Genitourinary fungal infections: a therapeutic conundrum.

Fungi cause 8% of nosocomial infections. This is caused, in part, by the increasing pool of immunocompromised patients. Elderly, transplant and HIV patients, as well as premature infants, have become prime candidates for invasive fungal infections. The widespread use of broad spectrum antibiotics plays a role. Utilisation of appropriate antifungal treatment modalities requires an understanding of the pathogenesis of infection. This is a challenging problem as fungi can cause different clinical manifestations that depend on the type of fungal species and patient response to the infection. Although Candida spp. are the most frequent pathogen, other species such as Aspergillus and Cryptococcus have become major pathogens. Environmental fungi which include Blastomyces, Coccidioides and Histoplasma have become more aggressive in the vulnerable patient. The genitourinary system can be a source or target of disseminated fungal infection. Diagnosis depends on clinical awareness, utilisation of appropriate diagnostic modalities, imaging modalities and a thorough clinical assessment. The treatment of primary (Blastomyces, Coccidioides, Histoplasma) infection generally requires amphotericin B (AmpB). The opportunistic infections (Aspergillus, Cryptococcus and Candida) may respond to the triazoles although AmpB remains the 'gold standard'. Infections caused by Candida spp. represents the greatest challenge to the clinician. The presence of Candida spp. in the urine may indicate colonisation or infection. Untreated, Candida can remain as a 'saprophyte' or develop ascending infection, sepsis or death. The prophylactic use of fluconazole may in itself result in resistant infection, hence the 'conundrum'.

Aging effects on contractility of longitudinal and circular detrusor and trigone of rat bladder.

PURPOSE: Aging is associated with bladder dysfunction, including difficult voiding and urinary leakage. Voiding involves reduction in the bladder lumen in all dimensions brought about by contraction of the meshwork of longitudinal, circular and oblique layers of detrusor smooth muscles. Most in vitro physiological studies of the effects of aging on bladder function used the longitudinal detrusor. To understand the region specific effects of aging on bladder function the contractile responses of longitudinal and circular detrusor, and trigone segments of the bladder from young and old rats were monitored. MATERIALS AND METHODS: These studies were performed using male Fisher 344 rats 6 months (young) and 27 months (old) old obtained through the National Institute on Aging. Each rat was anesthetized and the bladder was isolated. From each bladder a strip of longitudinal detrusor, circular detrusor and trigone was isolated and mounted in an in vitro multi-muscle chamber containing normal physiological solution at 37C. Isometric contractions of the 3 bladder strips were monitored after electrical field stimulation, 120 mM. potassium and 1 to 1,000 microM. bethanechol using a digital oscilloscope. RESULTS: In longitudinal detrusor from old rats there was no significant difference in the contractions evoked by electrical stimulation or high potassium but there was a significant reduction in contractions evoked by bethanechol compared with the responses of longitudinal detrusor from young rats. In circular detrusor from old rats there was a significant increase in contractions evoked by electrical stimulation and a slight increase in contractions produced by high potassium but no significant change in contractions evoked by bethanechol compared with the responses of circular detrusor from young rats. In trigone from old rats there was a significant decrease in contractions evoked by electrical stimulation, high potassium and bethanechol compared with young trigone. CONCLUSIONS: The reduction in contractions evoked by bethanechol suggests an age related reduction in muscarinic receptors in the longitudinal detrusor of aged rats. An increase in contractions evoked by electrical stimulation without a change in contractions evoked by bethanechol suggests a decrease in compliance caused by an increase in collagen in the circular detrusor of aged rats. A general decline in all contractile responses, including those evoked by high potassium, suggests reduced membrane depolarization in the trigone of aged rats. The effect of aging is specific to different regions and functional components of the bladder, probably due to changes in muscarinic receptors, collagen and depolarization.

Hormonal treatment of patients with benign prostatic hyperplasia: pros and cons.

The recognition that dihydrotestosterone is a "major player" in the development of benign prostatic hyperplasia (BPH) provided an impetus for the development of a 5a-reductase inhibitor, finasteride. During the past 5 years, a number of publications have noted that alpha blockers appear more efficacious than finasteride. This article reviews the role of hormones (particularly finasteride) in the treatment of lower urinary tract symptoms caused by BPH. These observations indicate that finasteride has a role in the management of larger prostates. Long-term use reduces the development of urinary retention and need for invasive procedures such as transurethral prostatectomy. The major adverse impact of finasteride is its effect on the patient's libido and sexual function. This is a less morbid problem for the elderly than the potential syncope associated with the use of alpha blockers. A greater understanding of the interaction of hormones on prostate receptors will provide newer tools for the treatment of BPH.

Cytokine variations in patients with hormone treated prostate cancer.

PURPOSE: We evaluated the immunological response in patients with hormone sensitive and refractory prostate cancer, and untreated benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Serum levels of pro-inflammatory and anti-inflammatory cytokines were measured by enzyme-linked immunosorbent assay in 3 groups of patients. The groups included 18 men with a mean age of 79 years who had hormone sensitive prostate cancer, mean prostate specific antigen (PSA) plus or minus standard deviation 1.03 +/- 2.65 ng./ml. and a mean of 35 months of treatment, 10 with a mean age of 86 years who had hormone refractory prostate cancer, mean PSA 27.52 +/- 42.23 ng./ml. and a mean of 42 months of treatment, and 19 with a mean age of 73 years who had BPH and mean PSA 3.37 +/- 2.47 ng./ml. Results were compared with those in 10 age matched, disease-free controls. In the hormone sensitive group PSA regressed to normal and there was clinical evidence of a response to hormone ablation therapy, including orchiectomy, luteinizing hormone releasing hormone analogue and androgen blockade. Hormone refractory cases had elevated PSA and/or clinical evidence of disease progression. RESULTS: Levels of the anti-inflammatory cytokines interleukin (IL)-4, IL-6 and IL-10 were significantly elevated in the hormone refractory group compared with values in the hormone sensitive group (p = 0.02, 0.01 and 0.0001, respectively). Abnormal anti-inflammatory cytokines in hormone resistant cases correlated with elevated PSA, while in the BPH group there was no significant difference from controls. Pro-inflammatory cytokines in the hormone sensitive and resistant groups were not significantly different from those in controls. CONCLUSIONS: Our study indicates that in hormone refractory prostate cancer a high level of the anti-inflammatory cytokines IL-4, IL-6 and IL-10 develops that is directly associated with elevated PSA. Changes in the level of anti-inflammatory cytokines when androgen independent cells exist may have an important role in the selection of a subset of hormone insensitive cells. These criteria may be used as a prognostic marker for the response to hormone ablation therapy in men with prostate cancer.

Prospective multicenter surveillance study of funguria in hospitalized patients. The National Institute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group.

Although fungal urinary tract infections are an increasing nosocomial problem, the significance of funguria is still not clear. This multicenter prospective surveillance study of 861 patients was undertaken to define the epidemiology, management, and outcomes of funguria. Diabetes mellitus was present in 39% of patients, urinary tract abnormalities in 37.7%, and malignancy in 22.2%; only 10.9% had no underlying illnesses. Concomitant nonfungal infections were present in 85%, 90% had received antimicrobial agents, and 83.2% had urinary tract drainage devices. Candida albicans was found in 51.8% of patients and Candida glabrata in 15.6%. Microbiological and clinical outcomes were documented for 530 (61.6%) of the 861 patients. No specific therapy for funguria was given to 155 patients, and the yeast cleared from the urine of 117 (75.5%) of them. Of the 116 patients who had a catheter removed as the only treatment, the funguria cleared in 41 (35.3%). Antifungal therapy was given to 259 patients, eradicating funguria in 130 (50.2%). The rate of eradication with fluconazole was 45.5%, and with amphotericin B bladder irrigation it was 54.4%. Only 7 patients (1.3%) had documented candidemia. The mortality rate was 19.8%, reflecting the multiple serious underlying illnesses found in these patients with funguria.

Fungal infections of the genitourinary system: manifestations, diagnosis, and treatment.

