Glycogen synthase kinase-3 regulation of chromatin segregation and cytokinesis in mouse preimplantation embryos

Glycogen synthase kinase-3 (GSK-3) is a highly conserved serine/threonine protein kinase implicated in diverse cellular processes. Activity of GSK-3 is essential for meiotic chromatin segregation in oocytes, yet expression and/or function of GSK-3 have not been reported in mammalian preimplantation embryos. Objectives of this study were to characterize GSK-3 protein expression/phosphorylation in mouse preimplantation embryos, to assess the effect of GSK-3 activity inhibition on early mitotic events, and to differentiate nuclear and cytoplasmic anomalies in GSK-3 inhibited embryos. Both GSK-3 isoforms were expressed during embryo development, with a differential expression of Α versus Β. Phosphorylation of GSK-3Α/Β at residues Y279/Y216 indicated constitutive activation throughout preimplantation development. Phosphorylation at N-terminal residues S21/S9 indicated inhibition of GSK-3Α/Β activity that was differentially regulated during early development; both Α and Β isoforms were phosphorylated during early divisions, whereas at the blastocyst stage, only Β was phosphorylated. Cytoplasmic microinjection of zygotes with anti-GSK-3Α/Β antibody significantly compromised embryonic development past the two-cell stage compared to controls. Reversibility of developmental block was tested via pharmacological inhibitors of GSK-3, lithium chloride (LiCl) and alsterpaullone. Similar to immunoneutralization, significantly fewer zygotes cultured with either LiCl or alsterpaullone developed past the two-cell stage compared to controls and this mitotic block was not reversible. Inhibition of GSK-3 activity significantly compromised timing of pronuclear membrane breakdown and mitosis initiation, nuclear development, and cytokinesis. Inhibition of GSK-3 also resulted in abnormal chromatin segregation, evidenced by incomplete karyokinesis and micronuclei formation. These results suggest that GSK-3 activity is critical for early preimplantation embryonic development. Mol. Reprod. Dev. © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55901/1/20495_ftp.pd

Longitudinal patterns of antidepressant prescribing in primary care in the UK: comparison with treatment guidelines

The objective of this study was to determine whether patients beginning therapy on the most common tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) differed in their likelihood of having antidepressant treatment that was consistent with recommended treatment guidelines in the UK. An analytical file constructed from a large general practitioner medical records database (DIN-LINK) from the UK for the years 1992-97 was constructed. A total of 16 204 patients with a new episode of antidepressant therapy who initiated therapy on one of the most often prescribed TCAs (amitriptyline, dothiepin, imipramine and lofepramine) or SSRIs (fluoxetine, paroxetine and sertraline) were analysed. A dichotomous measure was defined to indicate whether subjects were prescribed at least 120 days of antidepressant therapy at an adequate average daily dose within the first 6 months after initiation of therapy. Only 6.0% of patients initiating therapy on aTCA and 32.9% of patients initiating therapy on a SSRI were prescribed antidepressant treatment that was consistent with treatment guidelines. After controlling for observable characteristics, patients who initiated therapy on a SSRI were much more likely (odds ratio=7.473, p<0.001) to have a prescribed average daily dose and duration consistent with recommended treatment guidelines within the first 6 months of initiating therapy than were patients who initiated therapy on a TCA. These findings suggest that initial antidepressant selection is an important determinant of whether the subsequent course of treatment is consistent with current national guidelines for the treatment of depression in the UK.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68732/2/10.1177_026988119901300204.pd

A screening tool for clinically relevant urinary incontinence

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111206/1/nau22564.pd

Pilot and feasibility study of serum chemokines as markers to distinguish prostatic disease in men with low total serum PSA

BACKGROUND The incidence and prevalence of both benign prostatic hypertrophy (BPH) and prostate cancer (PCa) increase with the aging process. Our laboratory recently showed that the chemokines CXCL5 and CXCL12, which normally function as inflammatory mediators, are secreted at higher levels by aging prostate stromal fibroblasts and elicit proliferative responses from both prostate stromal fibroblast and epithelial cells. Because both CXCL5 and CXCL12 are secreted molecules, we hypothesized that their levels in patient serum might serve as biomarkers to distinguish between BPH and PCa. METHODS Serum CXCL5 and CXCL12 levels were determined using sandwich ELISAs for 51 men demonstrating low serum PSA values of ≤10 ng/ml who underwent diagnostic needle biopsy for the detection of PCa. The bivariate relationship of circulating chemokine levels, age, and disease status in the prostate was tested using the Wilcoxon rank-sum test. Results Total serum CXCL12 levels were significantly higher for men who were biopsy positive compared to those who were biopsy negative for cancer and histological prostatitis ( P  = 0.050). Among men who were biopsy negative for PCa, total serum CXCL5 levels were inversely associated with prostate volume and were significantly higher in men with concomitant BPH and histological prostatitis compared to those without evidence of prostatic disease ( P  < 0.003). CONCLUSIONS The results of this pilot and feasibility study suggest that serum or plasma CXCL5 and CXCL12 levels may potentially distinguish between BPH and PCa among patients presenting with low serum PSA, and may be useful toward facilitating decisions to perform diagnostic needle biopsy in this patient population. Prostate 68: 442–452, 2008. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57914/1/20717_ftp.pd

