RESUMEN
BACKGROUND: Bronchial thermoplasty is a device-based treatment for subjects ≥ 18 years of age with severe asthma poorly controlled with inhaled corticosteroids and long-acting beta-agonists. The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) study collected data on patients with severe asthma undergoing this procedure. RESEARCH QUESTION: What are the 5-year efficacy and safety results in patients with severe asthma who have undergone bronchial thermoplasty? STUDY DESIGN AND METHODS: This was a prospective, open-label, observational, multicenter study conducted in the United States and Canada. Subjects 18 to 65 years of age who were taking inhaled corticosteroids ≥ 1,000 µg/d (beclomethasone or equivalent) and long-acting beta-agonists ≥ 80 µg/d (salmeterol or equivalent) were included. Severe exacerbations, hospitalization, ED visits, and medication usage were evaluated for the 12 months prior to and at years 1 through 5 posttreatment. Spirometry was evaluated at baseline and at years 1 through 5 posttreatment. RESULTS: A total of 284 subjects were enrolled at 27 centers; 227 subjects (80%) completed 5 years of follow-up. By year 5 posttreatment, the proportion of subjects with severe exacerbations, ED visits, and hospitalizations was 42.7%, 7.9%, and 4.8%, respectively, compared with 77.8%, 29.4%, and 16.1% in the 12 months prior to treatment. The proportion of subjects on maintenance oral corticosteroids decreased from 19.4% at baseline to 9.7% at 5 years. Analyses of subgroups based on baseline clinical and biomarker characteristics revealed a statistically significant clinical improvement among all subgroups. INTERPRETATION: Five years after treatment, subjects experienced decreases in severe exacerbations, hospitalizations, ED visits, and corticosteroid exposure. All subgroups demonstrated clinically significant improvement, suggesting that bronchial thermoplasty improves asthma control in different asthma phenotypes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01350336; URL: www. CLINICALTRIALS: gov.
Asunto(s)
Asma , Termoplastia Bronquial , Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Asma/cirugía , Termoplastia Bronquial/métodos , Humanos , Estudios Prospectivos , Calidad de VidaRESUMEN
OBJECTIVES: Bronchial thermoplasty (BT) is a device-based treatment for subjects ≥18 years with severe asthma not well controlled with inhaled corticosteroids and long-acting beta-agonists. The Bronchial Thermoplasty Global Registry (BTGR) collected real-world data on subjects undergoing this procedure. DESIGN: The BTGR is an all-comer, prospective, open-label, multicentre study enrolling adult subjects indicated for and treated with BT. SETTING: Eighteen centres in Spain, Italy, Germany, the UK, the Netherlands, the Czech Republic, South Africa and Australia PARTICIPANTS: One hundred fifty-seven subjects aged 18 years and older who were scheduled to undergo BT treatment for asthma. Subjects diagnosed with other medical conditions which, in the investigator's opinion, made them inappropriate for BT treatment were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: Baseline characteristics collected included demographics, Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Test (ACT), medication usage, forced expiratory volume in one second and forced vital capacity, medical history, comorbidities and 12-month baseline recall data (severe exacerbations (SE) and healthcare utilisation). SE incidence and healthcare utilisation were summarised at 1 and 2 years post-BT. RESULTS: Subjects' baseline characteristics were representative of persons with severe asthma. A comparison of the proportion of subjects experiencing events during the 12 months prior to BT to the 2-year follow-up showed a reduction in SE (90.3% vs 56.1%, p<0.0001), emergency room visits (53.8% vs 25.5%, p<0.0001) and hospitalisations (42.9% vs 23.5 %, p=0.0019). Reductions in asthma maintenance medication dosage were also observed. AQLQ and ACT scores improved from 3.26 and 11.18 at baseline to 4.39 and 15.54 at 2 years, respectively (p<0.0001 for both AQLQ and ACT). CONCLUSIONS: The BTGR demonstrates sustained improvement in clinical outcomes and reduction in asthma medication usage 2 years after BT in a real-world population. This is consistent with results from other BT randomised controlled trials and registries and further supports improvement in asthma control after BT. TRIAL REGISTRATION NUMBER: NCT02104856.
