Acute intermittent hypoxia enhances regeneration of surgically repaired peripheral nerves in a manner akin to electrical stimulation.

The intrinsic repair response of injured peripheral neurons is enhanced by brief electrical stimulation (ES) at time of surgical repair, resulting in improved regeneration in rodents and humans. However, ES is invasive. Acute intermittent hypoxia (AIH) - breathing alternate cycles of regular air and air with ~50% normal oxygen levels (11% O2), considered mild hypoxia, is an emerging, promising non-invasive therapy that promotes motor function in spinal cord injured rats and humans. AIH can increase neural activity and under moderately severe hypoxic conditions improves repair of peripherally crushed nerves in mice. Thus, we posited an AIH paradigm similar to that used clinically for spinal cord injury, will improve surgically repaired peripheral nerves akin to ES, including an impact on regeneration-associated gene (RAG) expression-a predictor of growth states. Alterations in early RAG expression were examined in adult male Lewis rats that underwent tibial nerve coaptation repair with either 2 days AIH or normoxia control treatment begun on day 2 post-repair, or 1 h ES treatment (20 Hz) at time of repair. Three days post-repair, AIH or ES treatments effected significant and parallel elevated RAG expression relative to normoxia control at the level of injured sensory and motor neuron cell bodies and proximal axon front. These parallel impacts on RAG expression were coupled with significant improvements in later indices of regeneration, namely enhanced myelination and increased numbers of newly myelinated fibers detected 20 mm distal to the tibial nerve repair site or sensory and motor neurons retrogradely labeled 28 mm distal to the repair site, both at 25 days post nerve repair; and improved return of toe spread function 5-10 weeks post-repair. Collectively, AIH mirrors many beneficial effects of ES on peripheral nerve repair outcomes. This highlights its potential for clinical translation as a non-invasive means to effect improved regeneration of injured peripheral nerves.

The drebrin/EB3 pathway drives invasive activity in prostate cancer.

Prostate cancer is the most common cancer in men and the metastatic form of the disease is incurable. We show here that the drebrin/EB3 pathway, which co-ordinates dynamic microtubule/actin filament interactions underlying cell shape changes in response to guidance cues, plays a role in prostate cancer cell invasion. Drebrin expression is restricted to basal epithelial cells in benign human prostate but is upregulated in luminal epithelial cells in foci of prostatic malignancy. Drebrin is also upregulated in human prostate cancer cell lines and co-localizes with actin filaments and dynamic microtubules in filopodia of pseudopods of invading cells under a chemotactic gradient of the chemokine CXCL12. Disruption of the drebrin/EB3 pathway using BTP2, a small molecule inhibitor of drebrin binding to actin filaments, reduced the invasion of prostate cancer cell lines in 3D in vitro assays. Furthermore, gain- or loss-of-function of drebrin or EB3 by over-expression or siRNA-mediated knockdown increases or decreases invasion of prostate cancer cell lines in 3D in vitro assays, respectively. Finally, expression of a dominant-negative construct that competes with EB3 binding to drebrin, also inhibited invasion of prostate cancer cell lines in 3D in vitro assays. Our findings show that co-ordination of dynamic microtubules and actin filaments by the drebrin/EB3 pathway drives prostate cancer cell invasion and is therefore implicated in disease progression.

Testicular Microlithiasis: Is Sonographic Surveillance Necessary? Single Centre 14 Year Experience in 442 Patients with Testicular Microlithiasis.

