RESUMO
Objective: To identify whether splenectomy for treatment of hypersplenism has any impact on development of hepatocellular carcinoma(HCC) among patients with liver cirrhosis and hepatitis. Methods: Patients who underwent splenectomy for hypersplenism secondary to liver cirrhosis and portal hypertension between January 2008 and December 2012 were included from seven hospitals in China, whereas patients receiving medication treatments for liver cirrhosis and portal hypertension (non-splenectomy) at the same time period among the seven hospitals were included as control groups. In the splenectomy group, all the patients received open or laparoscopic splenectomy with or without pericardial devascularization. In contrast, patients in the control group were treated conservatively for liver cirrhosis and portal hypertension with medicines (non-splenectomy) with no invasive treatments, such as transjugular intrahepatic portosystemic shunt, splenectomy or liver transplantation before HCC development. All the patients were routinely screened for HCC development with abdominal ultrasound, liver function and alpha-fetoprotein every 3 to 6 months. To minimize the selection bias, propensity score matching (PSM) was used to match the baseline data of patients among splenectomy versus non-splenectomy groups. The Kaplan-Meier method was used to calculate the overall survival and cumulative incidence of HCC development, and the Log-rank test was used to compare the survival or disease rates between the two groups. Univariate and Cox proportional hazard regression models were used to analyze the potential risk factors associated with development of HCC. Results: A total of 871 patients with liver cirrhosis and hypertension were included synchronously from 7 tertiary hospitals. Among them, 407 patients had a history of splenectomy for hypersplenism (splenectomy group), whereas 464 patients who received medical treatment but not splenectomy (non-splenectomy group). After PSM,233 pairs of patients were matched in adjusted cohorts. The cumulative incidence of HCC diagnosis at 1,3,5 and 7 years were 1%,6%,7% and 15% in the splenectomy group, which was significantly lower than 1%,6%,15% and 23% in the non-splenectomy group (HR=0.53,95%CI:0.31 to 0.91,P=0.028). On multivariable analysis, splenectomy was independently associated with decreased risk of HCC development (HR=0.55,95%CI:0.32 to 0.95,P=0.031). The cumulative survival rates of all the patients at 1,3,5,and 7 years were 100%,97%,91%,86% in the splenectomy group,which was similar with that of 100%,97%,92%,84% in the non-splenectomy group (P=0.899). In total,49 patients (12.0%) among splenectomy group and 75 patients (16.2%) in non-splenectomy group developed HCC during the study period, respectively. Compared to patients in non-splenectomy group, patients who developed HCC after splenectomy were unlikely to receive curative resection for HCC (12.2% vs. 33.3%,χ²=7.029, P=0.008). Conclusion: Splenectomy for treatment of hypersplenism may decrease the risk of HCC development among patients with liver cirrhosis and portal hypertension.
Assuntos
Carcinoma Hepatocelular , Hipertensão Portal , Neoplasias Hepáticas , Estudos de Coortes , Humanos , Hipertensão Portal/complicações , Cirrose Hepática/complicações , Neoplasias Hepáticas/cirurgia , EsplenectomiaRESUMO
BACKGROUND: A key moderator of wound healing is oxygen. Wound healing is a dynamic and carefully orchestrated process involving blood cells, cytokines, parenchymal cells (i.e. fibroblasts and mesenchymal stem cells) and extracellular matrix reorganization. Human adipose derived stem cells as well as human fibroblasts produce soluble factors, exhibit diverse effects on inflammation and anti inflammation response and are involved in wound healing processes.Hyperbaric oxygen therapy is an effective adjunct treatment for ischemic disorders such as chronic infection or chronic wounds. In vitro effects of hyperbaric oxygen therapy on human cells were presented in many studies except for those on mono- and co-cultures of human adipose derived stem cells and fibroblasts. OBJECTIVE: The aim of this study was to investigate the effects of hyperbaric oxygen therapy on mono- and co-cultures of human adipose derived stem cells and fibroblasts. METHODS: Mono- and co-cultures from human adipose derived stem cells and fibroblasts were established. These cultures were exposed to hyperbaric oxygen therapy every 24âh for five consecutive days. Measuring experiments were performed on the first, third and fifth day. Therapy effects on the expression of VEGF, IL 6 and reactive oxygen species were investigated. RESULTS: After exposure to hyperbaric oxygen, cell culturess showed a significant increase in the expression of VEGF after 3 and 5 days. All cultures showed significantly reduced formation of reactive oxygen species throughout the experiments. The expression of IL-6 decreased during the experiment in mono-cultures of human adipose derived stem cells and co-cultures. In contrast, mono-cultures of human skin fibroblasts showed an overall significantly increased expression of IL-6. CONCLUSIONS: Hyperbaric oxygen therapy leads to immunmodulatory and proangiogenetic effects in a wound-like enviroment of adipose derived stem cells and fibroblasts.
Assuntos
Tecido Adiposo/metabolismo , Técnicas de Cocultura/métodos , Fibroblastos/metabolismo , Oxigenoterapia Hiperbárica/métodos , Células-Tronco/metabolismo , Cicatrização/fisiologia , Humanos , Estresse Oxidativo , Espécies Reativas de OxigênioRESUMO
BACKGROUND: Besides public awareness and specialist knowledge and training of physicians, their self-confidence plays a key role for clinical decision-making in the respective area. OBJECTIVE: This exploratory study investigated the influence of the discipline on differences in self-confidence in dealing with antibiotics and in the self-rated knowledge. METHODS: In 2015 the multi-institutional reconnaissance of practice with multiresistant bacteria (MR2) questionnaire containing items on antibiotic prescription and multiresistant pathogens was sent out to 1061 physicians working in departments for internal medicine, general surgery, gynecology and obstetrics and urology. In 2017 a similar MR2 survey was sent to 1268 specialist and assistant physicians in anesthesiology in Germany. Besides demographic data 4 items on self-confidence in the use of antibiotic treatment and 11 items concerning self-rated knowledge about rational antibiotic therapy and multiresistant pathogens were included in the present analysis. Logistic regression analysis, the χ2-test and the Kruskal-Wallis test were used for statistical analysis of the influence of the discipline on these items. RESULTS: The response rates were 43% (456 out of 1061) from the non-anesthetists and 56% (705 out of 1268) from the anesthetists. Of the non-anesthetists 44% and 57% of the anesthetists had had no advanced training on antibiotic stewardship during the year before the study. In the overall analysis anesthetists (mean±SD: 2.53±0.54) were significantly less self-confident about antibiotics than colleagues from other departments (internal medicine: 3.10±0.50, general surgery: 2.97±0.44, gynecology and obstetrics: 3.12±0.42 and urology: 3.15±0.44) in the unadjusted (all p<0.001) and adjusted comparison. The analysis of self-rated knowledge about rational antibiotic prescription showed similar results. Senior consultant status and advanced training in infectiology were significantly associated with self-confidence and self-rated knowledge about antibiotics. CONCLUSION: Anesthetists showed significantly less self-confidence in dealing with antibiotics than colleagues from other disciplines. Advanced training on a rational prescription of antibiotics was associated with a greater self-confidence, so that the implementation of compulsory courses on rational antibiotic stewardship in the respective residency curriculum needs to be considered.
