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Objective To determine if a modified cystoscopy technique utilizing the peak-end rule cognitive bias decreases pain and anxiety during flexible cystoscopy in patients who undergo cystoscopy. Methods A total of 85 participants undergoing their first diagnostic cystoscopy were enrolled in a blinded single-center, prospective, randomized controlled trial. Patients with lower urinary tract abnormalities, prior radiation and chronic pelvic pain were excluded. Participants were randomized to a standard cystoscopy (arm A) or a modified cystoscopy (arm B) where a two-minute period at the end of the procedure was completed during which the cystoscope was left in the bladder without being manipulated. Following the cystoscopy, participants completed a standard pain and anxiety questionnaire. Differences in mean pain and anxiety score between arms were evaluated using a Mann-Whitney test with a two-sided alpha of 0.05. Results Eighty-five patients were randomized and underwent flexible cystoscopy. Three participants were ineligible, one required secondary procedures, and two did not complete the questionnaires. Among the 82 eligible patients, 45 were randomized to standard cystoscopy (arm A) and 37 to the modified cystoscopy (arm B) with mean pain scores of 23.20 and 11.97, respectively (P = .039). Mean anxiety scores were 2.09 and 0.88 for arm A and B, respectively (P = .013). Conclusion This study demonstrated a clinically meaningful decrease in pain and anxiety for patients undergoing flexible cystoscopy when employing the modified cystoscopy technique versus the standard practice. This free and straightforward method to improve patient comfort and decrease stress during first time flexible cystoscopy should be considered by clinicians.

Background Testis cancer (TC) patients are young with excellent cancer prognosis. Hence, the risk of late-onset treatment-related morbidity and mortality is of concern due to longer survival after treatment. Objective We set to characterize long-term survival of TC patients through a Canadian population dataset. Design, setting, and participants We used a population-based dataset, the Canadian Census Health and Environment Cohort (CanCHEC), to identify individuals diagnosed with TC between 1991 and 2010. We compared them with all other male individuals without TC. Outcome measurements and statistical analysis The primary outcome was mortality due to cardiovascular disease (CVD) or nontesticular malignancy. Mann-Whitney or chi-square test was used where applicable. Data were analyzed using a Cox proportional hazard model with and without matching. Results and limitations We identified 1950 individuals with TC. We compared them with 1 300 295 men with no TC. There were 335 deaths in the study group during the study period (17.2%) with a mean follow-up of 19.6 yr. TC patients were at increased risk of death from secondary malignancies (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.39–1.91; p < 0.0001) with specific risks for hematologic neoplasms (HR 3.86, 95% CI 2.78–5.37; p < 0.001) and other malignancies (HR 2.41, 95% CI 1.76–3.29; p < 0.001). Gastrointestinal, hematologic, and respiratory toxicities were the most common secondary malignancies leading to death. When stratified according to histology, nonseminoma (NS) patients were at significantly increased risk of death from CVD (HR 2.03, 95% CI 1.27–3.25; p = 0.0032). Individuals with seminoma were at increased risk of death from other nontestis neoplasms (HR 1.46, 95% CI 1.17–1.82; p = 0.0007), specifically hematologic neoplasms (HR 2.09, 95% CI 1.18–3.72; p = 0.0118). Conclusions NS patients are at increased risk of CVD-related death, whereas seminoma patients are at increased risk of death from non–testis-related malignancies. Patient summary We report long-term mortality following diagnosis of testis cancer. Nonseminoma patients have an increased risk of death from cardiovascular disease, while seminoma patients have an increased risk of death from secondary malignancies., Take Home Message Testis cancer brings some serious treatment-related adverse effects. Nonseminoma testis cancer patients are at increased risk of cardiovascular-related mortality, while seminoma patients are at increased risk of death from secondary malignancies. These are very late in nature.

