A dynamic control technique was used to suppress a cardiac arrhythmia called an alternans rhythm in a piece of dissected rabbit heart. Our control algorithm adapted to drifting system parameters, making it well suited for the control of physiological rhythms. Control of cardiac alternans rhythms may have important clinical implications since they often precede serious cardiac arrhythmias and are a harbinger of sudden cardiac death.[S0031-9007 (97)03337-1] PACS numbers: 87.22. -q, 05.45. + b, 07.05.Dz, 87.10.+e Control techniques from the field of nonlinear dynamics [1] have been used to control both chaotic [2] and nonchaotic [3] dynamical systems. Since these control methods do not require knowledge of the system's governing equations, they are particularly applicable in biology where detailed mathematical models are usually unavailable. Control of biological dynamics is important for medical science since abnormal physiological rhythms can be life threatening [4]. Attempts have already been made to control both experimental [5] and model [6,7] biological systems. However, none of these studies used control algorithms which adapted to evolving system parameters. Since physiological environments typically drift over time, practical biological control schemes must adapt to these changes. Here, we utilize an algorithm which controls an evolving cardiac arrhythmia called an alternans rhythm in the rabbit heart.Cardiac alternans rhythms are characterized by an alternation of the timing or morphology of the heart's electrical activity from one beat to the next. While the clinical importance of cardiac alternans has only recently been recognized [8], their discovery dates back to the earliest recordings of cardiac electrical signals [9]. We generated cardiac alternans by electrically stimulating a piece of dissected rabbit heart [10]. Each stimulus delivered to the upper atrium caused a wave of electrical activity to propagate through the atrium, the atrioventricular (AV) node and out the His bundle which is the output of the AV node [ Fig. 1(a)]. We measured the electrical activity near an atrial input of the AV node and at the His bundle output [ Fig. 1(b)]. X was the time for the impulse to pass through the AV node. The output impulse was reinjected into the atrium after a time delay l. When l was made sufficiently small, the conduction time through the AV node began to alternate [11] [ Fig. 1(b)].The dynamics of AV nodal conduction can be characterized by a one-dimensional mapwhere X n is the AV nodal conduction time following the nth atrial stimulus, l is the time delay from His bundle activation to the next atrial stimulus, and f is a nonlinear, decreasing function of both arguments which relates the successive conduction times [11]. The map is represented as a graph in Fig. 2(a). This map determines the sequence of AV nodal conduction times, X 1 , X 2 , X 3 , . . . , X n given some initial conduction time, X 0 , for fixed l. The intersection of the curve with the line of identity (X n11 X n ) defines the period-...

Chronic liver failure leads to hyperammonemia, a central component in the pathogenesis of hepatic encephalopathy (HE); however, a correlation between blood ammonia levels and HE severity remains controversial. It is believed oxidative stress plays a role in modulating the effects of hyperammonemia. This study aimed to determine the relationship between chronic hyperammonemia, oxidative stress, and brain edema (BE) in two rat models of HE: portacaval anastomosis (PCA) and bile-duct ligation (BDL). Ammonia and reactive oxygen species (ROS) levels, BE, oxidant and antioxidant enzyme activities, as well as lipid peroxidation were assessed both systemically and centrally in these two different animal models. Then, the effects of allopurinol (xanthine oxidase inhibitor, 100 mg/kg for 10 days) on ROS and BE and the temporal resolution of ammonia, ROS, and BE were evaluated only in BDL rats. Similar arterial and cerebrospinal fluid ammonia levels were found in PCA and BDL rats, both significantly higher compared to their respective sham-operated controls (p < 0.05). BE was detected in BDL rats (p < 0.05) but not in PCA rats. Evidence of oxidative stress was found systemically but not centrally in BDL rats: increased levels of ROS, increased activity of xanthine oxidase (oxidant enzyme), enhanced oxidative modifications on lipids, as well as decreased antioxidant defense. In PCA rats, a preserved oxidant/antioxidant balance was demonstrated. Treatment with allopurinol in BDL rats attenuated both ROS and BE, suggesting systemic oxidative stress is implicated in the pathogenesis of BE. Analysis of ROS and ammonia temporal resolution in the plasma of BDL rats suggests systemic oxidative stress might be an important "first hit", which, followed by increases in ammonia, leads to BE in chronic liver failure. In conclusion, chronic hyperammonemia and oxidative stress in combination lead to the onset of BE in rats with chronic liver failure. HIGHLIGHTS► Hyperammonemia does not lead independently to brain edema in chronic liver failure. ► Systemic oxidative stress plays a role in brain edema in chronic liver failure. ► Systemic oxidative stress induces brain edema synergistically with hyperammonemia. ► Systemic oxidative stress is an important "first hit" in chronic liver failure.

