Class of 2011 Abstract / OBJECTIVES: To evaluate the appropriateness of discharge antimicrobial medications for UTI in an adult population based on therapy prescribed. METHODS: In this retrospective chart review study the appropriateness of discharge antimicrobial therapy for patients admitted to an academic medical center during 3 weeks in 2010 was assessed based on culture results, estimated renal function, reported drug allergies, route of administration, and change in UTI from in-house to discharge prescribed therapy. RESULTS: A total of 35 patients with discharge UTI antimicrobials within the study period met inclusion criteria and were evaluated. According to available urinary culture and susceptibility data, 22 of 35 (62.8%) of received an appropriate antimicrobial therapy. Based on reported gastrointestinal function, all 35 patients could take oral medications but two patients with an appropriate oral therapy option received intravenous therapy. All patients were discharged with antimicrobials that were appropriate according to patients’ reported drug allergies and only one patient received an antimicrobial agent that was inappropriately adjusted based on the patient’s estimated renal function. UTI antimicrobial therapies were the same at 24 hours prior to discharge and as the discharge antimicrobial in 100% of patient cases evaluated CONCLUSION: The antimicrobial UTI discharge therapy was evaluated for appropriateness based on urine culture results, patients’ allergies, and patients’ estimated renal function. Overall, antimicrobial therapy was only appropriate in 22 of 35 (62.8%) of patients based on the available culture results.

Urinary tract infections are generally preceded by transfer of organisms from the distal urethra to the bladder (20, 148). However, although urinary infections are predominantly due to pure cultures of Escherichia coli, the distal urethra contains a mixed flora in which E. coli is relatively uncommon and anaerobes predominate (73, 103). This discrepancy between the bladder and distal urethral flora may be due to differential adhesion or differential growth rates. In this dissertation I have tested the hypothesis that differential growth rates of urethral organisms in urine explains the predominance of E. coli as a pathogen. These experiments showed that the balance between bacterial growth and washout may have a pivotal role in the pathogenesis of infection and perhaps therefore in treatment. A model of the human bladder used for the pathogenesis studies was then used to study the activity of mecillinam and ampicillin under conditions simulating human urinary infection. The model proved realistic especially for synergy studies where shortcomings in conventional in vitro methods are a cause for concern. The following topics were studied. 1. Urine was chosen as a test medium for definitive experiments because growth rates of organisms other than E. coli were different in broth and in urine. A method for sterilizing urine in bulk was developed which did not affect growth supporting properties. 2. E. coli was shown to grow faster and to have a shorter lag period than almost all other organisms when studied in shake culture. 3. A continuous culture model of the human urinary bladder was employed for differential growth studies of organisms in sterilized human urine. This model reproduced many of the characteristics of the human lower urinary tract and enabled study of the balance between bacterial growth and the tendency of urine to wash organisms out of the tract. 4. Mixed cultures of approximately equal numbers of E. coli and a second potential urinary' pathogen were introduced into the bladder model and quantitative cultures performed at intervals up to 24 h. In 15 experiments E. coli eventually dominated the second pathogen which was sometimes undetectable at 24 h. Similar changes in bacterial populations seen in infected patients indicate that differential growth rates may be an important determinant of the pathogenicity of E. coli. 5. The use of the bladder model was then extended to investigations of antibiotic activity under realistic conditions. The value of the model for synergy studies with ampicillin and mecillinam was assessed by parallel conventional in vitro tests and an animal infection protection test*. The bladder model gave similar results to mammalian studies and appeared to be far superior to conventional methods. This model may be valuable in the initial assessment of new urinary antibiotics. 6. A representative array of organisms for the above study was selected following a survey of resistance patterns of 2000 clinical isolates of Enterobacteriaceae. An incidental by-product of this survey was the establishment of a breakpoint for mecillinam susceptibility in the Kirby-Bauer antibiotic disk test. 7. Work on the effect of mecillinam and/or ampicillin upon bacterial viability was extended to investigations of the relative contribution of permeability barriers and 3-lactamases to antibiotic susceptibility. Unlike ampicillin, mecillinam resistance of 77 clinical isolates of bacteria appeared to be independent of intracellular 3-lactamase levels, suggesting that the barrier effect may be more pronounced in bacterial resistance to mecillinam than to ampicillin. Kinetic studies using urine as a growth medium, and in particular the use of a bladder model have provided a unifying explanation of many features of both the pathogenesis and treatment of urinary infections. * Carried out by Dr. R.C. Cleeland. / Science, Faculty of / Microbiology and Immunology, Department of / Graduate