Ambulatory Surgery Centers and Their Intended Effects on Outpatient Surgery

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113726/1/hesr12278.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/113726/2/hesr12278-sup-0001-AppendixSA1.pd

Genetic polymorphisms in CYP17 , CYP3A4 , CYP19A1 , SRD5A2 , IGF-1 , and IGFBP-3 and prostate cancer risk in African-American men: The Flint Men's Health Study

BACKGROUND Association studies have examined the significance of several candidate genes based on biological pathways relevant to prostate carcinogenesis, including both the androgen and insulin-like growth factor pathways. Clinical and epidemiologic evidence suggest that androgens, specifically testosterone and dihydrotestosterone (DHT) are important not only in normal prostate growth but in the pathogenesis of prostate cancer. Similarly, the insulin-like growth factor-1 (IGF-1) signaling pathway regulates both cellular proliferation and apoptosis. Therefore, genes involved in the biosynthesis, activation, metabolism and degradation of androgens and the stimulation of mitogenic and antiapoptotic activities of prostate epithelial cells represent important candidates for affecting the development and progression of prostate cancer. METHODS Using resources from the Flint Men's Health Study, a population-based case control study of African-American men aged 40–79, we evaluated the associations between selected single-nucleotide polymorphisms (SNPs) in the CYP17 , CYP3A4 , CYP19A1 , SDR5A2 , IGF1 , and IGFBP3 genes and prostate cancer diagnosis in 473 men (131 prostate cancer cases and 342 disease-free controls). RESULTS We found a significant association between prostate cancer and selected CYP17 SNP genotypes, with the heterozygous genotype conferring decreased risk. Suggestive evidence for association between IGF1 SNPs and prostate cancer were also found. No significant associations were observed between SNPs in the other genes and prostate cancer. CONCLUSIONS These findings suggest that variation in or around CYP17 and/or IGF1 may be associated with prostate cancer development in the African-American population. Additional studies are needed to determine whether these polymorphisms are indeed associated with prostate cancer risk in African Americans. Prostate 68: 296–305, 2008. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57913/1/20696_ftp.pd

Measuring health-related quality of life outcomes in bladder cancer patients using the Bladder Cancer Index (BCI)

BACKGROUND. Health-related quality of life (HRQOL) has not been adequately measured in bladder cancer. A recently developed reliable and disease-specific quality of life instrument (Bladder Cancer Index, BCI) was used to measure urinary, sexual, and bowel function and bother domains in patients with bladder cancer managed with several different interventions, including cystectomy and endoscopic-based procedures. METHODS. Patients with bladder cancer were identified from a prospective bladder cancer outcomes database and contacted as part of an Institutional Review Board-approved study to assess treatment impact on HRQOL. HRQOL was measured using the BCI across stratified treatment groups. Bivariate and multivariable analyses adjusted for age, gender, income, education, relationship status, and follow-up time were performed to compare urinary, bowel, and sexual domains between treatment groups. RESULTS. In all, 315 bladder cancer patients treated at the University of Michigan completed the BCI in 2004. Significant differences were seen in mean BCI function and bother scores between cystectomy and native bladder treatment groups. In addition, urinary function scores were significantly lower among cystectomy patients treated with continent neobladder compared with those treated with ileal conduit (all pairwise P < .05). CONCLUSIONS. The BCI is responsive to functional and bother differences in patients with bladder cancer treated with different surgical approaches. Significant differences between therapy groups in each of the urinary, bowel, and sexual domains exist. Among patients treated with orthotopic continent urinary diversion, functional impairments related to urinary incontinence and lack of urinary control account for the low observed urinary function scores. Cancer 2007. © 2007 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55989/1/22556_ftp.pd

Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862)

