RESUMO
More than half of women will experience a urinary tract infection (UTI) with most cases caused by uropathogenic Escherichia coli (UPEC). Bacterial swimming motility enhances UPEC pathogenicity, resulting in more severe disease outcomes including kidney infection. Surprisingly, the connection between motility and iron limitation is mostly unexplored despite the lack of free iron available in the host. We sought to investigate a potential connection between iron restriction and regulation of motility in UPEC. We cultured E. coli CFT073, a prototypical UPEC strain, under iron limitation and observed that CFT073 had elevated fliC (flagella) promoter activity, and this iron-specific response was repressed by the addition of exogenous iron. We confirmed increased flagellar expression in CFT073 by measuring fliC transcript, FliC protein, and surface-expressed flagella under iron-limited conditions. Interestingly, known motility regulator flhDC did not have altered transcription under these conditions. To define the regulatory mechanism of this response, we constructed single knockouts of eight master regulators and found the iron-regulated response was lost in crp, arcA, and fis mutants. Thus, we focused on the five genes regulated by all three regulators. Of the five genes knocked out, the iron-regulated motility response was most strongly dysregulated in the lpdA mutant, which also resulted in significantly lowered fitness in the murine model of ascending UTI, both against the WT and a non-motile fliC mutant. Collectively, we demonstrated that iron-mediated motility in CFT073 is partially regulated by lpdA, which contributes to the understanding of how uropathogens differentially regulate motility mechanisms in the iron-restricted host. IMPORTANCE: Urinary tract infections (UTIs) are ubiquitous and responsible for over five billion dollars in associated health care costs annually. Both iron acquisition and motility are highly studied virulence factors associated with uropathogenic Escherichia coli (UPEC), the main causative agent of uncomplicated UTI. This work is innovative by providing mechanistic insight into the synergistic relationship between these two critical virulence properties. Here, we demonstrate that iron limitation has pleiotropic effects with consequences that extend beyond metabolism and impact other virulence mechanisms. Indeed, targeting iron acquisition as a therapy may lead to an undesirable enhancement of UPEC pathogenesis through increased motility. It is vital to understand the full breadth of UPEC pathogenesis to adequately respond to this common infection, especially with the increase of antibiotic-resistant pathogens.
Assuntos
Infecções por Escherichia coli , Proteínas de Escherichia coli , Regulação Bacteriana da Expressão Gênica , Infecções Urinárias , Escherichia coli Uropatogênica , Animais , Feminino , Camundongos , Modelos Animais de Doenças , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Flagelos/genética , Flagelos/metabolismo , Flagelina , Ferro/metabolismo , Locomoção , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/efeitos dos fármacos , Escherichia coli Uropatogênica/genética , Escherichia coli Uropatogênica/metabolismo , Escherichia coli Uropatogênica/patogenicidade , VirulênciaRESUMO
More than half of all women will experience a urinary tract infection (UTI) in their lifetime with most cases caused by uropathogenic Escherichia coli (UPEC). Bacterial motility enhances UPEC pathogenicity, resulting in more severe disease outcomes including kidney infection. Surprisingly, the connection between motility and iron limitation is mostly unexplored, despite the lack of free iron available in the host. Therefore, we sought to explore the potential connection between iron restriction and regulation of motility in UPEC. We cultured E. coli CFT073, a prototypical UPEC strain, in media containing an iron chelator. Under iron limitation, CFT073 had elevated fliC (flagella) promoter activity, driving motility on the leading edge of the colony. Furthermore, this iron-specific response was repressed by the addition of exogenous iron. We confirmed increased flagella expression in CFT073 by measuring fliC transcript, FliC protein, and surface-expressed flagella under iron-limited conditions. To define the regulatory mechanism, we constructed single knockouts of eight master regulators. The iron-regulated response was lost in crp, arcA, and fis mutants. Thus, we focused on the five genes regulated by all three transcription factors. Of the five genes knocked out, the iron-regulated motility response was most strongly dysregulated in an lpdA mutant, which also resulted in significantly lowered fitness in the murine model of ascending UTI. Collectively, we demonstrated that iron-mediated motility in CFT073 is regulated by lpdA , which contributes to the understanding of how uropathogens differentially regulate motility mechanisms in the iron-restricted host. Importance: Urinary tract infections (UTIs) are ubiquitous and responsible for over five billion dollars in associated health care costs annually. Both iron acquisition and motility are highly studied virulence factors associated with uropathogenic E. coli (UPEC), the main causative agent of uncomplicated UTI. This work is innovative by providing mechanistic insight into the synergistic relationship between these two critical virulence properties. Here, we demonstrate that iron limitation has pleiotropic effects with consequences that extend beyond metabolism, and impact other virulence mechanisms. Indeed, targeting iron acquisition as a therapy may lead to an undesirable enhancement of UPEC pathogenesis through increased motility. It is vital to understand the full breadth of UPEC pathogenesis to adequately respond to this common infection, especially with the increase of antibiotic resistant pathogens.
