Local nitric oxide production in viral and autoimmune diseases of the central nervous system.

Because of the short half-life of NO, previous studies implicating NO in central nervous system pathology during infection had to rely on the demonstration of elevated levels of NO synthase mRNA or enzyme expression or NO metabolites such as nitrate and nitrite in the infected brain. To more definitively investigate the potential causative role of NO in lesions of the central nervous system in animals infected with neurotropic viruses or suffering from experimental allergic encephalitis, we have determined directly the levels of NO present in the central nervous system of such animals. Using spin trapping of NO and electron paramagnetic resonance spectroscopy, we confirm here that copious amounts of NO (up to 30-fold more than control) are elaborated in the brains of rats infected with rabies virus or borna disease virus, as well as in the spinal cords of rats that had received myelin basic protein-specific T cells.

Bridging grafts and transient nerve growth factor infusions promote long-term central nervous system neuronal rescue and partial functional recovery.

Grafts of favorable axonal growth substrates were combined with transient nerve growth factor (NGF) infusions to promote morphological and functional recovery in the adult rat brain after lesions of the septohippocampal projection. Long-term septal cholinergic neuronal rescue and partial hippocampal reinnervation were achieved, resulting in partial functional recovery on a simple task assessing habituation but not on a more complex task assessing spatial reference memory. Control animals that received transient NGF infusions without axonal-growth-promoting grafts lacked behavioral recovery but also showed long-term septal neuronal rescue. These findings indicate that (i) partial recovery from central nervous system injury can be induced by both preventing host neuronal loss and promoting host axonal regrowth and (ii) long-term neuronal loss can be prevented with transient NGF infusions.

Parkinson's disease and gastrointestinal dysfunctions: morphological, neurochemical and functional modifications of the enteric nervous system associated with central dopaminergic impairment

Parkinson’s disease (PD) is frequently associated with gastrointestinal (GI) symptoms, mostly represented by abdominal distension, constipation and defecatory dysfunctions. Despite GI dysfunctions have a major impact on the clinical picture of PD, there is currently a lack of information on the neurochemical, pathological and functional correlates of GI dysmotility associated with PD. Moreover, there is a need of effective and safe pharmacological therapies for managing GI disturbances in PD patients. The present research project has been undertaken to investigate the relationships between PD and related GI dysfunctions by means of investigations in an animal model of PD induced by intranigral injection of 6-hydroxydopamine (6-OHDA). The use of the 6-OHDA experimental model of PD in the present program has allowed to pursue the following goals: 1) to examine the impact of central dopaminergic denervation on colonic excitatory cholinergic and tachykininergic neuromotility by means of molecular, histomorphologic and functional approaches; 2) to elucidate the role of gut inflammation in the onset and progression of colonic dysmotility associated with PD, characterizing the degree of inflammation and oxidative damage in colonic tissues, as well as identifying the immune cells involved in the production of pro-inflammatory cytokines in the gut; 3) to evaluate the impact of chronic treatment with L-DOPA plus benserazide on colonic neuromuscular activity both in control and PD animals. The results suggest that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory cholinergic neurotransmission and an enhanced tachykininergic control, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate. These motor alterations might result from the occurrence of a condition of gut inflammation associated with central intranigral denervation. The treatment with L-DOPA/BE following central dopaminergic neurodegeneration can restore colonic motility, likely through a normalization of the cholinergic enteric neurotransmission, and it can also improve the colonic inflammation associated with central dopaminergic denervation.

Robotic control systems based on bioinspired multi-agent systems: application of the principles of neuroscience to robotics

Robotics is a field that presents a large number of problems because it depends on a large number of disciplines, devices, technologies and tasks. Its expansion from perfectly controlled industrial environments toward open and dynamic environment presents a many new challenges, such as robots household robots or professional robots. To facilitate the rapid development of robotic systems, low cost, reusability of code, its medium and long term maintainability and robustness are required novel approaches to provide generic models and software systems who develop paradigms capable of solving these problems. For this purpose, in this paper we propose a model based on multi-agent systems inspired by the human nervous system able to transfer the control characteristics of the biological system and able to take advantage of the best properties of distributed software systems.

