MORPHOLOGIC SPECTRUM AND CLINICO-PATHOLOGICAL CORRELATION OF GASTROINTESTINAL STROMAL TUMOURS: AN EXPERIENCE OF SIX YEARS AT A TERTIARY CARE HOSPITAL.

Objective: The objective of this study was to determine the morphologic spectrum and risk category of gastrointestinal stromal tumour (GIST) and compare with overall patient survival.Materials and Methods: It is a descriptive observational study. The study was carried at Shifa International Hospital, Islamabad. Duration of the study was from January 2009 to January 2015. A total of 31 patients with the diagnosis of GIST were included, irrespective of age and gender. Data were retrieved from laboratory information system. Results were analysed by statistical software, Statistical Package of the Social Sciences. Morphologic type, site of tumour, risk category and overall survival were determined and mean, standard deviation, frequencies and percentages were calculated for age site and risk category. Results: Of 31 patients, 21 (67.7%) were male and 10 (32.3%) were female. Site of tumour was as follows: Gastric 13 (41.9%), extra visceral 6 (19.4%), small intestine 9 (29.0%), rectum 2 (6.5%) and pancreas 1 (3.2%). According to risk categorisation, one was categorised as (3.2%) very low risk, 3 (9.7%) low risk, 5 (16.1%) intermediate risk and 22 (71%) high risk. Follow-up was available in 21 patients. 7 patients (22.5%) lost to follow-up. 8 (25%) had recurrence and 4 (12.9%) died. Conclusion: Majority of cases diagnosed at our centre were gastric in origin followed by small intestine, and as per risk categorisation, most were high risk. Patient survival with high-risk tumours was dismal. Key words: Gastrointestinal stromal tumour, immunohistochemistry, risk categorisation

An overview of enhancing drought tolerance in cotton through manipulating stress resistance genes

Drought stress affects the normal growth of plant by influencing Physiological, morphological molecular and biochemical traits at cellular level. It is a polygenic trait, controlled by multiple genes, which makes its manipulation difficult by genetic engineering. It seems drought could be major threat in future to high yield of cotton in Pakistan as well around the globe because it is spontaneous and cannot be controlled with manuring and skilled agricultural practices. Gene manipulation could be a solution of this threat by producing transgenic cotton plants. As it is polygenic trait, so, understanding about cellular mechanism of drought tolerance is crucial to impart tolerance by controlling gene expression under stressed conditions. Universal Stress Proteins (USP) genes have already been identified in drought stressed leaves of Gossypium arboreum which make this variety of cotton a rich source of stress tolerance genes. USP genes could be manipulated for drought tolerant transgenic cotton with high yielding as well and it is most important family of proteins in this regard. This family encompasses a conserved group of proteins that has been reported in different organisms which are activating under various abiotic stress conditions. USP is also a regulatory protein; its activity can be increased by manipulating its interactions

Malignancy risk analysis in patients with inadequate fine needle aspiration cytology (FNAC) of the thyroid

Background Thyroid fine needle aspiration cytology (FNAC) is the standard diagnostic modality for thyroid nodules. However, it has limitations among which is the incidence of non-diagnostic results (Thy1). Management of cases with repeatedly non-diagnostic FNAC ranges from simple observation to surgical intervention. We aim to evaluate the incidence of malignancy in non-diagnostic FNAC, and the success rate of repeated FNAC. We also aim to evaluate risk factors for malignancy in patients with non-diagnostic FNAC. Materials and Methods Retrospective analyses of consecutive cases with thyroid non diagnostic FNAC results were included. Results Out of total 1657 thyroid FNAC done during the study period, there were 264 (15.9%) non-diagnostic FNAC on the first attempt. On repeating those, the rate of a non-diagnostic result on second FNAC was 61.8% and on third FNAC was 47.2%. The overall malignancy rate in Thy1 FNAC was 4.5% (42% papillary, 42% follicular and 8% anaplastic), and the yield of malignancy decreased considerably with successive non-diagnostic FNAC. Ultrasound guidance by an experienced head neck radiologist produced the lowest non-diagnostic rate (38%) on repetition compared to US guidance by a generalist radiologist (65%) and by non US guidance (90%). Conclusions There is a low risk of malignancy in patients with a non-diagnostic FNAC result, commensurate to the risk of any nodule. The yield of malignancy decreased considerably with successive non-diagnostic FNAC

High grade angiosarcoma arising in fibroadenoma

Primary angiosarcoma of the breast is a rare tumour that account for fewer than 0.05% of all malignant mammary tumours. Angiosarcoma may have an perfidious clinical onset. Radiologic findings are often nonspecific and may appear completely normal in one-third of cases with primary angiosarcoma. The prognosis is usually poor because of the high rates of local recurrence and early development of metastases. Aggressive surgical resection is the mainstay of treatment. The role of adjuvant therapy has not yet been well established

