RESUMO
The Sonic Hedgehog (SHh) precursor protein undergoes biosynthetic autoprocessing to cleave off and covalently attach cholesterol to the SHh signaling ligand, a vital morphogen and oncogenic effector protein. Autoprocessing is self-catalyzed by SHhC, the SHh precursor's C-terminal enzymatic domain. A method to screen for small molecule regulators of this process may be of therapeutic value. Here, we describe the development and validation of the first cellular reporter to monitor human SHhC autoprocessing noninvasively in high-throughput compatible plates. The assay couples intracellular SHhC autoprocessing using endogenous cholesterol to the extracellular secretion of the bioluminescent nanoluciferase enzyme. We developed a WT SHhC reporter line for evaluating potential autoprocessing inhibitors by concentration response-dependent suppression of extracellular bioluminescence. Additionally, a conditional mutant SHhC (D46A) reporter line was developed for identifying potential autoprocessing activators by a concentration response-dependent gain of extracellular bioluminescence. The D46A mutation removes a conserved general base that is critical for the activation of the cholesterol substrate. Inducibility of the D46A reporter was established using a synthetic sterol, 2-α carboxy cholestanol, designed to bypass the defect through intramolecular general base catalysis. To facilitate direct nanoluciferase detection in the cell culture media of 1536-well plates, we designed a novel anionic phosphonylated coelenterazine, CLZ-2P, as the nanoluciferase substrate. This new reporter system offers a long-awaited resource for small molecule discovery for cancer and for developmental disorders where SHh ligand biosynthesis is dysregulated.
Assuntos
Proteínas Hedgehog , Humanos , Colesterol/metabolismo , Proteínas Hedgehog/agonistas , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Ligantes , Proteínas Oncogênicas , EsteróisRESUMO
OBJECTIVES: Determine the long-term risk of hysterectomy and ectopic pregnancy in women using the quinacrine hydrochloride pellet system of permanent contraception (QS) relative to the comparable risk in women using Copper T intrauterine device (IUD) or tubal ligation surgery (TL) for long-term or permanent contraception. METHODS: This was a retrospective cohort study, conducted in the Northern Vietnamese provinces of Ha Nam, Nam Dinh, Ninh Binh and Thai Binh. Women who had their first QS procedure, last IUD insertion or TL between 1989 and 1996 were interviewed regarding post-procedure health outcomes approximately 16 years post exposure. RESULTS: A 95% response rate resulted in 21,040 completed interviews. Overall incidence rates were low for both outcomes (91/100,000 women years of follow-up and 22/100,000 women years of follow-up for hysterectomy and ectopic pregnancy, respectively). After accounting for variations in baseline characteristics between women choosing QS vs. the other two contraceptive methods, no significant excess hazard of either hysterectomy or ectopic pregnancy was associated with QS. CONCLUSIONS: No significant excess long-term risk of hysterectomy or ectopic pregnancy was found among a large group of women using QS vs. IUD or TL for contraception after an average 16 years of follow-up.
Assuntos
Histerectomia/estatística & dados numéricos , Dispositivos Intrauterinos/efeitos adversos , Gravidez Ectópica/etiologia , Quinacrina/efeitos adversos , Esterilização Tubária/efeitos adversos , Adolescente , Adulto , Feminino , Humanos , Incidência , Modelos Logísticos , Pessoa de Meia-Idade , Gravidez , Gravidez Ectópica/epidemiologia , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Vietnã/epidemiologia , Adulto JovemRESUMO
OBJECTIVES: To determine the long-term risk of reproductive tract cancer in women using the quinacrine hydrochloride pellet system of permanent contraception (QS) relative to the comparable risk in women using Copper T intrauterine device (IUD) or tubal ligation surgery (TL) for long-term or permanent contraception. METHODS: This was a retrospective cohort study, conducted in the Northern Vietnamese provinces of Ha Nam, Nam Dinh, Ninh Binh and Thai Binh. Women who had their first QS procedure, last IUD insertion or TL between 1989 and 1996 were interviewed regarding post-procedure health outcomes, particularly reproductive tract cancers. RESULTS: A 95% response rate resulted in 21,040 completed interviews. Reproductive cancer incidence rates were very low (5.77/100,000 women years of follow-up time; 95%CI = 3.72-8.94). No significant excess hazard of reproductive tract cancer was associated with QS. CONCLUSIONS: No significant excess long-term risk of reproductive tract cancer was found after an average 16 years of follow-up among a large group of women using QS vs. IUD/TL for contraception.