RESUMO
AIM: Precise biomarkers for predicting prognosis could help to identify high-risk Crohn's disease (CD) patients to facilitate better follow-up during the postoperative course. In this study, the primary aim is the identification of the most reliable nutrition marker that predicts surgical relapse in CD patients. METHOD: We first evaluated the predictive value of various nutrition markers for postoperative surgical relapse in CD patients and identified the advanced lung cancer inflammation index (ALI) as a promising biomarker. Then, we assessed the clinical significance of preoperative ALI in CD patients using two cohorts. RESULTS: Preoperative ALI showed the highest correlation with reoperation rate compared with other nutritional parameters in CD patients receiving surgical resection (sensitivity 53%, specificity 86%, area under the curve 0.71). Lower levels of preoperative ALI were significantly correlated with the presence of perianal disease. A lower level of preoperative ALI was an independent prognostic factor for reoperation rate after an intestinal resection (hazard ratio 3.37, 95% CI 1.38-10.12, P = 0.006), and the prognostic impact of preoperative ALI was successfully validated in an independent cohort using the same cut-off value. CONCLUSION: Preoperative ALI might be useful for postoperative management of CD patients.
Assuntos
Doença de Crohn , Neoplasias Pulmonares , Doença de Crohn/complicações , Doença de Crohn/cirurgia , Humanos , Inflamação , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
BACKGROUND: The optimal surgical approach for Siewert type II adenocarcinoma of the esophagogastric junction (AEG) has not yet been agreed. Here we investigated whether the distance from the esophagogastric junction (EGJ) to the distal end of the tumor was related to the distribution of involved abdominal lymph nodes in Siewert type II tumors. METHODS: A total of 288 patients with pT2-4 AEG Siewert II, treated by R0 surgical resection at 7 institutions in Japan, were retrospectively investigated. The distribution of involved abdominal nodes was correlated with the distance from the EGJ to the distal end of the tumor. RESULTS: In patients where the distance from the EGJ to the distal end of the tumor was ≤30 mm, the frequency of nodal involvement along the greater curvature or antrum was low (2.2%). In contrast, in patients where the distance was >50 mm, the incidence of this nodal involvement was 20.0%. In patients where the distance was 30-50 mm incidence was intermediate (8.0%). Multivariate analyses showed that the distance from the EGJ to the distal end of the tumor was significantly related to lymph node involvement along the greater curvature or antrum (odds ratio 3.7, 95% confidence interval 1.3-11, p = 0.006). CONCLUSIONS: When the distance from the EGJ to the distal end of the tumor is ≤ 30 mm for Siewert II AEG, esophagectomy or proximal gastrectomy is sufficient from the point of view of abdominal lymphadenectomy. However, a total gastrectomy should be considered for abdominal lymphadenectomy when this distance is > 50 mm.
Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Linfonodos/patologia , Neoplasias Gástricas/patologia , Abdome , Adenocarcinoma/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Esofágicas/cirurgia , Esofagectomia , Junção Esofagogástrica/cirurgia , Feminino , Gastrectomia , Humanos , Excisão de Linfonodo , Linfonodos/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia , Carga Tumoral , Adulto JovemRESUMO
BACKGROUND: Brain-derived neutrophic factor (BDNF) is a member of the neutrophin family that is known to activate the high-affinity tropomyosin-related receptor kinase B (TrkB). This study aimed to clarify the clinical and biological significance of the BDNF/TrkB pathway in gastric cancer. METHODS: We analysed BDNF and TrkB expression in gastric cancer samples by real-time reverse transcription PCR and immunohistochemistry. To investigate the biological role of BDNF/TrkB axis, recombinant human BDNF (rhBDNF) and the Trk antagonist K252a were used for in vitro and in vivo analysis. RESULTS: The BDNF expression at the invasive front of primary tumours was significantly elevated compared with that in the tumour core and adjacent normal mucosa. Increased BDNF expression at the invasive front was significantly correlated with factors reflecting disease progression, and poor prognosis. Increased co-expression of the BDNF/TrkB axis was significantly correlated with poor prognosis. Gastric cancer cells expressed BDNF, and administration of rhBDNF promoted proliferation, migration, invasion, and inhibition of anoikis. These effects were generally inhibited by K252a. In an in vivo assay, BDNF(+)/TrkB(+) gastric cancer cells injected into nude mice established peritoneal dissemination, whereas K252a inhibited tumour growth. CONCLUSION: The BDNF/TrkB pathway might be deeply involved in gastric cancer disease progression.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Receptor trkB/metabolismo , Neoplasias Gástricas/metabolismo , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Masculino , PrognósticoRESUMO
AIMS: To evaluate the relationship between vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) levels in gastric cancer tissue and clinicopathological features and to determine whether these factors were correlated with survival. MATERIALS AND METHODS: We analysed tissue samples from 58 patients with gastric cancer and used 24 normal gastric mucosae as controls. Tissue levels of VEGF and HGF were measured in tissue extracts by enzyme-linked immunosorbent assay. RESULTS: HGF and VEGF levels were significantly higher in gastric cancer tissue than in matched normal gastric mucosa. VEGF levels were significantly increased in cancer tissue from cases involving lymphatic invasion. HGF levels were significantly increased according to the disease stage. Patients with high levels of VEGF or HGF showed significantly worse survival rates than patients with low levels. Using multivariate analysis, a high level of VEGF or HGF was an independent factor predicting poor survival. CONCLUSIONS: Intratumoral levels of HGF and VEGF are an important prognostic determinant in gastric cancer. The current findings suggest that high concentrations of HGF and VEGF may induce aggressive tumour growth and metastasis.
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Fator de Crescimento de Hepatócito/metabolismo , Neoplasias Gástricas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Prognóstico , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/patologia , Análise de SobrevidaRESUMO
AIMS: HsMAD2 and BubR1 are crucial components of a functional mitotic checkpoint. Recently, impaired mitotic checkpoints or decreased expression of mitotic checkpoint genes have been associated with sensitivity to certain anticancer drugs. The current study aimed to evaluate the association of hsMAD2 and BubR1 with sensitivity to various anticancer drugs in oesophageal squamous cell carcinoma (ESCC) cell lines. We also investigated responses to 5-fluorouracil and cisplatin-based radiochemotherapy in ESCC patients. MATERIALS AND METHODS: HsMAD2 and BubR1 mRNA levels in six ESCC cell lines and 21 ESCC patients were determined by real-time reverse transcription polymerase chain reaction. Responses to 5-fluorouracil, cisplatin, paclitaxel and docetaxel in human oesophageal cancer cell lines, TE1 and TE2, were evaluated by WST-8 colorimetric assay. HsMAD2 and BubR1 levels were compared with clinicopathological characteristics and responses to radiochemotherapy. RESULTS: TE1, with lower hsMAD2 and BubR1, showed greater sensitivity to paclitaxel and docetaxel compared with TE2, with higher hsMAD2 and BubR1. HsMAD2 and BubR1 were significantly higher in cancer tissue than in adjacent normal tissue (P < 0.01). Tumoral hsMAD2 and BubR1 were significantly decreased after radiochemotherapy (P < 0.01). There was a significantly strong positive association between hsMAD2 and BubR1 in cancer tissue (P < 0.01). Neither clinicopathological characteristics nor the response to radiochemotherapy was associated with hsMAD2 or BubR1. CONCLUSION: The mitotic checkpoint genes, hsMAD2 and BubR1, were co-ordinately overexpressed in ESCC. Low hsMAD2 and BubR1 was associated with sensitivity to paclitaxel and docetaxel. Decreased hsMAD2 and BubR1 after radiochemotherapy may indicate the potential efficacy of taxanes as second-line chemotherapy for recurrent and metastatic oesophageal cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ligação ao Cálcio/genética , Carcinoma de Células Escamosas/genética , Proteínas de Ciclo Celular/genética , Cisplatino/administração & dosagem , Neoplasias Esofágicas/genética , Fluoruracila/administração & dosagem , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Linhagem Celular Tumoral , Terapia Combinada , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Feminino , Expressão Gênica , Humanos , Proteínas Mad2 , Masculino , Pessoa de Meia-IdadeRESUMO