Knowledge retention in ERP implementations: the context of UK SMEs

Knowledge retention (k-retention) is vital for various enterprise resource planning (ERP) implementations in small and medium-sized enterprises (SMEs), though it is a highly demanding and challenging task. The aim of this paper is to investigate different types of approaches to k-retention and factors influencing k-retention in SMEs. Our study adopts a grounded theory approach with cases based on 12 ERP implementations in UK SMEs. We analyze our data using thematic analysis. The findings reveal specific elements that support the k-retention of ERP package knowledge and business process knowledge. These elements are: k-retention tools, documentation, human capital and the understanding of k-retention challenges. In addition to insights from these aspects, our study reveals two additional factors (project management and organizational culture) that influence ERP package k-retention and business process k-retention. Based on these findings, we develop an ERP k-retention (EKR) framework that can be utilized by SMEs which are considering implementing ERP systems, to facilitate knowledge retention during implementation

Purification of Reversibly Oxidized Proteins (PROP) Reveals a Redox Switch Controlling p38 MAP Kinase Activity

Oxidation of cysteine residues of proteins is emerging as an important means of regulation of signal transduction, particularly of protein kinase function. Tools to detect and quantify cysteine oxidation of proteins have been a limiting factor in understanding the role of cysteine oxidation in signal transduction. As an example, the p38 MAP kinase is activated by several stress-related stimuli that are often accompanied by in vitro generation of hydrogen peroxide. We noted that hydrogen peroxide inhibited p38 activity despite paradoxically increasing the activating phosphorylation of p38. To address the possibility that cysteine oxidation may provide a negative regulatory effect on p38 activity, we developed a biochemical assay to detect reversible cysteine oxidation in intact cells. This procedure, PROP, demonstrated in vivo oxidation of p38 in response to hydrogen peroxide and also to the natural inflammatory lipid prostaglandin J2. Mutagenesis of the potential target cysteines showed that oxidation occurred preferentially on residues near the surface of the p38 molecule. Cysteine oxidation thus controls a functional redox switch regulating the intensity or duration of p38 activity that would not be revealed by immunodetection of phosphoprotein commonly interpreted as reflective of p38 activity

THE LIBERAL PEACE: CHALLENGES TO DEVELOPMENT, DEMOCRACY AND SOFT POWER

The term “liberal” peace refers to the absence of fatal conflict between democratic nations, which are also economically interdependent. This chapter sketches the ideal and economic versions of the liberal peace theory. Policies promoting globalization may engender social conflict risks, as they produce inequality. In developed countries, we are witnessing the rise of populism, and the rolling back of the liberal aspects of democracy in developing countries. The avoidance of these problems requires careful management such that growth is broad-based, and policies promoting greater openness are sufficiently cushioned to protect losers. It is also necessary to manage globalization, and limit its negative impact on domestic social contracts, particularly when it comes to inequality, worker rights, and fiscal austerity

Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoceptors

The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by β-adrenoceptors, in most species involving a strong β3-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of β-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to β-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in β-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and β-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder

Burden of non-communicable diseases among adolescents aged 10–24 years in the EU, 1990–2019: a systematic analysis of the Global Burden of Diseases Study 2019

Background Disability and mortality burden of non-communicable diseases (NCDs) have risen worldwide; however, the NCD burden among adolescents remains poorly described in the EU. Methods Estimates were retrieved from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Causes of NCDs were analysed at three different levels of the GBD 2019 hierarchy, for which mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) were extracted. Estimates, with the 95% uncertainty intervals (UI), were retrieved for EU Member States from 1990 to 2019, three age subgroups (10–14 years, 15–19 years, and 20–24 years), and by sex. Spearman's correlation was conducted between DALY rates for NCDs and the Socio-demographic Index (SDI) of each EU Member State. Findings In 2019, NCDs accounted for 86·4% (95% uncertainty interval 83·5–88·8) of all YLDs and 38·8% (37·4–39·8) of total deaths in adolescents aged 10–24 years. For NCDs in this age group, neoplasms were the leading causes of both mortality (4·01 [95% uncertainty interval 3·62–4·25] per 100 000 population) and YLLs (281·78 [254·25–298·92] per 100 000 population), whereas mental disorders were the leading cause for YLDs (2039·36 [1432·56–2773·47] per 100 000 population) and DALYs (2040·59 [1433·96–2774·62] per 100 000 population) in all EU Member States, and in all studied age groups. In 2019, among adolescents aged 10–24 years, males had a higher mortality rate per 100 000 population due to NCDs than females (11·66 [11·04–12·28] vs 7·89 [7·53–8·23]), whereas females presented a higher DALY rate per 100 000 population due to NCDs (8003·25 [5812·78–10 701·59] vs 6083·91 [4576·63–7857·92]). From 1990 to 2019, mortality rate due to NCDs in adolescents aged 10–24 years substantially decreased (–40·41% [–43·00 to –37·61), and also the YLL rate considerably decreased (–40·56% [–43·16 to –37·74]), except for mental disorders (which increased by 32·18% [1·67 to 66·49]), whereas the YLD rate increased slightly (1·44% [0·09 to 2·79]). Positive correlations were observed between DALY rates and SDIs for substance use disorders (rs=0·58, p=0·0012) and skin and subcutaneous diseases (rs=0·45, p=0·017), whereas negative correlations were found between DALY rates and SDIs for cardiovascular diseases (rs=–0·46, p=0·015), neoplasms (rs=–0·57, p=0·0015), and sense organ diseases (rs=–0·61, p=0·0005)

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution