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2.
Urology ; 94: 29-35, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27063610

RESUMEN

OBJECTIVE: To examine mild cognitive impairment (MCI) in a young and older adult urology population, and which external factors were associated with diminished cognitive status at baseline. METHODS: We enrolled patients >18 years of age presenting to a large, urban tertiary care center for a wide variety of urologic complaints. Cognitive status was determined by the Montreal Cognitive Assessment (MoCA) screening test. A score of 26-30 on the MoCA is considered cognitively intact, whereas <26 indicates MCI. Patient charts were retrospectively reviewed; a backwards-stepwise logistic regression was constructed to compare MCI with potential risk factors. RESULTS: One hundred ninety-seven patients were included. There were 10/33 (30%) patients aged 18-40 who had MCI. Moreover, 32/68 (47%) patients aged 41-64 had MCI. Of older adults age 65+, MCI was seen in 65/96 (68%) patients. Factors associated with MCI in age group 41-64 included opioid use. Patients with stone disease were less likely to demonstrate MCI, when compared to other general categories of urologic chief complaints. For patients in age group 65+, associations with MCI included a cancer-related chief complaint, increased age, depressive symptoms, and less education. There were no significant associations with MCI in age group 18-40. CONCLUSION: These results demonstrate a significant prevalence of MCI in an adult urology population and factors that may be associated with its prevalence. We believe that this study lays the groundwork for urology providers to be able to identify patients who may have MCI at baseline.


Asunto(s)
Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/epidemiología , Enfermedades Urológicas/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Adulto Joven
3.
Eur Urol Focus ; 2(3): 231-237, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28723368

RESUMEN

CONTEXT: There is currently no standardized definition of success for surgery for stress urinary incontinence (SUI) and voiding dysfunction (VD) in women. OBJECTIVE: To review the use of outcome measures (OMs) and definitions of success in the literature on SUI and VD surgery in women in an attempt to provide recommendations for future publications. EVIDENCE ACQUISITION: A PubMed search of all English language full-text articles on SUI and VD surgery in women published between 2010 and 2015 was performed. A list of randomized trials and prospective and retrospective studies was obtained. Specific objective and subjective OMs used to define success were reviewed. EVIDENCE SYNTHESIS: Some 95 articles met the inclusion criteria for SUI surgery outcomes. Most trials reported outcomes at 12 mo after surgery. The majority (n=48) reported their primary outcomes using both objective and subjective success measures, 24 defined success using subjective OMs alone, and 23 using objective OMs alone. The OMs most frequently used for objective success were a negative cough stress test (CST), a negative pad test, and the absence of retreatment for SUI. The definition of subjective success most often involved questionnaires. The questionnaires most frequently used were Patient Global Impression of Improvement (PGI-I), Urinary Distress Inventory (UDI)/UDI-6, International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) and Medical Epidemiologic and Social Aspects of Aging (MESA). Only 11 studies on OMs used for VD surgery were published between 2010 and 2015. The two most common criteria used for success were measurement of postvoid residual urine (PVR) and subjective resolution of VD symptoms. CONCLUSIONS: There is great heterogeneity in the definition of success used after surgery for SUI or VD in women. For SUI surgery, we recommend use of the CST and a 1-h pad test for the definition of objective success, and of the UDI/UDI-6, Incontinence Impact Questionnaire (IIQ), King's Health Questionnaire (KHQ), ICIQ-SF, or PGI-I questionnaire for subjective success. For VD surgery, cure should include measurement of PVR and self-reported resolution of VD symptoms. PATIENT SUMMARY: We looked at the definition of success used for surgery for stress urinary incontinence (SUI) and voiding dysfunction (VD) in women. We found that there is great heterogeneity among studies, making study comparison extremely difficult. According to the outcome measures used most frequently, we make recommendations regarding the definition of cure for SUI and VD in women to be used in future publications.

4.
Artículo en Inglés | MEDLINE | ID: mdl-24808798

RESUMEN

We report an intra-articular ganglion cyst (IAGC) presenting as knee pain and a mass in a patient with longstanding Juvenile Idiopathic Arthritis (JIA). We could not find a similar case of an IAGC occurring in the knee of JIA patients in the literature. IAGC may need to be included as a possibility in patients with inflammatory arthritis with new-onset knee pain, especially in those with a palpable mass. MRI was useful in distinguishing IAGC from more worrisome causes of a knee mass. Orthopedic input was helpful in diagnosis and treatment. In addition, methotrexate therapy was effective in bringing about a long-lasting remission.


