Safety and efficacy of tranexamic acid in minimizing perioperative bleeding in extrahepatic abdominal surgery: meta-analysis.

BACKGROUND: Perioperative bleeding is associated with increased morbidity and mortality in patients undergoing elective abdominal surgery. The antifibrinolytic agent tranexamic acid (TXA) has been shown to reduce perioperative bleeding and mortality risk in patients with traumatic injuries, but there is a lack of evidence for its use in elective abdominal and pelvic surgery. This meta-analysis of RCTs evaluated the effectiveness and safety of TXA in elective extrahepatic abdominopelvic surgery. METHODS: PubMed, Embase, and ClinicalTrial.gov databases were searched to identify relevant RCTs from January 1947 to May 2020. The primary outcome, intraoperative blood loss, and secondary outcomes, need for perioperative blood transfusion, units of blood transfused, thromboembolic events, and mortality, were extracted from included studies. Quantitative pooling of data was based on a random-effects model. RESULTS: Some 19 studies reporting on 2205 patients who underwent abdominal, pelvic, gynaecological or urological surgery were included. TXA reduced intraoperative blood loss (mean difference -188.35 (95 per cent c.i. -254.98 to -121.72) ml) and the need for perioperative blood transfusion (odds ratio (OR) 0.43, 95 per cent c.i. 0.28 to 0.65). TXA had no impact on the incidence of thromboembolic events (OR 0.49, 0.18 to 1.35). No adverse drug reactions or in-hospital deaths were reported. CONCLUSION: TXA reduces intraoperative blood loss during elective extrahepatic abdominal and pelvic surgery without an increase in complications.

Outcomes of surgery for post-cholecystectomy bile duct injuries: An audit from a tertiary referral center.

AIM OF THE STUDY: Bile duct injury (BDI) after cholecystectomy is a serious complication. It often requires surgical repair. The aim of this study was to report on the short and long-term outcomes of surgery for post-cholecystectomy BDI. PATIENTS AND METHODS: All the patients, who underwent surgery for post-cholecystectomy BDI between August 2007 and September 2017, were retrospectively reviewed. McDonald grading system was used to assess the long-term outcome. The risk factors for unsatisfactory long-term outcome were analyzed by univariate and multivatiate logistic regression analysis. RESULTS: In total, 228 patients had a Roux-en-Y hepaticojejunostomy. Open cholecystectomy was the major cause of BDI (61%). The median time from injury to definitive repair was 6 months. The types of BDI were as follows: E1 in 13 (5.7%), E2 in 68 (29.82%), E3 in 108 (47.36%), E4 in 28 (12.28%), and E5 in 11 (4.82%) patients respectively. Postoperative morbidity and mortality were 25% and 1.31% respectively. After a median follow-up of 58 months, 90% patients had excellent to good outcome. Recurrent stricture developed in 6 (3%) patients. On multivariate analysis, long injury-repair interval and previous attempt at repair were independent predictors for unsatisfactory long-term outcome. CONCLUSION: Surgical reconstruction affords excellent to good results for majority of the patients with post-cholecystectomy BDI. As longer delay in definitive repair and previous attempt at repair were associated with unsatisfactory long-term outcome, early referral to a specialized hepatobiliary surgery unit is recommended.

QSAR modelling on a series of arylsulfonamide-based hydroxamates as potent MMP-2 inhibitors.

Matrix metalloproteinase-2 (MMP-2) is a lucrative therapeutic target as far as anticancer drug discovery is concerned. Overexpression of MMP-2 is found to facilitate tumour propagation through the involvement of vascular endothelial growth factor (VEGF). However, even after different techniques, finding a target-specific MMP-2 inhibitor with respectable pharmacodynamic properties is still a challenging task. Regression-dependent quantitative structure-activity relationship (QSAR) strategies might be among the possible drug design methods to explore the essential structural features that would be valuable to find a suitable MMP-2 inhibitor. In this paper, 72 molecules were explored using the PaDEL descriptors and stepwise multiple linear regression (S-MLR). The partial least squares (PLS) method was also used to create a viable statistical model with an acceptable metric related to these models. The final statistical models were formed with statistical parameters within acceptable range (r2 = 0.797, Q2 = 0.725 and r2pred = 0.643 for the MLR model, and r2 = 0.780, Q2 = 0.685 and r2pred = 0.666 for the PLS model). The models were analysed and compared with those already published on the same endpoint.

