Vaginal mucosal immunization for recurrent urinary tract infection: phase II clinical trial

PURPOSE: Decreased local immunity to uropathogenic bacteria may be a factor predisposing women to recurrent urinary tract infections. Our phase I study demonstrated the safety of a multi-strain vaccine administered as a vaginal suppository. A phase II study was conducted to determine vaccine efficacy. MATERIALS AND METHODS: A total of 91 women susceptible to recurrent urinary tract infections was entered into the study and the courses were analyzed in a randomized, double-blind, placebo controlled trial of vaginal mucosal immunization. Subjects received 3 vaginal suppositories at weekly intervals. Depending on the treatment group each suppository contained 1 of 2 vaccine doses or suppository material only. Each patient was followed for 5 months to record infection episodes, and obtain urine, vaginal irrigates and serum to measure immunological responses. RESULTS: Immunogen treated women who were off antibiotic prophylaxis throughout the study had a significant delay in interval to reinfection during the first 8 weeks compared to women receiving placebo. Mean interval until reinfection was delayed from 8.7 weeks for placebo treated to 13 weeks for vaccine treated women. Immunological responses in serum, urine and vaginal fluid were variable. No serious adverse effects were observed. CONCLUSIONS: These data demonstrate that vaginal mucosal immunization can enhance resistance to urinary tract infections in susceptible patients.     

Prevention of reinfection by L-methionine in patients with recurrent urinary tract infection

PROBLEM: A great variety of different antimicrobial chemotherapeutics is available for the treatment of urinary tract infections. Influencing the course of chronic diseases is a problem because recurrent diseases may result in disturbances of renal and bladder functions as well as in irreversible damages of the renal parenchyma. The present investigations are expected to clarify whether an effective prevention of reinfection in patients with chronically recurrent urinary tract infection is possible by a regular administration of L-methionine (Acimethin). PATIENTS AND METHODS: 33 female patients were included in the examinations. Following acute disease, 23 females (aged: 47.4 +/- 13.3 years) were treated with 3 x 1 tablet of Acimethin (L-methionine) daily over a period of 26 months. Ten female patients (aged: 47.4 +/- 12.2 years) taking 1 tablet of Nevigramon (nalidixic acid) three times daily over 21.6 months served as a control group. Before starting treatment and in the middle of the therapy period control examinations were performed and following the last drug administration so as to assess the therapeutic result. RESULTS: No acute infection occurred during L-methionine treatment. All parameters of inflammation (leucocyte count, C-reactive protein, blood sedimentation rate, alpha 2-globulin concentration) were in the normal range; no impairment of renal function was observed. Although L-methionine, i.e. nalidixic acid, did not yield any significant changes in the range of bacteria, the adherence of uropathogenic microorganisms to the cells of the urinary tract was reduced. Before L-methionine treatment, the average load of the uroepithelial cells was 95.9 +/- 73.6 bacteria per cell. When the observation period was completed, 51.2 +/- 56.4 bacteria per cell were registered (p < 0.03). During nalidixic acid treatment, the rate of adherence was reduced from 74.0 +/- 88.4 to 34.4 +/- 37.8 bacteria per cell (p < 0.25). During L-methionine treatment, no Escherichia coli strains that are able to produce hemolysin or to form aerobactine were found. Among agents adhering to uroepithelial cells, however, an increase in their ability to produce mannose-resistant hemagglutination was conspicuous. CONCLUSION: L-methionine is suitable to prevent reinfection with chronic urinary tract infection. The therapeutic result is essentially due to its influence on bacterial cytoadherence. In contrast to the established recommendations concerning the prevention of reinfection by the use of antibiotics and sulphonamides selecting resistant strains during long-term treatment, nothing is known about the development of resistance to L-methionine.     

Urogenital atrophy and recurrent urinary tract infection in elderly patients

Postmenopausal lower urinary tract atrophy and its relations to recurrent urinary infections in elderly women are studied. Clinical aspects, functional and histological aspects and hypothetic mechanisms of atrophy are reported, epidemiologic data, mechanisms of urinary infections and of estrogen effects are reviewed and reports on the results of local or systemic use of drugs from the literature are presented. Local administration of estrogen seems to be efficient on the urinary tract. Local treatment is less dangerous and cheaper than systemic treatment. Hormonal treatment is one of the preventive measures against recurrent urinary infections in elderly women.     

Extracorporeal shock-wave lithotripsy in patients with manifestations of urinary tract infection

The urinary tract infection is very frequent, especially if calculosis of the urinary tract is present. Urinary infection is widespread, and it appears during the year. The people of all ages and both sexes are affected by urinary infection. In the last few years a reliable progress in the understanding and management of urinary tract infection is achieved. Numerous articles published in professional journals are a good proof of it. The urinary tract infection is frequent and is responsible for the use of large quantities of antibiotics which provoke great costs and make other problems. The role of laboratory tests in the diagnosis of infection is predominant. The clinician is completely dependent on his collegue, a bacteriologist, with regard to the results of urine culture. It is known that microorganisms grow better if they have good nourishment. Infections of the urinary tract were always a significant problem. However, over the last few decades, they became, according to some authors, the most frequent bacterial infection in humans, requiring the frequent administration of immunosuppressive agents, corticosteroids and cytostatics; and at the same time a great number of elder people and chronic patients with reduced immunity are involved. Taking into account that significant and insignificant infections of the urinary tract are frequent in nephropathology, particularly in renal and canalicular calculosis, the aim of the study was to point to extracorporeal shock wave lithotripsy without risk of impairment of already existing infections with and without administration of antibiotic and uroantiseptic agents for prophylactic purposes. A group of 5,078 patients with calculosis of the urinary tract was studied. Extracorporeal shock wave lithotripsy was performed in all patients by Siemens lithotriptor Lithostar (Germany). In patients with calculosis of the urinary tract subjected to extracorporeal lithotripsy bacteriuria was regularly followed. A group of 1,836 (36 percent) patients with urinary tract obstruction and 3,242 (64 percent) patients without urinary tract obstruction were treated (Table 1). In 895 (18 percent) patients with urinary tract obstruction infection was serious. In 321 (6 percent) patients without urinary tract infection, serious urinary tract infection was detected (Table 2). The most frequent causes of urinary tract infection are presented in Table 3. Table 4 shows a review of patients to whom antibiotic therapy, prior to extracorporeal lithotripsy, was prescribed. Infection of the urinary tract is responsible for great morbidity. The treatment of any type of urinary tract infection must include the examination of the effect of antibiotic agents. During the treatment of urinary tract infection with calculosis resistant microorganisms are also developed because of repeated administration of antibiotics to patients in health institutions, and especially to patients with ureteral catheters. The treatment of any type of urinary tract infection must include the examination of the effect of antibiotic agents used. The fundamental aims of the treatment of urinary tract infection are: the eradication of causes of infection and concurrent prevention or optimal control of recurrent infection. As long as the patients with urinary tract calculosis are susceptible of permanent infections. It is indispensable to perform sterilization, and thereafter to remove the stone from the urinary tract, because infection of the urinary tract may cause a series of sequelae in the function of the kidney. Frequently the successful urinary sterilization with antibiotic agents cannot be achieved, and consequently, the carrying out of extracorporeal lithotripsy together with administration of antibiotics, is impossible. Good results can be obtained by a combined therapy of antibiotics and extracorporeal lithotripsy in patients with urinary tract calculosis. (ABSTRACT TRUNCATED)     

Refractory mucosal candidiasis in patients with human immunodeficiency virus infection

Difficult-to-manage mucosal candidal infection has been a hallmark of individuals with advanced infection due to human immunodeficiency virus type 1. In this AIDS Commentary, Drs. Fichtenbaum and Powderly comprehensively review the literature and their experience with refractory candidiasis in such patients. Of interest is their delineation of resistance, a lack of susceptibility to an antifungal agent in vitro among patients with refractory or clinically unresponsive disease. These authors believe that the establishment of resistance should be based upon standards established by the National Committee on Clinical Laboratory Standards, which they propose to define as a failure to respond to systematic therapy with specific doses of itraconazole, fluconazole, or parenterally or orally administered amphotericin B within 14 days. There have been many definitions of "refractory candidiasis," and the one proposed by these authors will be debated; however, this definition has the advantage of establishing a standard by which to judge the efficacy of their proposed algorithm for the treatment of persistent or refractory oropharyngeal candidal infections. Drs. Fichtenbaum and Powderly have performed a useful service in their attempt to bring coherence to the management of this common and often vexing problem.     

