Accreditation of processes in hepatology

The Spanish Association for the Study of the Liver decided in 2006 to develop a project to assess the quality of the professionals, processes and medical units dealing with the management of patients with liver diseases in Spain. The current article reports the criteria proposed to assess the quality and the accreditation of the processes in hepatology. The processes considered include most patients with liver diseases and the accreditation system designed is highly specific. This document, together with a previous one published in gastroenterología y hepatología concerning the accreditation of the professionals and a third document dealing with the accreditation of liver units that will be published soon, form the basis of the quality assessment of hepatology in our country.     

Newly Described Autoinflammatory Diseases in Pediatric Dermatology

Specific gene mutations leading to dysregulation of innate immune response produce the expanding spectrum of monogenic autoinflammatory diseases (AIDs). They are characterized by seemingly unprovoked, recurrent episodes of systemic inflammation in which a myriad of manifestations usually affect skin. Novel genetic technologies have led to the discovery of new AIDs and phenotypes that were not previously clinically described. Consequently the number of AIDs is continuously growing and their recognition and the disclosure of their pathophysiology will prompt early diagnosis and targeted treatment of affected patients. The objective of the present work is to review those newly described AIDs with prominent dermatologic manifestations that may constitute a major criterion for their diagnosis.     

In Vivo Binding of Immunoglobulin M to the Surfaces of Babesia bigemina-Infected Erythrocytes

Babesia bigemina infection of mature bovine erythrocytes results in new proteins specifically exposed on the parasitized cell surface. Monoclonal antibody (MAb) 64/32 binds a protein, designated p94, on B. bigemina-infected erythrocytes but not on either uninfected or B. bovis-parasitized erythrocytes. However, p94 was not encoded by B. bigemina and was not a parasite-modified erythrocyte membrane protein. In contrast, we showed that p94 could be eluted from the infected erythrocyte surface and was identified as specifically bound immunoglobulin M (IgM) heavy chain for the following reasons: (i) MAb 64/32 bound a reduced molecule of 94 kDa in both infected erythrocyte lysates and normal bovine serum; (ii) MAb 64/32 bound a 94-kDa molecule in reduced preparations of purified IgM; (iii) an anti-bovine μ heavy-chain MAb, BIg73, reacted specifically with the surface of infected erythrocytes and bound the 94-kDa molecule in lysates of infected erythrocytes, normal bovine serum, and purified IgM; and (iv) immunoprecipitation of infected erythrocyte lysates with MAb 64/32 depleted the 94-kDa antigen bound by anti-μ MAb BIg73 and vice versa. Binding of IgM to the infected erythrocyte surface was detected in vivo early in acute parasitemia and occurred during both the trophozoite and merozoite stages of intraerythrocytic parasitism. The common feature of IgM binding to the parasitized erythrocyte surface among otherwise genetically and antigenically distinct B. bigemina strains is suggestive of an advantageous role in parasite survival in vivo.     

Coxsackievirus B3-Induced Myocarditis : Perforin Exacerbates Disease, But Plays No Detectable Role in Virus Clearance

Viral myocarditis is remarkably common, being detected in approximately 1% of unselected asymptomatic individuals. Many cases are attributable to enteroviral infection, and in particular to coxsackievirus B3. The underlying pathogenesis is controversial, but most studies admit the important immunopathological role of infiltrating CD8⁺ (cytotoxic) T lymphocytes (CTLs). We have previously shown that CTLs play conflicting roles in coxsackievirus B (CVB) myocarditis; they assist in controlling virus replication, but also are instrumental in causing the extensive inflammatory disease, which often results in severe myocardial scarring. A role for perforin, the major CTL cytolytic protein, in CVB myocarditis has been suggested, but never proven. In the present study we use perforin knockout (PKO) mice to show that perforin plays a major role in CVB infection; in broad terms, perforin is important in immunopathology, but not in CVB clearance. For example, PKO mice are better able to withstand a normally lethal dose of CVB (100% survival of PKO mice compared with 90% death in +/+ littermates). In addition, PKO mice given a nonlethal dose of CVB develop only a mild myocarditis, whereas their perforin⁺ littermates have extensive myocardial lesions. The myocarditis in PKO mice resolves more quickly, and these mice show minimal histological sequelae; in contrast, late in disease the perforin⁺ mice develop severe myocardial fibrosis. PKO mice, despite lacking this major CTL effector function, can control the infection and eradicate the virus; growth kinetics and peak CVB titers are indistinguishable in PKO and perforin⁺ mice. Therefore, the immunopathological and antiviral effects of CTLs can be uncoupled by ablation of perforin; this offers a promising target for therapy of myocarditis. Furthermore, we evaluate the possible roles of apoptosis, and of chemokine expression, in CVB infection. In perforin⁺ mice, apoptotic cells are detected within the inflammatory infiltrate, whereas in their PKO counterparts, apoptotic myocyte nuclei are seen. Chemokine expression in both PKO and perforin⁺ mice precedes and parallels the course of myocarditis. Several chemokines are detectable earlier in PKO mice than in perforin⁺ mice, but PKO mice show reduced peak levels, and chemokine expression decays sooner. In particular, MIP-1α expression is barely detectable at any time point in PKO mice, but it is readily identified in perforin⁺ animals, peaking just before the time of maximal myocarditis; this is particularly interesting, given that MIP-1α knockout mice are resistant to CVB myocarditis, but remain able to control viral infection. Thus, the chemokine pathway offers a second route of intervention to diminish myocarditis and its sequelae, while permitting the host to eradicate the virus.     

Progressive Neurodegeneration in Aspartylglycosaminuria Mice

Aspartylglycosaminuria (AGU) is one of the most common lysosomal storage disorders in humans. A mouse model for AGU has been recently generated through targeted disruption of the glycosylasparaginase gene, and at a young age the glycosyl asparaginase-deficient mice demonstrated many pathological changes found in human AGU patients (Kaartinen V, Mononen I, Voncken J-W, Gonzalez-Gomez I, Heisterkamp N, Groffen J: A mouse model for aspartylglycosaminuria. Nat Med 1996, 2:1375–1378). Our current findings demonstrate that after the age of 10 months, the general condition of null mutant mice gradually deteriorated. They suffered from a progressive motoric impairment and impaired bladder function and died prematurely. A widespread lysosomal hypertrophy in the central nervous system was detected. This neuronal vacuolation was particularly severe in the lateral thalamic nuclei, medullary reticular nuclei, vestibular nuclei, inferior olivary complex, and deep cerebellar nuclei. The oldest animals (20 months old) displayed a clear neuronal loss and gliosis, particularly in those regions, where the most severe vacuolation was found. The severe ataxic gait of the older mice was likely due to the dramatic loss of Purkinje cells, intensive astrogliosis and vacuolation of neurons in the deep cerebellar nuclei, and the severe vacuolation of the cells in vestibular and cochlear nuclei. The impaired bladder function and subsequent hydronephrosis were secondary to involvement of the central nervous system. These findings demonstrate that the glycosylasparaginase-deficient mice share many neuropathological features with human AGU patients, providing a suitable animal model to test therapeutic strategies in the treatment of the central nervous system effects in AGU.     

The influence of gender on symptoms associated with obstructive sleep apnea

Background

It has been reported that the clinical expression of obstructive sleep apnea (OSA) may differ in women and men.

Objective

The objective of this study was to evaluate the influence of gender on reported OSA-related symptoms in a large clinical population of patients.

Methods

The database from the sleep laboratory of a tertiary care center was examined. Adult patients who had undergone a diagnostic polysomnography and completed the Berlin questionnaire, a sleep questionnaire, and the Epworth sleepiness scale were selected. Multiple logistic regression analysis was performed to assess the relationship between OSA-associated symptoms and different potential explanatory variables.

Results

The study sample included 1084 patients, median age was 53 years, 46.5% (504) were women, 72.7% (788) had OSA (apnea/hypopnea index ≥?5), and 31.2% were obese. After adjusting for age, body mass index, and apnea/hypopnea index, men were more likely to report snoring (OR 4.06, p?<?0.001), habitual or loud snoring (OR 2.34, p?<?0.001; 2.14, p?<?0.001, respectively) and apneas (OR 2.44, p?<?0.001), than women. After controlling for multiple variables, female gender was an independent predictive factor for reported tiredness (OR 0.57, p 0.001), sleep onset insomnia (OR 0.59, p 0.0035), and morning headaches (OR 0.32, p?<?0.001). Reports of excessive daytime sleepiness, nocturia, midnight insomnia, and subjective cognitive complaints were not significantly associated with gender.

Conclusion

Women with OSA were more likely to report tiredness, initial insomnia, and morning headaches, and less likely to complain of typical OSA symptoms (snoring, apneas) than men.

     

Safety,tolerability, pharmacokinetics,and pharmacodynamics of a TLR7 agonist prodrug RO6870868 in healthy volunteers

RO6870868 is an oral prodrug of the toll‐like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first‐in‐human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200–2000 mg). Single oral doses were generally well‐tolerated with a predictable safety profile associated with dose‐dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half‐life ranging 2–6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC_0‐∞) increasing proportionally with dose. A pattern of dose and time‐dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose‐dependent manner with adequate safety and tolerability. Single‐dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Toll‐like receptor 7 (TLR7) agonists induce broad immune‐enhancing effects and may play a role in overcoming the adaptive and innate immune defects in chronic hepatitis B infection.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of RO6870868 (a prodrug of the specific TLR7 agonist RO6871765) in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

RO6870868 was safe and acceptably tolerated across the dose range in healthy volunteers. Oral administration results in the rapid appearance of the active TLR7 agonist RO6871765 and leads to a profile of gene expression typical for TLR7 agonism, including activation of interferon and interferon‐response genes. Gene activation occurs at RO6871765 exposure associated with single RO6870868 doses greater than or equal to 800 mg, with a plateau for several markers at doses between 1200 mg and 1600 mg.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The study results help to guide dose and regimen selection for clinical trials with RO6870868 and other potent TLR7 activators.