The pathogenesis of hepatic encephalopathy is multifactorial, involving gut-derived toxins such as ammonia, which has been demonstrated to induce oxidative stress. Therefore, a primary hepatic encephalopathy treatment target is reducing ammonia production in the gastrointestinal tract. AST-120, an oral adsorbent of engineered activated carbon microspheres with surface areas exceeding 1600 m(2) /g, acts as a sink for neurotoxins and hepatotoxins present in the gut. We evaluated the capacity of AST-120 to adsorb ammonia in vitro and to lower blood ammonia, oxidative stress and brain edema in cirrhotic rats. Cirrhosis was induced in rats by bile duct ligation for 6 weeks. AST-120 was administered by gavage preventively for 6 weeks (0.1, 1, and 4 g/kg/day). In addition, AST-120 was evaluated as a short-term treatment for 2 weeks and 3 days (1 g/kg/day) and as a sink to adsorb intravenously infused ammonium acetate. In vitro, AST-120 efficiently adsorbed ammonia. Ammonia levels significantly decreased in a dose-dependent manner for all AST-120-treated bile duct-ligated rats (nontreated: 177.3 ± 30.8 μM; AST-120, 0.1 g/kg/day: 121.9 ± 13.8 μM; AST-120, 1 g/kg/day: 80.9 ± 30.0 μM; AST-120, 4 g/kg/day: 48.8 ± 19.6 μM) and significantly correlated with doses of AST-120 (r = -0.6603). Brain water content and locomotor activity normalized after AST-120 treatments, whereas arterial reactive oxygen species levels remained unchanged. Furthermore, AST-120 significantly attenuated a rise in arterial ammonia after ammonium acetate administration (intravenously). Conclusion:AST-120 treatment decreased arterial ammonia levels, normalized brain water content and locomotor activity but did not demonstrate an effect on systemic oxidative stress. Also, AST-120 acts as an ammonia sink, efficiently removing blood-derived ammonia. Additional studies are warranted to evaluate the effects of AST-120 on hepatic encephalopathy in patients with advanced liver disease. (HEPATOLOGY 2011;)

Conclusion. This is the first report establishing that AFAs in SSc are strongly correlated with anti-topo I and, furthermore, that anti-topo I antibodies themselves display AFA activity by reacting with determinants at the fibroblast surface.

Ammonia‐scavenging transmembrane pH‐gradient poly(styrene)‐b‐poly(ethylene oxide) polymersomes are investigated for the oral treatment and diagnosis of hyperammonemia, a condition associated with serious neurologic complications in patients with liver disease as well as in infants with urea cycle disorders. While these polymersomes are highly stable in simulated intestinal fluids at extreme bile salt and osmolality conditions, they unexpectedly do not reduce plasmatic ammonia levels in cirrhotic rats after oral dosing. Incubation in dietary fiber hydrogels mimicking the colonic environment suggests that the vesicles are probably destabilized during the dehydration of the intestinal chyme. The findings question the relevance of commonly used simulated intestinal fluids for studying vesicular stability. With the encapsulation of a pH‐sensitive dye in the polymersome core, the local pH increase upon ammonia influx could be exploited to assess the ammonia concentration in the plasma of healthy and cirrhotic rats as well as in other fluids. Due to its high sensitivity and selectivity, this polymersome‐based assay could prove useful in the monitoring of hyperammonemic patients and in other applications such as drug screening tests.

The pathogenesis of brain edema in patients with chronic liver disease (CLD) and minimal hepatic encephalopathy (HE) remains undefined. This study evaluated the role of brain lactate, glutamine and organic osmolytes, including myo-inositol and taurine, in the development of brain edema in a rat model of cirrhosis.Six-week bile-duct ligated (BDL) rats were injected with (13)C-glucose and de novo synthesis of lactate, and glutamine in the brain was quantified using (13)C nuclear magnetic resonance spectroscopy (NMR). Total brain lactate, glutamine, and osmolytes were measured using (1)H NMR or high performance liquid chromatography. To further define the interplay between lactate, glutamine and brain edema, BDL rats were treated with AST-120 (engineered activated carbon microspheres) and dichloroacetate (DCA: lactate synthesis inhibitor).Significant increases in de novo synthesis of lactate (1.6-fold, p<0.001) and glutamine (2.2-fold, p<0.01) were demonstrated in the brains of BDL rats vs. SHAM-operated controls. Moreover, a decrease in cerebral myo-inositol (p<0.001), with no change in taurine, was found in the presence of brain edema in BDL rats vs. controls. BDL rats treated with either AST-120 or DCA showed attenuation in brain edema and brain lactate. These two treatments did not lead to similar reductions in brain glutamine.Increased brain lactate, and not glutamine, is a primary player in the pathogenesis of brain edema in CLD. In addition, alterations in the osmoregulatory response may also be contributing factors. Our results suggest that inhibiting lactate synthesis is a new potential target for the treatment of HE.Canadian Institutes of Health Research. CB:Fonds de recherche du Québec – Sant

A convenient approach to functionalize peptides either at the N-terminal or on a lysine side chain with 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) chelating unit has been developed on solid support. The chelate was assembled in a two-step process starting with bromo-acetylated peptides. Deprotection and cleavage of the resin-bound NOTA peptides were performed with use of trifluoroacetic acid (TFA) in the presence of thioanisole and water to give free NOTA peptides.

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