A record-linkage study of the development of hepatocellular carcinoma in persons with hepatitis C infection in Scotland

We investigated trends in first time hospital admissions and deaths attributable to hepatocellular carcinoma (HCC) in a large population based cohort of 22 073 individuals diagnosed with hepatitis C viral (HCV) infection through laboratory testing in Scotland in 1991 2006. We identified new cases of HCC through record linkage to the national inpatient hospital discharge database and deaths registry. A total of 172 persons diagnosed with HCV were admitted to hospital or died with first time mention of HCC. Hepatocellular carcinoma incidence increased between 1996 and 2006 (average annual change of 6.1, 95% confidence interval (CI):0.9 11.6%, P¼0.021). The adjusted relative risk of HCC was greater for males (hazard ratio¼2.7, 95% CI: 1.7 4.2), for those aged 60 years or older (hazard ratio ¼2.7, 95% CI: 1.9 4.1) compared with 50 59 years, and for those with a previous alcohol related hospital admission (hazard ratio¼2.5, 95% CI: 1.7 3.7). The risk of individuals diagnosed with HCV developing HCC was greatlyincreased compared with the general Scottish population (standardised incidence ratio¼127, 95% CI: 102 156). Owing to the advancing age of the Scottish HCV diagnosed population, the annual number of HCC cases is projected to increase, with a consequent increasing burden on the public healthcare system

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Structure of the TPR Domain of AIP: Lack of Client Protein Interaction with the C-Terminal alpha-7 Helix of the TPR Domain of AIP Is Sufficient for Pituitary Adenoma Predisposition

PMCID: PMC3534021This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Desynchronization of Diurnal Rhythms in Bipolar Disorder and Borderline Personality Disorder

It has long been proposed that diurnal rhythms are disturbed in bipolar disorder (BD). Such changes are obvious in episodes of mania or depression. However, detailed study of patients between episodes has been rare and comparison with other psychiatric disorders rarer still. Our hypothesis was that evidence for desynchronization of diurnal rhythms would be evident in BD and that we could test the specificity of any effect by studying borderline personality disorder (BPD). Individuals with BD (n = 36), BPD (n = 22) and healthy volunteers (HC, n = 25) wore a portable heart rate and actigraphy device and used a smart-phone to record self-assessed mood scores 10 times per day for 1 week. Average diurnal patterns of heart rate (HR), activity and sleep were compared within and across groups. Desynchronization in the phase of diurnal rhythms of HR compared with activity were found in BPD (+3 h) and BD (+1 h), but not in HC. A clear diurnal pattern for positive mood was found in all subject groups. The coherence between negative and irritable mood and HR showed a four-cycle per day component in BD and BPD, which was not present in HC. The findings highlight marked de-synchronisation of measured diurnal function in both BD but particularly BPD and suggest an increased association with negative and irritable mood at ultradian frequencies. These findings enhance our understanding of the underlying physiological changes associated with BPD and BD, and suggest objective markers for monitoring and potential treatment targets. Improved mood stabilisation is a translational objective for management of both patient groups

Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication

Background & Aims: The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. Methods: Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. Results: Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1–59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9–8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0–4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0–11.4) among those with cirrhosis (p = 0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0–5.5) among patients <45 years, 9.7% (95% CI 5.8–13.6) among patients from 45–60 years, and 12.2% (95% CI 5.3–19.1) among patients >60 years of age at start of therapy (p = 0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8 years 4.2% (95% CI 0.1–8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3–19.3) of patients with cirrhosis experienced clinical disease progression (p = 0.007). Conclusions: Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. Lay summary: Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer. 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserve

Association of patients' sex with treatment outcomes after intravesical bacillus Calmette-Guérin immunotherapy for T1G3/HG bladder cancer.

Purpose: To investigate the association of patients' sex with recurrence and disease progression in patients treated with intravesical bacillus Calmette-Guérin (BCG) for T1G3/HG urinary bladder cancer (UBC). Materials and methods: We analyzed the data of 2635 patients treated with adjuvant intravesical BCG for T1 UBC between 1984 and 2019. We accounted for missing data using multiple imputations and adjusted for covariate imbalance between males and females using inverse probability weighting (IPW). Crude and IPW-adjusted Cox regression analyses were used to estimate the hazard ratios (HR) with their 95% confidence intervals (CI) for the association of patients' sex with HG-recurrence and disease progression. Results: A total of 2170 (82%) males and 465 (18%) females were available for analysis. Overall, 1090 (50%) males and 244 (52%) females experienced recurrence, and 391 (18%) males and 104 (22%) females experienced disease progression. On IPW-adjusted Cox regression analyses, female sex was associated with disease progression (HR 1.25, 95%CI 1.01-1.56, p = 0.04) but not with recurrence (HR 1.06, 95%CI 0.92-1.22, p = 0.41). A total of 1056 patients were treated with adequate BCG. In these patients, on IPW-adjusted Cox regression analyses, patients' sex was not associated with recurrence (HR 0.99, 95%CI 0.80-1.24, p = 0.96), HG-recurrence (HR 1.00, 95%CI 0.78-1.29, p = 0.99) or disease progression (HR 1.12, 95%CI 0.78-1.60, p = 0.55). Conclusion: Our analysis generates the hypothesis of a differential response to BCG between males and females if not adequately treated. Further studies should focus on sex-based differences in innate and adaptive immune system and their association with BCG response

Lagrangian Lie subalgebroids generating dynamics for second-order mechanical systems on Lie algebroids

The study of mechanical systems on Lie algebroids permits an understanding of the dynamics described by a Lagrangian or Hamiltonian function for a wide range of mechanical systems in a unified framework. Systems defined in tangent bundles, Lie algebras, principal bundles, reduced systems, and constrained are included in such description. In this paper, we investigate how to derive the dynamics associated with a Lagrangian system defined on the set of admissible elements of a given Lie algebroid using Tulczyjew’s triple on Lie algebroids and constructing a Lagrangian Lie subalgebroid of a symplectic Lie algebroid, by building on the geometric formalism for mechanics on Lie algebroids developed by M. de León, J.C. Marrero and E. Martínez on “Lagrangian submanifolds and dynamics on Lie algebroids”publishe