Comparative in vivo study on the healing qualities of four different presealed vascular prostheses

PURPOSE: The purpose of this article is to assess the healing qualities of presealed knitted polyester prostheses. METHODS: Thoracic aortic replacement was performed with grafts with four different coating materials-collagen (CP), albumin (AP), and two with gelatin (GP1/GP2)-in four groups of 15 pigs each. Two weeks, 6 weeks, and 6 months after operation, five pigs of each group were killed. Healing quality was assessed by morphometric analysis of the remaining coating, the extent of tissue ingrowth, and the thickness of the inner layer. RESULTS: The sealant was rapidly absorbed in all prostheses except for the AP (remaining coating at 2 weeks: GP1 22.1%, GP2 34.7%, and CP 68.0% vs AP 97.1% [p < 0.05]), remaining coating at 6 weeks: GP1/GP2 0% and CP 2.5% vs AP 76.7% (p < .01). At 6 months, remaining coating was only detectable in AP (21.5%). At 2 weeks the extent of tissue ingrowth ranged from 65.7% in GP1 and 75.3% in CP to 80% in GP2 versus 8.9% in AP (p < 0.05). There was a slow increase of tissue ingrowth until the sixth postoperative week (GP1 74.4%, GP2 85.0%, and CP 91.3% versus AP 19.6% [p < 0.01]). Thickness of the internal layer varied from 0.11 to 0.21 mm at 2 weeks in all grafts studied and from 1.02 mm (AP) and 1.28 mm (GP2) to 1.39 mm (GP1), versus 0.41 mm in the CP (p < 0.01) after 6 months of implantation. CONCLUSIONS: The type of coating significantly influences the healing properties of knitted polyester prostheses. When used for thoracic aortic replacement in pigs, AP coating clearly results in inferior healing compared with GP1/GP2 or CP impregnation, with digestion of the coating material and tissue ingrowth used as parameters. The thinnest internal layer was found in the CP prostheses, reflecting superior healing properties of this coating in the model studied.

Self-sufficient control of urate homeostasis in mice by a synthetic circuit

Synthetic biology has shown that the metabolic behavior of mammalian cells can be altered by genetic devices such as epigenetic and hysteretic switches, timers and oscillators, biocomputers, hormone systems and heterologous metabolic shunts. To explore the potential of such devices for therapeutic strategies, we designed a synthetic mammalian circuit to maintain uric acid homeostasis in the bloodstream, disturbance of which is associated with tumor lysis syndrome and gout. This synthetic device consists of a modified Deinococcus radiodurans-derived protein that senses uric acids levels and triggers dose-dependent derepression of a secretion-engineered Aspergillus flavus urate oxidase that eliminates uric acid. In urate oxidase-deficient mice, which develop acute hyperuricemia, the synthetic circuit decreased blood urate concentration to stable sub-pathologic levels in a dose-dependent manner and reduced uric acid crystal deposits in the kidney. Synthetic gene-network devices providing self-sufficient control of pathologic metabolites represent molecular prostheses, which may foster advances in future gene- and cell-based therapies.

Influence of the magnesium aspartate hydrochloride administration to the maternal circuit on the aspartate concentration of the fetal circuit under in vitro perfusion of human placenta