PURPOSE: Increased prevalence of germ cell tumour (GCT) is seen with testicular microlithiasis (TM) suggesting TM is a premalignant condition with US surveillance advocated. We present a cohort of patients with TM followed up in a single centre and deliberate on the value of US surveillance. MATERIALS AND METHODS: A retrospective analysis of subjects with underlying US diagnosis of TM between 1998 and 2012. One-yearly US follow-up was offered to all patients with TM and a database maintained. Any co-existing tumour at presentation with TM was recorded. TM was divided into limited (< 5 microliths/field), classical (≥ 5 microliths/field) and florid ('snowstorm' appearance). Patient demographics, follow-up details and the development of any scrotal abnormalities were recorded. The radiological and histological findings were documented when a testicular lesion occurred during the follow-up period. RESULTS: 20 224 patients were examined: 867/20 224 (4.3 %) had TM. 21/867 (2.4 %) patients had histology proven malignant tumours at presentation. All TM patients consented to follow-up with 442/867 (51.0 %) achieving this and entering into a follow-up program (mean duration 28 months, range 8 - 165 months). Two patients developed primary GCT during the follow up period. One patient (limited TM) had undergone a previous orchiectomy for contralateral GCT and developed a palpable mass at follow up month 21. The other (limited TM) had an atrophic testis; a tumour was found on US at follow up month 62. CONCLUSION: Two patients of 442 (0.5 %) followed up for all forms of TM in a single centre developed a GCT over a mean duration of 28 months, both had independent risk factors for the development of GCT. These findings suggest that US surveillance is not required when TM is the only abnormality in the absence of any clinical risk factors for the development of GCT.

TOOKAD® Soluble focal therapy: pooled analysis of three phase II studies assessing the minimally invasive ablation of localized prostate cancer.

PURPOSE: To evaluate the 6-month effects of the recommended drug and light dosage in focal vascular-targeted photodynamic therapy (VTP) using TOOKAD(®) Soluble in patients with localized prostate cancer (LPCa). METHODS: We performed a pooled analysis of 117 men with LPCa, PSA <10 ng/mL, and Gleason score ≤ 7 (3 + 4), from 3 studies who received a 10-min intravenous infusion of a single dose of 4 mg/kg TOOKAD(®) Soluble, activated by a 753-nm light at 200 J/cm delivered in the prostate by transperineal fibres under transrectal ultrasound guidance. Primary endpoint was 6-month negative biopsies in the treated lobe(s). PSA was measured at month 1, 3, and 6. Magnetic resonance imaging was performed at day 7, month 3, and 6. International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5) and adverse events were reported at day 7, month 1, 3, and 6. RESULTS: Month 6 negative biopsy rate was 68.4 % in the overall evaluable population (N = 114) and 80.6 % for patients treated by hemiablation with light density index (LDI) ≥ 1 (N = 67). Mean prostate necroses at week-1 were 76.5 and 86.3 %, respectively. In both groups, PSA levels at month 6 decreased by 2.0 ng/mL. Small changes from baseline for IPSS and IIEF-5 indicated a slight improvement in urinary function and a slight deterioration in sexual function. CONCLUSIONS: Focal VTP treatment with TOOKAD(®) Soluble at 4 mg/kg and 200 J/cm resulted in a negative 6-month biopsy rate of 68.4 % for the whole population and 80.6 % for patients treated by hemiablation with LDI ≥ 1. The treatment was well tolerated. Two phase III studies will reach completion in early 2015.

Determining the biomass fraction of mixed waste fuels: A comparison of existing industry and (14)C-based methodologies.

(14)C analysis of flue gas by accelerator mass spectrometry (AMS) and liquid scintillation counting (LSC) were used to determine the biomass fraction of mixed waste at an operational energy-from-waste (EfW) plant. Results were converted to bioenergy (% total) using mathematical algorithms and assessed against existing industry methodologies which involve manual sorting and selective dissolution (SD) of feedstock. Simultaneous determinations using flue gas showed excellent agreement: 44.8 ± 2.7% for AMS and 44.6 ± 12.3% for LSC. Comparable bioenergy results were obtained using a feedstock manual sort procedure (41.4%), whilst a procedure based on selective dissolution of representative waste material is reported as 75.5% (no errors quoted). (14)C techniques present significant advantages in data acquisition, precision and reliability for both electricity generator and industry regulator.

Spiculated bladder calculi: the culprit for repeated catheter failure.

We report on the case of a frustrated 90-year-old gentleman who was seen in the Accident and Emergency department for the third time in four days with failure of his long-term urethral catheter. He reported that the catheter simply "fell out" with the balloon deflated. On each occasion previously, the catheter had been reinserted in A&E and the patient discharged home. These repeated visits to A&E were understandably a source of much frustration for the patient and his family. On the third presentation, plain abdominal radiography demonstrated a large spiculated bladder calculus.

Improving postgraduate clinical assessment tools: the introduction of video recordings to assess decision making.

