Tumor necrosis factor -α, interleukin-10, intercellular and vascular adhesion molecules are possible biomarkers of disease severity in complicated Plasmodium vivax isolates from Pakistan.

Background: Cytokine-mediated endothelial activation pathway is a known mechanism of pathogenesis employed by Plasmodium falciparum to induce severe disease symptoms in human host. Though considered benign, complicated cases of Plasmodium vivax are being reported worldwide and from Pakistan. It has been hypothesized that P.vivax utilizes similar mechanism of pathogenesis, as that of P.falciparum for manifestations of severe malaria. Therefore, the main objective of this study was to characterize the role of cytokines and endothelial activation markers in complicated Plasmodium vivax isolates from Pakistan. Methods and Principle Findings: A case control study using plasma samples from well-characterized groups suffering from P.vivax infection including uncomplicated cases (n=100), complicated cases (n=82) and healthy controls (n=100) were investigated. Base line levels of Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-10 (IL-10), Intercellular adhesion molecule-1 (ICAM-1), Vascular adhesion molecule-1(VCAM-1) and Eselectin were measured by ELISA. Correlation of cytokines and endothelial activation markers was done using Spearman’s correlation analysis. Furthermore, significance of these biomarkers as indicators of disease severity was also analyzed. The results showed that TNF-α, IL-10, ICAM-1and VCAM-1 were 3-fold, 3.7 fold and 2 fold increased between uncomplicated and complicated cases. Comparison of healthy controls with uncomplicated cases showed no significant difference in TNF-α concentrations while IL-6, IL-10, ICAM-1, VCAM-1 and E-selectin were found to be elevated respectively. In addition, significant positive correlation was observed between TNF-α and IL-10/ ICAM-1, IL-6 and IL-10, ICAM-1 and VCAM-1.A Receiver operating curve (ROC) was generated which showed that TNF-α, IL-10, ICAM-1 and VCAM-1 were the best individual predictors of complicated P.vivax malaria. Conclusion: The results suggest that though endothelial adhesion molecules are inducible by pro-inflammatory cytokine TNF-α, however, cytokine-mediated endothelial activation pathway is not clearly demonstrated as a mechanism of pathogenesis in complicated P.vivax malaria cases from Pakistan

Ectopic hyperprolactinaemia due to a malignant Uterine Tumor Resembling Ovarian Sex Cord Tumors (UTROCST)

Purpose Moderate hyperprolactinaemia (2–5 times upper limit of normal) occurring in a patient with a normal pituitary MRI is generally considered to be due to a lesion below the level of detection of the MRI scanner assuming macroprolactin and stress have been excluded. Most patients with mild-to-moderate hyperprolactinaemia and a normal MRI respond to dopamine agonist therapy. We present the rare case of a patient who had prolactin elevation typical of a prolactin-secreting pituitary macroadenoma,with a normal cranial MRI, and in whom the prolactin rose further with dopamine agonist treatment. Subsequent investigations revealed ectopic hyperprolactinaemia to a uterine tumor resembling ovarian sex cord tumor (UTROSCT) which resolved following tumor resection. Although mostly considered to be benign, the UTROSCT recurred with recurrent hyperprolactinaemia and intraabdominal metastases. Methods We have systematically and critically reviewed existing literature relating to ectopic hyperprolactinaemia in general and UTROCST specifically. Results Fewer than 80 cases of UTROSCTs have been reported globally of which about 23% have shown malignant behaviour. There are fewer than 10 cases of paraneoplastic hyperprolactinaemia originating from uterine neoplasms including one other case of ectopic hyperprolactinaemia to a UTROSCT. Conclusions Our case demonstrates the importance of screening for extracranial hyperprolactinaemia in the context of: (1) substantially raised prolactin (10× ULN) and (2) normal cranial MRI assuming macroprolactin has been excluded. The majority of extracranial ectopic prolactin-secreting tumors occur in the reproductive organs.Methods: We have systematically and critically reviewed existing literature relating to ectopic hyperprolactinaemia in general and UTROCST specifically. Results: Fewer than 80 cases of UTROSCTs have been reported globally of which about 23% have shown malignant behaviour. There are fewer than 10 cases of paraneoplastic hyperprolactinaemia originating from uterine neoplasms including one other case of ectopic hyperprolactinaemia to a UTROSCT. Conclusions: Our case demonstrates the importance of screening for extracranial hyperprolactinaemia in the context of: (1) substantially raised prolactin (10xULN) and (2) normal cranial MRI assuming macroprolactin has been excluded. The majority of extracranial ectopic prolactin-secreting tumors occur in the reproductive organs

Stone clearance in lower pole nephrolithiasis after extra corporeal shock wave lithotripsy – the controversy continues

