Genetics and phenotyping of urological chronic pelvic pain syndrome.

PURPOSE: Interstitial cystitis/painful bladder syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively renamed urological chronic pelvic pain syndromes, are a group of medically unexplained physical symptoms. Diagnosis depends on excluding all possible causes of pain and treatment targets symptoms alone. An emerging body of research implicates systemic factors in the pathogenesis of urological chronic pelvic pain syndromes including abnormal sympathetic nervous system and hypothalamic-pituitary-adrenal axis activity. Several new lines of evidence also suggest a genetic component to disease pathogenesis. Despite ongoing efforts, neither effective treatments nor mechanistic understanding of the pathogenesis of urological chronic pelvic pain syndromes exists. MATERIALS AND METHODS: We performed a survey of the available literature on urological chronic pelvic pain syndromes. We reviewed recent research implicating genetic mechanisms in the development of urological chronic pelvic pain syndromes to find a systematic approach of rigorous phenotyping on which to base further investigation of these chronic pain conditions. RESULTS: Three studies revealed identifying genetic risk factors for disease. In addition, increasing lines of evidence of familial clustering and twin studies suggested a genetic basis for disease. CONCLUSIONS: Given the success of genome-wide association studies in quantifying genetic risk in several polygenic diseases, we suggest a similar genome-wide approach to the study of urological chronic pelvic pain syndromes. As genome-wide association studies depend on carefully defined patient populations, we provide an outline for a thorough and multidisciplinary characterization of patient phenotypes. Although urological chronic pelvic pain syndromes continue to mystify clinicians and researchers alike, we believe the powerful new methods of unbiased interrogation of the whole genome based on systematically grouped patients possess enormous potential for progress in treating and understanding this disease.

A candidate serum biomarker for bladder pain syndrome/interstitial cystitis.

Reliable diagnostic markers for Bladder Pain Syndrome/Interstitial Cystitis (IC) currently are not available. This study evaluated the feasibility of diagnosing IC in humans and domestic cats from the spectra of dried serum films (DSFs) using infrared microspectroscopy. Spectra were obtained from films from 29 humans and 34 domestic cats to create classification models using Soft Independent Modeling by Class Analogy (SIMCA). Ultrafiltration of serum improved discrimination capability. The classification models for both species successfully classified spectra based on condition (healthy/sick), and a different set of masked spectra correctly predicted the condition of 100% of the subjects. Classification required information from the 1500-1800 cm(-1) spectral region to discriminate between subjects with IC, other disorders, and healthy subjects. Analysis of cat samples using liquid chromatography-mass spectroscopy revealed differences in the concentration of tryptophan and its metabolites between healthy and affected cats. These results demonstrate the potential utility of infrared microspectroscopy to diagnose IC in both humans and cats.

Urologic chronic pelvic pain syndrome--looking back and looking forward.

Urologic chronic pelvic pain syndrome (UCPPS) is a symptom-based umbrella term for interstitial cystitis/painful bladder syndrome (IC/PBS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in men. Unfortunately, no gold standard for diagnosis or treatment of UCPPS exists. We review several emerging theories on the etiology and pathogenesis of UCPPS with a special emphasis on genomic and proteomic technologies. We also propose a systems-biology approach to elucidating the pathogenetic mechanisms implicated in UCPPS and the discovery and validation of new biomarkers for UCPPS. Using data gleaned from high-throughput genomic and proteomic screens can help develop effective treatments for this enigmatic chronic pelvic pain syndrome.

Pharmacologic management of painful bladder syndrome/interstitial cystitis: a systematic review.

BACKGROUND: More than 180 different types of therapy have been used in the treatment and management of painful bladder syndrome/interstitial cystitis (PBS/IC), yet evidence from clinical trials remains inconclusive. This study aimed to evaluate the efficacy of pharmacologic approaches to PBS/IC, to quantify the effect size from randomized controlled trials, and to begin to inform a clinical consensus of treatment efficacy for PBS/IC. METHODS: We identified randomized controlled trials for the pharmacologic treatment of patients with PBS/IC diagnosed on the basis of National Institute of Diabetes and Digestive and Kidney Diseases or operational criteria. Study limitations include considerable patient heterogeneity as well as variability in the definition of symptoms and in outcome assessment. RESULTS: We included a total of 1470 adult patients from 21 randomized controlled trials. Only trials for pentosan polysulfate sodium had sufficient numbers to allow a pooled analysis of effect. According to a random-effects model, the pooled estimate of the effect of pentosan polysulfate therapy suggested benefit, with a relative risk of 1.78 for patient-reported improvement in symptoms (95% confidence interval, 1.34-2.35). This result was not heterogeneous (P = .47) and was without evidence of publication bias (P = .18). Current evidence also suggests the efficacy of dimethyl sulfoxide and amitryptyline therapy. Hydroxyzine, intravesical bacille Calmette-Guérin, and resiniferatoxin therapy failed to demonstrate efficacy, but evidence was inconclusive owing to methodological limitations. CONCLUSIONS: Pentosan polysulfate may be modestly beneficial for symptoms of PBS/IC. There is insufficient evidence for other pharmacologic treatments. A consensus on standardized outcome measures is urgently needed.

p53 mediates interstitial cystitis antiproliferative factor (APF)-induced growth inhibition of human urothelial cells.

