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Background: Axillary staging via sentinel lymph node biopsy (SLNB) is performed for clinically node-negative (N0) breast cancer patients. The Skåne University Hospital (SUS) nomogram was developed to assess the possibility of omitting SLNB for patients with a low risk of nodal metastasis. Area under the receiver operating characteristic curve (AUC) was 0.74. The aim was to validate the SUS nomogram using only routinely collected data from the Swedish National Quality Registry for Breast Cancer at two breast cancer centres during different time periods., Method: This retrospective study included patients with primary breast cancer who were treated at centres in Lund and Malmö during 2008-2013. Clinicopathological predictors in the SUS nomogram were age, mode of detection, tumour size, multifocality, lymphovascular invasion and surrogate molecular subtype. Multiple imputation was used for missing data. Validation performance was assessed using AUC and calibration., Results: The study included 2939 patients (1318 patients treated in Lund and 1621 treated in Malmö). Node-positive disease was detected in 1008 patients. The overall validation AUC was 0.74 (Lund cohort AUC: 0.75, Malmö cohort AUC: 0.73), and the calibration was satisfactory. Accepting a false-negative rate of 5 per cent for predicting N0, a possible SLNB reduction rate of 15 per cent was obtained in the overall cohort., Conclusion: The SUS nomogram provided acceptable power for predicting a disease-free axilla in the validation cohort. This tool may assist surgeons in identifying and counselling patients with a low risk of nodal metastasis on the omission of SLNB staging., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

Membrane processes represent one of the most promising technologies for separation and extraction in modern industries, because they have several advantages. Today these processes are an important research topic, including affinity polymer membranes that are highly efficient for oriented processes. Three affinity polymer membrane types containing lipophilic compounds, methyl cholate (MC) and cholic acid (CA) as extractive agents were prepared and characterized. They have been used to extract active ingredient paracetamol (acetaminophen), from concentrated solutions (0.08-0.01M). Substrate acetaminophen is an important active ingredient and its recovery as a pure compound, is very useful for the pharmaceutical industry. These affinity polymer membranes were adopted to perform experiments on a facilitated extraction process of this substrate at different medium acidities and temperatures. Macroscopic parameters, permeabilities (P) and initial fluxes (J 0 ) for a facilitated extraction of this substrate through each membrane were determined. The results indicate that values of initial fluxes (J 0 ) of the extracted substrate are related to its initial concentration C 0 by a saturation law, which allowed to determine microscopic parameters, apparent diffusion coefficients (D * ) and association constants (K ass ) of formed entity (substrate - extractive agent) (ST). The results show a clear influence of temperature and acidity factors on the evolution of these parameters and membrane performances in this studied process. Activation parameters (E a , ΔH ≠ , and ΔS ≠ ) were determined and the values indicate that high performances of these membrane types are certainly related to the movement nature of the substrate across the organic phase, and the structures of the substrate and the extractive agent., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We consider Hilbert's problem of the axioms of physics at a qualitative or conceptual level. This is more pressing than ever as we seek to understand how both general relativity and quantum theory could emerge from some deeper theory of quantum gravity, and in this regard I have previously proposed a principle of self-duality or quantum Born reciprocity as a key structure. Here, I outline some of my recent work around the idea of quantum space-time as motivated by this non-standard philosophy, including a new toy model of gravity on a space-time consisting of four points forming a square.This article is part of the theme issue 'Hilbert's sixth problem'., (© 2018 The Author(s).)

A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region-miR-383-is frequently downregulated in prostate cancer, has a critical role in determining tumor-initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor-initiating cells (TICs)/stem cells. Expression analyses of miR-383 in PCa clinical tissues established that low miR-383 expression is associated with poor prognosis. Functional data suggest that miR-383 regulates PCa tumor-initiating/stem-like cells via CD44 regulation. Ectopic expression of miR-383 inhibited tumor-initiating capacity of CD44+ PCa cells. Also, 'anti-metastatic' effects of ectopic miR-383 expression were observed in a PCa experimental metastasis model. In view of our results, we propose that frequent loss of miR-383 at chr8p22 region leads to tumor initiation and prostate cancer metastasis. Thus, we have identified a novel finding that associates a long observed genomic alteration to PCa stemness and metastasis. Our data suggest that restoration of miR-383 expression may be an effective therapeutic modality against PCa. Importantly, we identified miR-383 as a novel PCa tissue diagnostic biomarker with a potential that outperforms that of serum PSA.