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Asma , Termoplastia Bronquial , Adolescente , Adulto , Asma/tratamiento farmacológico , Asma/cirugía , Termoplastia Bronquial/métodos , Humanos , Estudios Prospectivos , Calidad de Vida , Sistema de Registros , Resultado del TratamientoRESUMEN
BACKGROUND: Bronchial thermoplasty is an endoscopic treatment for uncontrolled asthma. Previous randomised clinical trials have shown that bronchial thermoplasty reduces severe exacerbations in people with asthma. However, the long-term efficacy and safety of bronchial thermoplasty beyond 5 years is unknown. The BT10+ study aimed to investigate the efficacy and safety of bronchial thermoplasty after 10 or more years of follow-up. METHODS: BT10+ was an international, multicentre, follow-up study of participants who were previously enrolled in the AIR, RISA, and AIR2 trials and who had 10 or more years of follow-up since bronchial thermoplasty treatment. Data on patient demographics, quality of life, lung function, CT scans (AIR2 participants only), severe exacerbations, and health-care use during the previous year were collected at the BT10+ 10-year outcomes study visit. The primary effectiveness endpoint was durability of the thermoplasty treatment effect, determined by comparing the proportion of participants who had severe exacerbations during the first and fifth years after bronchial thermoplasty treatment with the proportion of participants who had severe exacerbations during the 12-month period before the BT10+ visit. The primary safety endpoint was the absence of clinically significant post-treatment respiratory image changes after bronchial thermoplasty, defined as bronchiectasis or bronchial stenosis as confirmed by pulmonary volumetric high-resolution CT scan at the BT10+ visit (AIR2 participants only). All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT03243292. The last patient was enrolled on Dec 11, 2018. The last patient completed follow-up on Jan 10, 2019. FINDINGS: The BT10+ study enrolled 192 (45%) of the 429 participants who were enrolled in the AIR, RISA, and AIR2 trials. The BT10+ participants comprised 136 who received bronchial thermoplasty (52% of the 260 participants who received bronchial thermoplasty in the original trials), and 56 sham or control participants (33% of 169 from the original trials). 18 (32%) sham or control participants received bronchial thermoplasty after the previous trials concluded. The participants included in BT10+ were followed for 10·8-15·6 years (median 12·1 years) post-treatment. Baseline characteristics were similar between participants enrolled in BT10+ and those not enrolled. Participants treated with bronchial thermoplasty had similar proportions of severe exacerbations at the BT10+ visit (34 [25%] of 136 participants) compared with 1 year (33 [24%] of 135 participants; difference 0·6%, 95% CI -9·7 to 10·8) and 5 years (28 [22%] of 130 participants; difference 3·5%, -6·7% to 13·6) after treatment. Quality of life measurements and spirometry were similar between year 1, year 5, and the BT10+ visit. At the BT10+ study visit, pulmonary high-resolution CT scans from AIR2 participants treated with bronchial thermoplasty showed that 13 (13%) of 97 participants had bronchiectasis. When compared with baseline high-resolution CT scans, six (7%) of 89 participants treated with bronchial thermoplasty who did not have bronchiectasis at baseline had developed bronchiectasis after treatment (5 classified as mild, 1 classified as moderate). Participants treated with bronchial thermoplasty after the original study and participants in the sham or control group also had reductions in severe exacerbations at the BT10+ visit compared with baseline. INTERPRETATION: Our findings suggest that efficacy of bronchial thermoplasty is sustained for 10 years or more, with an acceptable safety profile. Therefore, bronchial thermoplasty is a long-acting therapeutic option for patients with asthma that remains uncontrolled despite optimised medical treatment. FUNDING: Boston Scientific.
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Asma , Termoplastia Bronquial , Pulmón , Calidad de Vida , Asma/fisiopatología , Asma/psicología , Asma/terapia , Termoplastia Bronquial/efectos adversos , Termoplastia Bronquial/métodos , Broncoscopía/métodos , Demografía/estadística & datos numéricos , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria/métodos , Brote de los Síntomas , Tiempo , Resultado del TratamientoRESUMEN
Bronchial thermoplasty is an endoscopic therapy for severe asthma. The previously reported, randomised sham-controlled AIR2 (Asthma Intervention Research 2) trial showed a significant reduction in severe asthma exacerbations, emergency department visits and hospitalisations after bronchial thermoplasty. More "real-world" clinical outcome data is needed.This article compares outcomes in bronchial thermoplasty subjects with 3â years of follow-up from the ongoing, post-market PAS2 (Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma) study with those from the AIR2 trial.279 subjects were treated with bronchial thermoplasty in the PAS2 study. We compared the first 190 PAS2 subjects with the 190 bronchial thermoplasty-treated subjects in the AIR2 trial at 3 years of follow-up. The PAS2 subjects were older (mean age 45.9 versus 40.7â years) and more obese (mean body mass index 32.5 versus 29.3â kg·m-2) and took higher doses of inhaled corticosteroids (mean dose 2301 versus 1961â µg·day-1). More PAS2 subjects had experienced severe exacerbations (74% versus 52%) and hospitalisations (15.3% versus 4.2%) in the 12â months prior to bronchial thermoplasty. At yearâ 3 after bronchial thermoplasty, the percentage of PAS2 subjects with severe exacerbations, emergency department visits and hospitalisations significantly decreased by 45%, 55% and 40%, respectively, echoing the AIR2 results.The PAS2 study demonstrates similar improvements in asthma control after bronchial thermoplasty compared with the AIR2 trial despite enrolling subjects who may have had poorer asthma control.
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Asma , Termoplastia Bronquial , Glucocorticoides/uso terapéutico , Efectos Adversos a Largo Plazo , Complicaciones Posoperatorias , Calidad de Vida , Adulto , Asma/diagnóstico , Asma/psicología , Asma/terapia , Termoplastia Bronquial/efectos adversos , Termoplastia Bronquial/métodos , Termoplastia Bronquial/estadística & datos numéricos , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Hospitalización/estadística & datos numéricos , Humanos , Efectos Adversos a Largo Plazo/diagnóstico , Efectos Adversos a Largo Plazo/etiología , Efectos Adversos a Largo Plazo/psicología , Efectos Adversos a Largo Plazo/terapia , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/psicología , Complicaciones Posoperatorias/terapia , Vigilancia de Productos Comercializados , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Índice de Severidad de la EnfermedadAsunto(s)
Biomarcadores de Tumor/genética , Proteínas Portadoras/genética , Neoplasias Colorrectales/diagnóstico , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Neoplasias Colorrectales/genética , Diagnóstico Precoz , Marcadores Genéticos , Genoma Humano , Humanos , Masculino , Homólogo 1 de la Proteína MutL , Eliminación de SecuenciaRESUMEN
We aimed to evaluate potential correlation between ovarian activity during use of combined oral contraceptives and the incidence of intermenstrual bleeding. Data from seven prospective clinical studies with five different combined low-dose oral contraceptives were retrospectively analyzed to determine ovarian activity measured by the Hoogland Score (follicle diameter and endogenous hormone levels) and cycle control. A total of 227 young fertile women were evaluated over three treatment cycles each. Women with intermenstrual bleeding had statistically significantly higher estradiol levels than those without intermenstrual bleeding. Also, women with intermenstrual bleeding had significantly larger follicle-like structures than those without intermenstrual bleeding. For example, in the second treatment cycle the difference of the mean follicle diameters between women without intermenstrual bleeding (12.5 mm) and women with spotting (16.9 mm) or breakthrough bleeding (16.1 mm) was statistically significant (p = 0.0179). Less than 17% of women with Hoogland Score 1, 2 or 3 (low ovarian activity) reported intermenstrual bleeding. On the other hand, 35.2% of women with Hoogland Score 4 (active follicle-like structures) reported intermenstrual bleeding. The association between bleeding and Hoogland Score was statistically significant (p < 0.0011). The findings of this retrospective analysis provide evidence that high ovarian suppression is positively correlated with improved cycle control in terms of less frequent intermenstrual bleeding - slight and heavy.