Identifying key components for a psychological intervention for people with vitiligo - a quantitative and qualitative study in the United Kingdom using web-based questionnaires of people with vitiligo and healthcare professionals.

BACKGROUND: Psychological interventions are recommended as part of routine management of vitiligo. However, the development and effectiveness of such interventions have been rarely addressed. This study aimed to identify key components for a psychological intervention for people with vitiligo. This is the first time perspectives of people with vitiligo, and healthcare professionals (HCPs) have been directly explored to inform intervention content and delivery. OBJECTIVES: To identify 1. which psychological difficulties are highlighted that can be targeted by an intervention; 2. what is important in terms of intervention content and delivery. METHODS: Web-based questionnaires containing both quantitative and qualitative items were completed by people with vitiligo and HCPs. Questionnaires collected data from people with vitiligo on demographics, clinical features, psychological difficulties and priority areas for psychological interventions, including ideas on delivery and content. HCPs questionnaires collected data on psychological difficulties reported, use of psychological interventions and suitability within health services. Quantitative data were analysed using descriptive statistics, and qualitative data utilized thematic framework analysis. RESULTS: A total of 100 people with vitiligo (66% female, 92% Caucasian) and 39 HCPs (54% dermatologists) participated. Key areas of difficulty were the impact of vitiligo, coping, issues with appearance/body image and the sun, and medical interactions. Vitiligo on sensitive sites was associated with more psychological impact. Interventions directed at increasing acceptance, confidence and self-esteem, as well as managing embarrassment, were important. These issues could be managed through interventions such as cognitive behavioural therapy, mindfulness and acceptance and commitment therapy. Both people with vitiligo and HCPs favoured individual interventions. CONCLUSION: Vitiligo has significant impact, requiring ongoing psychosocial support. There is a strong need for a psychoeducational intervention with focus on acceptance and managing social impact. The results of this study are the first steps to informing the development of a patient-centred psychological intervention.

Chemopreventive action of Imatinib, a tyrosine kinase inhibitor in the regulation of angiogenesis and apoptosis in rat model of lung cancer.

The present study explored the events of angiogenesis and apoptosis in 7,12-dimethyl benz(a)anthracene (DMBA)-induced lung cancer in rat and its chemoprevention with Imatinib, a receptor tyrosine kinase inhibitor. Further, it includes  lipopolysaccharide (LPS) mediating inflammation along with DMBA for the promotion of lung carcinogenesis. The animals received a single intratracheal instillation of DMBA (20 mg/kg body weight) in olive oil and LPS (0.6 mg/kg body weight) to induce tumors in 16 weeks. Besides morphology and histology of the lung tissues, RT-PCR, western blots, and immunofluorescence were performed for the expression of apoptotic and angiogenic proteins. Apoptosis was studied by mitochondrial Bcl-2/Bax ratio and staining with the dyes Acridine orange/ethidium bromide of the isolated Broncho epithelial cells. Also, mitochondrial membrane potential (ΔΨM) was studied by JC-1. The study revealed that the expression of VEGF, MMP-2, MMP-9, and the chemokine MCP-1 to be very high in DMBA and DMBA + LPS groups, while Bcl-2 also shows an elevated expression. These results were restored with Imatinib treatment. The pro-apoptotic proteins, Bax, Bad, Apaf-1, and Caspase-3 were highly diminished in DMBA and DMBA + LPS groups which were recovered with Imatinib treatment.

Role of GSK-3ß in Regulation of Canonical Wnt/ß-catenin Signaling and PI3-K/Akt Oncogenic Pathway in Colon Cancer.

Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents because of their ability in blocking cellular proliferation, and thereby tumor development, and also by promoting apoptosis. GSK-3ß, a serine threonine kinase and a negative regulator of the oncogenic Wnt/ß-catenin signaling pathway, plays a critical role in the regulation of oncogenesis. Celecoxib and etoricoxib, the two cyclooxygenase-2 (COX-2) selective NSAIDs, and Diclofenac, a preferential COX-2 inhibitory NSAID, had shown uniformly the chemopreventive and anti-neoplastic effects in the early stage of colon cancer by promoting apoptosis as well as an over-expression of GSK-3ß while down-regulating the PI3-K/Akt oncogenic pathway.

Safe limit of arsenic in soil in relation to dietary exposure of arsenicosis patients from Malda district, West Bengal- A case study.

Safe limit of arsenic in soil in relation to dietary exposure of arsenicosis patients was established in Malda district of West Bengal. Out of 182 participants examined, 80 (43.9%) participants showed clinical features of arsenicosis, characterized by arsenical skin lesion (pigmentation and keratosis), while 102 participants did not have any such lesion (control). Experimental results of the twenty eight soils (own field) of the participants showed the mean Olsen extractable and total arsenic concentration of 0.206 and 6.70mgkg-1, respectively. Arsenic concentration in rice grain ranged from 2.00 to 1260µgkg-1 with the mean value of 146µgkg-1. The hazard quotient (HQ) for intake of As by human through consumption of rice varied from 0.03 to 3.52. HQ exceeds 1.0 for drinking water and rice grain grown in the study area in many cases. As high as 77.6% variation in As content in rice grain could be explained by the solubility-free ion activity model. Toxic limit of extractable As in soil for rice in relation to soil properties and human health hazard, associated with consumption of rice grain by human, was established. For example, the permissible limit of Olsen extractable As in soil would be 0.43mgkg-1 for rice cultivation, if soil pH and organic carbon content were 7.5% and 0.50%, respectively. However, the critical limit of Olsen extractable As in soil would be 0.54mgkg-1, if soil pH and organic carbon were 8.5% and 0.75%, respectively. The conceptual framework of fixing the toxic limit of arsenic in soils with respect to soil properties and human health under modeling-framework was established.

AxGxE: Using Flies to Interrogate the Complex Etiology of Neurodegenerative Disease.

Progressive and late-onset neurological disorders such as Parkinson's disease and Alzheimer's disease affect up to 50 million people globally-a number postulated to double every 20 years in a continually aging population. While predisposing allelic variants in several genes clearly confer risk, individual age and specific environmental influences are equally important discriminators of disease onset age and progression. However, none of these factors can independently predict disease with significant precision. Therefore, we must actively develop models that accommodate contributions from all factors, potentially resulting in an A × G × E (age-gene-environment) metric that reflects individual cumulative risk and reliably forecasts disease outcomes. This effort can only be enabled by a deep quantitative understanding of the contribution of these factors to neurodegenerative disease, both individually and in combination. This is also an important consideration because neuronal loss typically precedes clinical presentation and disease-modifying therapies are contingent on early diagnosis that is likely to be informed by an accurate estimation of individual risk. Although epidemiological studies continue to make strong advances in these areas with the advent of powerful "omics"-based approaches, systematic phenotypic modeling of AxGxE interactions is currently more feasible in model organisms such as Drosophila melanogaster where all three parameters can be manipulated with manageable experimental burden. Here, we outline the advantages of using fruit flies for investigating these complex interactions and highlight potential approaches that might help synthesize existing information from diverse fields into a cogent description of age-dependent, environmental, and genetic risk factors in the pathophysiology of neurological disorders.

Sesamol Induces Apoptosis by Altering Expression of Bcl-2 and Bax Proteins and Modifies Skin Tumor Development in Balb/c Mice.

