Revisiting predictors of virologic response to PEGIFN + RBV therapy in HIV-/HCV-coinfected patients: the role of metabolic factors and elevated GGT levels.

Evaluation of metabolic factors and elevated γ-glutamyltransferase (GGT) levels as independent predictors of treatment failure in a thoroughly documented cohort of HIV-/HCV-coinfected patients (HIV/HCV). Sixty-four HIV/HCV patients treated with pegylated interferon-α-2a plus ribavirin (PEGIFN + RBV) at the Medical University of Vienna within a prospective trial were included in this study. In addition, 124 patients with HIV/HCV from the AIFA-HIV and AHIVCOS cohorts were included as a validation cohort. Advanced liver fibrosis, GGT elevation, insulin resistance (IR) and low CD4+ nadir were defined as METAVIR F3/F4, GGT levels >1.5× sex-specific upper limit of normal, homoeostasis model assessment of insulin resistance >2 and CD4+ nadir <350 cells/µL, respectively. HCV-genotype 1/4 (OR26.3; P = 0.006), advanced liver fibrosis (OR20.2; P = 0.009), interleukin 28B rs12979860 non-C/C SNP (OR8.27; P = 0.02) and GGT elevation (OR7.97; P = 0.012) were independent predictors of treatment failure, while both IR (OR3.51; P = 0.106) and low CD4 + nadir (OR2.64; P = 0.263) were not independently associated with treatment failure. A statistically significant correlation between GGT elevation and prior alcohol abuse (r = 0.259; P = 0.039), liver steatosis (r = 0.301; P = 0.034) and low-density lipoprotein-cholesterol (r = -0.256; P = 0.041) was observed. The importance of GGT elevation as an independent predictor of treatment failure was confirmed in a validation cohort (OR2.76; P = 0.026). While GGT elevation emerged as an independent predictor of treatment failure in both the derivation and the validation cohort, no independent associations between metabolic factors and treatment failure were observed. Thus, our findings suggest that GGT elevation is an independent predictor of treatment failure in HIV/HCV that can easily be incorporated into predictive algorithms.

HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension.

Patients co-infected with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) are fraught with a rapid fibrosis progression rate and with complications of portal hypertension (PHT) We aimed to assess the influence of immune function [Centers of Disease Control and Prevention (CDC) stage] on development of PHT and disease progression in HIV-HCV co-infection. Data of 74 interferon-naïve HIV-HCV co-infected patients undergoing liver biopsy, measurement of portal pressure and of liver stiffness and routine laboratory tests (including CD4+ cell count, HIV and HCV viral load) were analysed. Time of initial exposure (risk behaviour) was used to assess fibrosis progression. Fibrosis progression, time to cirrhosis and portal pressure were correlated with HIV status (CDC stage). HIV-HCV patients had rapid progression of fibrosis [0.201 +/- 0.088 METAVIR fibrosis units/year (FU/y)] and accelerated time to cirrhosis (24 +/- 13 years), high HCV viral loads (4.83 x 10(6) IU/mL) and a mean HVPG at the upper limit of normal (5 mmHg). With moderate or severe immunodeficiency, fibrosis progression was even higher (CDC-2 = 0.177 FU/y; CDC-3 = 0.248 FU/y) compared with patients with higher CD4+ nadirs (CDC-1 = 0.120 FU/y; P = 0.0001). An indirect correlation between CD4+ cell count and rate of fibrosis progression (R = -0.6654; P < 0.001) could be demonstrated. Hepatic venous pressure gradient (HVPG) showed early elevation of portal pressure with median values of 4, 8 and 12 mmHg after 10, 15 and 20 years of HCV infection for CDC-3 patients. Patients treated with highly active anti-retroviral therapy (HAART) had similar rates of progression and portal pressure values than patients without HAART. Progression of HCV disease is accelerated in HIV-HCV co-infection, being more pronounced in patients with low CD4+ cell count. A history of a CD4+ cell nadir <200/microL is a risk factor for rapid development of cirrhosis and PHT. Thus, HCV treatment should be considered early in patients with HIV-HCV co-infection and largely preserved CD4+ cell counts.

