4R of rubber waste management: current and outlook.

Excessive accumulation of rubber waste necessitates the need to revisit the effectiveness of the existing rubber waste management system. This review provides an overview of the legislative frameworks, techniques, challenges, and trends of rubber waste management in various countries. The 4R (reduce, reuse, recycle and recover) framework applied in waste management system in some countries appears to be viable for the processing of rubber waste. Certain countries especially some of the European Union (EU) members have implemented extended producer responsibility (EPR) system to manage the collection of rubber waste, particularly used tires. The processing of rubber waste in each level of the 4R hierarchy was then discussed, with detailed elaboration on the most practiced 'R', recycling which encompasses the direct recycling of products, as well as material recycling via physical and/or chemical means. The challenges faced in the implementation of rubber waste management system in different countries were highlighted and recommendations for a more sustainable rubber consumption were provided at the end of this review.

Association Between Academic Medical Center Pharmaceutical Detailing Policies and Physician Prescribing.

IMPORTANCE: In an effort to regulate physician conflicts of interest, some US academic medical centers (AMCs) enacted policies restricting pharmaceutical representative sales visits to physicians (known as detailing) between 2006 and 2012. Little is known about the effect of these policies on physician prescribing. OBJECTIVE: To analyze the association between detailing policies enacted at AMCs and physician prescribing of actively detailed and not detailed drugs. DESIGN, SETTING, AND PARTICIPANTS: The study used a difference-in-differences multivariable regression analysis to compare changes in prescribing by physicians before and after implementation of detailing policies at AMCs in 5 states (California, Illinois, Massachusetts, Pennsylvania, and New York) that made up the intervention group with changes in prescribing by a matched control group of similar physicians not subject to a detailing policy. EXPOSURES: Academic medical center implementation of policies regulating pharmaceutical salesperson visits to attending physicians. MAIN OUTCOMES AND MEASURES: The monthly within-drug class market share of prescriptions written by an individual physician for detailed and nondetailed drugs in 8 drug classes (lipid-lowering drugs, gastroesophageal reflux disease drugs, diabetes drugs, antihypertensive drugs, hypnotic drugs approved for the treatment of insomnia [sleep aids], attention-deficit/hyperactivity disorder drugs, antidepressant drugs, and antipsychotic drugs) comparing the 10- to 36-month period before implementation of the detailing policies with the 12- to 36-month period after implementation, depending on data availability. RESULTS: The analysis included 16 121 483 prescriptions written between January 2006 and June 2012 by 2126 attending physicians at the 19 intervention group AMCs and by 24 593 matched control group physicians. The sample mean market share at the physician-drug-month level for detailed and nondetailed drugs prior to enactment of policies was 19.3% and 14.2%, respectively. Exposure to an AMC detailing policy was associated with a decrease in the market share of detailed drugs of 1.67 percentage points (95% CI, -2.18 to -1.18 percentage points; P < .001) and an increase in the market share of nondetailed drugs of 0.84 percentage points (95% CI, 0.54 to 1.14 percentage points; P < .001). Associations were statistically significant for 6 of 8 study drug classes for detailed drugs (lipid-lowering drugs, gastroesophageal reflux disease drugs, antihypertensive drugs, sleep aids, attention-deficit/hyperactivity disorder drugs, and antidepressant drugs) and for 9 of the 19 AMCs that implemented policies. Eleven of the 19 AMCs regulated salesperson gifts to physicians, restricted salesperson access to facilities, and incorporated explicit enforcement mechanisms. For 8 of these 11 AMCs, there was a significant change in prescribing. In contrast, there was a significant change at only 1 of 8 AMCs that did not enact policies in all 3 areas. CONCLUSIONS AND RELEVANCE: Implementation of policies at AMCs that restricted pharmaceutical detailing between 2006 and 2012 was associated with modest but significant reductions in prescribing of detailed drugs across 6 of 8 major drug classes; however, changes were not seen in all of the AMCs that enacted policies.

Pathogenic T cells persist after reversal of autoimmune disease by immunosuppression with regulatory T cells.

