The Success and Evolution of a Urological "Boot Camp" for Newly Appointed UK Urology Registrars: Incorporating Simulation, Nontechnical Skills and Assessment.

BACKGROUND: Urological training has dramatically changed in recent years. Training durations are shorter and a drive toward consultant led care has reduced trainees experience. Within the UK, approximately 50 registrars annually embark on a 5-year Urology training programme, with variable levels of basic urological experience. OBJECTIVE: To describe a simulation programme aimed at delivering the knowledge and skills necessary to safely and effectively start working as a registrar in Urology by intensive training with a 1:1 faculty to delegate ratio. DESIGN, SETTING, AND PARTICIPANTS: Our course content mirrors the UK training syllabus for junior Urology registrars. We delivered 8 modules over a 4-day programme with a fifth day of assessments. Delegates level of urological knowledge, operative competency and confidence pre-, immediately post-training and at 3-months postcourse were assessed. Objective delegate and faculty feedback was also collected. Technical skills modules include; inguinoscrotal surgery, ureteroscopy, transurethral resection, urodynamics, and Botox administration as well as basic reconstructive and laparoscopic operative skills. "Nontechnical" skills included simulated ward round, out-patient, and emergency scenarios. RESULTS: Feedback from delegates and faculty members has been overwhelmingly positive. We have used this feedback to tailor the content of the course for following years. An increased knowledge level (based on mean examination scores [precourse 55.5%, postcourse 70.1%]) and operative competency was observed in all skills assessed (transurethral resection of the prostate, transurethral resection of bladder tumor, Ureteroscopy, laparoscopic skills, and instrument assembly). Operative confidence was increased immediately and at 3-months postcourse. CONCLUSIONS: Our "boot camp" course provides a realistic introduction and foundation to begin Urological practice. Being delivered at the beginning of the training scheme, prior to intensive patient exposure, registrars are in an optimum position to develop their newly acquired knowledge and skills to enhance training and intends to improve patient safety and satisfaction.

Is pre-operative imaging essential prior to ureteric stone surgery?

INTRODUCTION: The aim of this study was to identify patients not requiring ureteric stone surgery based on pre-operative imaging (within 24 hours) prior to embarking on semirigid ureteroscopy (R-URS) for urolithiasis. METHODS: The imaging of all consecutive patients on whom R-URS for urolithiasis was performed over a 12-month period was reviewed. All patients had undergone a plain x-ray of the kidney, ureters and bladder (KUB), abdominal non-contrast computed tomography (NCCT-KUB) or both on the day of surgery. RESULTS: A total of 96 patients were identified for the study. Stone sizes ranged from 3 mm to 20 mm. Thirteen patients (14%) were cancelled as no stone(s) were identified on pre-operative imaging. Of the patients cancelled, 8 (62%) required NCCT-KUB to confirm spontaneous stone passage. CONCLUSIONS: One in seven patients were stone free on the day of surgery. This negates the need for unnecessary anaesthetic and instrumentation of the urinary tract, with the associated morbidity. Up-to-date imaging prior to embarking on elective ureteric stone surgery is highly recommended.

Antimicrobial effect and mode of action of terpeneless cold-pressed Valencia orange essential oil on methicillin-resistant Staphylococcus aureus.

AIMS: The objectives of this study were to evaluate the antistaphylococcal effect and elucidate the mechanism of action of orange essential oil against antibiotic-resistant Staphylococcus aureus strains. METHODS AND RESULTS: The inhibitory effect of commercial orange essential oil (EO) against six Staph. aureus strains was tested using disc diffusion and agar dilution methods. The mechanism of EO action on MRSA was analysed by transcriptional profiling. Morphological changes of EO-treated Staph. aureus were examined using transmission electron microscopy. Results showed that 0·1% of terpeneless cold-pressed Valencia orange oil (CPV) induced the cell wall stress stimulon consistent with the inhibition of cell wall synthesis. Transmission electron microscopic observation revealed cell lysis and suggested a cell wall lysis-related mechanism of CPV. CONCLUSIONS: CPV inhibits the growth of Staph. aureus, causes gene expression changes consistent with the inhibition of cell wall synthesis, and triggers cell lysis. SIGNIFICANCE AND IMPACT OF THE STUDY: Multiple antibiotics resistance is becoming a serious problem in the management of Staph. aureus infections. In this study, the altered expression of cell wall-associated genes and subsequent cell lysis in MRSA caused by CPV suggest that it may be a potential antimicrobial agent to control antibiotic-resistant Staph. aureus.

