Laparoscopic partial nephrectomy without ischemia.

The warm ischaemia time appears the most prominent modifiable risk factor for the development of renal impairment following laparoscopic partial nephrectomy. Historically, hilar clamping was the 'gold standard' technique, but now we are pushing our techniques to achieve the ultimate: 'zero ischaemia' approach. Results from 'early unclamping' techniques reinforced the importance of 'every minute counts' (28). Subsequent techniques in non-hilar clamping demonstrated that this approach was indeed feasible, but at the expense of higher bleeding, positive margins, and collecting system breach rates. With the advancement of technology, through the use of robotic assistance, improved haemostatic agents, as well as various imaging modalities (laparoscopic ultrasound, CT angiography), the surgeon can now potentially perform Nephron Sparing Surgery (NSS) in a more precise manner. Specifically, with the use of superselective clamping of the feeding vessel(s) to the tumour, the remaining healthy renal parenchyma should be less compromised, with associated low bleeding rates. NSS in the form of laparoscopic partial nephrectomy is clearly evolving, with increasing demands on the surgeon, requiring more expertise and experience, with the added assistance from other specialties (anaesthetists, radiologists etc). To be able to regularly perform Laparoscopic Partial Nephrectomy (LPN) without ischaemia safely, the laparoscopist must develop his / her experience in a stepwise fashion, perhaps commencing with artery-only clamping, leading on to early declamping, and then 'on demand' clamping. When moving on to LPN without ischaemia, patient selection is paramount. The ideal patient would harbour a single small, polar, exophytic renal mass with a normal functioning contralateral kidney. Although currently the techniques and outcomes laparoscopic partial nephrectomy without ischaemia published are limited to a few authors, with no current long term results to prove its full worth and reproducibility, early results are very encouraging. The pursuit of acquiring 'zero ischaemia' is clearly worthwhile, but needs to be measured against the potential risks of increased morbidity and positive margin rates.

8-isoprostane F2α up-regulates the expression of type 5 phosphodiesterase in cavernosal vascular smooth muscle cells: inhibition with sildenafil, iloprost, nitric oxide and picotamide.

OBJECTIVES: To explore the possible role of of 8-isoprostane F(2α) (8-IPF(2α) ) in the aetiology of erectile dysfunction (ED), as the over-production of superoxide (O(2)(-)) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase results in the formation of 8-IPF(2α) in vascular tissue, which has similar properties to thromboxane A(2) (TXA(2) ). TXA(2) is vasoconstrictor and up-regulates the expression of NADPH oxidase and phosphodiesterase type 5 (PDE5). MATERIALS AND METHODS: Cavernosal vascular smooth muscle cells (CVSMCs) were incubated with 8-IPF(2α) or the TXA(2) analogue, U46619, ±sildenafil, iloprost (a stable prostacyclin [PGI(2) ] analogue) or the nitric oxide (NO) donor NONOate for 16 h. The formation of O(2)(-) was then measured, PDE5 expression assessed using Western blotting and PGI(2) and 8-IPF(2α) formation measured using enzyme-linked immunoassays. RESULTS: 8-IPF(2α) promoted the formation of O(2)(-) , an effect inhibited by apocynin (an NADPH oxidase inhibitor) and up-regulated the expression of PDE5. Under identical incubation conditions, 8-IPF(2α) induced an increase in the formation of 8-IPF(2α) but reduced the formation of PGI(2) . All, these effects were reversed by sildenafil, iloprost, NONOate and picotamide. CONCLUSIONS: These data show that O(2) (-) derived from NADPH oxidase influences the relative balance of PGI(2) and 8-IPF(2α) in CVSMCs, which in turn alters the degree of PDE5 expression. This is a novel pathogenic mechanism underlying ED and a novel mechanism of action of sildenafil.

The administration of folic acid improves erectile function and reduces intracavernosal oxidative stress in the diabetic rabbit.

OBJECTIVE: To test the possibility that folic acid (FA) may be a means of treating erectile dysfunction (ED) in diabetes mellitus (DM), by studying the effect of FA administration to DM rabbits on cavernosal function and intrapenile oxidative stress. MATERIALS AND METHODS: To investigate the effect of administering FA to DM rabbits on erectile function and oxidative stress the formation of superoxide (O(2)(-)), 8-isoprostane F(2 alpha) (8-IPF(2 alpha)) and prostacyclin (as 6-keto-PGF(1 alpha)) were assessed, as well as carbachol- and electrical field stimulated (EFS) relaxation and p47(phox) content (active component of NADPH oxidase complex). Non-ketotic DM was induced in New Zealand rabbits with alloxan and FA administered orally daily for 1 month. Rabbits were killed, penises excised and segments prepared. These were mounted in an organ bath and relaxation elicited with carbachol or EFS. O(2)(-) release was measured spectrophotometrically, p47(phox) expression by Western blotting and 8-IPF(2 alpha) and 6-keto-PGF(1 alpha) formation by enzyme-linked immunosorbant assay. Blood was collected for measurement of homocysteine, red blood cell (RBC) folate and glucose. RESULTS: In cavernosal tissue from DM rabbits, carbachol-and EFS-induced relaxation was significantly impaired compared with the untreated controls. O(2)(-) release, p47(phox) expression and 8-IPF(2 alpha) formation were all enhanced and 6-keto-PGF(1 alpha) formation reduced compared with the controls. All these effects were reversed by FA. Plasma total homocysteine was reduced and RBC folate elevated. CONCLUSIONS: The administration of FA may constitute a strategy for reducing ED in patients with DM.

Effect of hydrogen sulphide-donating sildenafil (ACS6) on erectile function and oxidative stress in rabbit isolated corpus cavernosum and in hypertensive rats.

OBJECTIVE To study the effect of the H(2)S-donating derivative of sildenafil (ACS6) compared to sildenafil citrate and sodium hydrosulphide (NaHS) on relaxation, superoxide formation and NADPH oxidase and type 5 phosphodiesterase (PDE5) expression in isolated rabbit cavernosal tissue and smooth muscle cells (CSMCs), and in vivo on indices of oxidative stress induced with buthionine sulphoximine (BSO). MATERIALS AND METHODS Relaxation was studied in an organ bath in response to carbachol and after incubation with interleukin-1beta for 12 h. CSMCs were incubated with tumour-necrosis factor-alpha or the thromboxane A(2) (TXA(2)) analogue, U46619, with or with no sildenafil citrate, ACS6 or NaHS for 16 h. Superoxide formation and the expression of p47(phox) (an active subunit of the NADPH oxidase complex) and PDE5 protein was then assessed using Western blotting. Rats were also treated with BSO (with or with no sildenafil citrate or ACS6) for 7 days; cavernosal cGMP, cAMP, glutathionine and plasma TXA(2) and 8-isoprostane F(2alpha) was measured by enzyme-linked immunosorbent assay. RESULTS ACS6 and sildenafil citrate relaxed cavernosal smooth muscle equipotently; NaHS alone had little effect at up to 100 microm. The formation of superoxide and expression of p47(phox) and PDE5 was reduced by ACS6, sildenafil citrate and NaHS (order of potency: ACS6 > sildenafil citrate > NaHS). The effects of ACS6 were blocked by inhibitors of protein kinase A (PKA) and PKG. In rats treated with BSO, both ASC6 and sildenafil citrate reduced the increased plasma levels of TXA(2) and 8-isoprostane F(2alpha) but increased cGMP, cAMP and glutathionine levels in corpus cavernosum. CONCLUSIONS By virtue of a dual action on PKA and PKG activation, ACS6 not only promotes erection, acutely, but might also have a long-term beneficial effect through inhibition of oxidative stress and downregulation of PDE5.

