Mechanistic understanding on the uptake of micro-nano plastics by plants and its phytoremediation.

Contaminated soil is one of today's most difficult environmental issues, posing serious hazards to human health and the environment. Contaminants, particularly micro-nano plastics, have become more prevalent around the world, eventually ending up in the soil. Numerous studies have been conducted to investigate the interactions of micro-nano plastics in plants and agroecosystems. However, viable remediation of micro-nano plastics in soil remains limited. In this review, a powerful in situ soil remediation technology known as phytoremediation is emphasized for addressing micro-nano-plastic contamination in soil and plants. It is based on the synergistic effects of plants and the microorganisms that live in their rhizosphere. As a result, the purpose of this review is to investigate the mechanism of micro-nano plastic (MNP) uptake by plants as well as the limitations of existing MNP removal methods. Different phytoremediation options for removing micro-nano plastics from soil are also described. Phytoremediation improvements (endophytic-bacteria, hyperaccumulator species, omics investigations, and CRISPR-Cas9) have been proposed to enhance MNP degradation in agroecosystems. Finally, the limitations and future prospects of phytoremediation strategies have been highlighted in order to provide a better understanding for effective MNP decontamination from soil.

Primary Mesenchymal Chondrosarcoma of the Mediastinum with Adrenal Metastasis: A Rare Scenario.

Mesenchymal chondrosarcoma (MC) is a rare malignant tumor that represents <3% of all chondrosarcomas. Herein, we describe extraskeletal MC involving the mediastinum in a 24-year-old gentleman with a rare phenomenon of adrenal metastasis.

Insights into microbial diversity on plastisphere by multi-omics.

Plastic pollution is a major concern in marine environment as it takes many years to degrade and is one of the greatest threats to marine life. Plastic surface, referred to as plastisphere, provides habitat for growth and proliferation of various microorganisms. The discovery of these microbes is necessary to identify significant genes, enzymes and bioactive compounds that could help in bioremediation and other commercial applications. Conventional culture techniques have been successful in identifying few microbes from these habitats, leaving majority of them yet to be explored. As such, to recognize the vivid genetic diversity of microbes residing in plastisphere, their structure and corresponding ecological roles within the ecosystem, an emerging technique, called metagenomics has been explored. The technique is expected to provide hitherto unknown information on microbes from the plastisphere. Metagenomics along with next generation sequencing provides comprehensive knowledge on microbes residing in plastisphere that identifies novel microbes for plastic bioremediation, bioactive compounds and other potential benefits. The following review summarizes the efficiency of metagenomics and next generation sequencing technology over conventionally used methods for culturing microbes. It attempts to illustrate the workflow mechanism of metagenomics to elucidate diverse microbial profiles. Further, importance of integrated multi-omics techniques has been highlighted in discovering microbial ecology residing on plastisphere for wider applications.

Estimation of the latent therapeutic demand for immunoglobulin therapies in autoimmune neuropathies in the United States.

BACKGROUND AND OBJECTIVES: The use of immunoglobulin (IG) solutions as an immunomodulatory therapy in certain neurological conditions has become an established modality and represents a significant proportion of total IG use. The estimation of the evidence-based potential demand designated as the latent therapeutic demand (LTD) for IG in these diseases is required for adequate planning of the plasma supply required to manufacture the product. MATERIALS AND METHODS: The diseases studied included chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome (GBS) and multifocal motor neuropathy (MMN). The LTD for IG was assessed using a decision analysis model, using Microsoft Excel. The model analysed the epidemiological and clinical factors contributing to IG usage. One-way sensitivity analysis and probabilistic sensitivity analysis derived the LTD in grams per 1000 inhabitants. The key variables included the treatment schedule and the prevalence of the disease. RESULTS: The model estimates that an average annual IG demand and standard deviation for CIDP, GBS and MMN in the United States is 83.05 ± 24.5, 6.1 ± 3.2 and 36.1 ± 25.5 g/1000 inhabitants, respectively. CONCLUSION: Together with previous work on the LTD for IG in immunodeficiencies, these results indicate that current IG usage reflects the estimated LTD for the main indications for IG in the United States The wide range of LTD found in all these studies emphasizes the need for more precise assessment of the underlying variables, particularly disease prevalence and dosage. Further studies on other indications such as secondary immunodeficiencies will augment these results and will assist in guiding demand planning for IG use and plasma collection in the United States and inform blood policy in other countries.

