Nonresponse to Interferon-α Based Treatment for Chronic Hepatitis C Infection Is Associated with Increased Hazard of Cirrhosis

Background

The long-term consequences of unsuccessful interferon-α based hepatitis C treatment on liver disease progression and survival have not been fully explored.

Methods and Findings

We performed retrospective analyses to assess long-term clinical outcomes among treated and untreated patients with hepatitis C virus in two independent cohorts from a United States Veterans Affairs Medical Center and a University Teaching Hospital. Eligible patients underwent liver biopsy during consideration for interferon-α based treatment between 1992 and 2007. They were assessed for the probability of developing cirrhosis and of dying during follow-up using Cox proportional hazards models, stratified by pretreatment liver fibrosis stage and adjusted for known risk factors for cirrhosis and characteristics affecting treatment selection. The major predictor was a time-dependent covariate for treatment outcome among four patient groups: 1) patients with sustained virological response to treatment; 2) treatment relapsers; 3) treatment nonresponders; and 4) never treated patients. Treatment nonresponders in both cohorts had a statistically significantly increased hazard of cirrhosis compared to never treated patients, as stratified by pretreatment liver fibrosis stage and adjusted for clinical and psychosocial risk factors that disproportionately affect patients who were ineligible for treatment (Veterans Affairs HR = 2.35, CI 1.18–4.69, mean follow-up 10 years, and University Hospital HR = 5.90, CI 1.50–23.24, mean follow-up 7.7 years). Despite their increased risk for liver disease progression, the overall survival of nonresponders in both cohorts was not significantly different from that of never treated patients.

Conclusion

These unexpected findings suggest that patients who receive interferon-α based therapies but fail to clear the hepatitis C virus may have an increased hazard of cirrhosis compared to untreated patients.     

Alterations in NADPH oxidase expression and blood-brain barrier in bile duct ligation-treated young rats: effects of melatonin

Bile duct ligation (BDL)-treated rats exhibit cholestasis and increased systemic and brain oxidative stress. Activation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and disruption of the blood-brain barrier (BBB) are implicated as the pathogenetic mechanisms of brain dysfunction in BDL-treated adult rats. Young rats underwent sham ligation or BDL at day 17 for 2 or 4weeks. Treatment group rats were administered melatonin between day 17 and 45. We found a progressive increase in prefrontal cortex NADPH-dependent superoxide anion (O(2)(-)) production and increased expression of NADPH oxidase subunits in either the prefrontal cortex or the hippocampus in BDL-treated young rats. In addition, expression of intercellular adhesion molecule-1 (ICAM) and tissue plasminogen activator (t-PA) genes were increased in either the prefrontal cortex or the hippocampus. Prefrontal cortex capillary junctional complex proteins expressions including occludin, claudin-5, platelet endothelial cell adhesion molecule-1 and vascular endothelial cadherin were not altered. Melatonin lowered the prefrontal cortex NADPH-dependent O(2)(-) production and t-PA gene expression. We conclude that alterations in NADPH oxidase expression and BBB are involved in brain dysfunction in BDL-treated young rats. In addition, melatonin regulates NADPH oxidase activity and t-PA gene expression.     

Functional Significance of Calcium Binding to Tissue-Nonspecific Alkaline Phosphatase

The conserved active site of alkaline phosphatases (AP) contains catalytically important Zn²⁺ (M1 and M2) and Mg²⁺-sites (M3) and a fourth peripheral Ca²⁺ site (M4) of unknown significance. We have studied Ca²⁺ binding to M1-4 of tissue-nonspecific AP (TNAP), an enzyme crucial for skeletal mineralization, using recombinant TNAP and a series of M4 mutants. Ca²⁺ could substitute for Mg²⁺ at M3, with maximal activity for Ca²⁺/Zn²⁺-TNAP around 40% that of Mg²⁺/Zn²⁺-TNAP at pH 9.8 and 7.4. At pH 7.4, allosteric TNAP-activation at M3 by Ca²⁺ occurred faster than by Mg²⁺. Several TNAP M4 mutations eradicated TNAP activity, while others mildly influenced the affinity of Ca²⁺ and Mg²⁺ for M3 similarly, excluding a catalytic role for Ca²⁺ in the TNAP M4 site. At pH 9.8, Ca²⁺ competed with soluble Zn²⁺ for binding to M1 and M2 up to 1 mM and at higher concentrations, it even displaced M1- and M2-bound Zn²⁺, forming Ca²⁺/Ca²⁺-TNAP with a catalytic activity only 4–6% that of Mg²⁺/Zn²⁺-TNAP. At pH 7.4, competition with Zn²⁺ and its displacement from M1 and M2 required >10-fold higher Ca²⁺ concentrations, to generate weakly active Ca²⁺/Ca²⁺-TNAP. Thus, in a Ca²⁺-rich environment, such as during skeletal mineralization at pH 7.4, Ca²⁺ adequately activates Zn²⁺-TNAP at M3, but very high Ca²⁺ concentrations compete with available Zn²⁺ for binding to M1 and M2 and ultimately displace Zn²⁺ from the active site, virtually inactivating TNAP. Those ALPL mutations that substitute critical TNAP amino acids involved in coordinating Ca²⁺ to M4 cause hypophosphatasia because of their 3D-structural impact, but M4-bound Ca²⁺ is catalytically inactive. In conclusion, during skeletal mineralization, the building Ca²⁺ gradient first activates TNAP, but gradually inactivates it at high Ca²⁺ concentrations, toward completion of mineralization.     

Disputes over memory ownership: What memories are disputed?

The ownership of memories is sometimes disputed, particularly by twins. Examination of 77 disputed memories, 71 provided by twins, showed that most of the remembered events are negative and that the disputants appear to be self-serving. They claim for themselves memories for achievements and suffered misfortunes but are more likely to give away memories of personal wrongdoing. The research suggests that some of the memories in which we play a leading role might in fact have been the experiences of others.     

Signal transduction in maize and Arabidopsis mesophyll protoplasts.

Plant protoplasts show physiological perceptions and responses to hormones, metabolites, environmental cues, and pathogen-derived elicitors, similar to cell-autonomous responses in intact tissues and plants. The development of defined protoplast transient expression systems for high-throughput screening and systematic characterization of gene functions has greatly contributed to elucidating plant signal transduction pathways, in combination with genetic, genomic, and transgenic approaches.