There is an increasing pool of immunocompromised patients who are at an increased risk to fungi infections, which now cause 8% of nosocomial infections. Premature infants and elderly, transplant, and HIV patients are prime candidates for invasive fungal infections. The genitourinary system can be a source or target of disseminated fungal infection. Although candidal species are the most frequent pathogen, other species such as aspergila, cryptoccoccus have become major pathogens. "Environmental fungi," which include blastomyces, coccidioides and histoplasma, have become more aggressive in the vulnerable patient.

Immune response in patients with persistent candiduria and occult candidemia.

PURPOSE: We evaluated the immunological response in patients with persistent candiduria with or without occult candidemia. MATERIALS AND METHODS: Levels of Thl (pro-inflammatory interleukin [IL]-1, IL-2 and tumor necrosis factor-alpha) and Th2 (anti-inflammatory IL-4 and IL-10) cytokines were measured in the sera of patients with persistent candiduria. Polymerase chain reaction assessment of the 158 base pair candidal actin gene was used to detect Candida albicans in blood to identify occult candidemia. RESULTS: During a 14-month period 66 hospitalized patients with a mean age of 63 years (range 44 to 80) with persistent candiduria were evaluated. Occult candidemia developed in 27 patients (41%) as evidenced by detection of candidal actin gene in the sera by polymerase chain reaction. Risk factors included antibiotics in 27 patients (100%), central venous catheter in 22 (81%), urinary catheter in 21 (78%), total parenteral nutrition in 18 (66%), diabetes mellitus in 16 (59%) and abdominal surgery in 14 (52%). A total of 17 age matched patients with a mean age of 59 years hospitalized for elective general or vascular surgical procedures with no clinical or laboratory evidence of urinary or hematogenous fungal or bacterial infection served as controls. Serum levels of Th2 cytokines were elevated in 18 of 39 patients with persistent candiduria alone, and in 22 of 27 patients with candiduria and occult candidemia compared to controls (p<0.002). Th1 cytokines were within normal limits or slightly decreased in all patients with persistent candiduria with or without candidemia. CONCLUSIONS: These observations indicate that an abnormal immune response develops in patients with persistent candiduria with or without candidemia.

Function of M3 muscarinic receptors in the rat urinary bladder following partial outlet obstruction.

PURPOSE: Partial outlet obstruction of the rat urinary bladder leads to hypertrophy and alteration in contractility of the detrusor muscle involving changes in muscarinic receptors. m3 muscarinic receptor subtype has been known to play a predominant role in contractility of normal urinary bladder. The purpose of the present study was to assess the role of m3 receptors in contractility of the obstructed bladder. MATERIALS AND METHODS: In male rats, partial outlet obstruction of the urinary bladder was performed by surgically tying a 6-0 suture around the bladder neck, reducing the diameter of it by 2/3 of the original size. Four weeks after the surgery, the bladders were removed and thin strips were microdissected. Similarly, bladder strips from age matched unoperated normal rats were obtained. Sets of four strips from four normal or four obstructed rats were mounted in an in vitro multi-muscle chamber containing normal physiological solution at 37C. The tension responses evoked by optimal electrical field stimulation at 1, 10, 30, 50, and 100 Hz, and the contracture responses evoked by 120 mM potassium and 0.01 to 300.0 microM carbachol were recorded using a Nicolet digital oscilloscope. Similar responses were recorded in different sets of four strips following exposure to 10 and 100 nM 4-DAMP, which is a muscarinic antagonist with a high affinity for m3 and m1 receptor subtypes. RESULTS: The obstructed bladders showed 119% increase in weight. In control physiological solution, the obstructed bladder strips did not show significant difference in electrically-evoked tension or carbachol contractures, but showed significantly lower potassium contractures compared with normal bladder strips. 4-DAMP at 10 to 100 nM significantly reduced the electrically evoked tension responses by about the same degree in normal and obstructed bladders, without affecting the potassium contractures. It significantly increased the EC50 values for carbachol contractures in normal bladder, and to a significantly lesser extent in obstructed bladder. Schild plots using the Hill transformed EC50 values showed that the pA2 value for 4-DAMP was not significantly different in normal and obstructed bladders. CONCLUSIONS: Significantly smaller potassium contracture in the obstructed bladder indicates that depolarizability of the detrusor muscle membrane, and consequently the activity of voltage-gated Ca2+ channels may be reduced in the detrusor after partial outlet obstruction. Lack of a significant difference in the effect of 4-DAMP on the electrically evoked tension responses and in the pA2 values for 4-DAMP assessed by carbachol contractures, in normal and obstructed bladder strips, indicates that m3 muscarinic receptors still play a predominant role in causing detrusor contractility in the obstructed bladder, as in the normal bladder.

