Susan Keay

A Controlled Trial of Ganciclovir to Prevent Cytomegalovirus Disease after Heart Transplantation

BACKGROUND Because of the immunosuppression required, heart-transplant recipients frequently have complications caused by cytomegalovirus (CMV), including pneumonia, esophagitis, gastritis, and a syndrome of fever, hepatitis, and leukopenia. We undertook a controlled trial to evaluate the prophylactic administration of ganciclovir to prevent CMV-induced disease after heart transplantation. METHODS This randomized, double-blind, placebo-controlled trial was conducted at four centers. Before randomization, the patients were stratified into two groups: those who were seropositive for CMV before transplantation and those who were seronegative but who received hearts from seropositive donors. Ganciclovir was given intravenously at a dose of 5 mg per kilogram of body weight every 12 hours from postoperative day 1 through day 14, then at a dose of 6 mg per kilogram each day for 5 days per week until day 28. RESULTS Among the seropositive patients, CMV illness occurred during the first 120 days after heart transplantation in 26 of 56 patients given placebo (46 percent), as compared with 5 of 56 patients treated with ganciclovir (9 percent) (P less than 0.001). Among 37 seronegative patients, CMV illness was frequent in both groups (placebo, 29 percent; ganciclovir, 35 percent; P not significant). From day 15 through day 60, the patients who took ganciclovir had significantly fewer urine cultures positive for CMV, but by day 90 there was no difference. More of the ganciclovir-treated patients had serum creatinine concentrations greater than or equal to 221 mumol per liter (2.5 mg per deciliter) (18 percent vs. 4 percent in the placebo group), but those elevations were transient. CONCLUSIONS The prophylactic administration of ganciclovir after heart transplantation is safe, and in CMV-seropositive patients it reduces the incidence of CMV-induced illness.

AUGMENTED STRETCH ACTIVATED ADENOSINE TRIPHOSPHATE RELEASE FROM BLADDER UROEPITHELIAL CELLS IN PATIENTS WITH INTERSTITIAL CYSTITIS

PURPOSE Extracellular adenosine triphosphate (ATP) has been shown to mediate inflammation and nociception and, therefore, it may have a role in symptoms associated with interstitial cystitis. We theorized that the bladder uroepithelium releases ATP in response to stretch and, furthermore, this process is augmented in interstitial cystitis. MATERIALS AND METHODS We quantitated ATP using the luciferin-luciferase assay. Urinary ATP levels were compared in 35 patients with interstitial cystitis and in 33 normal controls after pH correction. Cultured interstitial cystitis and normal urothelial cells from the bladder biopsies of 5 patients each were stretched with the Flexcell 2000 machine (Flexcell International Corp., McKeesport, Pennsylvania) and supernatant ATP concentrations were measured. RESULTS Mean urinary ATP plus or minus standard error of mean was significantly higher in patients with interstitial cystitis than in controls (L value 985 +/- 161 versus 377 +/- 27, p = 0.0007). Supernatant ATP released by stretched interstitial cystitis cells was stretch intensity dependent when comparing 0%, 10% and 20% elongation, and was also significantly higher in stretched interstitial cystitis than in stretched normal cells. CONCLUSIONS Adenosine triphosphate was significantly elevated in the urine of individuals with interstitial cystitis and the stretch activated release of ATP was augmented in interstitial cystitis urothelium. Increased extracellular ATP may have a role in mechanosensory transduction and to our knowledge it represents a novel hypothesis.

Efficacy, Safety, and Tolerability of Herpes Zoster Vaccine in Persons Aged 50–59 Years

BACKGROUND Herpes zoster (HZ) adversely affects individuals aged 50-59, but vaccine efficacy has not been assessed in this population. This study was designed to determine the efficacy, safety, and tolerability of zoster vaccine for preventing HZ in persons aged 50-59 years. METHODS This was a randomized, double-blind, placebo-controlled study of 22 439 subjects aged 50-59 years conducted in North America and Europe. Subjects were given 1 dose of licensed zoster vaccine (ZV) (Zostavax; Merck) and followed for occurrence of HZ for ≥1 year (mean, 1.3 years) postvaccination until accrual of ≥96 confirmed HZ cases (as determined by testing lesions swabs for varicella zoster virus DNA by polymerase chain reaction). Subjects were followed for all adverse events (AEs) from day 1 to day 42 postvaccination and for serious AEs (SAEs) through day 182 postvaccination. RESULTS The ZV reduced the incidence of HZ (30 cases in vaccine group, 1.99/1000 person-years vs 99 cases in placebo group, 6.57/1000 person-years). Vaccine efficacy for preventing HZ was 69.8% (95% confidence interval, 54.1-80.6). AEs were reported by 72.8% of subjects in the ZV group and 41.5% in the placebo group, with the difference primarily due to higher rates of injection-site AEs and headache. The proportion of subjects reporting SAEs occurring within 42 days postvaccination (ZV, 0.6%; placebo, 0.5%) and 182 days postvaccination (ZV, 2.1%; placebo, 1.9%) was similar between groups. CONCLUSIONS In subjects aged 50-59 years, the ZV significantly reduced the incidence of HZ and was well tolerated. CLINICAL TRIALS REGISTRATION NCT00534248.