OBJECTIVES To report the 3-year follow-up of a Phase I study of magnetic resonance imaging (MRI)-guided transurethral ultrasound ablation (TULSA) in 30 men with localised prostate cancer. Favourable 12-month safety and ablation precision were previously described. PATIENTS AND METHODS As a mandated safety criterion, TULSA was delivered as near whole-gland ablation, applying 3-mm margins sparing 10% of peripheral prostate tissue in 30 men. After 12-month biopsy and MRI, biannual follow-up included prostate-specific antigen (PSA), adverse events (AEs), and functional quality-of-life assessment, with repeat systematic biopsy at 3 years. RESULTS A 3-year follow-up was completed by 22 patients. Between 1 and 3 years, there were no new serious or severe AEs. Urinary and bowel function remained stable. Erectile function recovered by 1 year and was stable at 3 years. The PSA level decreased 95% to a median (interquartile range) nadir of 0.33 (0.1-0.4) ng/mL, stable to 0.8 (0.4-1.6) ng/mL at 3 years. Serial biopsies identified clinically significant disease in 10/29 men (34%) and any cancer in 17/29 (59%). By 3 years, seven men had recurrence (four histological, three biochemical) and had undergone salvage therapy without complications (including six prostatectomies). At 3 years, three of 22 men refused biopsy, and two of the 22 (9%) had clinically significant disease (one new, one persistent). Predictors of salvage therapy requirement included less extensive ablation coverage and higher PSA nadir. CONCLUSION With 3-year Phase I follow-up, TULSA demonstrates safe and precise ablation for men with localised prostate cancer, providing predictable PSA and biopsy outcomes, without affecting functional abilities or precluding salvage therapy.

Abiraterone acetate (AA) is an inhibitor of androgen biosynthesis, though this cannot fully explain its efficacy against androgen-independent prostate cancer. Here, we demonstrate that androgen deprivation therapy depletes androgen-utilizing Corynebacterium spp. in prostate cancer patients and that oral AA further enriches for the health-associated commensal, Akkermansia muciniphila. Functional inferencing elucidates a coinciding increase in bacterial biosynthesis of vitamin K2 (an inhibitor of androgen dependent and independent tumor growth). These results are highly reproducible in a host-free gut model, excluding the possibility of immune involvement. Further investigation reveals that AA is metabolized by bacteria in vitro and that breakdown components selectively impact growth. We conclude that A. muciniphila is a key regulator of AA-mediated restructuring of microbial communities, and that this species may affect treatment response in castrate-resistant cohorts. Ongoing initiatives aimed at modulating the colonic microbiota of cancer patients may consider targeted delivery of poorly absorbed selective bacterial growth agents., Abiraterone acetate (AA) is indicated for the treatment of patients with metastatic castrate-resistant prostate cancer. Here, the authors show that, in prostate cancer patients, orally administered AA remodels the gut microbiome and promotes the enrichment of the commensal bacterium Akkermansia muciniphila at the expense of androgen-utilizing Corynebacterium species.

In men with recurrence of prostate cancer post radiation therapy, further treatment remains a challenge. The default salvage option of androgen-deprivation therapy (ADT) has adverse effects. Alternatively, selected men may be offered salvage therapy to the prostate. Herein, we present long-term oncological outcomes of two whole-gland ablation techniques, cryotherapy (sCT) and high-intensity-focused ultrasound (sHIFU). Men undergoing sCT (1995–2004) and sHIFU (2006–2018) at Western University were identified. Oncological endpoints included biochemical recurrence (BCR), ADT initiation, metastases, castration resistance (CRPC), and prostate cancer-specific mortality (PCSM). Survival analysis with competing risks of mortality was performed. Multivariable analysis was performed using Fine and Gray regression. A total of 187 men underwent sCT and 113 sHIFU. Mean (SD) age of the entire cohort was 69.9 (5.9 years), median pre-radiation PSA 9.6 ng/ml (IQR 6.1–15.2), and pre-salvage PSA 4.5 ng/ml (IQR 2.8–7.0). Median total follow-up was 116 months (IQR 67.5–173.8). A total of 170 (57.6%) developed BCR, 68 (23.4%) metastases, 143 (49.3%) were started on ADT, 58 (20.1%) developed CRPC, and 162 (56%) patients died of which 59 (36.4%) were of prostate cancer. On multivariable analysis, sHIFU (HR 1.65, 95% CI 1.15–2.36, p = 0.006) and pre-salvage PSA (HR 1.09, 95% CI 1.06–1.13, p

Objectives Self-regulated learning has been proposed as a resource saving alternative for learning knot tying. However, this may be hindered by the Dunning-Kruger effect. A potential alternative is guided video reflection. The objectives of this study are to compare the performance and self-assessment abilities amongst medical students learning knot tying using either a traditional self-regulated approach versus guided video reflection. Design This randomized, single-blinded, controlled trial used a pre-post-retention test design. All knot tying performances were video recorded and assessed nonsequentially by blinded evaluators using a modified Objective Structured Assessment of Technical Skills tool. Participants This study recruited 31 first- and second-year medical students and 6 senior urology residents from Western University in Canada. Results At baseline, the performances of the experts were significantly higher than the experimental groups (F3,85 = 9.080, p Conclusions Students using guided video reflection were able to achieve competency and maintained their knot tying skills to the same degree as those who used the self-regulated approach. These results may be due to the positive effects of reflection on self-assessment abilities and subsequent improvement in goal setting for further practice.

