Liver Function Test Abnormalities in Experimental and Clinical Plasmodium vivax Infection

Liver transaminase elevations after treatment in malaria volunteer infection studies (VISs) have raised safety concerns. We investigated transaminase elevations from two human Plasmodium vivax VISs where subjects were treated with chloroquine (n = 24) or artefenomel (n = 8) and compared them with studies in Thailand (n = 41) and Malaysia (n = 76). In the VISs, alanine transaminase (ALT) increased to ≥ 2.5 × upper limit of normal (ULN) in 11/32 (34%) volunteers, peaking 5–8 days posttreatment. Transaminase elevations were asymptomatic, were not associated with elevated bilirubin, and resolved by day 42. The risk of an ALT ≥ 2.5 × ULN increased more than 4-fold (odds ratio [OR] 4.28; 95% CI: 1.26–14.59; P = 0.02) for every log10 increase in the parasite clearance burden (PCB), defined as the log-fold reduction in parasitemia 24 hours post-treatment. Although an elevated ALT ≥ 2.5 × ULN was more common after artefenomel than after chloroquine (5/8 [63%] versus 6/24 [25%]; OR 5.0; 95% CI: 0.91–27.47; P = 0.06), this risk disappeared when corrected for parasite clearance burden (PCB). Peak ALT also correlated with peak C-reactive protein (R = 0.44; P = 0.012). Elevations in ALT (≥ 2.5 × ULN) were less common in malaria-endemic settings, occurring in 1/41 (2.5%) Thai patients treated with artefenomel, and in none of 76 Malaysians treated with chloroquine or artemisinin combination therapy. Post-treatment transaminase elevations are common in experimental P. vivax infection but do not appear to impact on participant safety. Although the mechanism of these changes remains uncertain, host inflammatory response to parasite clearance may be contributory

Optimization of the Kinematic Chain of the Thumb for a Hand Prosthesis Based on the Kapandji Opposition Test

Ponènica presentada a International Symposium on Computer Methods in Biomechanics and Biomedical Engineering - CMBBE 2019The thumb plays a key role in the performance of the hand for grasp-ing and manipulating objects. In artificial hands the complex thumb’s kinematic chain (TKC) is simplified and its five degrees of freedom are reduced to only one or two with the consequent loss of dexterity of the hand. The Kapandji op-position test (KOT) has been clinically used in pathological human hands for evaluating the thumb opposition and it has also been employed in some previ-ous studies as reference for the design of the TKC in artificial hands, but with-out a clearly stated methodology. Based on this approaches, in this study we present a computational method to optimize the whole TKC (base placement, link lengths and joint orientation angles) of an artificial hand based on its per-formance in the KOT. The cost function defined for the optimization (MPE) is a weighted mean position error when trying to reproduce the KOT postures and can be used also as a metric to quantify thumb opposition in the hand. As a case study, the method was applied to the improvement of the TKC of an artificial hand developed by the authors and the MPE was reduced to near one third of that of the original design, increasing significantly the number of reachable po-sitions in the KOT. The metric proposed based on the KOT can be used directly or in combination with other to improve the kinematic chain of artificial hands

Prodromal neuroinflammatory, cholinergic and metabolite dysfunction detected by PET and MRS in the TgF344-AD transgenic rat model of AD: A collaborative multi-modal study

