Longterm course of mixed cryoglobulinemia in patients infected with hepatitis C virus

OBJECTIVE: To describe epidemiological, clinical, and immunological characteristics and the longterm course of persistent mixed cryoglobulinemia (MC) in patients infected with hepatitis C virus (HCV). METHODS: Retrospective study of HCV infected patients (HCV RNA positive) who had persistent positive MC, with 2 immunochemical typings of MC carried out after 24-month minimum interval. RESULTS: In total, 125 patients were studied, aged 52 +/- 13 years at diagnosis of MC, with duration of HCV infection of 18 +/- 10 years. At entry, 60 patients had type II MC, 53 patients had type III, and 12 patients had the oligoclonal type. At the second immunochemical typing, after a mean interval of 45 +/- 20 months, MC was type II in 72 patients, type III in 39 patients, and the oligoclonal type in 14 patients. The proportion of cases of MC with the same immunochemical type was higher among patients with type II (78%) than type III (59%) or oligoclonal MC (17%) (p < 0.01). The MC that changed turned more to type II (55.5%) than type III (29%) or the oligoclonal type (15.5%) (p = 0.0002). MC vasculitis (purpura, arthralgia, peripheral neuropathy, renal involvement) and other extrahepatic manifestations (polyarteritis nodosa, lymphoma) in 60/125 patients was associated with advanced age (p < 0.01), a longer duration of infection (p < 0.05), type II MC (odds ratio = 5, p < 0.01), and a higher MC serum level (p < 0.01). CONCLUSION: During chronic active HCV infection, type II MC is more stable over time than type III and oligoclonal MC. The oligoclonal type appears to be an intermediate stage in the course of type III changing to type II MC. Symptomatic persistent HCV MC was associated with advanced age, longer duration of HCV infection, type II MC, and a higher MC serum level.     

Predictors of Congestive Heart Failure after Treatment with an Endothelin Receptor Antagonist

Background and objectives

The Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death (ASCEND) trial tested the renoprotective effect of the endothelin receptor antagonist avosentan in patients with diabetes and nephropathy, but the study was terminated due to an excess of congestive heart failure (CHF) events in the avosentan arms, likely due to fluid retention. The aim of this study was to identify risk markers of CHF after treatment with avosentan.

Design, setting, participants, & measurements

In a post hoc analysis of the ASCEND trial (N=1392 participants), we assessed which baseline characteristics predicted CHF risk during avosentan treatment. Furthermore, postrandomization changes between baseline and the first available measurement of body weight and hemoglobin were examined as potential clinical indicators of fluid retention for their relationship with CHF development.

Results

Relative to placebo, avosentan increased CHF risk (hazard ratio, 2.76; 95% confidence interval, 1.68 to 4.54). The avosentan-related CHF risk was higher with lower baseline cholesterol levels (P interaction=0.003) and concomitant statin use (P interaction=0.06), whereas it was lower with a lower estimated GFR (P interaction=0.04). Patients allocated to avosentan had a median body weight increase of 0.6 kg (interquartile range, 0.0 to 2.0 kg) and a median hemoglobin decrease of 1.4 g/dl (interquartile range, −2.1 to −0.7 g/dl) at the first postrandomization measurement. The body weight increase induced by avosentan was associated with CHF development (P interaction=0.04), whereas hemoglobin decrease was not (P interaction=0.64). The increase in body weight was particularly pronounced in patients with a cardiovascular disease history and in patients using statins.

Conclusions

In avosentan-treated patients, body weight increase, but not hemoglobin decrease, was associated with CHF development, indicating that close body weight monitoring could provide an early signal of CHF development in future trials with endothelin receptor antagonists.     