Assuntos
Anticoncepcionais Femininos/efeitos adversos , Dispositivos Anticoncepcionais/efeitos adversos , Neoplasias dos Genitais Femininos/epidemiologia , Quinacrina/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Estudos Retrospectivos , Fatores de Risco , Vietnã/epidemiologiaRESUMO
OBJECTIVE: The purposes of this study were to retrospectively assess the frequency of acute aortic intramural hematoma and evaluate whether the elimination of the unenhanced imaging acquisition series from the dual-phase MDCT angiography (CTA) protocol for chest pain might affect diagnostic accuracy in detecting intramural hematoma and justify the reduced radiation dose. MATERIALS AND METHODS: From October 2006 to November 2012, 306 patients (mean age, 65.0 years) with acute chest pain underwent emergency CTA with a 64-MDCT scanner. Two experienced cardiovascular radiologists, blinded to the diagnosis, assessed the images in two different sessions in which enhanced (single-phase CTA) and combined unenhanced and contrast-enhanced (dual-phase CTA) findings were evaluated. Sensitivity, specificity, and accuracy along with 95% CIs were calculated. Surgical and pathologic diagnoses, including findings at clinical follow-up and any subsequent imaging modality, were used as reference standards. RESULTS: Thirty-six patients were suspected of having intramural hematoma; 16 patients underwent both surgery and transesophageal echocardiography (TEE), and the remaining 20 underwent TEE. Single-phase CTA showed a higher number of false-negative and false-positive results than dual-phase CTA. With intramural hematoma frequency of 12% (95% CI, 8.38-15.91%), sensitivity, specificity, and accuracy were 94.4% (81.3-99.3%), 99.3% (97.4-99.9%), and 98.7% (96.7-99.6%) for combined dual-phase CTA and 68.4% (51.4-82.5%), 96.3% (93.2-98.2%), and 92.8% (89.3-95.4%) for single-phase CTA. Dual-phase was significantly better than single-phase CTA with respect to sensitivity (p=0.002), specificity (p=0.008), overall accuracy (p<0.001), and interrater agreement (p=0.001). CONCLUSION: The frequency of acute aortic intramural hematoma is similar to that previously reported. The acquisition of unenhanced images during the chest pain dual-phase CTA protocol significantly improves diagnostic accuracy over single-phase CTA.
Assuntos
Doenças da Aorta/diagnóstico por imagem , Angiografia Coronária/métodos , Hematoma/diagnóstico por imagem , Intensificação de Imagem Radiográfica/métodos , Imagem Radiográfica a Partir de Emissão de Duplo Fóton/métodos , Tomografia Computadorizada por Raios X/métodos , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Método Simples-CegoRESUMO
BACKGROUND: The objective of this study was to assess the ability of prenatal ultrasound to predict an unfavorable outcome and the need for postnatal surgery in cases of fetal hydronephrosis (HY). METHODS: Antenatal HY was classified according to the renal pelvis anteroposterior (AP) diameter in the third trimester. Postnatal outcome was considered favorable in the presence of spontaneous resolution or postnatal diagnosis of HY <20 mm, and unfavorable in the presence of postnatal diagnosis of >20 mm HY or urinary tract pathologies. RESULTS: Prenatal diagnosis of HY was made in 120 fetuses (for a total of 161 abnormal renal units). The rates of postnatal urinary tract pathology were 14, 27 and 53% for antenatal HY of ≤7, 8-15 and >15 mm, respectively. An AP diameter ≥7 mm in the third trimester had a sensitivity of 100% and a specificity of 23% to predict unfavorable outcome. A formula inclusive of AP diameter and presence or absence of urinary tract anomalies can predict the need for postnatal surgery. CONCLUSIONS: The majority of infants with congenital HY have a favorable postnatal outcome. Risk of unfavorable outcome increases with the degree of dilatation of the renal pelvis and the presence of urinary tract anomalies. An AP diameter ≥7 mm in the third trimester warrants postnatal follow-up.