The early radiological results of the uncemented Oxford medial compartment knee replacement.

We carried out a prospective investigation into the radiological outcomes of uncemented Oxford medial compartment unicondylar replacement in 220 consecutive patients (231 knees) performed in a single centre with a minimum two-year follow-up. The functional outcomes using the mean Oxford knee score and the mean high-activity arthroplasty score were significantly improved over the pre-operative scores (p < 0.001). There were 196 patients with a two-year radiological examination performed under fluoroscopic guidance, aiming to provide images acceptable for analysis of the bone-implant interface. Of the six tibial zones examined on each knee on the anteroposterior radiograph, only three had a partial radiolucent line. All were in the medial aspect of the tibial base plate (zone 1) and all measured < 1 mm. All of these patients were asymptomatic. There were no radiolucent lines seen around the femoral component or on the lateral view. There was one revision for loosening at one year due to initial inadequate seating of the tibial component. These results confirm that the early uncemented Oxford medial unicompartmental compartmental knee replacements were reliable and the incidence of radiolucent lines was significantly decreased compared with the reported results of cemented versions of this implant. These independent results confirm those of the designing centre.

Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial.

OBJECTIVES: To determine the efficacy of CP-690,550 in improving pain, function and health status in patients with moderate to severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate or a tumour necrosis factor alpha inhibitor. METHODS: Patients were randomised equally to placebo, CP-690,550 5, 15 or 30 mg twice daily for 6 weeks, with 6 weeks' follow-up. The patient's assessment of arthritis pain (pain), patient's assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) and Short Form-36 (SF-36) were recorded. RESULTS: At week 6, significantly more patients in the CP-690,550 5, 15 and 30 mg twice-daily groups experienced a 50% improvement in pain compared with placebo (44%, 66%, 78% and 14%, respectively), clinically meaningful reductions in HAQ-DI (> or =0.3 units) (57%, 75%, 76% and 36%, respectively) and clinically meaningful improvements in SF-36 domains and physical and mental components. CONCLUSIONS: CP-690,550 was efficacious in improving the pain, function and health status of patients with RA, from week 1 to week 6.

Genetic changes that correlate with the pine-oil disinfectant-reduced susceptibility mechanism of Staphylococcus aureus.

AIMS: To identify factors associated with the Staphylococcus aureus pine-oil disinfectant-reduced-susceptibility (PD(RS)) mechanism and to describe one possible PD(RS) model. METHODS AND RESULTS: Comparative genomic sequencing (CGS) and microarray analysis were utilized to detect mutations and transcriptome alterations that occur in a S. aureus PD(RS) mutant. Mutant analysis, antimicrobial gradient plates, growth studies and 3-hydroxy-3-methylglutaryl coenzyme A synthase assays were then performed to confirm the biological consequences of the 'omics' alterations detected in a PD(RS) mutant. CGS uncovered three mutations in a PD(RS) mutant in a(n): alcohol dehydrogenase (adh), catabolite control protein A (ccpA) and an NADPH-flavin oxidoreductase (frp). These mutations lead to increased growth rates; increased transcription of an NAD-dependent D-lactate dehydrogenase gene (ddh); and increased flux through the mevalonate pathway. PD(RS) mutants demonstrated reduced susceptibility to bacitracin and farnesol, and one PD(RS) mutant displayed upregulation of bacA, a bacitracin-resistance gene. Collectively, this evidence demonstrates altered undecaprenol metabolism in PD(RS) mutants. CONCLUSIONS: The PD(RS) mechanism proposed results from increased catabolic capabilities and increased flux through the mevalonate pathway as well as altered bactoprenol physiology. SIGNIFICANCE AND IMPACT OF THE STUDY: A novel mechanism that bacteria utilize to overcome the killing effects of PD formulations is proposed that is unique from the PD(RS) mechanism of the enterobacteraciae.