Interaction of sympathomimetics and insulin with hepatic glucose production by isolated perfused rat livers: effects of continuous versus pulsatile infusion.

To elucidate the efficacy of continuous vs. intermittent exposure to epinephrine, phenylephrine, and insulin, hepatic glucose production was monitored in isolated perfused rat livers (means +/- SE, n = 6 each). To this end livers of fed rats were perfused with 5 mM glucose Krebs-Ringer buffer in a nonrecirculating system. Using this model it was shown that intermittent exposure (3 min on/off period, dose reduction -50%) to epinephrine (0.4 microM, alpha + beta-agonist) and phenylephrine (5 microM, alpha-agonist) elicited an almost identical rise in hepatic glucose production [epinephrine: 0.72 +/- 0.08 mmol/(86 min X 100 g BW); phenylephrine: 0.68 +/- 0.07 mmol/(86 min X 100 g BW) as their continuous administration (epinephrine: 0.78 +/- 0.06 mmol/(86 min X 100 g BW); phenylephrine: 0.74 +/- 0.09 mmol/(86 min X 100 g BW)]. Inhibition by insulin (100 mU/liter) given either continuously or intermittently (3 min on/off intervals; dose reduction -50%) was equipotent for epinephrine- and phenylephrine-stimulated hepatic glucose production. When the off period was doubled to 6 min, thereby reducing the total insulin dose to 33%, no significant suppression of epinephrine- and phenylephrine-stimulated hepatic glucose production was observed. From this we conclude that 1) the effect on hepatic glucose production of pulsatile (3 min on/off, dose reduction 50%) and continuous administration is equipotent for the respective action of epinephrine, phenylephrine as well as of insulin; and 2) insulin is more effective (P less than 0.02) in inhibiting hepatic glucose production stimulated by an alpha-agonist (phenylephrine; 5.0 microM) than in counteracting alpha + beta-agonist action (epinephrine; 0.4 microM). The characteristics of hepatic glucose release as stimulated by alpha- and/or beta-adrenergic agonists and its inhibition by continuously or intermittently infused insulin were simulated and described by a computer model. Thereby, no qualitative difference could be demonstrated in alpha- vs. beta-adrenergic agonists action on stimulated hepatic glucose production.

Contribution by the glycogen pool and adenosine 3',5'-monophosphate release to the evanescent effect of glucagon on hepatic glucose production in vitro.

To elucidate in vitro the transience of glucagon-induced hepatic glucose release, the effects of glucagon on hepatic glucose production and cAMP release were evaluated in the isolated rat liver preparation perfused by a nonrecirculating system. Glucagon was added to the infusate in stepwise increasing concentrations at 0, 60, and 100 min to give final concentrations of 2.5 X 10(-11), 10(-9), and 5 X 10(-8) M, respectively. Glucagon at 2.5 X 10(-11) M caused cAMP release [basal (mean +/- SD), 11.2 +/- 3.0 pmol/(min X 100 g BW)] to rise rapidly and plateau at 23.3 +/- 7.0 pmol/(min X 100 g BW), whereas hepatic glucose production [basal, 3.7 +/- 1.6 mumol/(min X 100 g BW)] increased only transiently to a maximum of 15.3 +/- 3.1 mumol/(min X 100 g BW) and fell thereafter. The enhanced cAMP release during the consecutive glucagon infusion was accompanied by a transient rise in hepatic glucose production during the second, but not during a third, glucagon infusion. When 3-isobutyl-1-methylxanthine, a potent phosphodiesterase inhibitor, was added to the perfusion medium (0.5 mM), the cAMP response to 2.5 X 10(-11) M glucagon was enhanced [247 +/- 124 pmol/(min X 100 g BW)] as was hepatic glucose production (+ 21%; P less than 0.05). Further augmentation of the glucagon concentration was followed by an increase in hepatic cAMP, but not glucose, release. When glucagon infusion (2.5 X 10(-11) M) was repeated with a glucagon-free period of 30 min in between, no stimulation of cAMP and consecutive glucose release was found during the second period. However, when the second glucagon dose was increased to 10(-9) M, glucose and cAMP release were again stimulated to the same extent as in experiments with no glucagon-free period in between. We conclude that the size of the glycogen pool and the cAMP concentration directly modulate hepatic glucose production and are responsible for evanescent glucagon action. This mechanism can be described by computer simulation.

