Current psychosocial risk theories focus on different dimensions that it is necessary to understand each theory and approach to be able to adequately be analysed any psychosocial risk problem. Psychosocial hazards and risk, along with their relevant significant impacts, are often unrecognized by workers and management. This leads to increasing number of occupational accidents that are partly caused by psychosocial factors, in addition to physical, chemical, biological, and biomechanical factors. This review aims to obtain an in-depth understanding of the approaches/theories/models that are necessary to be able to comprehensively explain how psychosocial hazards and risk occur and their related impacts against workers in a workplace.
Current clinical practices focus on a small number of biochemical directly related to the pathophysiology with patients and thus only describe a very limited metabolome of a patient and fail to consider the interations of these small molecules. This lack of extended information may prevent clinicians from making the best possible therapeutic interventions in sufficient time to improve patient care. Various post-genomics '('omic)' approaches have been used for therapeutic interventions previously. Metabolomics now a well-established'omics approach, has been widely adopted as a novel approach for biomarker discovery and in tandem with genomics (especially SNPs and GWAS) has the potential for providing systemic understanding of the underlying causes of pathology. In this review, we discuss the relevance of metabolomics approaches in clinical sciences and its potential for biomarker discovery which may help guide clinical interventions. Although a powerful and potentially high throughput approach for biomarker discovery at the molecular level, true translation of metabolomics into clinics is an extremely slow process. Quicker adaptation of biomarkers discovered using metabolomics can be possible with novel portable and wearable technologies aided by clever data mining, as well as deep learning and artificial intelligence; we shall also discuss this with an eye to the future of precision medicine where metabolomics can be delivered to the masses.
The advantages of antibiotics have been most clearly seen in those acute bacterial infections which had a high mortality before the introduction of antibiotics. The reality of the potential harmful effects of antibiotics, both short term in individual patients and long term in favoring emergent resistance and opportunistic pathogens are discussed. Bacterial resistance makes the standard treatments ineffective, and increases the risk of infection spreading. The shortage of novel antibiotics has strengthened the efforts of genome sequencing to control bacterial resistance. The future would include novel approaches, based on a re-conceptualization of the nature of resistance, disease and prevention.
Knowledge extraction is an important part of e-Health system. However, datasets in health domain are highly imbalanced, voluminous, conflicting and complex in nature, and these can lead to erroneous diagnosis of diseases. So, designing accurate and robust clinical diagnosis models for such datasets is a challenging task in data mining. In literature, numerous standard intelligent models have been proposed for this purpose but they usually suffer from several drawbacks like lack of understandability, incapability of operating rare cases, inefficiency in making quick and correct decision, etc. In fact, specific health application using standard intelligent methods may not satisfy multiple criteria. However, recent research indicates that hybrid intelligent methods (integrating several standard ones, can achieve better performance for health applications. Addressing the limitations of the existing approaches, the present research introduces a new hybrid predictive model (integrating C4.5 and PRISM learners) for diagnosing effectively the diseases (instead of any specific disease) in comprehensible way by the practitioners with better prediction results in comparison to the traditional approaches. The empirical results (in terms of accuracy, sensitivity and false positive rate) obtained over fourteen benchmark datasets demonstrate that the model outperforms the base learners in almost all cases. The performance of the model also claims that it can be good alternative to the specialized learners (each designed for specific disease) published in the literature. After all, the presented intelligent system is effective in undertaking medical data classification task.
Urothelial bladder cancer is a common cancer associated with considerable burden for both patients and healthcare providers alike. The majority of patients present with non-muscle-invasive bladder cancer (NMIBC) which, although not immediately life-threatening, requires appropriate initial management and long-term surveillance which is both invasive and costly. Accurate diagnostic urinary biomarkers could be transformational in this setting, yet have proved to be a significant challenge to bladder cancer scientists over the last two decades. Such biomarkers would need to represent a range of tumour grades and stages, encompass inter- and intra-tumour heterogeneity, and compete with the current diagnostic gold standard of cystoscopy with a sensitivity and specificity of 85% and 87%, respectively. For the field to move forward in this current exciting era of high-throughput proteomics and genomics, bladder cancer scientists need to find a consensus on the optimal urinary substrate (DNA, RNA, protein, etc) and deliver robust well-designed studies in the correct populations with appropriate statistical input. Issues relating to tumour heterogeneity and anticipatory diagnosis also require considerable thought. The challenge remains unchanged.