The purpose of the present study was to investigate possible reproductive adverse effects of fipronil (Frontline TopSpot) in female Wistar rats. The pesticide was topically applied to rats (single dose) at different concentrations (70, 140 and 280 mg/kg) and hormonal analysis, estrous cycle, and pregnancy and outcome data were determined. Treatment with fipronil altered cyclicity of female rats lengthening the estrous cycle (days) after a single topic administration of 70 mg/kg (9.7+/-1.18) or 280 mg/kg (14.5+/-1.45) when compared to control (4.8+/-0.17). In the mating study fipronil reduced the pregnancy index (67%) in the highest dose group (280 mg/kg). Plasma progesterone and estradiol levels, obtained in different periods after treatment with fipronil (70 mg/kg), were significantly different 96 h after treatment, when compared to controls. In summary, the results of the present study indicate that fipronil may alter the normal functioning of the endocrine system and cause adverse reproductive effects in female rats.
Assuntos
Inseticidas/toxicidade , Pirazóis/toxicidade , Reprodução/efeitos dos fármacos , Animais , Estradiol/sangue , Estro/efeitos dos fármacos , Feminino , Gravidez , Resultado da Gravidez , Progesterona/sangue , Ratos , Ratos WistarRESUMO
Aplastic anemia has been a rare complication of thymic tumors documented in only a few cases. We now report that a previously healthy, 72-year-old woman had a well-differentiated squamous cell thymic carcinoma and severe aplastic anemia, as detected on a simultaneous basis. After extirpation of the thymic carcinoma, hematological recovery was achieved. While cyclosporine (CyA), prednisolone (PSL), and methenolone improved hematological data even more, a partial and stable remission has been sustained for 22 months. The patient's serum prior to the surgery had a suppressive effect on the formation of colonies of erythroid and nonerythroid colonies, as determined using the patient's bone marrow cells and compared with the patient's serum after the surgery and normal AB serum. This case report concerns a patient in whom we observed simultaneous occurrence of a thymic tumor and a sever marrow aplasia for which we describe our therapeutic approach.
Assuntos
Anemia Aplástica/etiologia , Timectomia , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/cirurgia , Idoso , Anemia Aplástica/patologia , Células da Medula Óssea/patologia , Feminino , Humanos , Neoplasias do Timo/patologia , Resultado do TratamentoRESUMO
BACKGROUND: The control of body weight and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome (OSAHS) are important because both factors have significant effects on the mortality of these patients. It has recently been reported that OSAHS has a significant effect on the secretion of leptin, a hormone involved in the control of body weight and sympathetic nerve activity. In addition to the circadian rhythm of leptin secretion, the effects of one night of treatment with nasal continuous positive airway pressure (nCPAP) and the mechanism of the effects of nCPAP on nocturnal leptin secretion in patients with OSAHS has not yet been elucidated. METHODS: Blood samples were obtained at 21.00 hours, 00.00 hours, 03.00 hours, and 06.30 hours from 21 subjects with OSAHS (mean apnoea and hypopnoea index 52.4/h), with and without nCPAP treatment. Iodine-123 (I(123))-meta-iodobenzylguanidine (MIBG) imaging was used to evaluate myocardial sympathetic function before nCPAP treatment. RESULTS: Plasma leptin reached a peak level at 00:00 hours (p<0.01) in patients with OSAHS, both with and without nCPAP treatment. The first night of nCPAP treatment significantly decreased the plasma leptin levels at 03.00 hours (without nCPAP: mean (SE) 21.6 (4.7) ng/ml; with nCPAP: 19.3 (4.1) ng/ml, p<0.02) and at 06.30 hours (without nCPAP: 17.6 (3.8) ng/ml; with nCPAP: 15.2 (3.2) ng/ml, p<0.01). The magnitude of the decrease in leptin levels after nCPAP treatment was significantly correlated with cardiac sympathetic function measured before nCPAP treatment (p<0.03). CONCLUSIONS: Patients with OSAHS undergo nocturnal increases in leptin levels in spite of interruption of sleep due to apnoea and hypopnoea, a trend seen in normal subjects. Plasma leptin levels in patients with OSAHS decreased significantly after the first night of nCPAP treatment. Enhanced cardiac sympathetic function in these patients may contribute to the leptin levels before nCPAP treatment and vice versa.