Autoimmune disease can be prevented with immunosuppressive agents; however, the effectiveness of these treatments in advanced stage of disease and the fate of pathogenic T cells following such treatments are not clear. In this study we demonstrate that a single dose of in vitro-induced Treg cells (iTreg cells) resulted in the functional repair and restitution of stomach tissue that had been severely damaged in advanced autoimmune gastritis. iTreg cells caused depletion or inactivation of autoreactive naïve T cells that were antigen inexperienced, however, autoreactive effector/memory T cells persisted in treated mice, resulting in residual cellular infiltrates within the repaired stomach tissue. The persisting autoreactive T cells were able to rapidly cause autoimmune disease if iTreg cells were removed. Similar data were obtained from mice treated continuously with corticosteroid, in that there was substantial restitution of the gastric mucosa; however, effector T cells persisted and rapidly caused pathology following drug removal. Therefore, iTreg cells or corticosteroid can suppress pathogenic autoreactive cells in advanced autoimmune disease, reversing tissue damage and improving tissue function. However, the persistence of pathogenic T cells represents a disease risk.

Both IFN-γ and IL-17 are required for the development of severe autoimmune gastritis.

IL-17, produced by a distinct lineage of CD4(+) helper T (Th) cells termed Th17 cells, induces the production of pro-inflammatory cytokines from resident cells and it has been demonstrated that over-expression of IL-17 plays a crucial role in the onset of several auto-immune diseases. Here we examined the role of IL-17 in the pathogenesis of autoimmune gastritis, a disease that was previously believed to be mediated by IFN-γ. Significantly higher levels of IL-17 and IFN-γ were found in the stomachs and stomach-draining lymph nodes of mice with severe autoimmune gastritis. Unlike IL-17, which was produced solely by CD4(+) T cells in gastritic mice, the majority of IFN-γ-producing cells were CD8(+) T cells. However, CD8(+) T cells alone were not able to induce autoimmune gastritis. T cells that were deficient in IL-17 or IFN-γ production were able to induce autoimmune gastritis but to a much lower extent compared with the disease induced by wild-type T cells. These data demonstrate that production of neither IL-17 nor IFN-γ by effector T cells is essential for the initiation of autoimmune gastritis, but suggest that both are required for the disease to progress to the late pathogenic stage that includes significant tissue disruption.

Arl5b is a Golgi-localised small G protein involved in the regulation of retrograde transport.

Regulation of membrane transport is controlled by small G proteins, which include members of the Rab and Arf families. Whereas the role of the classic Arf family members are well characterized, many of the Arf-like proteins (Arls) remain poorly defined. Here we show that Arl5a and Arl5b are localised to the trans-Golgi in mammalian cells, and furthermore have identified a role for Arl5b in the regulation of retrograde membrane transport from endosomes to the trans-Golgi network (TGN). The constitutively active Arl5b (Q70L)-GFP mutant was localised efficiently to the Golgi in HeLa cells whereas the dominant-negative Arl5b (T30N)-GFP mutant was dispersed throughout the cytoplasm and resulted in perturbation of the Golgi apparatus. Stable HeLa cells expressing GFP-tagged Arl5b (Q70L) showed an increased rate of endosome-to-Golgi transport of the membrane cargo TGN38 compared with control HeLa cells. Depletion of Arl5b by RNAi resulted in an alteration in the intracellular distribution of mannose-6-phosphate receptor, and significantly reduced the endosome-to-TGN transport of the membrane cargo TGN38 and of Shiga toxin, but had no affect on the anterograde transport of the cargo E-cadherin. Collectively these results suggest that Arl5b is a TGN-localised small G protein that plays a key role in regulating transport along the endosome-TGN pathway.

Cutting edge: pulmonary Legionella pneumophila is controlled by plasmacytoid dendritic cells but not type I IFN.