Oral immunization with attenuated Salmonella expressing human sperm antigen induces antibodies in serum and the reproductive tract

Induction of immune responses in the reproductive tract will be crucial for a functional gamete antigen-based antifertility vaccine. Here we describe the construction and development of an avirulent Salmonella as an oral vaccine delivery vector to elicit sperm-specific immune responses in reproductive tract secretions. A cDNA sequence encoding the human sperm antigen SP10 was cloned on an asd+vector and expressed to a high level in an avirulent delta cya, delta crp, and delta asd vaccine strain of Salmonella typhimurium. Oral immunization of female BALB/c mice with this recombinant Salmonella elicited high-titer anti-SP10 IgG antibodies in serum and IgA antibodies in vaginal secretions. Anti-SP10 antibody titers could be increased by secondary and tertiary oral administrations of the recombinant Salmonella. Induction of sperm-specific antibodies in the reproductive tract following oral administration of a recombinant Salmonella could lead to the development of a simple, safe, efficient, and easy-to-use antifertility vaccine.     

Routes of immunization and antigen delivery systems for optimal mucosal immune responses in humans

Numerous experiments performed in humans and animals have revealed that stimulation of mucosal lymphoid inductive sites such as intestinal Peyer's patches results in parallel immune responses manifested by the appearance of S-IgA antibodies in the external secretions of remote glands. However, recent experiments suggest that inductive sites associated with the upper respiratory tract, rectum, and perhaps genital tract may also function as sources of lymphoid cells that populate, with some selectivity, certain remote mucosal effector sites. Furthermore, antigen-specific IgA antibodies can be induced in certain secretions (e.g., female genital tract) not only by immunization in the vicinity of corresponding mucosal tissues (e.g., vagina and rectum) but also by oral and especially intranasal immunization. The ineffectiveness of simple delivery of soluble antigens to mucosal membranes for immunization has stimulated extensive studies of strategies for effective delivery systems that would (a) increase the antigen absorption, (b) prevent its degradation, and (c) skew the outcome of immunization to a desired goal (protective response to infectious diseases vs. tolerance; B vs. T cell responses; mucosal vs. systemic). The induction of immune responses at a desired mucosal site can be accentuated with the use of a suitable antigen-delivery system including relevant bacterial or viral vectors, edible transgenic plants expressing microbial antigens, incorporation of antigens in biodegradable microspheres or liposomes, and linkage or coadministration of antigens with cholera toxin B subunit. However, only a few antigen-delivery systems extensively used in animal experimentation have been evaluated for their efficacy in humans. The combination of various immunization routes and the use of suitable antigen-delivery systems may accomplish an important task-the induction of mucosal immune responses at a location relevant to the site of entry of a given pathogen.     

Comparison of enoxacin versus trimethoprim-sulfamethoxazole in the treatment of patients with complicated urinary tract infection

Given the prevalence of complicated urinary tract infection (UTI) and the resistance patterns of common uropathogens, antimicrobial therapy for complicated UTI must be carefully selected. For patients with complicated UTI who can be treated with oral medication, the quinolones or trimethoprim-sulfamethoxazole (TMP-SMX) are reasonable treatment choices. Enoxacin and TMP-SMX were compared for efficacy, safety, and bacteriologic response in this study. A total of 260 patients with complicated UTI were enrolled in a multicenter, open-label, randomized study and received enoxacin or TMP-SMX. Short-term assessments 5 to 9 days posttherapy and long-term assessments 4 to 6 weeks posttherapy included physical and clinical evaluations, laboratory testing, urine cultures, and susceptibility testing. Although enoxacin and TMP-SMX demonstrated comparable short-term efficacy rates, enoxacin exerted a potent, long-term bacteriologic response, particularly against Escherichia coli. Enoxacin therapy achieved a 94.7% long-term eradication rate against E coli compared with a 76.0% eradication rate against this pathogen with TMP-SMX. Most adverse events were mild, and a comparable incidence (approximately 17%) occurred in both treatment groups. These data indicate that enoxacin is an excellent addition to the armamentarium of agents commonly used in the treatment of patients with complicated UTI.     

