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Background: Vision impairment and blindness are significant global public health challenges, particularly in low- and middle-income countries, where access to eye care services remains limited. India has significantly reduced the prevalence of Blindness and Vision Impairment (VI) over the last two decades. This was achieved with the help of greater investments towards blindness control programs. The use of utility values helps in conducting economic evaluations of various eye health programs and empirically justify investing in these programs. This study aimed to estimate utility values for various childhood eye conditions in central India using the EuroQol-Five-Dimension-Youth (EQ-5D-Y) instrument., Methods: This is a before and after study with data collected at two time points for few participants and at only one time point for others. This study was undertaken at Shri Sadguru Netra Chikitsalaya (SNC) and included children representing central and north India. Participants were randomly sampled in the hospital. After comprehensive eye examination, participants completed the EuroQol-Five-Dimension-Youth (EQ-5D-Y) questionnaire along with EuroQol Visual Analogue Scale (EQ VAS) measurement to elicit their health state for their condition which was repeated after six months post-intervention to measure the change in utility value. We have used Indonesian value set to analyze the preference scores of each dimension of EQ-5D-Y., Results: Utility values of 16 eye conditions were estimated at baseline and seven conditions were followed up for post-intervention utility value estimation. There is a statistically significant improvement in the utility values post-intervention amongst six conditions. Blindness and Pediatric cataract had the greatest change (0.23 and 0.2 respectively) in utility value whereas mild Vision Impairment (VI) showed the least change (0.02) in the utility value post-intervention. Blindness had the lowest baseline (0.62) and post-intervention (0.85) utility value., Conclusion: The utility values estimated in this study showed that generic measures such as EQ-5D-Y may be used to elicit health states for various eye conditions amongst children. These estimates are helpful in undertaking cost-utility analyses of eye health programs and interventions aimed at these eye conditions., (© 2024. The Author(s).)

Background: Mentorship is seen as a continuous journey of discovery, shared learning, and personal and professional development to achieve leadership and excellence. Medical schools can be monitored with respect to the provision of mentorships as a quality characteristic. So, the aim of our study was to know the prevalence and the impact of mentorship program in medical schools of Nepal and the need of this program in medical schools all over Nepal., Methods: A descriptive cross-sectional study was conducted among medical students in medical schools in Nepal. Ethical approval from the Nepal Health Research Council (NHRC) was obtained (Ref. 667). The cumulative data obtained nationwide was entered in computerized spreadsheet software (Microsoft Excel) and analyzed using MS Excel and SPSS 16.0., Results: Patan Academy of Health Sciences (PAHS) 131 (50.8%) had highest prevalence of mentorship program. Out of 258 students, 110 (42.6%) knew that there was mentorship program in their medical schools. The study found the role of mentors in building rapport with faculties (61.82%), developing professional skills (81.82%) and learning evidence-based medicine (74.55%). 98.8% participants soughed for the need of this program in their medical schools., Conclusions: The prevalence of mentorship program among medical school in Nepal was found to be low. Individuals involved in the mentor-mentee relationship found the role of mentor not only on academics but also on their personal and social enterprises. Medical students who were familiar with the concept of this program reported its need in medical school.

Purpose: Currently, there are an estimated 4.95 million blind persons and 70 million vision impaired persons in India, out of which 0.24 million are blind children. Early detection and treatment of the leading causes of blindness such as cataract are important in reducing the prevalence of blindness and vision impairment. There are significant developments in the field of blindness prevention, management, and control since the "Vision 2020: The right to sight" initiative. Very few studies have analyzed the cost of blindness at the population level. This study was undertaken to update the information on the economic burden of blindness and visual impairment in India based on the prevalence of blindness in India. We used secondary and publicly available data and a few assumptions for our estimations., Methods: We used gross national income (GNI), disability weights, and loss of productivity metrics to calculate the economic burden of blindness and vision impairment based on the "cost of illness" methodology., Results: The estimated net loss of GNI due to blindness in India is INR 845 billion (Int$ 38.4 billion), with a per capita loss of GNI per blind person of INR 170,624 (Int$ 7,756). The cumulative loss of GNI due to avoidable blindness in India is INR 11,778.6 billion (Int$ 535 billion). The cumulative loss of GNI due to blindness increased almost three times in the past two decades. The potential loss of productivity due to vision impairment is INR 646 billion (Int$ 29.4 billion)., Conclusion: These estimates provide adequate information for budgetary allocation and will help advocate the need for accelerated adoption of all four strategies of integrated people-centered eye care (IPCEC). Early detection and treatment of blindness, especially among children, is very important in reducing the economic burden; thus, there is a need for integrating primary eye care horizontally with all levels of primary healthcare., Competing Interests: None