BACKGROUND: To determine factors influencing the clearance of fragments after extra-corporeal shock wave lithotripsy (ESWL) for lower pole calyceal (LPC) stones. METHODS: In the period between July 1998 and Oct 2001, 100 patients with isolated lower polar calyceal calculi ≤ 20 mm, in patients aged ≥ 14 years, were included in the study. Intravenous urograms (IVU) were reviewed to define the LPC anatomy (width of the infundibulum and pelvicalyceal angle). Study end points i.e. stone free status; number of shock waves used and number of sessions were correlated with variables like LPC anatomy, body mass index and stone size. RESULTS: At three months follow up the clearance for stone size ≤ 10 mm, 11–15 mm and 16–20 mm were 95, 96 and 90% respectively. Patients with acute LPC (<90°) and obtuse angle (>90°) had stone clearance of 94 and 100% respectively. For the infundibular width of < 4 mm, the stone clearance was 93% were as for > 4 mm, it was 100%. For body mass index (BMI) less than and > 30 kg/m(2), the stone clearance was 92 and 95% respectively. CONCLUSIONS: There is a trend towards more ESWL sessions and shock wave requirement in patients with acute pelvi-calyceal angle and narrow infundibulum but it is not statistically significant. Size (≤ 20 mm) and BMI has no relation with stone clearance. With modern lithotripter, stones up to 20 mm could primarily be treated by ESWL, irrespective of an un-favorable lower polar calyceal anatomy and body habitus

Aurora kinase-C-T191D is constitutively active mutant

<p>Abstract</p> <p>Background</p> <p>Aurora kinases (Aurora-A, B and C) belong to a family of conserved serine/threonine kinases which are key regulators of cell cycle progression. Aurora-A and Aurora-B are expressed in somatic cells and involved in cell cycle regulation while aurora-C is meiotic chromosome passenger protein. As Aurora kinase C is rarely expressed in normal somatic cells and has been found over expressed in many cancer lines. It is suggested that Aurora-C-T191D is not hyperactive mutant.</p> <p>Result</p> <p>Aurora-C-T191D variant form was investigated and compared with wild type. The overexpression of Aurora-C-T191D was observed that it behaves like Aurora-C wild type (aurC-WT). Both Aurora-C-T191D and aurC-WT induce abnormal cell division resulting in centrosome amplification and multinucleation in transiently transfected cells as well as in stable cell lines. Similarly, Aurora-C-T191D and aurC-WT formed foci of colonies when grown on soft agar, indicating that a gain of Aurora-C activity is sufficient to transform cells. Furthermore, we reported that NIH-3 T3 stable cell lines overexpressing Aurora-C-T191D and its wild type partner induced tumour formation when injected into nude mice, demonstrating the oncogenic activity of enzymatically active Aurora kinase C. Interestingly enough tumour aggressiveness was positively correlated with the rate of kinase activity, making Aurora-C a potential anti-cancer therapeutic target.</p> <p>Conclusion</p> <p>These findings proved that Aurora C-T191D is not hyperactive but is constitutively active mutant.</p

MAESTROS: multi-agent simulation of rework in Open Source software

Rework Management in software development is a challenging and complexissue. Defined as the effort spent to re-do some work, rework implies big costsgiven the fact that the time spent on rework does not count to the improvement of theproject. Predicting and controlling rework causes is a valuable asset for companies,which maintain closed policies on choosing team members and assigning activitiesto developers. However, a trending growth in development consists in Open SourceSoftware (OSS) projects. This is a totally new and diverse environment, in the sensethat not only the projects but also their resources, e.g., developers change dynamically.There is no guarantee that developers will follow the same methodologiesand quality policies as in a traditional and closed project. In such world, identifyingrework causes is a necessary step to reduce project costs and to help projectmanagers to better define their strategies. We observed that in real OSS projectsthere are no fixed team, but instead, developers assume some kind of auction inwhich the activities are assigned to the most interested and less-cost developer. Thislead us to think that a more complex auctioning mechanism should not only modelthe task allocation problem, but also consider some other factors related to reworkcauses. By doing this, we could optimise the task allocation, improving the developmentof the project and reducing rework. In this paper we presented MAESTROS,a Multi-Agent System that implements an auction mechanism for simulating taskallocation in OSS. Experiments were conducted to measure costs and rework withdifferent project characteristics. We analysed the impact of introducing a Q-learningreinforcement algorithm on reducing costs and rework. Our findings correspond to a reduction of 31 % in costs and 11 % in rework when compared with the simpleapproach. Improvements to MAESTROS include real projects data analysis and areal-time mechanism to support Project Management decisions

Nucleotide identity and variability among different Pakistani hepatitis C virus isolates