Mouse models of Alzheimer s disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing APP and PSEN1 mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-Adults (6 months (m)) to mid-(12 m) and advanced-stage (18 m, 25 m) of the disease. Methods: TgF344-AD rats and wild-Type (WT) littermates were imaged at 6 m, 12 m and 18 m with [18F]DPA-714 (TSPO, neuroinflammation), [18F]Florbetaben (A) and [18F]ASEM (7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[18F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, A, NeuN, NeuroChrom) and Tau (S)-[18F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. Results: [18F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. In vivo [18F]ASEM PET revealed an age-dependent increase uptake in the striatum and pallidum/nucleus basalis of Meynert in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. In vivo [18F]Florbetaben PET scanning detected A accumulation at 18 m, and (S)-[18F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. A plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to A plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohistochemistry revealed a loss of neuronal staining at the A plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both genotypes. Behavioural assessment using the novel object recognition task revealed that both WT & TgF344-AD animals discriminated the novel from familiar object at 3 m and 6 m of age. However, low levels of exploration observed in both genotypes at later time-points resulted in neither genotype successfully completing the task. Deficits in social interaction were only observed at 3 m in the TgF344-AD animals. By in vivo MRS, we showed a decrease in neuronal marker N-Acetyl-Aspartate in the hippocampus at 18 m (-18% vs age-matched WT, and-31% vs 6 m TG) and increased Taurine in the cortex of TG (+35% vs age-matched WT, and +55% vs 6 m TG). Conclusions: This multi-centre multi-modal study demonstrates, for the first time, alterations in brain metabolites, cholinergic receptors and neuroinflammation in vivo in this model, validated by robust ex vivo approaches. Our data confirm that, unlike mouse models, the TgF344-AD express Tau pathology that can be detected via PET, albeit later than by ex vivo techniques, and is a useful model to assess and longitudinally monitor early neurotransmission dysfunction and neuroinflammation in AD

Concentration-QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers.

AIMS: Given the increasing emergence of drug resistance in Plasmodium, new antimalarials are urgently required. P218 is an aminopyridine that inhibits dihydrofolate reductase being developed as a malaria chemoprotective drug. Assessing the effect of new compounds on cardiac intervals is key during early drug development to determine their cardiac safety. METHODS: This double-blind, randomized, placebo-controlled, parallel group study evaluated the effect of P218 on electrocardiographic parameters following oral administration of seven single-ascending doses up to 1000 mg in 56 healthy volunteers. Participants were randomized to treatment or placebo at a 3:1 ratio. P218 was administered in the fasted state with standardized lunch served 4 hours after dosing. 12-lead ECGs were recorded in triplicate at regular intervals on the test day, and at 48, 72, 120, 168, 192 and 240 hours thereafter. Blood samples for pharmacokinetic evaluations were collected at similar time points. Concentration-effect modelling was used to assess the effect of P218 and its metabolites on cardiac intervals. RESULTS: Concentration-effect analysis showed that P218 does not prolong the QTcF, J-Tpeak or TpTe interval at all doses tested. No significant changes in QRS or PR intervals were observed. Two-sided 90% confidence intervals of subinterval effects of P218 and its metabolites were consistently below the regulatory concern threshold for all doses. Study sensitivity was confirmed by significant shortening of QTcF after a meal. CONCLUSION: Oral administration of P218 up to 1000 mg does not prolong QTcF and does not significantly change QRS or PR intervals, suggesting low risk for drug-induced proarrhythmia

DEVELOPMENTAL EFFECTS OF DIETARY N-3 FATTY ACIDS ON ACTIVITY AND RESPONSE TO NOVELTY

Insufficient availability of n-3 polyunsaturated fatty acids (PUFA) during pre- and neonatal development decreases accretion of docosahexaenoic acid (DHA, 22:6n-3) in the developing brain. Low tissue levels of DHA are associated with neurodevelopmental disorders including attention deficit hyperactivity disorder (ADHD). In this study, 1st-and 2nd-litter male Long-Evans rats were raised from conception on a Control diet containing α-linolenic acid (4.20 g/kg diet), the dietarily essential fatty acid precursor of DHA, or a diet Deficient in α-linolenic acid (0.38 g/kg diet). The Deficient diet resulted in a decrease in brain phospholipid DHA of 48% in 1st-litter pups and 65% in 2nd-litter pups. Activity, habituation, and response to spatial change in a familiar environment were assessed in a single-session behavioral paradigm at postnatal days 28 and 70, inclusive. Activity and habituation varied by age with younger rats exhibiting higher activity, less habituation, and less stimulation of activity induced by spatial novelty. During the first and second exposures to the test chamber, 2nd-litter Deficient pups exhibited higher levels of activity than Control rats or 1st-litter Deficient pups and less habituation during the first exposure, but were not more active after introduction of a novel spatial stimulus. The higher level of activity in a familiar environment, but not after introduction of a novel stimulus is consistent with clinical observations in ADHD. The observation of this effect only in 2nd-litter rats fed the Deficient diet suggests that brain DHA content, rather than dietary n-3 PUFA content, likely underlies these effects

