Recurrence after postoperative intravesical instillation therapy in Hunner type interstitial cystitis.

We performed a prospective, single-arm study comparing outcomes between transurethral ablation plus postoperative instillation of hyaluronic acid and chondroitin sulfate (HACS group) and transurethral ablation only in patients with Hunner type interstitial cystitis (historical control group). A total of 78 patients were enrolled, and 51 were included in the per-protocol analysis set. The 2-year recurrence rate was 47.1% (95% CI, 32.9-61.5) in the HACS group, which was significantly lower than that in the control group (86.2%; 95% CI, 74.6-93.9, P < 0.001). After instillation therapy, the hazard ratio for recurrence was 0.38 (95% CI, 0.23-0.65, P < 0.001). The HACS group had an increased recurrence-free survival with the median interval not being reached, while it was 11.4 months in the control group (95% CI, 8.8-13.8, P < 0.001). Regardless of the instillation treatment, there were significant improvements in all symptom questionnaire scores and pain compared to the baseline. However, in the instillation group, improvement was stable even after 12 months. In patients with Hunner type interstitial cystitis, intravesical instillation of hyaluronic acid and chondroitin sulfate after transurethral ablation significantly reduced the recurrence rate and maintained symptom improvement for more than 1 year.

Utility of Contemporary Health Screening in the Diagnosis of Bladder Cancer.

BACKGROUND: To evaluate the utility of contemporary health screening (HS) in the diagnosis of bladder cancer (BCa). METHODS: We retrospectively reviewed 279,683 individuals who underwent HS between February 1995 and April 2015. Among these individuals, 74 were diagnosed with BCa within a year after the HS and were included in the analysis. Screen-detected BCa was defined as when a referral was made to a urologist due to microscopic hematuria (MH) on urinalysis, abnormal imaging, or any urological symptoms observed at the HS. Screen-undetected BCa was defined as when no referral was made to a urologist because of no abnormality observed at the HS, but a visit to a urological outpatient clinic later was followed by a BCa diagnosis. The incidences of screen-detected BCa and BCa in the Korean population were compared. Clinicopathological characteristics were compared between the screen-detected BCa and screen-undetected BCa groups. RESULTS: The detection rate of BCa was 17.2 per 100,000, which exceeded the 2020 estimated national crude incidence rate of 9.3 per 100,000 by approximately 1.7 times. Among the 74 patients diagnosed with BCa within a year after HS, 48 (64.9%) had screen-detected BCa. The screen-detected BCa group had a higher T stage (p = 0.009) and grade (p = 0.019) than the screen-undetected BCa group. However, the overall survival was not significantly different between the two groups (p = 0.677). A positive correlation between the MH grade and the T stage was identified (p = 0.001). CONCLUSION: Although HS is not focused on BCa screening, contemporary HS can contribute to the detection of BCa.

NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages.

Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 inflammasome activation. Furthermore, Nox4-deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1ß and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 inflammasome activation.

The High Mobility Group A1 (HMGA1) gene is highly overexpressed in human uterine serous carcinomas and carcinosarcomas and drives Matrix Metalloproteinase-2 (MMP-2) in a subset of tumors.

OBJECTIVES: Although uterine cancer is the fourth most common cause for cancer death in women worldwide, the molecular underpinnings of tumor progression remain poorly understood. The High Mobility Group A1 (HMGA1) gene is overexpressed in aggressive cancers and high levels portend adverse outcomes in diverse tumors. We previously reported that Hmga1a transgenic mice develop uterine tumors with complete penetrance. Because HMGA1 drives tumor progression by inducing MatrixMetalloproteinase (MMP) and other genes involved in invasion, we explored the HMGA1-MMP-2 pathway in uterine cancer. METHODS: To investigate MMP-2 in uterine tumors driven by HMGA1, we used a genetic approach with mouse models. Next, we assessed HMGA1 and MMP-2 expression in primary human uterine tumors, including low-grade carcinomas (endometrial endometrioid) and more aggressive tumors (endometrial serous carcinomas, uterine carcinosarcomas/malignant mesodermal mixed tumors). RESULTS: Here, we report for the first time that uterine tumor growth is impaired in Hmga1a transgenic mice crossed on to an Mmp-2 deficient background. In human tumors, we discovered that HMGA1 is highest in aggressive carcinosarcomas and serous carcinomas, with lower levels in the more indolent endometrioid carcinomas. Moreover, HMGA1 and MMP-2 were positively correlated, but only in a subset of carcinosarcomas. HMGA1 also occupies the MMP-2 promoter in human carcinosarcoma cells. CONCLUSIONS: Together, our studies define a novel HMGA1-MMP-2 pathway involved in a subset of human carcinosarcomas and tumor progression in murine models. Our work also suggests that targeting HMGA1 could be effective adjuvant therapy for more aggressive uterine cancers and provides compelling data for further preclinical studies.

Impaired oxidative phosphorylation regulates necroptosis in human lung epithelial cells.