Transport and deposition of nanoparticles in porous media is a multi-scale problem governed by several pore-scale processes, and hence, it is critical to link the processes at pore scale to the Darcy-scale behavior. In this study, using pore network modeling, we develop correlation equations for deposition rate coefficients for nanoparticle transport under unfavorable conditions at the Darcy scale based on pore-scale mechanisms. The upscaling tool is a multi-directional pore-network model consisting of an interconnected network of pores with variable connectivities. Correlation equations describing the pore-averaged deposition rate coefficients under unfavorable conditions in a cylindrical pore, developed in our earlier studies, are employed for each pore element. Pore-network simulations are performed for a wide range of parameter values to obtain the breakthrough curves of nanoparticle concentration. The latter is fitted with macroscopic 1-D advection-dispersion equation with a two-site linear reversible deposition accounting for both equilibrium and kinetic sorption. This leads to the estimation of three Darcy-scale deposition coefficients: distribution coefficient, kinetic rate constant, and the fraction of equilibrium sites. The correlation equations for the Darcy-scale deposition coefficients, under unfavorable conditions, are provided as a function of measurable Darcy-scale parameters, including: porosity, mean pore throat radius, mean pore water velocity, nanoparticle radius, ionic strength, dielectric constant, viscosity, temperature, and surface potentials of the particle and grain surfaces. The correlation equations are found to be consistent with the available experimental results, and in qualitative agreement with Colloid Filtration Theory for all parameters, except for the mean pore water velocity and nanoparticle radius., (Copyright © 2017. Published by Elsevier B.V.)

In this study we performed batch experiments to investigate the dissolution kinetics of trichloroethylene (TCE) and toluene vapors in water at room temperature and atmospheric pressure. The batch systems consisted of a water reservoir and a connected headspace, the latter containing a small glass cylinder filled with pure volatile organic compound (VOC). Results showed that air phase concentrations of both TCE and toluene increased relatively quickly to their maximum values and then became constant. We considered subsequent dissolution into both stirred and unstirred water reservoirs. Results of the stirred experiments showed a quick increase in the VOC concentrations with time up to their solubility limit in water. VOC vapor dissolution was found to be independent of pH. In contrast, salinity had a significant effect on the solubility of TCE and toluene vapors. VOC evaporation and vapor dissolution in the stirred water reservoirs followed first-order rate processes. Observed data could be described well using both simplified analytical solutions, which decoupled the VOC dynamics in the air and water phases, as well as using more complete coupled solutions. However, the estimated evaporation (k e ) and dissolution (k d ) rate constants differed by up to 70% between the coupled and uncoupled formulations. We also numerically investigated the effects of fluid withdrawal from the small water reservoir due to sampling. While decoupling the VOC air and water phase mass transfer processes produced unreliable estimates of k d , the effects of fluid withdrawal on the estimated rate constants were found to be less important. The unstirred experiments showed a much slower increase in the dissolved VOC concentrations versus time. Molecular diffusion of the VOCs within the aqueous phase became then the limiting factor for mass transfer from air to water. Fluid withdrawal during sampling likely caused some minor convection within the reservoir, which was simulated by increasing the apparent liquid diffusion coefficient., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A mathematical model is developed to simulate the co-transport of viruses and colloids in unsaturated porous media under steady-state flow conditions. The virus attachment to the mobile and immobile colloids is described using a linear reversible kinetic model. Colloid transport is assumed to be decoupled from virus transport; that is, we assume that colloids are not affected by the presence of attached viruses on their surface. The governing equations are solved numerically using an alternating three-step operator splitting approach. The model is verified by fitting three sets of experimental data published in the literature: (1) Syngouna and Chrysikopoulos (2013) and (2) Walshe et al. (2010), both on the co-transport of viruses and clay colloids under saturated conditions, and (3) Syngouna and Chrysikopoulos (2015) for the co-transport of viruses and clay colloids under unsaturated conditions. We found a good agreement between observed and fitted breakthrough curves (BTCs) under both saturated and unsaturated conditions. Then, the developed model was used to simulate the co-transport of viruses and colloids in porous media under unsaturated conditions, with the aim of understanding the relative importance of various processes on the co-transport of viruses and colloids in unsaturated porous media. The virus retention in porous media in the presence of colloids is greater during unsaturated conditions as compared to the saturated conditions due to: (1) virus attachment to the air-water interface (AWI), and (2) co-deposition of colloids with attached viruses on its surface to the AWI. A sensitivity analysis of the model to various parameters showed that the virus attachment to AWI is the most sensitive parameter affecting the BTCs of both free viruses and total mobile viruses and has a significant effect on all parts of the BTC. The free and the total mobile viruses BTCs are mainly influenced by parameters describing virus attachment to the AWI, virus interaction with mobile and immobile colloids, virus attachment to solid-water interface (SWI), and colloid interaction with SWI and AWI. The virus BTC is relatively insensitive to parameters describing the maximum adsorption capacity of the AWI for colloids, inlet colloid concentration, virus detachment rate coefficient from the SWI, maximum adsorption capacity of the AWI for viruses and inlet virus concentration., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Molecular pathways underlying the neurotoxicity and production of amyloid β protein (Aβ) represent potentially promising therapeutic targets for Alzheimer's disease (AD). We recently found that overexpression of the scaffolding protein RanBP9 increases Aβ production in cell lines and in transgenic mice while promoting cofilin activation and mitochondrial dysfunction. Translocation of cofilin to mitochondria and induction of cofilin-actin pathology require the activation/dephosphorylation of cofilin by Slingshot homolog 1 (SSH1) and cysteine oxidation of cofilin. In this study, we found that endogenous RanBP9 positively regulates SSH1 levels and mediates Aβ-induced translocation of cofilin to mitochondria and induction of cofilin-actin pathology in cultured cells, primary neurons, and in vivo. Endogenous level of RanBP9 was also required for Aβ-induced collapse of growth cones in immature neurons (days in vitro 9 (DIV9)) and depletion of synaptic proteins in mature neurons (DIV21). In vivo, amyloid precursor protein (APP)/presenilin-1 (PS1) mice exhibited 3.5-fold increased RanBP9 levels, and RanBP9 reduction protected against cofilin-actin pathology, synaptic damage, gliosis, and Aβ accumulation associated with APP/PS1 mice. Brains slices derived from APP/PS1 mice showed significantly impaired long-term potentiation (LTP), and RanBP9 reduction significantly enhanced paired pulse facilitation and LTP, as well as partially rescued contextual memory deficits associated with APP/PS1 mice. Therefore, these results underscore the critical importance of endogenous RanBP9 not only in Aβ accumulation but also in mediating the neurotoxic actions of Aβ at the level of synaptic plasticity, mitochondria, and cofilin-actin pathology via control of the SSH1-cofilin pathway in vivo.

