Non-coding RNAs in Cardiac Regeneration.

Cardiovascular disease is a leading cause of death worldwide, and with the dramatically increasing numbers of heart failure patients in the next 10 years, mortality will only increase [1]. For patients with end-stage heart failure, heart transplantation is the sole option. Regrettably, the number of available donor hearts is drastically lower than the number of patients waiting for heart transplantation. Despite evidence of cardiomyocyte renewal in adult human hearts, regeneration of functional myocardium after injury can be neglected. The limited regenerative capacity due to inadequate proliferation of existing cardiomyocytes is insufficient to repopulate areas of lost myocardium [2]. As a solution, the hypothesis that adult stem cells could be employed to generate functional cardiomyocytes was proposed. One of the early studies that supported this hypothesis involved direct injection of hematopoietic c-kit-positive cells derived from bone marrow into the infarcted heart [3]. However, in sharp contrast, more recent evidence emerged demonstrating that these hematopoietic stem cells only differentiate into cells down the hematopoietic lineage rather than into cardiomyocytes [4, 5], and the focus shifted towards stem cells residing in the heart, called cardiac progenitor cells. These CPCs were extracted and injected into the myocardium to regenerate the heart [6]. In recent years, over 80 pre-clinical studies employing cardiac stem cells in vivo in large and small animals to evaluate the effect on functional parameters were systematically reviewed, identifying differences between large and small animals [7]. Despite the positive outcome of these stem cell therapies on functional parameters, c-kit-positive cardiac progenitor cells were shown to contribute minimally to the generation of functional cardiomyocytes [8, 9]. This heavily debated topic is summarized concisely by van Berlo and Molkentin [10]. Recently, single-cell sequencing and genetic lineage tracing of proliferative cells in the murine heart in both homeostatic and regenerating conditions did not yield a quiescent cardiac stem cell population or other cell types that support transdifferentiation into cardiomyocytes, nor did it support proliferation of cardiac myocytes [11, 12]. Now, the focus is shifting towards exploiting the limited regenerative capacity of the cardiomyocytes themselves, by re-activating proliferation of existing cardiomyocytes through dedifferentiation, reentry into the cell cycle, and cytokinesis. This process is the new focus of research to promote cardiac regeneration, and can be controlled on multiple levels, including cell-cycle manipulation, reprogramming, small molecules, extra-cellular matrix (ECM), proteins, and RNA regulation [13].

Intrathecal Baclofen therapy in Germany: Proceedings of the IAB-Interdisciplinary Working Group for Movement Disorders Consensus Meeting.

Continuous intrathecal Baclofen application (ITB) through an intracorporeal pump system is widely used in adults and children with spasticity of spinal and supraspinal origin. Currently, about 1200 new ITB pump systems are implanted in Germany each year. ITB is based on an interdisciplinary approach with neurologists, rehabilitation specialists, paediatricians and neurosurgeons. We are presenting the proceedings of a consensus meeting organised by IAB-Interdisciplinary Working Group for Movement Disorders. The ITB pump system consists of the implantable pump with its drug reservoir, the refill port, an additional side port and a flexible catheter. Non-programmable pumps drive the Baclofen flow by the reservoir pressure. Programmable pumps additionally contain a radiofrequency control unit, an electrical pump and a battery. They have major advantages during the dose-finding phase. ITB doses vary widely between 10 and 2000 µg/day. For spinal spasticity, they are typically in the order of 100-300 µg/day. Hereditary spastic paraplegia seems to require particularly low doses, while dystonia and brain injury require particularly high ones. Best effects are documented for tonic paraspasticity of spinal origin and the least effects for phasic muscle hyperactivity disorders of supraspinal origin. Oral antispastics are mainly effective in mild spasticity. Botulinum toxin is most effective in focal spasticity. Myotomies and denervation operations are restricted to selected cases of focal spasticity. Due to its wide-spread distribution within the cerebrospinal fluid, ITB can tackle wide-spread and severe spasticity.

[Botulinum toxin in the treatment of adult spasticity. An interdisciplinary German 10-point consensus 2010]. / Botulinum-Neurotoxin in der Behandlung der Spastizität im Erwachsenenalter. Ein interdisziplinärer deutscher 10-Punkte-Konsensus 2010.

