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1.
Arch Gynecol Obstet ; 296(5): 947-956, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28875234

RESUMO

PURPOSE: To evaluate the occurrence of urogynecological symptoms in obese women treated in a university outpatient clinic for obesity, setting a focus on younger women. METHODS: In this explorative, prospective, cross-sectional, single-center, multidisciplinary clinical trial, all consecutively recruited women received the Prolapse Quality of Life questionnaire (P-QOL) for data acquisition. The total study population (TSP) and a subgroup (SG) aged 18-49 years were evaluated descriptively regarding symptom demonstration. RESULTS: Of the TSP (n = 166, mean age 40.2, standard deviation (SD) 12.98, mean body mass index (BMI) 45 kg/m2, SD 8.44) 105 (63%) and of the SG (n = 125, mean age 34.6, SD 9.29, mean BMI 44.9 kg/m2, SD 8.26) 72 (58%) women suffered from urinary incontinence (UI) being most impaired by stress urinary incontinence (SUI; TSP: 25%; SG: 27%) and least by urge urinary incontinence (UUI; TSP: 15%; SG: 11%). A significant correlation in the TSP between UI and age was detectable (p < 0.001, r φ = 0.37), but not between UI and BMI (p = 0.296, r φ = 0.08). The highest QOL impairment is detected for the domain general health perceptions [GHP; TSP & SG score >50 (score scale 0-100)]. Women with UI are significantly more affected than women with pelvic organ prolapse (GHP UI: TSP p = 0.04, SG p = 0.037; GHP POP: TSP p = 0.081, SG p = 0.659). CONCLUSIONS: A remarkable number of young obese women mentioned urogynecological symptoms and quality-of-life impairment. The P-QOL questionnaire proved to be an easily applicable tool to scan for concerned obese women. Its use in non-urogynecological departments, as performed, enables an early introduction of symptomatic women to urogynecologists, possibly preventing future growing urogynecological health issues.


Assuntos
Obesidade/complicações , Prolapso de Órgão Pélvico/epidemiologia , Incontinência Urinária por Estresse/epidemiologia , Incontinência Urinária de Urgência/epidemiologia , Adolescente , Adulto , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/psicologia , Prolapso de Órgão Pélvico/fisiopatologia , Prolapso de Órgão Pélvico/psicologia , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários , Incontinência Urinária , Incontinência Urinária por Estresse/fisiopatologia , Incontinência Urinária por Estresse/psicologia , Incontinência Urinária de Urgência/fisiopatologia , Incontinência Urinária de Urgência/psicologia , Adulto Jovem
2.
J Infect Dis ; 211(11): 1831-41, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25505299

RESUMO

BACKGROUND: The recombinant BCG ΔureC::hly (rBCG) vaccine candidate induces improved protection against tuberculosis over parental BCG (pBCG) in preclinical studies and has successfully completed a phase 2a clinical trial. However, the mechanisms responsible for the superior vaccine efficacy of rBCG are still incompletely understood. Here, we investigated the underlying biological mechanisms elicited by the rBCG vaccine candidate relevant to its protective efficacy. METHODS: THP-1 macrophages were infected with pBCG or rBCG, and inflammasome activation and autophagy were evaluated. In addition, mice were vaccinated with pBCG or rBCG, and gene expression in the draining lymph nodes was analyzed by microarray at day 1 after vaccination. RESULTS: BCG-derived DNA was detected in the cytosol of rBCG-infected macrophages. rBCG infection was associated with enhanced absent in melanoma 2 (AIM2) inflammasome activation, increased activation of caspases and production of interleukin (IL)-1ß and IL-18, as well as induction of AIM2-dependent and stimulator of interferon genes (STING)-dependent autophagy. Similarly, mice vaccinated with rBCG showed early increased expression of Il-1ß, Il-18, and Tmem173 (transmembrane protein 173; also known as STING). CONCLUSIONS: rBCG stimulates AIM2 inflammasome activation and autophagy, suggesting that these cell-autonomous functions should be exploited for improved vaccine design.