Preliminary investigation of the effects of low-level dietary inclusion of fragrant essential oils and oleoresins on pig performance and pork quality.

Since the tissue characteristics of monogastric species are readily influenced by the composition of the feeds they consume, the objectives of this preliminary study were to assess the performance of finisher pigs on diets containing 0.05% of essential oils or oleoresins of rosemary, garlic, oregano, or ginger, and to determine the effect of these diets on pork quality. The pigs preferred the garlic-treated diet, and feed intake and average daily gain were significantly increased although no difference in feed efficiency was observed. Carcass and meat quality attributes were unchanged by dietary treatment, although a tendency towards reduction of lipid oxidation was noted in oregano-fed pork. Sensory panelists were unable to detect a flavour/aroma difference between treated and control pork. These results indicate that a higher level of dietary supplementation may be required in order to effect observable differences in pork characteristics.

Changes in the forms of iron and in concentrations of taurine, carnosine, coenzyme Q(10), and creatine in beef longissimus muscle with cooking and simulated stomach and duodenal digestion.

Longissimus muscle samples from 31 Angus-cross heifers finished on either a high-concentrate feedlot diet or pasture were used to evaluate the effects of cooking (71°C) on the concentration and forms of iron in the meat, and also on concentrations of the bioactive compounds taurine, carnosine, coenzyme Q(10), creatine and creatinine. For a sub-sample of 15 the effects of pepsin and pancreatin digestion were assessed. For iron, cooking resulted in some overall loss together with a major change from soluble haem and non-haem iron to the insoluble forms, but solubility was regained to a significant extent following digestion. Total haem iron percentage, however, decreased at each step from an initial 88% to a final 61% of total iron. For the bioactive compounds, cooking led to a reduction in taurine, carnosine, coenzyme Q(10), and creatine. The effects of digestion on the bioactive compounds varied. No clear differences were shown in the way in which beef from pasture-finished and feedlot-finished cattle responded to cooking and digestion.

Modelling the electrical properties of bladder tissue--quantifying impedance changes due to inflammation and oedema.

Electrical impedance spectroscopy has been developed as a potential method for the diagnosis of carcinoma in epithelial tissues. An understanding of the influence of structural changes in the tissue on the properties measured using this technique is essential for interpreting measured data and optimization of probe design. In contrast to other tissue types, carcinoma in situ of the bladder gives rise to an increase in electrical impedance over the kHz-MHz frequency range in comparison to normal tissue. Finite element models of the urothelium and the underlying superficial lamina propria have been constructed and solved in order to ascertain the influence of structural changes associated with malignancy, oedema and inflammation on the measured electrical properties of the tissue. Sensitivity analysis of results from a composite tissue model suggests that the increase in lymphocyte density in the lamina propria associated with an inflammatory response to the infiltration of urine into the tissue may explain these unusual electrical properties.

Cooking temperature effects on the forms of iron and levels of several other compounds in beef semitendinosus muscle.

