RESUMO
AIM: There is little evidence regarding the role of adjuvant radiotherapy for colon cancer. Despite this, national consensus guidelines recommend consideration of radiation for patients with T4 colon cancer. Large comparative studies may be beneficial in clarifying the potential benefit of postoperative radiation for this cohort. METHOD: We compared the overall survival between patients treated with surgery with and without adjuvant radiation using the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results Program (SEER), as well as disease-specific survival using SEER. Cox proportional hazards models and propensity score matching were used to adjust for relevant confounders. RESULTS: There were a total of 18 776 patients in the NCDB cohort and 9926 patients in the SEER cohort. After propensity score matching, there was no statistically significant difference in overall mortality between surgery with and without radiation in the NCDB [hazard ratio (HR) 1.11; 95% CI 0.93-1.31; P = 0.25] or in SEER (HR 1.20; 95% CI 0.84-1.72; P = 0.32). Additionally, using SEER, we found no statistically significant difference in disease-specific mortality between these two groups (HR 1.13; 95% CI 0.76-1.67; P = 0.54). CONCLUSION: Using the NCDB and SEER, we found no statistically significant difference in overall survival or disease-specific survival between patients treated with and without adjuvant radiation. Further studies should evaluate the impact of adjuvant radiotherapy on local control and prevention of recurrence-related morbidity in patients with T4 colon cancer.
Assuntos
Neoplasias do Colo , Recidiva Local de Neoplasia , Neoplasias do Colo/patologia , Neoplasias do Colo/radioterapia , Neoplasias do Colo/cirurgia , Humanos , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Programa de SEER , Resultado do TratamentoRESUMO
The modulatory effect of endogenous diadenosine polyphosphates on synaptic transmission in the rat hippocampal slices has been re-examined with a non-hydrolysable Ap4A analogue diadenosine-5',5'>>-P1,P4-[beta,gamma-methylene]tetraphosphate (AppCH2ppA). We have shown that AppCH2ppA at low micromolar concentrations induce inhibition of orthodromically evoked population spikes, without affecting of excitatory postsynaptic currents and antidromic spikes recorded in the CA1 zone of hippocampus. Such a spatially selective neuronal inhibition may influence dendritic electrogenesis in pyramidal neurons and consequently mediate control of neuronal network activity in hippocampus.
Assuntos
Fosfatos de Dinucleosídeos/fisiologia , Hipocampo/fisiologia , Transmissão Sináptica/fisiologia , Potenciais de Ação/fisiologia , Animais , Fosfatos de Dinucleosídeos/farmacologia , Estimulação Elétrica , Eletrodos , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Técnicas de Patch-Clamp , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacosRESUMO
Analysis of viral replication and pathogenicity after in vivo selection of human immunodeficiency virus type 1 (HIV-1) attenuated in vitro will help to define the functions involved in replication and pathogenesis in vivo. Using the SCID-hu Thy/Liv mouse and human fetal thymus organ culture as in vivo models, we previously defined HIV-1 env determinants (HXB2/LW) which were reverted for replication in vivo (L. Su et al., Virology 227:46-52, 1997). In this study, we examined the replication of four highly related HIV-1 clones directly derived from Lai/IIIB or after selection in vivo to investigate the envelope gp120 determinants associated with replication in macrophages and in the thymus models in vivo. The LW/C clone derived from the IIIB-infected laboratory worker and HXB2/LW both efficiently infected monocyte-derived macrophages (MDM) and the human thymus. Although the laboratory worker (LW) isolates showed altered tropism from IIIB, they still predominantly used CXCR4 as coreceptors for infecting peripheral blood mononuclear cells, macrophages, and the thymus. Interestingly, a single amino acid mutation in the V3 loop associated with resistance to neutralizing antibodies was also essential for the replication activity of the LW virus in the thymus models but not for its activity in infecting MDM. The LW virions were equally sensitive to a CXCR4 antagonist. We further demonstrated that the LW HIV-1 isolate selected in vivo produced more infectious viral particles that contained higher levels of the Env protein gp120. Thus, selection of the laboratory-attenuated Lai/IIIB isolate in vivo leads to altered tropism but not coreceptor usage of the virus. The acquired replication activity in vivo is correlated with an early A-to-T mutation in the V3 loop and increased virion association of HIV-1 Env gp120, but it is genetically separable from the acquired replication activity in macrophages.