Assuntos
Doenças Fetais/diagnóstico por imagem , Hidronefrose/diagnóstico por imagem , Feminino , Humanos , Hidronefrose/cirurgia , Recém-Nascido , Masculino , Valor Preditivo dos Testes , Gravidez , Estudos Retrospectivos , Fatores de Risco , Ultrassonografia Pré-NatalRESUMO
BACKGROUND: Delayed recovery of gastrointestinal (GI) motility is a common complication following surgery. TZP-101/ulimorelin is a macrocyclic peptidomimetic ghrelin receptor agonist with GI promotility effects that significantly accelerates time to recovery of GI motility compared to placebo following partial colectomy. It is also well tolerated. The objectives of this analysis were to identify predictors of GI motility recovery in patients undergoing partial colectomy and to evaluate whether these factors affect ulimorelin acceleration of GI recovery. METHODS: Covariate analysis assessed the effect of eight variables-age, sex, body mass index, type of surgery (right colectomy, left colectomy, other), duration of surgery, blood loss, total opioid consumption, country-on recovery of GI motility in 236 patients randomized to ulimorelin (n = 168) or placebo (n = 68). The primary endpoint was the recovery of GI function (time from the end of surgery to first bowel movement). Stepwise regression identified a parsimonious model of the smallest subset of variables best predicting GI recovery. RESULTS: Recovery was shorter for segmental/subtotal colectomies vs. right colectomies (P = 0.016) and longer with increased total opioid use (P = 0.037). The remaining variables had no statistically significant effect on GI recovery. Effects of ulimorelin 480 µg/kg (the most effective dose) on time to GI tract recovery remained statistically and clinically significant (hazard ratio = 1.81, P = 0.014) when adjusted for surgery type and/or total opioid use. CONCLUSIONS: Two factors, type of surgery and total opioid use, independently modified times to recovery of GI motility following partial large bowel resection surgery. Acceleration of recovery of GI motility by ulimorelin was independent of these factors.
Assuntos
Analgésicos Opioides/uso terapêutico , Colectomia , Fármacos Gastrointestinais/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Grelina/agonistas , Compostos Macrocíclicos/farmacologia , Dor Pós-Operatória/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/efeitos adversos , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/administração & dosagem , Humanos , Compostos Macrocíclicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Recuperação de Função Fisiológica/efeitos dos fármacos , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: The objective of our study was to determine the relationship between the apparent diffusion coefficient (ADC) value on diffusion-weighted imaging (DWI) and Gleason score of prostate cancer and percentage of tumor involvement on prostate core biopsy. MATERIALS AND METHODS: We performed a retrospective study of 57 patients with biopsy-proven prostate cancer who underwent endorectal MRI with DWI between July 2007 and March 2008. Regions of interest (ROIs) were drawn on ADC maps at sites of visible tumor on DW images and ADC maps. A hierarchic mixed linear model was used to compare the ADC value of prostate cancer with the Gleason score and the percentage of tumor on core biopsy. RESULTS: Eighty-one sites of biopsy-proven prostate cancer were visible on DW images and ADC maps. The least-squares mean ADC for disease with a Gleason score of 6 was 0.860 x 10(-3) mm(2)/s (standard error of the mean [SEM], 0.036); Gleason score of 7, 0.702 x 10(-3) mm(2)/s (SEM, 0.030); Gleason score of 8, 0.672 x 10(-3) mm(2)/s (SEM, 0.057); and Gleason score of 9, 0.686 x 10(-3) mm(2)/s (SEM, 0.067). Differences between the mean ADC values for a prostate tumor with a Gleason score of 6 and one with a Gleason score of 7 (p = 0.0096) and for a prostate tumor with a Gleason score of 6 and one with a Gleason score of 8 (p = 0.0460) were significant. Comparison between the ADC and percentage of tumor on core biopsy showed a mean ADC decrease of 0.006 (range, 0.004-0.008 x 10(-3) mm(2)/s) for every 1% increase in tumor in the core biopsy specimen. CONCLUSION: DWI may help differentiate between low-risk (Gleason score, 6) and intermediate-risk (Gleason score, 7) prostate cancer and between low-risk (Gleason score, 6) and high-risk (Gleason score > 7) prostate cancer. There is an inverse relationship between the ADC and the percentage of tumor involvement on prostate core biopsies.
Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias da Próstata/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biópsia , Distribuição de Qui-Quadrado , Humanos , Interpretação de Imagem Assistida por Computador , Análise dos Mínimos Quadrados , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Estudos RetrospectivosRESUMO
PURPOSE: Ghrelin agonist TZP-101 is a potent prokinetic. This phase 2b study evaluated TZP-101 safety and efficacy in postoperative ileus management. METHODS: Adults undergoing open partial colectomy were adaptively randomized to receive 20, 40, 80, 160, 320, 480 or 600 microg/kg TZP-101 (n = 168) or the placebo (n = 68) by 30-minute IV infusion within 1 hour of surgical closure and then daily for up to 7 days. The primary efficacy end point was the time to first bowel movement. Secondary end points included the percentage of patients with return of gastrointestinal function within 72 hours, and the time to readiness for discharge. RESULTS: TZP-101 accelerated the time to first bowel movement in all groups, with Cox proportional hazard ratios of 1.57 (P = .056) for the low-efficacious dose (80 microg/kg) and 1.67 (P = .03) for the most efficacious dose (480 microg/kg). Using Kaplan-Meier analysis, the median time to first bowel movement was reduced in all TZP-101 groups by 10 to 22 hours vs. the placebo. A greater number of patients who received TZP-101 achieved recovery (P Assuntos
Grelina/agonistas
, Íleus/tratamento farmacológico
, Compostos Macrocíclicos/administração & dosagem
, Cuidados Pós-Operatórios/métodos
, Proctocolectomia Restauradora/efeitos adversos
, Relação Dose-Resposta a Droga
, Método Duplo-Cego
, Feminino
, Seguimentos
, Humanos
, Íleus/etiologia
, Infusões Intravenosas
, Compostos Macrocíclicos/uso terapêutico
, Masculino
, Pessoa de Meia-Idade
, Estudos Retrospectivos
, Resultado do Tratamento
RESUMO
BACKGROUND: This randomized double blind placebo controlled dual site clinical trial compared a probiotic dietary supplement to placebo regarding effects on gastrointestinal symptoms in adults with post-prandial intestinal gas-related symptoms (abdominal pain, distention, flatulence) but no gastrointestinal (GI) diagnoses to explain the symptoms. METHODS: Sixty-one adults were enrolled (age 36.5 +/- 12.6 years; height 165.1 +/- 9.2 cm; weight 75.4 +/- 17.3 kg) and randomized to either Digestive Advantage Gas Defense Formula - (GanedenBC30 Bacillus coagulans GBI-30, 6086): n = 30; or Placebo: n = 31. Study subjects were evaluated every two weeks over a four-week period using validated questionnaires and standard biochemical safety testing. Outcome criteria of interest included change from baseline in Gastrointestinal Symptom Rating Scale (GSRS) abdominal pain, abdominal distention, flatus, and the Severity of Dyspepsia Assessment (SODA) bloating and gas subscores over four weeks of product use. RESULTS: Measured against the placebo, subjects in the probiotic group achieved significant improvements in GSRS abdominal pain subscore (p = 0.046) and the GSRS total score (p = 0.048), with a strong trend for improvement on the GSRS abdominal distension subscore (p = 0.061). A strong placebo effect was evident which could explain the lack of statistical significant differences between the groups for many of the efficacy variables. CONCLUSION: In conclusion, the Bacillus coagulans-based product was effective in improving the quality of life and reducing gastrointestinal symptoms in adults with post prandial intestinal gas-related symptoms and no GI diagnoses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00881322.
Assuntos
Dor Abdominal/terapia , Bacillus , Flatulência/terapia , Probióticos/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Our objective was to determine whether obstetric history affects the efficacy of therapeutic cerclage. STUDY DESIGN: Data were gathered prospectively on patients receiving therapeutic cerclage, defined as midtrimester presentation with a cervical length less than 2.5 cm and prior preterm delivery or cervical dilatation with visible membranes on sterile speculum exam. Delivery outcomes based on cerclage type were compared between women with (n = 31) vs without prior term birth (n = 33). RESULTS: Patients with a history of a term birth were older than those without such history (P = .05) but otherwise similar with regard to ethnicity, body mass index, prior preterm birth, genitourinary infection, prior cervical surgery, gestational age at cerclage placement, and cerclage indication. Women with a therapeutic cerclage and a history of a prior term delivery were significantly more likely to deliver after 35 weeks (90% vs 48%, P < .001) and their babies were significantly larger (2942 +/- 812 g vs 1966 +/- 1069 g, P < .001) than women with no prior term delivery. CONCLUSION: Patients who develop cervical insufficiency after a term delivery may have better perinatal outcomes following therapeutic cerclage than those without a history of term delivery.