BACKGROUND: Competency in the management of acutely unwell patients has not previously been formally assessed as part of an objective structured clinical examination (OSCE). AIM: The reliability of the paediatric postgraduate OSCE was calculated. An objective structured video examination was designed to assess candidates' clinical decision making ability when managing acutely unwell children. METHODS: The performance of 3522 postgraduate paediatric trainees was assessed (2006-2008). OSCE reliability was determined using Cronbach's alpha and mean inter-item correlation. Performance in the video station was compared with overall performance (not including video station; Mann-Whitney U) and video station scores correlated with individual station scores (Spearman's Rho correlation coefficient). RESULTS: Clinical examination pass rates for the 684 UK graduates, 1608 overseas candidates training in the UK and 1104 overseas candidates training overseas were 69.7%, 28% and 22.3%, respectively (graduation information not available for 126 candidates). Cronbach's alpha was 0.62. Mean inter-item correlation was 0.15. Candidates who passed the OSCE overall had significantly higher scores on the video station (t(3520) = 14.48); p < 0.001). There was significant positive correlation between scores on the video station, individual stations and overall total score (r's = 0.300; p = 0.001). CONCLUSIONS: The postgraduate paediatric OSCE provides a sound and valid means of assessing clinical skills at the postgraduate level. The video station provides an important new method of assessment. Its use in other postgraduate clinical examinations should be explored.

Feedback on doctors' performance from parents and carers of children: a national pilot study.

OBJECTIVES: To evaluate the reliability and validity of a children's carers' feedback tool, to explore the feasibility of delivering this nationally and to determine acceptability to doctors of this assessment. PARTICIPANTS: 122 UK paediatricians on the specialist register undertaking outpatient consultations. DESIGN: Participants were each sent 50 forms for distribution to carers. Mean scores for each question, and for the overall pilot cohort were returned to participants with verbatim free text comments. Participating paediatricians' views were sought before and after receiving feedback. RESULTS: 122 doctors returned 4415 forms (mean 36 per doctor). All doctors scored highly with scores across all returned forms having a median of 4.58 (IQ range 0.17) where the maximum score was 5. Differences were observed between scores from female compared to male carers (p<0.05), from consultations rated by carer and child compared to carer alone (p<0.05) and from carers who had previously met the doctor compared to those in their first consultation (p<0.001). 'White' doctors received higher ratings than 'non-white' doctors (p<0.05) and white patients rated both white doctors and non-white doctors more highly than non-white patients (p<0.01). A minimum of 25 consultations rated by children's carers are needed for acceptable reliability. 93.9% of participants would be happy to be assessed in this way for the purposes of revalidation. CONCLUSIONS: National delivery of a valid and reliable method of carer feedback is feasible. The scores received and acceptability in these self-selected doctors was high. Confounding variables may influence feedback, so guidance on interpretation may be needed.

Clinical presentation and initial management of black men and white men with prostate cancer in the United Kingdom: the PROCESS cohort study.

BACKGROUND: In the United States, Black men have a higher risk of prostate cancer and worse survival than do White men, but it is unclear whether this is because of differences in diagnosis and management. We re-examined these differences in the United Kingdom, where health care is free and unlikely to vary by socioeconomic status. METHODS: This study is a population-based retrospective cohort study of men diagnosed with prostate cancer with data on ethnicity, prognostic factors, and clinical care. A Delphi panel considered the appropriateness of investigations and treatments received. RESULTS: At diagnosis, Black men had similar clinical stage and Gleason scores but higher age-adjusted prostate-specific antigen levels (geometric mean ratio 1.41, 95% confidence interval (95% CI): 1.15-1.73). Black men underwent more investigations and were more likely to undergo radical treatment, although this was largely explained by their younger age. Even after age adjustment, Black men were more likely to undergo a bone scan (odds ratio 1.37, 95% CI: 1.05-1.80). The Delphi analysis did not suggest differential management by ethnicity. CONCLUSIONS: This UK-based study comparing Black men with White men found no evidence of differences in disease characteristics at the time of prostate cancer diagnosis, nor of under-investigation or under-treatment in Black men.

Pathways to diagnosis for Black men and White men found to have prostate cancer: the PROCESS cohort study.