Multi-agent system for control of robots inspired on the distributed activity and hormonal regulation of humans

Robotics is an emerging field with great activity. Robotics is a field that presents several problems because it depends on a large number of disciplines, technologies, devices and tasks. Its expansion from perfectly controlled industrial environments toward open and dynamic environment presents a many new challenges. New uses are, for example, household robots or professional robots. To facilitate the low cost, rapid development of robotic systems, reusability of code, its medium and long term maintainability and robustness are required novel approaches to provide generic models and software systems who develop paradigms capable of solving these problems. For this purpose, in this paper we propose a model based on multi-agent systems inspired by the human nervous system able to transfer the control characteristics of the biological system and able to take advantage of the best properties of distributed software systems. Specifically, we model the decentralized activity and hormonal variation.

Control of neuronal signalling pathways by CYP46A1, an enzime involved in brain cholesterol homeostasis

Tese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2016

Nocardia infection in solid organ transplant recipients: a multicenter European case-control study.

BACKGROUND  Nocardiosis is a rare, life-threatening opportunistic infection, affecting 0.04% to 3.5% of patients after solid organ transplantation (SOT). The aim of this study was to identify risk factors for Nocardia infection after SOT and to describe the presentation of nocardiosis in these patients. METHODS  We performed a retrospective case-control study of adult patients diagnosed with nocardiosis after SOT between 2000 and 2014 in 36 European (France, Belgium, Switzerland, Netherlands, Spain) centers. Two control subjects per case were matched by institution, transplant date and transplanted organ. A multivariable analysis was performed using conditional logistic regression to identify risk factors for nocardiosis. RESULTS  One hundred and seventeen cases of nocardiosis and 234 control patients were included. Nocardiosis occurred at a median of 17.5 [range 2-244] months after transplantation. In multivariable analysis, high calcineurin inhibitor trough levels in the month before diagnosis (OR=6.11 [2.58-14.51]), use of tacrolimus (OR=2.65 [1.17-6.00]) and corticosteroid dose (OR=1.12 [1.03-1.22]) at the time of diagnosis, patient age (OR=1.04 [1.02-1.07]) and length of stay in intensive care unit after SOT (OR=1.04 [1.00-1.09]) were independently associated with development of nocardiosis; low-dose cotrimoxazole prophylaxis was not found to prevent nocardiosis. Nocardia farcinica was more frequently associated with brain, skin and subcutaneous tissue infections than were other Nocardia species. Among the 30 cases with central nervous system nocardiosis, 13 (43.3%) had no neurological symptoms. CONCLUSIONS  We identified five risk factors for nocardiosis after SOT. Low-dose cotrimoxazole was not found to prevent Nocardia infection. These findings may help improve management of transplant recipients.

The role of morphine-6-glucuronide (M6G) in pain control

Morphine-6beta-D-glucuronide (M6G) is an analgesically active metabolite of morphine, accounting for approximate to10% of the morphine dose when administered by systemic routes to humans. Although M6G is more hydrophilic than morphine, it crosses the blood-brain barrier, albeit relatively slowly. For this reason, it is generally thought that, after chronic dosing, M6G contributes significantly to the analgesic effects of systemically administered morphine. Owing to its polar nature, M6G is cleared from the systemic circulation primarily via renal elimination. As M6G accumulates in patients with renal impairment, there is an increased risk of M6G-induced respiratory depression in renal failure patients who are being dosed chronically with systemic morphine. Consistent with its analgesic and respiratory depressant properties, M6G binds to the p-opioid receptor in a naloxone-reversible manner. Although the affinity of M6G for the mu-opioid receptor is similar to or slightly less than that of morphine, preclinical studies in rodents show that M6G is one to two orders of magnitude more potent than morphine when administered by central routes. This major discrepancy between the markedly higher intrinsic antinociceptive potency of M6G relative to morphine, despite their similar p-opioid receptor binding affinities, is difficult to reconcile. It has been proposed that M6G mediates its pain-relieving effects through a novel 'M6G opioid receptor', while others have argued that M6G may have higher efficacy than morphine for transduction of intracellular events. When administered by parenteral routes to rodents, M6G's antinociceptive potency is no more than twofold higher than morphine. In humans, the analgesic efficacy and respiratory depressant potency of M6G relative to morphine have been assessed in a number of short-term studies involving the intrathecal or intravenous routes of administration. For example, in hip replacement patients, intrathecal M6G provided excellent postoperative analgesia but the occurrence of late respiratory depression in 10% of these patients raised serious concern about safety. In postoperative patients, intravenous M6G administered by means of patient-controlled analgesia (PCA), or bolus plus PCA, produced no analgesia in one study and limited analgesia in another. Similarly, there was a lack of significant analgesia in healthy volunteers who received intravenous M6G for the alleviation of experimental pain (carbon dioxide applied to the nasal mucosa). In contrast, satisfactory analgesia was produced by bolus doses of intravenous M6G administered to patients with cancer pain, and to healthy volunteers with experimentally-induced ischaemic, electrical or thermal (ice water) pain. Studies to date in healthy volunteers suggest that intravenous M6G may be a less potent respiratory depressant and have a lower propensity for producing nausea and vomiting than morphine. However, it is unclear whether equi-analgesic doses of M6G and morphine were compared. Clearly, more extensive short-term trials, together with studies involving chronic M6G administration, are necessary before the potential clinical utility of M6G as an analgesic drug in its own right can be determined.

