Monocrotophos Induced Apoptosis in PC12 Cells: Role of Xenobiotic Metabolizing Cytochrome P450s

Monocrotophos (MCP) is a widely used organophosphate (OP) pesticide. We studied apoptotic changes and their correlation with expression of selected cytochrome P450s (CYPs) in PC12 cells exposed to MCP. A significant induction in reactive oxygen species (ROS) and decrease in glutathione (GSH) levels were observed in cells exposed to MCP. Following the exposure of PC12 cells to MCP (10−5 M), the levels of protein and mRNA expressions of caspase-3/9, Bax, Bcl2, P53, P21, GSTP1-1 were significantly upregulated, whereas the levels of Bclw, Mcl1 were downregulated. A significant induction in the expression of CYP1A1/1A2, 2B1/2B2, 2E1 was also observed in PC12 cells exposed to MCP (10−5 M), whereas induction of CYPs was insignificant in cells exposed to 10−6 M concentration of MCP. We believe that this is the first report showing altered expressions of selected CYPs in MCP-induced apoptosis in PC12 cells. These apoptotic changes were mitochondria mediated and regulated by caspase cascade. Our data confirm the involvement of specific CYPs in MCP-induced apoptosis in PC12 cells and also identifies possible cellular and molecular mechanisms of organophosphate pesticide-induced apoptosis in neuronal cells

Vulval elephantiasis as a result of tubercular lymphadenitis: two case reports and a review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Elephantiasis as a result of chronic lymphedema is characterized by gross enlargement of the arms, legs or genitalia, and occurs due to a variety of obstructive diseases of the lymphatic system. Genital elephantiasis usually follows common filariasis and lymphogranuloma venereum. It may follow granuloma inguinale, carcinomas, lymph node dissection or irradiation and tuberculosis but this happens rarely. Vulval elephantiasis as a consequence of extensive lymph node destruction by tuberculosis is very rare. We present two very unusual cases of vulval elephantiasis due to tuberculous destruction of the inguinal lymph nodes.</p> <p>Case presentation</p> <p>Two Indian women - one aged 40 years and the other aged 27 years, with progressively increasing vulval swellings over a period of five and four years respectively - presented to our hospital. In both cases, there was a significant history on presentation. Both women had previously taken a complete course of anti-tubercular treatment for generalized lymphadenopathy. The vulval swellings were extremely large: in the first case report, measuring 35 × 25 cm on the right side and 45 × 30 cm on the left side, weighing 20 lb and 16 lb respectively. Both cases were managed by surgical excision with reconstruction and the outcome was positive. Satisfactory results have been maintained during a follow-up period of six years in both cases.</p> <p>Conclusions</p> <p>Elephantiasis of the female genitalia is unusual and it has rarely been reported following tuberculosis. We report two cases of vulval elephantiasis as a consequence of extensive lymph node destruction by tuberculosis, in order to highlight this very rare clinical scenario.</p

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs 1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). Interpretation: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury

Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. Methods: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. Findings: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. Interpretation: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

A Systematic Review of Ensemble Techniques for Software Defect and Change Prediction

Background: The use of ensemble techniques have steadily gained popularity in several software quality assurance activities. These aggregated classifiers have proven to be superior than their constituent base models. Though ensemble techniques have been widely used in key areas such as Software Defect Prediction (SDP) and Software Change Prediction (SCP), the current state-of-the-art concerning the use of these techniques needs scrutinization. Aim: The study aims to assess, evaluate and uncover possible research gaps with respect to the use of ensemble techniques in SDP and SCP. Method: This study conducts an extensive literature review of 77 primary studies on the basis of the category, application, rules of formulation, performance, and possible threats of the proposed/utilized ensemble techniques. Results: Ensemble techniques were primarily categorized on the basis of similarity, aggregation, relationship, diversity, and dependency of their base models. They were also found effective in several applications such as their use as a learning algorithm for developing SDP/SCP models and for addressing the class imbalance issue. Conclusion: The results of the review ascertain the need of more studies to propose, assess, validate, and compare various categories of ensemble techniques for diverse applications in SDP/SCP such as transfer learning and online learning

Software Change Prediction: A Systematic Review and Future Guidelines

Background: The importance of Software Change Prediction (SCP) has been emphasized by several studies. Numerous prediction models in literature claim to effectively predict change-prone classes in software products. These models help software managers in optimizing resource usage and in developing good quality, easily maintainable products. Aim: There is an urgent need to compare and assess these numerous SCP models in order to evaluate their effectiveness. Moreover, one also needs to assess the advancements and pitfalls in the domain of SCP to guide researchers and practitioners. Method: In order to fulfill the above stated aims, we conduct an extensive literature review of 38 primary SCP studies from January 2000 to June 2019. Results: The review analyzes the different set of predictors, experimental settings, data analysis techniques, statistical tests and the threats involved in the studies, which develop SCP models. Conclusion: Besides, the review also provides future guidelines to researchers in the SCP domain, some of which include exploring methods for dealing with imbalanced training data, evaluation of search-based algorithms and ensemble of algorithms for SCP amongst others

