Interstitial cystitis antiproliferative factor (APF) as a cell-cycle modulator

BACKGROUND: Interstitial cystitis (IC) is a chronic bladder disorder of unknown etiology. Antiproliferative factor (APF), a peptide found in the urine of IC patients, has previously been shown to decrease incorporation of thymidine by normal bladder epithelial cells. This study was performed to determine the effect of APF on the cell cycle of bladder epithelial cells so as to better understand its antiproliferative activity. METHODS: Explant cultures from normal bladder biopsy specimens were exposed to APF or mock control. DNA cytometry was performed using an automated image analysis system. Cell cycle phase fractions were calculated from the DNA frequency distributions and compared by two-way analysis of variance (ANOVA). RESULTS: APF exposure produced statistically significant increases in the proportion of tetraploid and hypertetraploid cells compared to mock control preparations, suggesting a G2 and/or M phase cell cycle block and the production of polyploidy. CONCLUSIONS: APF has a specific effect on cell cycle distributions. The presence of a peptide with this activity may contribute to the pathogenesis of interstitial cystitis through disruption of normal urothelial proliferation and repair processes

Applications of quark-hadron duality in F2 structure function

Inclusive electron-proton and electron-deuteron inelastic cross sections have been measured at Jefferson Lab (JLab) in the resonance region, at large Bjorken x, up to 0.92, and four-momentum transfer squared Q2 up to 7.5 GeV2 in the experiment E00-116. These measurements are used to extend to larger x and Q2 precision, quantitative, studies of the phenomenon of quark-hadron duality. Our analysis confirms, both globally and locally, the apparent violation of quark-hadron duality previously observed at a Q2 of 3.5 GeV2 when resonance data are compared to structure function data created from CTEQ6M and MRST2004 parton distribution functions (PDFs). More importantly, our new data show that this discrepancy saturates by Q2 ~ 4 Gev2, becoming Q2 independent. This suggests only small violations of Q2 evolution by contributions from the higher-twist terms in the resonance region which is confirmed by our comparisons to ALEKHIN and ALLM97.We conclude that the unconstrained strength of the CTEQ6M and MRST2004 PDFs at large x is the major source of the disagreement between data and these parameterizations in the kinematic regime we study and that, in view of quark-hadron duality, properly averaged resonance region data could be used in global QCD fits to reduce PDF uncertainties at large x.Comment: 35 page

Transverse momentum dependence of semi-inclusive pion production

Cross sections for semi-inclusive electroproduction of charged pions ($\pi^{\pm}$) from both proton and deuteron targets were measured for $0.2<x<0.5$, $2<Q^2<4$ GeV$^2$, $0.3<z<1$, and $P_t^2<0.2$ GeV$^2$. For $P_t<0.1$ GeV, we find the azimuthal dependence to be small, as expected theoretically. For both $\pi^+$ and $\pi^-$, the $P_t$ dependence from the deuteron is found to be slightly weaker than from the proton. In the context of a simple model, this implies that the initial transverse momenta width of $d$ quarks is larger than for $u$ quarks and, contrary to expectations, the transverse momentum width of the favored fragmentation function is larger than the unfavored one.Comment: 15 pages, 4 figures. Fit form changed to include Cahn effect Minor revisions. Added one new figur

The Onset of Quark-Hadron Duality in Pion Electroproduction

A large data set of charged-pion electroproduction from both hydrogen and deuterium targets has been obtained spanning the low-energy residual-mass region. These data conclusively show the onset of the quark-hadron duality phenomenon, as predicted for high-energy hadron electroproduction. We construct several ratios from these data to exhibit the relation of this phenomenon to the high-energy factorization ansatz of electron-quark scattering and subsequent quark-to- pion production mechanisms.Comment: 11 pages, 3 figures, accepted in Phys. Rev. Lett. Tables adde

Mast Cell-Derived Histamine Mediates Cystitis Pain

Background: Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC. Methods and Findings: Infection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology. Conclusions: These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, an

Effects of estrogens and bladder inflammation on mitogen-activated protein kinases in lumbosacral dorsal root ganglia from adult female rats

BACKGROUND: Interstitial cystitis is a chronic condition associated with bladder inflammation and, like a number of other chronic pain states, symptoms associated with interstitial cystitis are more common in females and fluctuate during the menstrual cycle. The aim of this study was to determine if estrogens could directly modulate signalling pathways within bladder sensory neurons, such as extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases. These signalling pathways have been implicated in neuronal plasticity underlying development of inflammatory somatic pain but have not been as extensively investigated in visceral nociceptors. We have focused on lumbosacral dorsal root ganglion (DRG) neurons projecting to pelvic viscera (L1, L2, L6, S1) of adult female Sprague-Dawley rats and performed both in vitro and in vivo manipulations to compare the effects of short- and long-term changes in estrogen levels on MAPK expression and activation. We have also investigated if prolonged estrogen deprivation influences the effects of lower urinary tract inflammation on MAPK signalling. RESULTS: In studies of isolated DRG neurons in short-term (overnight) culture, we found that estradiol and estrogen receptor (ER) agonists rapidly stimulated ER-dependent p38 phosphorylation relative to total p38. Examination of DRGs following chronic estrogen deprivation in vivo (ovariectomy) showed a parallel increase in total and phosphorylated p38 (relative to beta-tubulin). We also observed an increase in ERK1 phosphorylation (relative to total ERK1), but no change in ERK1 expression (relative to beta-tubulin). We observed no change in ERK2 expression or phosphorylation. Although ovariectomy increased the level of phosphorylated ERK1 (vs. total ERK1), cyclophosphamide-induced lower urinary tract inflammation did not cause a net increase of either ERK1 or ERK2, or their phosphorylation. Inflammation did, however, cause an increase in p38 protein levels, relative to beta-tubulin. Prior ovariectomy did not alter the response to inflammation. CONCLUSIONS: These results provide new insights into the complex effects of estrogens on bladder nociceptor signalling. The diversity of estrogen actions in these ganglia raises the possibility of developing new ways to modulate their function in pelvic hyperactivity or pain states

Electroproduction of Eta Mesons in the S11(1535) Resonance Region at High Momentum Transfer

The differential cross-section for the process p(e,e'p)eta has been measured at Q2 ~ 5.7 and 7.0 (GeV/c)2 for centre-of-mass energies from threshold to 1.8 GeV, encompassing the S11(1535) resonance, which dominates the channel. This is the highest momentum transfer measurement of this exclusive process to date. The helicity-conserving transition amplitude A_1/2, for the production of the S11(1535) resonance, is extracted from the data. Within the limited Q2 now measured, this quantity appears to begin scaling as 1/Q3 - a predicted, but not definitive, signal of the dominance of perturbative QCD, at Q2 ~ 5 (GeV/c)2.Comment: LaTeX, 30 pages, 29 figures, uses longtable.sty, slashbox.sty, ifthen.sty; (v2) corrected figure inclusions; (v3) changes in filenames for prc and added Report-no; (v4) correction based on comments from referee {small changes to abstract and conclusion, inserted figure 9, other small changes to the text} (v5) very minor additions to improve clarit