Spasticity is one of the major causes of functional impairment in adults with lesions of the central nervous system. For instance, approximately 30% of post-stroke patients suffer from different degrees of spasticity with possible consecutive impairments. Numerous studies or meta-analyses showed that local injections of botulinum toxin in spastic muscles lead to dose-dependent reduction in muscle tone and improvement of passive movements (e. g. facilitated care), especially following repeated injections.However, country-specific regulations and patient-remote administration in German health care often do not allow adequate provision of this therapy. Thus, the present consensus statement based on the EBM analyses of the published international literature tries to highlight recent advances and the standard in the field of local spasticity treatment, aiming to facilitate communication between the decision makers and German reimbursement institutions in health care. Prior to initiation of BoNT-A injections, patient-oriented goals should be identified in a multiprofessional context to assure realistic goals for this specific treatment and patient expectations. In Germany for the treatment of focal spasticity following stroke three products have been approved: Botox® (Pharm Allergan, Ettlingen), Dysport® (Ipsen Pharma, Ettlingen) and Xeomin® (Merz Pharma, Frankfurt/Main). For all preparations safety has been repeatedly shown. Functional improvements have also been illustrated for selected patients concerning hand/arm function and gait. The dose per muscle and the selection of muscles to be injected have to be individualized according to the patient's symptoms and should be accompanied by modern neurorehabilitative therapies such as redression or repetitive activation of the injected and antagonistic muscles.

Psychic trauma causing grossly reduced brain metabolism and cognitive deterioration.

While amnesia and other cognitive disturbances are usually caused by structural brain damage, there are a few instances in which environmental stress may induce neuronal death in memory-sensitive brain regions such as the hippocampus. Here we report on a patient who, after a single brief exposure to an event reminding him of a similar stressful event from his childhood, deteriorated immediately and persistently without manifesting structural, but manifesting functional, brain damage as measured by position emission tomography. This patient probably represents the first case in which a direct relation between a single psychic event and the occurrence of brain malfunctioning in cognition is documented by dynamic neuroimaging methods. Psychic shock may cause lasting reductions in brain metabolism with the consequence of severe intellectual malfunctioning.

Sequential treatment of Guillain-Barré syndrome with extracorporeal elimination and intravenous immunoglobulin.

Plasma exchange (PE) and administration of intravenous immunoglobulin (IgG) are established treatments for Guillain-Barré syndrome (GBS). Elimination of postulated pathogenetic factors by plasma exchange or similar methods, such as selective adsorption (SA) treatment using affinity-type adsorption columns and subsequent immunomodulation by intravenous IgG, may provide a more effective treatment. Forty-five patients with acute GBS were prospectively examined using a clinical score. We treated 11 patients by plasma exchange, 13 with selective adsorption using a tryptophan-linked polyvinyl alcohol gel adsorbent, and a group of 21 patients by selective adsorption followed by intravenous IgG. The patients treated sequentially by selective adsorption and intravenous IgG improved significantly better than the patients who received plasma treatment only. This pilot study suggests that sequential treatment of GBS may be superior to plasma treatment alone. The higher cost of this combined treatment might be offset by shorter hospital stays and lower overall expenditure. The preliminary results warrant further investigation in a multicenter trial.

Emulsion properties of casein and whey protein hydrolysates and the relation with other hydrolysate characteristics.

Casein and whey protein were hydrolyzed using 11 different commercially available enzyme preparations. Emulsion-forming ability and emulsion stability of the digests were measured as well as biochemical properties with the objective to study the relations between hydrolysate characteristics and emulsion properties. All whey protein hydrolysates formed emulsions with bimodal droplet size distributions, signifying poor emulsion-forming ability. Emulsion-forming ability of some casein hydrolysates was comparable to that of intact casein. Emulsion instability was caused by creaming and coalescence. Creaming occurred mainly in whey hydrolysate emulsions and in casein hydrolysate emulsions containing large emulsion droplets. Coalescence was dominant in casein emulsions with a broad particle size distribution. Emulsion instability due to coalescence was related to apparent molecular weight distribution of hydrolysates; a relative high amount of peptides larger than 2 kDa positively influences emulsion stability.

Sequential treatment of Guillain-Barré syndrome with extracorporeal elimination and intravenous immunoglobulin.

Plasma exchange and administration of intravenous immunoglobulin (IgG) are established treatments for Guillain-Barré syndrome (GBS). Elimination of postulated pathogenetic factors by plasma exchange or selective adsorption treatment using affinity-type adsorption columns and subsequent immunomodulation by intravenous IgG may provide a more effective treatment. Forty-five patients with acute GBS were prospectively examined using a clinical score. We treated 11 patients by plasma exchange, 13 patients by selective adsorption using a tryptophan-linked polyvinyl alcohol gel adsorbent, and 21 patients by selective adsorption followed by intravenous IgG. The patients treated sequentially by selective adsorption and intravenous IgG improved significantly better than the patients who received plasma treatment only. The results suggest that sequential treatment of GBS may be superior to plasma treatment alone. The higher cost of combined treatment may be offset by lower overall expenditure.

Immunoadsorption in Guillain-Barré syndrome and myasthenia gravis.