Occurrence of Alternariol and Alternariolmonomethyl ether in edible oils: Their thermal stability and intake assessment in state of Uttar Pradesh, India.

Alternariol (AOH) and Alternariol monomethyl ether (AME) mycotoxins are found to be present naturally in various food commodities, such as barley, oats, pepper, rye, sorghum, sunflower seeds, tomatoes, and wheat. A few epidemiological studies have correlated the consumption of Alternaria-contaminated cereal grains with higher occurrence of esophageal cancer in Chinese populations. In addition, several studies have reported the toxicological properties of Alternaria mycotoxins. However, surveillance data on AOH and AME occurrence are still limited. Therefore, the goal of this study was to determine the presence of AOH and AME in various commonly consumed, edible oils using HPLC-FLD method. Thirty four percent of samples were found positive for AOH and 35% for AME. Moreover, AOH retained 80% stability, while AME retained 84% stability, after deep frying for 25 min, which is an important factor with respect to Indian cooking style. To the best of our knowledge, this is the first report on the presence of Alternaria mycotoxins in edible oils and their probable dietary intake in Indian population. This surveillance study may help in formulating guidelines for Alternaria mycotoxin levels in India, which are not yet implemented by Food Safety and Standards Authority of India. PRACTICAL APPLICATIONS: At present, no safety guidelines exist for Alternaria mycotoxins in any part of the world. This study will help the regulatory bodies to set permissible levels of Alternaria mycotoxins to safeguard the health of consumers. This study shows that Alternaria mycotoxins are heat stable even after deep frying for 25 min. The data will also help to issue guidelines against exposure of these mycotoxins, keeping in the mind the heat stability factor.

Systemic Opioid Reduction and Discontinuation Following Implantation of Intrathecal Drug-Delivery Systems for Chronic Pain: A Retrospective Cohort Analysis.

OBJECTIVE: The study evaluated systemic opioid utilization before and after initiation of intrathecal drug therapy in patients with chronic, noncancer pain, as well as the effect of opioid elimination on payer costs. METHODS: This was a retrospective cohort analysis of administrative claims data (2011-2016), evaluating patients using systemic opioids for chronic, noncancer pain, newly implanted with an intrathecal drug-delivery system. Patients were excluded for spasticity, cancer, and device explant. The primary outcome was reduction or discontinuation of systemic morphine milligram equivalents during a 395-day follow-up period. The secondary outcome was total commercial insurer payments. RESULTS: Of 9223 total patients, 631 met selection criteria. From baseline to 395-day follow-up, average daily morphine milligram equivalents decreased in 81.5% of patients, and 43.3% discontinued systemic opioid therapy entirely. Among patients who continued systemic opioids, average daily morphine milligram equivalents decreased in 74.9% of patients. Logistic regression found that morphine milligram equivalents of <50 mg/day prior to initiation of intrathecal drug delivery was associated with two times the odds of discontinuation vs. ≥90 mg/day (odds ratio = 2.08, 95% confidence interval 1.42-3.02, p = 0.001). Mean annual payer costs were reduced 29% for patients who discontinued vs. continued systemic opioids (-$11,115 per patient). CONCLUSIONS: A meaningful proportion of patients discontinue or decrease systemic opioid use following initiation of intrathecal drug delivery. Standard of care should include opioid dose tapering prior to intrathecal drug delivery to maximize the probability of systemic opioid discontinuation.

Alternariol induced proliferation in primary mouse keratinocytes and inflammation in mouse skin is regulated via PGE2/EP2/cAMP/p-CREB signaling pathway.

