Shock, inflammation and PARP.

The activation of poly(ADP-ribose) polymerase (PARP) is well considered to play an important role in various patho-physiological conditions like inflammation and shock. A vast amount of circumstantial evidence implicates oxygen-derived free radicals (especially, superoxide and hydroxyl radical) and high-energy oxidants (such as peroxynitrite) as mediators of inflammation and shock. ROS (e.g., superoxide, peroxynitrite, hydroxyl radical and hydrogen peroxide) are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. During the last years, numerous experimental studies have clearly demonstrated the beneficial effects of PARP inhibition in cell cultures through rodent models and more recently in pre-clinical large animal models of acute and chronic inflammation. The aim of this review is to describe recent experimental evidence implicating PARP as a pathophysiological modulator of acute and chronic inflammation.     

Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu In vivo model of human multiple myeloma.

Interleukin-6 (IL-6) protects multiple myeloma cells against apoptosis induced by glucocorticoids. Here, we investigated whether inhibition of the IL-6 signaling pathway by the IL-6 receptor superantagonist Sant7 enhances the in vivo antitumor effects of dexamethasone on the IL-6-dependent multiple myeloma cell line INA-6. For this purpose, we used a novel murine model of human multiple myeloma in which IL-6-dependent INA-6 multiple myeloma cells were directly injected into human bone marrow implants in severe combined immunodeficient (SCID) mice (SCID-hu). The effect of in vivo drug treatments on multiple myeloma cell growth was monitored by serial determinations of serum levels of soluble IL-6 receptor (shuIL-6R), which is released by INA-6 cells and served as a marker of tumor growth. In SCID-hu mice engrafted with INA-6 cells, treatment with either Sant7 or dexamethasone alone did not induce significant reduction in serum shuIL-6R levels. In contrast, the combination of Sant7 with dexamethasone resulted in a synergistic reduction in serum shuIL-6R levels after 6 consecutive days of treatment. Gene expression profiling of INA-6 cells showed down-regulation of proliferation/maintenance and cell cycle control genes, as well as up-regulation of apoptotic genes in multiple myeloma cells triggered by Sant7 and dexamethasone combination. In vitro colony assays showed inhibition of myeloid and erythroid colonies from normal human CD34(+) progenitors in response to dexamethasone, whereas Sant7 neither inhibited colony growth nor potentiated the inhibitory effect of dexamethasone. Taken together, these results indicate that inhibition of IL-6 signaling by Sant7 significantly potentiates the therapeutic action of dexamethasone against multiple myeloma cells, providing the preclinical rationale for clinical trials of Sant7 in combination with dexamethasone to improve patient outcome in multiple myeloma.     

Role of Intraoperative Ultrasound to Extend the Application of Minimally Invasive Surgery for Treatment of Recurrent Gynecologic Cancer

Study Objective

To describe the potential role of intraoperative ultrasound (IOUS) in the detection and localization of recurrent disease in gynecologic cancer patients during minimally invasive surgery (MIS).

Influence of Cross-Section Shape and FRP Reinforcement Layout on Shear Capacity of Strengthened RC Beams

The evaluation of the shear capacity of an FRP-strengthened reinforced-concrete beam is challenging due to the complex interaction between different contributions provided by the concrete, steel stirrup and FRP reinforcement. The shape of the beam and the FRP inclination can have paramount importance that is not often recognized by the models that are suggested by codes. The interaction among different resisting mechanisms has a significant effect on the shear capacity of beams, since it can cause a reduction in the efficiency of some resisting mechanisms. A comparative study of the performance in the shear resistance assessment provided by three models with six different effectiveness factors (R) is performed, considering different cross-section shapes, FRP wrapping schemes, inclination and anchorage systems. The results revealed that the cross-section shape, the FRP inclination and the efficiency of the FRP anchorages have a significant effect on the shear strength of beams. The analysis results show that the three models are able to provide an accurate average estimation of shear strength (but with a coefficient of variation up to 0.35) when FRP reinforcement orthogonal to the beam axis is considered, while a significant underestimation (up to 19%) affected the results for inclined FRP reinforcement. Moreover, all the models underestimated the resistance of beams with a T section.     