After emerging in China in late 2019, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread worldwide, and as of mid-2021, it remains a significant threat globally. Only a few coronaviruses are known to infect humans, and only two cause infections similar in severity to SARS-CoV-2: Severe acute respiratory syndrome-related coronavirus , a species closely related to SARS-CoV-2 that emerged in 2002, and Middle East respiratory syndrome-related coronavirus , which emerged in 2012. Unlike the current pandemic, previous epidemics were controlled rapidly through public health measures, but the body of research investigating severe acute respiratory syndrome and Middle East respiratory syndrome has proven valuable for identifying approaches to treating and preventing novel coronavirus disease 2019 (COVID-19). Building on this research, the medical and scientific communities have responded rapidly to the COVID-19 crisis and identified many candidate therapeutics. The approaches used to identify candidates fall into four main categories: adaptation of clinical approaches to diseases with related pathologies, adaptation based on virological properties, adaptation based on host response, and data-driven identification (ID) of candidates based on physical properties or on pharmacological compendia. To date, a small number of therapeutics have already been authorized by regulatory agencies such as the Food and Drug Administration (FDA), while most remain under investigation. The scale of the COVID-19 crisis offers a rare opportunity to collect data on the effects of candidate therapeutics. This information provides insight not only into the management of coronavirus diseases but also into the relative success of different approaches to identifying candidate therapeutics against an emerging disease. IMPORTANCE The COVID-19 pandemic is a rapidly evolving crisis. With the worldwide scientific community shifting focus onto the SARS-CoV-2 virus and COVID-19, a large number of possible pharmaceutical approaches for treatment and prevention have been proposed. What was known about each of these potential interventions evolved rapidly throughout 2020 and 2021. This fast-paced area of research provides important insight into how the ongoing pandemic can be managed and also demonstrates the power of interdisciplinary collaboration to rapidly understand a virus and match its characteristics with existing or novel pharmaceuticals. As illustrated by the continued threat of viral epidemics during the current millennium, a rapid and strategic response to emerging viral threats can save lives. In this review, we explore how different modes of identifying candidate therapeutics have borne out during COVID-19.

The novel coronavirus SARS-CoV-2, which emerged in late 2019, has since spread around the world and infected hundreds of millions of people with coronavirus disease 2019 (COVID-19). While this viral species was unknown prior to January 2020, its similarity to other coronaviruses that infect humans has allowed for rapid insight into the mechanisms that it uses to infect human hosts, as well as the ways in which the human immune system can respond. Here, we contextualize SARS-CoV-2 among other coronaviruses and identify what is known and what can be inferred about its behavior once inside a human host. Because the genomic content of coronaviruses, which specifies the virus's structure, is highly conserved, early genomic analysis provided a significant head start in predicting viral pathogenesis and in understanding potential differences among variants. The pathogenesis of the virus offers insights into symptomatology, transmission, and individual susceptibility. Additionally, prior research into interactions between the human immune system and coronaviruses has identified how these viruses can evade the immune system's protective mechanisms. We also explore systems-level research into the regulatory and proteomic effects of SARS-CoV-2 infection and the immune response. Understanding the structure and behavior of the virus serves to contextualize the many facets of the COVID-19 pandemic and can influence efforts to control the virus and treat the disease. IMPORTANCE COVID-19 involves a number of organ systems and can present with a wide range of symptoms. From how the virus infects cells to how it spreads between people, the available research suggests that these patterns are very similar to those seen in the closely related viruses SARS-CoV-1 and possibly Middle East respiratory syndrome-related CoV (MERS-CoV). Understanding the pathogenesis of the SARS-CoV-2 virus also contextualizes how the different biological systems affected by COVID-19 connect. Exploring the structure, phylogeny, and pathogenesis of the virus therefore helps to guide interpretation of the broader impacts of the virus on the human body and on human populations. For this reason, an in-depth exploration of viral mechanisms is critical to a robust understanding of SARS-CoV-2 and, potentially, future emergent human CoVs (HCoVs).

The molecular mechanisms of olfaction, or the sense of smell, are relatively underexplored compared with other sensory systems, primarily because of its underlying molecular complexity and the limited availability of dedicated predictive computational tools. Odorant receptors (ORs) allow the detection and discrimination of a myriad of odorant molecules and therefore mediate the first step of the olfactory signaling cascade. To date, odorant (or agonist) information for the majority of these receptors is still unknown, limiting our understanding of their functional relevance in odor-induced behavioral responses. In this study, we introduce OdoriFy, a Web server featuring powerful deep neural network-based prediction engines. OdoriFy enables (1) identification of odorant molecules for wildtype or mutant human ORs (Odor Finder); (2) classification of user-provided chemicals as odorants/nonodorants (Odorant Predictor); (3) identification of responsive ORs for a query odorant (OR Finder); and (4) interaction validation using Odorant-OR Pair Analysis. In addition, OdoriFy provides the rationale behind every prediction it makes by leveraging explainable artificial intelligence. This module highlights the basis of the prediction of odorants/nonodorants at atomic resolution and for the ORs at amino acid levels. A key distinguishing feature of OdoriFy is that it is built on a comprehensive repertoire of manually curated information of human ORs with their known agonists and nonagonists, making it a highly interactive and resource-enriched Web server. Moreover, comparative analysis of OdoriFy predictions with an alternative structure-based ligand interaction method revealed comparable results. OdoriFy is available freely as a web service at https://odorify.ahujalab.iiitd.edu.in/olfy/., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

