Acyloxyacyl hydrolase modulates pelvic pain severity.

Chronic pelvic pain causes significant patient morbidity and is a challenge to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of interstitial cystitis/bladder pain syndrome (IC), we recently showed that pseudorabies virus (PRV) induces severe pelvic allodynia in BALB/c mice relative to C57BL/6 mice. Here, we report that a quantitative trait locus (QTL) analysis of PRV-induced allodynia in F2CxB progeny identified a polymorphism on chromosome 13, rs6314295 , significantly associated with allodynia (logarithm of odds = 3.11). The nearby gene encoding acyloxyacyl hydrolase ( Aoah) was induced in the sacral spinal cord of PRV-infected mice. AOAH-deficient mice exhibited increased vesicomotor reflex in response to bladder distension, consistent with spontaneous bladder hypersensitivity, and increased pelvic allodynia in neurogenic cystitis and postbacterial chronic pain models. AOAH deficiency resulted in greater bladder pathology and tumor necrosis factor production in PRV neurogenic cystitis, markers of increased bladder mast cell activation. AOAH immunoreactivity was detectable along the bladder-brain axis, including in brain sites previously correlated with human chronic pelvic pain. Finally, AOAH-deficient mice had significantly higher levels of bladder vascular endothelial growth factor, an emerging marker of chronic pelvic pain in humans. These findings indicate that AOAH modulates pelvic pain severity, suggesting that allelic variation in Aoah influences pelvic pain in IC.

Novel PI3Kγ mutation in a 44-year-old man with chronic infections and chronic pelvic pain.

A 44-year-old man is presented here with 14 years of chronic purulent sinusitis, a chronic fungal rash of the scrotum, and chronic pelvic pain. Treatment with antifungal therapy resulted in symptom improvement, however he was unable to establish an effective long-term treatment regimen, resulting in debilitating symptoms. He had undergone extensive work-up without identifying a clear underlying etiology, although Candida species were cultured from the prostatic fluid. 100 genes involved in the cellular immune response were sequenced and a missense mutation was identified in the Ras-binding domain of PI3Kγ. PI3Kγ is a crucial signaling element in leukotaxis and other leukocyte functions. We hypothesize that his mutation led to his chronic infections and pelvic pain.

Ca(2+)/calmodulin-dependent protein kinase II is associated with pelvic pain of neurogenic cystitis.

Interstitial cystitis/painful bladder syndrome is a chronic bladder inflammatory disease of unknown etiology that is often regarded as a neurogenic cystitis. Interstitial cystitis is associated with urothelial lesions, voiding dysfunction, and pain in the pelvic/perineal area. In this study, we used a murine neurogenic cystitis model to identify genes participating in the development of pelvic pain. Neurogenic cystitis was induced by the injection of Bartha's strain of pseudorabies virus (PRV) into the abductor caudalis dorsalis (tail base) muscle of female C57BL/6J mice. Mice infected with PRV developed progressive pelvic pain. The sacral spinal cord was harvested on postinfection days (PID) 2 and 4, and gene expression was analyzed by microarrays and confirmed by quantitative RT-PCR. On PID 2, the overall expression profile was similar to that of uninfected sacral spinal cord; by PID 4, there were substantial differences in expression of multiple functional classes of genes, especially inflammation. Analysis of pain-signaling pathways at the dorsal horn suggested that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) contributes to neurogenic cystitis pelvic pain. Consistent with this, CaMKIIδ expression exhibited a mast cell-dependent increase in the sacral spinal cord at the mRNA level, and phospho-CaMKII immunoreactivity in the dorsal horn was increased on postinfection day (PID) 4 during PRV infection. Finally, intrathecal injection of the CaMKII inhibitor KN-93 attenuated the PRV pain response. These data suggest that CaMKII plays a functional role in pelvic pain due to neurogenic cystitis.

Increased concentration of neutrophil elastase in urine from patients with interstitial cystitis.

OBJECTIVE: To identify proteins associated with interstitial cystitis (IC), protein profiles were analyzed using a proteomics-based approach. The study tested whether neutrophil elastase in urine correlates with the symptomatic condition of IC. MATERIAL AND METHODS: Proteins in urine from IC patients and healthy subjects were analyzed through a comparative proteomics approach using two-dimensional difference in-gel electrophoresis and nano-liquid chromatography-tandem mass spectrometry. Neutrophil elastase activity was measured by the digestion of peptide substrate. RESULTS: The urinary neutrophil elastase concentration was significantly higher in IC patients with pain than in healthy subjects. It was significantly increased in patients with small bladder capacity (median 6.31 ng/ml in IC with a bladder capacity < 200 ml vs 1.15 ng/ml in IC with a bladder capacity > or = 200 ml and 0.18 ng/ml in healthy bladders, p < 0.01). The concentration of neutrophil elastase did not correlate with the neutrophil count in the urine of IC patients. CONCLUSION: The concentration of neutrophil elastase increased in the urine of the IC patient subset with bladder pain and small bladder capacity.