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Anticonceptivos Orales Combinados/administración & dosificación , Ovario/fisiología , Hemorragia Uterina/epidemiología , Anticonceptivos Orales Combinados/efectos adversos , Estradiol/sangre , Femenino , Humanos , Folículo Ovárico/anatomía & histología , Progesterona/sangre , Estudios ProspectivosRESUMEN
OBJECTIVE: This study was undertaken to evaluate the effects on hemostatic factors of a low-dose preparation of levonorgestrel and ethinyl estradiol in a 12-cycle study. STUDY DESIGN: Thirty healthy women began taking 100 microg levonorgestrel and 20 microg ethinyl estradiol on the first day of the menstrual cycle, continued to take the preparation for the next 21 days, and then took placebo for 7 days. Mean changes in prothrombin time, partial thromboplastin time, and levels of factors VII and X, antithrombin, plasminogen, fibrinogen, protein S, thrombin-antithrombin complexes, and D-dimer were analyzed at baseline and at cycles 3, 6, and 12 with paired Student t tests. RESULTS: Factor X, plasminogen antigen and activity, and D-dimer levels were significantly increased (P =.01) during all 3 cycle periods. Antithrombin antigen and protein S total antigen levels were significantly (P =.001 ) decreased at cycles 3, 6, and 12, whereas factor VII and protein S activity levels were significantly (P =.05) decreased at cycle 3 and at cycles 3 and 6, respectively. CONCLUSION: The effects on hemostatic factors in healthy women of a monophasic preparation of 100 microg levonorgestrel and 20 microg ethinyl estradiol were similar to those of other low-dose oral contraceptives.
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Coagulación Sanguínea/efectos de los fármacos , Anticonceptivos Femeninos/administración & dosificación , Anticonceptivos Sintéticos Orales/administración & dosificación , Congéneres del Estradiol/administración & dosificación , Etinilestradiol/administración & dosificación , Hemostasis/efectos de los fármacos , Levonorgestrel/administración & dosificación , Adulto , Antitrombinas/análisis , Factores de Coagulación Sanguínea/análisis , Anticonceptivos Femeninos/uso terapéutico , Anticonceptivos Sintéticos Orales/uso terapéutico , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Congéneres del Estradiol/uso terapéutico , Etinilestradiol/uso terapéutico , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Levonorgestrel/uso terapéutico , Plasminógeno/análisis , Proteína S/análisisRESUMEN
A randomized, open-label, multicenter study was undertaken to compare the effects of oral contraceptives (OC) containing 100 micrograms levonorgestrel (LNG)/20 micrograms ethinyl estradiol (EE) (Aless/Loette) and 1000 micrograms norethindrone acetate (NETA)/20 micrograms EE (Loestrin Fe 1/20) on menstrual cycle control over four cycles of use. A total of 84 evaluable women provided 274 cycles of exposure in the LNG/EE group, and 89 women provided 289 cycles of exposure in the NETA/EE group. Overall, the LNG/EE group achieved a consistently higher percentage of normal menstrual cycles as well as a lower rate of intermenstrual bleeding and amenorrhea than the NETA/EE group. In cycle 4, 63.8% of cycles were normal in the LNG/EE group compared with 41.9% in the NETA/EE group (p < 0.005). Of the total cycles in the NETA/EE group, 10% were amenorrheic, compared with 1.1% in the LNG/EE group. The occurrence of bleeding and/or spotting was significantly lower in cycles 2 and 3 in the LNG/EE group (41.7% and 34.8%, respectively) compared with the NETA/EE group (62.3% and 56.3%; p < 0.05). Other cycle variables were generally similar between groups, as was the incidence of adverse events. These results demonstrate that good cycle control was achieved with an OC containing 20 micrograms EE and that 100 micrograms LNG/20 micrograms EE produces better cycle control than 1000 micrograms NETA/20 micrograms EE.
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Anticonceptivos Hormonales Orales , Etinilestradiol , Ciclo Menstrual/efectos de los fármacos , Etinilestradiol/administración & dosificación , Femenino , Hemorragia , Humanos , Levonorgestrel/administración & dosificaciónRESUMEN
One-lung ventilation is used to facilitate thoracic and cardiac surgery. This article describes the development and clinical use of a new device, the bronchial blocker tube, to establish one-lung ventilation. The bronchial blocker tube has two circular lumen joined together, one for ventilation and one for acceptance of a bronchial blocker. In this setting, the bronchial blocker is a separate device which is replaceable, rotatable, and removable. In the authors' experience, the bronchial blocker tube was effective and easy to use.
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Bronquios , Intubación/instrumentación , Respiración Artificial/instrumentación , Procedimientos Quirúrgicos Torácicos , Anciano , Diseño de Equipo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We describe the finding of an inversion (6)(p23q15) as the sole anomaly in short-term cultures from an intraosseous low-grade osteosarcoma.
