Feasibility study of an internally cooled bipolar applicator for RF coagulation of hepatic tissue: Experimental and computational study

Purpose: To study the capacity of an internally cooled radiofrequency (RF) bipolar applicator to create sufficiently deep thermal lesions in hepatic tissue. Materials and methods: Three complementary methodologies were employed to check the electrical and thermal behaviour of the applicator under test. The experimental studies were based on excised bovine (ex vivo study) and porcine liver (in vivo study) and the theoretical models were solved by means of the finite element method (FEM). Results: Experimental and computational results showed good agreement in terms of impedance progress and lesion depth (4 and 4.5 mm respectively for ex vivo conditions, and approximately 7 and 9 mm respectively for in vivo conditions), although the lesion widths were overestimated by the computer simulations. This could have been due to the method used to assess the thermal lesions; the experimental lesions were assessed by the white coagulation zone, whereas the tissue damage function was used to assess the computational lesions. Conclusions: The experimental results suggest that this applicator could create in vivo lesions to a depth of around 7mm. It was also observed that the thermal lesion is mainly confined to the area between both electrodes, which would allow lesion width to be controlled by selecting a specific applicator design. The comparison between the experimental and computational results suggests that the theoretical model could be usefully applied in further studies of the performance of this device. © 2012 Informa UK Ltd All rights reserved.This work received financial support from the Spanish Plan Nacional de I+D+I del Ministerio de Ciencia e Innovacion TEC2011-27133-C02-(01 and 02), from Universitat Politecnica de Valencia (INNOVA11-01-5502; and PAID-06-11 Ref. 1988). A. Gonzalez-Suarez is the recipient of grant VaLi+D (ACIF/2011/194) from the Generalitat Valenciana. The proof-reading of this paper was funded by the Universitat Politecnica de Valencia, Spain. The authors alone are responsible for the content and writing of the paper.González Suárez, A.; Trujillo Guillen, M.; Burdío Pinilla, F.; Andaluz Martínez, AM.; Berjano Zanón, E. (2012). Feasibility study of an internally cooled bipolar applicator for RF coagulation of hepatic tissue: Experimental and computational study. International Journal of Hyperthermia. 28(7):663-673. https://doi.org/10.3109/02656736.2012.716900S663673287Topp, S. A., McClurken, M., Lipson, D., Upadhya, G. A., Ritter, J. H., Linehan, D., & Strasberg, S. M. (2004). Saline-Linked Surface Radiofrequency Ablation. Annals of Surgery, 239(4), 518-527. doi:10.1097/01.sla.0000118927.83650.a4Gnerlich, J. L., Ritter, J. H., Linehan, D. C., Hawkins, W. G., & Strasberg, S. M. (2009). Saline-Linked Surface Radiofrequency Ablation. 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A structural MRI study in monozygotic twins concordant or discordant for attention/hyperactivity problems: Evidence for genetic and environmental heterogeneity in the developing brain.

Several structural brain abnormalities have been reported in patients with Attention Deficit Hyperactivity Disorder (ADHD). However, the etiology of these brain changes is still unclear. To investigate genetic and environmental influences on ADHD related neurobiological changes, we performed Voxel-Based Morphometry on MRI scans from monozygotic (MZ) twins selected from a large longitudinal population database to be highly concordant or highly discordant for ratings on the Child Behavior Checklist Attention Problem scale (CBCL-AP). Children scoring low on the CBCL-AP are at low risk for ADHD, whereas children scoring high on this scale are at high-risk for ADHD. Brain differences between concordant high-risk twin pairs and concordant low-risk twin pairs likely reflect the genetic risk for ADHD; brain differences between the low-risk and high-risk twins from discordant MZ twin pairs reflect the environmental risk for ADHD. A major difference between comparisons of high and low-risk twins from concordant pairs and high/low twins from discordant pairs was found for the prefrontal lobes. The concordant high-risk pairs showed volume loss in orbitofrontal subdivisions. High-risk members from the discordant twin pairs exhibited volume reduction in the right inferior dorsolateral prefontal cortex. In addition, the posterior corpus callosum was compromised in concordant high-risk pairs, only. Our findings indicate that inattention and hyperactivity symptoms are associated with anatomical abnormalities of a distributed action-attentional network. Different brain areas of this network appear to be affected in inattention/hyperactivity caused by genetic (i.e., high concordant MZ pairs) vs. environmental (i.e., high-low discordant MZ pairs) risk factors. These results provide clues that further our understanding of brain alterations in ADHD. © 2007 Elsevier Inc. All rights reserved

Strong mucosal immune responses in SIV infected macaques contribute to viral control and preserved CD4+ T-cell levels in blood and mucosal tissues

