The Effect of Arterial Curvature on Blood Flow in Arterio-Venous Fistulae: Realistic Geometries and Pulsatile Flow.

Arterio-Venous Fistulae (AVF) are regarded as the "gold standard" method of vascular access for patients with End-Stage Renal Disease (ESRD) who require haemodialysis. However, up to 60% of AVF do not mature, and hence fail, as a result of Intimal Hyperplasia (IH). Unphysiological flow and oxygen transport patterns, associated with the unnatural and often complex geometries of AVF, are believed to be implicated in the development of IH. Previous studies have investigated the effect of arterial curvature on blood flow in AVF using idealized planar AVF configurations and non-pulsatile inflow conditions. The present study takes an important step forwards by extending this work to more realistic non-planar brachiocephalic AVF configurations with pulsatile inflow conditions. Results show that forming an AVF by connecting a vein onto the outer curvature of an arterial bend does not, necessarily, suppress unsteady flow in the artery. This finding is converse to results from a previous more idealized study. However, results also show that forming an AVF by connecting a vein onto the inner curvature of an arterial bend can suppress exposure to regions of low wall shear stress and hypoxia in the artery. This finding is in agreement with results from a previous more idealized study. Finally, results show that forming an AVF by connecting a vein onto the inner curvature of an arterial bend can significantly reduce exposure to high WSS in the vein. The results are important, as they demonstrate that in realistic scenarios arterial curvature can be leveraged to reduce exposure to excessively low/high levels of WSS and regions of hypoxia in AVF. This may in turn reduce rates of IH and hence AVF failure.

The effect of in-plane arterial curvature on blood flow and oxygen transport in arterio-venous fistulae.

Arterio-Venous Fistulae (AVF) are the preferred method of vascular access for patients with end stage renal disease who need hemodialysis. In this study, simulations of blood flow and oxygen transport were undertaken in various idealized AVF configurations. The objective of the study was to understand how arterial curvature affects blood flow and oxygen transport patterns within AVF, with a focus on how curvature alters metrics known to correlate with vascular pathology such as Intimal Hyperplasia (IH). If one subscribes to the hypothesis that unsteady flow causes IH within AVF, then the results suggest that in order to avoid IH, AVF should be formed via a vein graft onto the outer-curvature of a curved artery. However, if one subscribes to the hypothesis that low wall shear stress and/or low lumen-to-wall oxygen flux (leading to wall hypoxia) cause IH within AVF, then the results suggest that in order to avoid IH, AVF should be formed via a vein graft onto a straight artery, or the inner-curvature of a curved artery. We note that the recommendations are incompatible-highlighting the importance of ascertaining the exact mechanisms underlying development of IH in AVF. Nonetheless, the results clearly illustrate the important role played by arterial curvature in determining AVF hemodynamics, which to our knowledge has been overlooked in all previous studies.

Contrast-enhanced ultrasonography in the diagnosis of upper urinary tract urothelial cell carcinoma: a preliminary study.

PURPOSE: The main objective was to assess the effectiveness of contrast-enhanced ultrasonography (CEUS) in the diagnosis of upper urinary tract malignancies by comparing with multidetector computed tomographic urography (MDCTU) and magnetic resonance urography (MRU). Secondary objectives were to compare the tumor size measured with CEUS, MDCTU and MRU and to assess the usefulness of CEUS in distinguishing high-grade tumors from low-grade ones. MATERIALS AND METHODS: In connection with this prospective study carried out from January 2009 to September 2011, 18 patients underwent MDCTU or MRU, grayscale ultrasonography (US), color Doppler ultrasonography and CEUS followed by surgery and histological examination of the specimen. Quantitative analysis was performed using perfusion software. Time intensity curves were extracted and the following parameters were considered: wash-in time, time-to-peak, maximum signal intensity and wash-out time. RESULTS: Grayscale US identified 15/18 lesions; color Doppler showed no flow signal in 8 lesions, low color signal in 9 lesions and an intense color signal in 1 lesion; CEUS identified 17/18 lesions with the undetected lesion being the smallest one (1.2 cm) located in the upper pelvicalyceal system. Semi-quantitative analysis produced different data for high-grade and low-grade urothelial cell carcinoma (UCC). All detected upper urinary tract masses were UCCs. MRU, MDCTU and grayscale US overestimated the tumor size, while CEUS was the most accurate. CONCLUSION: CEUS is useful for evaluating upper urinary tract masses as this method permits differentiation between high-grade and low-grade tumors as well as distinction of the tumor from the adjacent structures and accurate mass measurements.