Assuntos
Cerclagem Cervical , Nascimento Prematuro/prevenção & controle , Incompetência do Colo do Útero/cirurgia , Adulto , Feminino , Humanos , Análise Multivariada , Gravidez , Segundo Trimestre da Gravidez , Estudos Prospectivos , Análise de Regressão , Estados Unidos/epidemiologia , Incompetência do Colo do Útero/epidemiologiaRESUMO
OBJECTIVES: The aim of this study was to estimate the risk of further creatinine increase in patients with preexisting renal disease after the use of oral sodium phosphate (OSP) versus polyethylene glycol (PEG), and to study usage patterns of OSP in relation to renal function. METHODS: A cohort study was done using clinical records and electronic patient information from the Henry Ford Health System (HFHS) in patients who had used either OSP or PEG for colonoscopy between February 1999 and April 2006. Among patients with an estimated GFR < 60 ml/min before colonoscopy, we identified cases with an unexplained creatinine increase of > or = 0.5 mg/dl within 14 days after colonoscopy. RESULTS: We identified 7,971 OSP and 1,511 PEG users. Relative use of OSP versus PEG decreased from 88.0% before 2004 to 48.4% in 2006. 70.2% of OSP users had no recorded creatinine determination within 60 days before colonoscopy, and this proportion did not decrease over time. The study population included 317 patients with a baseline GFR < 60 ml/min, and we identified one case with an unexplained creatinine increase > or = 0.5 mg/dl among 191 PEG users (0.5%) versus eight cases among 126 OSP users (6.3%). Unadjusted and adjusted relative risk estimates on comparing OSP with PEG were 12.1 (95% CI, 1.5-95.8) and 12.6 (95% CI, 1.5-106.5), respectively. CONCLUSIONS: In patients with preexisting renal disease, OSP use was associated with an increased risk of aggravated renal dysfunction versus PEG. Creatinine measurement with GFR estimation should be done before OSP administration in order to avoid its use in patients with renal disease.
Assuntos
Catárticos/efeitos adversos , Fosfatos/efeitos adversos , Polietilenoglicóis/efeitos adversos , Insuficiência Renal/induzido quimicamente , Administração Oral , Idoso , Biomarcadores/sangue , Catárticos/administração & dosagem , Colonoscopia , Creatinina/sangue , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/efeitos dos fármacos , Nefropatias , Masculino , Fosfatos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Fatores de RiscoRESUMO
OBJECTIVES: We aimed to evaluate frequency, predictors, and monitoring of renal dysfunction related to the use of oral sodium phosphates for colonoscopy in clinical practice. METHODS: Cohort study using clinical records and electronic patient information from the Henry Ford Health System, Detroit, MI. We identified patients undergoing colonoscopy using sodium phosphate or polyethylene glycol (PEG), and estimated the risk of renal impairment associated with bowel preparation and other risk factors. RESULTS: Out of 7,897 patients, 6,833 had used sodium phosphate; 1,617 patients had renal dysfunction within 12 months prior to colonoscopy and 3,928 patients had no creatinine measurement within 12 months prior to or 6 months postcolonoscopy. Among the remaining 2,352 patients, 88 had incident renal dysfunction (glomerular filtration rate [GFR]<60 mL/min) after colonoscopy. The relative risk (RR) estimate for renal dysfunction comparing sodium phosphate with PEG was 1.13 (95% CI 0.58-2.23) without adjustment, and 1.14 (95% CI 0.55-2.39) after multivariate adjustment. Significant univariate risk factors were age>or=65 yr, African-American race, low baseline GFR, hypertension, and use of angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin-renin blockers, or thiazide diuretics. CONCLUSIONS: In patients without preexisting renal disease, the risk of renal impairment after colonoscopy appears to be similar between sodium phosphate and PEG users. Sodium phosphate use in patients with preexisting renal disease is not recommended, but common in clinical practice. Sodium phosphate should not be used in patients with preexisting serious renal disease, adequate hydration should be assured in all patients, and renal function should be monitored before and after colonoscopy in those at risk of renal dysfunction.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Catárticos/efeitos adversos , Colonoscopia , Fosfatos/efeitos adversos , Polietilenoglicóis/efeitos adversos , Idoso , Catárticos/administração & dosagem , Estudos de Coortes , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fosfatos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Fatores de Risco , SoluçõesRESUMO