The organization of human leucocyte antigen class I epitopes in HIV genome products: implications for HIV evolution and vaccine design

Knowledge of human leucocyte antigen (HLA) peptide binding motifs permits rapid selection of candidate viral protein fragments for induction of T cell-mediated immunity. A search for HLA class I peptide binding motifs in structural proteins of human immunodeficiency virus (HIV) of different genetic lineages provides a map of the genetic organization of potential T cell antigenic sites, and at the same time identifies all motifs in highly conserved regions of HIV-1 env, gag and pol. The density of motifs is anomalous at both the high and low end of the spectrum: local organization is characterized by clustering in relatively short regions, while large scale organization is characterized by anomalously long runs between motifs. The former is expected simply due to the fact that motifs often have overlapping anchor residue sets. A detailed statistical analysis of the latter, however, shows that the length of the runs cannot be accounted for by chance alone. Although motif clusters show no preference to be in either conserved or variable regions, low motif density stretches occur preferentially in variable portions of the protein sequence, which suggests that the virus may be mutating to evade the cellular arm of the immune system.     

Regression of pyuria during the treatment of symptomatic urinary tract infection in patients with spinal cord injury

Pyuria is frequently present in patients who require bladder instrumentation. Using the hemocytometer chamber method, we prospectively studied the regression of pyuria in 29 spinal cord-injured (SCI) men with symptomatic urinary tract infection (UTI) who were grouped according to the method of bladder drainage: (a) Intermittent catheterization program (ICP; 10 patients); (b) Suprapubic tube (SPT; 10 patients); and (c) Indwelling foley catheters (IFC; 9 patients). All of the patients experienced relief of presenting symptoms within 3-4 days of receiving appropriate antibiotic therapy. The clinical response was associated with > or = 65% and > or = 87% reduction in the levels of pyuria at mid-therapy and after completion of antimicrobial therapy, respectively. Using a one-way analysis of variance, the group of patients who underwent ICP had significantly lower residual levels of pyuria at mid-therapy and after completion of therapy when compared to the other two groups (P < 0.05). The findings of relatively lower absolute levels of pyuria in the ICP group vs the SPT and IFC group of patients suggest that the response of pyuria to appropriate therapy for symptomatic UTI can be assessed better and earlier in patients who undergo ICP.     

Options for the management of mucosal candidiasis in patients with AIDS and HIV infection

OBJECTIVE: To design a document model that provides reliable and efficient access to clinical information in patient reports for a broad range of clinical applications, and to implement an automated method using natural language processing that maps textual reports to a form consistent with the model. METHODS: A document model that encodes structured clinical information in patient reports while retaining the original contents was designed using the extensible markup language (XML), and a document type definition (DTD) was created. An existing natural language processor (NLP) was modified to generate output consistent with the model. Two hundred reports were processed using the modified NLP system, and the XML output that was generated was validated using an XML validating parser. RESULTS: The modified NLP system successfully processed all 200 reports. The output of one report was invalid, and 199 reports were valid XML forms consistent with the DTD. CONCLUSIONS: Natural language processing can be used to automatically create an enriched document that contains a structured component whose elements are linked to portions of the original textual report. This integrated document model provides a representation where documents containing specific information can be accurately and efficiently retrieved by querying the structured components. If manual review of the documents is desired, the salient information in the original reports can also be identified and highlighted. Using an XML model of tagging provides an additional benefit in that software tools that manipulate XML documents are readily available.     