Assuntos
Antibacterianos/uso terapêutico , Médicos/estatística & dados numéricos , Especialização/estatística & dados numéricos , Anestesiologistas/estatística & dados numéricos , Atitude do Pessoal de Saúde , Alemanha , Hospitais , Humanos , Prescrições , Autoimagem , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Perioperatively, patients' hemodynamics are modulated predominantly by intravenous fluid administration and vasoactive pharmacological support. Vasopressor agents are suspected to be detrimental on free flap survival by the cause of vasoconstriction of the pedicle with consecutive reduced overall flap perfusion and by aggravation of flap dissection. OBJECTIVE: A novel, standardized fluid restrictive perioperative hemodynamic management was assessed for its feasibility in clinical practice in free flap patients undergoing breast reconstruction. METHODS: Patients were randomized to two perioperative regimens with different fluid and vasopressor limits. The primary endpoint regarded flap survival. Secondary endpoints included surgery times, time of patient ambulation and length of hospital stay. RESULTS: There was one total flap failure with liberal fluid administration (LFA). No total or partial flap failure was noted in the fluid restrictive regimen with norepinephrine administration up to 0.04µg/kg/min (FRV). No delay regarding operation time (pâ=â0.217), patient mobilization (pâ=â0.550) or hospital discharge (pâ=â0.662) was registered in the FRV study subpopulation compared to LFA. CONCLUSIONS: The results of this prospective interventional trial could not detect any negative impact of vasopressors, neither for the primary endpoint of flap survival nor for the overall patient outcome. The fear of vasopressor associated flap complications has led to a traditional liberal fluid administration, which failed to demonstrate any benefits when compared to a fluid restrictive vasopressor strategy.
Assuntos
Artérias Epigástricas/fisiopatologia , Retalhos de Tecido Biológico/cirurgia , Hipodermóclise/métodos , Mamoplastia/métodos , Retalho Perfurante/cirurgia , Vasoconstritores/uso terapêutico , Feminino , Retalhos de Tecido Biológico/irrigação sanguínea , Humanos , Masculino , Pessoa de Meia-Idade , Retalho Perfurante/irrigação sanguínea , Estudos Prospectivos , Vasoconstritores/farmacologiaRESUMO
BACKGROUND: Fat present during blood salvage in orthopaedic or cardiac surgery can pose a risk of fat embolism and should be eliminated before transfusion. Based on observations of central fat accumulation at the bottom of Latham bowls, a fat reduction program was developed using two volume displacements, where blood temporarily is removed and respun in the bowl to force the fat through the RBC sediment. MATERIALS AND METHODS: Pooled ABO-matched RBC and FFP were adjusted to a haematocrit of 10%, and human fat tissue added to a concentration of 1·25 vol%. In six experiments, blood was processed with the new-generation cell salvage device CS Elite in a newly developed fat reduction program in bowls of three sizes. Volumetric quantification of fat was performed after centrifugation of blood samples in Pasteur pipettes. From volumes, haematocrits and the concentrations of fat, RBC recovery and fat elimination rates were calculated. RESULTS: Fat removal rates of 93·2 ± 2·8, 97·0 ± 2·1 and 99·6 ± 0·3% were observed with a 70-ml, 125-ml and 225-ml bowl, respectively, and even higher rates when removal rates were calculated one cycle. At the same time, high RBC recovery and plasma elimination rates were maintained, not significantly different to the default program mode. CONCLUSION: Modifications in process parameters and sequence led to a fat reduction program that significantly improves fat removal with the Cell Saver Elite from 77·4 ± 5·1% in the default mode to an average of 98·6 ± 1·1%, yielding results equivalent to the continuous cell salvage system (C.A.T.S).
Assuntos
Segurança do Sangue , Lipídeos/isolamento & purificação , Transfusão de Sangue Autóloga , Transfusão de Eritrócitos , Hematócrito , Humanos , Lipídeos/sangueRESUMO
BACKGROUND AND OBJECTIVES: Cell salvage plays a key role in blood conservation. To maintain high performance, quality management is recommended. Accordingly, a new-generation autotransfusion device was tested for its performance and compared with its predecessor. Two different calculations of quality parameters were applied. MATERIALS AND METHODS: In an experimental study, the continuous autotransfusion devices CATSmart and Continuous Autotransfusion System (C.A.T.S) plus were tested using banked blood adjusted to a haematocrit of 20% and anticoagulated with heparin 5 U/L. Test blood was processed using an emergency programme, a high-quality programme/smart wash programme and a low-volume wash programme. Samples were taken after the production of 200 mL of red blood cells (RBC) and after the final emptying of the separation chamber. In an additional set of tests, blood containing 1·25% fat was processed with both devices to examine fat removal. RESULTS: Both devices demonstrated an equally high performance with regards to product hematocrit (Hct); RBC recovery; and elimination rates of protein, heparin and fat. The high fat elimination rate (>99·8%) reported for C.A.T.S plus was confirmed for CATSmart, regardless of the used programme. Samples taken during the ongoing process show a higher haematocrit and RBC recovery rate than samples taken after the final emptying of the separation chamber. Interface sensors were not affected by fat in the blood. CONCLUSIONS: The new-generation autotransfusion device CATSmart is not inferior to its predecessor and shows high performance with regards to RBC recovery, plasma and fat elimination in all programme modes. Samples for quality controls should be taken during blood processing.