Black men in England have three times the age-adjusted incidence of diagnosed prostate cancer as compared with their White counterparts. This population-based retrospective cohort study is the first UK-based investigation of whether access to diagnostic services underlies the association between race and prostate cancer. Prostate cancer was ascertained using multiple sources including hospital records. Race and factors that may influence prostate cancer diagnosis were assessed by questionnaire and hospital records review. We found that Black men were diagnosed an average of 5.1 years younger as compared with White men (P<0.001). Men of both races were comparable in their knowledge of prostate cancer, in the delays reported before presentation, and in their experience of co-morbidity and symptoms. Black men were more likely to be referred for diagnostic investigation by a hospital department (P=0.013), although general practitioners referred the large majority of men. Prostate-specific antigen levels were comparable at diagnosis, although Black men had higher levels when compared with same-age White men (P<0.001). In conclusion, we found no evidence of Black men having poorer access to diagnostic services. Differences in the run-up to diagnosis are modest and seem insufficient to explain the higher rate of prostate cancer diagnosis in Black men.

Photoselective vaporization of the prostate (GreenLight PV): lessons learnt after 3500 procedures.

The technical recommendations of an international group of experts on photoselective vaporization of the prostate (PVP; GreenLight PV) for benign prostatic hyperplasia are described. Their experience stems from the treatment of over 3500 patients at five centres in Europe and the United States. The objectives of this physician-based initiative are to optimize the results achieved with PVP by standardizing the procedure, as well as to recommend training requirements.

To knot or not to knot? Sutureless haemostasis compared to the surgeon's knot.

INTRODUCTION: The aim of this study was to carry out an independent evaluation of the efficacy and security of a number of vessel ligation devices and ligatures. MATERIALS AND METHODS: A vascular ligation model was devised using fresh, ex vivo porcine internal carotid arteries of varying external diameters. Coloured normal saline was infused via a pressure/monitor device through the artery. The end lumen was occluded by five different techniques: (i) braided suture in a surgeon's knot; (ii) a monofilament suture in a granny knot; (iii) a metallic clip (Ligaclip, Johnson and Johnson); (iv) a bipolar diathermy system (Ligasure, ValleyLab); and (v) an ultrasonically activated scalpel (Harmonic Scalpel, Johnson and Johnson). The vessels were subjected to supraphysiological pressures. Loss of haemostasis was evident by leakage of coloured perfusion fluid. RESULTS: Secure haemostasis was obtained with all the techniques in all vessels below 5 mm in diameter. In vessels over 5 mm, secure haemostasis was obtained with all modalities except harmonic scalpel. With the harmonic scalpel, leaks occurred in 3/27 (11%) vessels between 5-6 mm and 3/5 (60%) vessels over 6 mm, confirming the manufacturer's instructions. CONCLUSIONS: In this first, independent, randomised study comparing vessel ligation devices and ligatures, the manufacturer's claims for each of the haemostatic methods were accurate. We find that all the modalities tested perform as well as the traditional surgeon's knot in vessels of 5 mm and below.

Racial origin is associated with poor awareness of prostate cancer in UK men, but can be increased by simple information.

Prostate cancer is the second most common cause of cancer death in UK men. We have shown a higher incidence and disease stage in black British men (unpublished), however there is no evidence regarding their awareness of prostate cancer and screening. We assessed the level of prostate cancer awareness and attitudes in Black and White men in the UK, and to see if written information would modify awareness. Information was collected from two groups of 871 men without prostate cancer using a new, validated, prostate cancer awareness questionnaire. The first group was asked to fill in the questionnaire, whereas the second group was initially given printed information on prostate cancer and requested to fill in the questionnaire. Data were compared between the two ethnic groups using SPSS statistical package. Changes in knowledge and attitudes after providing prostate health education were analysed. There was a significantly lower response from Black men. In the first group, Black men were unaware of their increased risk of developing the disease and demonstrated poor knowledge about the symptoms of prostate cancer (P<0.001) and also more negative attitudes about its control and treatment (P<0.01). In the second group, there were significant improvements in knowledge, risk awareness and attitudes following targeted education: this was true for Black and White men. Although Black British men have a high risk of prostate cancer, their knowledge of the disease is poor. Simple education methods can significantly improve awareness and knowledge in both Black and White men.