Objective: Rare co-existance of disease or pathology Background: The lipid-rich variant is a rare and aggressive type of urothelial carcinoma (UCa), with less than 40 cases reported in the literature. This variant usually presents as an advanced-stage primary tumor. Case Report: We report the case of a 61-year-old man with previous history of T1 high-grade conventional urothelial carcinoma treated with local therapy. The patient later presented with a new 6.5-cm exophytic bladder mass. Histopathological examination revealed a T2 urothelial carcinoma of the lipid-rich variant. Retrospective review of the previous biopsies confirmed conventional high-grade urothelial car0cinoma, but scattered rare individual or small clusters of cells that resemble the lipid-rich variant urothelial carcinoma were also noted. Conclusions: The findings in this case suggest that the differential sensitivity of conventional urothelial carcinoma to local therapy may have allowed the lipid-rich variant to predominate in the recurrence. Pathologists should be aware of the lipid-rich variant of urothelial carcinoma. The prognostic significance of rare lipoblast-like cells among predominantly conventional urothelial carcinoma may requires further study.

This study was conducted to test the hypothesis that, during renal development, the Na-K-2Cl cotransporter type 2 (NKCC2) activates the tonicity-responsive enhancer binding protein (TonEBP) transcription factor by creating medullary hypertonicity. TonEBP, in turn, drives the expression of aldose reductase (AR) and urea transporter-A (UT-A). Kidneys from 13- to19-day-old fetuses (F13-F19), 1- to 21-day-old pups (P1-P21), and adult mice were examined by immunohistochemistry. NKCC2 was first detected on F14 in differentiating macula densa and thick ascending limb (TAL). TonEBP was first detected on F15 in the medullary collecting duct (MCD) and surrounding endothelial cells. AR was detected in the MCD cells of the renal medulla from F15. UT-A first appeared in the descending thin limb (DTL) on F16 and in the MCD on F18. After birth, NKCC2-positive TALs disappeared gradually from the tip of the renal papilla, becoming completely undetectable in the inner medulla on P21. TonEBP shifted from the cytoplasm to the nucleus in both vascular endothelial cells and MCD cells on P1, and its abundance increased gradually afterward. Immunoreactivity for AR and UT-A in the renal medulla increased markedly after birth. Treatment of neonatal animals with furosemide dramatically reduced expression of TonEBP, AR, and UT-A1. Furosemide also prevented the disappearance of NKCC2-expressing TALs in the papilla. The sequential expression of NKCC2, TonEBP, and its targets AR and UT-A and the reduced expression TonEBP and its targets in response to furosemide treatment support the hypothesis that local hypertonicity produced by the activity of NKCC2 activates TonEBP during development.

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The side effects of testosterone for transgender men are often overlooked and under-researched. Urinary incontinence in the form of overactive bladder disorder, stress incontinence, and mixed incontinence may arise or be exacerbated by use of testosterone. Using menopause and other similar hormonal transitions such as pregnancy as a reference, the purpose of this thesis is to fully understand the effects of testosterone replacement therapy on transgender people assigned female at birth, and to fully understand the effect of testosterone replacement therapy on the pelvic floor and why there is a potential increased incidence of urinary incontinence. Menopause and pregnancy are used as reference because these are hormonal transitions associated with a decrease in estrogen levels. The decrease in estrogen causes a looseness in the connective tissue structures, which leads to a lack of support in the pelvic floor muscles, causing a urinary incontinence. With a comparison between menopause, pregnancy, and testosterone replacement therapy established, potential solutions to stress urinary incontinence and overactive bladder disorder will be explored.

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