OBJECTIVES: Magnesium aspartate hydrochloride (Magnesiocard, Mg-Asp-HCl) is proposed as a substitute of magnesium sulfate for the treatment of preeclampsia and premature labor. After an i.v. administration of a dose equivalent to that used in the treatment of preeclampsia to nonpregnant volunteers, a 10-fold increase of aspartic acid (Asp) over the physiological level was observed. Animal experiments have demonstrated that highly increased fetal levels of acidic amino acids such as Asp could be associated with neurotoxic damage in the fetal brain. The influence of such an elevation of Asp concentration in the maternal circuit on the fetal level, using the in vitro perfusion model of human placenta, was investigated. STUDY DESIGN: After a control phase (2h), a therapeutic dose of Mg combined with Asp (Magnesiocard, Mg-Asp-HCl) was applied to the maternal circuit approaching 10 times the physiological level of Asp. The administration was performed in two different phases simulating either a peak of maximum concentration (bolus application, 2h) or a steady state level (initially added, 4h). RESULTS: In four experiments, during experimental phases (6h) a slow increase in concentration in the fetal circuit was seen for Mg, AIB (alpha-aminoisobutyric acid, artificial amino acid) and creatinine confirming previous observations. In contrast, no net transfer of Asp across the placenta was seen. A continuous decrease in the concentration of Asp on both maternal and fetal side suggests active uptake and metabolization by the placenta. Viability control parameters remained stable indicating the absence of an effect on placental metabolism, permeability and morphology. CONCLUSION: Elevation of Asp concentration up to 10 times the physiological level by the administration of Mg-Asp-HCl to the maternal circuit under in vitro perfusion conditions of human placenta has no influence on the fetal level of Asp suggesting no transfer of Asp from the maternal to fetal compartment. Therefore, the administration of Mg-Asp-HCl to preeclamptic patients would be beneficial for the patients without any impact on placental or fetal physiology.

Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus.

Rapid-eye movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus. Lateral hypothalamus melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, but their effects on REM sleep remain unclear. Using optogenetic tools in newly generated Tg(Pmch-cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM, sleep episodes. In contrast, their acute silencing (eNpHR3.0, archaerhodopsin) reduced the frequency and amplitude of hippocampal theta rhythm without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory postsynaptic currents in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), and in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain.

Local changes in neocortical circuit dynamics coincide with the spread of seizures to thalamus in a model of epilepsy

During the generalization of epileptic seizures, pathological activity in one brain area recruits distant brain structures into joint synchronous discharges. However, it remains unknown whether specific changes in local circuit activity are related to the aberrant recruitment of anatomically distant structures into epileptiform discharges. Further, it is not known whether aberrant areas recruit or entrain healthy ones into pathological activity. Here we study the dynamics of local circuit activity during the spread of epileptiform discharges in the zero-magnesium in vitro model of epilepsy. We employ high-speed multi-photon imaging in combination with dual whole-cell recordings in acute thalamocortical (TC) slices of the juvenile mouse to characterize the generalization of epileptic activity between neocortex and thalamus. We find that, although both structures are exposed to zero-magnesium, the initial onset of focal epileptiform discharge occurs in cortex. This suggests that local recurrent connectivity that is particularly prevalent in cortex is important for the initiation of seizure activity. Subsequent recruitment of thalamus into joint, generalized discharges is coincident with an increase in the coherence of local cortical circuit activity that itself does not depend on thalamus. Finally, the intensity of population discharges is positively correlated between both brain areas. This suggests that during and after seizure generalization not only the timing but also the amplitude of epileptiform discharges in thalamus is entrained by cortex. Together these results suggest a central role of neocortical activity for the onset and the structure of pathological recruitment of thalamus into joint synchronous epileptiform discharges.

Psychomotor symptoms of schizophrenia map on the cerebral motor circuit

Schizophrenia is a devastating disorder thought to result mainly from cerebral pathology. Neuroimaging studies have provided a wealth of findings of brain dysfunction in schizophrenia. However, we are still far from understanding how particular symptoms can result from aberrant brain function. In this context, the high prevalence of motor symptoms in schizophrenia such as catatonia, neurological soft signs, parkinsonism, and abnormal involuntary movements is of particular interest. Here, the neuroimaging correlates of these motor symptoms are reviewed. For all investigated motor symptoms, neural correlates were found within the cerebral motor system. However, only a limited set of results exists for hypokinesia and neurological soft signs, while catatonia, abnormal involuntary movements and parkinsonian signs still remain understudied with neuroimaging methods. Soft signs have been associated with altered brain structure and function in cortical premotor and motor areas as well as cerebellum and thalamus. Hypokinesia is suggested to result from insufficient interaction of thalamocortical loops within the motor system. Future studies are needed to address the neural correlates of motor abnormalities in prodromal states, changes during the course of the illness, and the specific pathophysiology of catatonia, dyskinesia and parkinsonism in schizophrenia.