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Neoplasias Óseas/genética , Neoplasias Óseas/patología , Inversión Cromosómica , Cromosomas Humanos Par 6 , Osteosarcoma/genética , Osteosarcoma/patología , Neoplasias Óseas/cirugía , Neoplasias Óseas/terapia , Mapeo Cromosómico , Embolización Terapéutica , Femenino , Humanos , Cariotipificación , Persona de Mediana Edad , Osteosarcoma/cirugía , Osteosarcoma/terapiaRESUMEN
Purpose: This multicenter, randomized, open-label comparative study was designed to evaluate the effects on cycle control of the only two oral contraceptives (OCs) containing 20 µg ethinyl estradiol (EE) that are available in North America.Methods: Women of childbearing age who desired OCs for birth control were eligible to enroll in this study. Sixty-two subjects were randomly assigned to receive Alesse (levonorgestrel 0.1 mg and EE 20 µg) or Loestrin Fe 1/20(R) (norethindrone acetate 1.0 mg and EE 20 µg).Results: At the time of the interim analysis data cut-off 32 subjects had completed 3 cycles of Alesse and 30 had completed 3 cycles of Loestrin Fe 1/20. The groups were similar with regard to age, weight, height, race, and prior OC usage. A total of 22% of the subjects in the levonorgestrel group and 27% of those subjects in the norethindrone group had never used OCs. The remainder had not used OCs for at least 3 months before entering the trial. During the third cycle of use, the percentage of normal cycles was significantly greater in the levonorgestrel group (P <.05). Moreover, the rate of intermenstrual bleeding (breakthrough bleeding and/or spotting) in the norethindrone group (62.9%) was more than double that in the levonoregestrel group (29.0%). Cumulatively, from cycles 1 to 3, there was a higher incidence of absence of withdrawal bleeding with norethindrone when compared with levonorgestrel (27.7% vs 5.3%).Conclusion: The results of this study demonstrate that good cycle control can be achieved with an OC containing 20 µg EE. The superior cycle control of Alesse compared with Loestrin Fe 1/20 is consistent with that found in comparative studies of the cycle control of levonorgestrel, norethindrone, and norethindrone acetate containing OCs that had a higher dose of EE.
RESUMEN
Analogous to recommendations for treatment of side effects of early pregnancy and premenstrual syndrome, use of vitamin B6 has been recommended for the treatment of side effects of oral contraceptive (OC) use. A randomized, triple-blinded controlled trial of 124 women was done to evaluate the effect of taking 150 mg of vitamin B6 daily for 30 days on the severity of nausea, headache, vomiting, dizziness, depression, and irritability associated with the initiation of low-dose (30 micrograms norgestrel and 30 micrograms ethinyl estradiol) OG use. The severity of the symptoms was measured on a scale from 0 to 3 (not present to severe), and was evaluated at one month after admission. The two treatment groups (vitamin B, and placebo) had comparable baseline characteristics. From admission to follow up, there was a decrease in the severity of all symptoms in both groups. There was no statistically significant difference in the reductions found in the vitamin B6 and the placebo groups, although reductions in the severity of headache and dizziness were greater in the B6 group. The decrease in the severity of all OC side effects can be explained more by a placebo effect than by a marginal pharmacological effect of the vitamin B6.
PIP: Use of vitamin B-6 has been recommended for the treatment of side effects associated with combined oral contraceptive (OC) use. To evaluate this recommendation, a randomized, triple-blinded controlled trial of 124 women recruited from 2 health centers in Zacatecas, Mexico, was conducted. 62 women received 150 mg of vitamin B-6 daily for 30 days, while the remaining 62 received a placebo. All cases and controls were new or continuing users of an OC containing 30 mcg of norgestrel and 30 mcg of ethinyl estradiol. Women rated the severity of 6 common OC side effects (nausea, headache, vomiting, dizziness, depression, and irritability) on a scale from 0 to 3 at baseline and 30 days after admission. There was a decrease in the severity of all 6 symptoms in both groups. Although higher proportions of women in the vitamin B-6 group reported decreases in OC-related side effect severity between admission and the 30-day follow-up visit, these differences were appreciable only for headache and dizziness and none was statistically significant. No evidence of vitamin B-6 toxicity was observed. However, this study failed to substantiate a clinically important pharmacologic effect of vitamin B-6 on OC side effects.
