Functions and effects of creatine in the central nervous system

Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. Accordingly, the creatine kinase/phosphocreatine system plays a key role in cellular energy buffering and energy transport, particularly in cells with high and fluctuating energy requirements like neurons. Creatine kinases are expressed in the adult and developing human brain and spinal cord, suggesting that the creatine kinase/phosphocreatine system plays a significant role in the central nervous system. Functional impairment of this system leads to a deterioration in energy metabolism, which is phenotypic for many neurodegenerative and age-related diseases. Exogenous creatine supplementation has been shown to reduce neuronal cell loss in experimental paradigms of acute and chronic neurological diseases. In line with these findings, first clinical trials have shown beneficial effects of therapeutic creatine supplementation. Furthermore, creatine was reported to promote differentiation of neuronal precursor cells that might be of importance for improving neuronal cell replacement strategies. Based on these observations there is growing interest on the effects and functions of this compound in the central nervous system. This review gives a short excursion into the basics of the creatine kinase/phosphocreatine system and aims at summarizing findings and concepts on the role of creatine kinase and creatine in the central nervous system with special emphasis on pathological conditions and the positive effects of creatine supplementation.

Immunomodulatory lipids in plants: plant fatty acid amides and the human endocannabinoid system

Since the discovery that endogenous lipid mediators show similar cannabimimetic effects as phytocannabinoids from CANNABIS SATIVA, our knowledge about the endocannabinoid system has rapidly expanded. Today, endocannabinoid action is known to be involved in various diseases, including inflammation and pain. As a consequence, the G-protein coupled cannabinoid receptors, endocannabinoid transport, as well as endocannabinoid metabolizing enzymes represent targets to block or enhance cannabinoid receptor-mediated signalling for therapeutic intervention. Based on the finding that certain endocannabinoid-like fatty acid N-alkylamides from purple coneflower ( ECHINACEA spp.) potently activate CB2 cannabinoid receptors we have focused our interest on plant fatty acid amides (FAAs) and their overall cannabinomodulatory effects. Certain FAAs are also able to partially inhibit the action of fatty acid amide hydrolase (FAAH), which controls the breakdown of endocannabinoids. Intriguingly, plants lack CB receptors and do not synthesize endocannabinoids, but express FAAH homologues capable of metabolizing plant endogenous N-acylethanolamines (NAEs). While the site of action of these NAEs in plants is unknown, endogenous NAEs and arachidonic acid glycerols in animals interact with distinct physiological lipid receptors, including cannabinoid receptors. There is increasing evidence that also plant FAAs other than NAEs can pharmacologically modulate the action of these endogenous lipid signals. The interference of plant FAAs with the animal endocannabinoid system could thus be a fortunate evolutionary cross point with yet unexplored therapeutic potential.

[Prioritisation in the German health care system--an issue in ophthalmology?]

At the 111th German Medical Assembly in May 2008 in Ulm, Germany, a public debate on rationing of health care performances was started. Since the money in the German health care system is not enough to provide every diagnostic or therapy for every patient as a coverage of the compulsory medical insurances, a lot of specific health care performances have been rationed during the last years not to be covered by the regular medical insurance any more, such as, e. g., PSA measurements in urology or IOP measurements in ophthalmology. In contrast to the health care system in Scandinavia, where rationing of health care performances is publicly documented by the government, no similar public statements exist in Germany. Due to this, it is left to physicians to explain to their patients the "hidden" rationing of public health care performances, which also leads to an increase in individual health care performances (IGeL in Germany) to be paid for privately by the patient. It is undoubtedly true that not all medically possible performances need to be paid for by the health insurance; however, an official determination of these "out of pocket" health care performances is necessary. Therefore, it was the aim herein to work out possible "stop" criteria--according to the Scandinavian system--for common eye diseases and consecutive therapies, which need not be paid for or only be paid after a delay by the health insurances.