Pain differs from non-painful attention-demanding or stressful tasks in its effect on postural control patterns of trunk muscles

Pain changes postural activation of the trunk muscles. The cause of these changes is not known but one possibility relates to the information processing requirements and the stressful nature of pain. This study investigated this possibility by evaluating electromyographic activity (EMG) of the deep and superficial trunk muscles associated with voluntary rapid arm movement. Data were collected from control trials, trials during low back pain (LBP) elicited by injection of hypertonic saline into the back muscles, trials during a non-painful attention-demanding task, and during the same task that was also stressful. Pain did not change the reaction time (RT) of the movement, had variable effects on RT of the superficial trunk muscles, but consistently increased RT of the deepest abdominal muscle. The effect of the attention-demanding task was opposite: increased RT of the movement and the superficial trunk muscles but no effect on RT of the deep trunk muscles. Thus, activation of the deep trunk muscles occurred earlier relative to the movement. When the attention-demanding task was made stressful, the RT of the movement and superficial trunk muscles was unchanged but the RT of the deep trunk muscles was increased. Thus, the temporal relationship between deep trunk muscle activation and arm movement was restored. This means that although postural activation of the deep trunk muscles is not affected when central nervous system resources are limited, it is delayed when the individual is also under stress. However, a non-painful attention-demanding task does not replicate the effect of pain on postural control of the trunk muscles even when the task is stressful.

Are the changes in postural control associated with low back pain caused by pain interference?

Background: Voluntary limb movements are associated with involuntary and automatic postural adjustments of the trunk muscles. These postural adjustments occur prior to movement and prevent unwanted perturbation of the trunk. In low back pain, postural adjustments of the trunk muscles are altered such that the deep trunk muscles are consistently delayed and the superficial trunk muscles are sometimes augmented. This alteration of postural adjustments may reflect disruption of normal postural control imparted by reduced central nervous system resources available during pain, so-called pain interference, or reflect adoption of an alternate postural adjustment strategy. Methods: We aimed to clarify this by recording electromyographic activity of the upper (obliquus extemus) and lower (transversus abdominis/obliquus internus) abdominal muscles during voluntary arm movements that were coupled with painful cutaneous stimulation at the low back. If the effect of pain on postural adjustments is caused by pain interference, it should be greatest at the onset of the stimulus, should habituate with repeated exposure, and be absent immediately when the threat of pain is removed. Sixteen patients performed 30 forward movements of the right arm in response to a visual cue (control). Seventy trials were then conducted in which arm movement was coupled with pain (pain trials) and then a further 70 trials were conducted without the pain stimulus (no pain trials). Results: There was a gradual and increasing delay of transversus abdominis/obliquus internus electromyograph and augmentation of obliquus externus during the pain trials, both of which gradually returned to control values during the no pain trials. Conclusion: The results suggest that altered postural adjustments of the trunk muscles during pain are not caused by pain interference but are likely to reflect development and adoption of an alternate postural adjustment strategy, which may serve to limit the amplitude and velocity of trunk excursion caused by arm movement.

Molecular control of cell type diversity in the developing spinal cord

1, During embryonic development, a diverse array of neurons and glia are generated at specific positions along the dorsoventral and rostro-caudal axes of the spinal cord from a common pool of precursor cells. 2. This cell type diversity can be distinguished by the spatially and temporally coordinated expression of several transcription factors that are also linked to cell type specification at a very early stage of spinal cord development. 3, Recent studies have started to uncover that the generation of cell type diversity in the developing spinal cord. Moreover, distinct cell types in the spinal cord appear to be determined by the spatially and temporally coordinated expression of transcription factors. 4. The expression of these factors also appears to be controlled by gradients of factors expressed by ventral and dorsal midline cells, namely Sonic hedgehog and members of the transforming growth factor-beta family. 5, Changes in the competence of precursor cells and local cell interactions may also play important roles in cell type specification within the developing spinal cord.