Assuntos
Autofagia/imunologia , Vacina BCG/imunologia , Inflamassomos/imunologia , Tuberculose/imunologia , Vacinas Sintéticas/imunologia , Animais , Linhagem Celular , Feminino , Humanos , Inflamação , Interleucina-18/imunologia , Interleucina-1beta/imunologia , Linfonodos/química , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL
3.
Br J Haematol ; 162(2): 202-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23692564

RESUMO

This phase 1 dose finding study tested a combination of lenalidomide, bendamustine and prednisolone (RBP) in 21 patients in five cohorts with advanced multiple relasped/refractory myeloma (MM) to determine the maximum tolerable dose (MTD) of the combination. The first cohort received a starting dose of lenalidomide 10 mg/d, days 1-21, bendamustine 60 mg/m(2) /d, days 1-2, and prednisolone 100 mg/d, days 1-4. Dose escalation was done in cohorts of three to six patients with lenalidomide dose increasing to 15, 20 and 25 mg, and after reaching 25 mg/d, bendamustine was increased to 75 mg/m(2) . A total of 21 patients were enrolled and all completed at least two cycles. Two patients developed dose-limiting haemotoxicity: one patient on lenalidomide 25 mg/d and bendamustine 60 mg/m(2) and another patient at the highest dose level (lenalidomide 25 mg/d and bendamustine 75 mg/m(2) ). The MTD was not reached. Sixteen patients (76%) responded after at least two cycles of RBP with one stringent complete response (CR), one near CR, five very good partial response and nine partial response. After a median observation time of 16 months, progression-free survival at 18 months was 48% and overall survival was 64%. In conclusion, RBP with lenalidomide 25 mg/d, days 1-21 and bendamustine 75 mg/m(2) days 1-2 is well tolerated in patients with relapsed/refractory MM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cloridrato de Bendamustina , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Compostos de Mostarda Nitrogenada/administração & dosagem , Compostos de Mostarda Nitrogenada/efeitos adversos , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Recidiva , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/análogos & derivados
4.
Anal Biochem ; 417(2): 233-41, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21741950

RESUMO

To obtain accurate results in miRNA expression changes between different sample sets using real-time quantitative polymerase chain reaction (RT-qPCR) analyses, normalization to reference genes that are stably expressed across the sample sets is generally used. A literature search of miRNA expression studies in renal cell carcinoma (RCC) proved that non-miRNAs such as small RNAs or mRNAs have most frequently been used without preceding validation of their suitability. In this study, the most stably expressed miRNAs were ascertained from microarray-based data of miRNA expression in nonmalignant and malignant samples from clear cell RCC and from corresponding distant RCC metastases using the geNorm and NormFinder algorithms. Validation experiments with RT-qPCR were performed for the four best-ranked miRNAs (miR-28, miR-103, miR-106a, miR-151) together with the small RNU6B, RNU44, and RNU48 mostly described in literature. miR-28, miR-103, miR-106a, and RNU48 were proved as the most stably expressed genes. miR-28 is recommended as normalizer if only a single reference gene can be used, while the combinations of miR-28 and miR-103 or of miR-28, miR-103, and miR-106a, respectively, are preferred. RNU6B most frequently used as normalizer in miRNA expression studies should be abandoned in order to avoid misleading results.


Assuntos
Carcinoma de Células Renais/genética , Genes Neoplásicos , Neoplasias Renais/genética , MicroRNAs/análise , Carcinoma de Células Renais/secundário , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/patologia , MicroRNAs/genética , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , RNA Nuclear Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Padrões de Referência
5.
Int J Cancer ; 126(5): 1166-76, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19676045