Introduction: MRI-guided transurethral ultrasound ablation (TULSA) is a novel modality for minimally invasive ablation in patients with localised prostate cancer (PCa). A multi-national Phase 1 (30...

Salvage cryoablation (SCA) is an accepted treatment for radio-recurrent prostate cancer with well-established oncological and functional outcomes. Based on one of the longest reported prospective follow-ups in the literature (median 12 years) on 187 patients, this study reports what appears to be an under-appreciated finding in eight patients with dystrophic calcifications (DC) of the prostate following SCA, causing severe bladder outlet obstruction.Between 1995 and 2004, 187 patients underwent SCA, with a median follow-up of 12 years. This database was reviewed for functional and oncological outcomes and DC were evaluated.Functional data was available in 85 patients, amongst whom eight patients were found to develop DC (9.4%) proven when the patients presented with urinary difficulties and attempted transurethral resection was undertaken for bladder outlet obstruction. Mean time for emergence of significant symptoms of bladder outlet obstruction was 8.6 years from SCA (standard deviation (SD) = 6 years). All eightpatients required permanent drainage (seven suprapubic catheters, one nephrostomy). All patients with DC experienced biochemical recurrence (BCR), compared to 57.1% of the patients with no DC (DC following SCA appears to be an under-reported late adverse effect which may only become evident with long follow-up, and should be included in preoperative counselling.

The objective of this study was to examine the association between learner personality and capacity to be trained (i.e., performance improvement) on a surgical task, and how instructor perceptions of the learners' capacity to be trained interact with learner personality and performance during training and feedback. There is meaningful heterogeneity in the degree of learner surgical skills acquisition despite receiving the same amount of training. While learner personality may independently contribute to skill acquisition, the instructor-learner feedback process is also important to consider. To better understand this interpersonal relationship, it is necessary to also consider instructor factors (i.e., perceptions), and how this may contribute to learner variability in skills training.This exploratory study employed a prospective two-phase design. Medical and non-medical undergraduate students (N = 62) completed measures of personality and participated in two 20-minute training sessions with expert feedback 2 weeks apart, performing an end-to-side anastomosis on a low-fidelity model. Learner performance and instructors' perceptions of a learner's capacity to be trained were assessed.Sixty-two medical and non-medical undergraduate students.There was a significant interaction between learner Extraversion and instructor's perceptions of learner capacity to be trained. Higher learner Extraversion was only associated with an increase in performance improvement for those who were considered trainable (OR = 4.83, p = 0.017). Post hoc analysis revealed a significant difference in the amount of feedback provided to participants who were considered trainable (M = 9.45) versus not trainable (M = 16.48).This study highlights the importance of both individual learner factors and instructor perceptions on surgical skill acquisition.

Radiation refractory prostate cancer (RRPCa) is common and salvage cryotherapy for RRPCa is emerging as a viable local treatment option. However, there is a paucity of long-term data. The purpose of this study is to determine long-term outcomes following salvage cryotherapy for RRPca.Patients undergoing salvage cryotherapy for biopsy-proven, localized RRPCa from 1992 through 2004 were prospectively accrued at two centers. Preoperative characteristics, perioperative morbidity and postoperative data were reviewed from our database. The primary outcomes were overall survival (OS) and disease-specific survival (DSS). The secondary outcomes were freedom from castration-resistant prostate cancer (CRPC) and freedom from androgen deprivation therapy (ADT).A total of 268 patients were identified with a median followup of 10.3 years. A total of 223 complication events were recorded; of them, 168 were Clavien I-II events and 55 Clavien III events. At 10 years, 69% had freedom from ADT and 76% had freedom from CRPC. The 10-year DSS rate was 81%, and the 10-year OS rate was 77%. A pre-salvage prostate specific antigen level of10 ng/ml was associated with an increased risk of developing CRPC and initiation of ADT but was not associated with DSS or OS. The use of neoadjuvant ADT was associated with improved OS and DSS but did not affect freedom from CRPC or adjuvant ADT.Salvage cryotherapy for RRPCa provides excellent long-term freedom from ADT, CRPC and DSS with acceptable morbidity. OS at 10 years was 77%. Prospective trials are required for validation.