Assuntos
Transfusão de Sangue Autóloga/instrumentação , Eritrócitos , Lipídeos , Controle de Qualidade , Transfusão de Sangue Autóloga/métodos , Hematócrito , HumanosRESUMO
Recent data suggest that intraneuronal accumulation of metabolites of the amyloid-ß-precursor protein (APP) is neurotoxic. We observed that transgenic mice overexpressing in neurons a human APP gene harboring the APPE693Q (Dutch) mutation have intraneuronal lysosomal accumulation of APP carboxylterminal fragments (APP-CTFs) and oligomeric amyloid ß (oAß) but no histological evidence of amyloid deposition. Morphometric quantification using the lysosomal marker protein 2 (LAMP-2) immunolabeling showed higher neuronal lysosomal counts in brain of 12-months-old APPE693Q as compared with age-matched non-transgenic littermates, and western blots showed increased lysosomal proteins including LAMP-2, cathepsin D and LC3. At 24 months of age, these mice also exhibited an accumulation of α-synuclein in the brain, along with increased conversion of LC3-I to LC3-II, an autophagosomal/autolysosomal marker. In addition to lysosomal changes at 12 months of age, these mice developed cholinergic neuronal loss in the basal forebrain, GABAergic neuronal loss in the cortex, hippocampus and basal forebrain and gliosis and microgliosis in the hippocampus. These findings suggest a role for the intraneuronal accumulation of oAß and APP-CTFs and resultant lysosomal pathology at early stages of Alzheimer's disease-related pathology.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Proteínas/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/genética , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Fragmentos de Peptídeos/metabolismo , alfa-Sinucleína/metabolismoRESUMO
The inhibition of angiotensin-converting enzyme (ACE) or the blockade of angiotensin (Ang) AT-1 receptors affords protection against acute gastric mucosal injury, but whether the major metabolite of renin-angiotensin system (RAS), Ang-(1-7), accelerates the healing process of preexisting gastric ulcers remains unknown. Previous studies documented that Ang-(1-7) acting via its own Mas receptor exerts vascular responses opposing those of Ang II. We studied the effects of the Ang-(1-7)/Mas receptor axis on the healing rate of acetic-acid-induced gastric ulcers with or without the blockade of Mas receptors by A 779 and compared it with the effects of activation and blockade of the AT-1 receptor by the treatment with Ang II and losartan, respectively, the inhibition of ACE by lisinopril, the NO/cNOS inhibition by L-NAME and inhibition of prostaglandin/COX system by indomethacin in the presence of Ang-(1-7). Additionally, ex vivo metabolism of Ang I in gastric tissue was assessed by LC/MS method. At day 9 after ulcer induction, the area of these ulcers and the accompanying changes in total gastric blood flow (GBF) were determined as were gastric mucosal blood flow (GMBF) at ulcer margin and gastric oxygen uptake (GVO2). The gastric mucosal expression of mRNAs for constitutive nitric oxide synthase (cNOS), superoxide dismutase (SOD), and pro-inflammatory cytokines interleukin 1ß (IL-1ß) and tumor necrosis factor alpha (TNF-α) and plasma level of both cytokines were determined by RT-PCR and ELISA. The 9 days treatment with Ang II dose-dependently increased the area of gastric ulcers and this effect was accompanied by a significant fall in the GBF, GVO2 and GMBF at ulcer margin. In contrast, treatment with Ang-(1-7) which produced a significant rise in the luminal content of NO significantly reduced the area of gastric ulcer and significantly increased the GBF, GVO2 and the GMBF at ulcer margin. Similar GMBF changes and significant reduction the area of gastric ulcer was observed in rats with gastric ulcers treated with the agonist of Mas receptor, AVE 0991. These effects of Ang-(1-7) and AVE 0991 were eliminated by blockade of the Mas receptor with A779. Similarly to Ang-(1-7), treatment with losartan or lisinopril significantly reduced the area of gastric ulcers and the accompanying increase in the GMBF at ulcer margin and these effects were significantly attenuated by a concomitant administration of L-NAME and indomethacin. The rate of healing of ulcers was associated with a decrease in ex vivo Ang-(1-7) formation and this effect was attenuated by lisinopril. The treatment with Ang-(1- 7) or AVE 0991 increased the expression of mRNA for cNOS and SOD and downregulated that of IL-1ß and TNF-α followed by the decrease in the plasma IL-1ß and TNF-α levels. We conclude that the Ang-(1-7)/Mas receptor system accelerates the healing of preexisting gastric ulcers via an increase in the gastric macro- and microcirculations, and an increase in gastric tissue oxygenation. These effects are mediated by PG and NO derived from overexpression of cNOS, an increase in the expression of antioxidizing enzyme SOD 2 and an anti-inflammatory action involving the inhibition of expression and release of pro-inflammatory cytokines IL-1ß and TNF-α. Our results seem to underlie the importance of the Ang-(1-7), AT-1 and Mas receptors in the regulation of local vascular and metabolic effects associated with mechanism of gastric ulcer healing.
Assuntos
Angiotensina I/metabolismo , Citocinas/metabolismo , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/metabolismo , Prostaglandinas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Úlcera Gástrica/metabolismo , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Inibidores Enzimáticos/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Imidazóis/farmacologia , Indometacina/farmacologia , Interleucina-1beta/metabolismo , Lisinopril/farmacologia , Losartan/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/metabolismo , Proto-Oncogene Mas , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: Radical cystectomy (RC) can be associated with significant blood loss, whereas many patients are presenting with anemia preoperatively. To date, there is a lack of data addressing the impact of preoperative anemia (PA) on survival of patients undergoing RC for urothelial carcinoma of the bladder (UCB). METHODS: This retrospective multicenter study includes 684 patients with UCB undergoing RC with pelvic lymph node dissection. The median follow-up was 50 (IQR 29,78) months. Anemia was defined in line with the WHO classification (hemoglobin (Hb): male ≤13 g/dL, female ≤12 g/dL) and based on contemporary gender- and age-adjusted classification (Hb: white male aged <60 years: ≤13.7 g/dL; ≥60 years: ≤13.2 g/dL; white female of all ages ≤12.2 g/dL). Univariable and multivariable Cox regression analyses were used to assess the effects of PA on oncological outcomes. RESULTS: A total of 269 (39.3 %) and 302 (44.2 %) patients were anemic according to the WHO classification versus contemporary classification. Age, increased ECOG performance status, advanced tumor stages, lymph node metastasis, positive surgical margin and anemia were associated with disease recurrence (DR), cancer-specific mortality (CSM) and all-cause mortality (ACM). In multivariable analysis, anemia was an independent predictor of DR, CSM and ACM (WHO and/or contemporary classification). Blood transfusion was significantly associated with ACM in both classifications of anemia. CONCLUSIONS: PA is significantly associated with worse oncological outcome in patients undergoing RC. Based on the additional unfavorable influence of blood transfusion, this emphasizes the importance of early diagnosis and correction of anemia and implementation of alternative methods of blood volume management.