Polymerase chain reaction used to detect candidemia in patients with candiduria.

OBJECTIVES: Candiduria has been shown to be an early marker of disseminated fungal infection in critically ill patients who have undergone surgery. The management of candidemia and disseminated candidiasis depends on rapid and definitive identification of Candida. Routine or fungus-specific blood cultures are unreliable and require a large quantity of blood for incubation. We describe the importance of the polymerase chain reaction (PCR) procedure in the early detection of candidemia in critically ill patients who develop candiduria and the favorable outcome in treating these patients with systemic antifungal therapy. METHODS: We compared the results of cultures and PCR to detect the presence of C. albicans in the blood of two critically ill patients with clinical candidiasis and candiduria. RESULTS: PCR detected the presence of C. albicans deoxyribonucleic acid (DNA) in urine and blood specimens of both patients in spite of negative blood cultures and did not detect fungal DNA after systemic antifungal therapy. CONCLUSIONS: Candiduria manifests as an early sign of candidemia, and systemic antifungal therapy timed appropriately based on the clinical condition and onset of candiduria will improve outcome. Detection of fungal DNA in blood by PCR is of value in establishing the diagnosis. Additional studies with a larger sample size are required to evaluate the specificity and sensitivity of PCR as a routine diagnostic test for candidemia.

Molecular staging of prostate cancer. III. Effects of cystoscopy and needle biopsy on the enhanced reverse transcriptase polymerase chain reaction assay.

PURPOSE: We examined the effects of prostatic manipulations, including flexible cystoscopy and transrectal needle biopsy, on the enhanced reverse transcriptase polymerase chain reaction assay in 57 men. MATERIALS AND METHODS: The reverse transcriptase polymerase chain reaction assay was performed on 25 patients with clinically localized stages T1 to T2cN0M0 prostate cancer before and 30 minutes after cystoscopy. In addition, blood specimens from 32 patients with elevated serum prostate specific antigen and/or abnormal digital rectal examinations were tested immediately before and at 30 minutes after transrectal ultrasound guided prostate needle biopsy. RESULTS: We detected no difference between polymerase chain reaction results obtained immediately before and 30 minutes after cystoscopy in 25 men. Transrectal needle biopsy had no effect on the polymerase chain reaction results in 30 of 32 men. However, 2 men had positive reactions on post-biopsy specimens only. Pathological results of the biopsy revealed benign prostatic hyperplasia and prostatic intraepithelial neoplasia, respectively, in these 2 men. CONCLUSIONS: We conclude that cystoscopy has no clinically significant effect on the reverse transcriptase polymerase chain reaction assay. However, prostatic needle biopsy may cause a positive polymerase chain reaction for PSA in the immediate post-biopsy period.

Early identification of candiduria by polymerase chain reaction in high risk patients.

PURPOSE: Polymerase chain reaction amplification of Candida albicans deoxyribonucleic acid was evaluated as a diagnostic tool for candiduria. MATERIALS AND METHODS: Urine from 120 patients was tested for C. albicans 158 base pair deoxyribonucleic acid by polymerase chain reaction. The study groups included 30 patients with positive urine cultures, 60 critically ill patients and 30 healthy volunteers. RESULTS: All patients with proved candiduria had a positive polymerase chain reaction. Of the 60 critically ill patients 5 (8.3%) had a positive polymerase chain reaction for C. albicans 24 to 48 hours before identification with routine fungal culture. No healthy volunteer had a positive polymerase chain reaction. CONCLUSIONS: Polymerase chain reaction amplification is an effective laboratory tool for the early diagnosis of candiduria.