[Imaging for hepato-pancreatico-biliary diseases - a short review]

The purpose of this chapter is to give a practical and clinically-orientated overview over the best radiological imaging for the most frequent diseases of the hepato-pancreatico-biliary system. For this purpose the liver parenchyma, the biliary tree, the pancreas and the hepatic vasculature are dealt with separately. According to the presumed pathology, the most cost-saving and time-efficient radiological imaging can then be chosen.

Hemispheric lateralization of the corticostriatal glutamatergic system in the rat

Little is known about hemispheric lateralization of subcortical structures. Here, we show a higher expression of the subunit NR2A of the NMDA receptor mRNA in the striatum and of vGluT1 mRNA in the cingulate cortex, in the left hemisphere compared to the right one. This suggests a lateralization of the glutamatergic cortico-subcortical system, at the level of postsynaptic receptors as well as at the level of corticostriatal projections. Such lateralization could play a role in asymmetric diseases like Parkinson's disease.

Plasma levels of mannan-binding lectin (MBL)-associated serine proteases (MASPs) and MBL-associated protein in cardio- and cerebrovascular diseases

Growing evidence suggests a prominent role of the complement system in the pathogenesis of cardio- and cerebrovascular diseases (CVD). Mannan-binding lectin-associated serine proteases (MASPs) MASP-1 and MASP-2 of the complement lectin pathway contribute to clot formation and may represent an important link between inflammation and thrombosis. MBL-associated protein MAp44 has shown cardioprotective effects in murine models. However, MAp44 has never been measured in patients with CVD and data on MASP levels in CVD are scarce. Our aim was to investigate for the first time plasma levels of MAp44 and MASP-1, -2, -3 concomitantly in patients with CVD. We performed a pilot study in 50 healthy volunteers, in stable coronary artery disease (CAD) patients with one-vessel (n = 51) or three-vessel disease (n = 53) and age-matched controls with normal coronary arteries (n = 53), 49 patients after myocardial infarction (MI) and 66 patients with acute ischaemic stroke. We measured MAp44 and MASP-1 levels by in-house time-resolved immunofluorometric assays. MASP-2 and MASP-3 levels were measured using commercial enzyme-linked immunosorbent assay kits. MASP-1 levels were highest in subacute MI patients and lowest in acute stroke patients. MASP-2 levels were lower in MI and stroke patients compared with controls and CAD patients. MASP-3 and MAp44 levels did not differ between groups. MASP or MAp44 levels were not associated with severity of disease. MASP and MAp44 levels were associated with cardiovascular risk factors including dyslipidaemia, obesity and hypertension. Our results suggest that MASP levels may be altered in vascular diseases. Larger studies are needed to confirm our results and elucidate the underlying mechanisms.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units. © RSNA, 2014 Online supplemental material is available for this article.

Plakins, a Versatile Family of Cytolinkers: Roles in Skin Integrity and in Human Diseases

The plakin family consists of giant proteins involved in the cross-linking and organization of the cytoskeleton and adhesion complexes. They further modulate several fundamental biological processes, such as cell adhesion, migration, and polarization or signaling pathways. Inherited and acquired defects of plakins in humans and in animal models potentially lead to dramatic manifestations in the skin, striated muscles, and/or nervous system. These observations unequivocally demonstrate the key role of plakins in the maintenance of tissue integrity. Here we review the characteristics of the mammalian plakin members BPAG1 (bullous pemphigoid antigen 1), desmoplakin, plectin, envoplakin, epiplakin, MACF1 (microtubule-actin cross-linking factor 1), and periplakin, highlighting their role in skin homeostasis and diseases.