Evaluation of ideal irrigation fluid in 'Greenlight' photoselective vapourization of the prostate.

Although many anecdotal opinions are available that water gives a better visual quality, no studies have analysed the differences in the visual quality of the operative field with the use of either saline or sterile water. As part of a prospective audit we wished to assess the effect of differing irrigant fluids on intraoperative visibility during Greenlight photoselective vapourization of prostate (PVP). Twenty-nine consecutive patients with prostates less than 100 cm(3) who underwent PVP were studied. The irrigation fluid used was randomly connected on a bag-by-bag basis, with the surgeon blinded to the bag's contents. Towards the end of each bag the surgeon gave a score to the quality of vision. All surgeons were familiarized with the vision scoring system in advance. The scores were analysed in two ways. The mean scores for water and saline were compared. In addition, a mean score for each fluid in each patient where both fluids were used (n=24) was separately calculated and the means for each fluid compared. One hundred and twenty-four bags of fluid in 29 operative cases were analysed. The mean overall vision scores were 3.94% for saline and 4.01% for water (P=0.62). The paired data were analysed using the Student's t-test and there was no statistically significant difference (P=0.34). We showed no significant difference in visual quality between water and saline during PVP. Although fluid absorption is almost unknown with PVP, there seems to be no justification for using water irrigation if saline is available, particularly with a theoretical risk of absorption.

Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study.

Interest in lycopene has focused primarily on its use in the chemoprevention of prostate cancer (CaP); there are few clinical trials involving men with established disease. In addition, most data examining its mechanism of action have been obtained from experiments using immortal cell lines. We report the inhibitory effect(s) of lycopene in primary prostate epithelial cell (PEC) cultures, and the results of a pilot phase II clinical study investigating whole-tomato lycopene supplementation on the behavior of established CaP, demonstrating a significant and maintained effect on prostate-specific antigen velocity over 1 year. These data reinforce the justification for a large, randomized, placebo-controlled study.

Laparoscopic partial nephrectomy using the potassium titanyl phosphate laser in a porcine model.

INTRODUCTION: To evaluate the potential and feasibility of the potassium titanyl phosphate (KTP) Greenlight laser to perform partial nephrectomy in a porcine model. TECHNICAL CONSIDERATIONS: A total of 15 laparoscopic partial nephrectomies were performed in 4 Danish land-raised pigs under anesthesia. Transperitoneal access was obtained, and using a total of four ports, the 80-W KTP laser was used to perform bilateral upper and lower pole partial nephrectomy. The procedures were done successfully without renal cooling or clamping of the vessels. The estimated blood loss for each procedure was less than 30 mL. Only in one operation, in which a secondary renal vein was transected, was any additional hemostasis required (a single Endoclip). The mean operating time was 42 minutes (range 31 to 59) for each partial nephrectomy. As demonstrated on video, smoke formation was, at times, a problem during the procedure, because it reduced visibility, making only intermittent application of laser energy possible. Histopathologic analysis of the specimens showed a zone of loss of substance (less than 1 mm) at the resection line and narrow adjacent zones on both sides of the resection line with minimal changes. CONCLUSIONS: We have shown for the first time that normally perfused laparoscopic partial nephrectomy using the KTP laser is feasible and efficacious in the porcine model. This represents a novel application for the KTP laser, which produced excellent renal parenchymal hemostatic ablation. We are currently working on ways to improve the visibility by reducing smoke formation before undertaking a clinical trial in humans.

Use of expired breath ethanol measurements in evaluation of irrigant absorption during high-power potassium titanyl phosphate laser vaporization of prostate.