(Finite) statistical size effects on compressive strength

The larger structures are, the lower their mechanical strength. Already discussed by Leonardo da Vinci and Edmé Mariotte several centuries ago, size effects on strength remain of crucial importance in modern engineering for the elaboration of safety regulations in structural design or the extrapolation of laboratory results to geophysical field scales. Under tensile loading, statistical size effects are traditionally modeled with a weakest-link approach. One of its prominent results is a prediction of vanishing strength at large scales that can be quantified in the framework of extreme value statistics. Despite a frequent use outside its range of validity, this approach remains the dominant tool in the field of statistical size effects. Here we focus on compressive failure, which concerns a wide range of geophysical and geotechnical situations. We show on historical and recent experimental data that weakest-link predictions are not obeyed. In particular, the mechanical strength saturates at a nonzero value toward large scales. Accounting explicitly for the elastic interactions between defects during the damage process, we build a formal analogy of compressive failure with the depinning transition of an elastic manifold. This critical transition interpretation naturally entails finite-size scaling laws for the mean strength and its associated variability. Theoretical predictions are in remarkable agreement with measurements reported for various materials such as rocks, ice, coal, or concrete. This formalism, which can also be extended to the flowing instability of granular media under multiaxial compression, has important practical consequences for future design rules.Owing to its importance for structural design (1), the elaboration of safety regulations (2), or the extrapolation of laboratory results to geophysical field scales (3), the size effects on strength of materials are one of the oldest problems in engineering, already discussed by Leonardo da Vinci and Edmé Mariotte (4) several centuries ago, but still an active field of research (5, 6). As early as 1686, Mariotte (4) qualitatively introduced the weakest-link concept to account for size effects on mechanical strength, a phenomenon evidenced by Leonardo da Vinci almost two centuries earlier. This idea, which states that the larger the system considered is, the larger the probability to find a particularly faulty place that will be at the origin of global failure, was formalized much later by Weibull (7). Considering a chain of elementary independent links, the failure of the chain is obtained as soon as one link happens to break. By virtue of the independence between the potential breaking events, the survival probability of a chain of N links is obtained by the simple multiplication of the N elementary probabilities. Depending on the properties of the latter, the global survival probability converges toward one of the three limit distributions identified by Weibull (7), Gumbel (8), and Fréchet (8), respectively. Together with Fisher and Tippett (9), these authors pioneered the field of extreme value statistics.This purely statistical argument, undoubtedly valid in 1D, was extended by Weibull (7, 10) to account for the risk of failure of 3D samples or structures. Besides the hypothesis of independence, it thus requires an additional hypothesis of brittleness: The nucleation of any elementary crack at the microscopic scale from a preexisting flaw is assumed to immediately induce the failure at the macroscale. More specifically, following linear elastic fracture mechanics (LEFM) stating that crack initiation from a flaw of size s occurs at a stress , one gets a probability of failure of a system of size L under an applied stress σ, , that depends on the distribution of preexisting defect sizes. Assuming a power law tail for this distribution, Weibull statistics are expected(7), , whereas Gumbel statistics are expected for any distribution of defect sizes whose the tail falls faster than that of a power law (8, 11, 12), , where m is the so-called Weibull’s modulus, d is the topological dimension, and L₀ and σ_u are normalizing constants. For Weibull statistics, the mean strength and the associated SD δ(σ_f) then scale with sample size L as . This approach has been successfully applied to the statistics of brittle failure strength under tension (7, 13), with m in the range 6–30 (14). It implies a vanishing strength for L → +∞, although this decrease can be rather shallow, owing to the large values of m often reported.Although relying on strong hypotheses, this weakest-link statistical approach was almost systematically invoked until the 1970s to account for size effects on strength whatever the material and/or the loading conditions. However, as shown by Bazant (1, 5), in many situations the hypothesis of brittleness is not obeyed. This is in particular the case when the size of the fracture process zone (FPZ) becomes nonnegligible with respect to the system size. In this so-called quasi-brittle case, an energetic, nonstatistical size effect applies (15), which has been shown to account for a large variety of situations (5). Toward large scales, i.e., L → +∞, the FPZ becomes negligible compared with L, and the hypothesis of brittleness should therefore be recovered and statistical size effects should dominate. Statistical numerical models of fracture of heterogeneous media also revealed deviations from the extreme value statistics predictions (16) but, as stated by Alava et al. (ref. 11, p. 9), “the role of damage accumulation for fracture size effects in unnotched samples still remains unclear.” As shown below, compressive failure results from such progressive damage accumulation.In what follows, we do not consider (deterministic) energetic size effects and explore a situation, compressive failure, where both the hypotheses of brittleness (in the sense given above) and independence are not fulfilled, up to very large scales. Relaxing these initial hypotheses of the weakest-link theory, our statistical physics approach remains statistical by nature and relies on the interplay between internal disorder and stress redistributions. It is based on a mapping of brittle compressive failure onto the critical depinning transition of an elastic manifold, a class of models widely used in nonequilibrium statistical physics characterized by a dynamic phase transition (17). This approach does not consider a sample’s shape effects (18), only statistical size effects. The critical scaling laws associated to this phase transition naturally predict a saturation of the compressive strength at a large scale and are in remarkable agreement with measurements reported for various materials such as rocks, ice, coal, or concrete.     