OBJECTIVE: To report the rates of medical claims for sense of smell disturbance (SD) and their association with diseases and medications in a managed care population. DESIGN: Descriptive determination of demographics, prevalence, and incidence of SD and case-control analysis of risk factors. Preselected drug and disease groups were entered into a stepwise regression model to determine risk factors for SD. SETTING: Managed care organizations in the United States. PATIENTS: Patients identified through medical claims within IMS Health's LifeLink: Integrated Claims Solution (IMS) and i3 Magnifi Private Managed Care Organizations (MCO) medical insurance databases for 3-year observation periods. MAIN OUTCOME MEASURES: Prevalence and incidence of smell disturbance; adjusted odds ratios and 95% confidence intervals (CIs) of associated conditions and medications. RESULTS: The mean annual prevalence rate of SD was 26.2 per 100 000 for IMS (95% CI, 23.1-29.6) and 17.2 per 100 000 for MCO (95% CI, 15.6-18.7). The mean annual incidence per 100 000 was 26.3 for IMS (95% CI, 23.1-29.8) and 15.9 for MCO (95% CI, 14.5-17.5). The 5 strongest risk factors for SD were chronic sinusitis, oropharyngeal inflammatory disorders, other upper respiratory tract disease excluding sinusitis, cerebrovascular disease, and systemic viral disease. The regression model also retained 3 drug groups (corticosteroids, calcium channel blockers, and nasal and/or sinus products) among the significant risk factors for the presence of SD. CONCLUSIONS: The annual prevalence and incidence rates of SD are lower than prior estimates partly owing to reliance on specific medical claims. A number of conditions preceding the diagnosis of SD were significantly associated with the condition. Uses of certain medications were also risk factors for SD compared with controls.
Assuntos
Formulário de Reclamação de Seguro/estatística & dados numéricos , Classificação Internacional de Doenças , Transtornos do Olfato/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Demografia , Feminino , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Transtornos do Olfato/diagnóstico , Vigilância da População/métodos , Prevalência , Fatores de Risco , Distribuição por Sexo , Sinusite/epidemiologia , Estados UnidosRESUMO
We investigated the effects of chronic nicotine on alpha6- and beta3-containing nicotinic acetylcholine receptors (nAChRs) in two rat brain regions using three methodological approaches: radioligand binding, immunoprecipitation, and nicotine-stimulated synaptosomal release of dopamine. Nicotine was administered by osmotic minipumps for 2 weeks. Quantitative autoradiography with [(125)I]alpha-conotoxin MII to selectively label alpha6(*) nAChRs showed a 28% decrease in binding in the striatum but no change in the superior colliculus. Immunoprecipitation of nAChRs labeled by [(3)H]epibatidine in these two regions showed that chronic nicotine increased alpha4- and beta2-containing nAChRs by 39 to 67%. In contrast, chronic nicotine caused a 39% decrease in alpha6-containing nAChRs in striatum but no change in superior colliculus. No changes in beta3-containing nAChRs were seen in either region after chronic nicotine. The decreased expression of alpha6-containing nAChRs persisted for at least 3 days, recovering to baseline by 7 days after removal of the pumps. There was a small but significant decrease in total nicotine-stimulated dopamine release in striatal synaptosomes after nicotine exposure. However, the component of dopamine release that was resistant to alpha-conotoxin MII blockade was unaffected, whereas dopamine release that was sensitive to blockade by alpha-conotoxin MII was decreased by 56%. These findings indicate that the alpha6(*) nAChR is regulated differently from other nAChR subtypes, and they suggest that the inclusion of a beta3 subunit with alpha6 may serve to inhibit nicotine-induced down-regulation of these receptors.
Assuntos
Encéfalo/efeitos dos fármacos , Nicotina/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Autorradiografia , Conotoxinas/metabolismo , Dopamina/metabolismo , Imunoprecipitação , Masculino , Dados de Sequência Molecular , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/análiseRESUMO
OBJECTIVE: To evaluate whether body mass index (BMI) is an independent risk factor for survival in patients with endometrial adenocarcinoma. METHODS: Women treated for endometrial cancer at the State University of New York (SUNY), Downstate and Kings County Hospital between January 1982 and September 2003 were eligible. Patients were divided into groups based upon their histology at the time of diagnosis. The first included patients with low-grade endometrioid adenocarcinoma (FIGO grades 1 and 2); the second included grade 3 endometrioid adenocarcinoma; and the third contained papillary serous and clear cell carcinomas. Data regarding BMI, patient age, race, grade, and stage of disease and overall survival, were assessed by survival analysis, with P < 0.05 considered significant throughout. RESULTS: The analysis included 442 patients. Mean BMI was 32.6 +/- 8.2. There were 312 patients (70%) treated for low-grade endometrial adenocarcinoma; 64 patients (14%) for grade 3 endometrioid adenocarcinoma; and 71 patients (16%) for papillary serous and clear cell adenocarcinoma. Increased BMI was associated with improved overall survival (P = 0.003). BMI was also correlated to tumor grade, stage at diagnosis, age, and race. Tumor grade, stage, age, and race were correlated to survival. Statistical analyses revealed the majority of the association between BMI and survival can be attributed to the association between BMI and these other risk factors for survival in endometrial cancer. CONCLUSIONS: Increased BMI is associated with survival advantage among patients with endometrial cancer. Because of the relationship between obesity and other confounding variables obesity alone is not an independent predictor of survival.