A real-time COVID-19 detection system is an utmost requirement of the present situation. This article presents a chest X-ray image-based automated COVID-19 detection system which can be employed with the RT-PCR test to improve the diagnosis rate. In the proposed approach, the textural features are extracted from the chest X-ray images and local binary pattern (LBP) based images. Further, the image-based and LBP image-based features are jointly investigated. Thereafter, highly discriminatory features are provided to the classifier for developing an automated model for COVID-19 identification. The performance of the proposed approach is investigated over 2905 chest X-ray images of normal, pneumonia, and COVID-19 infected persons on various class combinations to analyze the robustness. The developed method achieves 97.97% accuracy (acc) and 99.88% sensitivity (sen) for classifying COVID-19 X-ray images against pneumonia infected and normal person's X-ray images. It attains 98.91% acc and 99.33% sen for COVID-19 X-ray against the normal X-ray classification. This method can be employed to assist the radiologists during mass screening for fast, accurate, and contact-free COVID-19 diagnosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: This study investigates how and in what circumstances a school-based eye health programme, the Refractive Errors Among CHildren (REACH) programme, achieved its desired outcomes: accessibility, standards of refractive care, fidelity and availability of comprehensive services, for over 2 million school children in six districts across India., Methods: We conducted a realist evaluation to identify programme aspects and their causal relationships with outcomes. Deductive and inductive thematic analysis of qualitative data included three phases: 1. theory gleaning, 2. eliciting programme theory, 3. revisiting programme theory. The Initial Programme Theories (IPTs) were developed and revised through review of the literature, programme documents and field notes. We reviewed informal and formal discussions from the participatory advisory workshops and conducted semi-structured interviews with key stakeholders for the development and refinement of the IPTs. We based our analysis on the programme designers' perspective; used contexts, mechanisms and outcomes configuration for the analysis and presentation of the findings and reported the revised IPTs for the REACH programme., Results: We identified four major programme aspects of the REACH programme for evaluation: programme governing unit, human resource, innovation and technology and funding. Based on the intended outcomes of the programme, themes and contexts were sorted and IPTs were defined. We revised the IPTs based on the analysis of the interviews (n = 19). The contexts and mechanisms that were reported to have potential influence on the attainment of favourable programme outcomes were identified. The revisions to the IPTs included: co-designing a collaborative model and involving local government officials to reinforce trust, community partnerships; local well-trained staff to encourage participation; use of the web-based data capturing system with built-in quality control measures and continued technical support; pre-determined costs and targets for the outputs promoted transparency and adherence with costs., Conclusion: This process provided a comprehensive understanding of the opportunities and possibilities for a large-scale school eye health programme in diverse local contexts in India. This illustrated the importance of embracing principles of system thinking and considering contextual factors for School Eye Health programmes in low and middle-income countries., (© 2021 The Authors Ophthalmic and Physiological Optics © 2021 The College of Optometrists.)

Alzheimer's disease (AD) is the most common cause of dementia, characterized by the deposition of Amyloid-beta (Aβ) plaques in the brain. We have previously developed Amytrap peptide (the active pharmacological ingredient, API) and linked it to a sepharose bead matrix by click chemistry to form Amytrapper matrix, which was able to bind and remove Aβ from human sera and plasma spiked with biotinylated Aβ42 (bio-Aβ42) in vitro . To extend the logic of the previous studies, the current study investigates whether the Amytrap peptide coated inside a medically viable polycarbonate catheter (Amytrapper catheter) could bind and retain Aβ from the human sera. The Amytrapper matrix and the novel Amytrapper catheter were able to bind and retain spiked bio-Aβ42 from human sera or native Aβ from plasma of AD patients. Additional characteristics of the Amytrapper catheter are evaluated and presented in this study. The results presented here provide a proof-of-principle for the first time that extracorporeal Amytrapper device aids clearance of native Aβ (from plasma of AD patients). Thus, our device Amytrapper, either in the form of Sepharose matrix or catheter, could become a novel therapeutic strategy to remove Aβ from circulation in AD patients., Competing Interests: Conflict of Interest We declare that there is no actual and potential conflict of interest on this study.

Purpose: To determine the effect of previous renal stone surgery on result and complications of percutaneous nephrolithotomy (PCNL)., Materials and Methods: Total 300 patients were enrolled in the study. We enrolled 100 surgery-naive cases (those with no history of any renal surgery) as control and labeled them as Group A. Group B comprised 100 cases who had PCNL in the past. Group C constituted 100 patients who had open renal stone surgery in the past. Stones were classified using Guy's stone score. PCNL was performed by standard technique in prone position and technical features encountered during operation and outcomes were compared between groups. Complications were graded using modified Clavien grading system., Results: There were no differences between the three groups in age, gender, body mass index, stone burden, and stone opacity. Multiple calyceal stones and distorted pelvicalyceal system anatomy were more in Group C, but stone score showed no statistically significant difference from other groups. The mean operative time (68.91 ± 21.27 min) and fluoroscopy time (264.40 ± 74.90 s) were longer in Group C, but there was no statistically significant difference between the groups. Multiple access was significantly more common in Group C compared to the other two groups ( P < 0.001). Access location too did not show any statistically significant difference between the groups. Postoperative complications were more in previous stone surgery patients, but did not show statistically significant difference., Conclusion: PCNL is a safe and effective treatment modality for patients with renal stones regardless of history of previous PCNL or open renal surgery., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Urology Annals.)

The time-series forecasting makes a substantial contribution in timely decision-making. In this article, a recently developed eigenvalue decomposition of Hankel matrix (EVDHM) along with the autoregressive integrated moving average (ARIMA) is applied to develop a forecasting model for nonstationary time series. The Phillips-Perron test (PPT) is used to define the nonstationarity of time series. EVDHM is applied over a time series to decompose it into respective subcomponents and reduce the nonstationarity. ARIMA-based model is designed to forecast the future values for each subcomponent. The forecast values of each subcomponent are added to get the final output values. The optimized value of ARIMA parameters for each subcomponent is obtained using a genetic algorithm (GA) for minimum values of Akaike information criterion (AIC). Model performance is evaluated by estimating the future values of daily new cases of the recent pandemic disease COVID-19 for India, USA, and Brazil. The high efficacy of the proposed method is convinced with the results., (© IEEE 2020.)