Alternariol (AOH) is a mycotoxin that contaminates various food stuffs as well as animal feed and may cause toxicity after consumption. However, a dermal toxic potential of AOH has not been explored so far. In the present study, skin toxicity after topical exposure of AOH and the involved mechanism/s are revealed. Single topical application of different AOH doses (12.5, 25, 50 µg/animal) caused increased bi-fold thickness as well as hyperplasia and higher production of prostaglandin E2 (PGE2) along with cAMP in the skin demonstrating its inflammatory potential. Western blot analysis showed that exposure of AOH lead to phosphorylation of CREB and increased the expression of COX-2, cyclin D1 as well as prostanoid EP2 receptor. Further studies on primary mouse keratinocytes (PMK) revealed that very low concentrations of AOH (50-500 nM) resulted in significant PMK proliferation. Additionally, using specific antagonist or agonist of prostanoid receptors, we delineated that EP2 receptor play a key role in AOH-induced PMKs proliferation. Collectively, our findings show that AOH can lead to dermal toxicity in mice by activating the EP2/cAMP/p-CREB signaling cascade.

Identification of a splice variant of optineurin which is defective in autophagy and phosphorylation.

Optineurin (Optn) is an autophagy receptor that performs various functions in cargo-selective and non-selective autophagy. Here, we have identified and characterized a splice variant of mouse optineurin mRNA, which produces a truncated protein lacking N-terminal 157 amino acids (d157mOptn). This mRNA and protein are expressed in several tissues and cells. d157mOptn has an intact LC3-interacting region and a serine (S187) in it. However, unlike normal optineurin, the d157mOptn was not phosphorylated at this site when expressed in mammalian cells, and showed reduced interaction with TBK1 (tank binding kinase) that mediates phosphorylation at S187 (S177 in human OPTN). This phosphorylation of Optn required intact N-terminal sequence as well as functional C-terminal ubiquitin-binding domain. Unlike normal optineurin, d157mOptn was unable to promote autophagosome and autolysosome formation upon expression in Optn-deficient cells. d157mOptn was recruited to mutant huntingtin aggregates, but unlike wild type optineurin, it was unable to clear these aggregates by autophagy in neuronal NSC-34 cells. Phospho-TBK1 was seen around mutant Huntingtin aggregates in Optn overexpressing cells but it was reduced in cells overexpressing d157mOptn. Thus, we have identified an isoform of mouse optineurin which is defective in cargo-selective and non-selective autophagy possibly due to loss of phosphorylation and impaired interaction with TBK1. This isoform, which inhibits autophagosome formation in neuronal cells, might be involved in selectively modulating some of the functions of Optn, such as autophagy. Our results provide an insight into the role of N-terminal domain of Optn in various autophagic functions.

Autophagy receptor optineurin promotes autophagosome formation by potentiating LC3-II production and phagophore maturation.

Autophagy is an essential physiological process that maintains cellular homeostasis by eliminating harmful protein aggregates, damaged organelles and certain pathogens through lysosomal degradation. During autophagy specialized structures, known as autophagosomes are formed that recruit the cargo through autophagy receptors, and deliver it to lysosomes. Optineurin (Optn) is an autophagy receptor that mediates cargo selective autophagy. Recently, we have identified a novel function of Optn that promotes autophagosome formation during non-selective autophagy. Optn-deficient cells show reduced formation of autophagosomal protein LC3-II and lower number of autophagosomes as well as autolysosomes. Interestingly, formation of phagophores is increased in Optn-deficient cells. This suggests that Optn promotes autophagosome formation by potentiating LC3-II production and phagophore maturation. Phosphorylation of Optn at Ser-177 is required for promoting autophagosome formation. Here, we discuss various aspects of the role of Optn in the formation of autophagosomes and Atg16L1-positive vesicles. We also discuss the potential role of Rab1a-Optn interaction.

COX-2/EP2-EP4/ß-catenin signaling regulates patulin-induced intestinal cell proliferation and inflammation.