Modified true-color computer-assisted image analysis versus subjective scoring of estrogen receptor expression in breast cancer: a comparison.

BACKGROUND: Hormone receptor expression can be quantified by computerized image analysis in immunohistochemically stained specimens. When comparing semiquantitative scoring with computerized image analysis a review of the literature shows contradictory findings concerning the correlation of these two methods. Recent technical approaches have been developed with true-color computer-assisted image analysis facilitating new measurement designs. We performed a study with a new approach using the principle of semiquantitative assessment of hormone receptor content and measuring two different binary images (immunohistochemically stained nuclear area and total nuclear area). MATERIAL AND METHODS: Eighty formalin-fixed, paraffin-embedded and immunohistochemically stained breast cancer specimens were assessed for estrogen receptor expression by true color computer-assisted image analysis and by conventional light microscopy scoring according to Remmele (immunoreactive score (IRS) = staining intensity (SI) x percentage of positive cells (PP)). The results of both methods were correlated. RESULTS: Mean optical density (MOD) and subjective scoring of SI as well as stained nuclear area vs. total nuclear area and subjective scoring of stained cells (PP) showed a high correlation (Spearman correlation coefficient: 0.95, p-value: 0.0001 and 0.64, p-value: 0.0001, respectively). CONCLUSION: On the basis of this new technical approach our results confirm the correlation of semiquantitative hormone receptor scoring and quantitative computer-assisted image analysis. We believe that by automating electronic analysis in the near future we will be able to establish reliable observer-independent evaluation of immunohistochemical variables ensuing comparability in multi-center trials and cost efficiency.

Blood glucose response to stress hormone exposure in healthy man and insulin dependent diabetic patients: prediction by computer modeling.

To establish a qualitative and quantitative model of blood glucose response to stress hormone exposure, healthy subjects (HS) on and off somatostatin (250 micrograms/h) as well as insulin dependent diabetic patients were infused with either epinephrine (E), glucagon (G), cortisol (F), growth hormone (GH) or with a cocktail of these hormones raising plasma stress hormones to values seen in severe diabetic ketoacidosis. The developed input/output model consists of two submodels interconnected in series plus two additional submodels for correction of gains describing both sensitivity of tissue response and utilisation as well as provision of glucose. It was shown and confirmed experimentally that blood glucose response to stress hormones was essentially nonlinear. Furthermore, the mathematical models for healthy subjects and for insulin dependent diabetic patients proved to be of the same structure and differed only in the values of some typical parameters. The model raises the possibility to describe and in part to predict blood glucose response to stress hormone exposure in healthy man and insulin dependent diabetic patients.

The association of smoking with IGRA and TST results in HIV-1-infected subjects.

OBJECTIVE: To assess the association of smoking with the interferon-gamma (IFN-γ) release assay and tuberculin skin test (TST) results in a comparative study on the detection of latent tuberculous infection (LTBI) in human immunodeficiency virus (HIV) 1-infected individuals. METHODS: In this cross-sectional study, 305 HIV-1-infected subjects were tested by the QuantiFERON-TB Gold In-Tube assay (QFT-GIT) and the TST. We evaluated the impact of smoking and other LTBI risk factors on QFT-GIT and TST results. RESULTS The concordance of both tests was 93% (κ = 0.71, P < 0.001). The following independent risk factors for both QFT-GIT and TST positivity were identified: birth in a high TB incidence country, self-reported contact with an active TB case and elevated CD4(+) T-cell count (P < 0.001). While smoking was not independently associated with a positive QFT-GIT (OR 1.2, 95%CI 0.5-2.8) or TST result (OR 1.8, 95%CI 0.6-5.9), there was an inverse correlation of the number of cigarettes smoked with IFN-γ levels measured using QFT-GIT (ρ = -0.14, P = 0.027). In addition, smoking was independently associated with a quantitative QFT-GIT response in linear regression analysis (ß = 0.129, P = 0.025). CONCLUSIONS: Although smoking may have a minor inhibitory effect on QFT-GIT response, QFT-GIT results seem not to be affected by smoking to a clinically significant extent.