A prospective randomized study to compare pelvic floor rehabilitation and dapoxetine for treatment of lifelong premature ejaculation.

Premature ejaculation (PE) is the most common male sexual disorder. We compared pelvic floor muscle rehabilitation to on-demand treatment with the selective serotonin reuptake inhibitor dapoxetine in 40 men with lifelong PE (baseline intra-vaginal ejaculatory latency time (IELT) ≤1 min). Subjects were randomized into the following two treatment groups: (1) PFM rehabilitation or (2) 30 or 60 mg of on-demand dapoxetine. Total treatment time for both groups was 12 weeks, at the end of which, IELT mean values were calculated to compare the effectiveness of the two different therapeutic approaches. At the end of treatment, 11 of the 19 patients (57%) treated with rehabilitation were able to control the ejaculation reflex, with a mean IELT of 126.6 sec (range: 123.6-152.4 sec). In the dapoxetine group, after 12 weeks of therapy, 5 of 8 (62.5%) patients in the 30 mg subgroup and five of seven (72%) in the 60 mg subgroup had an IELT >180 sec (mean: 178.2 and 202.8 sec, respectively). The results obtained in the group treated with pelvic floor rehabilitation are promising, and this treatment represents an important cost reduction if compared to dapoxetine on-demand treatment. The present study confirms the data that are previously available in the literature on the efficacy and safety of the new inhibitor of serotonin reuptake, dapoxetine, as well as proposes and evaluates a new type of physical treatment that may be a viable therapeutic option for treatment of PE.

CEUS in the differentiation between low and high-grade bladder carcinoma.

INTRODUCTION: Bladder cancer ranks 4th overall in the number of newly diagnosed cancers and 10th in causes of cancer deaths. More than 90% of all cases of bladder cancer are transitional cell carcinoma (TCC). The goal of this study is to confirm the usefulness of low mechanical index contrast-enhanced ultrasonography (CEUS), also in association with time-intensity curves, in the differentiation between high- and low-grade bladder malignant lesions. MATERIALS AND METHODS: From February 2006 to February 2012 we recruited 144 patients. All patients underwent grayscale ultrasonography (US), color-Doppler ultrasonography (CDUS) and contrast-enhanced ultrasonography (CEUS). Subsequently all patients underwent cystoscopy and TURB. RESULTS: HISTOLOGICAL DIAGNOSES WERE: 88 high-grade carcinomas (61.1%), and 56 low-grade carcinomas (38.9%). Sensitivity and specificity of CDUS were 87.5% (126/144) and 60%, respectively. Sensitivity and specificity of CEUS were 90.9% and 85.7%, respectively. Sensitivity and specificity of TIC were 91.6% (132/144) and 85.7%, respectively. DISCUSSION AND CONCLUSIONS: CEUS is a reliable noninvasive method for differentiating low- and high-grade bladder carcinomas since it provides typical enhancement patterns as well as specific contrast-sonographic perfusion curves.

Role of low-mechanical index CEUS in the differentiation between low and high grade bladder carcinoma: a pilot study.