Design of donecopride,a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

RS67333 is a partial serotonin subtype 4 receptor (5-HT₄R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer’s disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT₄R partial agonist (K_i = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC₅₀ = 16 nM) that further promotes sAPPα release (EC₅₀ = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.Among the large family of serotonin receptors (5-HTR), some of them, such as the subtype 4 (5-HT₄R), are of particular interest in improving memory performance and therefore, decreasing memory deficits, such as those that occur in Alzheimer''s disease (AD). In the CNS, they are located in structures that are primarily involved in cognitive functions, like the olfactory tubercles, basal ganglia, septum, substantia nigra, superior colliculi, hippocampus, and cortex. Several compounds act as agonists to 5-HT₄R (BIMU1, BIMU8, RS17017, SL65.0155, VRX-03011, prucalopride, RS67333, and RS67506). One of the most affine (pK_i = 7.88) and selective vs. other receptors is RS67333, which acts as a partial agonist (1). With respect to the potential therapeutic modulation of 5-HT₄R with RS67333 and excluding its putative antidepressant-like activity (2–4), most studies focused on the promnesic or antiamnesic actions of this compound. These effects on cognitive functions that concern learning and memory are probably, in part, because of the fact that the pharmacological stimulation of these receptors increases the release of ACh in the hippocampus and cortex, and it also increases serotonin, dopamine, and GABA release (5–13). Concerning the selective aspects of memory functions, RS67333 has been shown to improve object recognition in adult (14, 15) and aged animals (16, 17) and place recognition (10) in rodents. It also increases spatial learning on the Morris water maze task in rodents, and it even reverses the deleterious effect of atropine (18) or scopolamine during this same task.Based on the structural analogy existing between RS67333 and donepezil (Fig. 1), we postulated that RS67333 could improve learning and memory by not only activating 5-HT₄R but also, inhibiting acetylcholinesterase (AChE) activity. Indeed, several early studies reported that the inhibition of AChE improved cognition and that this effect is the main reason for the initial use of donepezil, galantamine, and rivastigmine as cognitive enhancers in AD (19, 20). AChE inhibition has also been reported to improve performances in healthy rodents or animal models of memory deficiency (21). The hypothesis of an involvement of AChE inhibition by RS67333 in memory improvement is an issue that has never been tested.Open in a separate windowFig. 1.RS67333 and donepezil are chemically close.Furthermore, such a pharmacological profile could be also exploited to lead to pleiotropic compounds that are theoretically useful in AD treatment. Indeed, today, it is well-established that 5-HT₄R activation not only favors ACh release but also, is involved in the nonamyloidogenic cleavage of amyloid precursor protein (APP) in the neurotrophic sAPPα fragment, with secretion that is detrimental to amyloid-β peptide (Aβ) production (22–24). However, inhibiting the catalytic activity of AChE is widely used to restore cholinergic neurotransmission in AD, and interacting with the peripheral anionic site (PAS) of this enzyme could also reduce amyloid aggregation, for which AChE would be responsible (25). These activities seem to be synergistic when they are associated in an AD animal model, which we have recently shown in mice (26). A second pharmacological approach based on the fact that a single compound may be able to hit multiple targets is now emerging. This concept, called multitarget-directed ligands (MTDLs) (27, 28), would have inherent advantages over a combination of drugs called multiple medication therapy. It would specially obviate the problems linked to the complexity of the pharmacokinetic profile of the combined drugs and the risk of drug–drug interactions. Moreover, MTDL could also alleviate compliance difficulties associated with multiple medication therapy. It has also been shown that MTDLs generally show a higher synergistic effect than that observed with a combination of drugs. Numerous examples of MTDL against AD have been recently described (27). Most of them associate an AChE inhibitory effect with another activity hitting another molecular target of AD, such as antioxidant effect, monoamine oxidase inhibition, calcium channel blocking effect, metal chelating activity, etc. However, no MTDLs associating an inhibition of AChE and 5-HT₄R agonist effect have been hitherto described. Among the different ways to synthesize such MTDLs, one of them is to merge the frameworks of two selective starting compounds, each one exerting an activity toward a sole target (28). This goal is even more easily reached if the starting compounds are structurally close, and it is the reason why we considered the structural analogy between donepezil and RS67333 as a good starting point to design MTDLs displaying both activities (AChE inhibition and 5-HT₄R agonist activities). We will, thus, provide proof of this concept with the synthesis and biological evaluation of MR31147 (donecopride) as conceived from the pharmacomodulation of RS67333.