A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Nonbladder related symptoms in patients with interstitial cystitis.

PURPOSE: Clinical experience and epidemiological studies suggest that patients with interstitial cystitis have multiple nonbladder related symptoms. However, to our knowledge this finding has not been tested with a validated questionnaire and matched controls. With the University of Wisconsin scale, we compare the scores for patients with interstitial cystitis to those for control subjects. This validated questionnaire includes 7 bladder and 18 reference symptoms not related to the bladder. MATERIALS AND METHODS: A total of 35 female patients with interstitial cystitis and 35 age matched female controls completed the University of Wisconsin questionnaire. RESULTS: For the 7 bladder symptoms the difference between interstitial cystitis and control groups was extremely significant (p = 0.0001). Patients with interstitial cystitis had higher scores than controls for 2 reference symptoms, including other pelvic discomfort, backache, dizziness, chest pain, aches in joints, abdominal cramps, nausea, heart pounding and headache (p <0.01). However, they did not have higher scores for blind spots and/or blurred vision, numbness and/or tingling in fingers or toes, swollen ankles, feeling of suffocation, sore throat, cough, flu, nasal congestion and ringing in ears. The majority of patients with interstitial cystitis had a 0 score for all but 2 of the reference symptoms. CONCLUSIONS: Patients with interstitial cystitis had increased scores for 9 reference symptoms but did not indiscriminately report high scores for generalized complaints. This result suggests that in some cases of interstitial cystitis the pathophysiology may affect other organ systems besides the bladder. Alternatively, some of these symptoms may result from changes in sleep pattern or other factors associated with interstitial cystitis.

Concordance of interstitial cystitis in monozygotic and dizygotic twin pairs.

Our objective was to determine whether there is a greater concordance of interstitial cystitis (IC) among monozygotic than dizygotic twins. Members of the Interstitial Cystitis Association (ICA) who responded to a survey about first-degree family members with IC symptoms or confirmed IC were requested to identify themselves if they were 1 of a twin pair. Each twin respondent and co-twin were then evaluated via a questionnaire and acquisition of hydrodistention reports as to their meeting modified National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria for IC. Of the co-twins of 8 monozygotic twin respondents, 2 had probable and 3 had confirmed IC compared with none of the co-twins of the 26 dizygotic twin respondents (including 15 female co-twins). There is a greater concordance of IC among monozygotic than dizygotic twin pairs suggesting a genetic susceptibility to IC.

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.

Pilot study of sequential oral antibiotics for the treatment of interstitial cystitis.

PURPOSE: Interstitial cystitis is a chronic disease of unknown etiology characterized by bladder pain, urgency and frequency. Although a single microbe has not been implicated as a cause of interstitial cystitis, several groups noted various organisms in the urine of some women with interstitial cystitis and some patients reported that antibiotics decrease symptoms. Consequently we performed a prospective, randomized, double-blinded, placebo controlled pilot study of sequential oral antibiotics. MATERIALS AND METHODS: We randomized 50 patients with interstitial cystitis to receive 18 weeks of placebo or antibiotics, including rifampin plus a sequence of doxycycline, erythromycin, metronidazole, clindamycin, amoxicillin and ciprofloxacin for 3 weeks each. RESULTS: Intent to treat analysis demonstrated that 12 of 25 patients (48%) in the antibiotic and 6 of 25 (24%) in the placebo group reported overall improvement (p = 0.14), while 10 and 5, respectively, noticed improvement in pain and urgency (p = 0.22). In the antibiotic group 20 participants (80%) had adverse effects compared with 10 (40%) in the placebo group (p = 0.009). CONCLUSIONS: Our findings suggest that these antibiotics alone or in combination may sometimes be associated with decreased symptoms in some patients but they do not represent a major advance in therapy for interstitial cystitis.

In vivo phase variation of Escherichia coli type 1 fimbrial genes in women with urinary tract infection.

Type 1 fimbriae, expressed by most Escherichia coli strains, are thought to attach to human uroepithelium as an initial step in the pathogenesis of urinary tract infections (UTI). Numerous reports using both in vitro and murine models support this role for type 1 fimbriae in colonization. Unfortunately, only a limited number of studies have directly examined the expression of fimbriae in vivo. To determine whether type 1 fimbrial genes are transcribed during an acute UTI, we employed a modification of an established method. The orientation (ON or OFF) of the invertible promoter element, which drives transcription of type 1 fimbrial genes, was determined by PCR amplification using primers that flank the invertible element, followed by SnaBI digestion. The orientation of the type 1 fimbrial switch was determined under three experimental conditions. First, E. coli strains from different clinical sources (acute pyelonephritis patients, cystitis patients, and fecal controls) were tested under different in vitro culture conditions (agar versus broth; aerated versus static). The genes in the more-virulent strains (those causing acute pyelonephritis) demonstrated a resistance, in aerated broth, to switching from OFF to ON, while those in fecal strains readily switched from OFF to ON. Second, bladder and kidney tissue from CBA mice transurethrally inoculated with E. coli CFT073 (an established murine model of ascending UTI) was assayed. The switches directly amplified from infected bladder and kidney tissues were estimated to be 33 and 39% ON, respectively, by using a standard curve. Finally, bacteria present in urine samples collected from women with cystitis were tested for type 1 fimbria switch orientation. For all 11 cases, an average of only 4% of the switches in the bacteria in the urine were ON. In 7 of the 11 cases, we found that all of the visible type 1 fimbrial switches were in the OFF position (upper limit of detection of assay, 98% OFF). Strains recovered from these urine samples, however, were shown after culture in vitro to be capable of switching the fimbrial gene to the ON position and expressing mannose-sensitive hemagglutinin. The results from experimental infections and cases of cystitis in women suggest that type 1 fimbrial genes are transcribed both in the bladder and in the kidney. However, those bacteria found in the urine and not attached to the uroepithelium are not transcriptionally active for type 1 fimbrial genes.

Identification of GPCMV infected cells in vitro and in vivo with a monoclonal antibody.

A monoclonal antibody was made which identifies a 160-180 kDa structural protein in guinea pig cytomegalovirus (GPCMV) infected cells by Western blot using non-reducing conditions. This protein was shown to be a virion structural protein by purification of GPCMV on a density viscosity gradient and Western blot analysis. Phosphoanacetic acid (PAA) experiments suggest that the protein is a late GPCMV protein. In vitro the monoclonal antibody labels a cytoplasmic protein in infected guinea pig embryo fibroblasts by 12 h postinfection. The monoclonal antibody also identifies GPCMV infected cells in vivo in paraffin embedded formalin fixed tissue.