Cellular metabolism can impact cell life or death outcomes. While metabolic dysfunction has been linked to cell death, the mechanisms by which metabolic dysfunction regulates the cell death mode called necroptosis remain unclear. Our study demonstrates that mitochondrial oxidative phosphorylation (OXPHOS) activates programmed necrotic cell death (necroptosis) in human lung epithelial cells. Inhibition of mitochondrial respiration and ATP synthesis induced the phosphorylation of mixed lineage kinase domain-like protein (MLKL) and necroptotic cell death. Furthermore, we demonstrate that the activation of AMP-activated protein kinase (AMPK), resulting from impaired mitochondrial OXPHOS, regulates necroptotic cell death. These results suggest that impaired mitochondrial OXPHOS contributes to necroptosis in human lung epithelial cells.

Percutaneous Ventricular Assist Devices and ECMO in the Management of Acute Decompensated Heart Failure.

The successful treatment of acute decompensated heart failure continues to evolve with an increasing utilization of nondurable mechanical support devices. Indications for acute support have broadened to include their use as a bridge to recovery or decision (for durable ventricular assist devices [VADs] or heart transplant). Available devices have improved in terms of effectiveness, ease of insertion, and reduction in complications. The commonly used devices (intra-aortic balloon pump, TandemHeart, Impella, and extracorporeal membrane oxygenation circuit), together with their mechanisms of action, are reviewed. Current considerations for support, specific to each device, are examined and future directions and indications for percutaneous VADs are explored.

Meaningful inclusion of consumers in research and service delivery.

OBJECTIVE: Although participatory methods have become increasingly popular, people with lived experience of mental illness and homelessness have been historically excluded from service planning and research. To better plan for meaningful inclusion of consumers, this study examines lessons learned from the People with Lived Experience Caucus in the Toronto Site of the At Home/Chez Soi Research Demonstration Project on Homelessness and Mental Health. METHOD: The inclusion of the People with Lived Experience Caucus was evaluated using qualitative methods and multiple data sources, including review of 42 documents, 11 individual interviews, and three focus groups. Caucus members were included in the study team. Transcripts were analyzed using grounded theory methodology. RESULTS: Findings revealed a complex story of Caucus engagement: Facing time constraints and given little direction, the Caucus developed through a tumultuous process related to both internal and external barriers to meaningful inclusion. Despite the challenges, the Caucus contributed meaningfully to various aspects of the research demonstration project. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: It is possible to successfully integrate psychiatric consumers with experience of homelessness in many aspects of research and service planning. Suggestions for future initiatives hoping to engage consumers include: early involvement, purposeful selection of members, clear communication of roles and responsibilities, a consumer coordinating group, and space for critical dialog throughout the process. Lessons learned can inform the inclusion of consumers in similar endeavors in other jurisdictions.

Prasugrel: a new antiplatelet drug for the prevention and treatment of cardiovascular disease.

Prasugrel, trade name Effient, is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration. It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine. Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic P2Y12 receptor on the platelet surface. Prasugrel has been shown to be a potent antiplatelet agent with a faster, more consistent, and greater inhibition of platelet aggregation compared with clopidogrel. It is debatable, however, how effectively these pharmacologic benefits will translate to clinical benefits. The results of the large TRITON-TIMI 38 trial, which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents, demonstrated a significant reduction in ischemic events, including stent thrombosis, with prasugrel, but with an increased risk of major bleeding. The exact role of prasugrel in the management of ischemic heart disease is still being defined, but the risk:benefit ratio will likely play a major role in directing the best place for therapy with this new agent.

Transmural heterogeneity of calcium handling in canine.

Spatial heterogeneity of the action potential and its influence on arrhythmia vulnerability is known. However, heterogeneity of intracellular calcium handling and, in particular, its effect on the electrophysiological substrate is less clear. Using optical mapping techniques, calcium transients and action potentials were recorded simultaneously from ventricular sites across the transmural wall of the arterially perfused canine left ventricular wedge preparation during steady-state baseline pacing and rapid pacing. During baseline pacing, the decay of intracellular calcium to diastolic levels and calcium transient duration were slower (70%, P<0.005) and longer (20%, P<0.005), respectively, closer to the endocardial surface compared with the epicardial surface. Tissue samples isolated from the left ventricular wall demonstrate that sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) expression was significantly less in the subendocardial and midmyocardial layers compared with the subepicardial layer. In contrast, no significant difference in the transmural expression of Na+-Ca2+ exchanger was observed. During rapid pacing, calcium transient alternans and increased levels of diastolic intracellular calcium were significantly greater (P<0.01) closer to the endocardium (101%+/-62% and 41%+/-15%, respectively) compared with the epicardium (12%+/-7% and 12%+/-14%, respectively). In conclusion, cells closer to the endocardium exhibit a slower decay of intracellular calcium compared with cells near the epicardium, which may be due in part to reduced expression of SERCA2a. As a possible consequence, calcium transient alternans and increased diastolic levels of intracellular calcium may occur preferentially closer to the endocardial surface.