Recently, a G84E mutation in HOXB13, a gene involved in prostate development, was shown to be strongly associated with an increased risk of prostate cancer. To confirm this association in a screening setting, we conducted a case-control study and sequenced germline DNA from peripheral leukocytes of 1843 men diagnosed with prostate cancer (case subjects) and 2225 men without prostate cancer (control subjects) for mutations in HOXB13. Subjects (aged 40-94 years) were prescreened and underwent a prostate biopsy at two tertiary care centers in Canada. The frequency of HOXB13 variants was determined in case subjects and control subjects by race, and odds ratios and 95% confidence intervals were based on 2×2 table analysis. All statistical tests were two-sided. Twelve men of white race were identified to be carriers of the G84E mutation. The G84E mutation was more frequent among white case subjects than among white control subjects (10 of 1525 [0.7%] vs 2 of 1757 [0.1%], P = .01) and was associated with an increased risk of prostate cancer (unadjusted odds ratio = 5.8, 95% confidence interval = 1.3 to 26.5, P = .01).

E.W. and P.P. contributed equally to this manuscript Objective• To examine the development of recurrent urinary tract infections (UTIs) in boys who have undergone hypospadias repair. Materials and Methods• We retrospectively reviewed the records of all boys who had recurrent UTIs after primary or redo tubularized incised plate (TIP) or transverse island flap (TVIF) repairs, between 1998 and 2009. • Data on age, operating details, postoperative complications and imaging studies were collected.• We attempted to identify risk factors for recurrent UTIs after hypospadias repair. Results• During the study period, 43/2249 boys (1.91%) were diagnosed with recurrent UTIs after hypospadias repair. The boys' mean (range) age at repair was 14 (6-24) months and the median (range) follow-up was 6.5 (1.5-11) years.• Primary TIP and TVIF were performed in 47% (20/43) and 35% (15/43) of the boys, respectively. Redo surgeries were performed in 18% of the boys (8/43). The initial meatal location was proximal in all TVIF and redo repairs, and in one of the TIP repairs.• Postoperative voiding cysto-urethrography, ultrasonography and dimercapto-succinic acid (DMSA) scans were performed in 58% (25/43), 90% (39/43) and 19% (8/43) of the boys, respectively. Abnormalities were noted.• Of those boys who underwent a TVIF repair, urethral diverticula were seen in 47% (7/15) and urethral fistulae were also seen in 47% (7/15). Conversely, in those who had a TIP repair, an elevated PVR and vesico-ureteric reflux were more common; they were found in 40% (8/20) and 50% (10/20) of patients, respectively. Conclusions• The pathophysiology of recurrent UTI is multifactorial, but postoperative complications seem to vary with type of procedure.• Recurrent UTIs after hypospadias surgery should prompt a specific assessment for potentially functionally relevant and correctable anatomical abnormalities.

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Parkinson disease (PD) is a complex disease affecting many facets of movement, especially gait abnormalities such as shuffling and freezing of gait. The nigrostriatal pathways of the basal ganglia are traditionally targeted by existing therapies; however, other pathways may be more relevant to gait, such as the pedunculopontine nucleus and the zona incerta (ZI). The A13 nucleus may be such a target as it has emerged as an area of interest in dopamine motor function. Yet, this area remains understudied compared to other dopamine nuclei, especially in animal models of PD. In 6-OHDA mice, we found a reduction in locomotion in the open field and gait dysfunction during treadmill tests. Medial ZI dopamine cells, containing the A13 nucleus, were preserved following 6-OHDA, in contrast to a marked reduction in substantia nigra pars compacta (SNc) neurons. There was extensive remodelling of the A13 afferent and efferent connectome following nigrostriatal lesions. Afferent input patterns displayed a marked reduction in cross-correlation across brain regions in 6-OHDA mice, while efferent projections showed an increase. In a human PD patient with advanced gait dysfunction we found that the A13 nucleus was preserved, suggesting that remodelling could also occur in humans. This work points to the A13 region as a potential therapeutic target in PD.

Introduction: The analgesic properties of CBD and THC in cannabis can potentially be leveraged for the treatment of neuropathic pain but have not been well investigated. Some commercial analgesics, such as opioids, have unfavourable side effects including addiction, which does not exist in cannabis. Combinations of CBD and THC may not only elicit stronger analgesic effects than single-compound drugs, but also curb the psychotropic effects commonly associated with THC. We present a novel protocol to find the ideal substance ratio in a CBD-THC mixture, which elicits maximum antinociception with the least psychotropic effect. Methods: BALB/c mice will be assigned to 12 different treatment groups, representing 9 different ratios of CBD-THC mixtures, 2 positive controls (URB937 and sertraline hydrochloride), and 1 vehicle. Each mouse will be administered a compound via intraperitoneal injection and then subjected to behavioural testing. Chronic constriction injury and the Hargreaves' Test (HT) will be used to test nociceptive behaviour while the Tail Suspension Test (TST) will be used to test depression-like behaviour. Expected Results: The ideal CBD-THC mixture will produce maximum withdrawal latency in the HT and maximum immobility time in the TST. Because the analgesic properties of combined CBD and THC still remain unclear in current literature, it is difficult to predict how withdrawal latency in the HT will change with varying CBD:THC ratios. Based on the psychotropic effects of THC, we expect increased THC concentrations to decrease immobility time in the TST. Conclusion: By determining the optimal ratio of CBD:THC for maximal pain suppression and minimal psychotropic effects, our protocol may provide justification for an alternative non-addictive therapeutic for treating neuropathic pain. In order to increase the generalizability and translatability of the results in a clinical setting, future studies could benefit from changes in dosing strategies, routes of administration, supplemental observation methods, and experimental timeframes.