PURPOSE: To assess the efficacy of low-mechanical index contrast-enhanced ultrasonography (CEUS) in the differentiation of a series of histologically proven bladder lesions identified via conventional cystoscopy and biopsied. MATERIALS AND METHODS: 36 patients (mean age: 62 years; range 45 - 72 years) with bladder lesions previously detected by color power Doppler ultrasonography (CDUS) were prospectively examined with low-mechanical index contrast-enhanced US after bolus administration of 2.4 ml of Sonovue (Bracco, Milan, Italy). All lesions were evaluated in real-time continuous scanning for 2 minutes and the videos were registered. Two ultrasound (US) experts evaluated the videos by consensus and assigned a score to the enhancement pattern. Subsequently, a specific sonographic quantification software (Qontrast, Bracco, Milan, Italy) based on pixel by pixel signal intensity over time was used to obtain contrast-enhanced sonographic perfusion maps for each lesion. Time-intensity curves (TICs) of each lesion were then extracted from the region of interest positioned within the lesion and in the closest bladder wall. The sensitivity and specificity of CDUS and CEUS were compared using McNemar's test. All patients subsequently underwent conventional cystoscopy with biopsy or transurethral resection. RESULTS: 22 high-grade and 14 low-grade transitional cell carcinomas (TCCs) were histologically diagnosed (mean diameter 2.1 cm; range: 1 - 4.5 cm). The sensitivity and specificity of CDUS were 86.4% (19 / 22; 95% CI = 66.7 - 95.3%) and 42.9% (6 / 14; 95% CI = 21.4 - 67.4%), respectively. The sensitivity and specificity of CEUS were 90.9% (20 / 22; 95% CI = 72.2 - 97.5%) and 85.7% (12 / 14; 95% CI = 60.1 - 95.9%), respectively. The sensitivity and specificity of CEUS using TICs were 95.4% (21 / 22; 95% CI = 78.2 - 99.2%) and 85.7% (12 / 14; 95% CI = 60.1 - 95.9%), respectively. There was no significant difference between the sensitivity of CDUS versus CEUS, CDUS versus TIC, and CEUS versus TIC (p > 0.05; McNemar's test). The specificity of CEUS and TIC was significantly higher than that of CDUS (p < 0.05; McNemar test). CONCLUSION: CEUS is a reliable noninvasive method for differentiating low- and high-grade bladder carcinomas since it provides typical enhancement patterns as well as specific contrast-sonographic perfusion curves. However, further studies involving larger patient populations is mandatory to confirm these promising results.

GolP: an atomistic force-field to describe the interaction of proteins with Au(111) surfaces in water.

A classical atomistic force field to describe the interaction of proteins with gold (111) surfaces in explicit water has been devised. The force field is specifically designed to be easily usable in most common bio-oriented molecular dynamics codes, such as GROMACS and NAMD. Its parametrization is based on quantum mechanical (density functional theory [DFT] and second order Möller-Plesset perturbation theory [MP2]) calculations and experimental data on the adsorption of small molecules on gold. In particular, a systematic DFT survey of the interaction between Au(111) and the natural amino acid side chains has been performed to single out chemisorption effects. Van der Waals parameters have been instead fitted to experimental desorption energy data of linear alkanes and were also studied via MP2 calculations. Finally, gold polarization (image charge effects) is taken into account by a recently proposed procedure (Iori, F.; Corni, S. J Comp Chem 2008, 29, 1656). Preliminary validation results of GolP on an independent test set of small molecules show the good performances of the force field.

Including image charge effects in the molecular dynamics simulations of molecules on metal surfaces.

Combinatorial bio-techniques have demonstrated that proteins can be good and even selective binders for several inorganic surfaces, including metals. However, the understanding of the basic physical mechanisms that govern such interactions did not keep up with the success in these experiments. The comprehension of such mechanisms would greatly benefit from the computational investigation of the problem. Because of the complexity of the system, classical molecular dynamics simulations based on an atomistic description appear to be the best compromise between reliability and feasibility. For proteins interacting with metal surfaces, however, methodological improvements with respect to standard Molecular Dynamics (MD) of proteins are needed, since the polarization of the metal induced by the protein (and the surrounding water) is not generally negligible. In this article, we present a simple approach to introduce metal polarization effects (often termed image effects) in MD simulations by exploiting standard features of bio-oriented MD codes such as the widely used GROMACS and NAMD. Tests to show the reliability of the proposed methods are presented, and the results for a model application showing the importance of image effects are also discussed.

Theoretical quantitative structure-activity relationships of flavone ligands interacting with cytochrome P450 1A1 and 1A2 isozymes.