A mathematical model is developed to simulate the transport and deposition of virus-sized colloids in a cylindrical pore throat considering various processes such as advection, diffusion, colloid-collector surface interactions and hydrodynamic wall effects. The pore space is divided into three different regions, namely, bulk, diffusion and potential regions, based on the dominant processes acting in each of these regions. In the bulk region, colloid transport is governed by advection and diffusion whereas in the diffusion region, colloid mobility due to diffusion is retarded by hydrodynamic wall effects. Colloid-collector interaction forces dominate the transport in the potential region where colloid deposition occurs. The governing equations are non-dimensionalized and solved numerically. A sensitivity analysis indicates that the virus-sized colloid transport and deposition is significantly affected by various pore-scale parameters such as the surface potentials on colloid and collector, ionic strength of the solution, flow velocity, pore size and colloid size. The adsorbed concentration and hence, the favorability of the surface for adsorption increases with: (i) decreasing magnitude and ratio of surface potentials on colloid and collector, (ii) increasing ionic strength and (iii) increasing pore radius. The adsorbed concentration increases with increasing Pe, reaching a maximum value at Pe=0.1 and then decreases thereafter. Also, the colloid size significantly affects particle deposition with the adsorbed concentration increasing with increasing particle radius, reaching a maximum value at a particle radius of 100nm and then decreasing with increasing radius. System hydrodynamics is found to have a greater effect on larger particles than on smaller ones. The secondary minimum contribution to particle deposition has been found to increase as the favorability of the surface for adsorption decreases. The sensitivity of the model to a given parameter will be high if the conditions are favorable for adsorption. The results agree qualitatively with the column-scale experimental observations available in the literature. The current model forms the building block in upscaling colloid transport from pore scale to Darcy scale using Pore-Network Modeling., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Melanoma is one of the most aggressive and deadly skin cancers, and, in its advanced stages, accounts for > 80% mortality. The incidence of melanoma is increasing worldwide; however, beyond surgical removal of the tumour, there is currently no curative therapy available, especially for its advanced stages. This may, in part, be owing to incomplete understanding of the molecular mechanisms that regulate the initiation and/or progression of melanoma to metastasis. The molecular mechanisms leading to the development and progression of melanoma are the focus of intense investigation, and many genetic/epigenetic alterations affecting melanoma progression and development have been identified. microRNAs (miRNAs) are emerging as important causal modulators in the development and progression of melanoma. The understanding of miRNA-mediated regulation of tumours has grown immensely over the last few years, as it has been understood to regulate most biological processes. Here, we review the currently available data on miRNAs associated with melanoma, highlighting those deregulated miRNAs that target important genes and pathways involved in the progression of melanocytes to primary and metastatic melanoma. We also review their potential clinical utility as biomarkers and potential use in targeted therapy., (© 2014 British Association of Dermatologists.)