International horse movements and spread of equine diseases: Equine Infectious Anaemia and Glanders - two examples

International trade with horses is important and continuously increasing. Therefore the risk of spread of infectious diseases is permanently present. Within this context the worldwide situation of equine vector-borne diseases and of other diseases which are notifiable to the World Organisation of Animal Health (OIE), is described. Furthermore it provides estimates of the numbers of horse movements between these countries, as well as information on import requirements and preventive measures for reducing the risk of disease spread. According to TRACES (Trade Control and Expert System of the European Union) data from 2009 and 2010 81 horses per week were imported from North America into Europe, 42 horses per week from South America, 11 horses per week from the North of Africa and the African horse sichness free-zone of South Africa, 28 per week from the Middle East and the rest of Asia and approximately 4 horses per week from Australia / Oceania. Trade within the European Union resulted amongst others in the introduction of Equine Infectious Anaemia (EIA) from Roma- nia into other European countries. Another example is the suspected case of glanders which occurred after importation of horses from Leb- anon via France and Germany into Switzerland in July 2011.

MR Spectroscopy and Spectroscopic Imaging for Evaluation of Skeletal Muscle Metabolism: Basics and Applications in Metabolic Diseases

Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) provide metabolic information on the musculoskeletal system, thus helping to understand the biochemical and pathophysiological nature of numerous diseases. In particular, MRS has been used to study the energy metabolism of muscular tissue since the very beginning of magnetic resonance examinations in humans when small-bore magnets for studies of the limbs became available. Even more than in other organs, the observation of non-proton-nuclei was important in muscle tissue. Spatial localization was less demanding in these studies, however, high temporal resolution was necessary to follow metabolism during exercise and recovery. The observation of high-energy phosphates during and after the application of workload gives insight into oxidative phosphorylation, a process that takes place in the mitochondria and characterizes impaired mitochondrial function. New applications in insulin-resistant patients followed the development of volume-selective 1H-MRS in whole-body magnets. Nowadays, multinuclear MRS and MRSI of the musculoskeletal system provide several windows to vital biochemical pathways noninvasively. It is shown how MRS and MRSI have been used in numerous diseases to characterize an involvement of the muscular metabolism.

The ovine cerebral venous system: comparative anatomy, visualization, and implications for translational research.

Cerebrovascular diseases are significant causes of death and disability in humans. Improvements in diagnostic and therapeutic approaches strongly rely on adequate gyrencephalic, large animal models being demanded for translational research. Ovine stroke models may represent a promising approach but are currently limited by insufficient knowledge regarding the venous system of the cerebral angioarchitecture. The present study was intended to provide a comprehensive anatomical analysis of the intracranial venous system in sheep as a reliable basis for the interpretation of experimental results in such ovine models. We used corrosion casts as well as contrast-enhanced magnetic resonance venography to scrutinize blood drainage from the brain. This combined approach yielded detailed and, to some extent, novel findings. In particular, we provide evidence for chordae Willisii and lateral venous lacunae, and report on connections between the dorsal and ventral sinuses in this species. For the first time, we also describe venous confluences in the deep cerebral venous system and an 'anterior condylar confluent' as seen in humans. This report provides a detailed reference for the interpretation of venous diagnostic imaging findings in sheep, including an assessment of structure detectability by in vivo (imaging) versus ex vivo (corrosion cast) visualization methods. Moreover, it features a comprehensive interspecies-comparison of the venous cerebral angioarchitecture in man, rodents, canines and sheep as a relevant large animal model species, and describes possible implications for translational cerebrovascular research.

Hyperplasia to neoplasia sequence of duodenal and pancreatic neuroendocrine diseases and pseudohyperplasia of the PP-cells in the pancreas.

Hyperplastic changes of the neuroendocrine cell system may have the potential to evolve into neoplastic diseases. This is particularly the case in the setting of genetically determined and hereditary neuroendocrine tumor syndromes such as MEN1. The review discusses the MEN1-associated hyperplasia-neoplasia sequence in the development of gastrinomas in the duodenum and glucagon-producing tumors in the pancreas. It also presents other newly described diseases (e.g., glucagon cell adenomatosis and insulinomatosis) in which the tumors are (or most likely) also preceded by islet cell hyperplasia. Finally, the pseudohyperplasia of PP-rich islets in the pancreatic head is defined as a physiologic condition clearly differing from other hyperplastic-neoplastic neuroendocrine diseases.