Assuntos
Anemia/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Transfusão de Sangue/métodos , Cistectomia/métodos , Feminino , Humanos , Excisão de Linfonodo/métodos , Metástase Linfática/patologia , Masculino , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Radical cystectomy (RC) can be associated with significant blood loss. Allogenic blood transfusion (ABT) may alter disease outcome because of a theoretical immunomodulatory effect. We evaluated the effects of ABT on overall survival (OS) and progression-free survival (PFS) of patients undergoing RC for urothelial carcinoma of the bladder (UCB). MATERIALS AND METHODS: This is a retrospective single-center study of 350 consecutive patients of a university health center with a median follow-up of 70.1 month. All patients underwent RC and pelvic lymph node dissection. The effect of ABT on OS and PFS was analyzed using univariable and multivariable Cox proportional hazards models. RESULTS: The overall ABT rate was 63 % (n = 219), with intraoperative blood transfusion and postoperative blood transfusion being performed in 183 patients (52 %) and 99 patients (28 %), respectively. Preoperative anemia was detected in 156 patients (45 %) with median estimated blood loss of 800 ml (IQR: 500-1,200). ABT was associated with significant decrease of OS and PFS in multivariable analyses (p < 0.001), whereas patients' prognosis worsened the more packed red blood cells (PRBC) were transfused (p < 0.001). The study is limited in part due to its retrospective design. CONCLUSIONS: We found that ABT and the number of PRBC transfused are associated with poor prognosis for UCB patients undergoing RC, whereas preoperative anemia had no influence on survival. This emphasizes the importance of surgeon's awareness for a strict indication for ABT. A prospective study will be necessary to evaluate the independent risks associated with ABT during surgical treatments.
Assuntos
Transfusão de Sangue , Carcinoma/mortalidade , Carcinoma/cirurgia , Cistectomia/efeitos adversos , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Anemia/complicações , Anemia/mortalidade , Anemia/cirurgia , Carcinoma/complicações , Cistectomia/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Cuidados Intraoperatórios , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/complicações , UrotélioRESUMO
Gastroesophageal reflux disease (GERD) is a global disease rapidly increasing among world population. The pathogenesis of reflux esophagitis which is considered as the early stage of GERD is complex, resulting from an imbalance between aggressive factors damaging the esophagus and a number of the natural defense mechanisms. The esophageal mucosa is in a state of continuous exposure to potentially damaging endogenous and exogenous factors. Important aggressive components of gastric refluxate include acid and pepsin and also pancreatic enzymes and bile. Among aggressive factors of exogenous origin, cigarette smoking, non-steroidal anti-inflammatory drugs (NSAID), and steroids are of the utmost importance. The basic level of esophageal defense against acid-pepsin damage consists of the anti-reflux mechanisms such as the luminal acid clearance and removal of the esophageal contents and neutralization of luminal acidity. In addition the esophageal mucosal protection includes the presence of pre-epithelial, epithelial and post-epithelial cellular and functional components. Recently, the progress have been made in the understanding of role of the heptapeptide member of the renin-angiotensin system (RAS), angiotensin-(1-7) (Ang-(1-7)) in the control of gastrointestinal functions. It has been shown that all components of local RAS including Ang-(1-7) are detectable in the gastrointestinal wall including not only the stomach but also the esophagus. Previous studies revealed that Ang-(1-7), which is an important component of the RAS, exerts vasodilatory, anti-inflammatory and antioxidant activities in the stomach. Ang-(1-7) was recently implicated in gastroprotection, but its effects on esophageal mucosa in a rodent model of reflux esophagitis and in human subjects presenting GERD symptoms have not been explored. The present study was aimed to evaluate the possible protective effects of Ang-(1-7) and Mas-receptors upon esophageal mucosal damage in acute reflux esophagitis (RE) induced in anesthetized rats by ligating the pylorus and the limiting ridge (a transitional region between the forestomach and the corpus of stomach). Consequently, the total gastric reservoir to store gastric juice was greatly diminished, resulting in the reflux of this juice into the esophagus. Because Mas receptors are functionally linked to nitric oxide (NO) formation, we also studied involvement of endogenous NO in the mediation of protective and circulatory effects of exogenous Ang-(1-7). Moreover, an attempt was made to assess the possible role of sensory neurons in the modulation of the protective effects exerted by Ang-(1-7)/Mas receptor system. Six series of rats were pretreated 30 min before induction of RE with 1) vehicle (saline), 2) Ang-(1-7) (5-50 µg/kg i.p.), 3) A779 (50 µg/kg i.p.), the selective Mas receptor antagonist applied alone, 4) Ang-(1-7) (50 µg/kg i.p.) combined with A779, 5) L-NNA (20 mg/kg i.p.) administered alone, and 6) Ang-(1-7) (50 µg/kg i.p.) combined with L-NNA. In separate group of rats, capsaicin (total dosage of 125 mg/kg within three days) was administered s.c. 2 weeks before the induction of RE to induce functional ablation of sensory nerves. Rats with intact sensory nerves and those with capsaicin-induced sensory denervation received vehicle (saline) or Ang-(1-7) (50 µg/kg i.p.) to determine whether this vasoactive metabolite of angiotensin I could be also effective in rats with capsaicin-induced impairment of the synthesis and release of sensory neuropeptides such as CGRP. Four hours after induction of RE, the mucosal damage was graded with mucosal lesion index (LI) from 0 to 6, the esophageal microcirculatory blood flow (EBF) was determined by H2-gas clearance technique and plasma level of pro-inflammatory cytokines interleukin-1b (IL-1ß), and tumor necrosis factor-α (TNF-α) was determined by ELISA. The expression of proinflammatory factors including COX-2, cytokine IL-1ß and hypoxia inducible factor 1alpha (Hif1α) was analyzed in the esophageal mucosal biopsies. In rats with RE, the esophageal LI was significantly elevated comparing its value observed in intact rats, and the EBF was significantly decreased as compared with intact mucosa. Pretreatment with Ang-(1-7) of control rats without esophagitis induced increase in EBF by about 25% without any macroscopic changes in the esophageal mucosa or in the plasma level of cytokines. In animals with RE, pretreatment with Ang-(1-7) significantly