Prognostic role of the recepteur d'origine nantais (RON) expression in ovarian cancer patients

ObjectiveThe aim of the study was to investigate the potential clinical relevance of immunohistochemically assessed RON expression in a large, single institution series of primary untreated advanced ovarian cancer patients.MethodsImmunohistochemical analysis was performed by using the polyclonal rabbit anti-RON-β antibody (C-20, clone sc-322, Santa Cruz, California). Results were expressed as the total proportion of immunostained tumor cells (RON positivity), or the percentage of cells showing strong staining of RON expression (H-RON positivity).ResultsIn the overall series RON positive immunoreaction was observed in 103/141 cases, while H-Ron positivity was detected in 577141 (40.4%) cases. No association between RON and H-RON expression with response to first-line treatment was documented. During the follow up period, progression and death of disease were observed in 111 (78.7%) and 76 (53.9%) cases, respectively. Cases with strong H-RON expression has a shorter overall survival (median = 35 months) than cases with low RON levels (median = 59 months) (X² = ? 2.1, p value = 0.032). In multivariate analysis, only platinum resistance, and extent of residual tumor retained an independent negative prognostic role for OS, with the percentages of H-RON positively immunostained cells showing a borderline statistical significance (p value = 0.0643). The unfavourable role of elevated percentages of H-RON expression was maintained only in the subgroup of platinum resistant recurrent ovarian cancer patients (X² = 3.89, p value = 0.048) compared to the platinum sensitive ones (X² = 1.98, p value = 0.16).ConclusionsThe assessment of RON expression deserves further attention as a parameter helpful to identify poor prognosis ovarian cancer patients potentially candidates to investigational agents.     

Efficacy of tolterodine in women with detrusor overactivity and anterior vaginal wall prolapse: is it the same?

The aim of this study was to assess the efficacy of tolterodine in women with overactive bladder (OAB) and concomitant anterior vaginal prolapse. In this prospective study, 235 consecutive women with OAB symptoms and urodynamic diagnosis of detrusor overactivity who either had no prolapse or had pure anterior vaginal prolapse were included: 184 women (group 1) had no prolapse and 51 women (group 2) had anterior prolapse greater than and equal to stage IIa. Tolterodine 4 mg slow release once a day was prescribed. After 12 weeks, women were reassessed using a 3-point scale (no change, improvement and cured). A total of 158 (85.9%) women in group 1 and 31 (60.8%) women in group 2 reported improvement or cure ( P = 0.0002). Women with OAB and significant anterior vaginal prolapse should be informed of a reduced efficacy of antimuscarinics in treating their urinary symptoms.     

Direct imaging of the pelvic floor muscles using two-dimensional ultrasound: a comparison of women with urogenital prolapse versus controls

Objective  To evaluate the anatomy of the levator ani muscle in women with urogenital prolapse versus matched controls without prolapse using real-time two-dimensional (2-D) ultrasound.
Design  Prospective observational study.
Setting  Tertiary referral urogynaecology unit.
Population  Forty-three women with pelvic organ prolapse (POP) and 24 women (controls) attending a gynaecology clinic without prolapse.
Methods  All participants completed a standardised symptom questionnaire.
Main outcome measures  The morphology of the vagina and paravaginal tissue was recorded at different levels. The thickness of the levator ani and the hiatal area were measured at rest. Reproducibility of the method was assessed by repeated measurements to assess intra-observer variability and inter-observer variability.
Results  This method showed good intra-observer and inter-observer reproducibility and reliability. In controls, the pubococcygeus muscle showed more regular echogenicity with no evidence of trauma, whereas in women with prolapse the muscle had mixed echogenicity. ( P = 0.002). The mean thickness of the pubococcygeus did not differ between groups. The levator hiatal area was significantly larger in women with pelvic floor prolapse versus controls (17.8 cm² versus 13.5 cm², P < 0.001). This increase in hiatal area positively and significantly correlated with prolapse severity ( P < 0.001).
Conclusions  Morphology and hiatal area can be reliably imaged using 2-D ultrasound. Prolapse was related to changes in pelvic floor morphology and increased levator hiatal area. The use of 2-D ultrasound provides an important insight into the pathophysiology of prolapse.