Purpose: To better understand barriers of costs and attitudes toward pediatric cataract surgery in China and India., Methods: From January 2014 to June 2015, families of children ≤ 10 years old about to undergo or having completed surgery for bilateral, non-traumatic cataract at two tertiary centers in China and India completed questionnaires regarding their demographic characteristics, financial status, living environment, health seeking behaviors, and medical burden., Results: In China, 38 children (23 boys [60.5%], mean age 3.11 ± 2.88 years) were un-operated, and 44 (26 boys [59.1%], mean age 5.09 +/- 2.17 years) had undergone surgery, while in India there were 60 (44 boys [73.3%], mean age 4.61 +/- 3.32 years) and 39 (29 boys [74.4%], mean age 6.45 +/- 2.74 years) children respectively, 181 in total. Chinese children were younger at presentation (p ≤ 0.03 for both operated and un-operated) and also when cataract was detected (median [inter quartile range] 10 [3-34] versus 24 [6-60] months [p = 0.06] for un-operated, 5 [2-12] versus 36 [8-72] months [p < 0.001] for operated). Maternal education levels were lower in India (48.3% and 51.3% with elementary education only among un-operated [p = 0.11] and operated [p = 0.006] families in India versus 27.0% and 20.5% in China), as were rates of consulting medical practitioners for illness (44.7% and 36.4% for un-operated [p < 0.001] and operated [p = 0.001] in China versus 10% and 5.13% in India)., Conclusions: Socioeconomic challenges to securing cataract surgery may be greater, and delays in obtaining surgery longer, in India compared to China, if these facilities are representative.

Background: Anterior crowding/ spacing are one of the major problems that inspire patients to undergo orthodontic treatment. Several factors associated with anterior crowding/ spacing includes arch width and length, mesio-distal tooth diameter and proportions. The aim of the present study was to evaluate the relationship of maxillary and mandibular base lengths to the amount of anterior dental crowding/ spacing in patients with complete class II malocclusions., Material and Methods: A retrospective study was done with 152 patients who were divided into four groups according to the severity of pre-treatment dental crowding/spacing present in the mandibular arch. Measurements were performed on the pre-treatment dental casts and lateral cephalograms. Statistical analysis was done using t-test and chi-square test., Results: Subjects with complete class II malocclusion and moderate to severe mandibular crowding [≥3mm] have significantly smaller base lengths as compared to the subjects with slight crowding or spacing [<3mm]., Conclusions: There exists an inverse correlation between maxillary and mandibular base lengths and the severity of dental crowding and direct correlation with spacing. Key words: Apical base lengths, Class II malocclusion, Crowding, Incisor inclination, Spacing., Competing Interests: Conflict of interest statement: None.

Optometric or visual acuity assessment is an essential part of ophthalmologic examination. Visual acuity measurement serves as a tool for screening of ophthalmic disorders, as well as diagnosis and monitoring of refractive errors and other causes of reduced acuity. Persons with diabetes may experience situations which impair visual acuity, or which impact the utility of refractive visual acuity assessment. This communication shares guidance as to when and when not to perform visual acuity charting in persons with diabetes.

Stress is integral to tumour evolution, and cancer cell survival depends on stress management. We found that cancer-associated stress chronically activates the bioenergetic sensor AMP kinase (AMPK) and, to survive, tumour cells hijack an AMPK-regulated stress response pathway conserved in normal cells. Analysis of The Cancer Genome Atlas data revealed that AMPK isoforms are highly expressed in the lethal human cancer glioblastoma (GBM). We show that AMPK inhibition reduces viability of patient-derived GBM stem cells (GSCs) and tumours. In stressed (exercised) skeletal muscle, AMPK is activated to cooperate with CREB1 (cAMP response element binding protein-1) and promote glucose metabolism. We demonstrate that oncogenic stress chronically activates AMPK in GSCs that coopt the AMPK-CREB1 pathway to coordinate tumour bioenergetics through the transcription factors HIF1α and GABPA. Finally, we show that adult mice tolerate systemic deletion of AMPK, supporting the use of AMPK pharmacological inhibitors in the treatment of GBM.

Context: Human leukocyte antigens (HLAs) have an important role in the determination of susceptibility and resistance to periodontal diseases in humans, which may vary from population to population., Aims: The aim of this study was to find out the association of HLA Classes I and II genes with chronic periodontitis in East Indian population., Materials and Methods: In a cross-sectional study design, a total of sixty participants of chronic periodontitis (CP) (mean age: 44.12 ± 5.85) and sixty subjects of periodontal disease-free controls (NP) Periodontitis free controls (mean age 41.85 ± 7.71) were analyzed for their various HLA combinations using serologic (microlymphocytotoxicity test) method. The results are further compared with the HLA profile of 100 samples of blood donors for which periodontal status was unknown. All the data were statistically analyzed by applying Chi-square test., Results: HLA-B7 ( P = 0.003), DR7 ( P = 0.001), DR53 ( P = 0.001), and DQ3 ( P = 0.001) were identified as susceptible phenotypes to CP, whereas HLA-A1 ( P = 0.010), A3 ( P = 0.001), and Cw4 ( P = 0.001) phenotypes were identified to be associated with disease resistance., Conclusion: The HLA-B7, DR7, DR53, and DQ3 alleles may represent as risk factors for CP in Eastern Population of India, whereas HLA-A1, A3, and Cw4 may indicate to protective factors for CP of the same., Competing Interests: There are no conflicts of interest.