<p>Abstract</p> <p>Background</p> <p>The variability within the hepatitis C virus (HCV) genome has formed the basis for several genotyping methods and used widely for HCV genotyping worldwide.</p> <p>Aim</p> <p>The aim of the present study was to determine percent nucleotide identity and variability in HCV isolates prevalent in different geographical regions of Pakistan.</p> <p>Methods</p> <p>Sequencing analysis of the 5'noncoding region (5'-NCR) of 100 HCV RNA-positive patients representing all the four provinces of Pakistan were carried out using ABI PRISM 3100 Genetic Analyzer.</p> <p>Results</p> <p>The results showed that type 3 is the predominant genotypes circulating in Pakistan, with an overall prevalence of 50%. Types 1 and 4 viruses were 9% and 6% respectively. The overall nucleotide similarity among different Pakistani isolates was 92.50% ± 0.50%. Pakistani isolates from different areas showed 7.5% ± 0.50% nucleotide variability in 5'NCR region. The percent nucleotide identity (PNI) was 98.11% ± 0.50% within Pakistani type 1 sequences, 98.10% ± 0.60% for type 3 sequences, and 99.80% ± 0.20% for type 4 sequences. The PNI between different genotypes was 93.90% ± 0.20% for type 1 and type 3, 94.80% ± 0.12% for type 1 and type 4, and 94.40% ± 0.22% for type 3 and type 4.</p> <p>Conclusion</p> <p>Genotype 3 is the most prevalent HCV genotype in Pakistan. Minimum and maximum percent nucleotide divergences were noted between genotype 1 and 4 and 1 and 3 respectively.</p

The mEPN scheme: an intuitive and flexible graphical system for rendering biological pathways

<p>Abstract</p> <p>Background</p> <p>There is general agreement amongst biologists about the need for good pathway diagrams and a need to formalize the way biological pathways are depicted. However, implementing and agreeing how best to do this is currently the subject of some debate.</p> <p>Results</p> <p>The modified Edinburgh Pathway Notation (mEPN) scheme is founded on a notation system originally devised a number of years ago and through use has now been refined extensively. This process has been primarily driven by the author's attempts to produce process diagrams for a diverse range of biological pathways, particularly with respect to immune signaling in mammals. Here we provide a specification of the mEPN notation, its symbols, rules for its use and a comparison to the proposed Systems Biology Graphical Notation (SBGN) scheme.</p> <p>Conclusions</p> <p>We hope this work will contribute to the on-going community effort to develop a standard for depicting pathways and will provide a coherent guide to those planning to construct pathway diagrams of their biological systems of interest.</p

Bank ownership structure, regulations and risk-taking : evidence from commercial banks in Pakistan

This paper conducts the first empirical assessment of the theories concerning the influence of ownership structure on bank risk-taking in the presence of regulations in Pakistan. The sample used in this paper comprises a panel data of 26 banks in Pakistan, for the period from 2000 to 2014. The analysis provides evidence that increase in ownership concentration leads to an increase in bank risk-taking. Managerial ownership is associated with high risk-taking at low and high levels of managerial ownership while at intermediate level, managerial ownership has negative impact on bank risk-taking. Different types of ownership of banks in Pakistan have different impact on risk-taking. While government, family and institutional ownership have a positive impact on bank risk-taking, foreign own- ership has a negative impact on bank risk-taking. Furthermore, the results show that capital regulations are important in influencing bank risk-taking with regard to higher ownership concentration. The findings of this paper suggest that the relation between bank risk-taking and capital regulations typically depends on the type of ownership.info:eu-repo/semantics/publishedVersio

Construction of a large scale integrated map of macrophage pathogen recognition and effector systems

<p>Abstract</p> <p>Background</p> <p>In an effort to better understand the molecular networks that underpin macrophage activation we have been assembling a map of relevant pathways. Manual curation of the published literature was carried out in order to define the components of these pathways and the interactions between them. This information has been assembled into a large integrated directional network and represented graphically using the modified Edinburgh Pathway Notation (mEPN) scheme.</p> <p>Results</p> <p>The diagram includes detailed views of the toll-like receptor (TLR) pathways, other pathogen recognition systems, NF-kappa-B, apoptosis, interferon signalling, MAP-kinase cascades, MHC antigen presentation and proteasome assembly, as well as selected views of the transcriptional networks they regulate. The integrated pathway includes a total of 496 unique proteins, the complexes formed between them and the processes in which they are involved. This produces a network of 2,170 nodes connected by 2,553 edges.</p> <p>Conclusions</p> <p>The pathway diagram is a navigable visual aid for displaying a consensus view of the pathway information available for these systems. It is also a valuable resource for computational modelling and aid in the interpretation of functional genomics data. We envisage that this work will be of value to those interested in macrophage biology and also contribute to the ongoing Systems Biology community effort to develop a standard notation scheme for the graphical representation of biological pathways.</p