RESUMO
BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.
Assuntos
Prostatectomia , Neoplasias da Próstata , Terapia de Salvação , Humanos , Masculino , Prostatectomia/métodos , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/patologia , Idoso , Terapia de Salvação/métodos , Pessoa de Meia-Idade , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/métodos , Antígeno Prostático Específico/sangue , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Gradação de Tumores , Fatores de TempoRESUMO
1. The non-steroidal anti-inflammatory drugs (NSAIDs) indomethacin, 10 and 100 microM, piroxicam, 100 microM, and sodium meclofenamate, 1 and 100 microM, potentiated the lipopolysaccharide (LPS)-stimulated release of interleukin-1 (IL-1)-like activity from mouse peritoneal macrophages. Aspirin up to 100 microM was without effect. The drugs did not themselves stimulate the release of IL-1-like activity at the concentrations used. 2. LPS, 1 microgram ml-1, stimulated prostaglandin E2 production by mouse peritoneal macrophages and this was totally inhibited by aspirin, 100 microM, indomethacin, 1 microM, piroxicam, 10 microM and sodium meclofenamate, 0.1 microM. 3. The potentiation of LPS-stimulated release of IL-1-like activity produced by indomethacin, 100 microM, piroxicam, 100 microM, or sodium meclofenamate, 10 microM, was inhibited by prostaglandin E2, (PGE2) 10 ng ml-1. 4. Aspirin, 100 microM, indomethacin, 100 nM to 10 microM, piroxicam, 1 to 100 microM, and sodium meclofenamate, 10 nM, all potentiated cell-associated IL-1-like activity in LPS- stimulated macrophages. The drugs had no effect on cell-associated IL-1-like activity by themselves. 5. Exogenous PGE2, 2 to 30 ng ml-1, inhibited the cell-accumulation of IL-1-like activity stimulated by LPS in the presence of indomethacin, 1 microM, or sodium meclofenamate, 0.1 microM. 6. The 5-lipoxygenase inhibitors BWA4C, 0.01 to 10 microM, and L-651,392, 0.01 to 10 microM, had no effect on LPS-stimulated released or cell-associated IL-1-like activity. Over the same concentration-ranges,neither of the 5-lipoxygenase inhibitors affected released or cell-associated IL-1-like activity in LPS stimulated mouse macrophages in the presence of indomethacin, 1 JM.7. The synthetic diacylglycerol, DiC8, 10 to 200 JAM, did not itself increase released or cell-associated IL-I-like activity but in the presence of the diacylglycerol kinase inhibitor, R59022, 10 JM, DiC8increased released and cell-associated IL-i-like activity. The activity of DiC8 on released and cell associated IL-l-like activity was not increased by indomethacin, 100 micro M.8. NSAIDs increase LPS-induced cell-associated IL-i-like activity in mouse macrophages by inhibiting the formation of cyclo-oxygenase products such as PGE2 but at higher concentrations the NSAIDs potentiate LPS-induced release of IL-I-like activity by a mechanism independent of cyclo-oxygenase inhibition. The potentiation of the release of IL-i-like activity appears not to be related to an effect of NSAIDs on either 5-lipoxygenase or diacylglycerol metabolism.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Interleucina-1/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Animais , Diglicerídeos/farmacologia , Dinoprostona/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/metabolismo , Masculino , CamundongosRESUMO
1. This paper compares the activity of a range of agonists as stimulants of the beta 3-adrenoceptor in rat isolated oesophagus with their ability to afford protection against indomethacin-induced gastric damage in the conscious rat. 2. The beta 3-adrenoceptor agonists, CL 316243 and BRL 37344, the non-selective beta-adrenoceptor agonist, isoprenaline and the selective beta 2-adrenoceptor agonist, salmeterol, all evoked concentration-dependent relaxation of precontracted muscularis mucosa from rat oesophagus. The rank order of agonist potency was BRL 37344 > CL 316243 > isoprenaline >> salmeterol. The selective beta 1-adrenoceptor agonist, denopamine, did not relax the preparation. 3. The relaxant responses to all agonists were resistant to blockade by atenolol (10 microM), and ICI 118551 (1 microM) thus suggesting that they were not mediated by either beta 1- or beta 2-adrenoceptor stimulation. In contrast, cyanopindolol and propranolol did inhibit responses to BRL 37344, CL 316243 and isoprenaline, giving pA2 values or pKB estimates which were consistent with an interaction at beta 3-adrenoceptors (i.e. approximately 8.0 and 6.5 respectively). However, responses to salmeterol were resistant to blockade by all the antagonists tested, which suggests that the high (> 1 microM) concentrations of salmeterol used exerted non-specific relaxant effects. 