The tumour suppressor gene p53 is mutated in approximately 50% of the human cancers. p53 is involved in genotoxic stress-induced cellular responses. The role of EGFR and ERK in DNA-damage-induced apoptosis is well known. We investigated the involvement of activation of ERK signalling as a consequence of non-functional p53, in sensitivity of cells to doxorubicin. We performed cell survival assays in cancer cell lines with varying p53 status: MCF-7 (wild-type p53, WTp53), MDA MB-468 (mutant p53, MUTp53), H1299 (absence of p53, NULLp53) and an isogenic cell line MCF-7As (WTp53 abrogated). Our results indicate that enhanced chemosensitivity of cells lacking wild-type p53 function is because of elevated levels of EGFR which activates ERK. Additionally, we noted that independent of p53 status, pERK contributes to doxorubicin-induced cell death.

Glioma stem-like cells (GSC) with tumor-initiating activity orchestrate the cellular hierarchy in glioblastoma and engender therapeutic resistance. Recent work has divided GSC into two subtypes with a mesenchymal (MES) GSC population as the more malignant subtype. In this study, we identify the FOXD1-ALDH1A3 signaling axis as a determinant of the MES GSC phenotype. The transcription factor FOXD1 is expressed predominantly in patient-derived cultures enriched with MES, but not with the proneural GSC subtype. shRNA-mediated attenuation of FOXD1 in MES GSC ablates their clonogenicity in vitro and in vivo Mechanistically, FOXD1 regulates the transcriptional activity of ALDH1A3, an established functional marker for MES GSC. Indeed, the functional roles of FOXD1 and ALDH1A3 are likely evolutionally conserved, insofar as RNAi-mediated attenuation of their orthologous genes in Drosophila blocks formation of brain tumors engineered in that species. In clinical specimens of high-grade glioma, the levels of expression of both FOXD1 and ALDH1A3 are inversely correlated with patient prognosis. Finally, a novel small-molecule inhibitor of ALDH we developed, termed GA11, displays potent in vivo efficacy when administered systemically in a murine GSC-derived xenograft model of glioblastoma. Collectively, our findings define a FOXD1-ALDH1A3 pathway in controling the clonogenic and tumorigenic potential of MES GSC in glioblastoma tumors. Cancer Res; 76(24); 7219-30. ©2016 AACR., Competing Interests: of Potential Conflicts of Interest No potential conflicts of interest were disclosed by the authors., (©2016 American Association for Cancer Research.)

Limited research exists regarding the most aggressive forms of hepatoblastoma. Cell lines of the rare subtypes of hepatoblastoma with poor prognosis are not only difficult to attain but also challenging to characterize histologically. A community-driven approach to educating parents and families, regarding the need for donated tissue, is necessary for scientists to have access to resources for murine models and drug discovery. Herein, we describe the currently available resources, existing gaps in research, and the path to move forward for uniform cure of hepatoblastoma.

AMP kinase (AMPK) is an evolutionarily conserved enzyme required for adaptive responses to various physiological and pathological conditions. AMPK executes numerous cellular functions, some of which are often perceived at odds with each other. While AMPK is essential for embryonic growth and development, its full impact in adult tissues is revealed under stressful situations that organisms face in the real world. Conflicting reports about its cellular functions, particularly in cancer, are intriguing and a growing number of AMPK activators are being developed to treat human diseases such as cancer and diabetes. Whether these drugs will have only context-specific benefits or detrimental effects in the treatment of human cancer will be a subject of intense research. Here we review the current state of AMPK research with an emphasis on cancer and discuss the yet unresolved context-dependent functions of AMPK in human cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We describe a novel "Cobbler's technique" for iridodialysis repair in the right eye of a patient aged 18 years, with a traumatic iridodialysis secondary to open globe injury with an iron rod. Our technique is simple with easy surgical maneuvers, that is, effective for repairing iridodialysis. The "Cobbler's technique" allows a maximally functional and cosmetic result for iridodialysis.

Aim: To evaluate the incidence of oral squamous cell carcinoma concomitant with oral sub mucous fibrosis in central India and to correlate precipitating factors associated with oral submucous fibrosis and oral squamous cell carcinoma. This paper also aims to study the incidence of oral squamous cell carcinoma arising secondary to untreated oral submucous fibrosis., Materials and Methods: Two hundred and twenty five cases of oral squamous cell carcinoma and one hundred and nineteen cases of oral submucous fibrosis of various regions in oral cavity were included in the study. All the included cases were clinically and histopathologically diagnosed and retrospective data was retrieved., Result: In the present study of 119 patients of oral submucous fibrosis, 97.4 % were found to have betel nut chewing habit. Incidence of malignant transformation to oral squamous cell carcinoma in patients of untreated oral submucous fibrosis was found to be 4.2 % in the present study. The incidence of oral cancer concomitant with oral submucous fibrosis was found to be 25.77 %, which is statistically significant., Conclusion: From the present study, it is evident that the malignant potential of OSF is underestimated. However, considering the small sample size and the fact that the study was carried out in a small geographical area, further study with a larger sample size and longer duration of follow up on a multicentric basis may be required to reveal the actual malignant potential of the disease.