Plasmacytoid dendritic cells (pDCs) are well known as the major cell type that secretes type I IFN in response to viral infections. Their role in combating other classes of infectious organisms, including bacteria, and their mechanisms of action are poorly understood. We have found that pDCs play a significant role in the acute response to the intracellular bacterial pathogen Legionella pneumophila. pDCs were rapidly recruited to the lungs of L. pneumophila-infected mice, and depletion of pDCs resulted in increased bacterial load. The ability of pDCs to combat infection did not require type I IFN. This study points to an unappreciated role for pDCs in combating bacterial infections and indicates a novel mechanism of action for this cell type.

Molecular pathogenesis of infections caused by Legionella pneumophila.

The genus Legionella contains more than 50 species, of which at least 24 have been associated with human infection. The best-characterized member of the genus, Legionella pneumophila, is the major causative agent of Legionnaires' disease, a severe form of acute pneumonia. L. pneumophila is an intracellular pathogen, and as part of its pathogenesis, the bacteria avoid phagolysosome fusion and replicate within alveolar macrophages and epithelial cells in a vacuole that exhibits many characteristics of the endoplasmic reticulum (ER). The formation of the unusual L. pneumophila vacuole is a feature of its interaction with the host, yet the mechanisms by which the bacteria avoid classical endosome fusion and recruit markers of the ER are incompletely understood. Here we review the factors that contribute to the ability of L. pneumophila to infect and replicate in human cells and amoebae with an emphasis on proteins that are secreted by the bacteria into the Legionella vacuole and/or the host cell. Many of these factors undermine eukaryotic trafficking and signaling pathways by acting as functional and, in some cases, structural mimics of eukaryotic proteins. We discuss the consequences of this mimicry for the biology of the infected cell and also for immune responses to L. pneumophila infection.

Recent development of biodegradable synthetic rubbers and bio-based rubbers using sustainable materials from biological sources.

Rubber is an amorphous hyperelastic polymer which is widely used in this modern era. Natural rubber is considered the ultimate rubber in terms of mechanical performance, but over the years, some limitations and challenges in natural rubber cultivation that could result in serious shortages in the supply chain had been identified. Since then, the search for alternatives including new natural and synthetic rubbers has been rather intense. The initiative to explore new sources of natural rubber which started during the 1940s has been reignited recently due to the increasing demand for natural rubber. The commercialization of natural rubber from the Parthenium argentatum and Taraxacum kok-saghyz species, with the cooperation from rubber product manufacturing companies, has somewhat improved the sustainability of the natural rubber supply chain. Meanwhile, the high demand for synthetic rubber drastically increases the rate of depletion of fossil fuels and amplifies the adverse environmental effect of overexploitation of fossil fuels. Moreover, rubber and plastic products disposal have been a major issue for many decades, causing environmental pollution and the expansion of landfills. Sustainable synthetic rubber products could be realized through the incorporation of materials from biological sources. They are renewable, low cost, and most importantly, biodegradable in nature. In this review, brief introduction to natural and synthetic rubbers, challenges in the rubber industry, alternatives to conventional natural rubber, and recent advances in biodegradable and/or bio-based synthetic rubbers are discussed. The effect of incorporating various types of biologically sourced materials in the synthetic rubbers are also elaborated in detail.

Evaluation of anthoxanthins and their actions on digestive enzyme inhibition when used independently and in combination.

Carbohydrate digestibility is a key determinant for elevated postprandial hyperglycemia (PPHG). Apart from dietary restrictions, one of the strategies to reduce PPHG is to limit the activity of carbohydrate digestive enzymes within the gastrointestinal tract in order to reduce monosaccharide absorption rates. The present work aimed to assess the inhibitory capabilities of digestive enzymes (e.g., α-glucosidase and α-amylase) by anthoxanthins when used independently, in combination with acarbose, or with a different anthoxanthin. Our results showed that quercetin, myricetin, and luteolin presented lower IC50 values than acarbose and inhibited α-glucosidase through mixed-type inhibition. On the other hand, acarbose when compared with these anthoxanthins, remained the most potent inhibitor of α-amylase. Combinatorial treatment (i) acarbose-quercetin and (ii) myricetin-luteolin showed synergistic activity (CI value less than 0.9) in α-glucosidase inhibition. An additive effect (CI value between 0.9 and 1.1) in α-glucosidase inhibition was observed when acarbose-myricetin, acarbose-luteolin or when a combination of two different anthoxanthins (quercetin-myricetin and quercetin-luteolin) was used. This study suggests the potential use of anthoxanthins as functional food ingredients to mitigate PPHG towards the management of T2DM.