Trazodone for the treatment of fibromyalgia: an open-label, 12-week study

Background: Despite its frequent use as a hypnotic, trazodone has not been systematically assessed in fibromyalgia patients. In the present study have we evaluated the potential effectiveness and tolerability of trazodone in the treatment of fibromyalgia. Methods: A flexible dose of trazodone (50-300 mg/day), was administered to 66 fibromyalgia patients for 12 weeks. The primary outcome measure was the Pittsburgh Sleep Quality Index (PSQI). Secondary outcome measures included the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression Scale (HADS), the Brief Pain Inventory (BPI), the Short-Form Health Survey (SF-36), and the Patients' Global Improvement Scale (PGI). Trazodone's emergent adverse reactions were recorded. Data were analyzed with repeated measures one-way ANOVA and paired Student's t test. Results: Trazodone markedly improved sleep quality, with large effect sizes in total PSQI score as well on sleep quality, sleep duration and sleep efficiency. Significant improvement, although with moderate effect sizes, were also observed in total FIQ scores, anxiety and depression scores (both HADS and BDI), and pain interference with daily activities. Unexpectedly, the most frequent and severe side effect associated with trazodone in our sample was tachycardia, which was reported by 14 (21.2%) patients. Conclusions: In doses higher than those usually prescribed as hypnotic, the utility of trazodone in fibromyalgia management surpasses its hypnotic activity. However, the emergence of tachycardia should be closely monitored. Trial registration: This trial has been registered with ClinicalTrials.gov number NCT-00791739

Mobility on the Surface of Phobos for the MMX Rover - Simulation-aided Movement planning

The MMX Rover, recently named IDEFIX, will be the first wheeled robotic system to be operated in a milli-g environment. The mobility in this environment, particularly in combination with the interrupted communication schedule and the activation of on-board autonomous functions such as attitude control requires efficient planning. The Mobility Group within the MMX Rovers Team is tasked with proposing optimal solutions to move the rover safely and efficiently to its destination so that it may achieve its scientific goals. These movements combine various commands to the locomotion system and to the navigation systems developed by both institutions. In the mission's early phase, these actions will rely heavily on manual driving commands to the locomotion system until the rover behavior and environment assumptions are confirmed. Planning safe and efficient rover movements is a multi-step process. This paper focuses on the challenges and limitations in sequencing movements for a Rover on Phobos in the context of the MMX Mission. The context in which this process takes place is described in terms of available data and operational constraints

Fats and Factors: Lipid Profiles Associate with Personality Factors and Suicidal History in Bipolar Subjects

Polyunsaturated fatty acids (PUFA) have shown efficacy in the treatment of bipolar disorder, however their specific role in treating the illness is unclear. Serum PUFA and dietary intakes of PUFA associate with suicidal behavior in epidemiological studies. The objective of this study was to assess serum n-3 and n-6 PUFA levels in bipolar subjects and determine possible associations with suicidal risk, including suicidal history and relevant personality factors that have been associated with suicidality. We studied 27 bipolar subjects using the NEO-PI to assess the big five personality factors, structured interviews to verify diagnosis and assess suicidal history, and lipomics to quantify n-3 and n-6 PUFA in serum. We found positive associations between personality factors and ratios of n-3 PUFA, suggesting that conversion of short chain to long chain n-3s and the activity of enzymes in this pathway may associate with measures of personality. Thus, ratios of docosahexaenoic acid (DHA) to alpha linolenic acid (ALA) and the activity of fatty acid desaturase 2 (FADS2) involved in the conversion of ALA to DHA were positively associated with openness factor scores. Ratios of eicosapentaenoic acid (EPA) to ALA and ratios of EPA to DHA were positively associated with agreeableness factor scores. Finally, serum concentrations of the n-6, arachidonic acid (AA), were significantly lower in subjects with a history of suicide attempt compared to non-attempters. The data suggest that specific lipid profiles, which are controlled by an interaction between diet and genetics, correlate with suicidal history and personality factors related to suicidal risk. This study provides preliminary data for future studies to determine whether manipulation of PUFA profiles (through diet or supplementation) can affect personality measures and disease outcome in bipolar subjects and supports the need for further investigations into individualized specific modulations of lipid profiles to add adjunctive value to treatment paradigms