RESUMO
OBJECTIVE: To compare the physical and emotional effects of two medical protocols for induced abortion during the second trimester. METHODS: The present study was part of a prospective randomized controlled trial comparing mifepristone followed by oxytocin or misoprostol that was conducted at the Hadassah Hebrew University Medical Center, Jerusalem, Israel, from January 10, 2009, to February 22, 2012. Inclusion criteria were pregnancy (14-24weeks), epidural analgesia, and medical induction of abortion (either elective or following missed abortion). A structured questionnaire was used to assess the participants' physical symptoms and emotional responses. The primary outcome for the present analysis was the degree of physical symptoms reported. RESULTS: Overall, 68 women in the oxytocin group and 67 in the misoprostol group received epidural analgesia and completed the questionnaire. As assessed using a five-point Likert scale, women in the misoprostol group were more likely than those in the oxytocin group to experience diarrhea (1.34±0.84 vs 1.10±0.55; P=0.05) and shivers (3.03±1.75 vs 1.75±1.21; P<0.001). No other between-group differences were detected for the physical or emotional variables evaluated. CONCLUSION: Differences in physical symptoms experienced by the two treatment groups did not influence the participants' subsequent emotional response. ClinicalTrials.gov: NCT00784797.
Assuntos
Abortivos/administração & dosagem , Aborto Induzido/psicologia , Mifepristona/administração & dosagem , Misoprostol/administração & dosagem , Ocitocina/administração & dosagem , Segundo Trimestre da Gravidez , Administração Intravaginal , Administração Intravenosa , Administração Oral , Adulto , Diarreia , Emoções , Feminino , Humanos , Israel , Gravidez , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , EstremecimentoRESUMO
AIM: Leiomyomas, monoclonal tumors developed by the transformation of myometrium somatic stem cells, are a major health concern that can severely impair quality of life. Pathological alterations of signaling pathways have been recognized as a key feature in a variety of human diseases. Our objective was to analyze treatment with all-trans-retinoic acid (ATRA) by suppression of the phosphoinositide 3-kinase (PI3K) pathway on growth, signaling pattern and interactions among PI3K/B-cell lymphoma 2 (Bcl2)/retinol leiomyoma proteins. METHODS: Cultures of paired myometrium and leiomyoma cells from premenopausal women undergoing hysterectomy were collected. Western blot and analysis of variance were used for analysis. RESULTS: Significant differences were detected between treatment with ATRA alone or with LY294002 (a PI3K growth suppressor) in response to treatment and among cell samples and cell numbers. Leiomyoma cells were less affected. Immunochemical analysis of signaling patterns demonstrated that treatments affected most of the examined protein levels differently. Significant differences between the cell type responses to treatment in pyruvate phosphate dikinase 1 (pPDK1), Bad and pß-catenin levels were identified. The pß-catenin level showed highly significant interaction between response to treatment and cell type. CONCLUSIONS: ATRA treatment on PI3K pathway suppression significantly affected growth, signaling pattern and interactions among PI3K/Bcl2/retinol proteins involved in the growth, survival and apoptosis of leiomyomas. Interpretation of our results suggests that increasing knowledge of the role of signaling interplay in the pathogenesis of leiomyomas may present an opportunity to use specific signal transduction inhibitors for treating and preventing this disorder.