The influence of final cooked temperature on the form of iron present and on the concentration of taurine, carnosine, coenzyme Q(10) and creatine was investigated in surface and inner parts of 30-mm thick steaks from beef semitendinosus muscle (n=6). The use of a fast, dry-heat cooking method with a Silex clam cooker (set at 200 °C) led to cooking times ranging from 5.6 to 8.6 min for final internal temperatures of 60 and 85 °C, respectively. The proportion of iron as soluble haem iron decreased from 65% in uncooked meat to 22% when cooked to 60 °C and then decreased more gradually with increases in final cooked temperature. The proportion of insoluble haem iron increased in a reciprocal manner, while changes in the proportions of soluble and insoluble non-haem iron were relatively small, but increases in the percentage of insoluble non-haem iron with increasing final temperature were significant (P<0.01). Changes in the forms of iron with cooking generally took place more rapidly in surface samples than inner samples. On a dry-matter basis, concentrations of taurine, carnosine, coenzyme Q(10), and creatine all decreased with cooking, but the decreases were greatest for taurine and creatine. Losses of creatine were at least partly due to conversion to creatinine, and, along with the other compounds, probably included some loss in cooking juices. It is concluded that despite these changes with cooking, beef semitendinosus muscle remains a good source of iron and a useful source of the potentially bioactive compounds taurine, carnosine, coenzyme Q(10) and creatine.

Afferent regulation of cytochrome-c and active caspase-9 in the avian cochlear nucleus.

During development, a subpopulation (approximately 30%) of neurons in the avian cochlear nucleus, nucleus magnocellularis (NM), dies following removal of the cochlea. It is clear that neuronal activity coming from the auditory nerve provides trophic support critical for cell survival in the NM. Several aspects of the intracellular signaling cascades that regulate apoptosis have been defined for naturally occurring, or programmed cell death, in neurons. These intracellular cascades involve the extrusion of cytochrome-c from the mitochondria into the cytosol and the subsequent activation of proteolytic caspase cascades, which ultimately act on substrates that lead to the death of the cell. In contrast, the intracellular signaling cascades responsible for deafferentation-induced cell death are not fully understood. In the present series of experiments, the potential extrusion of cytochrome-c from the mitochondria into the cytosol, and the activation of caspases were examined in the NM following deafferentation. Cytochrome-c immunoreactivity increased within 6 h following deafferentation and persisted for at least 3-5 days following surgery. However, cytochrome-c was not detectable within immunoprecipitates obtained from cytosolic fractions of deafferented NM neurons. This suggests that the increased immunoreactivity of cytochrome-c is related to mitochondrial proliferation. As a positive control, cytochrome-c was detected in cytosolic fractions of deafferented NM neurons treated with kainic acid, a substance known to cause cytochrome-c release into the cytosol. In addition, immunoreactivity for downstream active caspase-9 did increase following cochlea ablation. This increase was observed within 3 h following cochlea removal, but was not observed 4 days following surgery, a time point after the dying population of NM neurons have already degenerated. Together, these findings suggest that deafferentation of NM neurons results in caspase activation, but this activation may be cytochrome-c independent.

Activity-dependent regulation of the subcellular localization of neuronal calcium sensor-1 in the avian cochlear nucleus.

Neurons in the avian cochlear nucleus, nucleus magnocellularis (NM), are highly sensitive to manipulations of afferent input, and removal of afferent activity through cochlear ablation results in the death of approximately 20-40% of ipsilateral NM neurons. The intracellular cascades that determine whether an individual NM neuron will die or survive are not fully understood. One early event observed in NM following deafferentation is a rapid rise in intracellular calcium concentration. In most cellular systems, the activity of calcium-binding proteins is believed to accommodate calcium influx. The calcium-binding protein, neuronal calcium sensor-1 (NCS-1), is an intracellular neuronal calcium sensor belonging to the EF-hand superfamily. NCS-1 has been implicated in calcium-dependent regulation of signaling cascades. To evaluate NCS-1 action in NM neurons, the localization of NCS-1 protein was examined. Double-label immunofluorescence experiments revealed that NCS-1 expression is evident in both the presynaptic nerve terminal and postsynaptic NM neuron. The postsynaptic expression of NCS-1 typically appears to be closely associated with the cell membrane. This close proximity of NCS-1 to the postsynaptic membrane could allow NCS-1 to function as a modulator of postsynaptic signaling events. Following deafferentation, NM neurons were more likely to show diffuse cytoplasmic NCS-1 labeling. This increase in the number of cells showing diffuse cytoplasmic labeling was observed 12 and 24 h following cochlea ablation, but was not observed 4 days following surgery. This activity-dependent regulation of NCS-1 subcellular localization suggests it may be associated with, or influenced by, processes important for the survival of NM neurons.