The risk of infections in HIV-HCV coinfected patients during antiviral therapy with pegIFN+RBV.

OBJECTIVES: Antiviral treatment with pegIFN/RBV decreases ANC and CD4+ cell count. An association between neutropenia, a low CD4+ cell count and infections has not been demonstrated so far in HIV-HCV coinfected patients. METHODS: The incidence, type, and severity of infections were recorded in 85 HIV-HCV coinfected and 164 monoinfected patients receiving pegIFN/RBV for 48 weeks. ANC and CD4+ cell count were assessed every 4 weeks during therapy. RESULTS: The incidence of infections was significantly higher in HIV-HCV than HCV-Mono (38% vs. 15%; p = 0.001). Types of infections: pneumonia (n = 16/n = 24), bacteraemia/sepsis (n = 5/n = 2), skin infections (n = 15/n = 12), urinary tract infections (n = 4/n = 1), OIs (n = 10/n = 1). The incidence of neutropenia grade 1, 2 3 or 4 was similar in HIV-HCV and HCV-Mono, respectively. The incidence of infections was not associated with neutropenia (HCV-Mono: p = 0.584; HIV-HCV: p = 0.23) or with CD4+ cell counts <200/µL (HIV-HCV: p = 0.29). OIs occurred more often in HIV-HCV patients with CD4+ cell count <200/µL (p = 0.024). CONCLUSIONS: Up to 38% and 15% of HIV-HCV coinfected and HCV-monoinfected patients develop infections during pegIFN+RBV therapy but without any correlation to neutropenia. Antibacterial prophylaxis/treatment should be considered early in HIV-HCV coinfected patients developing CD4+ cell counts <200/µL during antiviral therapy as these patients have an increased risk of OIs.

Detection of hypervolemia with embedded systems.

This work presents methods of biomedical signal processing and interpretation to detect hypervolemia as a cause for oxygen delivery disturbances. A model of the disease patterns for this respiratory disorder is derived and implemented on an embedded system. The model is designed in stateflow and simulated with Matlab using a database of intensive care unit patients to proved inputs for verification. The implementation is done over a wireless micro controller network.

Epithelial and stromal estrogen and progesterone receptor expression in endometrial cancer: true color computer-assisted image analysis versus subjective scoring.

Immunohistochemical methods provide the opportunity to evaluate the staining reaction in different histologic compartments of malignant tumors. Eighty-four formalin-fixed, paraffin-embedded and immunohistochemically stained endometrial cancer specimens were assessed for estrogen receptor (ER) and progesterone receptor (PR) expression by conventional light microscopy, a light microscopy scoring system, and by true color computer-assisted image analysis. Measurements of mean optical density (MOD) in the epithelium as well as in the stroma of the tumor were performed. A negative correlation was established between the MOD of ER and PR staining in the nuclei of the epithelium and the MOD of PR staining in the stroma of the tumor vs histological stage (Spearman correlation coefficient -0.32/P < 0.004, -0.23/P < 0.03, -0.26/P < 0.02, respectively) and depth of myometrial invasion (Spearman correlation coefficient -0.34/P < 0.002, -0.24/P < 0.02, -0.25/P < 0.02, respectively). The staining pattern in endometrial cancer was heterogeneous and %PA (percentage of positive stained area) and MOD were therefore linked by multiplication in order to correct for this potentially confounding phenomenon. A negative correlation with histological stage (Spearman correlation coefficient -0.29/P < 0.007) and depth of myometrial invasion (Spearman correlation coefficient -0.34/P < 0.001) was found for PR staining in the stroma of the tumor. MOD and subjective ranking of staining intensity showed a high correlation as well as %PA and subjective estimation of stained surface. ER and PR content in the epithelium and also PR content in the stroma of endometrial cancer appear to be of value in the assessment of steroid hormone receptor status. This may be indicative of stromal-epithelial interaction.