RESUMO

This study aimed to investigate the microRNA (miRNA) profile in prostate carcinoma tissue by microarray analysis and RT-qPCR, to clarify associations of miRNA expression with clinicopathologic data and to evaluate the potential of miRNAs as diagnostic and prognostic markers. Matched tumor and adjacent normal tissues were obtained from 76 radical prostatectomy specimens. Twenty-four tissue pairs were analyzed using human miRNA microarrays for 470 human miRNAs. Differentially expressed miRNAs were validated by TaqMan RT-qPCR using all 76 tissue pairs. The diagnostic potential of miRNAs was calculated by receiver operating characteristics analyses. The prognostic value was assessed in terms of biochemical recurrence using Kaplan-Meier and Cox regression analyses. Fifteen differentially expressed miRNAs were identified with concordant fold-changes by microarray and RT-qPCR analyses. Ten microRNAs (hsa-miR-16, hsa-miR-31, hsa-miR-125b, hsa-miR-145, hsa-miR-149, hsa-miR-181b, hsa-miR-184, hsa-miR-205, hsa-miR-221, hsa-miR-222) were downregulated and 5 miRNAs (hsa-miR-96, hsa-miR-182, hsa-miR-182, hsa-miR-183, hsa-375) were upregulated. Expression of 5 miRNAs correlated with Gleason score or pathological tumor stage. Already 2 microRNAs classified up to 84% of malignant and nonmalignant samples correctly. Expression of hsa-miR-96 was associated with cancer recurrence after radical prostatectomy and that prognostic information was confirmed by an independent tumor sample set from 79 patients. That was shown with hsa-miR-96 and the Gleason score as final variables in the Cox models build in the 2 patient sets investigated. Thus, differential miRNAs in prostate cancer are useful diagnostic and prognostic indicators. This study provides a solid basis for further functional analyses of miRNAs in prostate cancer.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , MicroRNAs/análise , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Adulto , Idoso , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa
6.
J Cell Mol Med ; 13(9B): 3918-28, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19228262

RESUMO

MicroRNAs are short single-stranded RNAs that are associated with gene regulation at the transcriptional and translational level. Changes in their expression were found in a variety of human cancers. Only few data are available on microRNAs in clear cell renal cell carcinoma (ccRCC). We performed genome-wide expression profiling of microRNAs using microarray analysis and quantification of specific microRNAs by TaqMan real-time RT-PCR. Matched malignant and non-malignant tissue samples from two independent sets of 12 and 72 ccRCC were profiled. The microarray-based experiments identified 13 over-expressed and 20 down-regulated microRNAs in malignant samples. Expression in ccRCC tissue samples compared with matched non-malignant samples measured by RT-PCR was increased on average by 2.7- to 23-fold for the hsa-miR-16, -452*, -224, -155 and -210, but decreased by 4.8- to 138-fold for hsa-miR-200b, -363, -429, -200c, -514 and -141. No significant associations between these differentially expressed microRNAs and the clinico-pathological factors tumour stage, tumour grade and survival rate were found. Nevertheless, malignant and non-malignant tissue could clearly be differentiated by their microRNA profile. A combination of miR-141 and miR-155 resulted in a 97% overall correct classification of samples. The presented differential microRNA pattern provides a solid basis for further validation, including functional studies.


Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/genética , Feminino , Humanos , Masculino , Oncologia/métodos , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
7.
Stud Health Technol Inform ; 129(Pt 1): 237-41, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17911714

RESUMO

This paper describes how an understanding of everyday conflicts that have ethical implications - what we call 'situated ethics'- can be explored through ethnographic field techniques in healthcare settings. Our approach to ethics is followed by findings from two ethnographic case studies focussing on issues arising as information technologies such as electronic patient records and automatic drug dispensing machines are introduced into varied health sector workplaces. By close and careful observation of these technologies in use and by incorporating narrative accounts from different perspectives the complexity and entangledness of real life occurrences are revealed. Our data suggest that several types of ethical issues (e.g., issues related to intellectual property, literacy, standardization, transparency, work ethics, and equitable allocation of resources) can be identified through fieldwork, and can have an impact on identification of everyday ethics in healthcare.


Assuntos
Ética Institucional , Informática/ética , Sistemas Computadorizados de Registros Médicos/ética , Sistemas de Medicação no Hospital/ética , Instituições de Assistência Ambulatorial/ética , Instituições de Assistência Ambulatorial/organização & administração , Antropologia Cultural , Humanos , Oncologia/ética , Oncologia/organização & administração , Estudos de Casos Organizacionais
8.
J Am Coll Cardiol ; 45(12): 2054-60, 2005 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-15963409