4. The agonist effects of CL 316243 and BRL 37344 on beta 1- and beta 2-adrenoceptors were assessed on guinea-pig right atrium and precontracted trachea respectively. Both agonists had minimal activity as stimulants of heart rate, but did relax trachea, being 380 (CL 316243) and 21 (BRL 37344) fold less potent than isoprenaline. 5. CL 316243 and BRL 37344 were potent inhibitors of indomethacin-induced gastric antral ulceration in the conscious rat (ED50 values = 0.24 and 0.09 mumol kg-1, p.o.) Salmeterol was approximately 100 times less potent than BRL 37344 as a gastroprotective agent and denopamine was without effect. 6. The gastroprotective effects of CL 316243 and BRL 37344 were resistant to blockade by ICI 118551 (10 mg kg-1, p.o.) and propranolol (10 mg kg-1, p.o.). In contrast, both antagonists caused dose-related inhibition of the protective action of salmeterol (10 mg kg-1, p.o.). Cyanopindolol was not assessed as an antagonist in vivo because preliminary experiments revealed that it exacerbated indomethacin-induced gastric damage in its own right. 7. In conclusion, the beta 3-adrenoceptor agonists CL 316243 and BRL 37344 were potent inhibitors of indomethacin-induced gastric antral ulceration in the rat. These data suggest that an agonist which is potent and selective for the human beta 3-adrenoceptor may confer mucosal protection in man.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Antiulcerosos/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Albuterol/análogos & derivados , Albuterol/farmacologia , Animais , Anti-Inflamatórios não Esteroides , Dioxóis/farmacologia , Etanolaminas/farmacologia , Feminino , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Ratos , Ratos Wistar , Xinafoato de Salmeterol , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle , Traqueia/efeitos dos fármacosRESUMO
Death of young poults is described as probably due to abuse of carbaryl in turkey pens (14 times the recommended dose). Method of application was not as described by the manufacturer.
Assuntos
Carbaril/toxicidade , Doenças das Aves Domésticas/induzido quimicamente , Perus , Doença Aguda , Tecido Adiposo/análise , Animais , Carbaril/análise , Pele/análiseRESUMO
Two influenza viruses were isolated from turkeys in 1973. A/Turkey/Minn/PR/73 was isolated from a flock with a 75% mortality. Antigenically its hemagglutinin was not similar to that of A/Turkey/Wis/66 virus. A/Turkey/Minn/Kandi/73 was recovered from a flock with 67% mortality. This isolant was antigenically similar to A/Turkey/Wis/66.
Assuntos
Infecções por Orthomyxoviridae/veterinária , Orthomyxoviridae/isolamento & purificação , Doenças das Aves Domésticas/microbiologia , Perus , Animais , Antígenos Virais , Testes de Inibição da Hemaglutinação , Imunodifusão , Pulmão/microbiologia , Minnesota , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/microbiologia , Doenças das Aves Domésticas/imunologia , Traqueia/microbiologiaRESUMO
Serologic evidence of infection with influenza A viruses is reported in commercially raised guinea fowl and White Embden geese in Minnesota.
Assuntos
Gansos , Infecções por Orthomyxoviridae/veterinária , Doenças das Aves Domésticas/imunologia , Animais , Testes de Inibição da Hemaglutinação , Testes de Hemaglutinação , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/imunologia , Aves DomésticasRESUMO
Young turkey poults were experimentally infected with Salmonella heidelberg to evaluate the standard tube agglutination test (TAT) and direct fluorescent antibody test (DFAT), and to correlate results of these procedures with the spread pattern of the organisms in the feces using conventional culture procedures for the detection and isolation of S heidelberg from cloacal swabs. The DFAT test detected fecal excretors considerably longer than bacterial isolation and gave better results. The cultural method was not the most reliable and sensitive method, especially when compared with the DFAT. All control birds remained negative bacteriologically serologically, and with the DFAT during the observation period.