Concerns of Indian Mothers with Children Having Severe-to-Profound Hearing Impairment at Diagnosis and after 1–3 Years of Therapy

Counseling training in graduate programs continues to be underrepresented. If parental queries are not addressed adequately, they keep visiting one doctor after another. Objective. The aim of the study is to identify maternal needs of children with hearing impairment at two stages of habilitation, that is, just after diagnosis (group I) and after receiving 1 to 3 years of language therapy (group II). Methods. Two groups of mothers were asked to speak their queries about aural habilitation of their children. Queries were recorded, summarized, and categorized as per their priorities. Results. Group I mothers wanted to know about how the child would learn to listen and speak (45%), causes of hearing loss (33.7%), understanding the ear and hearing (10.2%), understanding the audiogram (7%), and coping with emotional aspects of hearing loss (5%), while group II parents had priorities concerning speech development (24.5%) followed by child independence and employment (17.3%), schooling (15.6%), problem behaviors (11%), amplification device (9.4%), duration of therapy (8%), future of the child (8%), and questions about how can my child get adjusted to the “normal” world (6%). Conclusions. Culture- and language-specific materials to explain these issues need to be developed

Apoptosis induction in PC12 cells exposed to MCP.

<p>(a) Apoptosis detection in PC12 cells exposed to MCP using Mitolight™ apoptosis detection kit (catalog no. APT142, Chemicon, USA). (A) Unstained cells; (B) Control cells; (C) PC12 cells exposed to MCP (10⁻⁶ M) for 6 h; (D) PC12 cells exposed to MCP (10⁻⁵ M) for 6 h; (E) PC12 cells exposed to MCP (10⁻⁴ M) for 6 h; (F) Experimental positive control- PC12 cells exposed to campothecin (3 µg/ml) for 6 h; (G) Cells pretreated with 10 µM NAC for 1 h and then exposed with MCP(10⁻⁵ M) for 6 h. (b) Apoptosis detection by Mitolight™ apoptosis detection kit using Upright Phasecontrast Microscope (Nikon 80i, Japan) at 10×100x oil immersion magnification. The images were snapped by Nikon DS-Ri1 (12.7 megapixel) camera. Figure A1- Control cells showing intense red color due to polymerization of Mitolight dye in mitochondria indicative of healthy mitochondria. Figure A2- green color indicates the accumulation of non-polymerized dye in cytoplasm. Figure A3- Nuclei stained with DAPI.Figure A4- Superimposed microphotographs showing healthy mitochondria with intact membrane. Figure B1-B4: PC12 cells exposed to MCP (10⁻⁶ M) for 6 h shows significant dissipation in Mitochondrial membrane potential. Figure C1–C4: PC12 cells exposed to MCP (10⁻⁵ M) for 6 h. C-3: cells showing nuclear condensation and fragmentations (D1 and D2 are magnified view highlighting the same). C-4: Superimposed microphotograph showing apoptotic events.</p

Reactive Oxygen Species (ROS) generation in PC12 cells exposed to MCP.

<p>(a) Representative microphotographs showing MCP-induced reactive oxygen species (ROS) generation in PC12 cells. ROS generation was studied using dichlorofluorescin diacetate (DCFH-DA) dye. Images were captured by Nikon phase contrast cum fluorescence microscope (model 80i) attached with 12.7 Megapixel Nikon DS-Ri1 digital CCD cool camera. (b) Percent change in ROS generation following 6, 12 and 24 h exposure of various concentrations of MCP in PC12 cells assessed by spectrofluorometric analysis. In brief, cells (1×10⁴ per well) were seeded in poly L-lysine pre-coated 96 well black bottom culture plates and allowed to adhere for 24 h in 5% CO₂–95% atmosphere at 37°C. Cells were exposed to MCP (10⁻⁴ to 10⁻⁸ M) for 6, 12 and 24 h. Following the exposure, cells were re-incubated with 2′, 7′ dichlorodihydrofluorescein-diacetate (DCFH-DA) (20 µM) for 30 min at 37°C and fluorescence intensity was measured using multiwall micro plate reader (Synergy HT, Bio-Tek, USA) on excitation wavelength at 485 nm and emission wavelength at 528 nm. The data are expressed in mean of percent of the unexposed control ± SEM, n = 8. *  = P<0.05, ** = p<0. 001.</p