BACKGROUND: This phase 2 trial was designed to evaluate the efficacy of vorinostat in chemotherapy-pretreated patients with metastatic castration-resistant prostate cancer. METHODS: Patients with disease progression on 1 prior chemotherapy, a prostate-specific antigen (PSA) ≥5 ng/mL, and adequate organ function were treated with 400 mg vorinostat orally daily. The primary endpoint was the 6-month progression rate. Secondary endpoints included safety, rate of PSA decline, objective response, overall survival, and effects of vorinostat on serum interleukin-6 (IL-6) levels. RESULTS: Twenty-seven eligible patients were accrued. The median number of cycles delivered was 2 (range, 1-7). All patients were taken off therapy before 6 months. The best objective response in the eligible patient was stable disease in 2 (7%) patients. No PSA decline of ≥50% was observed. There was 1 grade 4 adverse event (AE), and 44% of patients experienced grade 3 adverse events. The most common adverse events were fatigue (81%), nausea (74%), anorexia (59%), vomiting (33%), diarrhea (33%), and weight loss (26%). Median time to progression and overall survival were 2.8 and 11.7 months, respectively. Median IL-6 levels (pg/mL) were higher in patients removed from the protocol for toxicity compared with progression at all time points, including baseline (5.2 vs 2.1, P = .02), Day 15 Cycle 1 (9.5 vs 2.2, P = .01), Day 1 Cycle 2 (9.8 vs 2.2, P = .01), and end of study (11.0 vs 2.9, P = .09). CONCLUSIONS: Vorinostat at this dose was associated with significant toxicities limiting efficacy assessment in this patient population. The significant association between IL-6 levels and removal from the study for toxicities warrants further investigation. Cancer 2009. © 2009 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64445/1/24597_ftp.pd

Delays in diagnosis and bladder cancer mortality

BACKGROUND: Mortality from invasive bladder cancer is common, even with high-quality care. Thus, the best opportunities to improve outcomes may precede the diagnosis. Although screening currently is not recommended, better medical care of patients who are at risk (ie, those with hematuria) has the potential to improve outcomes. METHODS: The authors used the Surveillance, Epidemiology, and End Results-Medicare linked database for the years 1992 through 2002 to identify 29,740 patients who had hematuria in the year before a bladder cancer diagnosis and grouped them according to the interval between their first claim for hematuria and their bladder cancer diagnosis. Cox proportional hazards models were fitted to assess relations between these intervals and bladder cancer mortality, adjusting first for patient demographics and then for disease severity. Adjusted logistic models were used to estimate the patient's probability of receiving a major intervention. RESULTS: Patients (n = 2084) who had a delay of 9 months were more likely to die from bladder cancer compared with patients who were diagnosed within 3 months (adjusted hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.20-1.50). This risk was not markedly attenuated after adjusting for disease stage and tumor grade (adjusted HR, 1.29; 95% CI, 1.14-1.45). In fact, the effect was strongest among patients who had low-grade tumors (adjusted HR, 2.11; 95% CI, 1.69-2.64) and low-stage disease (ie, a tumor [T] classification of Ta or tumor in situ; adjusted HR, 2.02; 95% CI, 1.54-2.64). CONCLUSIONS: A delay in the diagnosis of bladder cancer increased the risk of death from disease independent of tumor grade and or disease stage. Understanding the mechanisms that underlie these delays may improve outcomes among patients with bladder cancer. Cancer 2010. © 2010 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78303/1/25310_ftp.pd

Complications following surgical intervention for stress urinary incontinence: A national perspective

Aims Stress urinary incontinence (SUI) impacts many women. Treatment is primarily surgical. Post-operative morbidity considerably affects individuals and the health care system. Our objective is to describe complications following surgery for SUI and how they affect resource utilization. Methods Utilizing the Nationwide Inpatient Sample (a nationally representative dataset), 147,473 patients who underwent surgery for SUI from 1988 to 2000 were identified by ICD-9 codes. Comorbid conditions/complications were extracted using ICD-9 codes, including complication rates, length of stay (LOS), hospital charges, and discharge status. Results Overall complication rate was 13.0% (not equal to sum of complication sub-types, as each woman may have had = 1 complication), with 2.8% bleeding, 1.4% surgical injury, 4.3% urinary/renal, 4.4% infectious, 0.1% wound, 1.1% pulmonary insufficiency, 0.5% myocardial infarction, 0.2% thromboembolic. The “gold standard” surgical technique for SUI, the pubovaginal sling, had the lowest morbidity at 12.5%. Mean LOS increased with morbidity: from 2.9 to 4.1 to 6.1 days for those with 0, 1, and =2 complications respectively ( P  < 0.001). Similarly, inflation-adjusted hospital charges increased with morbidity: from $7,918 to$9,828 to $15,181 for those with 0, 1, and =2 complications respectively ( P  < 0.001). The percentage of patients requiring post-discharge subacute or home care increased with morbidity: from 4.4% to 8.4% to 14.3% for those with 0, 1, and =2 complications ( P  < 0.001). Conclusions A substantial percentage of women experience complications following surgery for SUI. Post-operative morbidity leads to dramatically increased resource utilization. Prospective studies are needed to identify pre-operative risk factors and intraoperative process measures to optimize the quality of care. Neurourol. Urodynam. © 2005 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34912/1/20186_ftp.pd