Assuntos
Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/metabolismo , Receptores CXCR4/metabolismo , Replicação Viral , Animais , Linhagem Celular Transformada , Proteína gp120 do Envelope de HIV/genética , HIV-1/genética , HIV-1/fisiologia , Humanos , Macrófagos/metabolismo , Macrófagos/virologia , Fusão de Membrana , Camundongos , Camundongos SCID , Mutagênese Sítio-Dirigida , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Linfócitos T/virologia , Timo/virologia , Vírion/metabolismoRESUMO
Bipolar cells are not only important for visual processing but input from these cells may underlie the reorganization of ganglion cell dendrites in the inner plexiform layer (IPL) during development. Because little is known about the development of bipolar cells, here we have used immunocytochemical markers and dye labeling to identify and follow their differentiation in the neonatal ferret retina. Putative cone bipolar cells were immunoreacted for calbindin and recoverin, and rod bipolar cells were immunostained for protein kinase C (PKC). Our results show that calbindin-immunoreactive cone bipolar cells appear at postnatal day 15 (P15), at which time their axonal terminals are already localized to the inner half of the IPL. By contrast, recoverin-immunoreactive cells with terminals in the IPL are present at birth, but many of these cells may be immature photoreceptors. By the second postnatal week, recoverin-positive cells resembling cone bipolar cells were clearly present, and with increasing age, two distinct strata of immunolabeled processes occupied the IPL. PKC-containing rod bipolar cells emerged by the fourth postnatal week and at this age have stratified arbors in the inner IPL. The early bias of bipolar axonal arbors in terminating in the inner or outer half of the IPL is confirmed by dye labeling of cells with somata in the inner nuclear layer. At P10, several days before ribbon synapses have been previously observed in the ferret IPL, the axon terminals of all dye-labeled bipolar cells were clearly stratified. The results suggest that bipolar cells could provide spatially localized interactions that are suitable for guiding dendritic lamination in the inner retina.
Assuntos
Furões/anatomia & histologia , Interneurônios/citologia , Lipoproteínas , Proteínas do Tecido Nervoso , Vias Visuais/citologia , Animais , Animais Recém-Nascidos , Axônios/fisiologia , Calbindinas , Proteínas de Ligação ao Cálcio/metabolismo , Diferenciação Celular , Dendritos/fisiologia , Proteínas do Olho/metabolismo , Hipocalcina , Interneurônios/metabolismo , Microscopia Confocal , Proteína Quinase C/metabolismo , Recoverina , Células Fotorreceptoras Retinianas Cones/citologia , Células Fotorreceptoras Retinianas Bastonetes/citologia , Proteína G de Ligação ao Cálcio S100/metabolismoRESUMO
The 5' region of potato virus X (PVX) RNA contains a stem-loop structure, stem-loop 1 (SL1), that is required for efficient plus-strand RNA accumulation. To determine how changes to individual elements in SL1 are accommodated by the virus, we inoculated PVX transcripts containing modifications in the terminal tetraloop (TL), stem C (SC), and stem D (SD) regions onto Nicotiana benthamiana plants and analyzed progeny RNAs over a series of passages. Several progeny RNAs isolated from plants inoculated with the TL mutants containing changes to the first nucleotide of the GAAA motif or deletion of the entire TL sequence were found to contain multiple A insertions within the terminal loop region. The wild-type TL motif, GAAA, was recovered for all TL mutants by the second passage, suggesting that the sequence and potential structure of this element are crucial for PVX infection. Revertant RNAs isolated from plants inoculated with mutants in SD and the central region of SC indicated that increased stem length is tolerated. Restoration of SD length to the 4 bp typical of the wild-type PVX RNA was accompanied by A insertion into loop C. Mutants with a conversion of the C55-C78 mismatch to a G-C pair, relocation of this mismatch within the central region of SC, or deletion of C55-C78 were unable to infect protoplasts and plants. In contrast, the mutant with a conversion of the C55-C78 mismatch to an A-C mismatch, which exhibited low levels of PVX plus-strand RNA in protoplasts, was able to infect plants and quickly reverted to the wild-type C-C mismatch. These data indicate that important sequence and secondary structural elements within SL1 are required for efficient viral infection and that multiple A insertions within the TL and loop C regions, potentially by polymerase stuttering, accompany restoration of SL1 structure.