Patulin (PAT), a mycotoxin, is a natural contaminant that is produced by certain species of Penicillium, Aspergillus and Byssochlamys. The major contamination of PAT is in apple and apple based products. PAT is known to cause glutathione depletion, oxidative DNA damage and cell proliferation. Recently, in vitro studies have indicated that PAT can also increase the intestinal epithelial permeability, modulate tight junctions and decrease transepithelial electrical resistance. Nonetheless, no previous study has evaluated the mechanisms responsible for PAT-induced intestinal toxicity or its relevance to the in vivo situation. Here, Wistar rats were orally treated with 100 µg/kg body weight (b.wt.) of PAT, either alone or along with 100 mg/kg b. wt. of celecoxib for 3 days. We found that PAT exposure led to significantly higher levels of PGE2 in serum and intestinal tissue and high expression of COX-2 and Ki-67 compared to controls. Interestingly, our results showed that celecoxib treatment could decrease the PAT-induced PGE2 and reduce the PAT-induced intestinal damage. To study the mechanistic aspect, normal rat intestinal epithelial cells (IEC-6) were treated with non-toxic concentrations (100 nM, 250 nM and 500 nM) of PAT for 6 h. It was observed that PAT exposure caused enhanced proliferation, higher expression of COX-2, and EP2 and EP4 receptors, along with increased PGE2 secretion. Additionally, PAT exposure caused enhanced Akt expression, which in turn inhibits GSK-3ß and stabilizes ß-catenin. Overall, our study suggests that the COX-2/EP2-EP4/ß-catenin signaling cascades are involved in the regulation of PAT-induced intestinal cell proliferation and inflammation.

Impact of Reducing Glycated Hemoglobin on Healthcare Costs Among a Population with Uncontrolled Diabetes.

INTRODUCTION: Glycated hemoglobin (A1C) is considered a "gold standard" measure of glycemic control in patients with diabetes and is correlated with a lower risk of diabetes complications and cost savings. This retrospective claims-analysis assessed the impact of A1C reduction on healthcare costs in patients with uncontrolled Type 1 and Type 2 diabetes. METHODS: Using a large repository of US health plan administrative data linked to A1C values, patients with a diabetes diagnosis and at least two A1C values between 1 January 2009 and 31 December 2014 were selected to identify changes in A1C and associated changes in healthcare expenditure. We used all medical and pharmacy claims to calculate direct healthcare costs from 1 year prior to the index A1C to 2 years after the index A1C. A propensity score method was used to match patients with decreased A1C to patients whose A1C did not decrease, based on potentially confounding variables. Then, a generalized linear model regression was used to estimate the difference-in-difference (DD) effect on costs between the two groups. RESULTS: Of the 3,197 patients who had a first A1C ≥ 9%, 2,273 patients (71%) had a decrease in A1C (Decreasers) and 924 patients (27%) had an increase in A1C (Non-decreasers). After matching, we compared 912 Decreasers to 912 Non-decreasers. Patients in the former group had average annual healthcare costs that were 24% lower during the first year of follow-up and 17% lower during the second year of follow-up, compared to patients whose A1C did not decrease. This reflected a savings of US$2503 and US$1690, respectively. For both time periods, the outpatient category was the largest contributor to cost savings. DISCUSSION: In our analysis, A1C reduction among patients with T1DM and T2DM was associated with slower growth in healthcare costs within 1-2 years. These findings suggest that programs aimed at reducing A1C over a short timeframe may lead to substantial savings and may be worth pursuing by health plans and other payers.

Optineurin promotes autophagosome formation by recruiting the autophagy-related Atg12-5-16L1 complex to phagophores containing the Wipi2 protein.