Introduction: This study aims to assess the longer-term functional, anatomical, and metabolic outcomes of patients who underwent Studer neobladder (SNB) urinary diversion. Methods: A retrospective review of patients who underwent SNB at a single center from 1995–2017 (n=116) was performed. Demographics, comorbidities, pathological data, and longer-term functional, anatomical, and metabolic outcomes were collected from hospital records. The primary outcome was voiding function of patients at most recent followup. Secondary outcomes included postoperative complications, renal function, nephrolithiasis, infections, and metabolic outcomes. Results: Excluding those with incomplete followup data, 72 patients with minimum followup of one year were included for analysis. Median followup was 70±11 months, with 52.8% of patients having ≥5 years of followup. Clean intermittent catheterization (CIC) was used by 22.2% of patient at most recent followup, which was mostly necessitated by bladder overdistension, deteriorating renal function, or recurrent urosepsis despite timed voiding. Patients experienced more daytime and nighttime urinary incontinence in the early postoperative setting that improved over time. Generally, renal function declined over time; poorer long-term renal function was predicted by hydronephrosis within one year (p=0.002). Conclusions: Longer-term followup of SNB reveals significant but manageable complications. Gradual decline in renal function was common. Strict adherence to bladder emptying protocols (e.g., timed voiding or CIC) may reduce incidence of renal deterioration, metabolic disorders, and urinary dysfunction. Early onset (

Introduction: Some men who experience prostate cancer recurrence post-radiotherapy may be candidates for local salvage therapy, avoiding and delaying systemic treatments. Our aim was to assess the impact of clinical outcomes of adding salvage local treatment in prostate cancer patients who have failed radiation therapy. Methods: Following radiation biochemical failure, salvage transperineal cryotherapy (sCT, n=186), transrectal high intensity focused ultrasound ablation (sHIFU, n=113) or no salvage treatment (NST, identified from the pan-Canadian Prostate Cancer Risk Stratification [ProCaRS] database [n=982]) were compared with propensity-score matching. Primary endpoints were cancer-specific survival (CSS) and overall survival (OS). Results: Median followup was 11.6, 25.1, and 14.3 years following NST, sCT, and sHIFU, respectively. Two propensity-score matched analyses were performed: 1) 196 NST vs. 98 sCT; and 2) 177 NST vs. 59 sHIFU. In the first comparison, there were 78 deaths and 49 prostate cancer deaths for NST vs. 80 deaths and 24 prostate cancer deaths for sCT. There were significant benefits in CSS (p

In men with recurrence of prostate cancer post radiation therapy, further treatment remains a challenge. The default salvage option of androgen-deprivation therapy (ADT) has adverse effects. Alternatively, selected men may be offered salvage therapy to the prostate. Herein, we present long-term oncological outcomes of two whole-gland ablation techniques, cryotherapy (sCT) and high-intensity-focused ultrasound (sHIFU).Men undergoing sCT (1995-2004) and sHIFU (2006-2018) at Western University were identified. Oncological endpoints included biochemical recurrence (BCR), ADT initiation, metastases, castration resistance (CRPC), and prostate cancer-specific mortality (PCSM). Survival analysis with competing risks of mortality was performed. Multivariable analysis was performed using Fine and Gray regression.A total of 187 men underwent sCT and 113 sHIFU. Mean (SD) age of the entire cohort was 69.9 (5.9 years), median pre-radiation PSA 9.6 ng/ml (IQR 6.1-15.2), and pre-salvage PSA 4.5 ng/ml (IQR 2.8-7.0). Median total follow-up was 116 months (IQR 67.5-173.8). A total of 170 (57.6%) developed BCR, 68 (23.4%) metastases, 143 (49.3%) were started on ADT, 58 (20.1%) developed CRPC, and 162 (56%) patients died of which 59 (36.4%) were of prostate cancer. On multivariable analysis, sHIFU (HR 1.65, 95% CI 1.15-2.36, p = 0.006) and pre-salvage PSA (HR 1.09, 95% CI 1.06-1.13, p 0.0001) were associated with a higher risk of BCR. Similarly, sHIFU patients had a higher risk of CRPC (HR 2.31, 95% CI 1.23-4.35, p = 0.009). The cumulative incidence (for both treatments) of PCSM was 16.5% (95% CI 12.2-21.4%) at 10 years and 28.4% (95% CI 22.1-34.9%) at 20 years, with no difference between treatment modalities. Pre-salvage PSA was a common predictor for the measured oncological outcomes.Although sHIFU had higher BCR and CRPC rates, there were no differences in PCSM when compared with sCT. The long-term oncological data on two ablation techniques highlighted that only 50% of patients started ADT after 10-year follow-up.