Assuntos
Imunofluorescência , Doenças das Aves Domésticas/diagnóstico , Salmonelose Animal/diagnóstico , Perus , Testes de Aglutinação , Animais , Cloaca/microbiologia , Meios de Cultura , Fezes/microbiologia , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/microbiologia , Salmonella/crescimento & desenvolvimento , Salmonella/imunologia , Salmonella/isolamento & purificação , Salmonelose Animal/imunologia , Salmonelose Animal/microbiologiaRESUMO
Gulls ( Larvus pipixcan ) and mallards ( Anas platyrhynchos ) were experimentally exposed to a turkey influenza A isolant, A/turkey/Minn/BF/72 (Hav6Neq 2). No clinical signs of disease were observed in either species. Tracheal shedding of virus from the gulls persisted for 24 days post-inoculation but virus later than 6 days post exposure could not be demonstrated in either tracheal or cloacal samples from the mallards. Precipitating antibodies were not detected. Hemagglutination-inhibition antibodies were demonstrated in inoculated gulls but antibody levels were low and erratic in ducks.
RESUMO
Four type A infleunza viruses were isolated from tracheal swabs taken from apparently healthy ducks (mallards, Anas platyrhynchos) along the Mississippi flyway in Minnesota. Inital identification of group A influenza was made possible by the use of the agar gel precipitin test.
Assuntos
Patos/microbiologia , Orthomyxoviridae/isolamento & purificação , Animais , Testes de Hemaglutinação , Soros Imunes , Minnesota , Mississippi , Orthomyxoviridae/crescimento & desenvolvimento , Orthomyxoviridae/imunologia , Traqueia/microbiologia , Perus/imunologiaRESUMO
Twenty-seven chicken red blood cell agglutinating agents were isolated from 187 tracheal swabbings of apparently healthy migratory mallard ducks (Anas platyrhynchos) in the Mississippi flyway. Twenty-four of the isolants were type A influenza virus; 3 lentogenic Newcastle disease viruses were isolated. Isolations were not made from either 65 giant Canada geese (Branta canadensis) or 60 Franklins' gulls (Larus pipixcan).
Assuntos
Aves/microbiologia , Vírus da Influenza A/isolamento & purificação , Vírus da Doença de Newcastle/isolamento & purificação , Animais , Patos/microbiologia , Gansos/microbiologia , Vírus da Influenza A/imunologia , Mississippi , Traqueia/microbiologiaAssuntos
Ovos , Infecções por Enterobacteriaceae/veterinária , Enterobacteriaceae , Doenças das Aves Domésticas/etiologia , Perus , Testes de Aglutinação , Animais , Sangue/microbiologia , Cloaca/microbiologia , Enterobacteriaceae/imunologia , Enterobacteriaceae/isolamento & purificação , Infecções por Enterobacteriaceae/etiologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Intestinos/microbiologia , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/microbiologia , Salmonella/imunologia , Salmonella/isolamento & purificação , Salmonelose Animal/imunologia , Salmonelose Animal/microbiologia , Salmonella typhimurium/imunologia , Salmonella typhimurium/isolamento & purificaçãoRESUMO
Lipopolysaccharide (LPS) caused a concentration-dependent increase of released and cell-associated interleukin-1 (IL-1) in resident peritoneal macrophages from the mouse. LPS was about 30 times more potent at stimulating the level of cell-associated IL-1 than it was at stimulating the release of IL-1. Human recombinant tumour necrosis factor-alpha (TNF-alpha) and the calcium ionophores A23187 and ionomycin induced a concentration-dependent increase of cell-associated IL-1 but failed to cause release of IL-1 at concentrations producing maximal stimulation of cell-associated IL-1. The phorbol ester, 4 beta-phorbol dibutyrate, stimulated the release of IL-1 from mouse macrophages but failed to induce an increase in cell-associated IL-1. Substance P, neurokinin A, neurokinin B, calcitonin gene-related peptide and platelet-activating factor did not increase the released or cell-associated IL-1 in mouse macrophages. These agents also failed to alter released or cell-associated IL-1 stimulated by LPS, 1 microgram ml-1. It appears that a calcium signal is sufficient for the transcription and translation of IL-1 mRNA but does not result in the secretion of biologically active forms of IL-1. Our data also indicate that different intracellular signals may control the release and the cell accumulation of IL-1. We conclude that inflammatory mediators may independently increase either the release of, or the cell accumulation of IL-1.