Asunto(s)
Artritis Juvenil , Ganglión , Articulación de la Rodilla , Metotrexato/administración & dosificación , Succión/métodos , Adolescente , Antirreumáticos/administración & dosificación , Artralgia/etiología , Artritis Juvenil/complicaciones , Artritis Juvenil/diagnóstico , Artritis Juvenil/fisiopatología , Artritis Juvenil/terapia , Femenino , Ganglión/diagnóstico , Ganglión/etiología , Ganglión/fisiopatología , Ganglión/cirugía , Humanos , Articulación de la Rodilla/patología , Articulación de la Rodilla/fisiopatología , Imagen por Resonancia Magnética , Rango del Movimiento Articular , Resultado del Tratamiento
5.
J Neurosurg Spine ; 20(4): 421-9, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24527829

RESUMEN

Chordomas of the sacrum require en bloc resection to reduce the risk of recurrence, but this may sacrifice nerves vital to bladder, bowel, and sexual function. High, mid-, and low sacral amputations have been previously classified based on nerve root sacrifice, not bony amputation. Sacrifice of the S-2 nerves or those above results in a high sacral amputation, but preserving the S-2 nerves converts it into a midsacral amputation. Preservation of the S-2 nerves has been shown to improve functional outcome, despite the bony osteotomy being unchanged. Thus, keeping the same bony amputation while preserving the S-2 nerve roots may allow for improved functional outcome while still achieving the same goal of oncological resection. Preservation of the S-2 nerves may be particularly difficult during amputation at the S-2 pedicle or above, and the authors describe their technique for preserving the S-2 nerves during partial sacrectomy at or just above the S-2 pedicle. Four cases of sacral chordoma resections are presented to illustrate the technique.


Asunto(s)
Amputación Quirúrgica/métodos , Cordoma/cirugía , Procedimientos Neuroquirúrgicos/métodos , Sacro/cirugía , Neoplasias de la Columna Vertebral/cirugía , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
6.
Pulm Circ ; 3(2): 369-80, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24015338

RESUMEN

The diagnosis of pulmonary arterial hypertension (PAH) is frequently delayed. We hypothesized that circulating angiogenic modulatory protein levels might correspond with vascular remodeling activity and serve as sensitive biomarkers of PAH. Levels of soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR1), N-terminal brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and other biomarkers were measured in peripheral blood from 97 PAH patients, 16 first-degree relatives of idiopathic or heritable pulmonary arterial hypertension (HPAH) patients, and 56 controls, and correlated with disease, functional class, hemodynamic parameters, exercise capacity, and transplant-free survival. Endoglin expression was analyzed in lung tissues of six individuals with idiopathic or HPAH and four individuals without PAH. Levels of sEng, sVEGFR1, CRP, and NT-proBNP were elevated in Group I PAH of diverse etiologies, with sEng performing better than NT-proBNP in detecting PAH (receiver operator characteristic-area-under-the curve [ROC-AUC] of 0.82 ± 0.03 vs. 0.71 ± 0.05, P = 0.016). While sEng, sVEGFR1, and NT-proBNP correlated with New York Heart Association (NYHA) class, sEng levels were more sensitive than NT-proBNP in detecting NYHA Class I-II disease (ROC-AUC of 0.88 ± 0.05 vs. 0.67 ± 0.08, P = 0.028). sEng, sVEGFR1, CRP, and NT-proBNP predicted transplant-free survival by univariate Cox regression. After adjusting for NT-proBNP levels, each of the other three markers predicted transplant-free survival. In multivariate analysis, sEng and CRP were independent predictors of survival. Endoglin expression was markedly enhanced in the microvascular endothelium and endovascular lesions of PAH versus control lung tissues. Circulating angiogenic proteins sEng and sVEGFR1 are sensitive markers of prognosis and function in Group I PAH, including mildly symptomatic disease, and may provide unique noninvasive data reflecting underlying remodeling activity.

