RESUMEN
The control of the production of ozone-depleting substances through the Montreal Protocol means that the stratospheric ozone layer is recovering1 and that consequent increases in harmful surface ultraviolet radiation are being avoided2,3. The Montreal Protocol has co-benefits for climate change mitigation, because ozone-depleting substances are potent greenhouse gases4-7. The avoided ultraviolet radiation and climate change also have co-benefits for plants and their capacity to store carbon through photosynthesis8, but this has not previously been investigated. Here, using a modelling framework that couples ozone depletion, climate change, damage to plants by ultraviolet radiation and the carbon cycle, we explore the benefits of avoided increases in ultraviolet radiation and changes in climate on the terrestrial biosphere and its capacity as a carbon sink. Considering a range of strengths for the effect of ultraviolet radiation on plant growth8-12, we estimate that there could have been 325-690 billion tonnes less carbon held in plants and soils by the end of this century (2080-2099) without the Montreal Protocol (as compared to climate projections with controls on ozone-depleting substances). This change could have resulted in an additional 115-235 parts per million of atmospheric carbon dioxide, which might have led to additional warming of global-mean surface temperature by 0.50-1.0 degrees. Our findings suggest that the Montreal Protocol may also be helping to mitigate climate change through avoided decreases in the land carbon sink.
Asunto(s)
Secuestro de Carbono , Pérdida de Ozono/prevención & control , Ozono Estratosférico/análisis , Dióxido de Carbono/análisis , Secuestro de Carbono/efectos de la radiación , Calentamiento Global/prevención & control , Calentamiento Global/estadística & datos numéricos , Historia del Siglo XXI , Fotosíntesis/efectos de la radiación , Plantas/metabolismo , Plantas/efectos de la radiación , Temperatura , Rayos UltravioletaRESUMEN
Nine-membered 1,4,7-triphospha- and triarsamacrocycles with unsaturated benzo-backbones have been prepared using the [Cp(R)Fe](+) unit as a template. The cyclisation involves the attack of a coordinated phosphide (or arsenide) nucleophile at an activated, electrophilic ortho-fluorophenyl substituent on a neighbouring pnictide donor. The macrocycle assembly is of the 2 + 1 type where two new chelate rings are formed from appropriately derivatised bidentate and monodentate phosphines/arsines. Both [(η(5)-C(5)H(5))Fe](+) and [(η(5)-C(5)Me(5))Fe](+) may be employed for the cyclisation with higher yields generally being observed with the unsubstituted Cp. All new compounds have been characterised by spectroscopic and analytical methods including the single-crystal X-ray structure determination of [(η(5)-C(5)H(5))Fe(tribenzo-9aneP(3)-Ph,Ph(F)(2))](+), 3a, and [(η(5)-C(5)H(5))Fe(tribenzo-9aneAs(3)-Ph,Ph(F)(2))](+), 5, as the tetraphenylborate salts. The crystal structures are isomorphous and show the unique conformation of these new macrocycles with a 'cup shaped' cavity formed by the rigid benzo-backbones. The 9aneAs(3) derivative is the first example of a nine-membered triarsamacrocycle.
Asunto(s)
Técnicas de Química Sintética/métodos , Hierro/química , Compuestos Macrocíclicos/síntesis química , Benceno/química , Cristalografía por Rayos X , Ciclización , Compuestos Macrocíclicos/química , Modelos Moleculares , Fosfinas/químicaRESUMEN
Temporal and geographical variabilities in the future "world expected" UV environment are compared with the "world avoided", which would have occurred without the Montreal Protocol on Substances That Deplete the Ozone Layer and its subsequent amendments and adjustments. Based on calculations of clear-sky UV irradiances, the effects of the Montreal Protocol have been hugely beneficial to avoid the health risks, such as skin cancer, which are associated with high UV, while there is only a small increase in health risks, such as vitamin D deficiency, that are associated with low UV. However, interactions with climate change may lead to changes in cloud and albedo, and possibly behavioural changes that could also be important.