RESUMO

OBJECTIVES: The present study evaluates complete supra-annular bioprostheses in patients with an aortic annulus of 18 to 23 mm in diameter. BACKGROUND: Aortic valve replacement in patients with small aortic annulus using stented bioprostheses is often associated with unsatisfactory hemodynamic results and high incidence of patient-prosthesis mismatch. METHODS: Between February 2000 and January 2004, 156 patients with aortic valve disease and an aortic annulus of 18 to 23 mm in diameter received the stented bovine Soprano (Sorin Biomedica Cardio, Saluggia, Italy) (n = 18), Perimount (Edwards Lifesciences, Irvine, California) (n = 52), Perimount Magna (Edwards Lifesciences) (n = 42), or the stented porcine Mosaic (Medtronic Inc., Minneapolis, Minnesota) (n = 44) bioprostheses. Intraoperatively, the surgeon measured the aortic annulus diameter by inserting a hegar dilator. Thus, postoperative hemodynamic results could be referred to the patient's aortic annulus diameter instead of referring the results to the labeled valve size. This allows for objective comparisons between different valve types. RESULTS: There was no significant difference in hemodynamic results between the different valve types in patients with an aortic annulus 18 to 20 mm. In patients with an annulus 21 to 23 mm, the Magna was significantly superior to the other investigated devices in mean pressure gradient, effective orifice area, and incidence of patient-prosthesis mismatch. There was no significant difference between the complete supra-annular bioprostheses Mosaic and Soprano and the intra-supra-annular Perimount valve. CONCLUSIONS: In patients with an aortic annulus of 18 to 20 mm in diameter, hemodynamic performance is independent of the implanted stented valve type and the annular position. Root enlargement or stentless valves may be beneficial alternatives. Patients with annulus diameter 21 to 23 mm benefit from the Magna in complete supra-annular position leading to superior hemodynamic results.


Assuntos
Valva Aórtica , Bioprótese , Pressão Sanguínea/fisiologia , Doenças das Valvas Cardíacas/terapia , Próteses Valvulares Cardíacas , Volume Sistólico/fisiologia , Idoso , Idoso de 80 Anos ou mais , Desenho de Equipamento , Feminino , Doenças das Valvas Cardíacas/fisiopatologia , Implante de Prótese de Valva Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Stents , Resultado do Tratamento
9.
mBio ; 7(3)2016 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-27222470

RESUMO

UNLABELLED: The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve efficacy, we deleted the antiapoptotic virulence gene nuoG, encoding NADH dehydrogenase 1 subunit G, from BCG ΔureC::hly In vitro, deletion of nuoG unexpectedly led to strongly increased recruitment of the autophagosome marker LC3 to the engulfed vaccine, suggesting that nuoG also affects xenophagic pathways. In mice, BCG ΔureC::hly ΔnuoG vaccination was safer than BCG and improved protection over that of parental BCG ΔureC::hly, significantly reducing TB load in murine lungs, ameliorating pulmonary pathology, and enhancing immune responses. Transcriptome analysis of draining lymph nodes after vaccination with either BCG ΔureC::hly or BCG ΔureC::hly ΔnuoG demonstrated earlier and stronger induction of immune responses than that with BCG SSI and suggested upregulation of inflammasome activation and interferon-induced GTPases. In summary, BCG ΔureC::hly ΔnuoG is a promising next-generation TB vaccine candidate with excellent efficacy and safety. IMPORTANCE: Autophagy and apoptosis are fundamental processes allowing cells to degrade their components or kill themselves, respectively. The immune system has adopted these mechanisms to eliminate intracellular pathogens. Residing in host cells, the causative agent of tuberculosis, Mycobacterium tuberculosis, has evolved strategies to set cellular programs of autophagy and apoptosis "on hold." The mycobacterial gene nuoG was found to prevent host cell apoptosis. We have deleted nuoG in the live vaccine candidate BCG ΔureC::hly, which is in phase II clinical development, to leave cellular apoptosis "on go" upon immunization. In preclinical models, this strategy boosted immunity and improved protection from M. tuberculosis infection. Unexpectedly, we obtained compelling evidence that mycobacterial nuoG facilitates inhibition of autophagic pathways, suggesting a new role for this gene in the host-pathogen interplay in tuberculosis.