Assuntos
Adenocarcinoma/fisiopatologia , Índice de Massa Corporal , Neoplasias do Endométrio/fisiopatologia , Adenocarcinoma/mortalidade , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , New York , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Fatores de TempoRESUMO
OBJECTIVE: To study the causes of the observed association between presence of leiomyomata in pregnancy and increase in risk of cesarean delivery. METHODS: We accessed the obstetric database of women who underwent second-trimester ultrasound screening between January 1996 and December 2004 and who delivered at more than 22 weeks of gestation. Ultrasonographic characteristics of the leiomyomata, including number, maximum diameter, change in size during pregnancy, and location were recorded. Pregnancy outcome was compared between the cohort with large uterine leiomyomata (5 cm or more) (n=251) and those without leiomyomata (n=24,546) using chi(2), Fisher exact test, Student t test, and linear and logistic regression analysis, with an odds ratio (OR) with 95% confidence interval (CI) not inclusive of the unity considered significant. RESULTS: Women with large leiomyomata had higher rates of cesarean delivery before onset of labor (OR 3.1, 95% CI 2.2-4.2) but not during labor (OR 1.0, 95% CI 0.6-1.6). The association between leiomyomata and cesarean delivery before labor remained significant after controlling for maternal age, nulliparity, fetal malpresentation, and placenta previa (OR 2.1, 95% CI 1.4-3.1). The only ultrasonographic leiomyoma characteristic independently associated with cesarean delivery before labor after controlling for confounders was maximum diameter of the largest leiomyoma (OR 1.3, 95% CI 1.1-1.4, P=.001). CONCLUSION: Uterine leiomyomata 5 cm or larger are independently associated with cesarean delivery performed before labor, and the risk increases with the size of the leiomyoma. LEVEL OF EVIDENCE: II.
Assuntos
Cesárea/estatística & dados numéricos , Leiomioma/diagnóstico por imagem , Complicações Neoplásicas na Gravidez/diagnóstico por imagem , Neoplasias Uterinas/diagnóstico por imagem , Adulto , Estudos de Coortes , Feminino , Humanos , Trabalho de Parto , Leiomioma/patologia , Complicações do Trabalho de Parto/etiologia , Valor Preditivo dos Testes , Gravidez , Complicações Neoplásicas na Gravidez/patologia , Estudos Retrospectivos , Ultrassonografia Pré-Natal , Neoplasias Uterinas/patologiaRESUMO
OBJECTIVE: To assess the accuracy of vaginal fetal fibronectin (FFN) as a screening test for preterm delivery in a community hospital. STUDY DESIGN: A prospective cohort of patients at high risk for preterm delivery at a community hospital underwent testing with FFN over a 15 month-period (March 2004-May 2005). Indications for testing were preterm labor, multiple pregnancies, cervical shortening, and cerclage. Pregnancy characteristics were retrieved on all women with positive FFN results and controls in a 1:2 ratio. Outcome variables included interval to delivery; length of hospital stay; and rates of preterm delivery <37 weeks. In the presence of serial FFN testing, only the initial result was used for calculation of diagnostic indices. Statistical analysis utilized t-test, Fisher's exact test and logistic regression analysis to control for gestational age at testing, with P < 0.05 or odds ratio (OR) with 95% confidence interval (CI) not inclusive of the unity considered significant. RESULTS: Two hundred and fifty seven FFN tests were performed in 230 women, of which 33 (14.3%) had positive FFN results. Duration of hospital stay was significantly shorter for patients with negative than positive results (8 h vs. 2.1 days, P = 0.011). Women with positive FFN were more likely to deliver within 14 days (OR = 6.5, 95% CI 1.4; 30.7), within 21 days (OR = 4.8; 95% CI 1.4; 16.6), before 34 weeks (OR = 5.0, 95% CI 1.7; 14.8) and before 37 weeks (OR = 3.1; 95% CI 1.3; 7.1) than women with negative results. CONCLUSION: A negative FFN result provides enough reassurance to allow shorter hospital stay. In a real-world setting (a community hospital with a population heterogeneous for risk factors for preterm delivery, and in a non-protocol setting) the performance of FFN testing closely mirrors that obtained in academic institutions, where the test was studied in more uniform populations under strict protocols. The performance of vaginal fibronectin in patients with heterogeneous risk factors for preterm delivery closely mirrors that obtained in studies conducted in populations with homogeneous risk factors.