Assuntos
Doenças do Sistema Nervoso Autônomo/sangue , Cardiopatias/sangue , Leptina/sangue , Síndromes da Apneia do Sono/sangue , 3-Iodobenzilguanidina , Adulto , Idoso , Doenças do Sistema Nervoso Autônomo/diagnóstico por imagem , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Glicemia/análise , Cardiopatias/diagnóstico por imagem , Cardiopatias/fisiopatologia , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Respiração com Pressão Positiva/métodos , Cintilografia , Síndromes da Apneia do Sono/fisiopatologiaRESUMO
OBJECTIVES: To investigate the usefulness of digital rectal examination (DRE) and transrectal ultrasonography (TRUS) for prostate cancer diagnosis and to propose a diagnostic algorithm for individual-based cancer screening in subjects with prostate-specific antigen (PSA) levels of 4.0 ng/mL or less. METHODS: Between January 1992 and March 2000, 129 subjects with PSA levels of 4.0 or less and abnormal findings on DRE or TRUS underwent prostate biopsy. The subjects were divided into four groups according to the PSA range: 0 to 0.9 ng/mL, 1.0 to 1.9 ng/mL, 2.0 to 2.9 ng/mL, and 3.0 to 4.0 ng/mL. The reliability of the DRE and TRUS and the clinicopathologic features of prostate cancer were investigated among these four groups. RESULTS: Of the 129 subjects, 17 (13.2%) patients with prostate cancer were diagnosed. The detection rate was 2.2% (1 of 45), 0% (0 of 27), 20.6% (7 of 34), and 39.1% (9 of 23) in subjects with PSA levels of less than 1.0 ng/mL, 1.0 to 1.9 ng/mL, 2.0 to 2.9 ng/mL, and 3.0 to 4.0 ng/mL, respectively. The proportion of patients with Stage II, III, and IV was 58.8%, 41.2%, and 0%, respectively. The percentage with Gleason scores of 8 to 10 was 17.6%. The detection rate of abnormal findings on DRE and TRUS was 14.4% (13 of 90) and 9.5% (7 of 74), respectively. Adding TRUS to DRE in the screening program of subjects with PSA levels of 2.0 to 4.0 ng/mL, increased the detection rate of prostate cancer to 30.8% (4 of 13). CONCLUSIONS: Routine prostate biopsy should not be undertaken except for highly suspicious DRE findings in subjects with PSA levels less than 2.0 ng/mL. The additional use of TRUS in subjects with PSA levels of 2.0 to 4.0 ng/mL would improve the sensitivity of prostate cancer detection. The diagnostic algorithm proposed in the present study is useful as a screening method for prostate cancer in subjects with PSA levels of 4.0 ng/mL or less.
Assuntos
Algoritmos , Palpação/métodos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Reto , Reprodutibilidade dos Testes , Ultrassonografia/métodosRESUMO
A 55-year-old woman presented with fever and a stiff neck due to an intracranial poorly differentiated carcinoma at the right cerebellopontine angle. The patient suffered from typical trigeminal pain and had undergone a removal of the right cerebellopontine angle epidermoid 13 years before at another hospital. On admission, MRI imaging showed a lesion at the right cerebellopontine angle with marked contrast enhancement. Partial removal of the tumor was achieved. A histological examination of the tumor showed a poorly differentiated carcinoma accompanied by typical desquamated tissue of the epidermoid. The patient died 3 months after the operation because of aggressive meningeal carcinomatosis.
Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Cerebelares/patologia , Ângulo Cerebelopontino/patologia , Carcinoma de Células Escamosas/cirurgia , Transformação Celular Neoplásica , Neoplasias Cerebelares/cirurgia , Angiografia Cerebral , Evolução Fatal , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-IdadeRESUMO
BACKGROUND & AIMS: In colorectal adenoma and carcinoma, glutathione S-transferase-pi (GSTP1-1) is highly expressed. K-ras mutation is also known to occur frequently in colorectal adenoma and carcinoma, as well as in the putative precursor of adenoma, aberrant crypt foci (ACF). Further, forced expression of v-H-ras in rat liver epithelial cells has been shown to enhance rat pi-class GST expression. The aim of the present study is, therefore, to investigate the causative relationship between GSTP1-1 overexpression and K-ras mutation in these lesions. METHODS: Twenty-seven specimens of colorectal carcinoma, 24 of adenoma, and 28 of ACF were examined in this study. The expression of GSTP1-1 or p21(K-ras) was examined by immunohistochemistry. The GSTP1-1 messenger RNA levels were measured by TaqMan reverse-transcription polymerase chain reaction (PCR). K-ras mutation was detected by two-step PCR restriction fragment length polymorphism. v-K-ras transfection to RPMI-4788 colon carcinoma cells was carried out by the lipofection method. Activities of GSTP1-1 promoters containing AP-1 and Sp1 responsive elements in the v-K-ras transfectants were measured by a secreted form of human placental alkaline phosphatase (SEAP) assay. Nuclear protein from these transfectants bound to the GSTP1-1 promoter was analyzed by electrophoretic mobility shift assay (EMSA). RESULTS: In human colorectal carcinoma, adenoma, and ACF, close association of increased expression of GSTP1-1 with K-ras mutation was observed. v-K-ras transfectants showed significantly higher SEAP activity than that of mock-transfectant activity. EMSA showed specific interaction of AP-1 with promoter of GSTP1-1. CONCLUSIONS: It is highly plausible that GSTP1-1 overexpression in ACF, colorectal adenoma, and carcinoma is induced by K-ras mutation via AP-1 activation.
Assuntos
Neoplasias do Colo/enzimologia , Regulação Enzimológica da Expressão Gênica , Genes ras , Glutationa Transferase/genética , Mutação , Adenoma/enzimologia , Adenoma/patologia , Sequência de Bases , Carcinoma/enzimologia , Carcinoma/patologia , Neoplasias do Colo/patologia , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Ensaio de Imunoadsorção Enzimática , Glutationa S-Transferase pi , Humanos , Isoenzimas/genética , Dados de Sequência Molecular , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica , Transfecção , Células Tumorais CultivadasRESUMO
OBJECTIVES: To investigate whether in patients with obstructive sleep apnea syndrome (OSAS) the systemic immunity is disturbed and whether it changes with nasal continuous positive airway pressure (NCPAP) therapy. DESIGN: Polysomnography was performed on 18 OSAS patients (Group A) before NCPAP was started and again on the first night of NCPAP. Blood samples were collected at 8:00PM, 1:00AM and 6:00AM during each polysomnography. Lymphocyte subsets, lymphocyte blastformation, and natural killer (NK) cell activity were determined. Six normal subjects were also studied. A different six OSAS patients were studied over 6 days of NCPAP. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The only immunological parameter that significantly differed between the Group A OSAS patients either before or on the first night of NCPAP, and the normal subjects was the epinephrine level. Among the Group A OSAS patients, the following immunological parameters were significantly lower at 6:00AM on the first night of NCPAP than before NCPAP was started: percentage (49.4+/-1.9% before NCPAP vs 45.7+/-2.0% with NCPAP, mean+/-SEM, p<0.005) and absolute count of CD4+ cells (944.1+/-63.8 vs 829.6+/-71.3/mm3, p<0.05); absolute count of CD4+HLA-DR+ cells (91.9+/-13.3 vs 75.1+/-8.9/mm3, p<0.05); CD4+/CD8+ ratio (2.13+/-0.21 vs 1.91+/-0.18, p<0.05). The reduction in the percentage of CD4+ cells at 6:00AM was significantly correlated with the change in apnea-hypopnea index (AHI) (r=0.729, p<0.01). The CD4+ cell count recovered after 6 days of NCPAP. The lymphocyte blasfformation and NK cell activity levels did not change with NCPAP. CONCLUSIONS: First-night NCPAP therapy reduced the CD4+ cell count after sleep, which recovered after one week of NCPAP. OSAS patients do not have immunological abnormalities.