7.
Mol Cell Biol ; 33(12): 2413-24, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23572558

RESUMEN

Constitutively activating mutations in receptor kinases recruit downstream effector pathways independently of upstream signaling, with consequences ranging from developmental syndromes to cancer. Classic fibrodysplasia ossificans progressiva (FOP) is a congenital syndrome resulting from highly conserved activating mutations of the glycine-serine-rich (GS) regulatory domain of ACVR1, encoding bone morphogenetic protein (BMP) type I receptor ALK2, which lead to inappropriate signaling and heterotopic ossification of soft tissues. It is unclear if constitutively active mutant ALK2 receptors (caALK2) can function independently of signaling complexes with type II receptors and ligands. We found that ablation of BmpRII and ActRIIa abrogated BMP ligand-mediated and caALK2-mediated signaling and transcription in cells and disrupted caALK2-induced heterotopic ossification in mice. Signaling via GS domain ALK2 mutants could be restored by the expression of either BMP type II receptor. The contribution of BMP type II receptors was independent of their ligand-binding or kinase function but was dependent upon an intact cytoplasmic domain. These data demonstrate that GS domain ALK2 mutants act independently of upstream signaling but may require a nonenzymatic scaffolding function provided by type II receptors to form functional, apparently ligand-independent signaling complexes. These findings define the minimal requirements for signaling of GS domain ALK2 mutants, with implications for the therapeutic targeting of their activity in disease.


Asunto(s)
Receptores de Activinas Tipo II/metabolismo , Receptores de Activinas Tipo I/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Osificación Heterotópica/metabolismo , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo II/biosíntesis , Receptores de Activinas Tipo II/genética , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/biosíntesis , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Ratones , Ratones Transgénicos , Músculo Liso Vascular , Miositis Osificante , Estructura Terciaria de Proteína , Arteria Pulmonar , Interferencia de ARN , ARN Interferente Pequeño , Transducción de Señal/genética
8.
Urology ; 79(4): 955-7, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22342417

RESUMEN

OBJECTIVE: To describe the technique of concomitant bladder neck closure and augmentation cystoplasty in a 22-year-old woman with a history of bladder exstrophy and refractory urinary incontinence. This patient had prior augmentation cystoplasty and circumferential fascial urethral sling placement with continued incontinence. During closure of the bladder neck, the bladder neck was incorporated into the augmentation cystoplasty to help prevent failure of bladder neck closure. MATERIAL AND METHODS: The patient had previously undergone augmentation cystoplasty, circumferential fascial urethral sling placement, and antegrade collagen injection of the bladder neck. Despite these interventions, she continued to have refractory urinary incontinence. Her bladder neck was closed by incorporating the bladder neck into the cystotomy and using the bladder neck as an edge of anastomosis during augmentation cystoplasty. RESULTS: The patient tolerated the procedure well. She catheterizes easily through her appendicovesicostomy and has remained continent. She has no leakage from her closed bladder neck 30 months after closure. CONCLUSION: Incorporating the bladder neck into the cystotomy during a planned augmentation cystoplasty and bladder neck closure should be considered as an alternative to separate bladder neck closure, which can fail and can result in continued urinary incontinence.


Asunto(s)
Procedimientos de Cirugía Plástica/métodos , Vejiga Urinaria/cirugía , Incontinencia Urinaria/cirugía , Procedimientos Quirúrgicos Urológicos/métodos , Extrofia de la Vejiga/cirugía , Cistostomía , Femenino , Humanos , Urodinámica , Adulto Joven
9.
Blood ; 117(18): 4915-23, 2011 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-21393479

RESUMEN

Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6-induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.


Asunto(s)
Anemia/etiología , Anemia/prevención & control , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Inflamación/complicaciones , Animales , Péptidos Catiónicos Antimicrobianos/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/antagonistas & inhibidores , Proteínas Portadoras/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Hep G2 , Hepcidinas , Humanos , Interleucina-6/farmacología , Ratones , Ratones Endogámicos C57BL , Pirazoles/farmacología , Pirimidinas/farmacología , Proteínas Recombinantes/farmacología , Transducción de Señal/efectos de los fármacos , Trementina/toxicidad , Pez Cebra , Proteínas de Pez Cebra/metabolismo
10.
J Urol ; 185(5): 1710-5, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21420120