Assuntos
Vacina BCG/genética , Vacina BCG/imunologia , Complexo I de Transporte de Elétrons/genética , Deleção de Genes , Mycobacterium bovis/genética , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/prevenção & controle , Animais , Vacina BCG/administração & dosagem , Vacina BCG/efeitos adversos , Carga Bacteriana , Proteínas de Bactérias/genética , Perfilação da Expressão Gênica , Inflamassomos/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Linfonodos/imunologia , Linfonodos/microbiologia , Camundongos , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Vacinação
10.
J Thorac Cardiovasc Surg ; 129(5): 1056-63, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15867780

RESUMO

OBJECTIVE: This prospective randomized study compares a porcine with a bovine bioprosthesis in the aortic position with regard to hemodynamic performance during exercise. METHODS: Between August of 2000 and December of 2002, 136 patients underwent aortic valve replacement with the porcine Medtronic Mosaic (n = 66) or the bovine Carpentier-Edwards Perimount (n = 70) bioprosthesis. Transthoracic echocardiography was performed to assess hemodynamic and dimensional data preoperatively and 10 months postoperatively; the latter follow-up included stress echocardiography with treadmill exercise. RESULTS: At rest and during exercise (25 and 50 W), there was a significant difference in mean pressure gradient between the bovine and the porcine valves with labeled sizes 21 and 23, with superiority of the Perimount prosthesis. There was no difference in effective orifice area and incidence of patient-prosthesis mismatch among all sizes. The left ventricular mass index decreased significantly within 10 months postoperatively in the size 23 bovine group and the size 25 porcine group. CONCLUSIONS: Our data show a significant superiority of pressure gradients for the bovine bioprosthesis, especially with small valve sizes, when compared with the porcine device, which is more distinctive during exercise.


Assuntos
Estenose da Valva Aórtica/fisiopatologia , Bioprótese/normas , Pressão Sanguínea , Exercício Físico , Implante de Prótese de Valva Cardíaca/instrumentação , Próteses Valvulares Cardíacas/normas , Idoso , Idoso de 80 Anos ou mais , Animais , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Bovinos , Ecocardiografia , Teste de Esforço , Feminino , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Desenho de Prótese , Falha de Prótese , Ajuste de Prótese , Descanso , Volume Sistólico , Suínos , Resultado do Tratamento
11.
J Heart Valve Dis ; 14(6): 814-21; discussion 821, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16359064

RESUMO

BACKGROUND AND AIM OF THE STUDY: Stentless valves are considered to exhibit better hemodynamics after aortic valve replacement (AVR) compared to stented valves. However, a new generation of stented bioprostheses for completely supra-annular implantation has been designed to optimize the ratio of the effective orifice area (EOA) of the prosthesis and aortic annulus area. The study aim was to determine whether a stentless valve implanted in the subcoronary technique renders larger orifice areas and lower transvalvular pressure gradients at rest and exercise compared to a completely supra-annular stented device. METHODS: Twenty patients underwent AVR for aortic stenosis with the St. Jude Medical (SJM) Toronto Root stentless porcine bioprosthesis, using a subcoronary implantation technique. Through the authors' institutional database, 20 additional patients were identified who had undergone AVR with the Medtronic Mosaic stented completely supra-annular porcine bioprosthesis. The patient groups were not matched for labeled valve size, but for annulus diameter measured intraoperatively using Hegar's dilators. Hemodynamic performance was assessed by transthoracic echocardiography at discharge (early) and by rest and stress echocardiography at six months postoperatively (mid-term). RESULTS: Transvalvular mean pressure gradients (MPG) at rest were significantly lower in the stentless group, but cardiac output was similar in both groups. Stress echocardiography also revealed significantly lower gradients at 25 W and 50 W exercise in the stentless group. The EOA index (EOAI), grouped by annulus diameter, tended to be larger in the stentless group and showed no severe patient-prosthesis mismatch (PPM; EOAI <0.65 cm2/m2) which, in contrast, occurred in three patients (15%) in the stented group (p = 0.072). CONCLUSION: In summary, the SJM Toronto Root porcine stentless bioprosthesis in the subcoronary position showed lower MPGs and larger EOAs at rest and during exercise compared to the Medtronic Mosaic porcine stented bioprosthesis. Therefore, physically active patients in particular may benefit from use of the stentless valve. Because of its larger EOA, a stentless valve should be implanted if severe PPM is expected.