Assuntos
Hidrocortisona/imunologia , Imunoglobulinas/imunologia , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Respiração com Pressão Positiva/métodos , Apneia Obstrutiva do Sono/imunologia , Apneia Obstrutiva do Sono/terapia , Adulto , Idoso , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria/métodos , Oxigênio/sangue , Polissonografia/métodosRESUMO
BACKGROUND & AIMS: We have previously shown that aberrant crypt foci (ACF) are the putative precursor lesions of colorectal adenomas and subsequent cancer in humans using magnifying endoscopy. The present study was designed to investigate these genetic alterations in ACF biopsy specimens from normal subjects, familial adenomatous polyposis (FAP) or sporadic patients. METHODS: The non-FAP cases included 34 normal subjects, 35 colorectal adenoma patients, and 19 colorectal cancer patients; there were 4 FAP patients. Biopsies were performed on ACF by magnifying endoscopy. K-ras mutations were analyzed by 2-step polymerase chain reaction and restriction fragment length polymorphism, APC mutations by in vitro-synthesized protein assay, and beta-catenin mutations by direct sequencing. Full-length APC and beta-catenin were detected by immunofluorescence. RESULTS: In non-FAP cases, K-ras mutations were detected in 82% (89/106) of nondysplastic ACF and 63% (17/27) of dysplastic ACF. APC mutation and beta-catenin accumulation were not detected in non-FAP ACF, whereas in adenoma of these patients, positivity of APC mutation and beta-catenin accumulation were 78% (24/31), and that of K-ras mutation was 65% (20/31). FAP patients showed K-ras mutations in only 13% (1/8) of dysplastic ACF, which is the predominant form of ACF found in FAP. In FAP patients, somatic APC mutations were found in 100% of dysplastic ACF, as they are in adenoma. The frequency of K-ras mutations was 73% (8 of 11) in FAP adenoma. CONCLUSIONS: The data suggest that in sporadic colorectal carcinogenesis, assuming the biological implication of ACF as a precursor of adenomas, there is a route where K-ras mutation mainly occurs during the formation of ACF, which then become adenomas wherein APC mutation occurs. In FAP, however, somatic mutation of APC predominantly occurs during ACF formation, followed by K-ras mutation.
Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Proteínas do Citoesqueleto/genética , Genes ras/genética , Transativadores , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo , Adulto , Idoso , Biópsia , Neoplasias Colorretais/patologia , Proteínas do Citoesqueleto/análise , Progressão da Doença , Endoscopia Gastrointestinal , Feminino , Testes Genéticos , Humanos , Imuno-Histoquímica , Mucosa Intestinal/química , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Fragmento de Restrição , beta CateninaRESUMO
STUDY OBJECTIVES: In the absence of heme oxygenase-1 (HO-1), which catalyzes the oxidation of heme to generate carbon monoxide and indirect bilirubin, hypoxia induces severe right ventricular dilation and infarction. Despite severe hypoxemia during sleep, patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) rarely die during sleep. We hypothesized that apnea-related hypoxemia would induce HO-1 and increase bilirubin levels in the morning in OSAHS patients. Therefore, bilirubin levels in OSAHS patients were analyzed before and after nasal continuous positive airway pressure (nCPAP) therapy. DESIGN: Bilirubin levels in the afternoon before sleep and in the morning immediately after sleep were determined before and after nCPAP treatment. SETTING: University Hospital in Kyoto, Japan. PATIENTS: The subjects were 22 patients with OSAHS (mean (SEM) apnea and hypopnea index of 60 (5)) who were treated with nCPAP and 13 controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Before nCPAP treatment, total after-sleep bilirubin level was significantly higher than the pre-sleep level (p<0.0001). The difference between the serum indirect bilirubin levels in the morning versus in the previous afternoon [D-(M-A)-IB] decreased significantly with nCPAP treatment (p<0.01). The magnitude of decrease in D-(M-A)-IB after nCPAP treatment correlated significantly with changes in the percent time spent with arterial O2 saturation below 90% (r=0.44; p=0.04) and 85% (r=0.49; p=0.02), respectively, during sleep after nCPAP treatment. CONCLUSIONS: The increase in bilirubin level by HO-1 might protect OSAHS patients from disorders related to hypoxemia.