Assuntos
Leiomioma/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia , Neoplasias Uterinas/metabolismo , beta Catenina/metabolismo , Adulto , Linhagem Celular Tumoral , Cromonas/farmacologia , Feminino , Humanos , Histerectomia , Leiomioma/tratamento farmacológico , Pessoa de Meia-Idade , Morfolinas/farmacologia , Miométrio/efeitos dos fármacos , Miométrio/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Pré-Menopausa , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Tretinoína/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
OBJECTIVE: To compare two methods for induction of second-trimester abortion after priming the cervix with mifepristone. METHODS: This was a randomized prospective trial carried out between January 2009 and February 2012. The participants were healthy women between 14 and 24 weeks of gestation with missed miscarriage or need for termination of pregnancy. All participants received oral 200 mg mifepristone and, after 36 hours, after randomization, were given either a high-concentration oxytocin drip (maximal dose of 150 milli-international units/min) for up to 36 hours or 800 micrograms misoprostol vaginally followed by 400 micrograms oral misoprostol every 3 hours with a maximum of four oral doses. If expulsion of the fetus was not achieved, another 200 mg mifepristone was administered and another course of misoprostol was delivered as described previously. The primary outcome measure was success expulsion of the fetus in 36 hours since starting on uterotonic agent. Secondary outcomes included time until expulsion of the fetus and rate of adverse outcomes. RESULTS: Success rates in the mifepristone-misoprostol and mifepristone-oxytocin arms were 100% (70/70 patients) and 95.8% (69/72), respectively (relative risk 1.043, 95% confidence interval 0.99-1.10, P=.13). Time until fetal expulsion was shorter in the mifepristone-misoprostol arm (7.0 ± 4.9 hours compared with 11.3 ± 7.4 hours, P<.001). However, the rate of adverse effects in the misoprostol group was higher than in the oxytocin group. Factors associated with a shorter time until expulsion were missed miscarriage compared with therapeutic abortion, increased ultrasonographic gestational age, and increased parity. CONCLUSION: The two regimens studied had comparable efficacy for induction of second-trimester abortion; however, the mifepristone-oxytocin regimen has a longer time until expulsion but with fewer side effects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00784797. LEVEL OF EVIDENCE: : I.
Assuntos
Abortivos não Esteroides/administração & dosagem , Aborto Induzido/métodos , Misoprostol/administração & dosagem , Ocitócicos/administração & dosagem , Ocitocina/administração & dosagem , Abortivos não Esteroides/efeitos adversos , Abortivos Esteroides/administração & dosagem , Abortivos Esteroides/efeitos adversos , Adolescente , Adulto , Feminino , Humanos , Mifepristona/administração & dosagem , Mifepristona/efeitos adversos , Misoprostol/efeitos adversos , Ocitócicos/efeitos adversos , Ocitocina/efeitos adversos , Gravidez , Segundo Trimestre da Gravidez , Estudos Prospectivos , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: To detect changes induced by all-trans-retinoic acid (ATRA) on the expression and activation of target proteins of the retinoic acid (RA) and PI3K/Akt pathways involved in leiomyoma growth. DESIGN: A study on human tissue cultures. SETTING: Hadassah University Hospital. PATIENT(S): Premenopausal women with uterine leiomyomas. INTERVENTION(S): Paired cultures of normal myometrium and leiomyomas, from women undergoing hysterectomy, were obtained. MAIN OUTCOME MEASURE(S): The effect of ATRA was examined on the expression and phosphorylation of relevant RA, PI3K/Akt, and Bcl2 proteins (immunochemical analysis), cell proliferation, cell cycle distribution, and apoptosis. RESULT(S): Applying our cell culture model, we demonstrated that ATRA induced changes in the expression and activation of the RA and PI3K/Akt pathway proteins in leiomyoma cells, with significant increases of alcohol dehydrogenase 1 and cyclin D2 protein levels. In part of the leiomyoma cells, ATRA induced a relative increase of Bax (proapoptotic) as well as a relative decrease of phosphorylated glycogen synthase kinase 3ß (proapoptotic). CONCLUSION(S): Our results highlight the involvement of ATRA in the RA and PI3K/Akt pathways, whose specific signaling products may influence the outcome of leiomyoma growth by regulating cell proliferation, apoptosis, and survival. These results might be useful for the on-going research into alternative methods for treating and preventing this disorder.