Background: Tobacco smoking is a major established risk factor for pancreatic cancer (PC), increasing the incidence up to six fold depending on the duration and intensity of smoking. Nicotine is a key toxin in tobacco and cigarette, which may contribute to development of pancreatitis and PC. Our previous studies revealed an aberrant expression of Pak1 in PC as compared to normal pancreas and its association with cancer progression, tumor angiogenesis, drug resistance and metastasis. Here, we explore a potential link between Pak1 expression and smoking-mediated PC pathogenesis and the use of Pak1 inhibitors to curtail this association. Methods: Mia Pa Ca 2 cell line was obtained from NCCS, Pune and grown in the presence and absence of 0.5 mu M (0.112 mu g/ml) nicotine hemisulphate salt (5 h) and further nicotine exposed cells were treated with Pak1 inhibitor, IPA-3 (1 h). Protein, mRNA and kinase activity of Pak1 were evaluated. Using human pancreatic cancer tissue, mRNA from smokers (n = 10) and non -smokers (n = 10) were assessed for Pak1 expression. Results: Nicotine significantly enhanced the expression and kinase activity of Pak1, with subsequent activation of NF-kappa B signalling cascade in cooperation with other pathways, this effect was blocked by IPA-3. Also, it was observed that pharmacological blockage or silencing of alpha 7-nAChR abrogated nicotine mediated activation of Pak1/NF-kappa B. Additionally, we demonstrated up-regulated Pak1 mRNA expression in tissue sample from smokers compared to non-smokers. Conclusion: Our findings suggest probable mechanism of action of nicotine through Pak1 signalling on PC pathogenesis and this could be targeted using Pak1 inhibitors for PC treatment.
Schizophrenia (SCZ) is a severe psychiatric disorder affecting 0.7% of the population.[1] When inadequately treated, subjects with SCZ experience symptoms that render them dysfunctional and unable to discern aspects of reality. Despite the fact that the majority of subjects with SCZ are sporadic cases and do not have a known family history of SCZ, a family history is one of the largest risk factors for developing SCZ.[2-4] A large genome-wide association study (GWAS) recently pinpointed 108 significant loci within the human genome that contribute to SCZ pathogenesis.[5] While some loci include genes that have been previously implicated in SCZ, the majority, due to the unbiased nature of the genetic investigation, include genes with unknown relevance to SCZ. This investigation is based on the premise that: 1) at least one of the genes at the 108 loci contribute to SCZ etiology; 2) some of the genes contributing to SCZ etiology are in a common pathway; and 3) some genes in a common pathway will have correlated gene expression. Gene expression data available in the gene expression omnibus (GEO) was used to identify correlated expression among the 369 genes (853 isoforms) found at the 108 loci associated with SCZ. Expression data came from bone marrow CD34+ selected cells isolated from 66 individuals (GSE4619). First, correlation among genes related to the DRD2 pathway was analyzed to test the hypothesis that some SCZ genes are in a common pathway and have correlated expression. Then, two pathways were generated based on correlated expression of genes at the 108 loci. One pathway consisted of the largest number of genes with correlated expression (56) and included four genes from the DRD2 pathway and seven of the 33 genes that were previously implicated in SCZ. The second pathway, a novel pathway of 12 genes, was constructed by excluding both the 33 genes that were previously implicated in SCZ and other genes that exhibited significantly correlated expression with these 33 genes. Correlated expression analysis among SCZ-associated genes at the 108 loci provides evidence implicating those genes with correlated expression in SCZ pathogenesis. In addition, these analyses will facilitate pathway identification creating starting points for targeted experiments to verify or refute the hypothetical pathways generated here. Ultimately identifying the genes and pathways at the 108 loci involved in SCZ genesis will inform novel pharmaceutical development for treatment and prevention of SCZ.
