Targeting microRNAs involved in the BDNF signaling impairment in neurodegenerative diseases

Neurodegenerative diseases are becoming an ever-increasing problem in aging populations. Low levels of brain-derived neurotrophic factor (BDNF) have previously been associated with the pathogenesis of numerous neurodegenerative diseases. Recently, microRNAs (miRNAs) have been proposed as potential novel therapeutic targets for treating various diseases of the central nervous system (CNS), and interestingly, few studies have reported several miRNAs that downregulate the expression levels of BDNF. However, substantial challenges exist when attempting to translate these findings into practical anti-miRNA therapeutics, especially when the targets remain inside the CNS. Thus, in this review, we summarize the specific molecular mechanisms by which several miRNAs negatively modulate the expressions of BDNF, address the potential clinical difficulties that can be faced during the development of anti-miRNA-based therapeutics and propose strategies to overcome these challenges.

Infection of the central nervous system by Mycobacterium tuberculosis in patients infected with human immunodeficiency virus (the new neurotuberculosis)

Neurologic complications of HIV infection are numerous. This review focuses on the clinical presentation, diagnostic particularities and therapeutic issues of neurotuberculosis. The pertinent literature describing this important infection is succinctly summarized with a particular emphasis on the discussion of differences in clinical presentation between HIV-infected and -uninfected patients.

Production Diseases in European Organic Dairy Farms – Current Status and Identification of Drivers for Improvement by Means of a Systemic Approach

The aims of this thesis were to determine the animal health status in organic dairy farms in Europe and to identify drivers for improving the current situation by means of a systemic approach. Prevalences of production diseases were determined in 192 herds in Germany, France, Spain, and Sweden (Paper I), and stakeholder consultations were performed to investigate potential drivers to improve animal health on the sector level (ibid.). Interactions between farm variables were assessed through impact analysis and evaluated to identify general system behaviour and classify components according to their outgoing and incoming impacts (Paper II-III). The mean values and variances of prevalences indicate that the common rules of organic dairy farming in Europe do not result in consistently low levels of production diseases. Stakeholders deemed it necessary to improve the current status and were generally in favour of establishing thresholds for the prevalence of production diseases in organic dairy herds as well as taking actions to improve farms below that threshold. In order to close the gap between the organic principle of health and the organic farming practice, there is the need to formulate a common objective of good animal health and to install instruments to ensure and prove that the aim is followed by all dairy farmers in Europe who sell their products under the organic label. Regular monitoring and evaluation of herd health performance based on reference values are considered preconditions for identifying farms not reaching the target and thus in need of improvement. Graph-based impact analysis was shown to be a suitable method for modeling and evaluating the manifold interactions between farm factors and for identifying the most influential components on the farm level taking into account direct and indirect impacts as well as impact strengths. Variables likely to affect the system as a whole, and the prevalence of production diseases in particular, varied largely between farms despite some general tendencies. This finding reflects the diversity of farm systems and underlines the importance of applying systemic approaches in health management. Reducing the complexity of farm systems and indicating farm-specific drivers, i.e. areas in a farm, where changes will have a large impact, the presented approach has the potential to complement and enrich current advisory practice and to support farmers’ decision-making in terms of animal health.

Interspecies study of the enteric nervous system and related pathologies

The enteric nervous system (ENS) modulates a number of digestive functions including well known ones, i.e. motility, secretion, absorption and blood flow, along with other critically relevant processes, i.e. immune responses of the gastrointestinal (GI) tract, gut microbiota and epithelial barrier . The characterization of the anatomical aspects of the ENS in large mammals and the identification of differences and similarities existing between species may represent a fundamental basis to decipher several digestive GI diseases in humans and animals. In this perspective, the aim of the present thesis is to highlight the ENS anatomical basis and pathological aspects in different mammalian species, such as horses, dogs and humans. Firstly, I designed two anatomical studies in horses:  “Excitatory and inhibitory enteric innervation of horse lower esophageal sphincter”.  “Localization of 5-hydroxytryptamine 4 receptor (5-HT4R) in the equine enteric nervous system”. Then I focused on the enteric dysfunctions, including:  A primary enteric aganglionosis in horses: “Extrinsic innervation of the ileum and pelvic flexure of foals with ileocolonic aganglionosis”.  A diabetic enteric neuropathy in dogs: “Quantification of nitrergic neurons in the myenteric plexus of gastric antrum and ileum of healthy and diabetic dogs”.  An enteric neuropathy in human neurological patients: “Functional and neurochemical abnormalities in patients with Parkinson's disease and chronic constipation”. The physiology of the GI tract is characterized by a high complexity and it is mainly dependent on the control of the intrinsic nervous system. ENS is critical to preserve body homeostasis as reflect by its derangement occurring in pathological conditions that can be lethal or seriously disabling to humans and animals. The knowledge of the anatomy and the pathology of the ENS represents a new important and fascinating topic, which deserves more attention in the veterinary medicine field.