Assuntos
Leiomioma/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Tretinoína/metabolismo , Tretinoína/farmacologia , Neoplasias Uterinas/metabolismo , Adulto , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Leiomioma/patologia , Análise por Pareamento , Pessoa de Meia-Idade , Modelos Biológicos , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Neoplasias Uterinas/patologiaRESUMO
OBJECTIVE: To identify changes in the expression and phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt protein kinases controlling survival and/or apoptosis of in vitro cell cultures of uterine leiomyomas. DESIGN: Establishment of paired cell cultures of leiomyoma and myometrial specimens. SETTING: Hadassah gynecology research laboratory. PATIENT(S): Eleven white premenopausal women, 35 to 50 years of age, undergoing hysterectomy because of symptomatic uterine leiomyomas. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Immunochemical analysis of expression and phosphorylation of relevant PI3K/Akt and BCL2 proteins. RESULT(S): Analysis of total phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and of nonphosphorylated and phosphorylated (p) PDK1, Akt, glycogen synthase kinase 3 (GSK3), FKHR, tuberin (TSC2) and hamartin (TSC1) complex, and cyclin D2 proteins indicated that [1] the level of pGSK3alpha and cyclin D2 proteins was elevated significantly in the leiomyoma compared with the normal myometrium, [2] there was a significant interaction between PTEN- PDK1 and between pAkt-pGSK3beta in the leiomyoma compared with the myometrial cells, and [3] there was a significant interaction between pAkt-pGSK3alpha in the paired leiomyoma and myometrial cultures. CONCLUSION(S): Our study suggests that the downstream signaling components of the PI3K/Akt pathway, GSK3 (a regulator of apoptosis), and cyclin D2 (a promoter of G1/S progression), as well as the significant interaction between PTEN-PDK and between pAkt-pGSK3beta, are involved in the survival and proliferation of leiomyomas.
Assuntos
Ciclina D2/fisiologia , Quinase 3 da Glicogênio Sintase/fisiologia , Leiomioma/fisiopatologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Neoplasias Uterinas/fisiopatologia , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Miométrio/metabolismo , PTEN Fosfo-Hidrolase/fisiologia , Fosforilação , Proteínas Serina-Treonina Quinases/fisiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Allen-Masters syndrome, first described at 1955, is considered an uncommon etiology for chronic pelvic pain. The syndrome associates traumatic delivery to lacerations found on the posterior leaf of the broad Ligament. The authors report the clinical and laparoscopic findings of a female patient who was admitted to their department for evaluation due to chronic pelvic pain. The patient had a history of normal delivery six months before her admission. In the laparoscopy the authors reported finding bilateral Lacerations in the posterior leaf of the broad Ligament. Coagulation of both lacerations was performed and the patient reported significant improvement in her complaints. The relevant literature was reviewed and the article discusses the process of diagnosis and treatment.
Assuntos
Ligamento Largo/cirurgia , Dor Pélvica/etiologia , Dor Pélvica/cirurgia , Adulto , Ligamento Largo/patologia , Parto Obstétrico , Feminino , Humanos , Lacerações/patologia , Lacerações/cirurgia , Laparoscopia , Dor Pélvica/patologia , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/cirurgia , Gravidez , SíndromeRESUMO
Isolated fallopian tube torsion (ITT) is a rare condition defined as a total or partial rotation of the fallopian tube around its vascular axis. The torsion initiaLLy interferes with the venous and lymphatic circulation. If unrelieved in time, rapid progression occurs, occluding the arterial circulation and Leading to gangrene and hemorrhagic necrosis. The cLinicaL appearance usually includes sharp lower abdominal pain, with or without peritoneal signs. Urinary and gastrointestinal signs might also occur. isolated fallopian tube is a rare condition; the incidence s estimated to be 1:500,000 mostly in reproductive age women. ITT is most common in the right side, although several reports claim that there is no difference between the sides. The etiology is not completely understood, but tubal anomalies (anatomic or physiologic) as well as trauma or pelvic inflammation are predisposing factors. The clinical appearance and the imaging in these cases are not pathognomonic, and many cases are delayed by means of diagnosis and treatment. The treatment is surgical. Detorsion or salpingectomy is usually performed by laparoscopy. Three cases that were treated lately at the Department of Obstetrics and Gynecology at the Hadassah Medical Center are presented together with a review of the literature.