Electrical impedance spectroscopy and the diagnosis of bladder pathology: a pilot study.

PURPOSE: Carcinoma in situ is an aggressive form of bladder cancer with a high propensity for invasion if left untreated. On cystoscopy these flat lesions cannot be differentiated from other erythematous, potentially benign areas and they require biopsy for definitive diagnosis. Other methods of detecting carcinoma in situ remain experimental. We assessed the effectiveness of electrical impedance spectroscopy, a method that measures the variation of electrical current flow with frequency through the mucosa, for differentiating various pathological changes in the urothelium. MATERIALS AND METHODS: We obtained 250 impedance measurements immediately after resection in 35 cystectomy specimens using a custom designed probe. Three consecutive readings were recorded per point to assess reproducibility and punch biopsy was done at the measurement site. RESULTS: Changes in the urothelium were classified histologically into 7 subgroups according to the degree of edema and inflammation. Electrical impedance spectroscopy measurements were able to separate benign and malignant changes when tested as a group (p <0.001), although some individual points overlapped. Edema also had a significant effect on tissue impedance (p <0.001). CONCLUSIONS: Using measurements we established patterns of electrical impedance in the human bladder. Early results suggest that this minimally invasive technique is able to differentiate benign and malignant bladder pathologies. However, it requires further refinement and evaluation at lower frequencies, where the greatest impedance difference in benign and malignant tissues is expected.

Electrical impedance spectroscopy (EIS) in the urinary bladder: the effect of inflammation and edema on identification of malignancy.

Previous studies have shown that tetrapolar electrical impedance spectroscopy measurements can identify cervical interstitial neoplasia with the same sensitivity and specificity as cervical smears. In the urinary bladder, the same technique yields significant differences (p < 0.05 at seven frequencies between 9.6 and 614 kHz) between normal and malignant urothelium, but is unable to classify individual measurements. Detailed histological examination demonstrates that inflammation and edema--both of which are common in abnormal urothelium--alter the impedance spectrum significantly in opposing directions. Consideration of morphological changes in abnormal urothelium suggests alternative measurement strategies.

Ssh1p determines the translocation and dislocation capacities of the yeast endoplasmic reticulum.

Sec61p is required both for protein translocation and dislocation across the membrane of the endoplasmic reticulum (ER). However, the cellular role of the Sec61p homolog Ssh1p has not been clearly defined. We show that deltassh1 mutant cells have strong defects in both SRP-dependent and -independent translocation. Moreover, these cells were also found to be induced for the unfolded protein response and to be defective in dislocation of a misfolded ER protein. In addition, deltassh1 mutant cells rapidly became respiratory deficient. The other defects discussed above were suppressed in the respiratory-deficient state or under conditions where the rate of polypeptide translation was artificially reduced. These data identify Ssh1p as a component of a second, functionally distinct translocon in the yeast ER membrane.

Transdermal nicotine and haloperidol in Tourette's disorder: a double-blind placebo-controlled study.