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Anticonceptivos Orales Combinados/efectos adversos , Piridoxina/uso terapéutico , Adolescente , Adulto , Mareo , Etinilestradiol/administración & dosificación , Etinilestradiol/efectos adversos , Femenino , Cefalea , Humanos , Náusea , Norgestrel/administración & dosificación , Norgestrel/efectos adversos , Placebos , Embarazo , Piridoxina/administración & dosificaciónAsunto(s)
Neoplasias Óseas/genética , Citogenética/métodos , Southern Blotting , Análisis Mutacional de ADN , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor/genética , Humanos , Hibridación Fluorescente in Situ , Reacción en Cadena de la Polimerasa/métodos , Proto-Oncogenes/genética , Transcripción GenéticaRESUMEN
This report summarizes the data collected in pre-introductory Norplant implants clinical trials in 17 countries in Latin America, Asia and Africa that were coordinated by either the Population Council or Family Health International (FHI) between 1984 and 1991. A total of 16,282 women between the ages of 18 and 40 years participated in the studies with semi-annual or annual follow-up visits for up to 5 years. Gross cumulative pregnancy rates were < 0.6 per 100 women in the first year and < 1.5 in the second year in all countries. Significant differences in cumulative 5-year pregnancy rates were observed between weight groups 40-49 and 50-59 kg and between 50-59 and 60-69 kg body weight but not between 60-69 kg and those > or = 70 kg. Total cumulative discontinuation rates after five years of Norplant implants use ranged from 35.8 to 60.0 per 100 women. Younger age and low parity were associated with a higher discontinuation rate. Cumulative discontinuation rates for menstrual reasons more than doubled between the end of the first year and second year of use in 13 of 17 countries. This analysis and one previous review provide the only comparison of Norplant contraceptive system study results across a wide diversity of countries; thus allowing an appreciation of the range of clinical experience with Norplant implants and the regional differences in that experience.
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Anticonceptivos Femeninos/normas , Levonorgestrel/normas , Adolescente , Adulto , África , Asia , Peso Corporal/efectos de los fármacos , Ensayos Clínicos como Asunto , Anticonceptivos Femeninos/efectos adversos , Anticonceptivos Femeninos/farmacología , Implantes de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , América Latina , Levonorgestrel/efectos adversos , Levonorgestrel/farmacología , Tablas de Vida , Menstruación/efectos de los fármacos , Embarazo , Índice de EmbarazoRESUMEN
WT1 is a tumour suppressor gene expressed in a specific temporal and spatial pattern in the developing kidney. Up to 15% of Wilms tumours have point mutations in the WT1 gene coding sequence. We have now investigated whether mutations in the WT1 promoter could be associated with loss of control WT1 expression and subsequent Wilms tumour formation. Using single-strand conformational polymorphism (SSCP) analysis we analysed 39 sporadic Wilms tumours for WT1 promoter mutations. We found six linked common sequence polymorphisms and two unlinked less frequent polymorphisms which allowed us to identify four tumours with loss of heterozygosity but none with point mutations, small deletions, insertions or rearrangements. We therefore conclude that WT1 promoter mutations are unlikely to play an important role in Wilms tumorigenesis.
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Genes del Tumor de Wilms , Neoplasias Renales/genética , Mutación , Regiones Promotoras Genéticas , Tumor de Wilms/genética , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
BACKGROUND: Wilms' tumors are embryonic kidney neoplasms believed to result from a perturbation in the development of the metanephric blastema. A candidate gene (WT1) has been cloned that has been found to be mutated in a number of Wilms' tumors, consistent with its suggested role as a tumor suppressor gene. This gene has been shown to be essential to the normal development of the embryonic kidney. EXPERIMENTAL DESIGN: The aim of the present study was to provide information on the level at which the WT1 gene is regulated. Immunohistochemistry, immunofluorescence, and in situ hybridization was used to examine the localization of WT1 protein and mRNA, respectively. We further used immunofluorescence to examine the WT1 expression in seven Wilms' tumors. RESULTS: In fetal kidneys, WT1 transcripts were detected with increasing levels of hybridization signal in induced blastemal cells, renal vesicles, pre-podocytes of comma- and S-shaped bodies, and podocytes of glomeruli. WT1 protein, detected by an antibody raised against recombinant WT1 fusion protein, was seen in the nuclei of the same cell types mentioned above, and the staining intensity was comparable to the levels of WT1 transcripts. Immunostaining of seven Wilms tumors demonstrated that WT1 protein was expressed only in neoplastic structures whose normal counterparts also expressed WT1 protein. Neither stromal cells nor rhabdomyoblasts contained WT1 protein. CONCLUSIONS: The results show that in fetal kidney, WT1 transcripts and protein are coordinately expressed, and strongly associated with differentiation of metanephric blastemal cells into epithelial cells. Furthermore, the finding that WT1 transcripts and protein are coordinately expressed, suggests that WT1 gene expression is primarily regulated at the level of transcription.