Assuntos
Doenças das Tubas Uterinas/patologia , Anormalidade Torcional/patologia , Doenças das Tubas Uterinas/epidemiologia , Tubas Uterinas/irrigação sanguínea , Tubas Uterinas/patologia , Feminino , Lateralidade Funcional , Humanos , Incidência , RotaçãoRESUMO
BACKGROUND AND AIMS: microRNAs (miRNAs) are small noncoding RNAs that regulate cognate mRNAs post-transcriptionally. miRNAs have been implicated in regulating gene expression in embryonic developmental processes, including proliferation and differentiation. The liver is a multifunctional organ, which undergoes rapid changes during the developmental period and relies on tightly-regulated gene expression. Little is known regarding the complex expression patterns of both mRNAs and miRNAs during the early stages of human liver development, and the role of miRNAs in the regulation of this process has not been studied. The aim of this work was to study the impact of miRNAs on gene expression during early human liver development. METHODS: Global gene and miRNA expression were profiled in adult and in 9-12w human embryonic livers, using high-density microarrays and quantitative RT-PCR. RESULTS: Embryonic liver samples exhibited a gene expression profile that differentiated upon progression in the developmental process, and revealed multiple regulated genes. miRNA expression profiling revealed four major expression patterns that correlated with the known function of regulated miRNAs. Comparison of the expression of the most regulated miRNAs to that of their putative targets using a novel algorithm revealed a significant anti-correlation for several miRNAs, and identified the most active miRNAs in embryonic and in adult liver. Furthermore, our algorithm facilitated the identification of TGFbeta-R1 as a novel target gene of let-7. CONCLUSIONS: Our results uncover multiple regulated miRNAs and genes throughout human liver development, and our algorithm assists in identification of novel miRNA targets with potential roles in liver development.
Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Fígado/embriologia , Fígado/metabolismo , MicroRNAs/genética , Algoritmos , Diferenciação Celular , Proliferação de Células , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Hepatócitos/metabolismo , Humanos , Fígado/crescimento & desenvolvimento , MicroRNAs/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Serina-Treonina Quinases/biossíntese , RNA Mensageiro/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: To study the effect of mifepristone for priming and induction of second-trimester abortion in conjunction with a high-concentration oxytocin drip. STUDY DESIGN: Prospective, randomized, placebo-controlled, pilot study. Thirty patients with 14-25 weeks' gestational age abortion received either 600 mg of mifepristone or placebo in 3 identical capsules followed, 48 hours later, by a high-concentration oxytocin drip (HCOD). RESULTS: The mifepristone group showed significantly higher success rates as compared to the placebo group (92.3% vs. 52.9%, p<0.05). The time interval to abortion (from beginning of HCOD) was also significantly shorter in the mifepristone group as compared to the placebo group (11.3 +/- 6.0 hours vs. 17.6 +/- 6.5 hours, p <0.05). Probability of success as calculated by the Kaplan-Meier method was found to be highly significant (log rank test p = 0.001). CONCLUSION: Our results suggest that mifepristone is very effective for priming and induction of second-trimester abortion and shortens significantly the time interval to evacuation following HCOD.
Assuntos
Abortivos/administração & dosagem , Aborto Induzido , Mifepristona/administração & dosagem , Ocitocina/administração & dosagem , Segundo Trimestre da Gravidez , Aborto Retido/terapia , Administração Oral , Adulto , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Projetos Piloto , Placebos , Gravidez , Adulto JovemRESUMO
BACKGROUND: Secondary post-partum hemorrhage (PPH) is defined as any abnormal bleeding from the birth canal occurring between 24 hours and 12 weeks postnatally. Treatment usually falls into one of the two categories: surgical evacuation of the uterus or medical treatment. OBJECTIVE: To compare the two different clinical approaches and the implications on future fertility. STUDY DESIGN: A retrospective study. SETTING: From 1990 to 2002, 168 women diagnosed with late PPH were admitted to the Hadassah Medical Centers in Jerusalem. The cases were divided into two groups according to the planned initial treatment: primary surgical treatment vs. primary medical treatment. RESULTS: Primary surgical treatment was associated with significantly more primary negative events (p=0.01). After the primary event, primary surgical treatment was associated with fewer future deliveries (p=0.04) and resulted in increased rate of secondary infertility of borderline significance (p=0.06). CONCLUSIONS: Our results show that secondary PPH is related to high rates of immediate and long-term complications. It is possible that a conservative medical approach for secondary PPH may be superior to surgical treatment.