Volatile organic compounds (VOCs) may frequently contaminate groundwater and pose threat to human health when migrating into the unsaturated soil zone and upward to the indoor air. The kinetic of chemical oxidation has been investigated widely for dissolved VOCs in the saturated zone. But, so far there have been few studies on the use of in situ chemical oxidation (ISCO) of vapour phase contaminants. In this study, batch experiments were carried out to evaluate the oxidation of trichloroethylene (TCE), ethanol, and toluene vapours by solid potassium permanganate. Results revealed that solid potassium permanganate is able to transform the vapour of these compounds into harmless oxidation products. The degradation rates for TCE and ethanol were higher than for toluene. The degradation process was modelled using a kinetic model, linear in the gas concentration of VOC [ML(-3)] and relative surface area of potassium permanganate grains (surface area of potassium permanganate divided by gas volume) [L(-1)]. The second-order reaction rate constants for TCE, ethanol, and toluene were found to be equal to 2.0×10(-6) cm s(-1), 1.7×10(-7) cm s(-1), and 7.0×10(-8) cm s(-1), respectively., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Colorectal cancer (CRC) commonly known as bowel cancer is the third most common cause of cancer-related deaths in the western world and has been reported to show geographical variation in its incidence. Cancer development and progression is a complex process dictated by changes in expression and regulation of various genes which include tumor suppressor genes, DNA repair genes, translation regulatory genes and others. The aim of this case control study was to analyze the promoter hypermethylation at CpG islands of p16 gene in CRC patients among the Kashmiri population and co- relate it with expression pattern of p16. Genomic DNA was isolated from surgically resected tumor and adjacent normal samples and was modified using bisulphite modification kit. Methylation-specific polymerase chain reaction (PCR) was setup for the analysis of the promoter hypermethylation of p16 gene. The epigenetic analysis revealed that unlike other high risk regions, Kashmiri population has a different promoter hypermethylation profile of p16 gene as 66 percent of the cases showed p16 promoter hypermethylation in comparison to 20 percent of the normal cases which also showed promoter hypermethylation of p16 gene. The association of promoter hypermethylation with colorectal cancer was found to be significant (P=0.0006). Occurrence of p16 promoter hypermethylation was found to be unequally distributed in males and females with more frequency in males than in females but the difference was not statistically significant(P =0.7635). Similarly, frequency of p16 promoter hypermethylation was found to be certainly higher in Stage III/IV (83.33 percent) compared to Stage I/II (56.25 percent) but the difference was not statistically significant (P =0.0673). Also, the degree of p16 promoter hypermethylation increased with the increasing severity of the lesion but the difference was not again statistically significant (P =0.6145). Promoter hypermethylation correlated with the decrease in expression of the p16 gene in CRC patients leading to the diseased phenotype. These results suggest that p16 aberrant promoter hypermethylation in Kashmiri population contributes to the process of carcinogenesis in CRC and may be developed into a valuable tool for CRC diagnosis at early stages.