Assuntos
Colo do Útero/química , Fibronectinas/análise , Programas de Rastreamento/métodos , Trabalho de Parto Prematuro/prevenção & controle , Vagina/química , Adulto , Biomarcadores/análise , Peso ao Nascer , Feminino , Idade Gestacional , Hospitais Comunitários , Humanos , Tempo de Internação/estatística & dados numéricos , Gravidez , Estudos Prospectivos , Fatores de Risco , Fatores de TempoAssuntos
Dor Abdominal/etiologia , Doenças do Colo/diagnóstico por imagem , Fibromatose Abdominal/diagnóstico por imagem , Intussuscepção/diagnóstico por imagem , Adulto , Fatores Etários , Doenças do Colo/fisiopatologia , Doenças do Colo/cirurgia , Fibromatose Abdominal/fisiopatologia , Humanos , Masculino , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: The purpose of this study was to assess whether the duration of labor has any effect on the occurrence of cerebral white-matter damage in very preterm infants who are delivered in the presence of intrauterine infection. STUDY DESIGN: From a cohort of infants who were born spontaneously at <32 weeks of gestation for whom placental information was available and who survived 7 days from birth, 126 infants had clinical, laboratory, or histologic evidence of intrauterine infection. Among them, variables were compared between those infants with white-matter damage (defined as intraventricular hemorrhage grade 3 plus, periventricular leukomalacia, or ventriculomegaly not associated with hydrocephaly [n = 13]) and those infants without it (n = 113). Comparisons were made with t test, chi-squared test, and survival analysis; a probability value of <.05 was considered significant. RESULTS: There were no differences between the 2 groups in gestational age at delivery and rates of labor or cesarean delivery. Duration of active labor (66 +/- 45 minutes vs 88 +/- 75 minutes; P =.49) and of clinical chorioamnionitis (310 +/- 186 minutes vs 529 +/- 544 minutes; P =.44) were similar in cases with and without neonatal white-matter damage. CONCLUSION: In 126 infants who were born at <32 weeks of gestation with intrauterine infection, we found no correlation between the duration of labor or clinical chorioamnionitis and neonatal white-matter damage.
Assuntos
Corioamnionite/epidemiologia , Doenças do Prematuro/epidemiologia , Trabalho de Parto , Leucomalácia Periventricular/epidemiologia , Adulto , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Gravidez , Fatores de Risco , Fatores de TempoRESUMO
OBJECTIVE: Gestational age at delivery and spontaneous prematurity are independent risk factors for white matter damage (WMD). However, among infants delivered spontaneously after preterm premature rupture of membranes (PPROM), latency of PPROM has been inconsistently correlated with risk of WMD. We have explored whether gestational age at membrane rupture is independently associated with WMD. STUDY DESIGN: Using a cohort of 196 liveborn singleton nonanomalous neonates born at 24.0 to 33.6 weeks from January 1993 to December 2002 after pPROM and who survived 7 days, we compared the characteristics of those who developed WMD (n = 15) with those who did not (n = 181) using Fisher exact test, Student t test, and logistic regression analysis, with a 2-tailed P < .05 or odds ratio (OR) with 95% CI not inclusive of the unity considered significant. RESULTS: Stepwise logistic regression analysis demonstrated that gestational age at PPROM (P < .001, OR 0.79) was significantly associated with WMD. The association was independent of corticosteroid administration (P = .016), latency interval (P = .69), gestational age at delivery (P = .99), and birth weight (P = .62). CONCLUSION: Among premature infants born at <34 weeks after pPROM, gestational age at diagnosis is independently associated with WMD.