Assuntos
Bilirrubina/sangue , Ritmo Circadiano/fisiologia , Heme Oxigenase (Desciclizante)/biossíntese , Apneia Obstrutiva do Sono/sangue , Heme Oxigenase-1 , Humanos , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Polissonografia , Respiração com Pressão Positiva , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/terapiaRESUMO
PURPOSE: Obstructive sleep apnea syndrome is common in middle-aged men and may be associated with an increased risk of cardiovascular disease. We investigated the effect of nasal continuous positive airway pressure (CPAP) treatment on levels of soluble cell adhesion molecules-which have been shown to be associated with the development of atherosclerosis-in these patients. SUBJECTS AND METHODS: We studied 23 patients with obstructive sleep apnea syndrome diagnosed by polysomnography who were treated with nasal CPAP. Serum soluble intercellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 levels were measured before nasal CPAP was started, and after 3 or 4 days (n = 19), 1 month (n = 23), or 6 months (n = 11) of treatment. RESULTS: After 3 to 4 days of nasal CPAP therapy, the mean (+/- SD) soluble E-selectin level had decreased from 89 +/- 44 ng/mL to 69 +/- 28 ng/mL (P = 0.002). After 1 month, the soluble intercellular adhesion molecule-1 level had decreased from 311 +/- 116 ng/mL to 249 +/- 74 ng/mL (P = 0.02). After 6 months, soluble vascular cell adhesion molecule-1 levels had not changed significantly, while the mean soluble intercellular adhesion molecule-1 level (212 +/- 59 ng/mL) had decreased further (P = 0.02). Before treatment, soluble intercellular adhesion molecule-1 levels and the apnea and hypopnea index were correlated (r = 0.43, P = 0.04). CONCLUSIONS: Obstructive sleep apnea and hypopnea have a significant adverse effect on serum soluble cell adhesion molecule-1 levels that may be reduced by nasal CPAP treatment.
Assuntos
Moléculas de Adesão Celular/sangue , Respiração com Pressão Positiva , Apneia Obstrutiva do Sono/sangue , Apneia Obstrutiva do Sono/terapia , Adulto , Peso Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Colesterol/sangue , Selectina E/sangue , Humanos , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Nariz , Polissonografia , Respiração com Pressão Positiva/métodos , Risco , Fatores de Risco , Fases do Sono , Fatores de Tempo , Molécula 1 de Adesão de Célula Vascular/sangueRESUMO
A 79-year-old female presented with subarachnoid hemorrhage due to rupture of a rare true posterior communicating artery (PCoA) aneurysm and with poor general condition. Endovascular therapy was performed in the chronic stage. Right carotid angiography just before embolization demonstrated unusual multiple aneurysms of the internal carotid artery (ICA)-PCoA complex. Superselective angiography and aneurysmography using microcatheter revealed two separate aneurysms arising from the PCoA and the ICA-PCoA junction. Endovacular embolization using Guglielmi detachable coils (GDCs) was successfully performed for both aneurysms and complete occlusions were achieved with the PCoA fully patent. Embolization with GDCs is a good alternative to surgical clipping for PCoA aneurysm after careful evaluation of superselective angiography.
Assuntos
Aneurisma Roto/terapia , Artéria Carótida Interna/diagnóstico por imagem , Embolização Terapêutica/métodos , Aneurisma Intracraniano/terapia , Hemorragia Subaracnóidea/terapia , Idoso , Angiografia Cerebral , Artérias Cerebrais/diagnóstico por imagem , Doença Crônica , Feminino , Humanos , Aneurisma Intracraniano/diagnóstico , Hemorragia Subaracnóidea/diagnósticoRESUMO
The main medical treatment of moderate to severe obstructive sleep apnea/hypopnea syndrome is nasal continuous positive airway pressure(nCPAP). When compliance of the patient is low due to nasal or oral dryness, heated humidifier is added to nCPAP. In Japan frequent complaints such as nasal cold and dryness were observed in winter because of infrequent air conditioning in the sleeping room. In the case of dyspnea using nCPAP, bilevel PAP or auto CPAP is recommended. We treated 384 patients with nCPAP and 24% of the patients were added heated humidifier. Auto CPAP and bilevel PAP was administered in 10% and 6% of the patients indicated for PAP treatment, respectively.