RESUMEN

PURPOSE: HIV/AIDS is a worldwide epidemic. Limited evidence suggests that men infected with HIV/AIDS are at increased risk for lower urinary tract symptoms. We determined whether HIV/AIDS status is an independent risk factor for self-reported bothersome lower urinary tract symptoms in a large contemporary cohort. MATERIALS AND METHODS: We performed a cross-sectional, Internet based survey of urinary quality of life outcomes in adult HIV infected and HIV uninfected men who have sex with men. The main outcome measure was International Prostate Symptom Score. RESULTS: Of respondents with complete data 1,507 were HIV uninfected (median age 42 years, mean 43) and 323 HIV infected (median age 45 years, mean 45.1). Of the HIV infected respondents 148 were nonAIDS defining HIV infected and 175 were AIDS defining HIV infected. After adjusting for age and other comorbid conditions, nonAIDS defining HIV infected and AIDS defining HIV infected status increased the odds of severe lower urinary tract symptoms by 2.07 (95% CI 1.04-3.79) and 2.49 (95% CI 1.43-4.33), respectively. HIV infected men had a worse total International Prostate Symptom Score for all domains including quality of life compared to HIV uninfected men. Within the population of men with HIV, those with AIDS had worse mean total International Prostate Symptom Score and all individual International Prostate Symptom Score components relative to nonAIDS defining HIV infected men. CONCLUSIONS: HIV status is an independent risk factor for bothersome lower urinary tract symptoms. The odds of severe lower urinary tract symptoms are greater in HIV infected men with a history of AIDS.


Asunto(s)
Infecciones por VIH/complicaciones , Trastornos Urinarios/epidemiología , Trastornos Urinarios/etiología , Adulto , Estudios Transversales , Humanos , Internet , Modelos Logísticos , Masculino , Calidad de Vida , Factores de Riesgo , Estadísticas no Paramétricas , Encuestas y Cuestionarios
11.
Med Clin North Am ; 95(1): 101-9, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21095414

RESUMEN

Urinary incontinence is a common and vexing problem that affects millions of adults. The main types of incontinence in women are stress, urge, and mixed. It is important to delineate the different types to target the treatment options better. Treatments include conservative or behavioral modifications, pharmacotherapy, and surgical interventions.


Asunto(s)
Incontinencia Urinaria/tratamiento farmacológico , Factores de Edad , Femenino , Conductas Relacionadas con la Salud , Humanos , Estilo de Vida , Atención Primaria de Salud , Factores de Riesgo , Incontinencia Urinaria/diagnóstico , Incontinencia Urinaria/terapia , Incontinencia Urinaria de Esfuerzo/terapia , Incontinencia Urinaria de Urgencia/terapia
12.
Nat Med ; 14(12): 1363-9, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19029982

RESUMEN

Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues and is without known effective treatments. Affected individuals harbor conserved mutations in the ACVR1 gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2). Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref. 6), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.


Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/antagonistas & inhibidores , Osificación Heterotópica/tratamiento farmacológico , Osificación Heterotópica/metabolismo , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Miositis Osificante/genética , Miositis Osificante/metabolismo , Miositis Osificante/patología , Osificación Heterotópica/genética , Osificación Heterotópica/patología , Pirazoles/química , Pirazoles/uso terapéutico , Pirimidinas/química , Pirimidinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Tomografía Computarizada por Rayos X
13.
Bioorg Med Chem Lett ; 18(15): 4388-92, 2008 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-18621530

RESUMEN

A structure-activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma t(1/2)=1.6h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.


Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Proteínas Morfogenéticas Óseas/metabolismo , Piperazinas/síntesis química , Piperazinas/farmacología , Pirazoles/síntesis química , Pirimidinas/síntesis química , Pirimidinas/farmacología , Transducción de Señal , Animales , Técnicas Químicas Combinatorias , Femenino , Masculino , Ratones , Estructura Molecular , Piperazinas/química , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Relación Estructura-Actividad
14.
Nat Chem Biol ; 4(1): 33-41, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18026094

