic cancer.

Pancreatic cancer is a devastating condition that is most often characterized by a poor prognosis. Microarray technologies are promising screening methods for the identification of potential markers for early diagnosis and chemotherapeutic intervention. In this article, we review the current state of pancreatic cancer research as it relates to the measurement of gene transcript levels by DNA microarray analysis.

Endoscopic ultrasonography and pancreatic cancer.

Despite extensive multidisciplinary efforts, the five-year survival rate for all patients with pancreatic adenocarcinoma remains less than 3%. In the last twenty years, endoscopic ultrasound (EUS) has developed into an indispensable tool for the diagnosis and staging of malignant pancreatic lesions. EUS, in combination with helical and multidetector computed tomography scans, is currently 80-90% accurate in determining the tumor TNM stage. EUS fine-needle aspiration obtains diagnostic pathologic samples in approximately 80% of cases, and intraductal ultrasound has augmented the ability to determine the malignant potential of pancreatic strictures. In patients at high-risk for pancreatic malignancy, EUS has been advocated as a screening tool for malignancy. Finally, exciting new developments suggest the potential of EUS as a therapeutic tool, both for the management of pain from pancreatic cancer and as a novel therapeutic-delivery device.

Superoxide dismutase in diabetic polymorphonuclear leukocytes.

The level of superoxide anion was found to be significantly elevated in polymorphonuclear leukocytes (PMNL) from diabetic subjects as compared with those from normal subjects. This elevation was attributed to the significant reduction in the activities of both cytoplasmic and mitochondrial superoxide dismutase (SOD), the effect being more pronounced in the cytoplasmic fraction. Although the content of copper decreased considerably in the diabetic PMNL, the decrease in the zinc content was less significant, with an insignificant alteration in the content of manganese. PMNL obtained from insulin-treated diabetic patients showed considerable alleviation of SOD levels. The implication of these results are discussed herein.

Fibrocalculous pancreatic diabetes. Long-term survival analysis.

OBJECTIVE: To determine the long-term survival and causes of death in fibrocalculous pancreatic diabetes, a form of diabetes secondary to tropical chronic pancreatitis. RESEARCH DESIGN AND METHODS: A cohort of 370 patients with fibrocalculous pancreatic diabetes were analyzed with respect to survival time from the date of occurrence of the first symptom of the disease as well as after the onset of diabetes. The cause of death was analyzed in the patients who died. Cumulative survival rates were calculated by the actuarial method, and life table graphs were plotted by mathematical calculations. RESULTS: Long-term survival of patients with fibrocalculous pancreatic diabetes is much better today than that described 30 years ago. About 80% of patients were alive 35 years after the first episode of abdominal pain. The median survival time after the diagnosis of diabetes was 25 years. These figures, however, are still considerably lower than the life expectancy of the age- and sex-matched general population. Diabetic nephropathy was the main cause of death. Pancreatic cancer and other chronic pancreatitis-related causes as well as malnutrition and infections were also important contributors to mortality. CONCLUSIONS: The overall prognosis for patients with fibrocalculous pancreatic diabetes appears to have improved possibly because of earlier diagnosis, better management of diabetes, and improved nutrition.

Exocrine pancreatic function in tropical fibrocalculous pancreatic diabetes.

Exocrine pancreatic function was studied by fecal chymotrypsin test in three groups of diabetic patients seen in southern India. Exocrine pancreatic insufficiency, as shown by low fecal chymotrypsin levels, was seen in 87.5% of patients with fibrocalculous pancreatic diabetes (FCPD), in 23.5% of insulin-dependent diabetes mellitus patients, and in 4.5% of non-insulin-dependent diabetes mellitus patients. There was no correlation between fecal chymotrypsin levels and serum amylase, serum lipase, age, body mass index, duration of diabetes, fasting plasma glucose, or glycosylated hemoglobin levels. The fecal chymotrypsin test is a useful additional investigation for the diagnosis of FCPD found in tropical countries.

Inhibition of progesterone secretion in cultured human granulosa cells by a low molecular weight fraction of human follicular fluid.

