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Berger M.B.,University of Michigan | Berger M.B.,1500 dical Center Drive | Doumouchtsis S.K.,St Georges, University of London | DeLancey J.O.,University of Michigan
International Urogynecology Journal and Pelvic Floor Dysfunction | Year: 2013

Introduction and hypothesis Bony pelvis dimensions have been shown to differ in women with and without pelvic floor dysfunction. The goal of this study was to determine whether bony pelvis dimensions are different when comparing women with severe bilateral levator ani defects (LAD) with those with normal muscles. Methods This is a secondary analysis of a case-control study comparing women with and those without pelvic organ prolapse. Subjects underwent pelvic organ prolapse quantification (POP-Q) examination and were classified as either having prolapse or being normal. All underwent pelvic magnetic resonance imaging (MRI). Levator defects were assessed based on the muscles' appearance on imaging and subjects were stratified into two groups-women with normal muscles (n=99) and women with severe bilateral LAD (n=50). Bony pelvis dimensions were measured via MRI pelvimetry. The subpubic angle, interspinous and intertuberous diameters, and the sacrococcygeal joint-to-infrapubic point (SCIPP) lengths were compared. Results Both groups had similar demographics. The SCIPP length was 2.5 % (3 mm) shorter in women with severe LAD than in those without defects (P=0.02). The SCIPP measured 4%(5mm) less inwomen with prolapse and severe LADthan in subjects with prolapse but normal muscles (P=0.01). Logistic regression identified SCIPP length and history of forceps delivery as being independent predictors of severe bilateral LAD. Conclusions Severe bilateral LAD are associated with shorter SCIPP length and forceps-assisted vaginal delivery. © The International Urogynecological Association 2013. Source

Berger M.B.,University of Michigan | Berger M.B.,1500 dical Center Drive | Morgan D.M.,University of Michigan | DeLancey J.O.,University of Michigan
International Urogynecology Journal and Pelvic Floor Dysfunction | Year: 2014

Introduction and hypothesis: The goal of this study was to use a well-described system of quantifying levator ani defect (LAD) severity using magnetic resonance imaging (MRI) to examine the relationship between defect severity and the presence or absence of prolapse.Methods: This is a secondary analysis of two case–control studies comparing 284 cases (with prolapse) to 219 controls (normal support) defined by using Pelvic Organ Prolapse Quantification (POP-Q) exams. LAD were assessed on MRI, with scores from 0 (no defects) to 6 (complete, bilateral defects). The number of cases and controls at each score were compared. Logistic regression and receiver operating characteristic (ROC) analyses were used to quantify relationships between LAD and prolapse.Results: The proportion of cases exceeds the overall prolapse rate in this study at LAD scores ≥3, with higher rates of prolapse at higher LAD scores (p < 0.0000001). Prolapse risk stratifies into low risk at LAD scores 0–2, moderate at 3–5, and high at 6. ROC analysis for classification of prolapse based on LAD scores has an area under the curve of 69.9 % (p < 0.001), suggesting LAD alone can discriminate between normal support and prolapse for nearly 70 % of patients. Logistic regression identified higher parity and higher LAD scores as independent predictors of prolapse.Conclusions: There are three clusters of prolapse risk: low (0–2), moderate (3–5), and high (6). Although LAD have a dose-response-like effect for prolapse, other factors are clearly involved. © 2014, The International Urogynecological Association. Source

Chattopadhyay M.,University of Michigan | Zhou Z.,University of Michigan | Zhou Z.,University of North Carolina at Chapel Hill | Hao S.,University of Michigan | And 4 more authors.
Molecular Pain | Year: 2012