Nitrofurantoin prophylaxis for bacteriuria and urinary tract infection in children with neurogenic bladder on intermittent catheterization

OBJECT: This study was undertaken to determine the efficacy of preoperative erythropoietin administration in infants scheduled for craniofacial surgery and, in so doing, to minimize problems associated with blood transfusions. METHODS: Families were offered the option of having their children receive erythropoietin injections before undergoing craniofacial surgery. The children whose families accepted this option received daily iron and 300 U/kg erythropoietin three times per week for 3 weeks preoperatively. Weekly complete blood counts with reticulocyte counts were measured and transfusion requirements were noted. Blood transfusions were administered depending on the clinical condition of the child. A case-matched control population was also evaluated to compare initial hematocrit levels and transfusion requirements. Thirty patients in the erythropoietin treatment group and 30 control patients were evaluated. The dose of erythropoietin administered was shown to increase hematocrit levels from 35.4 +/- 0.9% to 43.3 +/- 0.9% during the course of therapy. The resulting hematocrit levels in patients treated with erythropoietin at the time of surgery were higher compared with baseline hematocrit levels obtained in control patients at the time of surgery (34.2 +/- 0.5%). Transfusion requirements also differed: all control patients received transfusions, whereas 64% (19 of 30) of erythropoietin-treated patients received transfusions. CONCLUSIONS: The authors conclude that treatment with erythropoietin in otherwise healthy young children will increase hematocrit levels and modify transfusion requirements. Erythropoietin therapy for elective surgery in children of this age must be individualized according to the clinical situation, family and physician beliefs, and cost effectiveness, as evaluated at the individual center.     

Comparison between reagent strips used for detection of urinary tract infection in the elderly

A comparison was made between the accuracy of Ames and Boehringer reagent strips for detecting urinary tract infections in 100 elderly patients (50 acutely ill patients admitted to hospital and 50 attending the day hospital). The results for urinary nitrite, blood and protein for both strips were documented. Nitrite provided the highest sensitivities and specificities. In the acute hospital patients, the sensitivities were 83% for the Ames and Boehringer strips respectively, while for the day hospital patients the sensitivities were 90% for both strips. Specificities were 100% for both strips in each group of patients. There was thus little difference between the accuracy of the Ames and Boehringer reagent strips in detecting urinary tract infection.     

Risk of recurrent biliary tract disease after cholecystectomy in patients with duodenal diverticula

OBJECTIVE: To determine if the presence of duodenal diverticula predisposes to the development of common bile duct stones. DESIGN: Cohort study; median follow-up, 10.0 years (25th and 75th percentiles, 5.2 and 16.1 years, respectively). SETTING: Tertiary care center. PATIENTS: One hundred fifty-seven patients with radiologically diagnosed duodenal diverticula who had undergone cholecystectomy from 1950 through 1987 and were asymptomatic at the initiation of follow-up. MAIN OUTCOME MEASURES: All patients were followed up for evidence of recurrent biliary tract disease to the following end points: (1) evidence of choledocholithiasis demonstrated by radiologic surgical, or biochemical means and (2) clinical or biochemical evidence of biliary pancreatitis. RESULTS: Of the 157 patients in the study cohort, 13 patients were categorized as having had recurrent biliary tract disease. Using the Kaplan-Meier survivorship method, the cumulative probabilities of recurrent biliary tract disease in patients with radiologically diagnosed duodenal diverticula were 3.6% at 5 years (95% confidence interval, 0.5-6.9), 5.5% at 10 years (95% confidence interval, 1.5-9.4), and 10.2% at 15 years (95% confidence interval, 3.8-16.7). Age, common bile duct exploration and choledochotomy, and the presence of common bile duct dilatation were not found to be significantly associated with recurrence based on a univariate analysis of risk factors by means of the log-rank statistic. CONCLUSIONS: For patients with radiologically diagnosed, second-portion duodenal diverticula, the risk of developing recurrent bile duct stones after cholecystectomy is lower than has been suggested in previous studies. In the absence of concurrent choledocholithiasis, sphincterotomy or biliary bypass at the time of cholecystectomy seems unwarranted.     

Association of HLA phenotype and response to interferon-alpha in patients with chronic myelogenous leukemia