ResumoO envolvimento renal ocorre em 1% a 12% dos pacientes com esclerose sistêmica juvenil (ESJ) e manifesta‐se principalmente como hipertensão arterial, proteinúria e crise renal da esclerodermia. Relata‐se o caso de uma paciente que manifestou síndrome nefrótica (SN) como a primeira manifestação da ESJ com glomeruloesclerose segmentar e focal (GESF). A paciente apresentou SN sensível a corticosteroides aos 12 anos. Aos 14 anos, manifestou edema orbital e de membros inferiores, hipertensão arterial, esclerodactilia e esclerose da pele proximal. Na capilaroscopia periungueal, foram observadas dilatação capilar moderada e desvascularização focal leve, compatíveis com uma esclerodermia em fase inicial (padrão de esclerodermia). A biópsia renal percutânea guiada por ultrassonografia revelou glomeruloesclerose segmentar e focal. A imunofluorescência direta foi negativa. Portanto, a paciente atendeu aos critérios de classificação provisória para ESJ. Ela foi tratada com 25‐hidroxivitamina D por via oral (800 UI/dia), metotrexato (0,5mg/kg/semana) e amlodipina (0,15mg/kg). Foi administrada prednisona (60mg/m2/dia) durante quatro semanas consecutivas, seguida por dois meses consecutivos de uso em dias alternados (40mg/m2), com redução progressiva das doses por quatro meses e depois por interrupção dessa medicação. Atualmente, é tratada com 15mg/semana de metotrexato e não apresenta edema nem proteinúria. Em conclusão, relata‐se um caso raro de SN com GESF como a primeira manifestação da esclerodermia. Portanto, a biópsia renal é obrigatória em pacientes com ESJ com proteinúria sustentada ou SN.AbstractRenal involvement occurs in 1%–12% in juvenile systemic sclerosis (JSSc) patients, mainly with arterial hypertension, proteinuria and scleroderma renal crisis. We report herein a patient who presented nephrotic syndrome (NS) as the first manifestation of JSSc with focal segmental glomerulosclerosis (FSGS). A female patient presented steroid‐sensitive NS at the age of 12 years. At 14 years, she had orbital and lower limbs edema, arterial hypertension, sclerodactyly and proximal skin sclerosis. Moderate capillary dilation and mild focal devascularization were observed in nailfold capillaroscopy, compatible with early stage of scleroderma (scleroderma pattern). Percutaneous renal biopsy guided by ultrasound revealed focal segmental glomerulosclerosis and direct immunofluorescence were negative. Therefore, she fullfilled the provisional classification criteria for JSSc. Patient was treated with oral 25‐hydroxyvitamin D (800 IU/day), methotrexate (0.5mg/kg/week) and amlodipin (0.15 mg/kg). Prednisone (60 mg/m2/day) was administered for 4 consecutive weeks, followed by alternate‐day (40mg/m2) for 2 consecutive months, with tapering for 4 months and then stopping this medication. Currently she is being treated with methotrexate 15 mg/week, without edema and proteinuria. In conclusion, we reported a rare case of NS with FSGS as the first manifestation of scleroderma. Therefore, renal biopsy is mandatory in JSSc patients with sustained proteinuria or NS.