Theoretical descriptors obtained from quantum mechanical calculations on isolated ligands in different media and molecular dynamics simulations of ligand-enzyme complexes have been used to obtain a quantitative rationalization of the inhibition of CYP1A2 and CYP1A2 by three series of flavonoids. Predictive models obtained through one-descriptor QSAR studies and mechanistic explanations have been obtained for recognition and selectivity.

Clinical and pressure-flow changes after long-term treatment with alfuzosin SR.

OBJECTIVES: The aim of our study was to evaluate the symptomatic and urodynamic changes after 1-5 years of treatment with alfuzosin in patients with benign prostatic hyperplasia. METHODS: Out of 255 patients with lower urinary tract symptoms observed from 1992 to 1997, who completed the International Prostatic Symptom Score (I-PSS) and underwent full urodynamic investigation, 161 were found to be obstructed (Schäfer classes 2-6). One hundred and two subsequently consented to a second clinical and urodynamic evaluation. Out of these, 46 underwent surgical treatment, 20 were elected for watchful waiting (WW) and 36 received a medical treatment. Twenty out of these, with a mean age of 65 years, a mean prostatic volume of 44 ml (20-70) a median Schäfer's obstruction class of 3 (range 2-5) were treated with slow release alfuzosin 5 mg twice a day. We re-evaluated these 20 patients with a second I-PSS and pressure-flow study after 1-5 years (mean: 2 years) of treatment. The patients in the WW group with comparable baseline characteristics were considered as controls. The Wilcoxon matched-pairs signed rank test and the Kruskal-Wallis test were used for statistical analysis. RESULTS: In the group treated with alfuzosin, no differences were noted for I-PSS (14.9 +/- 6,8; 13.3 +/- 5); maximum flow (124 +/- 6; 14 +/- 6) and projected isometric pressure (105 +/- 36; 105 +/- 26). Statistically significant differences were noted for residual urine (103 +/- 100; 33 +/- 38, p = 0.02); detrusor pressure at maximum flow (64.4 +/- 23; 53 +/- 12, p = 0.04), minimum urethral opening pressure (36.5 +/- 9; 31 +/- 9, p = 0.02), Schäfer class (2.7 +/- 0.7; 2 +/- 0.8, p = 0.04); urethral resistance algorithm (34.7 +/- 11; 27 +/- 7, p = 0.02). Statistically significant differences between baseline and follow-up were noted for none of the clinical and urodynamic parameters in the WW group. CONCLUSIONS: Patients with bladder outlet obstruction seem to remain clinically stable and to improve urodynamically when treated with alfuzosin for a long period of time.

Long-term maintenance bacille Calmette-Guérin therapy in high-grade superficial bladder cancer.

OBJECTIVES: To assess the long-term results of intravesical bacille Calmette-Guérin (BCG) induction plus long-term maintenance treatment for high-grade superficial bladder cancer. METHODS: Between 1994 and 2000, 41 patients who presented to our clinic with superficial urothelial carcinoma of the bladder (T1G3, T1G3 plus carcinoma in situ, or recurrent TaG2-3) were treated by transurethral resection of all visible tumor and an induction cycle of BCG plus a long-term maintenance BCG course consisting of 11 monthly instillations followed by 4 quarterly instillations and then by 6 six-monthly instillations. The median follow-up was 40 months. RESULTS: Thirty patients remained tumor free throughout the follow-up period. Ten patients had a recurrence of superficial tumor, 9 patients during the monthly instillation course and 1 patient during the quarterly instillation course. One patient presented with progression. CONCLUSIONS: Adjuvant immunotherapy with BCG after complete transurethral resection of bladder tumor represents a highly effective primary treatment for high-grade superficial bladder cancer. Our maintenance course of BCG seemed to improve the worldwide accepted effectiveness of the BCG induction course without any important side effects.

Technical modification of Mainz pouch II urinary diversion: preliminary experience.

Use of the Mainz pouch II technique leads to a reduction in the complications frequently observed because of the high pressure associated with ureterosigmoidostomy. A technical variation of the procedure is described in which reimplantation of the left ureter in the rectosigmoid is carried out to avoid the risk of stretching and kinking and the need to fix the pouch to the sacrum. Furthermore, this procedure is easier to perform and less time consuming.