OBJECTIVES: Bone metabolism is an important target for GH replacement therapy. However, in adults, treatment periods exceeding 12 months are required for a positive effect of GH on bone mineral density. Thus, to detect an early effect of GH on bone, markers of bone turn-over are important. Pyridinoline (PYR) and deoxypyridinoline (DPYR) are well-defined sensitive markers of bone resorption, but to date only urinary assays have been available. We report the use of a novel assay to measure changes in serum PYR and DPYR in GH deficient (GHD) adults during GH replacement therapy. STUDY DESIGN: The study consisted of a 6-month randomized, double-blind, placebo-controlled study of the administration of GH (Genotropin) (0.25 IU/Kg/week (0.125 IU/kg/week for the first four weeks)) followed by a 6-month open phase of GH therapy. PATIENTS: Thirty-five GHD adults (17 women; mean age 39.8 years; range 21.1-59.9) on conventional hormone replacement therapy as required, were studied. MEASUREMENTS: Bone formation was analysed using serum bone alkaline phosphatase (BAP) and serum osteocalcin (OC). Bone resorption was analysed using serum pyridinoline (PYR) and serum deoxypyridinoline (DPYR). Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry (DEXA). RESULTS: After 6 months placebo treatment there were no significant changes in any of the bone markers analysed, nor in BMD. In the active arm of the study there was a significant increase in serum OC, BAP, PYR and DPYR (P = 0.03, P = 0.004, P = 0.003 and P = 0.01, respectively), remaining significantly elevated over their baseline levels for the subsequent 6 months of treatment (P = 0.04, P = 0.009, P = 0.003 and P = 0.04, respectively). No changes were observed in BMD in any of the groups after 6 months GH treatment. In the active arm of the study, after 12 months GH treatment there was a significant increase in BMD at both the lumbar spine and femoral neck (P = 0.01 for both sites). CONCLUSIONS: In summary, the present study confirms that administration of GH treatment to GHD adult patients significantly activates bone remodelling, with the effect of GH both in bone formation and bone resorption markers being maximal after 6 months of treatment. The serum assay for PYR and DPYR has a number of practical and theoretical advantages over the urine assay and gave similar results to those previously reported for the urine assay.     

Comparison of the oral, rectal, and vaginal immunization routes for induction of antibodies in rectal and genital tract secretions of women

To determine which mucosal immunization routes may be optimal for induction of antibodies in the rectum and female genital tract, groups of women were immunized a total of three times either orally, rectally, or vaginally with a cholera vaccine containing killed Vibrio cholerae cells and the recombinant cholera toxin B (CTB) subunit. Systemic and mucosal antibody responses were assessed at 2-week intervals by quantitation of CTB-specific antibodies in serum and in secretions collected directly from mucosal surfaces of the oral cavity, rectum, cervix, and vagina with absorbent wicks. The three immunization routes increased levels of specific immunoglobulin G (IgG) in serum and specific IgA in saliva to similar extents. Rectal immunization was superior to other routes for inducing high levels of specific IgA and IgG in rectal secretions but was least effective for generating antibodies in female genital tract secretions. Only vaginal immunization significantly increased both specific IgA and specific IgG in both the cervix and the vagina. In addition, local production of CTB-specific IgG in the genital tract could be demonstrated only in vaginally immunized women. Vaginal immunization did not generate antibodies in the rectum, however. Thus, generation of optimal immune responses to sexually transmitted organisms in both the rectal and the genital mucosae of women may require local immunization at both of these sites.     

Safety and efficacy of isolated perfusion of extremities for recurrent tumor in elderly patients

Intracellular localization of specific mRNAs is known to be a mechanism for targeting proteins to specific sites within the cell. Previous studies from this laboratory have demonstrated co-localization of mRNAs and proteins for a number of genes in absorptive enterocytes of fetal rat intestine. The present study was undertaken to examine in human enterocytes the intracellular localization patterns of mRNAs for the microvillous membrane proteins lactase-phlorizin hydrolase (LPH), sucrase-isomaltase (SI), and intestinal alkaline phosphatase (IAP), and the cytoskeletal protein beta-actin. In sections of human jejunum, mRNAs were localized by in situ hybridization using digoxigenin-labeled anti-sense RNA probes. Both LPH and SI mRNAs were localized to the apical region of villous enterocytes, whereas IAP and beta-actin mRNAs were detected both apically and basally relative to the nucleus. Therefore, in contrast to LPH, SI, and beta-actin mRNAs, which co-localize with their encoded proteins, that of IAP is present in the basal region of the cell where IAP protein has not directly been demonstrated to be present. Absorptive enterocytes from humans possess the mechanisms for intracellular mRNA localization, but not all mRNAs co-localize with their encoded proteins.