Diagnosis of interstitial cystitis

We reviewed clinical and histological findings in 55 patients with interstitial cystitis and 21 with voiding dysfunction secondary to other pathological conditions. Of our interstitial cystitis patients 36% would fail to meet the research definition proposed at a recent National Institutes of Health workshop. Detrusor mastocytosis was present in 64% of our interstitial cystitis patients compared to 80% of the noninterstitial cystitis group. There was no statistically significant difference in mean detrusor mast cell counts between interstitial cystitis and noninterstitial cystitis patients. Biopsies of 12 patients who did meet the proposed National Institutes of Health research definition were evaluated by immunohistochemical techniques. Early results are inconclusive. These studies indicate that interstitial cystitis is a complex disease whose diagnosis presently still must be made from a symptom complex rather than from objective histological criteria, including mastocytosis or the presence of any specific immunoreactive cell.

A comparison of multiple urine markers for interstitial cystitis.

PURPOSE We measured several urine markers in 24-hour specimens from patients with interstitial cystitis and healthy controls. For each marker we determined whether the urine level was significantly different in interstitial cystitis and control cases, and whether the marker level correlated with the symptom score. MATERIALS AND METHODS Study participants included 36 female patients with interstitial cystitis and 36 age matched female volunteers. Multiple urine aliquots were obtained to measure the various markers. RESULTS Certain markers were significantly increased in interstitial cystitis, including anti-proliferative factor, epidermal growth factor, insulin-like growth factor (IGF) binding protein-3 and interleukin (IL)-6. Markers significantly decreased in interstitial cystitis were heparin-binding epidermal growth factor-like growth factor, cyclic guanosine monophosphate and methylhistamine. Other markers were not significantly different in the interstitial cystitis and control groups, including total glycosaminoglycans, epitectin, hyaluronic acid, IL-8, IL-1 and nitrates plus nitrites. IGF-1 was undetectable in 24-hour urine samples but spot voided samples from the same interstitial cystitis population had IGF-1 levels similar to previously reported levels. The only significant association of marker with symptom score was a positive correlation of IL-6 with nocturia. For all markers the conclusions were the same whether the marker was normalized to creatinine or to 24 hours. CONCLUSIONS This study confirmed several previously reported urine alterations in interstitial cystitis, including increased anti-proliferative factor, epidermal growth factor, IGF binding protein-3 and IL-6, and decreased heparin-binding epidermal growth factor-like growth factor and cyclic guanosine monophosphate. Of all markers studied anti-proliferative factor had the least overlap in the interstitial cystitis and control groups, and so it is the most likely candidate to become a diagnostic test.

Persistence of the Efficacy of Zoster Vaccine in the Shingles Prevention Study and the Short-Term Persistence Substudy

BACKGROUND The Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Study 403) demonstrated that zoster vaccine was efficacious through 4 years after vaccination. The Short-Term Persistence Substudy (STPS) was initiated after the SPS to further assess the persistence of vaccine efficacy. METHODS The STPS re-enrolled 7320 vaccine and 6950 placebo recipients from the 38 546-subject SPS population. Methods of surveillance, case determination, and follow-up were analogous to those in the SPS. Vaccine efficacy for herpes zoster (HZ) burden of illness, incidence of postherpetic neuralgia (PHN), and incidence of HZ were assessed for the STPS population, for the combined SPS and STPS populations, and for each year through year 7 after vaccination. RESULTS In the STPS as compared to the SPS, vaccine efficacy for HZ burden of illness decreased from 61.1% to 50.1%, vaccine efficacy for the incidence of PHN decreased from 66.5% to 60.1%, and vaccine efficacy for the incidence of HZ decreased from 51.3% to 39.6%, although the differences were not statistically significant. Analysis of vaccine efficacy in each year after vaccination for all 3 outcomes showed a decrease in vaccine efficacy after year 1, with a further decline thereafter. Vaccine efficacy was statistically significant for the incidence of HZ and the HZ burden of illness through year 5. CONCLUSIONS Vaccine efficacy for each study outcome was lower in the STPS than in the SPS. There is evidence of the persistence of vaccine efficacy through year 5 after vaccination but, vaccine efficacy is uncertain beyond that point.

Long-Term Persistence of Zoster Vaccine Efficacy

BACKGROUND The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination. METHODS Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups. RESULTS The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8. CONCLUSIONS Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8.

Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor–like growth factor, and epidermal growth factor as urine markers for interstitial cystitis ☆

We previously determined that the urine of interstitial cystitis (IC) patients specifically contains a factor (antiproliferative factor [APF]) that inhibits primary bladder epithelial cell proliferation, and that it has significantly decreased levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and increased levels of epidermal growth factor (EGF) compared with urine from asymptomatic controls and patients with bacterial cystitis. We sought to confirm the specificity of these findings for IC using a larger patient population, including control patients with a variety of urogenital disorders. Clean catch urine specimens were collected from 219 symptomatic IC patients, 113 asymptomatic controls without bladder disease, and 211 patients with various urogenital diseases including acute bacterial cystitis, vulvovaginitis, chronic nonbacterial prostatitis, overactive bladder, hematuria, stress incontinence, neurogenic bladder, benign prostatic hyperplasia, bladder or pelvic pain without voiding symptoms, bladder cancer, prostate cancer, or miscellaneous diagnoses including anatomic disorders. APF activity was determined by (3)H-thymidine incorporation into primary normal adult human bladder epithelial cells. HB-EGF and EGF levels were determined by enzyme-linked immunosorbent assay. APF activity was present significantly more often in IC than control urine specimens (P <0.005 for IC vs any control group; sensitivity = 94%, specificity = 95%, P <10(-82) for IC vs all controls). HB-EGF levels were also significantly lower and EGF levels significantly higher in IC urine than in specimens from controls (P <10(-84) and P <10(-36), respectively). These findings confirm the utility of APF, HB-EGF, and EGF as markers for IC. Understanding the reasons for altered levels of these markers may lead to understanding the pathogenesis of this disorder.

BLADDER EPITHELIAL CELLS FROM PATIENTS WITH INTERSTITIAL CYSTITIS PRODUCE AN INHIBITOR OF HEPARIN-BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH FACTOR PRODUCTION

PURPOSE The etiology of interstitial cystitis is unknown. We previously identified an interstitial cystitis urine factor, antiproliferative factor, that inhibits proliferation of bladder epithelial cells in vitro and complex changes in epithelial growth factor levels, including profound decreases in heparin-binding epidermal growth factor-like growth factor (HB-EGF). Bladder and renal pelvic catheterization of patients with interstitial cystitis indicated that the antiproliferative factor is made and/or activated in the distal ureter or bladder. Therefore, we determined whether bladder epithelial cells from interstitial cystitis cases produced the antiproliferative factor and whether purified antiproliferative factor could alter production of growth factors known to be abnormal in interstitial cystitis. MATERIALS AND METHODS Antiproliferative factor activity was determined by 3H-thymidine incorporation into primary bladder epithelial cells. The antiproliferative factor was purified by size fractionation followed by sequential chromatography involving ion exchange, hydrophobic interaction and high performance liquid chromatography. HB-EGF, epidermal growth factor, insulin-like growth factor and insulin-like growth factor binding protein 3 levels were determined by enzyme-linked immunosorbent assay. RESULTS Bladder epithelial cells from patients with interstitial cystitis produced a single antiproliferative factor with the same purification profile as that purified from interstitial cystitis urine. Purified antiproliferative factor specifically inhibited HB-EGF production by bladder epithelial cells in vitro, and the effect of interstitial cystitis urine or purified antiproliferative factor on bladder cell proliferation was inhibited by recombinant human HB-EGF in a dose dependent manner. Similar to urine HB-EGF, serum HB-EGF was also significantly lower in interstitial cystitis cases than in controls. CONCLUSIONS Bladder epithelial abnormalities in interstitial cystitis may be caused by a negative autocrine growth factor that inhibits cell proliferation by down-regulating HB-EGF production. Furthermore, decreased levels of urine and serum HB-EGF indicate that interstitial cystitis may be a urinary tract manifestation of a systemic disorder.

Percutaneous sacral third nerve root neurostimulation improves symptoms and normalizes urinary HB-EGF levels and antiproliferative activity in patients with interstitial cystitis

OBJECTIVES A highly effective treatment for interstitial cystitis (IC) remains elusive. We determined whether sacral third nerve root (S3) percutaneous neurostimulation (PNS) might be effective in relieving symptoms of IC, as well as in normalizing urinary factors that are specifically altered in IC. METHODS Six consecutive patients with symptoms and cystoscopic findings compatible with IC underwent 5 days of continuous S3 neurostimulation by way of leads placed percutaneously into the S3 foramen. Patients filled out voiding frequency diaries and pain and urgency questionnaires before PNS and at the end of PNS when the leads were removed. Urine specimens were collected at these two time points and measured for heparin-binding epidermal growth factor-like growth factor (HB-EGF) by enzyme-linked immunosorbent assay and for antiproliferative factor (APF) activity by (3)H-thymidine uptake by normal human bladder urothelial cells. RESULTS S3 PNS significantly improved all measured parameters toward normal values. Voiding frequency decreased twofold from 23.1 +/- 4.6 to 10.6 +/- 4.0 voids daily during PNS (P = 0.0001). Pelvic pain on a scale of 1 to 10 decreased from 7.0 +/- 1.6 to 2.3 +/- 3.2 (P = 0.05). Urinary urgency on a scale of 1 to 10 decreased from 6.0 +/- 2.2 to 1.8 +/- 1.7 (P = 0. 02). Urinary HB-EGF concentration increased sevenfold from 1.5 +/- 2. 1 to 11.0 +/- 1.7 ng/mL (P <0.0001), and urinary APF activity decreased from -76.1% +/- 31% to -4.5% +/- 8.8% (P = 0.005). CONCLUSIONS S3 PNS significantly decreased symptoms and normalized urinary HB-EGF and APF activity in patients with IC. These results suggest that permanent S3 PNS may be beneficial in treating IC.