Superficial bladder tumors in patients under 40 years of age: clinical, prognostic and cytogenetic aspects.

Bladder carcinoma with transitional cells is the most frequent neoplasia in the urinary system, but it is quite rare in patients under 40 years of age (0.4-2%). An analysis of 21 patients under 40 and a review of other reports show that tumors in patients under 20 years old have little tendency to recur and to progress, while tumors in patients aged between 21 and 40 have a behavior pattern similar to older age groups regarding recurrence and disease progression. Preliminary results of a study using fluorescent in situ hybridization with probes for the centromere of chromosomes 7 and 17 showed a high incidence of aneusomy with regard to these chromosomes and a genetic difference between superficial tumors in the young and in adults. Using probes from chromosomes already described in bladder carcinogenesis, we obtained higher sensitivity and specificity in detecting aneuploid events.

DNA aberrations in urinary bladder cancer detected by flow cytometry and FISH: prognostic implications.

We evaluated the genetic changes in bladder cancer biopsy by fluorescence in situ hybridization (FISH) and related them to stage and grade of the tumor, ploidy (FCM) and clinical outcome, to determine a simple method to identify tumors with a poorer prognosis. Using FISH the numerical aberrations of chromosomes 1, 7, 9, 17 in tumor's imprints of 70 patients with transitional cell cancer (TCC) were determined. First of all, the data demonstrated that the sensitivity of FISH in detecting quantitative DNA aberrations exceeds FCM's sensitivity. The frequency of chromosome 1 and 9 aberrations did not show significant differences in diploid and aneuploid tumors in different stage and grade. On the contrary, the chromosome 7 and 17 aneusomy showed greater differences between pT1 and pT2-3 tumors (p<0.032 and p<0.0006, respectively) than between stage pTa and pT1. In our investigation, an increasing number of aberrations was observed in all chromosomes examined in tumors of patients who afterwards underwent cystectomy and/or had recurrent tumors. These results suggest that chromosome 7 and 17 aneusomy could be predictive of adverse outcome in a subgroup of patients with superficial tumors at presentation.

Role of 5-aminolevulinic acid in the diagnosis and treatment of superficial bladder cancer: improvement in diagnostic sensitivity.

OBJECTIVES: To use 5-aminolevulinic acid (5-ALA) in diagnostic cystoscopy and during transurethral resection of the bladder (TURB) to treat transitional cell carcinoma. The efficacy of this new technique was compared with standard cystoscopy. METHODS: The 5-ALA, instilled in the bladder 2 hours before cystoscopy, makes the pathologic tissue fluorescent when illuminated with blue light (375 to 400 nm). This allows a better recognition of the neoplastic forms for both diagnostic and therapeutic purposes during TURB. This method has been used since May 1997 on 49 patients in whom bladder tumor was diagnosed either immediately or during postchemotherapy follow-up. RESULTS: One hundred seventy-nine biopsies were taken of fluorescent and nonfluorescent areas (3.5 per patient) to check the effectiveness of the new method compared with standard cystoscopy. A good correlation was found between 5-ALA cystoscopy and the histopathologic diagnosis, with a good sensitivity (87%). The 5-ALA cystoscopy allowed the diagnosis of a tumor in 24 patients with negative standard cystoscopic findings. Furthermore, 5-ALA cystoscopy detected 7 cases of carcinoma in situ. Neither local nor systemic (because of endovesical instillation) side effects were noted. CONCLUSIONS: We believe that 5-ALA could be routinely used in the diagnosis of superficial bladder tumors, as it was shown to improve the diagnostic sensitivity for carcinoma in situ and to reduce the risk of recurrence related to missed cancerous lesions or incomplete TURB.

Percutaneous sclerotization of simple renal cysts with 95% ethanol followed by 24-48 h drainage with nephrostomy tube.