Assuntos
Hemorragia Pós-Parto/terapia , Adulto , Estudos de Coortes , Parto Obstétrico/efeitos adversos , Feminino , Técnicas Hemostáticas , Humanos , Histerectomia , Hemorragia Pós-Parto/etiologia , Hemorragia Pós-Parto/patologia , Recidiva , Retratamento , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoAssuntos
Fumarato Hidratase/metabolismo , Leiomioma/epidemiologia , Leiomioma/metabolismo , Miométrio/metabolismo , Neoplasias Uterinas/metabolismo , Células Cultivadas , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leiomioma/genética , Leiomioma/patologia , Miométrio/citologia , Estudos Retrospectivos , Fatores de Risco , Neoplasias Uterinas/patologiaRESUMO
OBJECTIVE: To examine the effect of alcohol and its derivatives on leiomyomata versus normal myometrium in cell culture. DESIGN: A study on human tissue cultures. SETTING: A tertiary-care university hospital. PATIENT(S): Premenopausal women with uterine myomas. INTERVENTION(S): Obtaining paired cultures of normal myometrium and myomas from women undergoing hysterectomy. MAIN OUTCOME MEASURE(S): Analysis of the effect of ethanol and acetaldehyde on cell growth and the expression of relevant proteins. RESULT(S): Acetaldehyde statistically significantly inhibited the growth of myoma cells compared with normal myometrium. The level of alcohol dehydrogenase 1 (ADH1) protein was lower in myoma than in myometrial cells. The acetaldehyde dehydrogenase 1 (ALDH1) protein level was higher in myoma cells. Treatment with acetaldehyde resulted in a relative reduction of ALDH1 level in the myoma cells. CONCLUSION(S): Acetaldehyde has an inhibitory effect on cell growth of myoma compared with normal myometrium. The reduced level of ADH1 and the increased level of ALDH1 proteins observed in myoma cell culture reduces the acetaldehyde level and thus may be involved in myoma cell growth.
Assuntos
Acetaldeído/toxicidade , Proliferação de Células/efeitos dos fármacos , Etanol/toxicidade , Leiomioma/patologia , Miométrio/efeitos dos fármacos , Neoplasias Uterinas/patologia , Acetaldeído/metabolismo , Álcool Desidrogenase/metabolismo , Aldeído Desidrogenase/metabolismo , Família Aldeído Desidrogenase 1 , Relação Dose-Resposta a Droga , Etanol/metabolismo , Feminino , Humanos , Isoenzimas/metabolismo , Leiomioma/enzimologia , Leiomioma/metabolismo , Miométrio/enzimologia , Miométrio/metabolismo , Miométrio/patologia , Retinal Desidrogenase , Fatores de Tempo , Células Tumorais Cultivadas , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/metabolismoRESUMO
OBJECTIVE: To study whether osteopenia occurs following pregnancy and to evaluate its severity in young primiparas. STUDY DESIGN: A prospective case control study. Sixty-one young primigravidae early after birth and 59 nulligravidae matched for age and BMI participated in the study. Bone status was examined using ultrasonic bone transmission velocity over the tibia; Z-score and T-score for bone density were calculated. Serum bone alkaline phosphatase, osteocalcin and urinary N-telopeptide crosslinks were evaluated as bone remodeling biochemical markers. RESULTS: Ultrasonic parameters of bone status following delivery were significantly lower in the puerperal group as compared to the nulligravida group. Serum mean bone alkaline phosphatase levels and urinary N-telopeptide crosslinks secretion were higher by 50% in the puerperal group, while serum osteocalcin levels were significantly lower (by 25%) than in the nulligravida controls. A positive correlation between ultrasonic measurements and biochemical markers was demonstrated in the postpartum group, whereas the control group showed a negative correlation. CONCLUSION: Women at their early puerperium demonstrate a significant cortical bone mass reduction as measured by ultrasonograph and markers of bone turnover. It appears that pregnancy is a state of unbalanced accelerated bone turnover that may be associated with reduced osteoblastic activity.