Background: Laparoscopic Roux-en-Y gastric bypass (LRYGB) has been established as a safe and effective procedure for morbid obesity management. Amongst some of the postoperative complications are gastrojejunal (GJ) anastomotic strictures, with an incidence of 3 to 27 % in some series. This study evaluates the incidence of GJ strictures using a 21-mm circular stapling device and its response to treatment with endoscopic balloon dilation., Methods: A retrospective chart review was conducted of patients who underwent LRYGB between January 2007 and September 2010. We used our previously published technique of retrocolic, retrogastric Roux-en-Y bypass, using a 21-mm circular stapler to construct the gastrojejunostomy. Postoperatively, patients with persistent food intolerance underwent an endoscopy. Those found to have a GJ stricture (defined as inability to pass the endoscope beyond he anastomotic site) underwent pneumatic dilation with a 12-mm balloon., Results: A total of 338 patients underwent LRYGB. Median follow-up was 57.6 weeks (8-137). Twenty-two patients underwent an endoscopy due to food intolerance. Sixteen patients (4.7 %, 16/338) were identified with GJ stricture and received at least one endoscopic dilation. The other six patients had a normal endoscopic evaluation. GJ strictures presented at an average of 35 days (13 to 90 days) postoperatively. Four patients underwent two endoscopic interventions, and one underwent three endoscopic interventions., Conclusions: We hereby demonstrate that the construction of GJ anastomosis with a 21-mm circular stapler is associated with a low stricture rate using our standardized technique. Strictures are amenable to balloon dilatation with subsequent long-term resolution of symptoms.

Marginal ulcers are a well described complication following Roux-en-Y gastric bypass. These may be a cause for perforation. We describe a case of upper gastrointestinal perforation 18 months following a laparoscopic Roux-en-Y gastric bypass that appeared to be caused by a food bezoar. The perforation occurred at the site of the jejunojejunal anastomosis and was repaired after an exploratory laparotomy. After extracting the food debris (phytobezoar) through the perforation, direct closure resulted in an uneventful post-operative recovery. To our knowledge, this is the first description of a food bezoar causing an intestinal perforation in such a manor after bariatric surgery. Patients should be educated carefully on what and how to eat after having undergone surgery for superobesity.

Background and Study Aims: Guidelines and practices differ regarding evaluation of young patients with fresh bleeding per rectum (FBPR). The aim of this study was to determine the frequency and site of endoscopic lesions in young patients with FBPR, and to thereby determine whether full colonoscopic examination is necessary in these patients., Methods: Consecutive patients aged 18-50 years who were scheduled to undergo full colonoscopy for FBPR at Aga Khan University Hospital between May 2007 and October 2009 were enrolled in the study after giving informed consent. FBPR was defined as the passing of fresh blood per rectum with or without stools and/or noticing blood in the toilet bowl. Lesions were characterized as proximal or distal to the splenic flexure. Patients with positive family history of colorectal cancer, bleeding requiring blood transfusion, bleeding diathesis, or iron deficiency anemia were excluded., Results: A total of 379 patients met the inclusion criteria and were analyzed. Of these, 248 patients (65.4%) were under 40 years of age and 131 (34.6%) were aged 40-50 years. Mean hemoglobin was 12.93 ± 1.78 g/dL. In patients < 40 years, seven (2.8%) adenomatous polyps and malignant lesions were found, all of which were located in the distal colon. In patients aged 40-50 years, 10 (7.6%) adenomatous polyps and malignant lesions were detected, one of which was located in the proximal colon. On univariate analysis, malignant and adenomatous lesions were significant in the 40-50 years age group (P = 0.031; OR, 2.84; 95% CI 1.05-7.65)., Conclusion: Endoscopic lesions in patients younger than 40 years with FBPR are found mostly in the distal colon and hence flexible sigmoidoscopy seems to be a reasonable evaluation tool in young patients with no other alarm symptoms., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in numerous cellular processes. Recent studies have shown aberrant expression of miRNAs in prostate cancer tissues and cell lines. On the basis of miRNA microarray data, we found that miR-145 is significantly downregulated in prostate cancer., Methods and Results: We investigated the expression and functional significance of miR-145 in prostate cancer. The expression of miR-145 was low in all the prostate cell lines tested (PC3, LNCaP and DU145) compared with the normal cell line, PWR-1E, and in cancerous regions of human prostate tissue when compared with the matched adjacent normal. Overexpression of miR-145 in PC3-transfected cells resulted in increased apoptosis and an increase in cells in the G2/M phase, as detected by flow cytometry. Investigation of the mechanisms of inactivation of miR-145 through epigenetic pathways revealed significant DNA methylation of the miR-145 promoter region in prostate cancer cell lines. Microarray analyses of miR-145-overexpressing PC3 cells showed upregulation of the pro-apoptotic gene TNFSF10, which was confirmed by real-time PCR and western analysis., Conclusion: One of the genes significantly upregulated by miR-145 overexpression is the proapoptotic gene TNFSF10. Therefore, modulation of miR-145 may be an important therapeutic approach for the management of prostate cancer.