RESUMEN

Bone morphogenetic protein (BMP) signals coordinate developmental patterning and have essential physiological roles in mature organisms. Here we describe the first known small-molecule inhibitor of BMP signaling-dorsomorphin, which we identified in a screen for compounds that perturb dorsoventral axis formation in zebrafish. We found that dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6 and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation. Using dorsomorphin, we examined the role of BMP signaling in iron homeostasis. In vitro, dorsomorphin inhibited BMP-, hemojuvelin- and interleukin 6-stimulated expression of the systemic iron regulator hepcidin, which suggests that BMP receptors regulate hepcidin induction by all of these stimuli. In vivo, systemic challenge with iron rapidly induced SMAD1/5/8 phosphorylation and hepcidin expression in the liver, whereas treatment with dorsomorphin blocked SMAD1/5/8 phosphorylation, normalized hepcidin expression and increased serum iron levels. These findings suggest an essential physiological role for hepatic BMP signaling in iron-hepcidin homeostasis.


Asunto(s)
Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Hierro/metabolismo , Osteogénesis/efectos de los fármacos , Pirazoles/farmacología , Pirimidinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Pez Cebra , Animales , Péptidos Catiónicos Antimicrobianos/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/antagonistas & inhibidores , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Hepcidinas , Hierro/sangre , Ratones , Ratones Endogámicos C57BL , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Fosforilación , Transducción de Señal , Proteínas Smad/metabolismo , Transcripción Genética/efectos de los fármacos , Pez Cebra/embriología , Pez Cebra/metabolismo
15.
J Biol Chem ; 283(7): 3877-88, 2008 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-18042551

RESUMEN

Bone morphogenetic protein (BMP) signals regulate the growth and differentiation of diverse lineages. The association of mutations in the BMP type II receptor (BMPRII) with idiopathic pulmonary arterial hypertension suggests an important role of this receptor in vascular remodeling. Pulmonary artery smooth muscle cells lacking BMPRII can transduce BMP signals using ActRIIa (Activin type II receptor). We investigated whether or not BMP signaling via the two receptors leads to differential effects on vascular smooth muscle cells. BMP4, but not BMP7, inhibited platelet-derived growth factor-activated proliferation in wild-type pulmonary artery smooth muscle cells, whereas neither ligand inhibited the growth of BMPRII-deficient cells. Adenoviral gene transfer of BMPRII enabled BMP4, as well as BMP7, to inhibit proliferation in BMPRII-deficient cells. BMP-mediated growth inhibition was also reconstituted by the BMPRII short isoform, lacking the C-terminal domain present in the long form. BMP4, but not BMP7, induced the expression of osteoblast markers in wild-type cells, whereas neither ligand induced these markers in BMPRII-deficient cells. Overexpression of short or long forms of BMPRII in BMPRII-deficient cells enabled BMP4 and BMP7 to induce osteogenic differentiation. Although signaling via BMPRII or ActRIIa transiently activated SMAD1/5/8, only BMPRII signaling led to persistent SMAD1/5/8 activation and sustained increases in Id1 mRNA and protein expression. Pharmacologic blockade of BMP type I receptor function within 24 h after BMP stimulation abrogated differentiation. These data suggest that sustained BMP pathway activation, such as that mediated by BMPRII, is necessary for growth and differentiation control in vascular smooth muscle.


Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo II/fisiología , Proteínas Morfogenéticas Óseas/fisiología , Diferenciación Celular/fisiología , División Celular/fisiología , Músculo Liso Vascular/citología , Arteria Pulmonar/citología , Animales , Secuencia de Bases , Cartilla de ADN , Inmunoprecipitación , Ratones , Ratones Noqueados , ARN Interferente Pequeño
16.
Neurourol Urodyn ; 26(1): 46-52, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17149713

RESUMEN

AIMS: Midurethral slings have become the mainstay of stress urinary incontinence (SUI) treatment due to their efficacy and low complication rates. The purpose of this study was to report the presentation and treatment of major complications from these minimally invasive treatments presented to a tertiary referral practice and to highlight a discrepancy in major complications between literature and the food and drug administration (FDA) device failure database. METHODS: From 2001 through 2005, we reviewed all cases of midurethral sling complications that presented to our institution. A literature review of all complications due to midurethral slings during the same time period was performed as was the FDA manufacturer and user facility device experience (MAUDE) database queried for self-reported complications. RESULTS: A total of 26 patients referred to UCLA with voiding dysfunction after sling placement was found to have mesh in the urethra or bladder. Treatments required a combination of urethrolysis with mesh removal, urethral reconstruction with graft, and bladder excision. These were compared to major complications reported in the world literature of <1%. The MAUDE database contained 161 major complications out of a total of 928 complications reported for suburethral slings. There was significantly more major complications reported in MAUDE than in published literature. CONCLUSIONS: Although rare, major complications of midurethral slings are more common than appear in literature. Devastating complications involving urethral and bladder perforations can present with mild urinary symptoms and thus are likely under-diagnosed and under-reported. Most of these cases need to be managed with additional reconstructive surgery.