Autophagy is a quality-control mechanism that helps to maintain cellular homeostasis by removing damaged proteins and organelles through lysosomal degradation. During autophagy, signaling events lead to the formation of a cup-shaped structure called the phagophore that matures into the autophagosome. Recruitment of the autophagy-associated Atg12-5-16L1 complex to Wipi2-positive phagophores is crucial for producing microtubule-associated protein 1 light chain 3-II (LC3-II), which is required for autophagosome formation. Here, we explored the role of the autophagy receptor optineurin (Optn) in autophagosome formation. Fibroblasts from Optn knock-out mouse showed reduced LC3-II formation and a lower number of autophagosomes and autolysosomes during both basal and starvation-induced autophagy. However, the number of Wipi2-positive phagophores was not decreased in Optn-deficient cells. We also found that the number of Atg12/16L1-positive puncta and recruitment of the Atg12-5-16L1 complex to Wipi2-positive puncta are reduced in Optn-deficient cells. Of note, Optn was recruited to Atg12-5-16L1-positive puncta, and interacted with Atg5 and also with Atg12-5 conjugate. A disease-associated Optn mutant, E478G, defective in ubiquitin binding, was also defective in autophagosome formation and recruitment to the Atg12-5-16L1-positive puncta. Moreover, we noted that Optn phosphorylation at Ser-177 was required for autophagosome formation but not for Optn recruitment to the phagophore. These results suggest that Optn potentiates LC3-II production and maturation of the phagophore into the autophagosome, by facilitating the recruitment of the Atg12-5-16L1 complex to Wipi2-positive phagophores.

Functional analysis of optineurin and some of its disease-associated mutants.

Optineurin is a multifunctional protein involved in a variety of cellular functions such as protein trafficking by vesicles, autophagy, and signal transduction. Certain mutations in optineurin (gene OPTN) are associated with neurodegenerative diseases like glaucoma and amyotrophic lateral sclerosis (ALS). Optineurin is also seen in pathological structures present in several other neurodegenerative diseases. In glaucoma, loss of vision occurs due to progressive degeneration of retinal ganglion cells, and perhaps loss of photoreceptor cone cells as well. Most of the glaucoma-associated mutations of optineurin are heterozygous missense mutations, whereas the ALS-associated mutations include deletion, truncation, and missense mutations. Optineurin mediates its functions by interacting with various proteins, often acting as an adaptor to provide a link between two or more proteins. Disease-causing mutations alter these interactions leading to functional defects in membrane vesicle trafficking, autophagy, signaling, aggregate formation, and other processes. Some of these functional defects, caused by glaucoma-associated mutants of optineurin, led to retinal cell death mediated by apoptosis and therefore may contribute to pathogenesis directly. Other mutations are likely to cause glaucoma by indirect mechanisms involving other cell types. Mechanisms of ALS pathogenesis by optineurin mutations are yet to be investigated in detail; however, some ALS-associated mutants cause defects in signaling, autophagy, and ubiquitin binding, which might contribute to pathogenesis.

Diffuse large B-cell non-Hodgkin lymphoma of the prostate presenting with urinary outlet obstruction: A case report.

Large B-cell non-Hodgkin lymphoma involving the prostate accounts for 0.09% and 0.1% of non-Hodgkin lymphoma. We report a case of prostatic large B-cell non-Hodgkin lymphoma in a 77-year-old male with symptoms of urinary retention most probably due to benign prostate hyperplasia. He underwent multiple needle core biopsies through transrectal ultrasound of the prostate. Histopathological examination of the core biopsies revealed diffuse infiltration by atypical lymphoid cells in the prostatic stroma, which was strongly positive for leukocyte common antigen and CD20. CD3, CK, PSA, BCL2, k-light chain, Cyclin D1 and synaptophysin were negative. Histopathology and immunohistochemical profile in the case was consistent with the diagnosis of diffuse large B-cell non-Hodgkin lymphoma of the prostate.

Central nervous system mycosis: analysis of 10 cases.