The ability of herbicides to be adsorbed by the soil and sediment and their tendency to be desorbed are some of the most important factors affecting soil and water contamination. Therefore, a sorption study was conducted to evaluate the adsorption of cyhalofop-butyl, butyl (2R)-2-[4-(4-cyano-2-fluorophenoxy) phenoxy] propanoate, in the sandy clay loam and clayey soils using a batch equilibrium method. The adsorption of cyhalofop-butyl was found positively related with the clay and organic carbon content. Freundlich constants (Kf) of cyhalofop-butyl in the clayey and sandy clay loam were found to be 13.39 and 2.21, respectively. Sorption coefficients (Koc) and distribution coefficients (Kd) were found to be 265.38 and 2,092.79, and 1.38 and 11.48, for sandy clay loam and clayey soils, respectively. The adsorption isotherm suggested a relatively higher affinity of cyhalofop-butyl to the adsorption sites at low equilibrium concentrations. The low value of the soil organic carbon partition coefficient (Koc) of cyhalofop-butyl in the sandy loam soil suggested its weaker adsorption in soil and thus increased its risk of mobility into water sources; hence, it should be used judiciously to prevent groundwater contamination.

We report the successful use of an extended lateral gastrocnemius myocutaneous flap for coverage of the midlateral femur using successive delayed elevations. A 62-year-old man underwent wide resection of a liposarcoma of the right anterior thigh with free flap reconstruction and subsequent radiation therapy 10 years before. Four years later, the patient fractured his irradiated femur and was treated with a retrograde intramedullary nail, which subsequently became infected, causing osteomyelitis of the distal femur, septic arthritis of the knee joint, and nonunion of his pathologic fracture. Although advised by numerous surgeons to undergo above-knee amputation, we offered our motivated patient a multidisciplinary approach to clear his infection and pathology; implanted new orthopedic hardware; performed delayed flap reconstruction; and rehabilitated him back to painless, unassisted ambulation. The extended lateral gastrocnemius myocutaneous flap used provided perfused soft tissues and durable coverage for the patient's exposed orthopedic hardware of the midlateral femur, 14 cm above the joint line of the knee. By using this flap to cover a femur defect well above published heights, our patient avoided amputation after years of worsening incapacitation.

Seckel syndrome (SS) is a rare, autosomal recessive syndrome; characterized by severe intrauterine and postnatal growth retardation, microcephaly, mental retardation, and typical facial appearance with beaklike protrusion of the midface (bird headed). In addition to the characteristic craniofacial dysmorphism and skeletal defects, abnormalities have been described in the cardiovascular, hematopoietic, endocrine, gastrointestinal, and central nervous systems. Usually such patients have poor psychomotor development. This case report presents an 8-year-old child with SS born to parents, exposed in Bhopal gas disaster.

AMP-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor important for cell growth, proliferation, survival, and metabolic regulation. Active AMPK inhibits biosynthetic enzymes like mTOR and acetyl CoA carboxylase (required for protein and lipid synthesis, respectively) to ensure that cells maintain essential nutrients and energy during metabolic crisis. Despite our knowledge about this incredibly important kinase, no specific chemical inhibitors are available to examine its function. However, one small molecule known as compound C (also called dorsomorphin) has been widely used in cell-based, biochemical, and in vivo assays as a selective AMPK inhibitor. In nearly all these reports including a recent study in glioma, the biochemical and cellular effects of compound C have been attributed to its inhibitory action toward AMPK. While examining the status of AMPK activation in human gliomas, we observed that glioblastomas express copious amount of active AMPK. Compound C effectively reduced glioma viability in vitro both by inhibiting proliferation and inducing cell death. As expected, compound C inhibited AMPK; however, all the antiproliferative effects of this compound were AMPK independent. Instead, compound C killed glioma cells by multiple mechanisms, including activation of the calpain/cathepsin pathway, inhibition of AKT, mTORC1/C2, cell-cycle block at G2-M, and induction of necroptosis and autophagy. Importantly, normal astrocytes were significantly less susceptible to compound C. In summary, compound C is an extremely potent antiglioma agent but we suggest that caution should be taken in interpreting results when this compound is used as an AMPK inhibitor., (©2014 AACR.)

Patients with congenital lymphedema who experience pain report more functional interference and psychiatric disturbances than those without pain. These patients also have body image disturbance. We hereby report a case illustrating how pain relief can help in rehabilitative aspect and improve the quality of life and also help to overcome psychiatric manifestation. Pain related to lymphedema is often a neglected aspect of this overlooked problem.