A pilot study on the off-label use of valproic acid to treat adenomyosis.

Following on the heels of the discovery that endometriosis is an epigenetic disease, we conducted a pilot study on the off-label use of valproic acid to treat adenomyosis. We found that by the end of the 3-month treatment, all three recruited patients reported complete disappearance of dysmenorrhea, with an average of one-third reduction in uterus size.

Alteration of focal adhesion kinase expression in eutopic endometrium of women with endometriosis.

OBJECTIVE: To investigate whether focal adhesion kinase (FAK) expression is altered in eutopic endometrium of women with endometriosis. DESIGN: Experimental study using human endometrial tissue. SETTING: Academic research center. PATIENT(S): Women with or without endometriosis who were undergoing surgery for benign indications. INTERVENTION(S): Endometrial biopsy. MAIN OUTCOME MEASURE(S): Expression of FAK was assessed by immunohistochemistry, Western blotting analysis, and reverse-transcription polymerase chain reaction. RESULT(S): At secretory phase, the average level of endometrial FAK expression of women with endometriosis was significantly higher than that of controls, but no significant difference was found between the two groups at proliferative phase. There was a positive correlation between FAK expression in secretory endometrial tissues and disease stage and pelvic pain in women with endometriosis. Furthermore, the endometrial FAK protein expression varied with the serum E(2) at proliferative phase and with the ratio of E(2) to P at secretory phase. CONCLUSION(S): The study showed a significant increase of FAK expression in the secretory endometrial tissues of women with endometriosis, a relationship between FAK expression and disease stage, pelvic pain, and serum steroid hormones. Those results suggest that FAK may play a role in the pathogenesis of endometriosis and be regulated by steroid hormones.

Manganese superoxide dismutase polymorphism in chronic pelvic pain syndrome patients.

Chronic pelvic pain syndrome (CPPS) is a common and serious health problem affecting the quality of life in men. In this study, we aim to investigate the manganese superoxide dismutase (MnSOD) polymorphism at nucleotide 47 as a result of the change of Ala to Val on the protein sequence in CPPS patients. The frequencies were 0.45 and 0.38 for the Ala and 0.55 and 0.62 for Val in National Institutes of Health category 3a and 3b groups. The differences between control and CPPS patients were statistically significant (P<0.05). However, frequencies recorded in 3a and 3b groups were not statistically different (P>0.05). Same results were obtained for enzyme analysis of MnSOD and glutathione peroxidase. Control group antioxidant enzyme levels were higher than patients' samples. The low antioxidant status of CPPS patients might be the clue for pathophysiological problems, and highly distributed Val allele frequency can be a mediator point of the illness. Our findings lead to the suggestion that oxidative disorder-linked medical health problems can be associated with genetic risk factors such as polymorphisms.

X Chromosomal short tandem repeat polymorphisms near the phosphoglycerate kinase gene in men with chronic prostatitis.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) causes substantial morbidity afflicting approximately 10% of adult males. Treatment is often empirical and ineffective since the etiology is unknown. Other prostate and genitourinary diseases have genetic components suggesting that CP/CPPS may also be influenced by genetic predisposition. We recently reported a highly polymorphic short tandem repeat (STR) locus near the phosphoglycerate kinase gene within Xq11-13. Because this STR is in a region known to predispose towards other prostate diseases, we compared STR polymorphisms in 120 CP/CPPS patients and 300 control blood donors. Nine distinct allele sizes were detected, ranging from 8 to 15 repeats of the tetrameric STR plus a mutant allele (9.5) with a six base deletion in the flanking DNA sequence. The overall allele size distribution in the CP/CPPS patients differed from controls (Chi-square=19.252, df=8, P=0.0231). Frequencies of two specific alleles, 9.5 and 15, differed significantly in CP/CPPS vs. control subjects and allele 10 differed with marginal significance. Alleles 9.5 and 10 were both more common in CP/CPPS patients than controls while allele 15 was less common. These observations suggest that Xq11-13 may contain one or more genetic loci that predispose toward CP/CPPS. Further investigations involving family studies, larger patient populations, and other control groups may help elucidate this potential genetic predisposition in CP/CPPS.