Assuntos
Pareamento Incorreto de Bases/genética , Conformação de Ácido Nucleico , Potexvirus/genética , RNA Viral/química , RNA Viral/metabolismo , Adenosina/genética , Pareamento de Bases/genética , Sequência de Bases , Regulação Viral da Expressão Gênica , Genoma Viral , Mutagênese Sítio-Dirigida , Mutação/genética , Fenótipo , Plantas Tóxicas , Potexvirus/crescimento & desenvolvimento , Protoplastos/virologia , RNA Mensageiro/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/biossíntese , RNA Viral/genética , Termodinâmica , Nicotiana/citologia , Nicotiana/virologia , Replicação Viral/genéticaRESUMO
Computer-generated thermodynamic predictions and solution structure probing indicated two stem-loop structures, stem-loop 1 (SL1; nt 32-106) and stem-loop 2 (SL2; nt 143-183), within the 5' 230 nt of potato virus X (PVX) RNA. Because the existence of SL1 was further supported by covariation analysis of several PVX strains, the functional significance of this structure was investigated by site-directed mutational analysis in a tobacco protoplast system. In general, mutations that reduced genomic plus-strand RNA accumulation similarly affected coat protein accumulation, indicating that subgenomic plus-strand RNA was also affected. In contrast, minus-strand RNA levels remained relatively unchanged. Mutational analysis of the stem C (SC) region of SL1 indicated that pairing was more important than sequence, which was consistent with the covariation analysis. Alterations that increased length and stability of either SC or stem D (SD) were deleterious to plus-strand RNA accumulation. The formation of internal loop C between SC and SD, as well as specific nucleotides within this loop, were also required. Several modifications were made to the terminal GAAA tetraloop, a motif known for enhanced RNA stability. Both GANA and GAAG motifs resulted in wild-type levels of RNA accumulation. However, a UUCG tetraloop was detrimental, indicating that the sequence of this element was important beyond just providing stabilization of the structure. These data indicate that multiple features of SL1 are critical for accumulation of PVX plus-strand RNA.
Assuntos
Genoma Viral , Conformação de Ácido Nucleico , Potexvirus/genética , RNA Viral/química , Sequência de Bases , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Plantas Tóxicas , Protoplastos/virologia , RNA Viral/metabolismo , Termodinâmica , Nicotiana/metabolismo , Nicotiana/virologiaRESUMO
A decade of research has proven that plants can be genetically engineered to resist virus infection through expression of viral CP genes, as well as other viral genes and sequences. Additional opportunities for development of resistant plants will require research focused on mechanisms of protection, improvements in expression vector design, and transformation of new crop species. As each of these technologies is utilized singly or in combination to generate resistant crop varieties, the full impact of such engineered resistance will be realized.