Assuntos
Densidade Óssea , Doenças Ósseas Metabólicas/diagnóstico , Transtornos Puerperais/diagnóstico , Tíbia/diagnóstico por imagem , Adulto , Fosfatase Alcalina/sangue , Biomarcadores/análise , Estudos de Casos e Controles , Colágeno Tipo I/urina , Feminino , Humanos , Osteocalcina/sangue , Paridade , Peptídeos/urina , Gravidez , Estudos Prospectivos , UltrassonografiaRESUMO
BACKGROUND: Paraneoplastic degeneration (PCD) is an immune-mediated disorder affecting the cerebellum, characterized by subacute onset of cerebellar dysfunction progressing to severe disability, and is associated with an underlying malignancy. Ovarian carcinoma and breast carcinoma are commonly implicated. CASE: We report a rare case PCD in an elderly woman, later diagnosed with endometrial carcinoma. CONCLUSION: PCD is an unusual and rare manifestation of gynecological malignancies, including endometrial carcinoma, and a high degree of suspicion is required in these cases in order to make the correct diagnosis.
Assuntos
Neoplasias do Endométrio/diagnóstico , Degeneração Paraneoplásica Cerebelar/diagnóstico , Idoso , Neoplasias do Endométrio/imunologia , Feminino , Humanos , Degeneração Paraneoplásica Cerebelar/imunologiaRESUMO
STUDY OBJECTIVE: To investigate the actual complication rate of hysteroscopic surgery performed by experienced endoscopic surgeons in a single medical center. DESIGN: A prospective descriptive study (Canadian Task Force classification III). SETTING: An endoscopic gynecology unit at a tertiary care university hospital. PATIENTS: Women from 21 to 82 (median 45.0) years, undergoing operative hysteroscopy for uterine disease. INTERVENTION: Operative hysteroscopy with glycine or saline solution used as an irrigation medium. MEASUREMENTS AND MAIN RESULTS: Data of short-term complications were prospectively collected during surgery and at the 2-week follow-up visit. Six hundred procedures were investigated. The total complication rate was 3%, with 1% of uterine perforations. Two-thirds of the complications were related to cervical dilation or uterine entry, and infertility was found to be a risk factor. CONCLUSIONS: Hysteroscopic surgery, performed by a well-trained hysteroscopic surgeon, is a safe procedure with an overall complication rate of 3%. Most complications are related to cervical dilation or uterine entry techniques. Efforts therefore should be focused on identifying the patients at risk and finding novel techniques for cervical priming.
Assuntos
Histeroscopia/efeitos adversos , Perfuração Uterina/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestesia/efeitos adversos , Feminino , Humanos , Infertilidade Feminina/cirurgia , Complicações Intraoperatórias/epidemiologia , Pessoa de Meia-Idade , Pós-Menopausa , Complicações Pós-Operatórias/epidemiologia , Pré-Menopausa , Estudos Prospectivos , Hemorragia Uterina/cirurgia , Útero/lesõesRESUMO
OBJECTIVE: To determine the potency of TKS050, a new epidermal growth factor receptor (EGFR) inhibitor and genistein, a naturally occurring protein tyrosine kinase inhibitor, to inhibit leiomyoma cell proliferation in vitro. DESIGN: Establishment of paired cultures of leiomyoma and normal myometrial samples. SETTING: University clinical research laboratory. PATIENT(S): Hysterectomy specimens from premenopausal women affected by uterine leiomyomas. INTERVENTION(S): The suppressive effect of TKS050 and genistein on the cells, before and after steroidal hormone treatment, was examined. MAIN OUTCOME MEASURE(S): Cell proliferation, recovery after treatment, cell cycle analysis, and immunochemical analysis of relevant proteins were performed. RESULT(S): TKS050 (2 micromol/L) and genistein (50 micromol/L) completely suppressed leiomyoma cell proliferation, and the cells did not recover after cessation of treatment. TKS050 induced cell cycle arrest and apoptosis in a dose- and time-dependent manner. Cells accumulated in the G(0)/G(1) phase of the cell cycle at the expense of the S and G(2)+M phases. Treatment of cells with TKS050 resulted in a dose-dependent inhibition of EGFR autophosphorylation and of phosphorylated signal transducer and activator of transcription 3 (Stat3). Genistein inhibited the phosphorylated Stat3 but did not affect EGFR autophosphorylation. The inhibitory effects of TKS050 or genistein were unaffected by the presence of physiologic concentrations of estradiol-17beta. CONCLUSION(S): Leiomyoma cell growth is effectively blocked by TKS050 and genistein. The inhibitory action of newly developed and natural inhibitors derived from diet may be useful as a possible alternative therapy for leiomyomas.