RESUMEN
Naturally occurring vitamin K compounds comprise a plant form, phylloquinone (vitamin K(1)) and a series of bacterial menaquinones (MKs) (vitamin K(2)). Structural differences in the isoprenoid side chain govern many facets of metabolism of K vitamins including the way they are transported, taken up by target tissues, and subsequently excreted. In the post-prandial state, phylloquinone is transported mainly by triglyceride-rich lipoproteins (TRL) and long-chain MKs mainly by low-density lipoproteins (LDL). TRL-borne phylloquinone uptake by osteoblasts is an apoE-mediated process with the LRP1 receptor playing a predominant role. One K(2) form, MK-4, has a highly specific tissue distribution suggestive of local synthesis from phylloquinone in which menadione is an intermediate. Both phylloquinone and MKs activate the steroid and xenobiotic receptor (SXR) that initiates their catabolism, but MK-4 specifically upregulates two genes suggesting a novel MK-4 signalling pathway. Many studies have shown specific clinical benefits of MK-4 at pharmacological doses for osteoporosis and cancer although the mechanism(s) are poorly understood. Other putative non-cofactor functions of vitamin K include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis. Anticoagulant drugs block vitamin K recycling and thereby the availability of reduced vitamin K. Under extreme blockade, vitamin K can bypass the inhibition of Gla synthesis in the liver but not in the bone and the vessel wall. In humans, MK-7 has a greater efficacy than phylloquinone in carboxylating both liver and bone Gla proteins. A daily supplement of phylloquinone has shown potential for improving anticoagulation control.
Asunto(s)
Hepatocitos/metabolismo , Osteocitos/metabolismo , Deficiencia de Vitamina K/metabolismo , Vitamina K/metabolismo , Animales , Anticoagulantes/química , Anticoagulantes/farmacocinética , Proteínas Sanguíneas/metabolismo , Humanos , Vitamina K/química , Vitamina K 1/química , Vitamina K 1/farmacocinética , Vitamina K 2/química , Vitamina K 2/farmacocinéticaRESUMEN
BACKGROUND/AIMS: Urocortin II (UcnII) is a neuropeptide that binds with high affinity to the corticotropin-releasing hormone receptor 2 (CRHR2) in peripheral tissues. UcnII is synthesised in the intestine, but its role in human intestinal inflammation is largely unknown. METHODS: Responses of human colonic epithelial cells expressing CRHR2 to stimulation by UcnII were measured using ELISA, western blot analysis, real-time reverse transcription-PCR (RT-PCR) and interleukin (IL)8 promoter activity. Expression levels of CRHR2 and UcnII in human colitis were determined by immunofluorescence and real-time RT-PCR in mucosal biopsies from patients with Crohn's and ulcerative colitis, and in human intestinal xenografts after exposure to Clostridium difficile toxin A. RESULTS: It is reported here that expression of CRHR2 mRNA and protein in human colonic epithelial cells (HT-29) are increased by exposure to C difficile toxin A or tumour necrosis factor (TNF)alpha. Stimulation of non-transformed NCM460 colonocytes overexpressing CRHR2alpha receptor with UcnII resulted in a time- and concentration-dependent increase in IL8 production. UcnII stimulation also led to activation of nuclear factor-kappaB (NF-kappaB) and mitogen-acivated protein (MAP) kinase in these cells, as evidenced by degradation of IkappaBalpha and phosphorylation of the p65 subunit of NF-kappaB and extracellularly regulated kinase (ERK) 1/2. Furthermore, expression of UcnII and CRHR2 mRNA was increased in mucosal samples of patients with inflammatory bowel disease, and after exposure of human intestinal xenografts to C difficile toxin A. CONCLUSIONS: These results suggest that UcnII has pro-inflammatory effects in human intestinal cells via the CRHR2alpha receptor and may play an important role in the pathophysiology of colitis in humans.