Role of regulatory T cells in gastrointestinal inflammatory disease.

Regulatory T cells curb unwanted immune responses and regulate responses to microflora and it is now clear that regulatory T cells play an important role in a number of chronic inflammatory diseases of the gut. First, regulatory T cells are crucial in controlling immune responses to gastric autoantigens and thus preventing autoimmune gastritis and pernicious anemia. Second, regulatory T cells may modulate the response to Helicobacter pylori, thus affecting the ability of the immune system to clear the pathogen and mediate damage to the gastric mucosa. Finally, regulatory T cells play an important role in preventing damaging inflammatory responses to commensal organisms in the lower gut, thus guarding against inflammatory bowel diseases. In the present review, we examine the actions of regulatory T cells in the gut and conclude that further understanding of regulatory T cell biology may lead to new therapeutic approaches to chronic gastrointestinal disease.

Restrictions on pharmaceutical detailing reduced off-label prescribing of antidepressants and antipsychotics in children.

The treatment of pediatric depression is controversial because it includes substantial prescribing of drugs for uses that have not been approved by the Food and Drug Administration ("off label") and are not evidence based. Some academic medical centers (AMCs) restrict "detailing" by pharmaceutical sales representatives, or the promoting of drugs directly to physicians via sales calls, to reduce the effect of such marketing on physician prescribing. With data from thirty-one geographically diverse AMCs and their affiliated hospitals, we used a difference-in-differences model to estimate the effect of anti-detailing policies on off-label prescribing of antidepressants and antipsychotics by pediatricians and by child and adolescent psychiatrists in the period January 2006-June 2009. We found that after the introduction of such policies, prescriptions for off-label use of promoted drugs fell by 11 percent, consistent with the ongoing presence of off-label marketing to physicians. Prescriptions for on-label use of promoted drugs fell by 34 percent after the adoption of the policies. Conversely, prescriptions for on-label use of nonpromoted drugs rose by 14 percent, and those for off-label use of nonpromoted drugs rose by 35 percent. These results suggest that pharmaceutical sales representatives promoted drugs not approved for pediatric use and that policies that restrict detailing by those representatives reduced such off-label prescribing.

A method for quantifying pulmonary Legionella pneumophila infection in mouse lungs by flow cytometry.

BACKGROUND: Pulmonary load of Legionella pneumophila in mice is normally determined by counting serial dilutions of bacterial colony forming units (CFU) on agar plates. This process is often tedious and time consuming. We describe a novel, rapid and versatile flow cytometric method that detects bacteria phagocytosed by neutrophils. FINDINGS: Mice were infected with L. pneumophila via intratracheal or intranasal administration. At various times after bacteria inoculation, mouse lungs were harvested and analysed concurrently for bacterial load by colony counting and flow cytometry analysis. The number of L. pneumophila-containing neutrophils correlated strongly with CFU obtained by bacteriological culture. CONCLUSIONS: This technique can be utilised to determine pulmonary bacterial load and may be used in conjunction with other flow cytometric based analyses of the resulting immune response.

Immune Control of Legionella Infection: An in vivo Perspective.

Legionella pneumophila is an intracellular pathogen that replicates within alveolar macrophages. Through its ability to activate multiple host innate immune components, L. pneumophila has emerged as a useful tool to dissect inflammatory signaling pathways in macrophages. However the resolution of L. pneumophila infection in the lung requires multiple cell types and abundant cross talk between immune cells. Few studies have examined the coordination of events that lead to effective immune control of the pathogen. Here we discuss L. pneumophila interactions with macrophages and dendritic cell subsets and highlight the paucity of knowledge around how these interactions recruit and activate other immune effector cells in the lung.