reduced gross and histological esophageal mucosal injury and significantly increased EBF in comparison to vehicle-pretreated animals. The observed gross and histologic esophagoprotective effect of Ang-(1-7) was totally abolished by A779 so in rats with combined treatment of A779 with Ang-(1-7), the LI was identical with this observed in control RE and the EBF was decreased in these animals by about 39%. Inhibition of NO synthase by L-NNA significantly reduced the LI and the rise in EBF caused by Ang-(1-7). Similarly, the capsaicin denervation also significantly attenuated the vasodilatory and the esophagoprotective effects of Ang-(1-7). The expression of proinflammatory factors COX-2, Hif1α and IL-1ß which was negligible in intact esophageal mucosa, was upregulated in esophageal mucosa of rats with RE. In contrast, the administration of Ang-(1-7) resulted in a downregulation of mRNA for COX-2, Hif1 and IL-1ß in esophageal mucosa an this effect was abolished in A779-dependent manner. The Ang-(1-7) significantly decreased the RE-induced elevation of plasma levels of IL-1ß and TNF-α, and this effect was also reversed by pretreatment with A779, and significantly attenuated by pretreatment with L-NNA and capsaicin-induced sensory denervation. The present study indicates that the protective effect of Ang-(1-7) observed in the esophageal mucosa during early acute stage of gastroesophageal reflux depends upon the enhancement of esophageal microcirculatory blood flow via the activation of Mas receptor possibly due to NO synthase/NO system activation, stimulation of sensory nerves, the inhibition of expression of pro-inflammatory factors including COX-2, Hif1α and IL-1ß and release of proinflammatory cytokines IL-1ß and TNF-α.
Assuntos
Angiotensina I/uso terapêutico , Esofagite Péptica/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Angiotensina I/farmacologia , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Animais , Ciclo-Oxigenase 2/genética , Modelos Animais de Doenças , Esofagite Péptica/metabolismo , Esofagite Péptica/patologia , Esofagite Péptica/fisiopatologia , Esôfago/irrigação sanguínea , Esôfago/metabolismo , Esôfago/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Interleucina-1beta/sangue , Interleucina-1beta/genética , Masculino , Mucosa/efeitos dos fármacos , Mucosa/metabolismo , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/farmacologia , Substâncias Protetoras/farmacologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/antagonistas & inibidores , RNA Mensageiro/metabolismo , Ratos Wistar , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Fluxo Sanguíneo Regional/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
PURPOSE: To evaluate the extent to which MRE can be used as an observer-independent, objective imaging method for the diagnosis and evaluation of CD with respect to the detection of inflammatory changes of the small bowel and lymphadenopathy as diagnostic criterion and bowel distension as a quality criterion. MATERIALS AND METHODS: MRE scans of 84 patients (42 female, median age 37 years) were evaluated independently by 4 experienced radiologists. Analysis of inflammatory changes of the bowel wall, lymphadenopathy and adequate bowel distension was conducted separately for the jejunum, ileum and terminal ileum. The Kendall's W-test was used for the statistical comparison of concordance. RESULTS: In a total of 55 patients, inflammatory activity of the bowel wall was detected and MRE was found to have a high interobserver reproducibility concerning inflammatory changes of the intestinal wall (Kendall's W 0.527 - 0.823). Concerning lymphadenopathy (31 cases, 36.9 %), a low to moderate consensus could be shown with a Kendall's W value of 0.402 - 0.505. For the assessment of adequate bowel distension, a moderate concordance between the operators could be found (Kendall's W 0.497 - 0.581). CONCLUSION: MRE has proven high interobserver agreement with respect to the diagnosis of inflammatory disease activity of the bowel as a diagnostic criterion in patients with CD. Concerning adequate bowel distension as a quality criterion of the examination itself and lymphadenopathy as a diagnostic criterion, moderate interobserver agreement could be found. This is thought to have a rather small effect on the diagnostic significance and conclusiveness of the method in the daily routine. KEY POINTS: ⶠMR enterography as observer independent diagnostic procedure in patients with Chron's Disease. ⶠHighest interobserver concordance for the criterion of inflammatory bowel wall affection. ⶠModerate interobserver concordance for lymphadenopathy and bowel distension.
Assuntos
Doença de Crohn/diagnóstico , Íleo/patologia , Interpretação de Imagem Assistida por Computador/métodos , Jejuno/patologia , Imageamento por Ressonância Magnética/métodos , Adulto , Meios de Contraste , Diagnóstico Diferencial , Feminino , Seguimentos , Gadolínio DTPA , Humanos , Linfonodos/patologia , Doenças Linfáticas/diagnóstico , Masculino , Variações Dependentes do Observador , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
PURPOSE: To evaluate a routine MR enterography (MRE) protocol for patients with Crohn's disease (CD) in order to assess and rank the subjectively most important sequences regarding diagnostic decisions. MATERIALS AND METHODS: We prospectively examined 84 patients (42 male) with known CD using a coronal T2 / T1-weighted balanced SSFP (TrueFISP), axial T2-weighted single shot TSE (HASTE) as well as an axial T1-weighted gradient-echo sequence (2D-FLASH) before intravenous contrast application and a 2D-FLASH sequence with axial and coronal orientation after intravenous contrast application. 4 experienced radiologists subjectively evaluated the sequences independently using a scale between 1 and 5 (1 = excellent; 5 = non-diagnostic) regarding their diagnostic significance for a final radiologic decision. The ranking of the different sequences was statistically tested by the Friedman analysis. RESULTS: The following ranking was found: HASTE sequences were ranked prior to contrast-enhanced axial gradient-echo (2D-FLASH). The third to fifth ranking was TrueFISP, the axial contrast-enhanced 2D-FLASH and the 2D-FLASH without contrast, respectively. Differences between the first and second rank were significant (p < 0.05), and all other differences were highly significant (p < 0.01). CONCLUSION: The stable and fast T2-weighted MR sequences without intravenous contrast represented by axial HASTE and coronal TrueFISP were ranked as number 1 and 3. The examination protocol should be completed by a coronal T1-weighted gradient-echo-sequence after contrast injection, which can be supplemented by an axial acquisition. The T1-weighted gradient-echo sequence without contrast could be omitted.