Assuntos
Proteínas do Capsídeo , Plantas/virologia , Vírus do Mosaico do Tabaco/fisiologia , Proteínas Virais/fisiologia , Genes Virais , Doenças das Plantas , Plantas/genética , Plantas/imunologia , Plantas Geneticamente Modificadas , Plantas Tóxicas , Nicotiana/genética , Nicotiana/virologia , Vírus do Mosaico do Tabaco/genética , Proteínas Virais/genéticaRESUMO
The presence of angiotensinogen messenger RNA (mRNA) was assessed in total RNA extracted from hepatoma, glioma, neuroblastoma, and glioma-neuroblastoma hybrid cell lines. Total RNA from 1 X 10(7) cells was extracted, transferred to a membrane, and hybridized with a 32P-labeled, full-length (1650-base pair) rat angiotensinogen complementary DNA (cDNA). Angiotensinogen RNA sequences could be definitively detected only in hepatoma cells. Steroids were used in an attempt to increase the angiotensinogen mRNA level. Dexamethasone (2 X 10(-6) M) or 17 beta-estradiol (1 X 10(-7) M) was added to the cultures 18 to 24 hours prior to harvest. Dexamethasone treatment of the hepatoma cells resulted in a large increase in angiotensinogen mRNA, whereas estradiol had no effect. Steroids failed to induce detectable levels of angiotensinogen mRNA in total RNA from the other cell lines. That the RNA was intact was ensured by hybridizing duplicate Northern blots to a 32P-labeled actin cDNA. Actin mRNA sequences were detected in all cell lines. Blot hybridization of poly(A)+RNA resulted in the visualization of a weak angiotensinogen mRNA signal for a glioma cell line and a glioma-neuroblastoma hybrid line. However, the ability to detect angiotensinogen mRNA in a cell may depend on the phenotype expressed, which can be governed by culture conditions.
Assuntos
Angiotensinogênio/genética , RNA Mensageiro/metabolismo , Animais , Linhagem Celular , Meios de Cultura , Densitometria , Dexametasona/farmacologia , Estradiol/farmacologiaRESUMO
Dichloroacetate (DCA) is known to prevent the phosphorylation of the pyruvate dehydrogenase complex (PDHC) by blocking the action of PDH kinase. This action allows the active PDHC to exert its effect on the metabolism of glucose, lactate and alanine to acetyl CoA. DCA has been shown to reduce serum lactate levels in humans and animals in such conditions as diabetes, phenformin-induced hepatic failure, exercise, and endotoxin-induced shock. Lactic acidosis in the brain has often been postulated as a cause of neuronal damage following ischemia and hypoxia. Therefore, we examined the effect of intravenously administered DCA (100 mg/kg) in rats that were rendered hyperglycemic by intravenous glucose (2 g/kg), and then made to undergo 15 minutes of incomplete cerebral ischemia by bilateral carotid ligation and systemic hypotension (mean arterial pressure of 50 mm Hg). DCA significantly reduced serum lactate levels pre-ischemia, but had no effect on serum lactate levels after ischemia induction. Brain levels of lactate, ATP and PCr after 15 minutes of incomplete ischemia were unaffected by DCA. We conclude that in this in-vivo model the control of PDHC activity in the brain may be different than that in the periphery, and that DCA was not effective in reducing brain tissue lactate levels.