Background: Painful neuropathy is a common complication of diabetes. Previous studies have identified significant increases in the amount of voltage gated sodium channel isoforms NaV1.7 and NaV1.3 protein in the dorsal root ganglia (DRG) of rats with streptozotocin (STZ)-induced diabetes. We found that gene transfer-mediated release of the inhibitory neurotransmitters enkephalin or gamma amino butyric acid (GABA) from DRG neurons in diabetic animals reduced pain-related behaviors coincident with a reduction in NaV1.7 protein levels in DRG in vivo. To further evaluate the role of NaVα subunit levels in DRG in the pathogenesis of pain in diabetic neuropathy, we constructed a non-replicating herpes simplex virus (HSV)-based vector expressing a microRNA (miRNA) against NaVα subunits.Results: Subcutaneous inoculation of the miRNA-expressing HSV vector into the feet of diabetic rats to transduce DRG resulted in a reduction in NaVα subunit levels in DRG neurons, coincident with a reduction in cold allodynia, thermal hyperalgesia and mechanical hyperalgesia.Conclusions: These data support the role of increased NaVα protein in DRG in the pathogenesis of pain in diabetic neuropathy, and provide a proof-of-principle demonstration for the development of a novel therapy that could be used to treat intractable pain in patients with diabetic neuropathy. © 2012 Chattopadhyay et al; licensee BioMed Central Ltd. Source

Schneider B.J.,New York Medical College | Kalemkerian G.P.,University of Michigan | Kalemkerian G.P.,500 dical Center Drive | Bradley D.,Duke University | And 9 more authors.
Investigational New Drugs | Year: 2012

Introduction Vorinostat is an inhibitor of histone deacetylase 6, which acetylates tubulin and stabilizes microtubules. Since taxanes also stabilize microtubules, we hypothesized that the administration of vorinostat followed by docetaxel should result in synergistic cytotoxicity. We conducted a phase I trial to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in =30%of patients. Methods Eligible patients had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after =1 prior chemotherapy regimen not containing docetaxel, performance status of 0-2, and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle, with docetaxel given intravenously over 1 h on day 4. The time-to-event continuous reassessment method (TITE-CRM) guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m2, respectively. Pharmacokinetic studies were performed on days 1 and 4 of cycle 1. Results Twelve patients were enrolled: median age 65 years (range 49-74); 9 male, 3 female; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles administered was 2. Two patients were treated at DL -1, 4 at DL 0, 5 atDL 1 and 1 at DL 2. Five DLTs occurred in 5 patients: neutropenic fever/sepsis (2), anaphylactic reaction (1), myocardial infarction (1) and gastrointestinal bleed (1). Other toxicities included grade 3/4 neutropenia (4), peripheral neuropathy (1), and gastrointestinal bleed (n=1). The estimated probability of DLT for DL -1 was 0.32 (90% posterior probability interval [PI], 0.11 to 0.53) for DL 0, 0.38 (90% PI, 0.16 to 0.58) and for DL 1, 0.43 (90% PI, 0.23 to 0.64). The trial was stopped due to excessive toxicity. No responses were noted. Conclusions The combination of vorinostat and docetaxel was poorly tolerated with excessive DLTs that required early study termination. No responses were identified. Vorinostat and docetaxel pharmacokinetics were comparable to previous reports in the literature, without obvious drug-drug interactions. © Springer Science+Business Media, LLC 2010. Source

Berger M.B.,University of Michigan | Berger M.B.,1500 dical Center Drive | Ramanah R.,Besancon University Medical Center | Guire K.E.,University of Michigan | DeLancey J.O.L.,University of Michigan
International Urogynecology Journal and Pelvic Floor Dysfunction | Year: 2012

Introduction and hypothesis It is commonly believed that pelvic organ prolapse (POP) is associated with cervical elongation. However, cervical lengths have not been formally compared between women with prolapse and those with normal support. Methods Cervix and uterine corpus lengths were measured on magnetic resonance images in a case-control study of 51 women with prolapse and 46 women with normal support determined by the Pelvic Organ Prolapse Quantification (POP-Q) examination. Group matching ensured similar demographics in both groups. Ranges for normal cervical lengths were determined from the values in the control group in order to evaluate for cervical elongation amongst women with prolapse. Results The cervix is 36.4 % (8.6 mm) longer in women with prolapse than inwomenwith normal pelvic support (p<0.001). Linear regression modeling suggests the feature most highly associated with cervical length is the degree of uterine descent (POP-Q point C). Approximately 40 % of women with prolapse have cervical elongation; 57 % of cervical elongation in prolapse can be explained by a logistic regression-based model including POP-Q point C, body mass index, and menopausal status. Conclusions Cervical elongation is found in one third of women with POP, with the extent of elongation increasing with greater degrees of uterine descent. © The International Urogynecological Association 2012. Source

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