Antiproliferative factor (APF) is a sialoglycopeptide elevated in the urine of patients with interstitial cystitis, a urinary bladder disorder of unknown etiology that is characterized by chronic pelvic pain. The present study was directed toward uncovering a pathway through which APF signals. Treatment of human urothelial cells with native APF resulted in growth inhibition accompanied by blockade of cell cycle transit and increased p53. Reduced expression of p53 by RNA interference diminished, while ectopic expression of p53 mimicked, the effects of APF. These are the first findings implicating the network of p53 target genes in urothelial defects associated with interstitial cystitis.

Nonspecific granulomatous prostatitis with calculous ductal ectasia and extensive Paneth cell-like epithelial metaplasia. Case report.

We present a case of nonspecific granulomatous prostatitis in combination with calculous ductal ectasia and extensive epithelial Paneth cell-like metaplasia in a TURP-specimen. Our report highlights the importance of calculous ductal obstruction and stasis of secretions in the etiopathogenesis of this type of prostatitis. The observed extensive Paneth cell-like metaplastic change in adjacent epithelial cells most likely represents a phenotypic adaptive mechanism directed against foreign antigens and nondegradable lipids in the stagnant intraluminal debris.

Pathologic features of necrotizing adenoviral prostatitis in an AIDS patient.

Adenovirus has been implicated as a cause of opportunistic infections in immunocompromised patients, frequently with multiorgan involvement and a fatal outcome. We describe a case of necrotizing adenoviral prostatitis in a 35-year-old man with terminal AIDS and generalized adenoviral infection. The histopathologic findings of intraacinar necrotizing inflammation, prominent viral nuclear inclusions in residual epithelium, and mild T-lymphocyte and macrophageal inflammatory reaction were observed in the prostate. The presence of adenovirus was confirmed by electron microscopy and immunohistochemistry. Squamous metaplasia was present in the surrounding acini. This case of adenoviral prostatitis appears to be the first report of its kind in medical literature and demonstrates another aspect of the diversity of organ manifestations seen in this infection. This lesion should be included in the differential diagnosis of necrotizing prostatic diseases.

Autosomal recessive polycystic kidney disease. Clinical and genetic profile. (Review and a case report).

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder inherited in a recessive manner. The ARPKD gene is located on chromosome 6. The disease is characterised by specific changes in the kidney and liver. AIM: To make a review of modern achievements in studying the clinical, genetic and diagnostic problems concerning ARPKD and contribute an illustrative case. RESULTS: We reviewed modern research on the molecular genetics of autosomal recessive polycystic kidney disease related to PKHD1 gene located on chromosome 6p21-cen, as well as on the role of fibrocystin in the terminal differentiation of the collecting and biliary ductules. The clinical manifestations of the disease in infancy and in early childhood are analysed. A diagnostic algorithm is proposed incorporating both clinical and genetic methods. The illustrative case we reported of a 22-year-old patient with ARPKD supports the view that the disease occurs, though rarely, later than in childhood. CONCLUSION: The authors recommend that in cases with late manifestation of the disease in adolescence with chronic renal failure, possibilities be searched for extracorporeal replacement (renal transplantation) when this is allowed by the complications associated with the congenital liver fibrosis.

Ten-year clinical and ultrasonographic follow-up of siblings from families with autosomal dominant polycystic kidney disease.

We conducted a ten-year clinical and ultrasound follow-up study of 120 siblings with ADPKD (68 men and 52 women, aged 19-40). 40 subjects had polycystic kidney disease. During the study period, the number and size of the cysts increased. Symptoms and signs also changed: at baseline 51% of the subjects were asymptomatic dropping subsequently to 2%. Initially, 32 subjects had 1-5 cysts in one or both kidneys and they were classified as suspected of having ADPKD. Significant changes were found in this group at the end of the follow-up. In 12 of them (37.50%) subsequent ultrasonograms revealed an increase in the number and size of the cysts--i.e. evolution towards ADPKD. None of the subjects in this group had a decrease in the number of cysts. In the control group, three had multiple cysts but most subjects were ultrasonographically negative for polycystic kidney disease. In conclusion, the authors recommend a clinical and ultrasonographic long-term follow-up of subjects at risk for ADPKD which should allow early diagnosis as well as prevention of the complications which result in chronic renal failure.