Assuntos
Acetatos/farmacologia , Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Ácido Dicloroacético/farmacologia , Hiperglicemia/metabolismo , Lactatos/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Glicemia/metabolismo , Feminino , Hipotensão/metabolismo , Lactatos/sangue , Masculino , Fosfocreatina/metabolismo , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
The authors studied 12 patients who required deliberate hypotension for spinal fusion operations in order to investigate the efficacy of captopril for reducing dose requirement for sodium nitroprusside (SNP). Six patients, selected at random, were pretreated with captopril, 3 mg/kg po, and the remaining six patients served as controls. All patients received a similar anesthetic technique, consisting of thiopental 3 mg/kg, pancuronium 0.1 mg/kg, morphine 0.5 mg/kg, plus nitrous oxide 70% in oxygen. SNP was used to maintain mean arterial pressure (MAP) at 50-55 mmHg during deliberate hypotension lasting 140 +/- 13 minutes (mean +/- SE). Patients who received captopril required less SNP than untreated patients both early during hypotension (1.4 +/- 0.5 micrograms X kg-1 X min-1 vs. 4.8 +/- 0.8 micrograms X kg-1 X min-1, P less than 0.05), as well as late during hypotension (2.2 +/- 0.2 micrograms X kg-1 X min-1 vs. 5.6 +/- 0.6 micrograms X kg-1 X min-1, P less than 0.05). Whole blood cyanide was significantly lower in the patients pretreated with captopril than the untreated controls both early in the hypotensive period (2.7 +/- 0.6 mumol/l vs. 13 +/- 4 mumol/l, P less than 0.05) and also late in the hypotensive period (3.7 +/- 0.8 mumol/l vs. 30 +/- 10 mumol/l, P less than 0.05). MAP was reduced by captopril pretreatment both following induction of anesthesia (64 +/- 4 mmHg captopril vs. 80 +/- 4 mmHg control, P less than 0.05) and during surgery before deliberate hypotension (86 +/- 5 mmHg captopril vs. 100 +/- 4 control, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anestesia Endotraqueal , Captopril/farmacologia , Ferricianetos/farmacologia , Hipotensão Controlada/métodos , Nitroprussiato/farmacologia , Medicação Pré-Anestésica , Prolina/análogos & derivados , Adolescente , Adulto , Criança , Cianetos/sangue , Relação Dose-Resposta a Droga , Interações Medicamentosas , Epinefrina/sangue , Hemodinâmica/efeitos dos fármacos , Humanos , Norepinefrina/sangue , Peptidil Dipeptidase A/sangue , Renina/sangue , Escoliose/fisiopatologia , Escoliose/cirurgia , Fusão VertebralRESUMO
From human plasma of healthy subject, an inhibitor of Na+, K+-ATPase was prepared, using a gel filtration followed by anion exchange chromatography and by HPLC on reverse phase. This low molecular weight (less than 1,500 dalton) inhibitor is a substance which possesses anionic charges, and is absorbed on reverse phase. It inhibits Na+, K+-ATPase activity and the 3H-ouabain binding on human red blood cells.
Assuntos
Inibidores Enzimáticos/isolamento & purificação , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Animais , Cães , Inibidores Enzimáticos/farmacologia , Membrana Eritrocítica/metabolismo , Humanos , Rim/enzimologia , Ouabaína/metabolismo , Ligação Proteica , Receptores de Droga/metabolismoRESUMO
The control of arterial pressure in normal and pathological states is governed by many mechanisms. The renin-angiotensin-aldosterone system is one mechanism which may be activated. The formation of the potent vasoconstrictor angiotensin II and the synthesis of aldosterone provide a means of arterial pressure regulation. With the recent introduction of specific agents which block the renin-angiotensin system, new appreciation of the role of this system is being formed. It is premature to predict whether we, as anaesthetists, will use such agents in our anaesthetic practice. However, we will see some patients who present for surgery taking such medication. How this will influence the patient's response to surgery is unknown. Inhibition of the renin-angiotensin system may allow better perfusion of vital organs. It may, however, be detrimental to the patient who needs this defense mechanism for support of his arterial pressure. At the present time these are all unsettled questions. Through the use of specific inhibitors of the renin-angiotensin system its importance will be defined, much as alpha- and beta-adrenoceptor antagonists have clarified our understanding of the sympathetic nervous system.