Previous studies demonstrated that a low molecular weight peptide fraction (G10-3) from human follicular fluid (FFl) could inhibit steroidogenesis by rat granulosa cells in vitro. In the present study this FFl fraction was tested upon human granulosa cells. The G10-3 fraction (less than 1000 mol wt) was obtained by sequential gel filtration on Sephadex G50 and G10 of a steroid-free extract of a pool of human FFl collected from various-sized follicles at different stages of the menstrual cycle. Human granulosa cells were obtained from large, healthy follicles in the mid- to late follicular phase of eight patients, and cultured for 4-6 days in the absence or presence of G10-3. In all cases G10-3 produced a dose-dependent inhibition of basal progesterone secretion and, when tested, also of FSH-stimulated progesterone secretion. Inhibition of progesterone secretion appeared to be greater in cells obtained from less mature follicles as compared to cells obtained from follicles that were periovulatory. The results suggest the presence of a low molecular weight luteinizing inhibitor in human FFl.

Interaction of nitric oxide synthase inhibitors and their D-enantiomers with rat neutrophil luminol dependent chemiluminescence response.

1. Formyl-methionyl-leucyl-phenylalanine (FMLP) or arachidonic acid (AA) induced luminol dependent chemiluminescence (LCL) response of rat polymorphonuclear leukocytes (PMNLs) was found to be inhibited by nitric oxide synthease inhibitors and their D-enantiomers. 2. Rat PMNLs LCL response was inhibited by NG-nitro-L-arginine methyl ester (L-NAME), D-NAME, NG-monomethyl-L-arginine (L-NMMA) or D-NMMA, in a concentration- and time-dependent manner. 3. It was observed that both L- and D-enantiomers of the arginine analogues (1000 microM) did not inhibit AA induced lucigenin-dependent chemiluminescence (LUCDCL) response and cytochrome c reduction, used for estimating the NADPH-oxidase activity in the cells and in the cell free system, respectively. 4. None of the L- and D-enantiomers had any effect on either rat basal PMNLs or AA-induced oxygen consumption. 5. In addition, neither the L nor D-enantiomers of NAME altered either AA-induced release or the activity of myeloperoxidase from rat PMNLs azurophilic granules. 6. The results obtained indicate that the attenuation of the LCL response by L- and D-enantiomers of arginine analogues, is a non-specific effect as there was no inhibition of NADPH-oxidase and MPO activity, MPO release or oxygen consumption. Therefore, the data obtained indicate that these agents should be used with caution to analyse the role of nitric oxide in rat PMNLs LCL response.

Inhibition of FIV replication by a ribozyme that targets the Rev response element.

The feline immunodeficiency virus (FIV) Rev protein and its cognate sequence the Rev response element (RRE) are essential for virus replication. Thus, the inhibition of either Rev or RRE function can significantly inhibit FIV replication. In the present study, we constructed a ribozyme that targets the RRE sequence and determined its ability to inhibit FIV replication. The RRE ribozyme cleaved the target molecule both in vitro and in FIV-infected cells. Furthermore, FIV replication was reduced significantly in the presence of the RRE ribozyme. FIV provides a good animal model system with which to develop novel antiviral strategies for the human immunodeficiency virus.

Isolation of luteinising hormone receptor binding inhibitor from bovine corpus luteum.

A luteinising hormone receptor binding inhibitor (LHRBI) has been purified from bovine corpus luteum (CL). Steroid-free extract of the CL was subjected to successive chromatographies on Sephadex G-50, Q-Sepharose, Orange A dye and metal chelate affinity columns followed by high performance-reverse phase and gel filtration columns. Purification was monitored by the ability of the fractions to inhibit the binding of 125I-human chorionic gonadotropin (hCG) to porcine granulosa cells in vitro. The final isolate showed an 8000-fold enrichment of activity. It was also capable of inhibiting porcine granulosa cell secretion of estradiol and progesterone (P) in vitro. Administration of LHRBI into follicle-stimulating hormone (FSH)-stimulated, immature rats strongly inhibited the ovarian ovulatory response to hCG as revealed by decreased P levels and the number of ova released. The M(r) of LHRBI as assessed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis was ca. 15 kDa and the pI was between 5.0 and 5.5.

On the identity of bovine seminal plasma inhibin.