Asunto(s)
Complicaciones Posoperatorias/mortalidad , Cabestrillo Suburetral/efectos adversos , Incontinencia Urinaria/mortalidad , Incontinencia Urinaria/cirugía , Bases de Datos Factuales/estadística & datos numéricos , Humanos , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Procedimientos Quirúrgicos Mínimamente Invasivos/mortalidad , Complicaciones Posoperatorias/cirugía , Falla de Prótesis , Reoperación , Estudios Retrospectivos , Cabestrillo Suburetral/estadística & datos numéricos , Estados Unidos , United States Food and Drug Administration/estadística & datos numéricos
17.
Can Urol Assoc J ; 1(3): 256-63, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18542800

RESUMEN

INTRODUCTION: We tested the hypothesis that extended-term (5-week) estrogen therapy would negatively impact voiding function in a postpartum, ovariectomized rat model. METHODS: Immediately after delivery, 30 primiparous Sprague-Dawley rats underwent intravaginal balloon dilation, followed by ovariectomy 1 week later. Cystometry at postpartum week 2 determined normal or abnormal voiding patterns. After randomization, one-half the normal and abnormal voiding rats received 5 weeks of estrogen therapy, while the remainder received placebo. Estrogen effect was determined by repeat cystometry and immunohistochemical analysis of the urethra and vagina. RESULTS: Abnormal voiding increased from 60.0% to 73.3% in the estrogen- treated group and declined from 60% to 33% for the placebo group. Rats were then divided into 4 groups for comparison: normal voiding versus placebo (group 1), abnormal voiding versus placebo (group 2), normal voiding versus estrogen (group 3) and abnormal voiding versus estrogen (group 4). Bladder capacity, leak point pressure and maximum voiding pressure were most depressed in group 4. Estrogen treatment was associated with a significant downregulation of alpha(1A) and alpha(1D)-adrenoceptors in the urethral submucosa but an upregulation of nNOS in the urethral smooth muscle. CONCLUSION: Extended-term estrogen therapy in a rat model of simulated birth trauma and ovariectomy resulted in a higher rate of incontinence. Immunohistochemical examination demonstrated significant downregulation of urethral alpha(1A)- and alpha(1D)-adrenoceptors and upregulation of neuronal nitric oxide synthase (nNOS) in the urethra of estrogen-treated groups. These studies question the use of hormone replacement therapy in the treatment of postmenopausal incontinence.

18.
J Urol ; 175(6): 2182-5, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16697835

RESUMEN

PURPOSE: Stimulation of the sacral nerves is a commonly used treatment for frequency, urgency, urge incontinence, retention and other types of voiding dysfunction. Minimally invasive placement of a percutaneous permanent quadripolar tined lead into the sacral foramen has been described. No lead migration has been reported. We report on our experience with lead migration and the subsequent failure of InterStim in a large cohort of patients with a focus on possible diagnostic and salvage techniques. MATERIALS AND METHODS: Between February 2002 and April 2005 tined lead electrodes were implanted in the S3 foramen in 235 patients using the InterStim system. Patients with a good response during the testing phase (greater than 50% improvement) underwent placement of an implantable pulse generator. Position was confirmed by radiographic evaluation intraoperatively. Sacral radiographs were obtained at the first postoperative visit, after IPG placement and whenever there was a change in symptomatic response. RESULTS: There were 5 patients (2.1%) in whom treatment failed after a successful trial of stimulation due to lead migration. This was seen as early as 3 weeks and as late as 8 months. Migration of the lead occurred between first and second stage implantation in 1 of the 5 cases, and occurred after the second stage in 4 of 5. Anterior migration was noted in 4 patients and posterior migration was noted in 1. CONCLUSIONS: Lead migration after placement of the tined lead can occur and thus sacral radiographs should be routinely used. This complication can be easily resolved without significant morbidity to the patient.