Assuntos
Doença de Crohn/diagnóstico , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Reconhecimento Automatizado de Padrão/métodos , Técnica de Subtração , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
PURPOSE: To evaluate the extent to which MRE can be used as an observer-independent, objective imaging method for the diagnosis and evaluation of CD with respect to the detection of inflammatory changes of the small bowel and lymphadenopathy as diagnostic criterion and bowel distension as a quality criterion. MATERIALS AND METHODS: MRE scans of 84 patients (42 female, median age 37 years) were evaluated independently by 4 experienced radiologists. Analysis of inflammatory changes of the bowel wall, lymphadenopathy and adequate bowel distension was conducted separately for the jejunum, ileum and terminal ileum. The Kendall's W-test was used for the statistical comparison of concordance. RESULTS: In a total of 55 patients, inflammatory activity of the bowel wall was detected and MRE was found to have a high interobserver reproducibility concerning inflammatory changes of the intestinal wall (Kendall's W 0.527 0.823). Concerning lymphadenopathy (31 cases, 36.9 %), a low to moderate consensus could be shown with a Kendall's W value of 0.402 0.505. For the assessment of adequate bowel distension, a moderate concordance between the operators could be found (Kendall's W 0.497 0.581). CONCLUSION: MRE has proven high interobserver agreement with respect to the diagnosis of inflammatory disease activity of the bowel as a diagnostic criterion in patients with CD. Concerning adequate bowel distension as a quality criterion of the examination itself and lymphadenopathy as a diagnostic criterion, moderate interobserver agreement could be found. This is thought to have a rather small effect on the diagnostic significance and conclusiveness of the method in the daily routine.
Assuntos
Doença de Crohn/diagnóstico , Mucosa Intestinal/patologia , Linfonodos/patologia , Imageamento por Ressonância Magnética/métodos , Adulto , Meios de Contraste , Doença de Crohn/patologia , Feminino , Gadolínio DTPA , Humanos , Íleo/patologia , Aumento da Imagem/métodos , Jejuno/patologia , Masculino , Variações Dependentes do Observador , Sensibilidade e EspecificidadeRESUMO
Gonadal dysgenesis (GD) is a rare congenital malformation that affects about one in 3,000 births. The authors present a case of a 17-year-old woman with primary amenorrhea and poor breast development. They conducted a laparoscopic surgery and bilaterally removed hypoplastic streak gonads. Histopathology of the ovaries revealed bilateral streak gonads with gonadoblastomas and a right-sided dysgerminoma.
Assuntos
Disgerminoma/complicações , Disgenesia Gonadal 46 XY/complicações , Neoplasias Ovarianas/complicações , Adolescente , Amenorreia/etiologia , Disgerminoma/patologia , Disgerminoma/cirurgia , Feminino , Gonadoblastoma/complicações , Gonadoblastoma/patologia , Gonadoblastoma/cirurgia , Humanos , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgiaRESUMO
BACKGROUND: The aim of this study was to conduct an audit of a university inpatient pain consultation service and to examine the quality and the implementation of the recommended therapeutic measures. Factors that influenced the implementation should be identified. PATIENTS AND METHODS: All inpatients treated by the consultation service in the years 2009 and 2010 were analyzed retrospectively. Demographic patient characteristics as well as quality parameters of the consultation service and pharmacological and non-pharmacological recommendations and their implementation were analyzed. RESULTS: In total 1,048 requests for the consultation service were processed of which 39.7% of the requests were for patients with acute pain, 33.8% with chronic and 19.9% with tumor-associated pain. Measures recommended most were medication, physiotherapy and psychological treatment. Recommended medications were actually prescribed in more than 80%, physiotherapy recommended in about 75% and psychological treatment recommended in 47% of the cases. Only a few influencing factors for the implementation of the recommended measures could be identified. CONCLUSION: Many different pain states are seen in an inpatient pain consultation service. The recommendations given are implemented in most cases especially concerning the medication.
Assuntos
Comportamento Cooperativo , Hospitalização , Comunicação Interdisciplinar , Manejo da Dor/métodos , Encaminhamento e Consulta/organização & administração , Dor Aguda/psicologia , Dor Aguda/terapia , Idoso , Analgésicos/uso terapêutico , Dor Crônica/psicologia , Dor Crônica/terapia , Terapia Combinada , Feminino , Alemanha , Fidelidade a Diretrizes , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Clínicas de Dor , Medição da Dor , Dor Intratável/psicologia , Dor Intratável/terapia , Modalidades de Fisioterapia/psicologia , Psicoterapia , Garantia da Qualidade dos Cuidados de Saúde , Estudos RetrospectivosRESUMO
Gastric microcirculation plays an important role in the maintenance of the mucosal gastric integrity and the mechanism of injury as well as providing protection to the gastric mucosa. Disturbances in the blood perfusion, through the microcapillaries within the gastric mucosa may result in the formation of mucosal damage. Acute gastric mucosal lesions constitute an important clinical problem. Originally, one of the essential component of maintaining the gastric mucosal integrity was the biosynthesis of prostaglandins (PGs), an issue that has captured the attention of numerous investigations. PGs form due to the activity of cyclooxygenase (COX), an enzyme which is divided into 2 isoforms: constitutive (COX-1) and inducible (COX-2) ones. The inhibition of COX-1 by SC-560, or COX-2 by rofecoxib, reduces gastric blood flow (GBF) and impairs gastric mucosal integrity. Another detrimental effect on the gastric mucosal barrier results from the ablation of sensory afferent nerves by neurotoxic doses of capsaicin. Functional ablation of the sensory afferent nerves by capsaicin attenuates GBF and also renders the gastric mucosa more susceptible to gastric mucosal damage induced by ethanol, aspirin and stress. However, the role of reactive oxygen species (ROS) in the interaction between COX specific inhibitors and afferent sensory nerves has not been extensively studied. The aim of our present study was to determine the participation of ROS in pathogenesis of stress-induced gastric lesions in rats administered with SC-560 or rofecoxib, with or without ablation of the sensory afferent nerves. ROS were estimated by measuring the gastric mucosal tissue level of MDA and 4-HNE, the products of lipid peroxidation by ROS as well as the SOD activity and reduced glutathione (GSH) levels, both considered to be scavengers of ROS. It was demonstrated that exposure to 3.5 h of WRS resulted in gastric lesions, causing a significant increase of MDA and 4-HNE in the gastric mucosa, accompanied by a decrease of SOD activity and mucosal GSH level. Pretreatment with COX-1 and COX-2 inhibitors (SC-560 and rofecoxib, respectively) aggravated the number of gastric lesions, decreased GBF, attenuated GSH level without further significant changes in MDA and 4-HNE tissue levels and SOD activity. Furthermore, the capsaicin--nactivation of sensory nerves resulted in exaggeration of gastric mucosal damage induced by WRS and this was further augmented by rofecoxib. We conclude that oxidative stress, as reflected by an increase of MDA and 4-HNE tissue concentrations (an index of lipid peroxidation), as well as decrease of SOD activity and the fall in GSH tissue level, may play an important role in the mechanism of interaction between the inhibition of COX activity and afferent sensory nerves releasing vasoactive neuropeptides. This is supported by the fact that the addition of specific COX-1 or COX-2 inhibitors to animals with capsaicin denervation led to exacerbation of gastric lesions, and further fall in the antioxidizing status of gastric mucosa exposed to stress.