The functional surfaces of the porcelain fused to metal fixed partial dentures are often abraded to adjust occlusion, such restorations are often found to fail in service. This study was therefore conducted to study the effect of surface abrasion on flexural strength of glazed porcelain fused to metal samples. It was also the aim of this study to find the effect of re-glazing on flexural strength of abraded samples. A total of ninety glazed porcelain fused to metal bar samples of the dimension 15 mm × 2 mm × 1.5 mm were fabricated. These samples were then divided into three groups (30 samples each) according to the surface treatments: group A-glazed (control); group B-abraded and group C-abraded and then re-glazed (self-glazed). Flexural strength was measured by using three point bend test on universal testing machine (texture analyser) with a cross-head speed of 0.6 mm/min. Peak force at the time of failure for all the samples was recorded. Statistical analysis found that mean flexural strength was highest for group A-80.65 ± 12.81 MPa; as compared to group B-74.18 ± 10.74 MPa and group C-77.85 ± 9.39 MPa. Student's t test indicated that the difference in the flexural strength between groups A and B was significant while it was non-significant between groups B and C and also between groups A and C. The 'f' test indicated that the difference between the groups was non-significant. This study therefore showed that there is a marked decrease in the flexural strength of the porcelain fused to metal restorations after occlusal abrasion. The study also found that reglazing of these restorations may not restore their flexural strength significantly.

The multifunctional AMPK-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that plays an important role in cell proliferation, growth, and survival. It remains unclear whether AMPK functions as a tumor suppressor or a contextual oncogene. This is because although on one hand active AMPK inhibits mammalian target of rapamycin (mTOR) and lipogenesis--two crucial arms of cancer growth--AMPK also ensures viability by metabolic reprogramming in cancer cells. AMPK activation by two indirect AMPK agonists AICAR and metformin (now in over 50 clinical trials on cancer) has been correlated with reduced cancer cell proliferation and viability. Surprisingly, we found that compared with normal tissue, AMPK is constitutively activated in both human and mouse gliomas. Therefore, we questioned whether the antiproliferative actions of AICAR and metformin are AMPK independent. Both AMPK agonists inhibited proliferation, but through unique AMPK-independent mechanisms and both reduced tumor growth in vivo independent of AMPK. Importantly, A769662, a direct AMPK activator, had no effect on proliferation, uncoupling high AMPK activity from inhibition of proliferation. Metformin directly inhibited mTOR by enhancing PRAS40's association with RAPTOR, whereas AICAR blocked the cell cycle through proteasomal degradation of the G2M phosphatase cdc25c. Together, our results suggest that although AICAR and metformin are potent AMPK-independent antiproliferative agents, physiological AMPK activation in glioma may be a response mechanism to metabolic stress and anticancer agents., Competing Interests: The authors declare no conflict of interest.

This study was conducted to evaluate cyhalofop-p-butyl mobility in a sandy loam soil and subsequent distribution of residues at various depths under field conditions. Soil samples were taken from 0 to 150 cm depths at 3-90 d after rains in lysemeter of 1 and 2 m depths. Cyhalofop-p-butyl application at two rates and subsequent precipitation had a significant impact on soil, physico-chemical properties and herbicide mobility. Precipitation caused substantial mobility of cyhalofop-p-butyl in the soil and 1.1-7.6 μg L(-1) of cyhalofop-p-butyl was found in leachates. Cyhalofop-p-butyl residues in the leachates were probably due to preferential flow through the soil. Cyhalofop-p-butyl residues were detected in significant amounts from the soil up to 10 d, later, residues were found below the detection limit but its three transformation products viz., cyhalofop acid, diacid, and phenol were detected.

Purpose: Classical pharmacology allows the use and development of conventional phytomedicine faster and more economically than conventional drugs. This approach should be tested for their efficacy in terms of complementarity and disease control. The purpose of this study was to determine the molecular mechanisms by which nimbolide, a triterpenoid found in the well-known medicinal plant Azadirachta indica, controls glioblastoma growth., Experimental Design: Using in vitro signaling, anchorage-independent growth, kinase assays, and xenograft models, we investigated the mechanisms of its growth inhibition in glioblastoma., Results: We show that nimbolide or an ethanol soluble fraction of A. indica leaves (Azt) that contains nimbolide as the principal cytotoxic agent is highly cytotoxic against glioblastoma multiforme in vitro and in vivo. Azt caused cell-cycle arrest, most prominently at the G1-S stage in glioblastoma multiforme cells expressing EGFRvIII, an oncogene present in about 20% to 25% of glioblastoma multiformes. Azt/nimbolide directly inhibited CDK4/CDK6 kinase activity leading to hypophosphorylation of the retinoblastoma protein, cell-cycle arrest at G1-S, and cell death. Independent of retinoblastoma hypophosphorylation, Azt also significantly reduced proliferative and survival advantage of glioblastoma multiforme cells in vitro and in tumor xenografts by downregulating Bcl2 and blocking growth factor-induced phosphorylation of Akt, extracellular signal-regulated kinase 1/2, and STAT3. These effects were specific because Azt did not affect mTOR or other cell-cycle regulators. In vivo, Azt completely prevented initiation and inhibited progression of glioblastoma multiforme growth., Conclusions: Our preclinical findings demonstrate nimbolide as a potent anti-glioma agent that blocks cell cycle and inhibits glioma growth in vitro and in vivo.

Benzimidazole and their metal analogs that can act as multimodal agent and have non-peptidic CCK-B receptor antagonist were synthesized and characterized on the basis of spectroscopic techniques such as FT-IR, NMR, FAB-MS and also evaluated for biologic efficacy. The ligands showed binding to most of the organs, known to express CCK receptors in biodistribution studies. Cholecystokinin (CCK1 and CCK2) receptor binding affinities of these analogs (IC50) are 0.802 ± 0.007 for compound C and 0.326 ± 0.012 for compound D in rat pancreatic acini. These studies have provided a new template for further development of novel agents for various related diseases.