Elimination of circulating antibodies by hemapheresis is an empirical treatment concept in various neuroimmunological diseases. Plasma exchange (PE) has been shown to be superior to symptomatic treatment in Guillain-Barré syndrome (GBS) in two large multicenter studies. It is also effective in myasthenia gravis (MG), although no comparative studies have been performed. Immunoadsorption (IA) using polyvinyl alcohol gel columns to which phenylalanin (IM-PH) or tryptophan (IM-TR) are covalently bound is an alternative to PE, and seems to have equal efficacy and comparable side effects. This method also obviates the need for replacement of plasma with human albumin or plasma. We compared the treatment results of 11 patients with GBS treated by PE to those of 13 patients treated by IA using an IM-TR column. Here, we found no statistically significant differences with regard to efficacy and clinical or procedural complications. From these data we conclude that immunoadsorption can be used as an equal alternative to PE. A large multicenter study comparing PE, intravenous immunoglobulins (IVIG), and the combination of both in the treatment of GBS revealed no significant difference between the 3 treatment groups. In MG, only 2 small studies have been performed using IA, and no studies comparing PE or other treatments to IA have been conducted. Both investigations of IA therapy demonstrated a marked reduction in the acetylcholine receptor (AchR) antibodies and a sustained improvement of the clinical signs. These results therefore show that IA is an effective treatment for myasthenia gravis.

Apheresis and selective adsorption plus immunoglobulin treatment in Guillain-Barré syndrome.

Plasma exchange (PE) and administration of intravenous immunoglobulin (i.v. IgG) are established treatments for Guillain-Barré syndrome (GBS). Combination treatment with elimination of postulated pathogenetic factors by PE or selective adsorption (SA) treatment and subsequent immunomodulation by intravenous IgG may provide a more effective treatment. In a single-center randomized study, 45 patients with acute GBS were prospectively examined using a clinical score. We treated 11 patients by PE, 13 with SA using a tryptophan-linked polyvinyl alcohol gel adsorbent, and 21 with SA followed by intravenous IgG. The patients treated sequentially by selective adsorption and intravenous IgG improved significantly better than the patients who received plasma treatment only. The results suggest that combination treatment of GBS may be superior to plasma treatment alone.

Neuroimaging and behavioral correlates of recovery from mnestic block syndrome and other cognitive deteriorations.

OBJECTIVE: We conducted a follow-up study on a patient with enduring psychic shock-induced cognitive impairment to study by neuropsychological and functional imaging methods the degree of his recovery process on the brain and cognitive levels. BACKGROUND: Based on the assumption that trauma and stress conditions can alter the functions of the nervous systems, we report on a patient whom we studied 2 and 12 months after he suffered "mnestic block syndrome" and additional cognitive deterioration symptoms. METHODS: We report on a patient studied 2 and 12 months after he suffered "mnestic block syndrome" and additional cognitive deterioration symptoms. Magnetic resonance imaging and fluorodeoxyglucose positron emission tomography were used for neural and detailed neuropsychological testing for cognitive deficits. RESULTS: The patient initially manifested severe intellectual decline, including severe anterograde and retrograde amnesia. His symptoms were correlated with major, although selective, reductions in his brain metabolism (2-3 SD below those of controls). Presently, he shows a normal brain metabolism and has regained parts of his memory and many of his other intellectual capabilities. Nevertheless, he still has long-term memory impairments. CONCLUSIONS: This case demonstrates a close relation between brain metabolism and cognitive performance, with major deficits of both at 2 months and major recovery of both at 12 months after a shocking event. It can serve as an example for possible stress-related deteriorations in certain brain regions, which can be partly corrected by psychotherapeutic interventions, passing time, and favorable environmental conditions.

Stereoselective carveol dehydrogenase from Rhodococcus erythropolis DCL14. A novel nicotinoprotein belonging to the short chain dehydrogenase/reductase superfamily.

A novel nicotinoprotein, catalyzing the dichlorophenolindophenol-dependent oxidation of carveol to carvone, was purified to homogeneity from Rhodococcus erythropolis DCL14. The enzyme is specifically induced after growth on limonene and carveol. Dichlorophenolindophenol-dependent carveol dehydrogenase (CDH) is a homotetramer of 120 kDa with each subunit containing a tightly bound NAD(H) molecule. The enzyme is optimally active at pH 5.5 and 50 degrees C and displays a broad substrate specificity with a preference for substituted cyclohexanols. When incubated with a diastereomeric mixture of (4R)- or (4S)-carveol, CDH stereoselectively catalyzes the conversion of the (6S)-carveol stereoisomers only. Kinetic studies with pure stereoisomers showed that this is due to large differences in V(max)/K(m) values and simultaneous product inhibition by (R)- or (S)-carvone. The R. erythropolis CDH gene (limC) was identified in an operon encoding the enzymes involved in limonene degradation. The CDH nucleotide sequence revealed an open reading frame of 831 base pairs encoding a 277-amino acid protein with a deduced mass of 29,531 Da. The CDH primary structure shares 10-30% sequence identity with members of the short chain dehydrogenase/reductase superfamily. Structure homology modeling with trihydroxynaphthalene reductase from Magnaporthe grisea suggests that CDH from R. erythropolis DCL14 is an alpha/beta one-domain protein with an extra loop insertion involved in NAD binding and a flexible C-terminal part involved in monoterpene binding.