Evaluation of Swiss slaughterhouse data for integration in a syndromic surveillance system

BACKGROUND: We evaluated Swiss slaughterhouse data for integration in a national syndromic surveillance system for the early detection of emerging diseases in production animals. We analysed meat inspection data for cattle, pigs and small ruminants slaughtered between 2007 and 2012 (including emergency slaughters of sick/injured animals); investigating patterns in the number of animals slaughtered and condemned; the reasons invoked for whole carcass condemnations; reporting biases and regional effects. RESULTS: Whole carcass condemnation rates were fairly uniform (1-2‰) over time and between the different types of production animals. Condemnation rates were much higher and less uniform following emergency slaughters. The number of condemnations peaked in December for both cattle and pigs, a time when individuals of lower quality are sent to slaughter when hay and food are limited and when certain diseases are more prevalent. Each type of production animal was associated with a different profile of condemnation reasons. The most commonly reported one was "severe lesions" for cattle, "abscesses" for pigs and "pronounced weight loss" for small ruminants. These reasons could constitute valuable syndromic indicators as they are unspecific clinical manifestations of a large range of animal diseases (as well as potential indicators of animal welfare). Differences were detected in the rate of carcass condemnation between cantons and between large and small slaughterhouses. A large percentage (>60% for all three animal categories) of slaughterhouses operating never reported a condemnation between 2007 and 2012, a potential indicator of widespread non-reporting bias in our database. CONCLUSIONS: The current system offers simultaneous coverage of cattle, pigs and small ruminants for the whole of Switzerland; and traceability of each condemnation to its farm of origin. The number of condemnations was significantly linked to the number of slaughters, meaning that the former should be always be offset by the later in analyses. Because this denominator is only communicated at the end of the month, condemnations may currently only be monitored on a monthly basis. Coupled with the lack of timeliness (30-60 days delay between condemnation and notification), this limits the use of the data for early-detection.

Prophylaxis of infectious complications with colony-stimulating factors in adult cancer patients undergoing chemotherapy-evidence-based guidelines from the Infectious Diseases Working Party AGIHO of the German Society for Haematology and Medical Oncology (DGHO).

BACKGROUND Current evidence on myelopoietic growth factors is difficult to overview for the practicing haematologist/oncologist. International guidelines are sometimes conflicting, exclude certain patient groups, or cannot directly be applied to the German health system. This guideline by the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Medical Oncology (DGHO) gives evidence-based recommendations for the use of G-CSF, pegylated G-CSF, and biosimilars to prevent infectious complications in cancer patients undergoing chemotherapy, including those with haematological malignancies. METHODS We systematically searched and evaluated current evidence. An expert panel discussed the results and recommendations. We then compared our recommendations to current international guidelines. RESULTS We summarised the data from eligible studies in evidence tables, developed recommendations for different entities and risk groups. CONCLUSION Comprehensive literature search and expert panel consensus confirmed many key recommendations given by international guidelines. Evidence for growth factors during acute myeloid leukaemia induction chemotherapy and pegfilgrastim use in haematological malignancies was rated lower compared with other guidelines.

The interplay between the gut microbiota and the immune system.

The impact of the gut microbiota on immune homeostasis within the gut and, importantly, also at systemic sites has gained tremendous research interest over the last few years. The intestinal microbiota is an integral component of a fascinating ecosystem that interacts with and benefits its host on several complex levels to achieve a mutualistic relationship. Host-microbial homeostasis involves appropriate immune regulation within the gut mucosa to maintain a healthy gut while preventing uncontrolled immune responses against the beneficial commensal microbiota potentially leading to chronic inflammatory bowel diseases (IBD). Furthermore, recent studies suggest that the microbiota composition might impact on the susceptibility to immune-mediated disorders such as autoimmunity and allergy. Understanding how the microbiota modulates susceptibility to these diseases is an important step toward better prevention or treatment options for such diseases.