Background: Finasteride and dutasteride were developed originally as 5α-reductase inhibitors to block the conversion of testosterone to dihydrotestosterone (DHT). These drugs may possess off-target effects on the androgen receptor (AR) due to their structural similarity to DHT., Methods: A total of four human prostate cancer cell models were examined: LNCaP (T877A mutant AR), 22Rv1 (H874Y mutant AR), LAPC4 (wild-type AR), and VCaP (wild-type AR). Cells were cultured in 10% charcoal-stripped fetal bovine serum, either with or without DHT added to the medium. AR activity was evaluated using the ARE-luciferase assay or the expression of AR regulated genes., Results: Dutasteride was more potent than finasteride in interfering with DHT-stimulated AR signaling. Disruption of AR function was accompanied by decreased cell growth. Cells that rely on DHT for protection against death were particularly vulnerable to dutasteride. Different prostate cancer cell models exhibited different sensitivities to dutasteride and finasteride. LNCaP was most sensitive, LAPC4 and VCaP were intermediate, while 22Rv1 was least sensitive. Regardless of the AR genotype, if AR was transfected into drug-sensitive cells, AR was inhibited by drug treatment; and if AR was transfected into drug-resistant cells, AR was not inhibited., Conclusions: The direct inhibitory effect of dutasteride or finasteride on AR signaling is cell line specific. Mutations in the ligand binding domain of AR do not appear to play a significant role in influencing the AR antagonistic effect of these drugs. Subcellular constituent is an important factor in determining the drug effect on AR function., (Copyright © 2013 Wiley Periodicals, Inc.)

A great deal of research has gone into the development of robust confidence in prediction and applicability domain (AD) measures for quantitative structure-activity relationship (QSAR) models in recent years. Much of the attention has historically focused on structural similarity, which can be defined in many forms and flavors. A concept that is frequently overlooked in the realm of the QSAR applicability domain is how the local activity landscape plays a role in how accurate a prediction is or is not. In this work, we describe an approach that pairs information about both the chemical similarity and activity landscape of a test compound's neighborhood into a single calculated confidence value. We also present an approach for converting this value into an interpretable confidence metric that has a simple and informative meaning across data sets. The approach will be introduced to the reader in the context of models built upon four diverse literature data sets. The steps we will outline include the definition of similarity used to determine nearest neighbors (NN), how we incorporate the NN activity landscape with a similarity-weighted root-mean-square distance (wRMSD) value, and how that value is then calibrated to generate an intuitive confidence metric for prospective application. Finally, we will illustrate the prospective performance of the approach on five proprietary models whose predictions and confidence metrics have been tracked for more than a year.

Purpose: To compare the clinical and histologic healing of intraoral wounds closed using No. 3-0 silk suture with that obtained with isoamyl 2-cyanoacrylate glue., Materials and Methods: We performed alveoloplasty in 30 cases in the mandibular anterior region of edentulous arches; the length of incision in all cases was the same distance from the midline. The closure was performed on 1 side with No. 3-0 silk suture, and the other side was closed with isoamyl 2-cyanoacrylate. The surgical sites were evaluated on the first, seventh, fourteenth, and twenty-first postoperative days for tenderness and erythema. In 15 cases (group A), incisional biopsies on both sutured and glued sides were performed on the seventh postoperative day. In the other 15 patients, similar biopsies were executed on the fourteenth postoperative day (group B). All specimens were examined under a microscope for inflammatory cell infiltration, vascularity, and fibroblastic activity., Results: The incidence of tenderness and erythema was increased on the sutured side on the first, seventh, and fourteenth postoperative days but was similar to that on the glued side on the twenty-first postoperative day. In the patients biopsied on the seventh postoperative day, values of inflammatory cell infiltration and vascularity were higher on the sutured side, whereas in patients biopsied on the fourteenth postoperative day, only vascularity was higher on the sutured side., Conclusion: On the seventh postoperative day, both clinical and histologic indicators of inflammation were higher on the sutured side, but these indicators had reached similar values on the fourteenth postoperative day on both the sutured and glued sides. This suggests that isoamyl 2-cyanoacrylate may aid initial healing., (Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Ligand-dependent and ligand-independent endocytic trafficking of G-protein coupled receptors (GPCRs) is critical for accurate receptor-mediated signaling and its regulation. Metabotropic glutamate receptor 5 (mGluR5) is a GPCR that plays a crucial role in circuit formation in the brain and also in various forms of synaptic plasticity including learning and memory. Outside the central nervous system this receptor also plays very important role in various other non-neuronal cells like heart cells, skin cells, hepatocytes, etc. Although the ligand-mediated endocytosis of mGluR5 has been studied in some detail, ligand-independent/constitutive endocytosis of the receptor has not been properly studied. Here, we have investigated the constitutive endocytosis of mGluR5 and also the sub-cellular fate of the receptor subsequent to internalization. We show here that mGluR5 undergoes constitutive internalization in HEK293 cells. Following endocytosis, the receptor enters the recycling compartment and no localization of the receptor was observed in the lysosome. In addition, we also report here that most of the receptors recycle to the cell surface subsequent to constitutive internalization. Thus, our data demonstrate that mGluR5 receptors internalize without the application of ligand and the internalized receptors recycle back to the cell surface following constitutive endocytosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)