BACKGROUND: Preclinical animal and open-trial clinical trials using nicotine gum and the transdermal nicotine patch found that treatment with nicotine potentiates the effects of neuroleptics in reducing the dyskinetic symptoms of Tourette's disorder. We sought to verify and expand these findings in a prospective double-blind placebo-controlled trial. METHOD: Seventy patients with DSM-IV Tourette's disorder were treated with either transdermal nicotine (7 mg/24 hours) or placebo patches in a 33-day, randomized, double-blind study. Each patient received an individually based optimal dose of haloperidol for at least 2 weeks prior to random assignment to nicotine or placebo treatment. A new patch was worn each day for the first 5 days. On the sixth day, the dose of haloperidol was reduced by 50%. Daily patch applications were then continued for an additional 2 weeks (through day 19), at which time the patch was discontinued, but the 50% dose of haloperidol was continued for an additional 2 weeks (through day 33). Clinical and safety assessments were made at each visit. RESULTS: Patients who completed all 19 days of nicotine (N = 27) or placebo (N = 29) patch treatment were used in efficacy analyses. As documented by the Clinician- and Parent-rated Global Improvement scales, transdermal nicotine was superior to placebo in reducing the symptoms of Tourette's disorder. The Yale Global Tic Severity Scale was less sensitive in detecting a placebo/drug difference than were the global improvement scores, suggesting that some of the improvement may not have been related to treatment-related changes in tic severity, but to the emotional and behavioral symptoms. The side effects of nausea and vomiting were significantly more common in the nicotine group (71% [N = 25] and 40% [N = 14]) than in the placebo group (17% [N = 6] and 9% [N = 3]) (nausea, p = .0001; vomiting, p = .004). CONCLUSION: Transdermal nicotine was superior to placebo in reducing behavioral symptoms when patients were receiving an optimal dose of haloperidol, when the dose of haloperidol was reduced by 50%, and when the patch had been discontinued for 2 weeks. These findings confirm earlier open-label findings and suggest that combining nicotinic receptor modulation and neuroleptics could be a therapeutic option for the treatment of Tourette's disorder. While side effects limit chronic use of nicotine, it may be useful on a p.r.n. basis. Further clinical research is warranted to investigate the use of novel nicotinic receptor modulating agents with improved safety profiles over nicotine.

Combinatorial biosynthesis of polyketides and nonribosomal peptides.

The engineering of polyketide biosynthesis has begun to provide robust targeted libraries for screening against pharmaceutically relevant targets. New technologies that offer methodology for the rapid generation of more structurally diverse libraries have now been demonstrated.

Imiquimod 5% cream in the treatment of Bowen's disease.

BACKGROUND: Large-diameter lesions of Bowen's disease at sites such as the shin may be difficult to treat surgically and may require alternate treatment modalities. OBJECTIVE: We investigated whether imiquimod 5% cream, a topical immune response modifier that stimulates the production of interferon alfa and other cytokines, is an effective topical treatment for Bowen's disease. METHODS: This was a phase II, open-label study in 16 patients, treating a single biopsy-proven plaque of Bowen's disease that was 1 cm or larger in diameter, with once-daily self-application of imiquimod 5% cream for 16 weeks. A biopsy was performed on the treated area 6 weeks after the end of treatment, with patient follow-up at 3 and 6 months. Lymphocyte CD4/CD8 ratios were analyzed in pretreatment and posttreatment biopsy specimens by immunophenotyping the lymphocytic infiltrate. RESULTS: Sixteen patients with Bowen's disease lesions ranging from 1 to 5.4 cm in diameter (0.7-21.6 cm(2) in area) were treated. Fifteen of these lesions were on the legs, and one was on the shoulder. Fourteen of the 15 patients (93% per protocol analysis) had no residual tumor present in their 6-week posttreatment biopsy specimens. One patient died of unrelated intercurrent illness before a biopsy specimen could be obtained. The median CD4/CD8 lymphocyte ratio in pretreatment biopsy specimens was 2:1, and this was reversed to a median of 1:2.2 in the posttreatment specimens. Ten patients completed 16 weeks of treatment, but 6 patients ceased treatment early (between 4 and 8 weeks) because of local skin reactions. CONCLUSION: Imiquimod 5% cream appears to be an effective treatment for Bowen's disease on the lower limbs. The 93% positive treatment response in biopsy-proven cases (excludes patient who died from an intercurrent illness who did not undergo a posttreatment biopsy) compares favorably with other current treatment modalities. The dosing schedule and length of treatment for Bowen's disease require further evaluation.