<p>Abstract</p> <p>Background</p> <p>Since there is still no protective HIV vaccine available, better insights into immune mechanism of persons effectively controlling HIV replication in the absence of any therapy should contribute to improve further vaccine designs. However, little is known about the mucosal immune response of this small unique group of patients. Using the SIV-macaque-model for AIDS, we had the rare opportunity to analyze 14 SIV-infected rhesus macaques durably controlling viral replication (controllers). We investigated the virological and immunological profile of blood and three different mucosal tissues and compared their data to those of uninfected and animals progressing to AIDS-like disease (progressors).</p> <p>Results</p> <p>Lymphocytes from blood, bronchoalveolar lavage (BAL), and duodenal and colonic biopsies were phenotypically characterized by polychromatic flow cytometry. In controllers, we observed higher levels of CD4+, CD4+CCR5+ and Gag-specific CD8+ T-cells as well as lower immune activation in blood and all mucosal sites compared to progressors. However, we could also demonstrate that immunological changes are distinct between these three mucosal sites.</p> <p>Intracellular cytokine staining demonstrated a significantly higher systemic and mucosal CD8+ Gag-specific cellular immune response in controllers than in progressors. Most remarkable was the polyfunctional cytokine profile of CD8+ lymphocytes in BAL of controllers, which significantly dominated over their blood response. The overall suppression of viral replication in the controllers was confirmed by almost no detectable viral RNA in blood and all mucosal tissues investigated.</p> <p>Conclusion</p> <p>A strong and complex virus-specific CD8+ T-cell response in blood and especially in mucosal tissue of SIV-infected macaques was associated with low immune activation and an efficient suppression of viral replication. This likely afforded a repopulation of CD4+ T-cells in different mucosal compartments to almost normal levels. We conclude, that a robust SIV-specific mucosal immune response seems to be essential for establishing and maintaining the controller status and consequently for long-term survival.</p

Heritability of seed weight in Maritime pine, a relevant trait in the transmission of environmental maternal effects

Quantitative seed provisioning is an important life-history trait with strong effects on offspring phenotype and fitness. As for any other trait, heritability estimates are vital for understanding its evolutionary dynamics. However, being a trait in between two generations, estimating additive genetic variation of seed provisioning requires complex quantitative genetic approaches for distinguishing between true genetic and environmental maternal effects. Here, using Maritime pine as a long-lived plant model, we quantified additive genetic variation of cone and seed weight (SW) mean and SW within-individual variation. We used a powerful approach combining both half-sib analysis and parent-offspring regression using several common garden tests established in contrasting environments to separate G, E and G x E effects. Both cone weight and SW mean showed significant genetic variation but were also influenced by the maternal environment. Most of the large variation in SW mean was attributable to additive genetic effects (h(2) = 0.55-0.74). SW showed no apparent G x E interaction, particularly when accounting for cone weight covariation, suggesting that the maternal genotypes actively control the SW mean irrespective of the amount of resources allocated to cones. Within-individual variation in SW was low (12%) relative to between-individual variation (88%), and showed no genetic variation but was largely affected by the maternal environment, with greater variation in the less favourable sites for pine growth. In summary, results were very consistent between the parental and the offspring common garden tests, and clearly indicated heritable genetic variation for SW mean but not for within-individual variation in SW.This study was financed by the Spanish National Research Grants RTA2007-100 and AGL2012-40151 (FENOPIN), both co-financed by EU-FEDER. The progeny trials and the clonal seed orchards are part of the experimental set up of the Maritime pine breeding programme developed by the Centro de Investigacion Forestal de Lourizan, Xunta de Galicia.Spanish National Research Grant RTA2007-100Spanish National Research Grant AGL2012-40151 (FENOPIN)EU-FEDERPeer reviewe

BRAF Activation Initiates but Does Not Maintain Invasive Prostate Adenocarcinoma

Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAFV600E–a mutation found in ∼10% of human prostate tumors–was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAFV600E in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAFV600E is not required for its maintenance

Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer

Secreted Frizzled-related protein-1 (sFRP1) associates with Wnt proteins and its loss can lead to activation of Wnt/β-catenin signalling. It is frequently downregulated in cancer, including prostate cancer, but its function in prostate cancer is unclear because it can increase proliferation of prostate epithelial cells. We investigated the function of sFRP1 in androgen-dependent prostate cancer and found that sFRP1 inhibited androgen receptor (AR) transcriptional activity. In addition, sFRP1 inhibited the proliferation of androgen-dependent LNCaP cells but not of an androgen-independent subline LNCaP-r, suggesting a role in androgen-dependent growth. The inhibition of AR by sFRP1 was unaffected by co-expression of Wnt3a, stabilised β-catenin or β-catenin shRNA, suggesting it does not involve Wnt/β-catenin signalling. Wnt5a also inhibited AR and expression of Wnt5a and sFRP1 together did not further inhibit AR, suggesting that Wnt5a and sFRP1 activate the same signal(s) to inhibit AR. However, sFRP1 inhibition of AR was unaffected by inhibitors of kinases involved in Wnt/Ca2+ and Wnt/planar cell polarity non-canonical Wnt signalling. Interestingly, the cysteine-rich domain of sFRP1 interacted with Frizzled receptors expressed in prostate cancer cells, suggesting that sFRP1/Frizzled complexes activate a signal that leads to repression of AR. Taken together, these observations highlight the function of β-catenin-independent Wnt signalling in the control of AR activity and provide one explanation for sFRP1 downregulation in prostate cancer

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually