Real‐time shear wave elastography (SWE) is a novel, noninvasive method to assess liver fibrosis by measuring liver stiffness. This single‐center study was conducted to assess the accuracy of SWE in ...patients with chronic hepatitis C (CHC), in comparison with transient elastography (TE), by using liver biopsy (LB) as the reference standard. Consecutive patients with CHC scheduled for LB by referring physicians were studied. One hundred and twenty‐one patients met inclusion criteria. On the same day, real‐time SWE using the ultrasound (US) system, Aixplorer (SuperSonic Imagine S.A., Aix‐en‐Provence, France), TE using FibroScan (Echosens, Paris, France), and US‐assisted LB were consecutively performed. Fibrosis was staged according to the METAVIR scoring system. Analyses of receiver operating characteristic (ROC) curve were performed to calculate optimal area under the ROC curve (AUROC) for F0‐F1 versus F2‐F4, F0‐ F2 versus F3‐F4, and F0‐F3 versus F4 for both real‐time SWE and TE. Liver stiffness values increased in parallel with degree of liver fibrosis, both with SWE and TE. AUROCs were 0.92 (95% confidence interval CI: 0.85‐0.96) for SWE and 0.84 (95% CI: 0.76‐0.90) for TE (P = 0.002), 0.98 (95% CI: 0.94‐1.00) for SWE and 0.96 (95% CI: 0.90‐0.99) for TE (P = 0.14), and 0.98 (95% CI: 0.93‐1.00) for SWE and 0.96 (95% CI: 0.91‐0.99) for TE (P = 0.48), when comparing F0‐F1 versus F2‐ F4, F0‐ F2 versus F3‐F4, and F0 ‐F3 versus F4, respectively. Conclusion: The results of this study show that real‐time SWE is more accurate than TE in assessing significant fibrosis (≥F2). With respect to TE, SWE has the advantage of imaging liver stiffness in real time while guided by a B‐mode image. Thus, the region of measurement can be guided with both anatomical and tissue stiffness information. (HEPATOLOGY 2012;56:2125–2133)
AIM:To estimate the validity of the point shear-wave elastography method by evaluating its reproducibility and accuracy for assessing liver stiffness.METHODS:This was a single-center,cross-sectional ...study.Consecutive patients with chronic viral hepatitis scheduled for liver biopsy(LB)(Group 1)and healthy volunteers(Group 2)were studied.In each subject 10 consecutive point shear-wave elastography(PSWE)measurements were performed using the iU22 ultrasound system(Philips Medical Systems,Bothell,WA,United States).Patients in Group 1 underwent PSWE,transient elastography(TE)using FibroScan(Echosens,Paris,France)and ultrasound-assisted LB.For the assessment of PSWE reproducibility two expert raters(rater 1 and rater 2)independently performed the examinations.The performance of PSWE was compared to that of TE using LB as a reference standard.Fibrosis was staged according to the METAVIR scoring system.Receiver operating characteristic curve analyses were performed to calculate the area under the receiver operating characteristic curve(AUC)for F≥2,F≥3and F=4.The intraobserver and interobserver reproducibility of PSWE were assessed by calculating Lin’s concordance correlation coefficient.RESULTS:To assess the performance of PSWE,134consecutive patients in Group 1 were studied.The median values of PSWE and TE(in kilopascals)were 4.7(IQR=3.8-5.4)and 5.5(IQR=4.7-6.5),respectively,in patients at the F0-F1 stage and 3.5(IQR=3.2-4.0)and 4.4(IQR=3.5-4.9),respectively,in the healthy volunteers in Group 2(P<10-5).In the univariate analysis,the PSWE and TE values showed a high correlation with the fibrosis stage;low correlations with the degree of necroinflammation,aspartate aminotransferase and gamma-glutamyl transferase(GGT);and a moderate negative correlation with the platelet count.A multiple regression analysis confirmed the correlations of both PSWE and TE with fibrosis stage and GGT but not with any other variables.The following AUC values were found:0.80(0.71-0.87)for PSWE and 0.82(0.73-0.89)for TE(P=0.42);0.88(0.80-0.94)for PSWE and 0.95(0.88-0.98)for TE(P=0.06);and 0.95(0.89-0.99)for PSWE and 0.92(0.85-0.97)for TE(P=0.30)for F≥2,F≥3 and F=4,respectively.To assess PSWE reproducibility,116 subjects were studied,including 47consecutive patients scheduled for LB(Group 1)and 69 consecutive healthy volunteers(Group 2).The intraobserver agreement ranged from 0.83(95%CI:0.79-0.88)to 0.96(95%CI:0.95-0.97)for rater 1 and from 0.84(95%CI:0.79-0.88)to 0.96(95%CI:0.95-0.97)for rater 2.The interobserver agreement yielded values from0.83(95%CI:0.78-0.88)to 0.93(95%CI:0.91-0.95).CONCLUSION:PSWE is a reproducible method for assessing liver stiffness,and it compares with TE.Compared with patients with nonsignificant fibrosis,healthy volunteers showed significantly lower values.
AIM:To assess the performance of controlled attenuation parameter(CAP)in patients with chronic viral hepatitis.METHODS:CAP is a new technique that measures the attenuation in the liver of an ...ultrasound beam,which is directly related to lipid accumulation.Consecutive patients undergoing liver biopsy for chronic viral hepatitis were studied using the M probe of FibroScan device(Echosens,Paris,France).The device estimates liver st-eatosis in decibel per meter(dB/m).An expert operator performed all measurements.Steatosis was graded according to Kleiner’s classification.Pearson or Spearman rank coefficient was used to test correlation between two study variables.Linear regression was used for multivariate model to assess the association between CAP and other variables.Receiver operating characteristic curve analysis was performed to calculate area under the curve(AUROC)for S0 vs S1-S3 and S0-S1 vs S2-S3.RESULTS:115 subjects(85 males and 30 females)were prospectively studied.The mean values of CAP were 227.1±43.1 for S0;254.6±38.9 for S1;297.8±49.4 dB/m for S2-S3.In univariate analysis CAP showed a significant correlation with age,body mass index(BMI),degree of steatosis,and cholesterol.Multivariate regression analysis confirmed the correlation with the degree of steatosiscoefficient,1.2(0.60-1.83);P<10-5and BMIcoefficient,4.1(0.5-7.8);P=0.03but not with all other variables.Optimal cutoff values for S≥1 and S≥2 were 219 dB/mAUROC,0.76(0.67-0.84);sensitivity,91.1%(78.8-97.5);specificity,51.6%(38.7-64.2);positive predictive value,56.9%(44.7-68.6);negative predictive value,89.2%(74.3-97.0);positive likelihood ratio,1.88(1.4-2.5);negative likelihood ratio,0.17(0.07-0.5)and 296 dB/mAUROC,0.82(0.74-0.89);sensitivity,60.0%(32.3-83.7);specificity,91.5%(83.9-96.3);positive predictive value,52.9%(27.8-77.0);negative predictive value,93.5%(86.3-97.6);positive likelihood ratio,7.05(3.2-15.4);negative likelihood ratio,0.44(0.2-0.8),respectively.CONCLUSION:Controlled attenuation parameter could be a useful tool in the clinical management of patients with chronic viral hepatitis for detecting liver steatosis.
HIV co-infection influences the course and natural history of hepatitis B virus (HBV) infection by impairing the quantity and quality of the innate and adaptive immune response. The rates of ...spontaneous resolution after acute infection and spontaneous anti-HBe and anti-HBs seroconversions are decreased, and levels of HBV replication are increased in HIV-infected patients. A more rapid progression of liver fibrosis and a higher rate of cirrhosis decompensation (but not hepatocellular carcinoma) have been demonstrated in co-infected patients. The risk of HBV-associated end-stage liver disease and liver-related mortality may be increased by HIV co-infection. Antiretroviral therapy may trigger spontaneous anti-HBe and anti-HBs seroconversion and/or a better immune control of HBV replication by restoring adaptive immunity, but can also increase hepatitis flares. Reactivation of chronic hepatitis B has been observed after suspension of anti-retrovirals with anti-HBV activity or after occurrence of HBV resistance to lamivudine. Future research should focus on: the impact of HIV-induced changes in innate and adaptive immune response and modifications induced by anti-retroviral therapy that may impact on progression of advanced chronic hepatitis B; the association between HBV genotype and clinical course of disease; and the role of occult HBV infection as a co-factor with other causes of liver injury.
The purpose of this article is to evaluate the diagnostic performance of transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index in assessing fibrosis in patients ...with chronic hepatitis C by using histologic Metavir scores as reference standard.
Consecutive patients with chronic hepatitis C scheduled for liver biopsy were enrolled. Liver biopsy was performed on the same day as transient elastography and real-time strain elastography. Transient elastography and real-time strain elastography were performed in the same patient encounter by a single investigator using a medical device based on elastometry and an ultrasound machine, respectively. Diagnostic performance was assessed by using receiver operating characteristic curves and area under the receiver operating characteristic curve (AUC) analysis.
One hundred thirty patients (91 men and 39 women) were analyzed. The cutoff values for transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index were 6.9 kPa, 1.82, and 0.37, respectively, for fibrosis score of 2 or higher; 7.3 kPa, 1.86, and 0.70, respectively, for fibrosis score of 3 or higher; and 9.3 kPa, 2.33, and 0.70, respectively, for fibrosis score of 4. AUC values of transient elastography, real-time strain elastography, aspartate-to-platelet ratio index were 0.88, 0.74, and 0.86, respectively, for fibrosis score of 2 or higher; 0.95, 0.80, and 0.89, respectively, for fibrosis score of 3 or higher; and 0.97, 0.80, and 0.84, respectively, for fibrosis score of 4. A combination of the three methods, when two of three were in agreement, showed AUC curves of 0.93, 0.95, and 0.95 for fibrosis scores of 2 or higher, 3 or higher, and 4, respectively.
Transient elastography, real-time strain elastography, and aspartate-to-platelet ratio index values were correlated with histologic stages of fibrosis. Transient elastography offered excellent diagnostic performance in assessing severe fibrosis and cirrhosis. Real-time elastography does not yet have the potential to substitute for transient elastography in the assessment of liver fibrosis.
To compare the accuracy of ultrasound imaging technique to that of clinical diagnosis in evaluating subcutaneous fat changes in HIV-infected subjects.
HIV-uninfected control subjects (Group A), ...HIV-infected subjects with clinically assessed lipoatrophy (Group B), and HIV-infected subjects without clinical lipoatrophy (Group C) underwent ultrasound measurements of subcutaneous fat thickness at facial, brachial and thigh regions. ROC curve analyses were used to estimate ultrasound prediction accuracy and cut-off values of subcutaneous fat thickness.
228 subjects were enrolled: 78 in Group A, 73 in Group B, and 77 in Group C. Facial lipoatrophy: ROC curve analysis identified optimal cut-off value of 13.3 mm sensitivity, 96.0%; specificity, 76.9% AUC 0.92, 5.0 mm sensitivity, 71.4%; specificity, 92.3%; AUC 0.90 and 11.2 mm sensitivity, 95.8%; specificity, 89.7%; AUC 0.97 for females and 12.05 mm sensitivity, 51.2%; specificity, 87.2%; AUC 0.74, 4.1 mm sensitivity, 76.2%; specificity, 89.7%; AUC 0.85 and 4.35 mm sensitivity, 60.0%; specificity, 89.7%; AUC 0.82 for males in assessing facial, brachial and crural lipoatrophy respectively. Using this cut-off values, 12/25 (48%) females and 17/49 (34.7%) males, 12/28 (42.9%) females and 23/49 (46.9%) males, 19/28 (67.9%) females and 12/49 (24.5%) males in Group C would be classified as "sub-clinical" facial, brachial and crural lipoatrophy respectively.
The results of our study show that in the assessment of subtle subcutaneous fat changes ultrasound is more accurate than clinical evaluation and confirm the usefulness of ultrasound imaging technique in identifying lipoatrophy at an early stage.
The risk of hepatotoxicity associated with different highly active antiretroviral therapy (HAART) regimens (containing multiple-protease inhibitors, single-protease inhibitors or non nucleoside ...reverse transcriptase inhibitors) in HIV-HCV co-infected patients has not been fully assessed.
Retrospective analysis of a prospective cohort of 1,038 HIV-HCV co-infected patients who commenced a new HAART in the Italian MASTER database. Patients were stratified into naïve and experienced to antiretroviral therapy before starting the study regimens. Time to grade > or =III hepatotoxicity (as by ACTG classification) was the primary outcome. Secondary outcome was time to grade IV hepatotoxicity.
Incidence of grade > or =III hepatotoxicity was 17.71 per 100 patient-years (p-yr) of follow up in naïve patient group and 8.22 per 100 p-yrs in experienced group (grade IV: 4.13 per 100 p-yrs and 1.08 per 100 p-yrs, respectively). In the latter group, the only independent factors associated with shorter time to the event at proportional hazards regression model were: previous liver transaminase elevations to grade > or =III, higher baseline alanine amino-transferase values, and use of a non nucleoside reverse transcriptase inhibitor based regimen. In the naive group, baseline aspartate transaminase level was associated with the primary outcome.
Use of a single or multiple protease inhibitor based regimen was not associated with risk of hepatotoxicity in either naïve or experienced patient groups to a statistically significant extent. A cautious approach with strict monitoring should be applied in HIV-HCV co-infected experienced patients with previous liver transaminase elevations, higher baseline alanine amino-transferase values and who receive regimens containing non nucleoside reverse transcriptase inhibitors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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Paclitaxel loaded solid lipid nanoparticles (SLN) of behenic acid were prepared with the coacervation technique. Generally, spherical shaped SLN with mean diameters in the range ...300–600nm were obtained. The introduction of charged molecules, such as stearylamine and glycol chitosan into the formulation allowed to obtain positive SLN with Zeta potential in the 8–20mV range and encapsulation efficiency in the 25–90% range.
Blood–brain barrier (BBB) permeability, tested in vitro through hCMEC/D3 cells monolayer, showed a significantly increase in the permeation of Coumarin-6, used as model drug, when vehicled in SLN. Positive-charged SLN do not seem to enhance permeation although stearylamine-positive SLN resulted the best permeable formulation after 24h.
Cytotoxicity studies on NO3 glioblastoma cell line demonstrated the maintenance of cytotoxic activity of all paclitaxel-loaded SLN that was always unmodified or greater compared with free drug. No difference in cytotoxicity was noted between neutral and charged SLN.
Co-culture experiments with hCMEC/D3 and different glioblastoma cells evidenced that, when delivered in SLN, paclitaxel increased its cytotoxicity towards glioblastoma cells.
OBJECTIVESMetabolic syndrome is a cluster of risk factors, such as central obesity, dyslipidemia, glucose intolerance, hypertension, related to insulin resistance. In HIV patients insulin resistance ...and several metabolic abnormalities of the metabolic syndrome have been described, but few and conflicting studies have investigated the behaviour of blood pressure. The aims of the present study were to evaluate the prevalence of hypertension in a large group of HIV-patients on highly active antiretroviral therapy (HAART) and to investigate the relationship between hypertension, metabolic syndrome and insulin resistance.
DESIGNCase control study
METHODSWe enrolled 287 HIV-positive patients on HAART (mean age 41.1 ± 7.5 years) and 287 age- and sex-matched controls. Insulin resistance was estimated by the homeostasis model insulin resistance assessment (HOMA) index. Metabolic syndrome was defined according to the European Group for the Study of Insulin Resistance.
RESULTSHIV patients showed a prevalence of subjects with hypertension (34.2 versus 11.9%; P < 0.0001) and metabolic syndrome (33.1 versus 2.4%; P < 0.0001) higher than controls. HOMA was higher in HIV-patients than controls (3.3 ± 1.2 versus 2.0 ± 0.9; P < 0.0001). HOMA (3.7 ± 1.0 versus 3.1 ± 1.2; P < 0.001) and the prevalence of subjects with the metabolic syndrome (64.3 versus 16.9%; P < 0.0001) were greater in HIV-patients with than in those without hypertension. Multiple logistic regression analysis showed that family history of hypertension (odds ratio (OR)8.73; 95% confidence interval (CI)4.31–17.70; P < 0.0001, metabolic syndrome (OR6.79; 95% CI3.27–14.10; P < 0.0001), lipodystrophy (OR4.80; 95% CI2.43–9.85; P < 0.0001) and HOMA (OR4.13; 95% CI1.14–14.91; P < 0.05) were predictors of hypertension in HIV-patients.
CONCLUSIONSThe present study shows that hypertension is frequent in HIV patients on HAART and that hypertension appears to be linked to insulin resistance; in particular, hypertension seems to be a part of the metabolic syndrome.
Tuberculosis is the deadliest infectious disease in the world. The variable efficacy of the current treatments highlights the need for more effective agents against this disease. In the past few ...years, we focused on the investigation of antigenic glycoconjugates starting from recombinant Ag85B (rAg85B), a potent protein antigen from
. In this paper, structural modifications were rationally designed in order to obtain a rAg85B variant protein able to maintain its immunogenicity after glycosylation. Lysine residues involved in the main T-epitope sequences (namely, K30 and K282) have been substituted with arginine to prevent their glycosylation by a lysine-specific reactive linker. The effectiveness of the mutation strategy and the detailed structure of resulting neo-glycoconjugates have been studied by intact mass spectrometry, followed by peptide and glycopeptide mapping. The effect of K30R and K282R mutations on the T-cell activity of rAg85B has also been investigated with a preliminary immunological evaluation performed by enzyme-linked immunospotting on the different variant proteins and their glycosylation products. After glycosylation, the two variant proteins with an arginine in position 30 completely retain the original T-cell activity, thus representing adequate antigenic carriers for the development of efficient glycoconjugate vaccines against tuberculosis.
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