In light of current discussions on multiple forms of inhibin, it was thought of interest to ascertain the identity of the postulated 'iso-hormones' of bull seminal plasma inhibin (Chari et al., 1978). By subjecting the biologically active fraction, obtained by Sephadex G-100 gel filtration of bull seminal plasma acetone powder, to extensive dialysis in distilled water adjusted to pH 5.8, it was possible to remove the bulk of inert protein as a precipitate. The resulting active preparation could be readily fractionated by preparative iso-electric focusing in the pH range 4.0-6.5 yielding 2 distinct homogeneous peptides, alpha and beta, capable of suppressing hCG-induced uterine weight increase in immature mice, in a 'reversed Steelman-Pohley' assay design. However, of these, alpha alone was able to suppress post-castrational serum gonadotropin rise in appropriate animal models. This peptide is highly acidic in nature (iso-electric point congruent to 2.2) and has a molecular weight (Mr) of 18200 and a Stokes radius of 1.90 nm. On the basis of currently available evidence, it is concluded that the molecule consists of a single peptide chain.

Regulators of steroid secretion and inhibin activity in human ovarian follicular fluid.

Inhibin activity from human follicular fluid was purified by successive chromatographies on Sephadex G-50, DEAE-Biogel A and orange A dye matrix. Inhibin activity was associated only with the protein(s) that bound to orange A (OrA-2). Daily injection of OrA-2, 1 h prior to hMG into 10-day-old female rats for 4 days caused a significant inhibition of hMG-induced estradiol secretion. In vitro, OrA-2 dose-dependently inhibited the amounts of estradiol secreted by porcine granulosa cells during a 3-h incubation. Orange A-unbound proteins, on the other hand, induced a dose-dependent increase in estradiol as well as progesterone secretion by porcine granulosa cells in vitro. Separation of stimulator from the inhibitor by orange A chromatography led to an increase in the relative inhibin activity (25-50-fold) as well as aromatisation-suppressing activity (60-fold). The results indicate a possible local action of hFF inhibin to regulate aromatisation activity.

Oocyte maturation as regulated by follicular factors.

Follicular fluid (FFl), obtained from 24 women treated with clomiphene/hCG in an in vitro fertilization program, was characterized with respect to steroid hormone levels and oocyte maturation inhibitor (OMI) activity. Three FFl samples apparently were derived from cystic follicles and contained low steroid levels and no OMI activity in an in vitro rat oocyte assay. The remaining 21 follicles contained normal preovulatory steroid levels and mature and generally fertilizable oocytes. In 7 of these follicles the FFl (at 50% concentration) significantly inhibited rat oocyte meiosis, while 14 exerted no OMI activity. The results confirm earlier work on porcine and human FFl, suggesting that the putative OMI activity declines with follicular maturation.

Comparison of two dose-response techniques to study the pancreatic secretory response to intraduodenal tryptophan in the absence and presence of the M1-receptor antagonist telenzepine.

To answer the questions if the type of continuous dose-response technique influences the pancreatic secretory response to intraduodenal tryptophan and if the M1-receptor antagonist telenzepine influences the intestinal absorption of tryptophan, we determined, in 12 conscious dogs with chronic gastric and duodenal fistulas, pancreatic bicarbonate and protein secretion and tryptophan plasma concentrations following intraduodenal tryptophan perfusion using two dose-response techniques. With an ascending continuous dose-response technique (aDRT), tryptophan was perfused in loads ranging from 0.12 to 10.0 mmol h-1, starting with the lowest load and tripling it every 45 min. With the descending continuous dose-response technique (dDRT), the order of tryptophan loads was reversed, with the highest load being given first. All studies were done on a fixed background of intravenous secretin (20.5 pmol kg-1 h-1) and repeated in the presence of the anticholinergic M1-receptor antagonist telenzepine (243 nmol kg-1 h-1). The bicarbonate and protein response as well as tryptophan plasma concentrations to the same loads of tryptophan did not differ significantly between the two techniques. Using both techniques, telenzepine significantly (p < 0.05) inhibited the overall pancreatic protein response by 65% (dDRT) to 81% (aDRT). The overall bicarbonate response was only numerically, and not statistically significantly, inhibited by telezepine. Tryptophan plasma concentrations after duodenal perfusion with tryptophan were neither influenced by the order of tryptophan loads nor altered by telenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)