Assuntos
Proliferação de Células/efeitos dos fármacos , Genisteína/administração & dosagem , Leiomioma/metabolismo , Leiomioma/patologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/administração & dosagem , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Células Tumorais CultivadasRESUMO
Atherosclerosis is epidemiologically associated with postmenopausal osteoporosis presumably by common etiologic factors, reflecting a state of comorbidity in aging. Osteoblasts make a significant facet of this comorbidity state. The present study shows that LDL (native and oxidized) separated by conventional density ultracentrifugation induces osteoblast cell growth arrest in culture. Since the density unltracentrifugation is a tedious procedure we examined, in the present study, the option of LDL purification by ionic strength elution from LDL-apheresis cartridges. We tested the ability of LDL and oxidized LDL (oxLDL) from apheresis columns to induce apoptosis in human Saos2 osteoblasts. Isotonic NaCl effluent washed from LDL-apheresis columns (before starting elution of LDL) induced cell proliferation. In some of the effluent fractions that stimulated Saos2 osteoblasts, up to 15% of the stimulation levels could be significantly inhibited with antilipoprotein A antibodies. After the isotonic washing (150 mM NaCl), upon elution with high ionic strength, 0.2-0.3 M NaCl, some front-runner LDL eluate fractions also induced cell growth and others did not inhibit Saos2 cell growth. This indicates that these fractions might have been contaminated with apolipoprotein A or with other mitogenic compounds. In contrast, the late-to-elute (last 1/3) LDL portion, with a mean density of 1.042 g/mL, killed the cells as expected. This suggests that only the very last one third of LDL eluted by high ionic strength (0.3-0.5 M) is free of osteoblast-mitogenic compounds or lipoprotein-A containing particles. This approach to LDL purification might serve as a convenient and economic method for studying the composition of individual LDL particles and their interaction with cells in culture.
Assuntos
Apoptose/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Lipoproteínas LDL/isolamento & purificação , Lipoproteínas LDL/farmacologia , Osteoblastos/efeitos dos fármacos , Linhagem Celular/efeitos dos fármacos , Cromatografia por Troca Iônica/métodos , Hemadsorção , Humanos , Lipoproteínas LDL/químicaRESUMO
Atherosclerosis is epidemiologically associated with postmenopausal osteoporosis (OP) presumably by common etiologic factors, reflecting a state of co-morbidity in aging. Osteoblasts make a significant facet of this co-morbidity state. Since oxidized low-density lipoprotein (oxLDL) is a major factor in generation of vascular wall pathology, we examined the ability of native LDL (nLDL) and oxLDL to induce Saos2 osteoblasts growth arrest. OxLDL induced Saos2 cell death with morphological features of apoptosis that was inhibited mainly by caspase-9 and partially by caspase-3 but not by caspase-8 inhibitors. nLDL, like oxLDL, has induced cell death, where 60% (P = 0.00033) and 30% (P = 0.075, ns) of the cell death, respectively, could be inhibited by scyphostatin (a neutral sphingomyelinase [nSMase] inhibitor). Upon similar condition, nLDL inhibited the phosphorylation of Akt and two of its downstream targets, fork head receptor (FKHR) and glycogen synthase kinase-3 (GSK3). This is a pathway that stimulates cell survival and proliferation. nLDL has also induced an increase in the proapoptotic Bcl-Xs and it has diminished the potential antiapoptotic Src kinase activity. At the 4 h time-point, upon a substantial decrease in nLDL-induced Akt phosphorylation, scyphostatin has inhibited the reduction in FKHR and GSK3 phosphorylation but inexplicably not that of Akt. Scyphostatin has also corrected the reduction in Src kinase activity. Taken together, the results indicate that nLDL has induced apoptosis in Saos2 osteoblasts by inactivation of the pathway downstream to Akt using nSMase, and by involvement of Src kinase. Inferring that caspase-9 was the main executioner (rather than caspase-8 and-3) in Saos2 cell death, indicates that the nSMase-induced release of ceramide, directly activated the intrinsic mitochondrial apoptotic pathway. With regard to the Akt inactivation by nLDL, Saos2 osteoblasts responded in an opposite fashion to the response reported by others, in macrophages.