AIM OF THE STUDY: We propose some technique devices for treating simple renal cysts with percutaneous puncture (PCN) to reduce recurrences. MATERIALS AND METHODS: Between January 1995 and December 1998, a series of 42 patients, 13 females and 29 males, ranging in age between 49 and 73 were treated for symptomatic kidney cystic disease. The cysts varied between 7.4 and 13.6 cm in diameter and from 100 to 570 cm(3) in volume. This technique consists of echo-guided emptying of the cyst, and slowly inserting a quantity of pure 95% ethanol, equivalent to about 1/3 of the cyst volume, into the cavity. This acts as a sclerosant agent on the cyst walls. The protocol of this technique also includes positioning a curled drainage catheter, for 24-48 h, in suction, to ensure a correct collapse of the cyst walls and to avoid cyst recurrence. RESULTS: Of the 42 patients treated, only 4 did not complete the protocol. In 3 cases, the patients were not able to stand the procedure because of intense pain during cyst filling with alcohol. The other patient had intracystic hemorrhage. The results were evaluated by ultrasonography at 7 days post-operatively and then at 1, 3, 6, 9 and 12 months later. There was a further follow-up lasting from 12 to 36 months. Of 38 patients treated, 29 (76%) did not have any recurrence. 8 patients (21%) developed a small liquid layer of 3-4 cm, which did not enlarge in subsequent check-ups. We observed a recurrence, which spontaneously reduced in volume, only in 1 patient. CONCLUSIONS: This procedure was simple to apply in an out-patient setting and used low-cost materials which are easily obtained. Moreover, the results appear to confirm the validity of this technique.

Interphase cytogenetics of bladder cancer progression: relationship between aneusomy, DNA ploidy pattern, histopathology, and clinical outcome.

In the present study, different stages of transitional cell carcinoma of the bladder were analyzed by fluorescent in situ hybridization, using probes specific for pericentromeric classical satellite. Seventy primary tumors were evaluated for chromosomes 1, 7, 9, 17, and ploidy by flow cytometry. The results were correlated, after a mean follow-up period, with ploidy, histopathological characteristics, recurrence, and progression. Firstly, our data demonstrated that the sensitivity of fluorescence in situ hybridization in detecting quantitative DNA aberrations exceeds that of flow cytometry. The frequency of chromosome 1 and 9 aberrations was not significantly different in diploid and aneuploid tumors of different stage and grade. In contrast, the chromosome 7 and 17 aneusomy showed greater differences between pT1 and pT2-3 tumors (P<0.032 and P<0.0006, respectively) than between stage pTa and pT1. An increasing number of aberrations was observed in all chromosomes examined from tumors of patients that afterwards underwent cystectomy and/or had recurrent tumors. This study indicates that fluorescence in situ hybridization could be used to detect genetic changes relevant to patient outcome. These genetic changes could identify patients at high risk of recurrence and possible progression.

Challenging the role of cremasteric reflux in the pathogenesis of varicocele using a new venographic approach.

PURPOSE: Cremasteric or extrafunicular reflux is considered by many a major cause of primary and recurrent varicocele. Therefore, surgical techniques that allow ligation of the intrafunicular and extrafunicular veins are often performed. We evaluated the incidence of cremasteric reflux in patients with primary or recurrent varicocele with a new and simple venographic technique. MATERIALS AND METHODS: A series of 73 patients with primary (54) or recurrent (19) varicocele underwent venography of the left iliac vein while standing and performing Valsalva's maneuver to reveal the possible presence of reflux in cremasteric or other extrafunicular veins. In patients with recurrent varicocele antegrade transcrotal spermatic venography was also performed immediately before surgery. RESULTS: None of the patients presented with reflux of contrast material from the left iliac vein to the left pampiniform plexus via the extrafunicular veins. Cremasteric veins, in particular, were always continent at the confluence with the epigastric vein even when grossly dilated at spermatic antegrade venography in recurrent cases. CONCLUSIONS: Cremasteric reflux seems to have a limited role if any in the pathogenesis of primary and even recurrent varicocele. Dilatation of the extrafunicular veins is not necessarily a sign of reflux but may represent only a consequence of venous overflow due to insufficiency of the internal spermatic vein and possibly partial obstruction of the left iliac vein. The rationale of surgical treatments aimed at ligation of the extrafunicular veins should be questioned.