Assuntos
Inibidores de Ciclo-Oxigenase/efeitos adversos , Mucosa Gástrica/metabolismo , Lactonas/efeitos adversos , Pirazóis/efeitos adversos , Células Receptoras Sensoriais/efeitos dos fármacos , Estresse Psicológico/metabolismo , Sulfonas/efeitos adversos , Aldeídos/metabolismo , Animais , Capsaicina , Mucosa Gástrica/irrigação sanguínea , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional , Células Receptoras Sensoriais/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Ghrelin is an important hormone involved in the control of the human appetite center. Recently, protective properties of this hormone have been recognized in various models of impairment of the gastric mucosa, including stress, ischemia and reperfusion (I/R). Ghrelin is predominantly secreted by the gastric mucosa of stomach, but there are other sources of ghrelin, for example in the hypothalamus and various parts of the central nervous system (CNS) that should be taken into consideration. This hormone exerts biological effects via the activation of growth hormone secretagogue receptor (GHSR), the presence of which was confirmed in different parts of the gastrointestinal (GI) tract and midbrain structures. Although substantial evidence of the divergent biological effects of ghrelin and the mechanism of its action has been emphasized, the precise mechanisms of ghrelin which affords GI protection is still unclear. Particularly, there is a sparse amount of evidence concerning its action on the GI system. The major aim of the present study was to evaluate the importance of peripherally and centrally administered ghrelin at different times of the ischemia and reperfusion (I/R period in the modulation of resistance of the intestinal mucosa to the injury induced by ischemia and subsequent reperfusion. Secondly, we wanted to evaluate the possible mechanism of the action of ghrelin with a particular focus on its influence on the intestinal blood flow. Male Wistar rats were divided into 4 series (A-D) of the experimental groups (n=7). In series A the importance of peripherally administered ghrelin at different time of I/R period was studied. In series B the importance of centrally administered ghrelin at different time of I/R period was evaluated. In series C and D, the mechanisms of peripherally and centrally administered hormone were examined, respectively. Two models of the I/R period were selected: short lasting (30/60 min) and long lasting (60/120 min). The following drugs were used: ghrelin (50 µg/kg i.p. or 1 nmol in 10 µl i.c.v.), 6 hydroxy dopamine (50 mg/kg i.p.), nadolol (0.5 mg/kg i.p.), calcitonin gene related peptide fragment (CGRP(8-37), 100 µg /kg i.p.), capsaicin (5-10 mg/100 ml solution s.c.). The mesenteric blood flow (MBF-ml/min), the intestinal microcirculatory blood flow (LDBF-PU), the arterio-venous oxygen difference (AVO(2)-ml/O(2)/100 ml blood), and the intestinal oxygen uptake (VO(2)) in ml O(2)/min were measured. Mucosal impairment was assessed planimetrically with the use of a digital photo analyzer (LA) and histologically with the use of the six-point Park/Chiu scale. Peripheral administration of ghrelin evoked marked increase of MBF and LDBF by 42% and 48%, respectively, with significant reduction of LA by 38%. When ghrelin was administered at the beginning of the reperfusion period during the short I/R period or prior to the long lasting I/R period, the vascular reactions and protective effects were reduced, but not completely abolished. The central administration of ghrelin before the short I/R period significantly increased the MBF and LDBF by about 32% and 35%, respectively, as well as LA reduction by about 20% in comparison to the control group. However, when ghrelin was administered prior to the long I/R period or after the onset of completed ischemia, neither vascular nor protective effects were noticed. Sensory denervation and the blockade of the CGRP1 receptors totally blocked the protective and hyperemic effects of the peripherally administered ghrelin. Selective blockade of the adrenergic system or blunting of the vagal nerves (vagotomy) significantly but not totally eliminated the effects of centrally applied ghrelin, which were abolished when both adrenergic and parasympathetic pathways were ablated. These results indicate that ghrelin applied centrally or peripherally markedly increases resistance of the intestinal tissue during the I/R period induced mucosal and hyperemic impairment evoked by I/R. Ghrelin is an important mediator of the increase in the intestinal microcirculation and elevation of the intestinal metabolism, which seems to be, at least in part, responsible for the observed protection of the intestine subjected to I/R. Impairment of this microvasculature response due to I/R seems to be responsible for a markedly observed weaker effect of ghrelin when this hormone was administered after the ischemic period. The lack of a protective effect observed after central administration of this peptide against a long lasting I/R period is probably due to damage of neural pathways caused by I/R. Finally, the peripheral activity of ghrelin in the intestine is mediated by the sensory neurons with a prominent role of CGRP released from their endings. However, this peripheral action of ghrelin depends upon the proper functioning of both the sympathetic and parasympathetic system.