Placental soluble fms-like tyrosine-kinase-1 (sFlt-1) in pregnant women with preeclampsia.

UNLABELLED: The pathophysiology of preeclampsia remains largely unknown. A number of circulating placenta-produced factors have been implicated in causing the endothelial dysfunction and the clinical phenotype characteristic of preeclampsia. AIM: Determination of serum levels of placental soluble fms-like tyrosine-kinase-1 (sFlt-1) in pregnant women with preeclampsia. Eleven pregnant women with preeclampsia and 11 healthy women (controls) were included in the study. Determination of sFlt-1 was done with ELISA. The mean serum sFlt-1 levels of pregnant women with preeclampsia were twice as high as that of women with normal pregnancy. The highest level of sFlt-1 was found in women with severe preeclampsia. In women with mild form of preeclampsia the sFlt-1 level was close to that of the controls. sFlt-1 appears to be involved in the pathogenesis of preeclampsia and its serum levels can be used as a diagnostic marker of preeclampsia.

Effect of mycophenolate mofetil (Cell Cept) in the treatment of immune glomerulopathies.

AIM: To study the effect of mycophenolate mofetil (Cell Cept) in treating patients with various types of chronic glomerulonephritis and other immune nephropathies. MATERIAL AND METHODS: Between 2000 and 2003 we treated 35 patients (18 women, 17 men) with Cell Cept (La Roche). In 32 patients the diagnosis was confirmed by kidney biopsy (immunofluorescence, light and electron microscopy). RESULTS: Treatment with Cell Cept was very successful in 22 of the patients in the study (62.86%). Proteinuria was significantly reduced and firmly maintained well below 0.5 g/l; serum protein levels were elevated to normal values, the edemas disappeared. In 12 patients the drug had a good effect: there was a significant reduction of proteins in the urea within 1.2 - 2.0 g/l, an increase of total protein and albumins in plasma but after three months of treatment. The therapy was with no effect only in one patient with primary amyloidosis of kidneys. CONCLUSIONS: Treatment with mycophenolate mofetil (Cell Cept) is an alternative modality for the management of immune glomerulopathies resistant to conventional and pulse pathogenetic therapeutic regimens. It can be a treatment of first choice.

New treatments for chronic prostatitis/chronic pelvic pain syndrome.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition among men of a wide age range, with detrimental effects on quality of life. The etiology, pathogenesis, and optimal treatment of CP/CPPS remain unknown, although progress has been made in these domains in recent years. A wide variety of pharmacologic and nonpharmacologic therapies have been studied in clinical trials, but most have shown limited efficacy in symptom alleviation. CP/CPPS is increasingly viewed as a condition that involves variable degrees of neuropathic pain. Medications such as gabapentin, pregabalin, memantine, and tricyclic antidepressants are often used in other neuropathic pain conditions and, therefore, are considered potential treatments for CP/CPPS. Few studies of these agents in patients with CP/CPPS have been reported, but future clinical trials should help to determine their utility and to characterize the pathogenetic mechanisms of pain in CP/CPPS. Combining treatment trials with biomarker, genomic, and imaging studies, in addition to epidemiologic and symptom-based assessments, will maximize the ability to probe disease etiology and pathogenesis, as well as identify effective treatment.

Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome.

OBJECTIVES: To identify adrenocortical hormone abnormalities as indicators of endocrine dysfunction in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: We simultaneously measured the serum concentrations of 12 steroids in patients with CP/CPPS and controls, using isotope dilution liquid chromatography, followed by atmospheric pressure photospray ionization and tandem mass spectrometry. RESULTS: We evaluated 27 patients with CP/CPPS and 29 age-matched asymptomatic healthy controls. In the mineralocorticoid pathway, progesterone was significantly greater, and the corticosterone and aldosterone concentrations were significantly lower, in the patients with CP/CPPS than in the controls. In the glucocorticoid pathway, 11-deoxycortisol was significantly lower and the cortisol concentrations were not different between the patients and controls. In the sex steroid pathway, the androstenedione and testosterone concentrations were significantly greater in those with CP/CPPS than in the controls. The estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate concentrations were not different between the patients and controls. The National Institutes of Health-Chronic Prostatitis Symptom Index total and pain domain scores correlated positively with the 17-hydroxyprogesterone and aldosterone (P <0.001) and negatively with the cortisol (P <0.001) concentrations. CONCLUSIONS: Our results suggest reduced activity of CYP21A2 (P450c21), the enzyme that converts progesterone to corticosterone and 17-hydroxyprogesterone to 11-deoxycortisol. Furthermore, these results provide insights into the biologic basis of CP/CPPS. Follow-up studies should explore the possibility that patients with CP/CPPS meet the diagnostic criteria for nonclassic congenital adrenal hyperplasia and whether the hormonal findings improve or worsen in parallel with symptom severity.