Assuntos
Aldosterona/fisiologia , Angiotensina II/fisiologia , Pressão Sanguínea , Hipertensão/fisiopatologia , Renina/fisiologia , Angiotensina II/antagonistas & inibidores , Humanos , Hipertensão/sangue , Renina/sangue , Renina/metabolismoRESUMO
Severe postoperative pain, which may persist for up to 3 days and may lead to postoperative complications, due to the patient's inability to breathe deeply and cough, is frequently experienced in the area of the incision and chest tubes by thoracotomy patients. Eighteen patients undergoing routine thoracotomies were tested preoperatively for arterial blood gases and pulmonary function and given chest x-rays. Anesthesia consisted of thiopental, succinylcholine, N2O, enflurane, and pancuronium. Before incision closure, 6 intercostal spaces were injected by the surgeon with 3 ml of a randomly determined drug mixture. Patients received either bupivacaine and saline solution, bupivacaine and LMW dextran 40, or saline and LMW dextran 40. Arterial blood gases, pulmonary function, chest x-rays, narcotic dosage, sensory level, and subjective responses were evaluated for 3 days postoperatively. Results demonstrate that intercostal nerve blocks can markedly reduce postoperative pain and improve pulmonary function in such patients. Significant differences from controls were seen in Pao2, Paco2, vital capacity, forced expiratory flow rates, analgesic requirements, and patient comfort. The duration of the block with bupivacaine and saline was less than 12 hours, while the mean duration of the block with bupivacaine and dextran 40 was 36 hours.
Assuntos
Bupivacaína/administração & dosagem , Bloqueio Nervoso , Dor Pós-Operatória/prevenção & controle , Cirurgia Torácica , Tórax/cirurgia , Idoso , Anestesia Geral , Dextranos/administração & dosagem , Sinergismo Farmacológico , Enflurano/administração & dosagem , Humanos , Hipotensão/etiologia , Nervos Intercostais , Pessoa de Meia-Idade , Morfina/administração & dosagem , Bloqueio Nervoso/efeitos adversos , Óxido Nitroso/administração & dosagem , Atelectasia Pulmonar/etiologia , RespiraçãoRESUMO
Ten consecutive adult patients undergoing elective cardiac surgery with extracorporeal circulation were anesthetized using morphine (1-3 mg/kg) and nitrous oxide. Pre-bypass plasma renin activity showed a 3.5-fold elevation (P smaller than 0.001) over baseline values. This correlated with maximal blood pressure elevation. Plasma renin activity remained elevated during bypass. High baseline aldosterone levels increased 3.4-fold (P smaller than 0.001) after 15 minutes on bypass and 4.0-fold by the end of bypass. Plasma potassium decreased from 3.9 mEq/1 before bypass to 3.2 mEq/1 (P smaller 0.0001) during bypass, and the fractional urinary excretion of potassium was 32 per cent before bypass with a mean of 34.4 per cent during bypass. Urinary output remained high during bypass despite a progressive decrease in glomerular filtration rate. Catecholamine levels showed no significant change. The data suggest that the renin-angiotensin-aldosterone system may play a role in blood pressure regulation during cardiopulmonary bypass and may result in the excessive urinary excretion of potassium and decrease in plasma potassium levels.
Assuntos
Anestesia por Inalação , Angiotensina II/sangue , Procedimentos Cirúrgicos Cardíacos , Morfina , Óxido Nitroso , Renina/sangue , Pressão Sanguínea , Ponte Cardiopulmonar , Catecolaminas/sangue , Taxa de Filtração Glomerular , Humanos , Injeções Intramusculares , Intubação Intratraqueal , Morfina/administração & dosagem , Morfina/farmacologia , Óxido Nitroso/farmacologia , Concentração Osmolar , Potássio/sangue , Potássio/urina , Escopolamina/administração & dosagem , Sódio/sangue , UrinaRESUMO
Constriction of the renal artery and controlled reduction of renal perfusion pressure is followed by a prompt increase in systemic renin activity and a concomitant rise in blood pressure in trained, unanesthetized dogs. The elevated blood pressure induced by the renal artery stenosis can be prevented by prior treatment with the nonapeptide Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro, which blocks conversion of angiotensin I to angiotensin II. Further, the nonapeptide can restore systemic pressure to normnal in the early phase of renovascular hypertension. These results offer strong evidence that the renin-angiotensin system is responsible for the initiation of hypertension in the unilaterally nephrectomized dog with renal artery constriction.