Assuntos
Valva Aórtica/cirurgia , Bioprótese , Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Hemodinâmica , Stents , Idoso , Estenose da Valva Aórtica/cirurgia , Ecocardiografia Doppler , Ecocardiografia sob Estresse , Feminino , Humanos , Masculino , Desenho de Prótese
12.
J Heart Valve Dis ; 14(6): 822-7, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16359065

RESUMO

BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the clinical and hemodynamic performance of the Sorin Soprano bioprosthesis in the aortic position. METHODS: Rest and stress echocardiography were performed at six months after surgery in 57 patients who underwent aortic valve replacement with the stented Soprano bioprosthesis. The exercise protocol included workloads of 25, 50, 75 and 100 W, each of 2 min duration. RESULTS: Thirty-day mortality was 1.8% (n = 1). Due to malperfusion of the coronary arteries, two Soprano prostheses had to be replaced by a different prosthesis, and one patient received coronary artery bypass grafts. One patient developed bacterial endocarditis of his prosthesis at seven months postoperatively and died as a result of a fulminant sepsis. There were no other prosthesis-related adverse events. Mean pressure gradients (MPG) ranged from 7.8 to 15.9 mmHg, effective orifice areas (EOA) from 1.25 to 2.98 cm2, EOA index (EOAI) from 0.79 to 1.43 cm2/m2, and EOA fraction from 34 to 45%. Stress echocardiography showed no significant increase in MPG up to 50 W, and MPGs did not exceed 35 mmHg at 75 and 100 W. CONCLUSION: Initial hemodynamic results showed low MPGs during rest and exercise. The EOAI was large due to completely supra-annular placement of the Soprano valve. The difficulty of complete supraannular placement is that the prosthesis is positioned relatively high, especially in narrow aortic roots, and this may handicap coronary artery perfusion. Patient selection with suitable aortic root anatomy is crucial to achieve the benefit of completely supra-annular implantation without coronary ostium deterioration.


Assuntos
Valva Aórtica/cirurgia , Bioprótese , Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Idoso , Valva Aórtica/fisiopatologia , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Feminino , Humanos , Masculino , Desenho de Prótese , Falha de Prótese , Stents
13.
J Mol Diagn ; 15(5): 695-705, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23945108

RESUMO

Bladder cancer is a common cancer in the Western world. The current prognosticators such as tumor grade, stage, size, and multifocality do not accurately reflect the clinical outcome. It is of clinical interest to identify biomarkers that could improve diagnostic and/or prognostic predictions. The objectives of this study were to identify deregulated miRNAs in bladder cancer samples and evaluate their potential as diagnostic and prognostic biomarkers. We screened 723 miRNAs by microarray and selected a subset of 15 distinctively deregulated miRNAs for further validation by real-time quantitative RT-(q)PCR. Seven miRNAs (miR-20a, miR-106b, miR-130b, miR-141, miR-200a, miR-200a*, and miR-205) were found to be up-regulated and eight miRNAs (miR-100, miR-125b, miR-130a, miR-139-5p, miR-145*, miR-199a-3p, miR-214, and miR-222) were found to be down-regulated in malignant bladder tissue samples compared to healthy tissue. Four miRNAs that have already been described in the literature (miR-141, miR-199a-3p, miR-205, and miR-214) were significantly differentially expressed between nonmuscle-invasive and muscle-invasive bladder cancer. Furthermore, real-time RT-qPCR of all miRNAs provided high overall correct classification (>75%) of bladder cancer diagnosis. Two miRNAs (miR-141 and miR-205) were associated with overall survival time. The verification of tumor-specific miRNA expression profile, together with the observed association of miR-141 and miR-205 expression with overall survival, underline the potential of miRNAs to function as diagnostic and/or prognostic markers of bladder cancer.


Assuntos
Perfilação da Expressão Gênica , MicroRNAs/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes
14.
J Cancer Res Clin Oncol ; 139(3): 499-508, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23184429