Background Optimal management of isolated local recurrence of prostate cancer after primary radiotherapy remains to be defined. Up-front androgen deprivation therapy (ADT) is widely used but may adversely affect the quality of life and is essentially a palliative treatment. Local salvage carries a different side-effect profile and is potentially curative, but it has not been compared to ADT. Materials and methods We conducted a propensity-matched analysis of cohorts of men treated with either whole gland cryotherapy (CRYO) or primary ADT following the diagnosis of locally recurrent prostate cancer. Our specific objectives were to compare overall survival (OS) and prostate cancer-specific mortality (PCSM) between CRYO vs. ADT. Results After a one-to-one matching, 169 patients from each cohort were included in comparisons. Median follow-up time was 6.7 years (ADT) vs. 18 years (CRYO). The 10-year PCSM was 18.5% (ADT) vs. 16.2% (CRYO), which was not statistically different [hazard ratioo (HR): 0.69, 95% CI: 0.36-1.34, p=0.27]. The median OS was 12.3 years (CRYO) versus 10.2 years (ADT) (HR: 0.63, 95% CI: 0.42-0.95, p=0.03). Conclusions While PCSM was similar between the two strategies, CRYO was associated with a longer OS compared to primary ADT. Given the retrospective nature of the trial, these results should be considered hypothesis-generating, and phase III trials comparing these two options are required to further explore these findings.

INTRODUCTION AND OBJECTIVE:MRI-guided transurethral ultrasound ablation (TULSA) is a minimally-invasive procedure for customized ablation of benign and malignant prostate tissue. We report five-yea...

INTRODUCTION AND OBJECTIVE:Adverse effects (AE) following salvage cryoablation (SC) for radio-recurrent prostate cancer include urethral sloughing and urethro-rectal fistula. Prostate dystrophic ca...

© 2020 Wiley Periodicals LLC Background & Objectives: Radical inguinal lymph node dissections (rILND) for penile cancer risk significant postoperative lymphocele and lymphedema. However, reducing the risk of lymphatic complications is limited by our understanding of lymphatic anatomy. Therefore, this study aims to elucidate the lymphatic anatomy within the current surgical borders of a rILND. Methods: To visualize the position of the lymph nodes, tissue packets excised from the inguinal region of five fresh, male cadavers were imaged using microcomputed tomography (µCT). To standardize the position, rotation and size between specimens, each lymph node packet was aligned using a Generalized Procrustes analysis. Results: There was a median of 13.5 lymph nodes (range = 8-18) per packet, with the majority (99%) clustered within a 6 cm radius of the saphenofemoral junction; a region 39%-41% smaller than current surgical borders. No difference existed between the number of nodes between sides, or distribution around the saphenofemoral junction. Conclusions: This study provides the first 3D, in situ, standardized characterization of lymph node anatomy in the inguinal region using µCT. By using knowledge of the normal lymphatic anatomy, this study can help inform the reduction in borders of rILND to limit disruption and ensure a complete lymphadenectomy.

Mannitol for renal protection during partial nephrectomy is common but unsupported by evidence from clinical trials. The impact of mannitol on renal physiology includes both beneficial and harmful effects. Current understanding of renal ischemia reperfusion injury suggests potentially targetable processes that have a lower potential risk.

INTRODUCTION AND OBJECTIVES:Orthotopic neobladder (NB) offers patients distinct advantages over an ileal conduit for urinary diversion following radical cystectomy. These include the potential for ...

INTRODUCTION AND OBJECTIVES:Recurrent prostate cancer after primary radiotherapy occurs despite dose escalation, especially in higher risk groups. Local recurrence/failure can be treated using salv...

INTRODUCTION AND OBJECTIVES:Local prostate cancer recurrences after primary radiotherapy can occur, even with dose-escalation schedules. Salvage therapies can defer the use of subsequent systemic t...