Homocysteine and copper interact to promote type 5 phosphodiesterase expression in rabbit cavernosal smooth muscle cells.

AIM: To study the effects of homocysteine and copper on type 5 phosphodiesterase (PDE5) expression in cavernosal vascular smooth muscle cells (CVSMCs) and to investigate superoxide (O(2)(.-)) derived from nicotinamide adenine dinucleotide phosphate oxidase as homocysteine and copper generate O(2)(.-), and O(2)(.-) upregulates PDE5 expression. METHODS: CVSMCs derived from rabbit penis were incubated with homocysteine or copper chloride with or without superoxide dismutase (SOD), catalase, sildenafil citrate, or apocynin (nicotinamide adenine dinucleotide phosphate inhibitor) for 16 h. The expression of PDE5 and of glyceraldehyde-3-phosphate dehydrogenase (internal standard) was assessed using Western blot analysis. In parallel, O(2)(.-) was measured spectrophotometrically. RESULTS: CuCl(2) alone (up to 10 micromol/L) and homocysteine alone (up to 100 micromol/L) had no effect on O(2)(.-) formation in CVSMCs compared to controls. In combination, however, homocysteine and CuCl(2) markedly increased O(2)(.-) formation, an effect blocked by SOD, catalase, apocynin, and sildenafil (1 micromol/L) when co-incubated over the same time course. PDE5 expression was also significantly increased in CVSMCs incubated with homocysteine and CuCl(2), compared to controls. This effect was also negated by 16-h co-incubation with SOD, catalase, apocynin and sildenafil. CONCLUSION: This represents a novel pathogenic mechanism underlying ED, and indicates that the therapeutic actions of prolonged sildenafil use are mediated in part through inhibition of this pathway.

Gout and subsequent erectile dysfunction: a population-based cohort study from England.

BACKGROUND: An association has been suggested between gout and erectile dysfunction (ED), however studies quantifying the risk of ED amongst gout patients are lacking. We aimed to precisely determine the population-level absolute and relative rate of ED reporting among men with gout over a decade in England. METHODS: We utilised the UK-based Clinical Practice Research Datalink to identify 9653 men with incident gout age- and practice-matched to 38,218 controls. Absolute and relative rates of incident ED were calculated using Cox regression models. Absolute rates within specific time periods before and after gout diagnosis were compared to control using a Poisson regression model. RESULTS: Overall, the absolute rate of ED post-gout diagnosis was 193 (95% confidence interval (CI): 184-202) per 10,000 person-years. This corresponded to a 31% (hazard ratio (HR): 1.31 95%CI: 1.24-1.40) increased relative risk and 0.6% excess absolute risk compared to those without gout. We did not observe statistically significant differences in the risk of ED among those prescribed ULT within 1 and 3 years after gout diagnosis. Compared to those unexposed, the risk of ED was also high in the year before gout diagnosis (relative rate = 1.63 95%CI 1.27-2.08). Similar findings were also observed for severe ED warranting pharmacological intervention. CONCLUSIONS: We have shown a statistically significant increased risk of ED among men with gout. Our findings will have important implications in planning a multidisciplinary approach to managing patients with gout.

What is the significance of pT0 at cystectomy?

The current treatment for muscle invasive bladder cancer is radical cystectomy. However, this approach leads to significant changes in the patient's quality of life, as well as potential treatment failure. And so, with the introduction of alternative and neoadjuvant therapies available, the presence of pT0 tumour at cystectomy confers a number of issues. The variability in numbers of pT0 tumours at cystectomy highlights the importance of adequate clinical staging, as well as the increasing successful use of neoadjuvant chemotherapy. Although current literature is limited, patients with prior clinical stage of muscle-invasive but node-negative disease are likely to demonstrate the most improvement in survivability if they subsequently develop pT0 at cystectomy. This review also highlights the importance of response to chemotherapy as an indicator of subsequent prognosis. With increasing numbers of pT0 tumours seen at radical cystectomy, it is suggested that more conservative measures, such as re-staging following neoadjuvant chemotherapy and even 'selective bladder preservation' treatment, may be the future for the management of muscle invasive bladder cancer.