Asunto(s)
Colon/inmunología , Hormona Liberadora de Corticotropina/inmunología , Células Epiteliales/inmunología , Receptores de Hormona Liberadora de Corticotropina/inmunología , Animales , Toxinas Bacterianas/inmunología , Línea Celular , Colitis/inmunología , Colitis Ulcerosa/inmunología , Colon/citología , Enfermedad de Crohn/inmunología , Enterotoxinas/inmunología , Regulación de la Expresión Génica/inmunología , Humanos , Interleucina-8/inmunología , Intestinos/trasplante , Ratones , Ratones SCID , Proteínas Quinasas Activadas por Mitógenos/inmunología , FN-kappa B/inmunología , ARN Mensajero/análisis , Trasplante Heterólogo , Factor de Necrosis Tumoral alfa/inmunología , UrocortinasRESUMEN
BACKGROUND & AIMS: Barrier functions across epithelia and endothelia are essential for homeostatic tissue regulation. Astroglia interact with cerebral endothelia to maintain the blood-brain barrier. Whether similar interactions between astrocyte-like enteric glia and epithelia regulate intestinal barrier function is not known. METHODS: Fluorescent permeability markers were used to measure intestinal barrier function in vivo after conditional ablation of enteric glia in transgenic mice. Enteric glial cell regulation of epithelial barrier integrity then was modeled in vitro using coculture. Glial-derived barrier-inducing factors were characterized using size-exclusion chromatography and mass spectrometry. Epithelial barrier integrity was assessed by transepithelial resistance readings and by quantitative measurement of tight-junction-associated protein expression by quantitative polymerase chain reaction and Western blot. RESULTS: We show that ablation of enteric glial cells in transgenic mice causes intestinal mucosal barrier dysfunction, resulting in inflammation. Glial-derived s-nitrosoglutathione (GSNO) was identified as a potent inducer of mucosal barrier function in vitro and in vivo and of attenuated tissue inflammation after ablation of enteric glia in transgenic mice. GSNO regulation of mucosal barrier function was associated directly with an increased expression of perijunctional F-actin and tight-junction-associated proteins zonula occludens-1 and occludin. GSNO also significantly restored mucosal barrier function in colonic biopsy specimens from patients with Crohn's disease, a well-described inflammatory permeability disorder associated with enteric glial-cell disruption. CONCLUSIONS: Enteric glia therefore share the ability of astrocytes to regulate tight-junction integrity, and cellular interactions comparable with those maintaining blood-brain barrier function also regulate epithelial permeability at mucosal surfaces.
Asunto(s)
Astrocitos/fisiología , Colitis/metabolismo , Sistema Nervioso Entérico/fisiología , Mucosa Intestinal , S-Nitrosoglutatión/metabolismo , Actinas/genética , Adolescente , Adulto , Anciano , Animales , Biopsia , Western Blotting , Células Cultivadas , Colitis/patología , Colitis/fisiopatología , Colon/metabolismo , Colon/patología , Dextranos/farmacocinética , Perros , Combinación de Medicamentos , Sistema Nervioso Entérico/cirugía , Ensayo de Inmunoadsorción Enzimática , Epitelio/metabolismo , Estradiol/análogos & derivados , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacocinética , Expresión Génica , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/inervación , Mucosa Intestinal/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Noretindrona , Ocludina , Permeabilidad , Reacción en Cadena de la Polimerasa , ARN/genética , Ratas , Testosterona/análogos & derivados , Proteína de la Zonula Occludens-2RESUMEN
Intestinal epithelial cells (IEC) are constantly exposed to bacterial components, such as LPS, without triggering proinflammatory immune responses. This study demonstrates that chronic exposure of human-derived IEC to LPS induces tolerance to an endogenous inflammatory cytokine (IL-1beta) activated IL-8 response that occurs independently of TLR-4/MD-2 signaling. IL-8 production in response to activation by unrelated TNF-alpha and PMA signaling pathways is also inhibited, indicating a broad-spanning tolerance. Quantitative rtPCR and IL-8 promoter-luciferase assays demonstrate that tolerance is regulated at the transcriptional level and occurs independently of IEC cytodifferentiation. By contrast, LPS does not significantly alter other proinflammatory signaling cascades in IEC that function independently of IL-8 production, e.g., IL-6 secretion and PEEC (Hepoxilin A3)-induced neutrophil transepithelial migration in response to invasive Salmonella typhimurium. Human IEC have therefore developed LPS-induced signaling cascades that promote an IL-8 hyporesponsiveness to proinflammatory cytokines while LPS exposure does not compromise the ability of IEC to mount other proinflammatory immune responses to invasive enteropathogens.