INTRODUCTION AND OBJECTIVES:Testosterone and dihydrotestosterone (DHT) stimulate the growth of prostate cancer by activating androgen receptors. Androgen deprivation therapy (ADT), the first line o...

Ischaemic stroke is one of the leading causes of morbidity and mortality worldwide. While recombinant tissue plasminogen activator can be administered to produce thrombolysis and restore blood flow to the ischaemic brain, therapeutic benefit is only achieved in a fraction of the subset of patients eligible for fibrinolytic intervention. Neuroprotective therapies attempting to restrict the extent of brain injury following cerebral ischaemia have not been successfully translated into the clinic despite overwhelming pre-clinical evidence of neuroprotection. Therefore, an adequate treatment for the majority of acute ischaemic stroke patients remains elusive. In the stroke literature, the use of therapeutic gases has received relatively little attention. Gases such as hyperbaric and normobaric oxygen, xenon, hydrogen, helium and argon all possess biological effects that have shown to be neuroprotective in pre-clinical models of ischaemic stroke. There are significant advantages to using gases including their relative abundance, low cost and feasibility for administration, all of which make them ideal candidates for a translational therapy for stroke. In addition, modulating cellular gaseous mediators including nitric oxide, carbon monoxide, and hydrogen sulphide may be an attractive option for ischaemic stroke therapy. Inhalation of these gaseous mediators can also produce neuroprotection, but this strategy remains to be confirmed as a viable therapy for ischaemic stroke. This review highlights the neuroprotective potential of therapeutic gas therapy and modulation of gaseous mediators for ischaemic stroke. The therapeutic advantages of gaseous therapy offer new promising directions in breaking the translational barrier for ischaemic stroke.

Summary Currently there are few effective therapeutic interventions for the acute treatment of ischaemic stroke. The few that do exist are primarily thrombolytics such as recombinant tissue plasminogen activator, which reperfuse the ischaemic brain region but do not otherwise aid in neuroprotection. One of the principal explanations as to why the vast majority of neuroprotective drug trials have failed is that the drugs’ therapeutic windows were too narrow to be clinically effective. The inflammatory reaction post-stroke makes a significant contribution to the neurological deterioration witnessed in patients. Since inflammatory mediators have been shown to be upregulated from 1 h to 3 months post-stroke, they represent an ideal target to exploit for therapeutic interventions as their ‘actions’ can potentially be halted within a clinically relevant therapeutic window. There is also mounting evidence that ischaemic stroke can be exacerbated by a predisposition to chronic inflammation and autoimmunity. This review details the role of inflammation and autoimmunity in stroke and how mediators of these pathways can be developed for therapeutic interventions. Recommendations are also made for an ideal therapy regime for acute ischaemic stroke, utilizing currently available, clinically proven treatments. Lastly, novel strategies for future experimental and clinical stroke research are discussed.

The efficacy of melatonin treatment in experimental stroke has been established. Some of the neuroprotective properties have been attributed to its anti-oxidant and anti-inflammatory effects. Nitric oxide synthases (NOS) and cyclooxygenases (COX) are considered to have a significant role in the inflammatory milieu occurring in acute stroke. While previous reports have shown that pretreatment with melatonin in a stroke model can modulate NOS isoforms, the effect of post-treatment with melatonin on l-arginine metabolism has not been investigated. This study initially examined the effect of melatonin (1 nm-1 mm) on l-arginine metabolism pathways in human fibrosarcoma fibroblasts (HT-1080) fibroblasts. Evidence of neuroprotection with melatonin was evaluated in rats subjected to middle cerebral artery occlusion (MCAO). Animals were treated with three daily doses of 5 mg/kg i.p., starting 1 hr after the onset of ischemia. Constitutive NOS activity but not expression was significantly increased by in vitro exposure (72 hr) to melatonin. In addition, melatonin treatment increased arginase activity by increasing arginase II expression. In vivo studies showed that melatonin treatment after MCAO significantly inhibited inducible NOS activity and attenuated expression of the inducible isoform, resulting in decreased total NOS activity and tissue nitrite levels. COX activity was significantly reduced with melatonin treatment. The neuroprotective anti-inflammatory effects of melatonin were consistent with the substantial reduction in infarct volume throughout the cortex and striatum and recovery of mitochondrial enzyme activities. The evidence presented here suggests that modulation of l-arginine metabolism by melatonin make it a valuable neuroprotective therapy for stroke.