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Proteínas de Unión al ADN/análisis , Neoplasias Renales/química , Riñón/química , Riñón/embriología , Tumor de Wilms/química , Western Blotting , ADN/análisis , ADN/genética , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación in Situ , Riñón/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , ARN Mensajero/análisis , ARN Mensajero/genética , Transcripción Genética , Proteínas WT1 , Tumor de Wilms/genética , Tumor de Wilms/metabolismoRESUMEN
WT1 is a tumor suppressor gene that has been implicated in Wilms tumor, and is expressed in cells of mesodermal origin. The Wit-1 gene is located approximately 2 kb from the WT1 gene, and is expressed coordinately with WT1. WT1 and Wit-1 are bi-directionally transcribed from the same promoter region. We have screened a human fetal kidney cDNA library to identify novel WT1 cDNA clones. Here we report the cloning of cDNA clones which span part of intron 1 of WT1, exon 1, upstream sequences between WT1 and Wit-1 and part of the Wit-1 gene. Northern blot and RNAase protection analysis using subcloned fragments of the cDNAs corresponding to regions from within intron 1 of WT1 suggest that a 7-10 Kb RNA is expressed in human fetal kidney, which overlaps with WT1 and is transcribed in the same direction as Wit-1.
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Genes del Tumor de Wilms , Oligonucleótidos Antisentido/genética , Transcripción Genética , Secuencia de Bases , Clonación Molecular , ADN Complementario , Humanos , Intrones , Riñón/embriología , Riñón/metabolismo , Datos de Secuencia MolecularRESUMEN
A non-comparative study of a progestin-only oral contraceptive (POC) containing 75 micrograms norgestrel was conducted at 22 sites in 14 countries. This study was designed to evaluate safety, contraceptive efficacy, and the overall acceptability of a POC in breastfeeding women. A total of 4,088 women entered the study over a three-year period and 29,399 woman-months of experience was gathered. Women had follow-up visits at 2, 6, and 11 months after admission. Headaches and vaginal discharge were the medical complaints most commonly reported by women, both prior to and after admission. Menstrual problems were reported by 59% of the women after admission. Of the 3,714 women who returned for at least one follow-up visit, 1,101 (29.6%) discontinued through month 11. The 11-month total discontinuation percentage, including those lost to follow-up (25.3%) was 51.6%. The most common reason given for discontinuation was a woman's desire for a change in contraceptive method. Only 4.9% discontinued pill use for menstrual problems, a percentage far below those generally reported for POCs. Twenty-nine unintended pregnancies occurred through 11 months giving a gross cumulative life table rate of 1.2 per 100 women (Pearl Index = 1.4). The POC appears to be a safe, effective and acceptable contraceptive option for postpartum breastfeeding women.
Asunto(s)
Anticonceptivos Hormonales Orales/farmacología , Lactancia , Norgestrel/efectos adversos , Adolescente , Adulto , Anticonceptivos Hormonales Orales/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Tablas de Vida , Menstruación/efectos de los fármacos , Norgestrel/farmacología , Cooperación del Paciente , Satisfacción del Paciente , Periodo Posparto , EmbarazoRESUMEN
While most new contraceptives currently in development incorporate existing contraceptive agents into new delivery systems, several types of contraceptives with novel mechanisms of action are making steady progress. The antiprogestin mifepristone (better known as RU 486) is being tested as an ovulation inhibitor, as a once-a-month pill, and as a postcoital contraceptive. An antiestrogen, Centchroman (Hindustan Latex, India), is in use in India as a once-a-week, nonsteroidal pill. The development of more potent pituitary gonadotropin antagonists has improved their potential to block ovulation in women and to inhibit spermatogenesis in men (which requires concurrent administration of testosterone). Another promising male contraceptive is an intraluminal vas occlusion plug tested extensively in China that can be removed with no apparent detriment to future fertility. Finally, several types of immunocontraceptives could become the most specific form of fertility control by directing an antibody response against the fertilized or unfertilized egg or against sperm.