To aim of this study is to analyse the survival rate and prognostic indicators of systemic lupus erythematosus (SLE) in Pakistani population. A total of 198 patients with SLE diagnosed between 1992 and 2005 were reviewed retrospectively. Clinical features at presentation, subsequent evolving features, autoantibody profile, damage scores and mortality data were obtained. Prognostic factors for survival were studied by statistical analysis. Of 198 SLE patients studied, 174 were women and 24 were men. The women to men ratio was 7.2:1. Mean age at presentation was 31 years (range 14-76). Mean duration of symptoms before diagnosis was 2.8 years. Mean duration of follow-up was 34.21 months (+/-33.69). Mean disease duration was 15.6 years. At diagnosis, arthritis, malar rash, oral ulcers and alopecia were the commonest features. During the follow-up, the prevalence of nephritis, arthritis, neurological and hematological disease increased significantly. About 76% (n = 151) of the patients had organ damage at the time of data analysis, and renal disease was the commonest cause. Univariate analysis revealed that renal disease (P = 0.000), seizures (P = 0.048), pleural involvement (P = 0.019), alopecia (P = 0.000) and discoid lesions (P = 0.005) were predictors for damage. Multivariate model, however, revealed that only renal disease was independent risk factor for damage (P = 0.002). During the study period, 47 patients (24%) died (five due to disease-related complications and rest as a result of infections). The 3-, 5-, 10-, 15- and 20-year survival rates of our cohort were 99, 80, 77, 75 and 75%, respectively. Cox regression analysis revealed that renal involvement (P = 0.002) and infections (P = 0.004) were independent risk factors for mortality. The survival of our Pakistani SLE patients was significantly lower compared to that of the Caucasian series reported in last decade. Nephritis not only contributes to organ damage but also acts a major determinant for survival. Infection remains the commonest cause of death. Renal involvement and infections are independent risk factors for mortality. Judicious use of immunosuppressive agents is necessary to improve the short-term survival of lupus patients.

Astrocyte-elevated gene-1 (AEG-1) has been reported to be upregulated in several malignancies and play a critical role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase/AKT signaling pathway. However, the role of AEG-1 in prostate cancer (PC) has never been reported. We now show that AEG-1 is overexpressed in clinical PC tissue samples and cultured PC cells compared to benign prostatic hyperplasia tissue samples and normal prostate epithelial cells. Interestingly, AEG-1 knockdown induced cell apoptosis through upregulation of forkhead box (FOXO) 3a activity. This alteration of FOXO3a activity was dependent on reduction of AKT activity in LNCaP and PC-3 cells with high constitutive AKT activity, but not in DU145 cells with low constitutive AKT activity, although AEG-1 knockdown had no impact on phosphatase and tensin homolog expression in these cells. AEG-1 knockdown also attenuated the constitutive activity of the nuclear factor kappaB (NF-kappaB) and the activator protein 1 (AP-1) with a corresponding depletion in the expression of NF-kappaB and AP-1-regulated genes (interleukin (IL)-6, IL-8 and matrix metalloproteinase-9) and significantly decreased cell invasion properties of PC-3 and DU145 cells. Overall, our findings suggest that aberrant AEG-1 expression plays a dominant role as a positive auto-feedback activator of AKT and as a suppressor of FOXO3a in PC cells. AEG-1 may therefore represent a novel genetic biomarker to serve as an attractive molecular target for new anticancer agents to prevent PC cell progression and metastasis.