BACKGROUND: Chemoprevention using natural agents has emerged as a new and promising strategy for reducing cancer burden. Sesamol, a water soluble lignin, is a potent antioxidant with potential anticancer activities. Its small size (molecular weight: 138.34g) coupled with easy permeability (log P: 1.29) results in its excessive systemic loss therefore, compromising local bioavailability. Furthermore, irritant nature of sesamol limits its application on skin per se. OBJECTIVE: Present study aims to evaluate chemopreventive efficacy of free and encapsulated (SLNs) sesamol, at gross and molecular level, in DMBA induced skin cancer animal model. METHODS: Evaluation is done in terms of tumor burden quantification, histological evaluation of skin, determination of oxidative stress, and quantification of apoptotic proteins, bcl-2 and bax, using both western blot analysis and immunofluorescence studies. RESULTS: Sesamol administration (both in free and encapsulated form) significantly decreased the tumor burden and lipid peroxidation level and increased anti-oxidant levels, thereby hampering the development and promotion of skin tumors. Further, downregulation of bcl-2 and stimulation of bax protein expression on treatment with both free and encapsulated sesamol was responsible for the induction of apoptosis in tumor cells. Encapsulating sesamol into SLNs not only reduced its irritant nature which limits its direct topical application but also improved its local targeting to skin. CONCLUSION: Both free and encapsulated sesamol demonstrated the inhibition of tumor progression by inducing skin cell apoptosis via bcl-2/bax mediated pathway.

Plant Stress Responses Mediated by CBL-CIPK Phosphorylation Network.

At any given time and location, plants encounter a flood of environmental stimuli. Diverse signal transduction pathways sense these stimuli and generate a diverse array of responses. Calcium (Ca2+) is generated as a second messenger due to these stimuli and is responsible for transducing the signals downstream in the pathway. A large number of Ca2+ sensor-responder components are responsible for Ca2+ signaling in plants. The sensor-responder complexes calcineurin B-like protein (CBL) and CBL-interacting protein kinases (CIPKs) are pivotal players in Ca2+-mediated signaling. The CIPKs are the protein kinases and hence mediate signal transduction mainly by the process of protein phosphorylation. Elaborate studies conducted in Arabidopsis have shown the involvement of CBL-CIPK complexes in abiotic and biotic stresses, and nutrient deficiency. Additionally, studies in crop plants have also indicated their role in the similar responses. In this chapter, we review the current literature on the CBL and CIPK network, shedding light into the enzymatic property and mechanism of action of CBL-CIPK complexes. We also summarize various reports on the functional modulation of the downstream targets by the CBL-CIPK modules across all plant species.

Aggregates of quadrupolar dyes for two-photon absorption: the role of intermolecular interactions.

We present a theoretical investigation of small aggregates of quadrupolar (A-π-D-π-A or D-π-A-π-D) charge-transfer dyes, with attention focused on the role of intermolecular interactions in determining their optical properties. We tackle the theoretical issue by adopting essential-state models (ESMs), which describe an isolated molecule in terms of a minimal number of electronic states, corresponding to the resonance structures. ESMs quite naturally describe intermolecular interactions relaxing the dipolar approximation and accounting for molecular polarizabilities. The approach is applied to curcuminoid and squaraine dyes, two families of chromophores with weak and strong quadrupolar character, respectively. The method is validated against experiment and for curcuminoids also against time-dependent density functional theory. ESMs rationalize the strong ultra-excitonic effects recurrently observed in the experimental optical spectra of aggregates of highly polarizable quadrupolar dyes, offering a valuable tool to exploit the supramolecular design of material properties.

Chemopreventive action of non-steroidal anti-inflammatory drugs on the inflammatory pathways in colon cancer.

Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents against a variety of cancers owing to their capability in blocking the tumor development by cellular proliferation and by promoting apoptosis. Inflammation is principal cause of colon carcinogenesis. A missing link between inflammation and cancer could be the activation of NF-κB, which is a hallmark of inflammatory response, and is commonly detected in malignant tumors. Therefore, targeting pro-inflammatory cyclooxygenase enzymes and transcription factors will be profitable as a mechanism to inhibit tumor growth. In the present study, we have studied the role of various pro-inflammatory enzymes and transcription factors in the development of the 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colorectal cancer and also observed the role of three NSAIDs, viz., Celecoxib, Etoricoxib and Diclofenac. Carcinogenic changes were observed in morphological and histopathological studies, whereas protein regulations of various biomolecules were identified by immunofluorescence analysis. Apoptotic studies was done by TUNEL assay and Hoechst/PI co-staining of the isolated colonocytes. It was found that DMH-treated animals were having an over-expression of pro-inflammatory enzymes, aberrant nuclear localization of activated cell survival transcription factor, NF-κB and suppression of anti-inflammatory transcription factor PPAR-γ, thereby suggesting a marked role of inflammation in the tumor progression. However, co-administration of NSAIDs has significantly reduced the inflammatory potential of the growing neoplasm.

Falciform ligament flap for the protection of the gastroduodenal artery stump after pancreaticoduodenectomy: A single center experience.

AIM OF THE STUDY: Delayed hemorrhage, though rare, remains a significant source of morbidity and mortality after pancreaticoduodenectomy (PD). An important cause of this delayed hemorrhage is erosion or pseudoaneurysm formation of the gastroduodenal artery (GDA) by pancreatic enzymes and adjacent intra-abdominal sepsis. So protection of the GDA stump may avoid this devastating complication. PATIENTS AND METHODS: This is a retrospective observational study. All patients, who underwent a PD between August 2007 and December 2014, were included in the study. We used pedicled falciform ligament flap to protect the GDA stump. After PD, pedicled falciform ligament flap was spread widely over the skeletonized hepatic artery including the GDA stump and was fixed to the surrounding retroperitoneal connective tissue. This procedure allowed complete separation of the GDA stump from the pancreatic stump. RESULTS: We performed 182 cases of PD during the study period. Although, 27 (15%) patients developed pancreatic fistula and six patients developed intra-abdominal abscess, no one experienced hemorrhage due to erosion or pseudoaneurysm formation of the GDA. CONCLUSION: The present surgical option seems to be an effective measure for the prevention of erosion and pseudoaneurysm formation of the GDA after PD.

Downregulation of telomerase activity by diclofenac and curcumin is associated with cell cycle arrest and induction of apoptosis in colon cancer.

Uncontrolled cell proliferation is the hallmark of cancer, and cancer cells have typically acquired damage to genes that directly regulate their cell cycles. The synthesis of DNA onto the end of chromosome during the replicative phase of cell cycle by telomerase may be necessary for unlimited proliferation of cells. Telomerase, a ribonucleoprotein enzyme is considered as a universal therapeutic target of cancer because of its preferential expression in cancer cells and its presence in 90 % of tumors. We studied the regulation of telomerase and telomerase reverse transcriptase catalytic subunit (TERT) by diclofenac and curcumin, alone and also in combination, in 1, 2-dimethylhydrazine dihydrochloride-induced colorectal cancer in rats. The relationship of telomerase activity with tumors suppressor proteins (p51, Rb, p21), cell cycle machinery, and apoptosis was also studied. Telomerase is highly expressed in DMH group and its high activity is associated with increased TERT expression. However, telomerase is absent or is present at lower levels in normal tissue. CDK4, CDK2, cyclin D1, and cyclin E are highly expressed in DMH as assessed by RT-PCR, qRT-PCR, Western blot, and immunofluorescence analysis. Diclofenac and curcumin overcome these carcinogenic effects by downregulating telomerase activity, diminishing the expression of TERT, CDK4, CDK2, cyclin D1, and cyclin E. The anticarcinogenic effects shown after the inhibition of telomerase activity by diclofenac and curcumin may be associated with upregulation of tumor suppressor proteins p51, Rb, and p21, whose activation induces the cells cycle arrest and apoptosis.