Asunto(s)
Enterocitos/inmunología , Interleucina-8/biosíntesis , Lipopolisacáridos/farmacología , Antígeno 96 de los Linfocitos/metabolismo , Receptor Toll-Like 4/metabolismo , Citocinas/farmacología , Enteritis/inmunología , Enterocitos/efectos de los fármacos , Regulación de la Expresión Génica , Humanos , Tolerancia Inmunológica , Interleucina-1/metabolismo , Interleucina-8/genética , Lipopolisacáridos/inmunología , Transducción de Señal , Transcripción Genética , Células Tumorales CultivadasRESUMEN
Federal law permits physicians to "opt out" of Medicare. When a radiation oncologist chooses this option, he or she may neither bill nor collect from Medicare, but may legally attempt to charge and collect what he or she considers the value of services provided to Medicare-eligible patients. Many academic faculty practice plans permit members to opt out. Even if it is permissible for a radiation oncologist to opt out of Medicare, is it appropriate? The question raises significant ethical and economic issues as one attempts to balance the good of the individual faculty member against the good of the clinical faculty as a whole. In this commentary, the authors offer the principal arguments in favor of and against permitting a faculty radiation oncologist to opt out. They conclude by recommending broad faculty oversight over such decisions.
Asunto(s)
Centros Médicos Académicos/organización & administración , Docentes Médicos/normas , Medicare Assignment , Auto Remisión del Médico/estadística & datos numéricos , Administración de la Práctica Médica/economía , Oncología por Radiación/economía , Actitud del Personal de Salud , Ahorro de Costo , Análisis Costo-Beneficio , Planes de Aranceles por Servicios , Costos de la Atención en Salud , Humanos , Reembolso de Seguro de Salud , Auto Remisión del Médico/ética , Administración de la Práctica Médica/ética , Oncología por Radiación/ética , Estados UnidosRESUMEN
An 83-year-old woman presented with primary multifocal cutaneous B-cell lymphoma, presenting as discrete nodules on the right pinna and nail-bed of the left middle finger, diffuse swelling and erythema of several other nail-beds of the fingers and toes, with associated pincer nail deformity and rhinophyma. Because of the involvement of several sites not amenable to radiotherapy, she was treated with oral cyclical chlorambucil with good result.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Clorambucilo/uso terapéutico , Neoplasias del Oído/tratamiento farmacológico , Oído Externo/patología , Linfoma de Células B/tratamiento farmacológico , Enfermedades de la Uña/tratamiento farmacológico , Neoplasias Nasales/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inducción de RemisiónRESUMEN
Vitamin K is essential for the gamma-carboxylation of Gla-containing bone proteins such as osteocalcin and a suboptimal vitamin K status has been linked to osteoporosis but nothing is known of how the lipoprotein-borne vitamin accesses the bone matrix. We have studied the mechanism of transport of lipoproteins labeled with [3H]-phylloquinone (vitamin K1 [K1]) into osteoblasts using both tumor-derived cell lines and normal osteoblast-rich cell populations. We also investigated the effect of heparin in this model since long-term heparin treatment causes osteopenia and the anticoagulant is known to impair normal lipoprotein metabolism. Heparinase treatment, which removes heparan sulfate proteoglycans (HSPG), reduced uptake of [3H]-K1 from triglyceride-rich lipoproteins (TRL) and low-density lipoproteins (LDL). The effect of heparin in this model was complex depending on cell type, concentration, and time but, overall, the results were consistent with an inhibition of vitamin K uptake by osteoblasts. Anti-apolipoprotein E (apoE) antiserum reduced uptake of TRL-[3H]-K1 by 55 +/- 4% and LDL-[3H]-K1 uptake by 35 +/- 2%. Exogenous apoE4 increased uptake of TRL-[3H]-K1 by 90 +/- 1% compared with 53 +/- 11% for apoE3 and 52 +/- 5% for apoE2. Our findings show that HSPG on the cell surface and apoE in the lipoprotein particles contribute to lipoprotein-K1 uptake by osteoblasts as is known for lipoprotein uptake by hepatocytes. This mechanism is significant in view of the epidemiological association of both undercarboxylation of osteocalcin and the presence of an apo epsilon4 allele with increased fracture risk and reduced bone mineral density (BMD). The inhibition by heparin of lipoprotein-mediated carriage of vitamin K and possibly other lipids to bone may provide a basis for the future understanding of heparin-induced osteoporosis.