Mutations leading to aberrant cytoplasmic localization of Nucleophosmin 1 (NPM1) have been recently identified as the most frequent genetic alteration in acute myelogenous leukemia. However, the oncogenic potential of this nucleophosmin mutant (NPMc+) has never been established, which casts doubt on its role in leukemogenesis. By performing classical transformation assays, we find that NPMc+, but not wild-type NPM, cooperates specifically with adenovirus E1A to transform primary mouse embryonic fibroblasts in soft agar. We demonstrate that NPMc+ blocks the p19(Arf) (Arf) induction elicited by E1A. Surprisingly, however, we find that NPMc+ induces cellular senescence and that E1A is able to overcome this response. We propose a model whereby the NPMc+ pro-senescence activity needs to be evaded for oncogenic transformation, even though NPMc+ can concomitantly blunt the Arf/p53 pathway. These findings identify for the first time NPMc+ as an oncogene and shed new unexpected light on its mechanism of action.

Objective: To assess the level of knowledge regarding viral hemorrhagic fever (VHF) among healthcare personnel at two largest tertiary care hospitals in Karachi, Pakistan., Methods: A cross sectional convenience survey was conducted in February 2001 among doctors, nurses, laboratory technicians and janitors/orderlies of Jinnah Postgraduate Medical Centre and Civil Hospital, Karachi. The questionnaire included demographic information with their designation and knowledge level regarding VHF management, spread and prevention. Frequencies of the answers to each question were calculated for all questions and scores were assigned. The frequencies were also calculated on the basis of the designation of the respondent so that each group could be examined separately., Results: A total of 187 healthcare personnel (121 doctors, 31 nurses, 19 laboratory technicians and 16 janitors/orderlies) were interviewed. Forty three percent (81) respondents were males and 57% (106) were females. By designation 90% doctors, 71% nurses, 32% laboratory technicians and 6% janitors knew about VHF. Only 57% doctors (69) knew the common signs and symptoms of VHF. Isolation for affected patients was suggested by 65% nurses and 6% janitors. Knowledge regarding burial procedure of dead patients was low in all groups., Conclusion: Differences in knowledge of different groups is obvious but it is essential to raise the knowledge regarding VHF at all levels including the housekeeping staff. There is also a need for continuing medical education (CME) for all health care personnel for the emerging health problems in Pakistan.

Guillain-Barré syndrome is a rare complication of cytomegalovirus infection in the healthy adult. We report a new case with good spontaneous outcome. Cytomegalovirus has been recognized in about 15% of Guillain-Barré syndromes. Clinical and biological presentation, and outcome are common and prognosis is often good. Etiopathogenic mechanism is unclear.

Objective: To evaluate endometrial cryoablation (ECA) as a treatment for menorrhagia., Method: Prospective study of 67 women. ECA uses the Joule Thompson principle of expanding gases. The ECA probe has a channel to inject saline solution into the uterine cavity. The probe is introduced into the uterine cavity, which is distended with 5 ml saline solution. The device is activated for two freeze-thaw cycles. The saline solution forms an ice mold of the uterine cavity which can be observed by ultrasound scan., Results: No surgical or long-term complications were observed. Two-thirds of patients followed up for > 3 months were completely satisfied., Conclusions: ECA is technically very easy, can be learned quickly, is free of complications and led to improvement of menstrual symptoms in 63% of patients followed up for 3-18 months. The device is virtually maintenance-free and requires only a small initial investment, while running costs are negligible.

Addition of ellagic acid (EA) to liver microsomes of mice resulted in a steady increase in inhibition of NADPH-dependent lipid peroxidation up to 2 mM concentration. The maximum of 70% inhibition of ascorbate-dependent lipid peroxidation was achieved at 1 mM concentration of EA. Feeding of EA significantly increased the levels of reduced glutathione and glutathione reductase in liver and lungs of male and female mice. However, there were no changes in the activities of catalase and superoxide dismutase. On the other hand, microsomes from liver and lungs of EA fed animals showed significantly suppressed NADPH- and ascorbate-dependent lipid peroxidation.

Treatment of guinea pigs on adequate ascorbic acid (AA) with 20-methylcholanthrene (MCA) and phenobarbital (PB) significantly increased hepatic arylhydrocarbon hydroxylase (AHH), cytochrome P-450 and cytochrome-b5 activities. In lungs, only MCA treatment significantly enhanced the activities of AHH, cytochrome P-450 and cytochrome b5. In animals on excessive doses of AA, there was inhibition of hepatic AHH, cytochrome P-450 and cytochrome b5 levels by treatment with these xenobiotics. Also, inhibition was observed in pulmonary AHH and cytochrome P-450 levels. The relevance of these observations in excessive AA-fed guinea pigs to carcinogenesis requires further extensive investigations.