The regional and cellular distribution of heme oxygenase (HO)-1 and -2 following cerebral ischemia has not been ascertained. Employing the transient middle cerebral artery occlusion (MCAO) and hypoxia-ischemia (HI) models of unilateral brain injury, the aim was to elucidate immunolocalization of HO-1 and HO-2. Animals were sacrificed 3 days post-ischemia and immunohistochemistry and Western blotting were utilized to determine HO-1 and HO-2 expression. In the ipsilateral hemisphere following HI, HO-1 immunoreactivity was significantly upregulated in many neuronal and glial populations (including the cortex, hippocampus and thalamus). HO-1 was also detected in macrophages/microglia within the infarct. In addition to widespread neuronal HO-2 labelling, HO-2 was also expressed in vascular endothelial cells. Inflammatory cells within the infarct of MCAO and HI animals were surprisingly immunoreactive for HO-2, but only HI animals had significantly elevated HO-2 protein expression in the ipsilateral hemisphere. This may be due to the presence of global hypoxia in the HI model which can upregulate vascular endothelial growth factor and subsequent proliferation of endothelial cells. This report of HO-2 protein expression upregulation following HI coupled with an increase in HO-1 immunoreactivity suggests that this response may be implicated in reducing cell death or repairing damage induced by cerebral ischemia.

Until recently the cannabinoid CB2 receptor was believed to be absent from the central nervous system. In this study we have identified CB2 expressing cells that appear in the rat brain following stroke and hypoxic-ischemia. At 3 days following surgery CB2-positive macrophages, deriving from resident microglia and/or invading monocytes appear on the lesioned side of the brain. By day 7, a mixed population of CB2-positive cells is present. Microglia-derived macrophages are the key cells in the first stages of brain inflammation, and a pivotal step in the neurodegeneration that follows the acute stage of injury. Thus, CB2 may be important in the brain during injury, and in inflammatory neurodegenerative disorders. The presence of CB2-positive cells in the brain following stroke may provide a novel strategy for cannabinoid-mediated intervention into stroke induced neurodegeneration without the psychoactive effects of CB1 receptor stimulation.

This study examined the neuroprotective effects and possible hepatotoxicity of (-)-epigallocatechin gallate (EGCG) in a rat model of transient focal cerebral ischemia. Male Sprague-Dawley rats (265-295 g) were treated with either 50 mg kg(-1) of EGCG or saline, i.p., immediately post-ischemia and every day thereafter, in a middle cerebral artery occlusion model of stroke. Sacrifice occurred 72 h post-ischemia and 2,3,5-triphenyltetrazolium chloride staining was used to quantify neuronal infarction. Hepatotoxicity was determined by taking blood samples for plasma alanine aminotransferase (ALT) activity. Spleen, kidney, liver and testes wet weights were also recorded. Total infarct volume was significantly (P0.05) reduced in the EGCG-treated group as compared to controls. Analysis of the mean infarct area showed a significant (P0.05) decrease in slices 6 and 7 in the EGCG-treated group. No significant differences were found in organ weights or ALT levels between treatment groups. Our findings, in part, validate and extend previous observations illustrating that 50 mg kg(-1), i.p. EGCG is non-toxic and neuroprotective. However, we also found that EGCG treatment appreciably increased (50%) the number of animals that developed an intracerebral hemorrhage. We therefore conclude that 50 mg kg(-1) EGCG is not a viable intervention for the acute treatment of cerebral ischemia, as it is likely to increase the risk of intracerebral hemorrhaging.

Background There is a shortage of health professionals in Pacific Island states and territories, and a need in New Zealand for Pacific health professionals to serve Pacific communities. Methods A cross-sectional postal survey was conducted to investigate retention of Pacific graduates. All graduates of Pacific ethnicity or nationality from the University of Otago in the years 1994 to 2004 in medicine, dentistry, pharmacy, physiotherapy and medical laboratory science were included. Results The response rate was 59% (75 out of 128). Only 7% of respondents were working in the Pacific Islands (12% of non-residents and 4% of New Zealand residents), though the proportion in the whole cohort could be up to 20%. One third intended to work in Pacific communities in New Zealand or the Pacific Islands in the future. Factors that would favour such an intention were an adequate income, job availability, and good working conditions. Conclusions Retention of graduates in the Pacific Islands is poor and measures to improve retention are needed.