RESUMO

INTRODUCTION: Bortezomib (Velcade) is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination with other cytostatic agents in multiple myeloma (MM). In the present protocol, bortezomib was combined with other active substances like bendamustine and prednisone (BPV), in order to assess the efficacy and toxicity of the combination therapy in patients with relapsed or refractory MM. METHODS: Between January 2005 and December 2011, 78 patients with relapsed or refractory MM were treated with bendamustine 60 (-120) mg/m(2) on days 1 and 2, bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11. The median number of prior therapies was 2 with a wide range of 1-9. Thirty-three patients had pre-existing severe thrombocytopenia and/or neutropenia (WHO grade 3 or 4). RESULTS: A median number of two (range 1-7) BPV treatment cycles were given to the patients. The majority of the patients (n = 54; 69 %) responded after at least one cycle of chemotherapy with 3 CR, 10 nCR, 10 VGPR and 31 PR. Median PFS and OS for patients without severe hematological toxicities due to previous treatments (n = 45) were 11 and 50 months, respectively. Outcome for these patients was significantly better than that for patients with severe hematological toxicities (grade 3 or 4, n = 33) with a PFS, and OS of 3 months (p < 0.05) and 5 months (p < 0.001), respectively. The regimen was well tolerated with few significant side effects in patients without severe hematological toxicities due to previous treatments. These results indicate that the combination of bortezomib, bendamustine and prednisone is well tolerated in patients with relapsed or refractory MM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Compostos de Mostarda Nitrogenada/administração & dosagem , Prednisona/administração & dosagem , Pirazinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina , Ácidos Borônicos/efeitos adversos , Bortezomib , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Compostos de Mostarda Nitrogenada/efeitos adversos , Prednisona/efeitos adversos , Pirazinas/efeitos adversos , Recidiva , Estudos Retrospectivos
15.
PLoS One ; 7(6): e39309, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22745731

RESUMO

BACKGROUND/OBJECTIVE: Reverse transcription quantitative real-time PCR (RT-qPCR) is widely used in microRNA (miRNA) expression studies on cancer. To compensate for the analytical variability produced by the multiple steps of the method, relative quantification of the measured miRNAs is required, which is based on normalization to endogenous reference genes. No study has been performed so far on reference miRNAs for normalization of miRNA expression in urothelial carcinoma. The aim of this study was to identify suitable reference miRNAs for miRNA expression studies by RT-qPCR in urothelial carcinoma. METHODS: Candidate reference miRNAs were selected from 24 urothelial carcinoma and normal bladder tissue samples by miRNA microarrays. The usefulness of these candidate reference miRNAs together with the commonly for normalization purposes used small nuclear RNAs RNU6B, RNU48, and Z30 were thereafter validated by RT-qPCR in 58 tissue samples and analyzed by the algorithms geNorm, NormFinder, and BestKeeper. PRINCIPAL FINDINGS: Based on the miRNA microarray data, a total of 16 miRNAs were identified as putative reference genes. After validation by RT-qPCR, miR-101, miR-125a-5p, miR-148b, miR-151-5p, miR-181a, miR-181b, miR-29c, miR-324-3p, miR-424, miR-874, RNU6B, RNU48, and Z30 were used for geNorm, NormFinder, and BestKeeper analyses that gave different combinations of recommended reference genes for normalization. CONCLUSIONS: The present study provided the first systematic analysis for identifying suitable reference miRNAs for miRNA expression studies of urothelial carcinoma by RT-qPCR. Different combinations of reference genes resulted in reliable expression data for both strongly and less strongly altered miRNAs. Notably, RNU6B, which is the most frequently used reference gene for miRNA studies, gave inaccurate normalization. The combination of four (miR-101, miR-125a-5p, miR-148b, and miR-151-5p) or three (miR-148b, miR-181b, and miR-874,) reference miRNAs is recommended for normalization.


Assuntos
MicroRNAs/genética , Neoplasias da Bexiga Urinária/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real
16.
J Cancer Res Clin Oncol ; 138(8): 1405-12, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22526157

RESUMO

PURPOSE: Renal failure is a frequent complication of multiple myeloma (MM) and, if present at diagnosis, a considerable risk factor for outcome. Treatment with chemotherapy and/or new agents may result in recovery of renal function in up to 50 % of patients. The window of opportunity to reverse renal impairment is, however, rather small, making an immediate and highly active treatment strategy mandatory. Bortezomib as well as bendamustine has been demonstrated to be potent drugs in the treatment of MM. METHODS: A total of 18 patients with newly diagnosed/untreated MM and renal insufficiency (GFR < 35 ml/min) were treated with bendamustine, prednisone, and bortezomib (BPV). RESULTS: The majority of them (n = 15; 83 %) responded after at least one cycle of chemotherapy with three sCR, five nCR, five VGPR, and two PR. With a median follow-up of 17 months, PFS at 18 months was 57 % and OS was 61 %. The myeloma protein decreased rapidly, reaching the best response after the first cycle in four and after the second cycle in additional seven patients. Thirteen patients (72 %) improved their renal function after treatment. CONCLUSION: We conclude that the combination of bortezomib, bendamustine, and prednisone is effective and well tolerated in patients with a newly diagnosed MM and renal failure.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Insuficiência Renal/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Náusea/induzido quimicamente , Compostos de Mostarda Nitrogenada/administração & dosagem , Compostos de Mostarda Nitrogenada/efeitos adversos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Insuficiência Renal/complicações , Estudos Retrospectivos , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Vômito/induzido quimicamente
17.
Int J Biol Sci ; 8(10): 1363-74, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23139634