OBJECTIVES: To evaluate formally the risk and levels of irrigant absorption during high-power potassium titanyl phosphate (KTP) laser vaporization of the prostate by the Greenlight PV system using the expired breath ethanol technique. METHODS: Forty consecutive patients underwent laser vaporization of the prostate. Of these patients, 17 had a preoperative transrectal ultrasound estimation of the prostate volume (mean 97 cm3). All procedures were performed under general anesthesia, by either of two consultants or a trainee. A 1% ethanol solution was used as irrigation fluid. Throughout the operation, the expired breath was analyzed for ethanol using a standard alcometer "plumbed" into the anesthetic circuit. Venous blood samples were taken immediately before and after the procedure for measurements of serum sodium and plasma alcohol levels. RESULTS: On average, 155,000 J of laser energy was delivered in 47 minutes. In all patients and on all occasions, the expired breath ethanol remained at 0. No statistically significant change was found in the serum sodium concentration during the procedure (P = 0.42), and no patient displayed any clinical evidence of transurethral resection syndrome. CONCLUSIONS: The results of this study have confirmed, for the first time, the lack of significant absorption of irrigation fluid during high-power KTP vaporization of the prostate using a recognized sensitive technique and the safety of using sterile water as that irrigant. This was the case even in those patients with very large prostates who are usually considered at high risk of experiencing the clinical consequences of fluid absorption during transurethral resection of the prostate and regardless of the experience of the surgeon.

Beliefs about illness and quality of life among men with erectile dysfunction.

The objective of the study was to apply an illness representations framework to examine patients' beliefs about erectile dysfunction (ED) and the association between those beliefs and reported quality of life. A total of 41 patients attending two secondary care clinics at a teaching hospital completed questionnaires examining quality of life, sexual functioning, illness representations (cause, time-line, coherence, consequences, cure, control and emotion) and perceptions of masculinity. Masculinity, sexual function, emotions and beliefs about consequences were found to be significantly correlated with quality of life. Multiple regression analysis revealed a model that accounted for almost 35% of the variance in quality of life of ED patients. The strongest predictor of higher quality of life was better sexual functioning (beta = -0.342, P < 0.05) followed by more positive beliefs about the effects of ED on masculinity (beta = 0.323, P < 0.05). The results suggest that when assessing the quality of life of men with ED, patients' illness representations should be considered along with their level of sexual functioning and the effects of ED on masculinity. Patients may benefit from an intervention programme that includes an educational component, thereby providing patients with more information about treatment options and available support.

Phentolamine re-dosing during penile dynamic colour Doppler ultrasound: a practical method to abolish a false diagnosis of venous leakage in patients with erectile dysfunction.

Increased sympathetic tone may cause an equivocal response to a prostaglandin E1 (PGE1) penile Doppler ultrasound (US) examination interpreted as a venous leak. We evaluated the US parameters and erectile response to the addition of phentolamine to a PGE1 penile Doppler US examination to ascertain whether addition of phentolamine would abolish a suboptimal response. 32 patients (median age 29 years, range 17-70 years) with either a previous Doppler US pattern of venous leakage or a clinical suspicion of venogenic impotence, underwent Doppler US after a total dose of 20 microg of PGE1. Peak systolic velocity (PSV), end diastolic velocity (EDV) and grade of erection were documented. If erectile response was suboptimal irrespective of the EDV measurement, 2 mg-intracavernosal phentolamine was administered and measurements repeated. Six patients had a normal erectile response, the remaining 26 received phentolamine. A significant increase in PSV between baseline and 20 microg PGE1 (p<0.001) was observed in all cases. Following phentolamine there was a significant increase in grade of erection (p=0.0001) and a significant reduction in the EDV (p=0.0001). A reduction of the EDV to below 0.0 cm s(-1) was observed in 16 patients. Four patients with EDV <5.0 cm s(-1) but >0.0 cm s(-1) had improved erectile response following phentolamine while six showed persistent EDV elevation >5 cm s(-1). No priapism was documented. It is essential to ensure cavernosal relaxation using phentolamine before a Doppler US diagnosis of venous leak is made. This two-stage assessment will allow this to be done efficiently and with a low risk of priapism.

Behavioural analysis of the efficacy of treatments for injuries to the spinal cord in animals.

There have been very few clinical trials evaluating therapies for naturally occurring spinal cord injury in dogs and cats. This review describes the methods suitable for evaluating the behavioural recovery of animals with spinal cord injuries, in either a clinical or a laboratory setting. A list of commonly used methods for evaluating behavioural recovery in animals is provided, both in the clinical and laboratory setting; the tests, their limitations and benefits and specific recommendations for their use are also discussed in more depth.