Assuntos
Interleucina-1/metabolismo , Macrófagos Peritoneais/metabolismo , Animais , Calcimicina/farmacologia , Técnicas In Vitro , Ionomicina/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Neuropeptídeos/farmacologia , Dibutirato de 12,13-Forbol/farmacologia , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
The potential involvement of leukotrienes in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum has been studied. Pretreatment with the leukotriene biosynthesis inhibitor, MK886 (30 mg/kg p.o.), inhibited the increases in blood and antral leukotriene B4 release ex vivo associated with the evolution of antral ulceration. Despite this, however, there was no significant reduction in either the area of antral ulceration, or in the associated blood neutrophilia and neutrophil infiltration into the gastric antrum. Similarly, pretreatment with the leukotriene B4 antagonist, SC41930 (50 mg/kg p.o.) or the peptidyl leukotriene antagonist ICI198,615 (50 mg/kg p.o.) did not inhibit the area of antral ulceration induced by indomethacin. Thus, in contrast to published reports studying fundic ulceration, our results suggest that leukotrienes do not play a major role either in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum or neutrophil infiltration into the damaged antrum.
Assuntos
Indóis/farmacologia , Indometacina/toxicidade , Antagonistas de Leucotrienos , Leucotrieno B4/antagonistas & inibidores , Antro Pilórico/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Administração Oral , Animais , Benzopiranos/administração & dosagem , Benzopiranos/farmacologia , Feminino , Indazóis/administração & dosagem , Indazóis/farmacologia , Indóis/administração & dosagem , Indometacina/administração & dosagem , Injeções Subcutâneas , Leucotrieno B4/sangue , Microscopia Eletrônica , Antro Pilórico/lesões , Ratos , SRS-A/antagonistas & inibidoresRESUMO
We have previously suggested (Trevethick et al., Gut 34, 156-160) that indomethacin-induced ulceration of the rat gastric antrum may be a neutrophil-dependent process. Accordingly, in this study we have used an anti-neutrophil serum (ANS) to investigate the effects of neutrophil depletion on this pathology. In animals pretreated with the ANS to induce a nearly total neutropaenia, indomethacin-induced increases in blood neutrophilia and cell infiltration into the gastric antrum (assessed as LTB4 release ex vivo) were eliminated. In marked contrast, however, ANS pretreatment affected neither the area of mucosa damaged nor the microscopic characteristics or distribution of the lesions. These results suggest that, in contrast to the published reports examining indomethacin-induced ulceration of the gastric fundus, neutrophil infiltration is not involved in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum.
Assuntos
Indometacina/toxicidade , Neutrófilos/fisiologia , Antro Pilórico/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Animais , Feminino , Neutrófilos/efeitos dos fármacos , Antro Pilórico/patologia , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/patologia , Úlcera Gástrica/fisiopatologiaRESUMO
Jejunal villi undergo early histological shortening and vascular injury in indomethacin-induced ulcerative enteropathy in the rat. The protective effects of the beta 3-adrenoceptor agonist CL316243 on this rat model and the mechanism of action were examined using histological techniques. Groups of rats received oral indomethacin (15 mg/kg) and oral CL316243 (0, 0.01-10 mg/kg) 0.5 h beforehand. Jejunal ulceration was assessed 48 h after indomethacin. Other groups received CL316243 either 6 h before or 3 or 6 h after indomethacin. Plasma indomethacin and jejunal prostaglandin E2 levels were determined in groups of rats with and without prior CL316243. CL316243 was a potent dose-dependent inhibitor of jejunal ulceration (> 98 percent inhibition at doses > or = 0.1 mg/kg; ED50 = 0.025 mg/kg) but was not protective when given 6 h after indomethacin. CL316243, 1 mg/kg, reversed early villous shortening and vascular injury. CL316243 did not affect either indomethacin bioavailability or the inhibition of prostaglandin E2. To conclude, the beta 3-adrenoceptor agonist CL316243 is a potent inhibitor of indomethacin-induced jejunal ulceration and the mechanism of protection involves reversal of both villous shortening and vascular injury, which are usefully assessed by histomorphological techniques.