RESUMO

MicroRNAs (miRNAs) play a pivotal role in cancerogenesis and cancer progression, but their specific role in the metastasis of clear cell renal cell carcinomas (ccRCC) is still limited. Based on microRNA microarray analyses from normal and cancerous samples of ccRCC specimens and from bone metastases of ccRCC patients, we identified a set of 57 differentially expressed microRNAs between these three sample groups of ccRCC. A selected panel of 33 miRNAs was subsequently validated by RT-qPCR on total 57 samples. Then, 30 of the 33 examined miRNAs were confirmed to be deregulated. A stepwise down-regulation of miRNA expression from normal, over primary tumor to metastatic tissue samples, was found to be typical. A total of 23 miRNAs (miR-10b/-19a/-19b/-20a/-29a/-29b/-29c/-100/-101/-126/-127/-130/-141/-143/-145/-148a/-192/-194/-200c/-210/-215/-370/-514) were down-regulated in metastatic tissue samples compared with normal tissue. This down-regulated expression in metastatic tissue in comparison with primary tumor tissue was also present in 21 miRNAs. In cell culture experiments with 5-aza-2'-deoxycytidine and trichostatin A, epigenetic modifications were shown as one reason of this down-regulation. The altered miRNA profiles, comprising newly identified metastasis-associated miRNAs, termed metastamir and the predicted miRNA-target interactions together with the significant correlations of miRNAs that were either lost or newly appeared in the studied sample groups, afford a solid basis for further functional analyses of individual miRNAs in RCC metastatic progression.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/secundário , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , MicroRNAs/fisiologia , Epigênese Genética , Humanos , Neoplasias Renais/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Células Tumorais Cultivadas
19.
Pain ; 152(2): 285-290, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20947251

RESUMO

Posttraumatic TNF-alpha signaling may be one of the factors responsible for pain and hyperalgesia in complex regional pain syndromes (CRPS). In order to further specify the role of TNF-alpha we investigated tissue (skin) and serum concentrations in three different patient groups: patients with osteoarthritis and planned surgery, with acute traumatic upper limb bone fracture waiting for surgery, and with CRPS I. Thirty patients (10 in each group) were recruited. Mean CRPS duration was 36.1 ± 8.1 weeks (range 8- 90 weeks). Skin punch biopsies were taken at the beginning of the surgery in osteoarthritis and fracture patients and from the affected side in CRPS patients. Blood samples were taken before the respective procedures. Skin and serum TNF-alpha levels were quantified by ELISA. Compared to patients with osteoarthritis, skin TNF-alpha was significantly elevated in CRPS (p<0.001) and fracture patients (p<0.04). Skin TNF-alpha in CRPS patients was higher than in patients with acute bone fracture (p<0.02). In contrast, serum TNF-alpha values were the same in osteoarthritis and CRPS, and lower in fracture patients (p<0.03). Our results indicate a local but not systemic increase of TNF-alpha in CRPS patients. This increase persists for months after limb trauma and may offer the opportunity for targeted treatment.


Assuntos
Síndromes da Dor Regional Complexa/sangue , Fator de Necrose Tumoral alfa/sangue , Ferimentos e Lesões/sangue , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndromes da Dor Regional Complexa/diagnóstico , Síndromes da Dor Regional Complexa/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Fraturas Ósseas/sangue , Fraturas Ósseas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/sangue , Osteoartrite/patologia , Projetos Piloto , Pele/metabolismo , Pele/patologia , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima/fisiologia , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/patologia
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