Assuntos
Lipoproteínas LDL/farmacologia , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Amidas/farmacologia , Morte Celular/efeitos dos fármacos , Células Cultivadas , Ativação Enzimática , Humanos , Osteoblastos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pironas/farmacologia , Esfingomielina Fosfodiesterase/metabolismo , Proteína bcl-X/metabolismo , Quinases da Família src/metabolismoRESUMO
BACKGROUND: Behçet's disease (BD) is a multisystem inflammatory chronic disorder, which is characterized by relapsing oral and genital ulceration and iridocyclitis. While being of unknown etiology, vasculitic changes of possible autoimmune origin are common to all involved organs, and thrombotic complications, which may adversely affect gestation, are frequently seen. Very little is known to date about the reciprocal influence of BD and pregnancy. We have undertaken to explore the mutual effect of BD and pregnancy with emphasis on maternal and fetal complications. METHODS: In this case-control study, we have evaluated pregnancies that occurred in women suffering from BD, who were treated in our institution during the last 25 years. All records were reviewed, and data were confirmed by a telephone interview and compared with a matched control group. To review the current knowledge, a Medline search together with a manual search of selected articles was performed. RESULTS: Thirty-one Behçet's patients who had 135 pregnancies were studied. Remissions were significantly more frequent during both pregnancy and postpartum periods, while exacerbations were observed only in one-sixth of the patients (P < 0.001). Pregnancy complications (P < 0.001), cesarean section (P < 0.001), and miscarriage (P < 0.02) rates, however, were significantly higher in the study group. CONCLUSIONS: Our study suggests that pregnancy does not have a deleterious effect on the course of BD and may possibly ameliorate its course. However, it seems that BD may adversely affect pregnancy. The miscarriage rate was higher, and the pregnancy complications and cesarean section rates were significantly elevated.
Assuntos
Síndrome de Behçet/epidemiologia , Complicações na Gravidez/epidemiologia , Aborto Espontâneo , Adulto , Síndrome de Behçet/etiologia , Estudos de Casos e Controles , Cesárea , Feminino , Humanos , Israel/epidemiologia , Gravidez , Complicações na Gravidez/etiologiaRESUMO
Ulcerative colitis is a chronic inflammatory bowel disease. The onset peaks at age 15-30 years and coincides with the reproductive period. We screened and summarized the relevant English-language publications (Entrez-PubMed) on ulcerative colitis, fertility and pregnancy. The presence of ulcerative colitis per se does not seem to significantly alterfertility in young women. However, associated conditions, such as active disease, surgical interventions and medication, may interfere with reproduction. It is difficult to draw conclusions regarding the effect of ulcerative colitis on pregnancy outcome in terms of pregnancy loss, intrauterine growth restriction, low birth weight, preterm labor, stillbirth and perinatal mortality. Nevertheless, it appears that major complications do not occur in ulcerative colitis patients more frequently than in healthy women. The rate of exacerbation is probably the same for pregnant and nonpregnant women. Disease control during pregnancy is of the utmost importance. Fortunately, most drugs can by used safely during pregnancy.