Bilateral renal oncocytomatosis in a patient with renal failure.

Bilateral multifocal renal oncocytomas are very rare disorders with only 6 previously reported cases in the world literature, of which only 3 have had pathologic confirmation. We present the first reported case of diffuse, bilateral, multifocal renal oncocytomatosis in a patient with end-stage renal disease requiring hemodialysis. Our patient was found to have hundreds of nodular tumors in both kidneys on exploration, representing the second such reported finding.

Staphylococcus periprostatic abscess: an unusual cause of acute urinary retention.

Prostatic abscess has occasionally been known to present with urinary retention. We report an unusual case of a Staphylococcus aureus periprostatic abscess causing acute urinary retention. Diagnosis was made by transrectal sonogram and computed tomography scan, and the patient was treated successfully with intravenous antibiotics, perineal exploration, and drainage.

Fungal infections of the perivesical space.

We describe 3 patients with fungal infection in the perivesical space who manifested lower abdominal pain and urinary tract symptomatology. Imaging studies demonstrated perivesical abnormalities. Urine culture was positive for fungus in only 1 patients. Management required surgical exploration, drainage, débridement of necrotic tissue and in 1 patient partial bladder resection. Systemic antifungal therapy was administered postoperatively. All patients had a successful outcome.

Sensitive detection of prostatic hematogenous tumor cell dissemination using prostate specific antigen and prostate specific membrane-derived primers in the polymerase chain reaction.

We developed a polymerase chain reaction based assay enabling sensitive detection of hematogenous tumor cell dissemination in patients with prostate cancer. We performed "nested polymerase chain reaction," amplifying messenger ribonucleic acid sequences unique to prostate specific antigen (PSA) and to the prostate specific membrane antigen, and compared the respective results. Prostatic tumor cells were detected in 2 of 30 patients (6.7%) by polymerase chain reaction with PSA derived primers, while prostate specific membrane primers detected tumor cells in 19 (63.3%). All 16 negative controls had negative PSA and prostate specific membrane polymerase chain reaction. Assays were repeated to confirm results, and polymerase chain reaction products were verified by deoxyribonucleic acid sequencing and Southern analysis. Patients harboring circulating prostatic tumor cells as detected by prostate specific membrane and not by PSA polymerase chain reaction included 7 of 13 previously treated by radical prostatectomy who had nonmeasurable serum PSA levels at the time of this assay. The significance of these findings with respect to future disease recurrence and progression will be investigated.

Sensitive nested reverse transcription polymerase chain reaction detection of circulating prostatic tumor cells: comparison of prostate-specific membrane antigen and prostate-specific antigen-based assays.

A highly sensitive nested reverse transcriptase-PCR assay, with primers derived from the prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) cDNA sequences, has been used to detect occult hematogenous micrometastatic prostate cells. In 77 patients with prostate cancer, PSM and PSA primers detected circulating prostate cells in 48 (62.3%) and 7 (9.1%) patients, respectively. In treated stage D disease patients, PSM primers detected cells in 16 of 24 patients (66.7%), while PSA primers detected cells in 6 of 24 (25%). In post-radical prostectomy patients with negative serum PSA values, PSM primers detected metastases in 21 of 31 patients (67.7%), whereas PSA primers detected cells in only 1 of 33 (3.0%), indicating that micrometastatic spread may be a relatively early event in prostate cancer. The analysis of 40 individuals without known prostate cancer provides evidence that this assay is highly specific and suggests that PSM expression may predict the development of cancer in patients without clinically apparent prostate cancer. Using PSM primers, we detected micrometastases in 4 of 40 controls, 2 of whom had known benign prostatic hyperplasia and were later found to have previously undetected prostate cancer. The clinical significance of detection of hematogenous micrometastic prostate cells using PSM primers and potential applications of this molecular assay, as well as the assay for PSA, merit further study.