AIM: To describe the clinicopathological features in patients with fungal infections of the central nervous system (CNS) presenting as mass lesions. MATERIALS AND METHODS: A retrospective analysis of records obtained from 10 patients was done with histopathologically confirmed fungal infections presenting as ICSOL, diagnosed in the department of pathology. Clinical features at presentation, findings of radiological investigations performed and histopathology were noted for each patient and subjected for analysis. RESULTS: Infection was higher in males, and paranasal sinusitis was the most common predisposing factor. Location was intraparenchymal followed by sphenoid wing. Four dural-based lesions mimicked meningioma clinically. The most common fungus identified was zygomycosis (seven cases), followed by phaeohyphomycosis (two cases) and aspergillosis (one case). CONCLUSION: There is a rising trend of CNS mycosis, both in immunocompromised and immunocompetent patients. Intracranial fungal granuloma may mimic radiologically as glioma or meningioma, therefore a high index of suspicion is needed to detect early CNS fungal infections, especially in immunocompetent young patients with no predisposing illness. Fungi should always be excluded in patients with inflammatory or granulomatous pathology of CNS.

Cost effectiveness of duloxetine for osteoarthritis: a Quebec societal perspective.

OBJECTIVE: To assess the cost effectiveness of duloxetine compared to other oral postacetaminophen treatments for osteoarthritis (OA) from a Quebec societal perspective. METHODS: A cost-utility analysis was performed enhancing the Markov model from the 2008 OA guidelines of the National Institute for Health and Clinical Excellence (NICE). The NICE model was extended to include opioid and antidepressant comparators, adding titration, discontinuation, and relevant adverse events (AEs). Comparators included duloxetine, celecoxib, diclofenac, naproxen, hydromorphone, and oxycodone extended release (oxycodone). AEs included gastrointestinal and cardiovascular events associated with nonsteroidal antiinflammatory drugs (NSAIDs), as well as fracture, opioid abuse, and constipation, among others. Costs and incremental cost-effectiveness ratios (ICERs) were estimated in 2011 Canadian dollars. The base case modeled a cohort of 55-year-old patients with OA for a 12-month period of treatment, followed by treatment from a basket of post-discontinuation oral therapies until death. Sensitivity analyses (one-way and probabilistic) were conducted. RESULTS: Overall, naproxen was the least expensive treatment, whereas oxycodone was the most expensive. Duloxetine accumulated the highest number of quality-adjusted life years (QALYs), with an ICER of $36,291 per QALY versus celecoxib. Duloxetine was dominant over opioids. In subgroup analyses, ICERs for duloxetine versus celecoxib were $15,619 and $20,463 for patients at high risk of NSAID-related AEs and patients ages >65 years, respectively. CONCLUSION: Duloxetine was cost effective for a cohort of 55-year-old patients with OA, and more so in older patients and those with greater AE risks.

Choice of Fluids in Severe Septic Patients - A Cost-effectiveness Analysis Informed by Recent Clinical Trials.

Fluid resuscitation with colloids is an established second line therapy for septic patients. Evidence of relative efficacy outcomes is tempered by considerations of the relative costs of the individual fluids. An assessment of recent large clinical trials was performed, resulting in a ranking in the efficacy of these therapies. Probabilities for mortality and the need for renal replacement therapy (RRT) were derived and used to inform a decision analysis model comparing the effect of crystalloid, albumin and hydroxyethyl starch solutions in severe septic patients followed from hospital admission to 90 days in intensive care. The US payer perspective was used. Model inputs for costs and efficacy were derived from the peer-reviewed literature, assuming that that all fluid preparations are bio-equivalent within each class of these therapies. Probabilities for mortality and the need for renal replacement therapy (RRT) data were synthesized using a Bayesian meta-analysis. Relative to crystalloid therapy, 0.21 life years were gained with albumin and 0.85 life years were lost with hydroxyethyl starch. One-way sensitivity analysis showed that the model's outcomes were sensitive to the cost of RRT but not to the costs of the actual fluids or any other costs. We conclude that albumin may be the most cost-effective treatment in these patients when the total medical costs and iatrogenic morbidities involved in treating sepsis with fluids are considered. These results should assist and inform decision making in the choice of these drugs.