Tuberculosis, a rare cause of haematuria.

Tuberculosis of the bladder is a rare pathology in the western world and often not considered as a differential when seeing patients with common urological presentations. This case illustrates a 69-year-old woman in rural England who presented with visible haematuria and was subsequently diagnosed with tuberculosis of the bladder. The case aims to highlight the significance of early diagnosis and treatment, which in turn may help prevent disease progression and organ dysfunction.

Port site hernias following robot-assisted laparoscopic prostatectomy.

Port site herniation is a rare but potentially major complication of laparoscopic surgery, but its importance within the context of robot-assisted laparoscopic prostatectomy (RALP) is less understood. We describe two cases that developed port site hernias following RALP, within a single surgeon case series of over 500 cases. Both patients re-presented with vague abdominal symptoms early following surgery, with a subsequent Computer tomography scan demonstrating small bowel herniation through the abdominal wall defect at the right lateral assistant 12 mm port site. Both required surgical exploration and successful repair. Following review of these cases and the current literature, we have since adapted our surgical approach. We recommend the routine use of a 'nonbladed' trocar for all 12 mm ports, which should also be formally closed incorporating all fascial layers. Early post-operative abdominal signs should alert the surgeon to its presence, and management should include immediate abdominal CT scanning and surgical re-exploration.

Sildenafil inhibits the up-regulation of phosphodiesterase type 5 elicited with nicotine and tumour necrosis factor-alpha in cavernosal vascular smooth muscle cells: mediation by superoxide.

OBJECTIVES: To determine whether there is an association between vascular phosphodiesterase type 5 (PDE-5) and NADPH oxidase (NOX) in cavernosal vascular smooth muscle cells (CVSMCs), and to study the actions of the PDE-5 inhibitor sildenafil; the pro-erectile actions of nitric oxide (NO) are reduced by PDE-5 which hydrolyses cGMP to inactive GMP, thus an up-regulation of PDE-5 and over-production of O(2)(-) derived from NOX might promote erectile dysfunction (ED). MATERIALS AND METHODS: To study the effects of nicotine and tumour necrosis factor-alpha (TNF-alpha) on superoxide (O(2)(-)) production and PDE-5 expression, CVSMCs from rabbit penis were incubated with nicotine or TNF-alpha, and superoxide dismutase (SOD), catalase, sildenafil citrate, or apocynin (NADPH inhibitor) for 16 h. The expression of PDE-5 and of glyceraldehyde-3-phosphate dehydrogenase (internal standard) was assessed using Western blotting. O(2)(-) was measured spectrophotometrically. RESULTS: After a 16-h incubation, both nicotine (maximal at 10 microm) and TNF-alpha (10 ng/mL) significantly increased O(2)(-) formation in CVSMCs; this effect was blocked by co-incubating with SOD, catalase, and sildenafil (1 microm). Apocynin also inhibited O(2)(-) formation when added after 16-h incubation with nicotine (10 microm) or TNF-alpha. PDE-5 expression was also significantly increased in CVSMCs incubated with nicotine and TNF-alpha. This effect was negated by 16-h co-incubation with SOD, catalase, apocynin, and sildenafil. CONCLUSIONS: Nicotine and TNF-alpha up-regulate PDE-5 expression in CVSMCs through an a priori up-regulation of NOX and formation of O(2)(-). As PDE-5 hydrolyses cGMP, this effect might 'blunt' the pro-erectile actions of NO. Sildenafil inhibits O(2)(-) formation, and 'normalizes' PDE-5 expression. This represents a novel pathogenic mechanism underlying ED, and a novel mechanism of action of sildenafil.