A convenient model of severe, high incidence autoimmune gastritis caused by polyclonal effector T cells and without perturbation of regulatory T cells.

Autoimmune gastritis results from the breakdown of T cell tolerance to the gastric H(+)/K(+) ATPase. The gastric H(+)/K(+) ATPase is responsible for the acidification of gastric juice and consists of an α subunit (H/Kα) and a ß subunit (H/Kß). Here we show that CD4(+) T cells from H/Kα-deficient mice (H/Kα(-/-)) are highly pathogenic and autoimmune gastritis can be induced in sublethally irradiated wildtype mice by adoptive transfer of unfractionated CD4(+) T cells from H/Kα(-/-) mice. All recipient mice consistently developed the most severe form of autoimmune gastritis 8 weeks after the transfer, featuring hypertrophy of the gastric mucosa, complete depletion of the parietal and zymogenic cells, and presence of autoantibodies to H(+)/K(+) ATPase in the serum. Furthermore, we demonstrated that the disease significantly affected stomach weight and stomach pH of recipient mice. Depletion of parietal cells in this disease model required the presence of both H/Kα and H/Kß since transfer of H/Kα(-/-) CD4(+) T cells did not result in depletion of parietal cells in H/Kα(-/-) or H/Kß(-/-) recipient mice. The consistency of disease severity, the use of polyclonal T cells and a specific T cell response to the gastric autoantigen make this an ideal disease model for the study of many aspects of organ-specific autoimmunity including prevention and treatment of the disease.

Extrathymic mechanisms of T cell tolerance: lessons from autoimmune gastritis.

While the thymus plays a key role in the prevention of many autoimmune phenomena it is clear that robust mechanisms external to the thymus are also vital in controlling self-reactive T cells. Here we review the current concepts in the field of extrathymic tolerance and use recent studies of autoimmune gastritis to illustrate how T cells directed to a prominent, clinically relevant autoantigen, namely the gastric proton pump, can be silenced with little or no thymic involvement. Autoimmune gastritis represents one of the most thoroughly characterised autoimmune systems and the knowledge and tools available to study this disease will continue to allow a thorough assessment of the genetic, cellular and molecular events that underlie tolerance and autoimmunity.

Two genetic loci independently confer susceptibility to autoimmune gastritis.

Autoimmune gastritis is a CD4+ T cell-mediated disease induced in genetically susceptible mice by thymectomy on the third day after birth. Previous linkage analysis indicated that Gasa1 and Gasa2, the major susceptibility loci for gastritis, are located on mouse chromosome 4. Here we verified these linkage data by showing that BALB.B6 congenic mice, in which the distal approximately 40 Mb of chromosome 4 was replaced by C57BL/6 DNA, were resistant to autoimmune gastritis. Analysis of further BALB.B6 congenic strains demonstrated that Gasa1 and Gasa2 can act independently to cause full expression of susceptibility to autoimmune disease. Gasa1 and Gasa2 are located between D4Mit352-D4Mit204 and D4Mit343-telomere, respectively. Numerical differences in Foxp3+ regulatory T cells were apparent between the BALB/c and congenic strains, but it is unlikely that this phenotype accounted for differences in autoimmune susceptibility. The positions of Gasa1 and Gasa2 correspond closely to the positions of Idd11 and Idd9, two autoimmune diabetes susceptibility loci in nonobese diabetic (NOD), mice and this prompted us to examine autoimmune gastritis in NOD mice. After neonatal thymectomy, NOD mice developed autoimmune gastritis, albeit at a slightly lower incidence and severity of disease than in BALB/c mice. Diabetes-resistant congenic NOD.B6 mice, harbouring a B6-derived interval encompassing the Gasa1/2-Idd9/11 loci, demonstrated a slight reduction in the incidence of autoimmune gastritis. This reduction was not significant compared with the reduction observed in BALB.B6 congenic mice, suggesting a difference in the genetic aetiology of autoimmune gastritis in NOD and BALB mice.