Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells–macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.

Isometric tension measurement using a selective Rho-kinase inhibitor ( þ )-(R)-trans4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide (Y-27632) and a selective myosin light chain kinase (MLCK) inhibitor 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML7) were used in rabbit clitoral cavernosum smooth muscle (CSM). N G -nitro-L-arginine methyl ester (L-NAME) was used to evaluate the relationship between NO release and Rho-kinase. Y-27632 significantly attenuated contractions induced by ANG II, dose-dependently. However, ML7 did not affect the contractile response to ANG II except in the high concentrations of ML7. Y-27632 inhibited contraction with phenylephrine (PhE), but ML7 did not inhibit contraction with PhE. Nitric oxide synthase inhibitor (NAME) did not affect the Y-27632-induced relaxation in the pre-contracted strip with PhE. The present study demonstrates that G-protein-coupled increase in myofilament Ca 2þ sensitivity mediated through the RhoA=Rho-kinase signal pathway is involved in the control by ANG II of the clitoral CSM tone. RhoA=Rho-kinase pathway acts in the ANG IIinduced contraction independently of the NO pathway.

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There are limited data on the clinical significance of positive central venous catheter (CVC) tip cultures associated with concomitant negative blood cultures performed at the time of CVC removal. A retrospective cohort study of all patients who yielded isolated positive CVC tip cultures was conducted in a tertiary-care hospital with 2200 beds during a 10-year period. All patients with isolated positive CVC tip cultures were observed for the development of subsequent bacteraemia or fungaemia between 2 and 28 days after CVC removal. An isolated positive CVC tip culture was defined as a case in which (i) a CVC tip culture yielded > or = 15 colonies using a semiquantitative culture method and (ii) at least two sets of blood samples revealed no organism at, or close to, the time of CVC removal (48 h before to 48 h after CVC removal). During the study period, 312 patients with isolated positive CVC cultures were enrolled. Eight (2.6%; 95% CI 1.2-5.1) of the 312 patients yielding isolated bacterial or fungal CVC tip cultures developed subsequent bloodstream infection (BSI) caused by the same species as that isolated from the tip culture (Staphylococcus aureus, 1: Enterococcus spp.; 2: Pseudomonas aeruginosa; and 3: Candida spp.). Among 125 patients from whose CVC tips the above four organisms were grown, seven (12.3%) of 57 patients who did not receive appropriate antibiotic therapy within 48 h after CVC removal subsequently developed BSI, but only one (1.5%) of 68 patients who did receive appropriate therapy developed BSI (OR 0.11, p 0.02).

This retrospective study was conducted to determine the risk factors for resistance to extended-spectrum cephalosporins (ESCs) and to examine the influence of previous use of an aminoglycoside with an ESC on resistance to ESCs in patients with Enterobacter bacteremia from January 1991 through December 2000. A total of 423 episodes of Enterobacter bacteremia among 414 patients were documented during the 10-year study period. Three hundred thirty-two (78%) isolates were Enterobacter cloacae, 72 (17%) Enterobacter aerogenes, and 19 (4%) other Enterobacter species. Causative isolates exhibited resistance to ESCs in 225 episodes and susceptibility in 198 episodes. Nosocomial acquisition was an independent risk factor for resistance to ESCs (odds ratio [OR], 3.4; 95% confidence interval [95%CI], 1.7-6.8). The median number of antibiotics used was significantly greater in cases caused by resistant isolates than in cases caused by susceptible isolates (OR, 1.8; 95%CI, 1.2-2.6). Resistance to ESCs was associated with previous use of any ESC (OR, 5.0; 95%CI, 2.5-10.2). The proportion of resistant episodes in patients treated previously with an aminoglycoside plus an ESC was not different from that in patients treated with an ESC alone. In conclusion, previous use of ESCs was associated with resistance to ESCs in patients with Enterobacter bacteremia; moreover, previous use of an aminoglycoside with an ESC did not significantly decrease the risk of resistance to ESCs.

Paradoxical response presents late in about one third of non-HIV-infected patients with lymph node TB who experience a response. Although anti-tuberculosis treatment is commonly prolonged in patients with late paradoxical response, post-treatment lymph node enlargement is more frequent in these patients.

Background: Retrospective observational study to determine diagnostic yield and utility of genetic testing in children with epilepsy attending the Epilepsy Clinic at Children’s Hospital, London, Ontario, Canada. Methods: Children (birth–18 years) with epilepsy, who were seen in a 10-year period (January 1, 2008–March 31, 2018), were selected using defined inclusion criteria and by combining clinic datasets and laboratory records. Results: In total, 105 children (52.38% male and 47.61% female) with a variety of seizures were included in the analysis. Developmental delay was documented in the majority (83; 79.04%). Overall, a genetic diagnosis was established in 24 (22.85%) children. The diagnostic yield was highest for whole-exome sequencing (WES), at 35.71%. The yield from microarray was 8.33%. Yields of single-gene testing (18.60%) and targeted multigene panel testing (19.23%) were very similar. Several likely pathogenic and pathogenic variants not previously reported were identified and categorized using ACMG criteria. All diagnosed patients underwent a review of anti-seizure medication management and received counseling on natural history of their disease, possible complications, recurrence risks, and possibilities of preimplantation or prenatal genetic diagnosis. Conclusions: Our study confirms the multiple benefits of detecting a genetic etiology in children with epilepsy. Similar yields in single versus multigene testing underscore the importance of accurate clinical phenotyping. Patients with epilepsy and their caregivers in Ontario would undoubtedly benefit from repatriation of multigene panels and WES to the province.

Background: There is evidence that male neonates have higher incidences of ischemic stroke and associated limitations in brain repair compared to female neonates. We used data from the International Maternal Newborn Stroke Registry (IMNSR) to further explore neonatal sex differences in demographics, birth characteristics, stroke onset, and maternal factors. Methods: Eleven international sites participated; 8 entered data for this analysis. Eligible participants with newborn (28 weeks gestation to 28 postnatal days) ischemic or hemorrhagic stroke or cerebral venous thrombosis were identified prospectively and retrospectively and enrolled. Preterm infants born before 28 weeks and neonates with germinal matrix intraventricular hemorrhage were excluded. We collected APGAR scores at 1 and 5 minutes, resuscitation status, demographics, stroke type, maternal and gestational age at birth, and mother’s health conditions at birth. Descriptive statistics were performed to identify differences in female versus male neonate cases related to demographics, pregnancy-related factors, and birth-related factors. Results: We analyzed 68 cases, 38 males and 30 females. Median maternal age for all cases was 31 y (IQR 29-34). Compared to females, males were more likely to have a lower APGAR 1 score and receive resuscitation, and more likely to have a stroke onset within the first week of life. This data set did not show significant gender-related differences in stroke type, or maternal health concerns during pregnancy (Table). Conclusions: We found that males with newborn strokes had more complications at birth and were more likely to have strokes present in the first week of life than females. Further research on the reasons for these sex differences is needed.