Asunto(s)
Terapia por Estimulación Eléctrica/instrumentación , Migración de Cuerpo Extraño , Prótesis e Implantes/efectos adversos , Trastornos Urinarios/terapia , Algoritmos , Electrodos , Diseño de Equipo , Falla de Equipo , Migración de Cuerpo Extraño/diagnóstico , Humanos , Plexo Lumbosacro , Insuficiencia del Tratamiento
19.
J Urol ; 175(5): 1794-8; discussion 1798-9, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16600764

RESUMEN

PURPOSE: Female patients with severe urethral incompetence are a unique surgical challenge. Urethral closure and continent diversion are often the next step in the treatment of these patients. We present a technique that provides circumferential coaptation of the urethra as a salvage procedure in this severe subset of patients. MATERIALS AND METHODS: We prospectively evaluated 47 patients who had a spiral sling. A 1 x 15 cm piece of soft polypropylene mesh was prepared with a zero polyglactin suture applied at each end. A clamp was used to pass the mesh between the urethra and pubis. The ends of the mesh were crossed at the ventral aspect of the urethra, creating a complete circle around the urethra. The sutures were transferred to the suprapubic area and tied without tension. The surgical outcome was determined by patient self-assessment, including symptom, bother and quality of life questionnaires. RESULTS: Mean patient age was 59 years. At presentation patients had undergone a mean of 2.6 incontinence procedures and wore a mean of 6 pads daily. Mean daily pad use decreased to 0.9 (p <0.005). Preoperatively mean SUI symptom severity and bother scores were 2.8 and 2.9, respectively, on a scale of 0--none to 3--severe. Postoperatively these values decreased to 0.6 and 0.4, respectively (each p <0.005). There was a mean 87% overall improvement in symptoms. CONCLUSIONS: The spiral sling is an effective salvage transvaginal procedure that may be considered in a small subset of female patients with a nonfunctional urethra as a last resort before urethral closure procedures.


Asunto(s)
Polipropilenos , Prótesis e Implantes , Uretra , Incontinencia Urinaria de Esfuerzo/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Procedimientos Quirúrgicos Urológicos/métodos
20.
Neurourol Urodyn ; 24(7): 654-8, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16208661

RESUMEN

AIMS: The sacrouterine ligament/cardinal (SULC) complex and prerectal fascia attach at the perineal body, forming a single support unit preventing levator descent. Many patients with vault prolapse have levator descent and widening of the hiatus. Existing transvaginal procedures do not address pelvic floor descent. We describe a technique utilizing polypropylene mesh to repair pelvic floor relaxation and prevent levator descent, along with restoration of the SULC complex in vaginal vault repair. MATERIALS AND METHODS: We prospectively evaluated 50 patients who had a transvaginal mesh vault/posterior wall reconstruction. A T-shaped soft prolene mesh is prepared fixing the two arms of the mesh and recreating the SULC complex in support of the cuff. The vertical segment of the mesh is transferred over the prerectal fascia and secured to the pelvic floor musculature. The rectocele is repaired incorporating the mesh distally preventing pelvic floor descent. Surgical outcome was determined by patient self-assessment including quality of life (QoL) measure as well as pelvic examination using POP-Q staging. RESULTS: Mean age was 67 years. Mean follow-up was 6 months (range 3-12). There were no intraoperative complications. There have been two apical (4%) recurrences. Mean QoL score postoperatively on a 0-6 scale was 0.74 (0 = delighted, 1 = pleased). Pelvic floor descent has been repaired on all patients. Postoperative POP-Q reveals restoration of normal anatomy. CONCLUSIONS: We report a new technique that recreates the SULC complex in support of the vaginal vault with the aid of prolene mesh. It is the first transvaginal procedure described to reconstruct the pelvic floor in attempt to prevent pelvic floor descent.


Asunto(s)
Diafragma Pélvico/cirugía , Mallas Quirúrgicas , Prolapso Uterino/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Procedimientos Quirúrgicos Ginecológicos/instrumentación , Procedimientos Quirúrgicos Ginecológicos/métodos , Humanos , Persona de Mediana Edad , Satisfacción del Paciente , Polipropilenos , Periodo Posoperatorio , Rectocele/cirugía
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