Assuntos
Grelina/administração & dosagem , Grelina/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Oclusão Vascular Mesentérica/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Vias Aferentes/efeitos dos fármacos , Animais , Capsaicina/farmacologia , Modelos Animais de Doenças , Esquema de Medicação , Grelina/metabolismo , Grelina/farmacologia , Injeções Intraperitoneais , Injeções Intraventriculares , Mucosa Intestinal/irrigação sanguínea , Mucosa Intestinal/inervação , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestino Delgado/irrigação sanguínea , Intestino Delgado/inervação , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Masculino , Oclusão Vascular Mesentérica/etiologia , Oclusão Vascular Mesentérica/metabolismo , Oclusão Vascular Mesentérica/patologia , Microcirculação/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Grelina/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Circulação Esplâncnica/efeitos dos fármacos , Simpatectomia Química , Fatores de Tempo , VagotomiaRESUMO
The purpose of this study was to develop an acute animal model of reflux esophagitis, which would be suitable to induce the esophageal damage caused by gastric acid reflux, thus mimicking the esophageal injury of human gastroesophageal reflux disease (GERD). Global research indicates that GERD is rapidly increasing among the world's population. NSAIDs are known to induce gastrointestinal damage and low doses of aspirin (ASA) have been shown to increase the incidences of GERD in humans. Gastric acid and pepsin secretion and enhanced COX-2 expression were implicated in the pathogenesis of reflux esophagitis, but the effect of selective COX-2 inhibitors against lesions induced by the reflux of gastric acid content into esophagus has not been thoroughly studied. Here, we compared the effect of aspirin (ASA) and so called "safe" nitric oxide (NO) derivative of ASA with those of non-selective and selective cyclooxygenase (COX)-1 and COX-2 in rat model of reflux esophagitis. Reflux esophagitis was induced in anesthetized rats by ligating the pylorus and limiting ridge transitional region between the forestomach and the corpus of stomach. Subsequently, the total gastric reservoir to store gastric juice was greatly diminished, resulting in the reflux of this juice into the esophagus. Rats with esophagitis received intragastric (i.g.) pretreatment either with: 1) vehicle (saline), 2) ASA or NO-ASA (100 mg/kg); 3) the non-selective COX inhibitor, indomethacin (5 mg/kg); 4) the selective COX-1 inhibitor, SC-560 (10 mg/kg), and 5) the selective COX-2 inhibitor, celecoxib (5 mg/kg). In a separate series of rats with reflux oesophagitis, the efficacy of ASA combined with a donor of NO, glyceryl trinitrate (GTN; 10 mg/kg i.g.) to prevent esophageal mucosal injury was investigated. Four hours after induction of esophagitis the gross mucosal damage was graded with a macroscopic lesion index (LI) from 0-6. The esophageal blood flow (EBF) was determined by H2-gas clearance technique, the oesophageal mucosal and blood samples were collected for histology and analysis of the RT-PCR expression and release of proinflammatory cytokines IL-1ß, TNF-α and IL-6 using specific ELISA. The exposure of the esophagus to reflux of gastric acid time-dependently increased the esophageal LI and morphologic damage, and decreased EBF with the most significant changes observed at 4 hrs after the ligation procedure. The pretreatment with native ASA in the dose that suppressed the generation of mucosal PGE2, enhanced gross and histologic esophageal damage and produced a significant fall in EBF. NO-ASA or ASA coupled with GTN counteracted the aggravation of the damage and accompanying fall in EBF when compared with native ASA applied alone to rats with esophagitis. The proinflammatory cytokines IL-1ß and TNF-α were overexpressed in rats with esophagitis and those pretreated with ASA but this effect was significantly attenuated by NO-ASA. Plasma IL-1ß, TNF-α and IL-6 were negligible in the intact rats but significantly increased in those with esophagitis, with this effect being further enhanced by non-selective (indomethacin) and selective (SC-560, celecoxib) COX-1 and COX-2 inhibitors. We conclude that conventional NSAID such as aspirin augments esophagitis, while NO-ASA exerts the beneficial protective effect against reflux esophagitis via the enhancement of esophageal microcirculation due to NO release and an inhibitory effect on expression and release of pro-inflammatory cytokines.
Assuntos
Aspirina/análogos & derivados , Citocinas/biossíntese , Esofagite Péptica/tratamento farmacológico , Esofagite Péptica/metabolismo , Esôfago/efeitos dos fármacos , Esôfago/patologia , Doadores de Óxido Nítrico/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Celecoxib , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Citocinas/sangue , Citocinas/genética , Dinoprostona/metabolismo , Esofagite Péptica/induzido quimicamente , Esofagite Péptica/patologia , Esôfago/irrigação sanguínea , Esôfago/metabolismo , Ácido Gástrico/metabolismo , Humanos , Indometacina/farmacologia , Masculino , Óxido Nítrico/farmacologia , Nitroglicerina/farmacologia , Pirazóis/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar , Sulfonamidas/farmacologiaRESUMO
This review summarizes the involvement of centrally and peripherally applied melatonin, a major hormone of pineal gland, in the mechanism of gastric mucosal integrity, gastroprotection and ulcer healing. Melatonin was originally shown to attenuate gastric mucosal lesions but the controversy exists in the literature as to whether melatonin derived from the pineal gland, considered as the major source of this indole or rather that locally generated from L-tryptophan within gastric mucosa, plays predominant role in the mechanism of gastrointestinal integrity. Both, intragastric (i.g.) and intracerebroventricular (i.c.v.) administration of melatonin and its precursor, L-tryptophan to rats without or with removed pineal gland by pinealectomy attenuates in the dose-dependent manner the formation of on gastric lesions induced by topical irritants and water immersion restraint stress (WRS). Melatonin accelerated the gastric ulcer healing and this was accompanied by the rise in gastric blood flow (GBF), the plasma melatonin and gastrin levels, the mucosal generation of PGE(2) and luminal NO content. Pinealectomy, which suppresses the plasma melatonin levels, markedly aggravated the gastric lesions induced by WRS. Concurrent supplementation of pinealectomized animals with melatonin or L-tryptophan, the melatonin precursor, attenuated the lesions induced by WRS. Treatment with luzindole, an antagonist of Mel(2) receptors, or with L-NNA, the NO-synthase inhibitor, significantly attenuated melatonin- and L-tryptophan-induced protection and the acceleration of ulcer healing and the accompanying increase in the GBF and luminal content of NO. We conclude that 1) exogenous melatonin and that released from the L-tryptophan attenuate lesions induced by topical irritant such as ethanol and WRS via interaction with MT(2) receptors and due to an enhancement of gastric microcirculation, probably mediated by NO and PG derived from cNOS, iNOS and COX-2 overexpression and activity, and 2) the pineal gland plays an important role in the limitation of WRS-induced gastric lesions and acceleration of ulcer healing via releasing melatonin predominately at night time, that exerts gastroprotective and ulcer healing actions.