Performance of serum marker panels for liver fibrosis in chronic hepatitis C

BACKGROUND/AIMS: Chronic hepatitis C (CHC) is characterised by hepatic fibrosis, used as a proxy measure of prognosis. Liver biopsy is a flawed reference standard and serum markers of fibrosis offer an attractive alternative. METHODS: A systematic review was conducted to assess the performance of panels of serum markers of hepatic fibrosis in CHC, incorporating analyses placing markers in a clinical context. RESULTS: 14 studies were included with 10 different panels. Median AUC in validation populations was 0.77 and training populations 0.81. Likelihood ratios (LR) ranged from -LR 0.1 to 0.9, + LR 1.2 to 33.1, diagnostic odds ratios (DOR) were 9.0 (median) with a range of 5 to 27- mostly below values of robust tests. Tests perform with either high sensitivity with low specificity or vice versa. Cut-off levels that gave clinically relevant predictive values for the presence/absence of significant fibrosis were applicable to 35% of the population. CONCLUSIONS: Serum markers can rule-in or rule-out fibrosis in up to 35% of patients, but cannot differentiate stages of fibrosis reliably. Improvement of index and reference test in needed including evaluation of clinical outcomes as reference. Improved test reporting is needed to derive LR and DOR as performance indicators.     

Imaging Techniques for Detecting Prokaryotic Viruses in Environmental Samples

Viruses are the most abundant biological entities on Earth with an estimate of 10³¹ viral particles across all ecosystems. Prokaryotic viruses—bacteriophages and archaeal viruses—influence global biogeochemical cycles by shaping microbial communities through predation, through the effect of horizontal gene transfer on the host genome evolution, and through manipulating the host cellular metabolism. Imaging techniques have played an important role in understanding the biology and lifestyle of prokaryotic viruses. Specifically, structure-resolving microscopy methods, for example, transmission electron microscopy, are commonly used for understanding viral morphology, ultrastructure, and host interaction. These methods have been applied mostly to cultivated phage–host pairs. However, recent advances in environmental genomics have demonstrated that the majority of viruses remain uncultivated, and thus microscopically uncharacterized. Although light- and structure-resolving microscopy of viruses from environmental samples is possible, quite often the link between the visualization and the genomic information of uncultivated prokaryotic viruses is missing. In this minireview, we summarize the current state of the art of imaging techniques available for characterizing viruses in environmental samples and discuss potential links between viral imaging and environmental genomics for shedding light on the morphology of uncultivated viruses and their lifestyles in Earth’s ecosystems.     

Pan-Asian Consensus on Calcium Hydroxyapatite for Skin Biostimulation,Contouring, and Combination Treatments

BackgroundSeveral usage guidelines for calcium hydroxylapatite (CaHA), a dermal filler material, exist for non-Asian patients, making it necessary to determine whether their findings and consensuses are applicable to Asian patients who have distinct anatomies, cultural preferences, and aesthetic requests.ObjectiveWe sought to develop a Pan-Asian consensus on CaHA use in skin biostimulation, contouring, and combination treatments for face and body indications.MethodsA survey on CaHA usage for contouring and biostimulation indications in Asian patients was conducted, followed by discussions to establish consensus statements and topics for examination.ResultsSeveral aspects of facial shaping and contouring or skin biostimulation with CaHA were agreed on, including that dilution is not a key consideration, that microfocused ultrasound with visualisation precedes CaHA in same day or session treatments, and that cannulas should be used. Among the many agreements on interventions in specific facial and body areas, there were also disagreements due to the diverse Asian patient presentations, requests, and access to tools or products; for example, CaHA should be placed in the interfascial layer for temple contouring, CaHA should not be injected directly into the infraorbital area for safety, and diluted CaHA should be injected subdermally for nonfacial or whole-face biostimulation and contouring.ConclusionOur disagreements highlight the diversity of Asian facial morphotypes and desired aesthetic outcomes and underscore the need for customized aesthetic strategies to accommodate the heterogeneity of Asian anatomies, cultural preferences, and aesthetic ideals. Establishing consensus statements on critical aspects of Asian patient considerations, efficacy and safety, is crucial. This document provides strategic guidance on the use of classic, diluted CaHA for biostimulation or undiluted Radiesse^®(+) (Merz Pharma GmbH & Co. KGaA, Frankfurt, Germany) for lifting and contouring to ensure consistent CaHA delivery for successful patient outcomes.     

Evaluation of area-based collagen scoring by nonlinear microscopy in chronic hepatitis C-induced liver fibrosis

In this paper we analyze a fibrosis scoring method based on measurement of the fibrillar collagen area from second harmonic generation (SHG) microscopy images of unstained histological slices from human liver biopsies. The study is conducted on a cohort of one hundred chronic hepatitis C patients with intermediate to strong Metavir and Ishak stages of liver fibrosis. We highlight a key parameter of our scoring method to discriminate between high and low fibrosis stages. Moreover, according to the intensity histograms of the SHG images and simple mathematical arguments, we show that our area-based method is equivalent to an intensity-based method, despite saturation of the images. Finally we propose an improvement of our scoring method using very simple image processing tools.OCIS codes: (180.4315) Nonlinear microscopy, (170.1610) Clinical applications, (170.3880) Medical and biological imaging, (170.4580) Optical diagnostics for medicine, (110.2960) Image analysis     

Phosphatidylinositol 3'-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN.

PURPOSE: Medulloblastomas represent the most frequent malignant brain tumors of childhood. They are supposed to originate from cerebellar neural precursor cells. Recently, it has been shown that Sonic Hedgehog-induced formation of medulloblastoma in an animal model is significantly enhanced by activation of the phosphatidylinositol 3'-kinase (PI3K) signaling pathway. EXPERIMENTAL DESIGN: To examine a role for PI3K/AKT signaling in the molecular pathogenesis of human medulloblastoma, we did an immunohistochemical study of the expression of Ser473-phosphorylated (p)-AKT protein in 22 medulloblastoma samples: All samples displayed p-AKT expression. To investigate if an activated PI3K/AKT pathway is required for medulloblastoma cell growth, we treated five human medulloblastoma cell lines with increasing concentrations of the PI3K inhibitor LY294002 and analyzed cellular proliferation and apoptosis. The antiproliferative effect could be antagonized by overexpressing constitutively active AKT. As the activation of PI3K/AKT signaling may be associated with alterations of the PTEN gene located at 10q23.3, a chromosomal region subject to frequent allelic losses in medulloblastoma, we screened PTEN for mutations and mRNA expression. RESULTS: Proliferation of all of the medulloblastoma cell lines was dependent on PI3K/AKT signaling, whereas apoptosis was not prominently affected. Allelic loss was detected in 16% of the cases. One medulloblastoma cell line was found to carry a truncating mutation in the PTEN coding sequence. Even more important, PTEN mRNA and protein levels were found to be significantly lower in medulloblastomas compared with normal cerebellar tissue of different developmental stages. Reduction of PTEN expression was found to be associated with PTEN promoter hypermethylation in 50% of the tumor samples. CONCLUSIONS: We conclude that activation of the PI3K/AKT pathway constitutes an important step in the molecular pathogenesis of medulloblastoma and that dysregulation of PTEN may play a significant role in this context.     

Biological Indices Evaluation of Various Treatment Techniques for Left-Sided Breast Treatment

PurposeTo compare dose to organs at risk (OARs) and biological evaluation using normal tissue complication probability (NTCP) for left-sided breast radiation therapy in 4 techniques: supine free breathing (SFB), supine deep inspiration breath hold (SDIBH), prone free breathing (PFB), and prone deep inspiration breath hold (PDIBH).Methods and MaterialsTwenty-five patients with left-sided breast cancer suitable for this study underwent a computed tomography scan using SFB, SDIBH, PFB, and PDIBH. One radiation oncologist contoured the planning target volume and OAR (cardiac components). Dose-volume histograms and NTCPs for the heart, left ventricle (LV), left anterior descending artery (LAD), and left lung were calculated for all 4 techniques.ResultsThe mean heart dose in PDIBH is 0.77 Gy, which is statistically significantly lower than in SFB (1.88 Gy, P < .0001), SDIBH (0.97 Gy, P < .001), and PFB (0.85 Gy, P < .001). The mean left lung dose is 0.69 Gy in PFB and 0.88 Gy in PDIBH. PFB and PDIBH have statistically significantly lower doses compared with SFB (6.09 Gy, P < .0001) and SDIBH (5.41 Gy, P < .0001). The mean NTCP in SFB for the heart, LV, and LAD is 0.27%, 0.62%, and 4.23%, respectively, and it is negligible for other techniques.ConclusionsWe found that PDIBH had a dosimetrically lower mean dose for the heart and LV compared with the other 3 techniques. In addition, SDIBH, PFB and PDIBH had statistically significantly lower NTCP for the heart, LV, and LAD compared with SFB. NTCP for the left lung was statistically significantly lower for prone techniques compared with supine techniques. Therefore we concluded that, compared with SDIBH, PDIBH provides the added benefit of sparing the heart while keeping the benefit of sparing the lung as in the prone technique.     

Effect of Azone upon the in vivo antiviral efficacy of cidofovir or acyclovir topical formulations in treatment/prevention of cutaneous HSV-1 infections and its correlation with skin target site free drug concentration in hairless mice

The purpose of this study is to examine the influence of Azone upon the skin target site free drug concentration (C(*)) and its correlation with the in vivo antiviral efficacies of cidofovir (HPMPC) and acyclovir (ACV) against HSV-1 infections. Formulations of HPMPC and ACV with or without Azone were used. The in vitro skin flux experiments were performed and the C(*) values were calculated. For the in vivo efficacy studies, hairless mice cutaneously infected with HSV-1 were used and three different treatment protocols were carried out. The protocols were chosen based upon when therapy is initiated and terminated in such a way to assess the efficacy of the test drug to cure and/or prevent HSV-1 infections. A finite dose of the formulation was topically applied twice a day for the predetermined time course for each protocol and the lesions were scored on the fifth day. For ACV formulation with Azone, the C(*) values and hence the in vivo efficacy were much higher than those for that without Azone. In protocol #1, however, early treatment did not increase the in vivo efficacy of ACV when compared with the standard treatment protocol #3. In protocol #2 where the treatment was terminated on the day of virus inoculation, the efficacies for both ACV formulations were completely absent. Although the estimated C(*) values for HPMPC formulations with and without Azone were comparable, formulation with Azone was much more effective than that without Azone in all treatment protocols. HPMPC formulations with Azone at similar flux values were much more effective in "treating and preventing" HSV-1 infections than those without Azone. For ACV formulations, in contrast, addition of Azone has failed to show any effect on the preventive in vivo antiviral efficacy and the enhancement of ACV in vivo antiviral efficacy was merely the skin permeation enhancement effect of Azone.