Background: Lung transplantation is the choice of therapy in severe cases of idiopathic pulmonary fibrosis (IPF) but is compounded with post-transplant complications. The paucity of deceased organ donations underlines the need for alternate approaches that improves the quality of life. Herein, we attempted to develop an autologous adult bone marrow derived mesenchymal stromal cell (BMSC) therapy via central line access, and evaluated the safety of a single dose (similar to 13 x 106 cells/mL), in treating "no option" IPF. Method: The study included severe IPF subjects (n = 6) both male and female, aged 40-70 years of age with a forced vital capacity < 50%, diffusing capacity of lung for carbon monoxide (DLco) < 35% of predicted, and/or oxygen (SpO(2)) saturation < 88% on 6 min walk distance (6 MWD). BMSCs at passage 2 were suspended in 30.0 mL normal saline and dispensed through the central line route in a respiratory intensive care unit of Gleneagles Global Hospitals. The subjects were monitored for the first 24 h for serious adverse events and hemodynamic parameters. They were followed up periodically at intervals of 1, 4, and 9 months for safety and monitoring of adverse events, including secondary objectives of changes in pulmonary function test, DLco, 6 MWD, and quality of life as per the study protocol. Results: It was observed that central line infusions were well tolerated by all subjects. Furthermore, there was an improved quality of life. Conclusions: BMSC central line infusion in "no option" IPF cases provided an insight into the strategies in improving the quality of life for patient and thereby increasing the therapeutic window period for lung transplantation.
Large numbers of machine learning approaches have been developed for analysis of medical data in recent years. These approaches have also proved their significance through accurate and earlier diagnosis of diseases. The objective of this work is to develop a diagnostic model for earlier diagnosis of dengue disease. Dengue fever is spread through the bite of the female mosquito (Aedes aegypti). The symptoms of this fever are similar to other fever such as that of Viral influenza, Chikungunya, Zika fever, and so on. However, in this fever, human life can be at risk due to severe depletion of blood platelets. Therefore, early diagnosis of dengue disease can help in protecting human lives by making a preventive move before it turns into an infectious disease. In this work, an effort is made to develop a PSO-ANN based diagnostic model for earlier diagnosis of dengue fever. In the proposed model, PSO technique is applied to optimize the weight and bias parameters of ANN method. Further, PSO optimized ANN approach is used to detect dengue patients. The effectiveness of the proposed model is evaluated based on accuracy, sensitivity, specificity, error rate and AUC parameters. The results of the proposed model have been compared with other existing approaches like ANN, DT, NB, and PSO. It is observed that the proposed diagnostic model is a proficient and powerful model for more accurate and earlier detection of dengue fever.
6-nitrobenzofuran-2-carbohydrazide Schiff base derivatives have been synthesized and their structure has been confirmed via H1NMR, Mass spectrometry and elemental (CHN/S) analysis. These synthesized analogs showed significant cytotoxic and antioxidant activity. Doxorubicin (IC50 = 0.94 ± 0.20μM) and n-propyl gallate (IC50 = 30.30 ± 0.40μM) were used as standard in cytotoxic and antioxidant activities, respectively. Compound 1 (IC50 = 3.30 ± 0.90μM), 2 (IC50 = 2.70 ± 0.25μM), 3 (IC50 = 2.70 ± 0.25μM), 10 (IC50 = 2.70 ± 1.10μM), 11 (IC50 = 1.00 ± 1.20μM), and 17 (IC50 = 3.75 ± 0.90μM) showed excellent while 21 (IC50 = 7.50 ± 0.60μM) and 28 (IC50 = 7.50 ± 0.66μM) showed moderate anti cancer activity. Furthermore, compound 10 (IC50 = 17.50 ± 0.85μM), 11 (IC50 = 24.20 ± 0.55μM), 12 (IC50 = 21.10 ± 1.58μM), 13 (IC50 = 14.60 ± 0.32μM), 14 (IC50 = 29.20 ± 0.75μM) and 15 (IC50 = 9.26 ± 0.15μM) showed better antioxidant activity than the standard n-propyl gallate. This study will be useful to develop potential lead molecules with cytotoxic and antioxidant potential.
Latest advances in genetics have prompted swift progress towards the efficient identification of genes tangled in complex diseases. Still, the comprehensive understanding of the relation between the physiological and molecular mechanism of genes and how they affect disease phenotypes remains a challenge for researchers and clinicians. Here, we wish to identify the osteoporosis disease module, i.e. the indigenous neighborhood of the interactome whose agitation is associated with osteoporosis, and endorse it for functional and pathophysiological application, using both computational and experimental methodologies. Recent studies in osteoporosis suggest that against certain genetic variations, the expression level of genes were different in both diseased and normal conditions. The osteoporosis disease module supplemented with uncertain GWAS p-values may also contain mechanisms that are collective with other disease modules. We, therefore, constructed the gene-gene and protein-protein interaction network for 104 genes with 173 reported SNPs accompanied by GO functional enrichment and KEGG pathway enrichment analysis and recognized the substantial genes of osteoporosis along with their molecular functions. Our analyses exposed polymorphism in SOST and LRP5 as significantly conservative SNPs. Focal points: Benchside: Robust and concise curation of raw data for osteoporosis will help to make the presymptomatic data more valuable to perform wet lab studies. Bedside: Bioinformatics network studies are crucial in finding drug targets so it becomes necessary to process the huge data for osteoporosis to curate and produce significance targets. Further, unpredicted pathways and genes could be explored to support clinical studies. Industry: Data from disease network studies is essential for predicting clinical and non-clinical follow-ups for better drug development. Community: Ratification and standardization of redundant osteoporosis and gene polymorphism data helps to improvise clinical validation of drug targets. It is important that the data is upto the proper stringency level. Government: As for the ultimate purpose of drug development, refined gene expression data is the key in developing clinical products. Financial support from government to produce and validate such products is important as with time these will help both the patients and clinicians as well.
Background: The Bone Morphogenetic Protein 4 (BMP4) is identified to play a significant role in cardiac remodelling; gene polymorphism and its resulting associations with Left Ventricular Hypertrophy (LVH) in diabetic Chronic Kidney Disease (CKD) patients of this protein are yet to be established. Aim: To analyse the association between BMP4 gene polymorphism and LVH in diabetic CKD patients. Materials and methods: Isolation of DNA from whole blood samples of 50 patients each; patients diagnosed LVH with diabetic CKD and also from LVH patients without diabetic CKD, diabetic CKD without LVH and also normal patients as control were extracted. The gene of interest (BMP4 gene) purified from various samples digested using zero-cutter restriction endonucleases (Hind III and Bam HI) by employing the Restriction Fragment Length Polymorphism (RFLP) technique. The restriction has been analysed using 1% agarose gel Electrophoresis. Results: The gene from patient having LVH without diabetic CKD when digested with Hind III showed fragmentation, more specifically, it presented three/four fragments which were at a comparable distance corresponding with the following size reference markers at 2000 bp(few cases), 1500 bp, between 700-600 bp and the last one near 100 bp. This fragmentation pattern was repeated identically for the gene from blood sample of patient having LVH with diabetic CKD which was also digested with Hind III. A similar fragmentation was not visualized for sample from patient having diabetic CKD without LVH when digested with Hind III. But no such fragments were noted for the samples from the same patients when digested with Bam HI. Conclusion: BMP4 gene polymorphism has been confirmed in patients having LVH regardless of the presence or absence of diabetic CKD along with it. Benchside: Left ventricular (LV) hypertrophy is a strong autonomous predictor of increased cardiovascular morbidity and mortality in clinical and population-based samples. Thus understanding the correlation of LVH with BMP4 gene is necessitated to provide alternate therapeutics strategy at genome level. Eventually, genetic investigations provide high assurance for future prevention, early intervention and treatment of this major public health issue. Bedside: Determination of BMP4 Polymorphism would raise a new drug development target using single nucleotide polymorphism. They also serve as molecular marker for next generation therapeutics of personalized medicine at genome level. Community: The patient's therapeutic quality would be high due target specific approach with the understanding of personalized medicine. This can prevent unwanted treatment that can guide way to side-effects in the system. Governments: Funding bodies should continue to acknowledge the importance that the BMP4 gene plays a role in LVH, which can be a causative agent for many other cardio-disorders. Overtime, this will help in benefiting patients and healthcare institutions.
Despite of decades of research in conventional drug delivery systems many challenges are unconfronted in treatment of chronic diseases at a personalized medicine level. So there is a need for development of targeted and efficient drug delivery systems at such levels of treatment. Microelectromechanical systems have some unique characteristics like analyte sensitivity, electrical responsiveness, temporal control and sizes similar to cells and organelles that has led to engineering of implants for drug delivery in various chronic diseases.Targeting can be achieved through the use of this technology as the drugs are released at the site of action as well as in minimal effective concentrations, thus avoiding side-effects also. This review gives a general overview about the Bio Microelectromechanical systems used in targeting with some relevant examples. Hence Microelectromechanical systems prove to be a promising contender for development of drug delivery systems and targeting in pharmaceutical field.
Treatment of fungal infections of nails such as onychomycosis, nail psoriasis involved oral therapy with antifungals, but it caused systemic side effects such as liver toxicity and bioavailability problems due to first pass metabolism and drug interactions. Therefore topical delivery through nails also known as transungual drug delivery system came into picture. But transungual delivery had its own challenges. Nail plate is made up of cross linked keratin linkages which impart extensive bonding responsible for hardness of the nail plate. To overcome these problems mechanical and chemical approaches were studied. Chemical ones included use of penetration enhancers which weaken the integrity of nail, enhancing flux through nails. In spite of using these approaches topical permeability was limited by its barrier properties. This necessitated lookout for novel approaches which enhanced treatment efficacy and reduced treatment time. Approaches such as Iontophoresis, Ultrasound mediated drug delivery, Etching were investigated. Novel nail plate made up of human hair keratin was also investigated as an alternative model for studying flux across nail. Nail lacquers serve as most optimum carrier for antifungals. Development of newer penetration enhancers, studies on water based nail lacquers, nail varnish with antimycotic agent, are being studied extensively. Patch based delivery made up of an occlusive backing layer and a pressure sensitive adhesive matrix layer with the active agent, is also being investigated as an alternative treatment for onychomycosis. Efforts are made in inventing devices by which penetration through nail can be enhanced using a laser or by use of germicidal light for treating various skin infections. Newer technologies exhibit a lot of potential with fruitful results. Microneedles and UV light are under investigation for the scope in transungual drug delivery systems. The purpose of this review is to provide an overview of current approaches and promising approaches to treat nail infections, which could widen boundaries of this system.
VEGF is expressed in central nervous system and its expression increases in hypoxia and in inflammatory brain disorders. A wealth of data suggests that VEGF may exert neuroprotective activities and promote neuroregeneration in disease status. Moreover, the risk of developing certain neurological disorders may be dependent on dysfunction in the VEGF system. Therefore, a strong rationale does exist to suggest that VEGF-based therapeutics could be implemented in conditions such as stroke or amyotrophic lateral sclerosis and experimental data supporting this hypothesis have been obtained. However, the unfavorable pharmacokinetic profile of this growth factor, and concerns on its safety have limited the development of VEGF as a therapeutic tool for neurological disorders. In this review, we discuss why a new class of VEGF-mimic peptides holds promises to become a safer, cheaper and more easily manageable tool for central nervous system therapeutics.
Solid tumours comprise, not only malignant cells but also a variety of stromal cells and extracellular matrix proteins. These components interact via an array of signalling pathways to create an adaptable network that may act to promote or suppress cancer progression. To date, the majority of anti-tumour chemotherapeutic agents have principally sought to target the cancer cell. Consequently, resistance develops because of clonal evolution, as a result of selection pressure during tumour expansion. The concept of activating or inhibiting other cell types within the tumour microenvironment is relatively novel and has the advantage of targeting cells which are genetically stable and less likely to develop resistance. This review outlines key players in the stromal tumour microenvironment and discusses potential targeting strategies that may offer therapeutic benefit.
The number of biosimilar medicines on the market is steadily increasing, due, in part, to patent expiration of several top-selling biologic medicines. These three e-learning modules discuss the basic concepts behind biosimilar medicines and highlight key regulatory considerations when using biosimilar medicines in medical practice.
