The locus coeruleus Is Directly Implicated in L-DOPA-Induced Dyskinesia in Parkinsonian Rats: An Electrophysiological and Behavioural Study

Despite being the most effective treatment for Parkinson's disease, L-DOPA causes a development of dyskinetic movements in the majority of treated patients. L-DOPA-induced dyskinesia is attributed to a dysregulated dopamine transmission within the basal ganglia, but serotonergic and noradrenergic systems are believed to play an important modulatory role. In this study, we have addressed the role of the locus coeruleus nucleus (LC) in a rat model of L-DOPA-induced dyskinesia. Single-unit extracellular recordings in vivo and behavioural and immunohistochemical approaches were applied in rats rendered dyskinetic by the destruction of the nigrostriatal dopamine neurons followed by chronic treatment with L-DOPA. The results showed that L-DOPA treatment reversed the change induced by 6-hydroxydopamine lesions on LC neuronal activity. The severity of the abnormal involuntary movements induced by L-DOPA correlated with the basal firing parameters of LC neuronal activity. Systemic administration of the LC-selective noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine did not modify axial, limb, and orolingual dyskinesia, whereas chemical destruction of the LC with ibotenic acid significantly increased the abnormal involuntary movement scores. These results are the first to demonstrate altered LC neuronal activity in 6-OHDA lesioned rats treated with L-DOPA, and indicate that an intact noradrenergic system may limit the severity of this movement disorder.

New insights into the formation and modification of carbonate-bearing minerals and methane gas in geological systems using multiply substituted isotopologues

This thesis describes the use of multiply-substituted stable isotopologues of carbonate minerals and methane gas to better understand how these environmentally significant minerals and gases form and are modified throughout their geological histories. Stable isotopes have a long tradition in earth science as a tool for providing quantitative constraints on how molecules, in or on the earth, formed in both the present and past. Nearly all studies, until recently, have only measured the bulk concentrations of stable isotopes in a phase or species. However, the abundance of various isotopologues within a phase, for example the concentration of isotopologues with multiple rare isotopes (multiply substituted or 'clumped' isotopologues) also carries potentially useful information. Specifically, the abundances of clumped isotopologues in an equilibrated system are a function of temperature and thus knowledge of their abundances can be used to calculate a sample’s formation temperature. In this thesis, measurements of clumped isotopologues are made on both carbonate-bearing minerals and methane gas in order to better constrain the environmental and geological histories of various samples.

Clumped-isotope-based measurements of ancient carbonate-bearing minerals, including apatites, have opened up paleotemperature reconstructions to a variety of systems and time periods. However, a critical issue when using clumped-isotope based measurements to reconstruct ancient mineral formation temperatures is whether the samples being measured have faithfully recorded their original internal isotopic distributions. These original distributions can be altered, for example, by diffusion of atoms in the mineral lattice or through diagenetic reactions. Understanding these processes quantitatively is critical for the use of clumped isotopes to reconstruct past temperatures, quantify diagenesis, and calculate time-temperature burial histories of carbonate minerals. In order to help orient this part of the thesis, Chapter 2 provides a broad overview and history of clumped-isotope based measurements in carbonate minerals.

In Chapter 3, the effects of elevated temperatures on a sample’s clumped-isotope composition are probed in both natural and experimental apatites (which contain structural carbonate groups) and calcites. A quantitative model is created that is calibrated by the experiments and consistent with the natural samples. The model allows for calculations of the change in a sample’s clumped isotope abundances as a function of any time-temperature history.

In Chapter 4, the effects of diagenesis on the stable isotopic compositions of apatites are explored on samples from a variety of sedimentary phosphorite deposits. Clumped isotope temperatures and bulk isotopic measurements from carbonate and phosphate groups are compared for all samples. These results demonstrate that samples have experienced isotopic exchange of oxygen atoms in both the carbonate and phosphate groups. A kinetic model is developed that allows for the calculation of the amount of diagenesis each sample has experienced and yields insight into the physical and chemical processes of diagenesis.

The thesis then switches gear and turns its attention to clumped isotope measurements of methane. Methane is critical greenhouse gas, energy resource, and microbial metabolic product and substrate. Despite its importance both environmentally and economically, much about methane’s formational mechanisms and the relative sources of methane to various environments remains poorly constrained. In order to add new constraints to our understanding of the formation of methane in nature, I describe the development and application of methane clumped isotope measurements to environmental deposits of methane. To help orient the reader, a brief overview of the formation of methane in both high and low temperature settings is given in Chapter 5.

In Chapter 6, a method for the measurement of methane clumped isotopologues via mass spectrometry is described. This chapter demonstrates that the measurement is precise and accurate. Additionally, the measurement is calibrated experimentally such that measurements of methane clumped isotope abundances can be converted into equivalent formational temperatures. This study represents the first time that methane clumped isotope abundances have been measured at useful precisions.

In Chapter 7, the methane clumped isotope method is applied to natural samples from a variety of settings. These settings include thermogenic gases formed and reservoired in shales, migrated thermogenic gases, biogenic gases, mixed biogenic and thermogenic gas deposits, and experimentally generated gases. In all cases, calculated clumped isotope temperatures make geological sense as formation temperatures or mixtures of high and low temperature gases. Based on these observations, we propose that the clumped isotope temperature of an unmixed gas represents its formation temperature — this was neither an obvious nor expected result and has important implications for how methane forms in nature. Additionally, these results demonstrate that methane-clumped isotope compositions provided valuable additional constraints to studying natural methane deposits.

Progressive Decrease in the Potential Usefulness of Meningococcal Serogroup B Vaccine (4CMenB, Bexsero (R)) in Gipuzkoa, Northern Spain

The effectiveness of a vaccine is determined not only by the immunogenicity of its components, but especially by how widely it covers the disease-causing strains circulating in a given region. Because vaccine coverage varies over time, this study aimed to detect possible changes that could affect vaccine protection during a specific period in a southern European region. The 4CMenB vaccine is licensed for use in Europe, Canada, and Australia and is mainly directed against Neisseria meningitidis serogroup B. This vaccine contains four main immunogenic components: three recombinant proteins, FHbp, Nhba and NadA, and an outer membrane vesicle [PorA P1.4]. The allelic distribution of FHbp, Nhba, NadA, and PorA antigens in 82 invasive isolates (B and non-B serogroups) isolated from January 2008 to December 2013 were analyzed. 4CMenB was likely protective against 61.8% and 50% of serogroup B and non-B meningococci, respectively, in the entire period, but between 2012 and 2013, the predicted protection fell below 45% (42.1% for serogroup B isolates). The observed decreasing trend in the predicted protection during the 6 years of the study (X-2 for trend = 4.68, p=0.03) coincided with a progressive decrease of several clonal complexes (e. g., cc11, cc32 and cc41/44), which had one or more antigens against which the vaccine would offer protection.

The E2F2 Transcription Factor Sustains Hepatic Glycerophospholipid Homeostasis in Mice

Increasing evidence links metabolic signals to cell proliferation, but the molecular wiring that connects the two core machineries remains largely unknown. E2Fs are master regulators of cellular proliferation. We have recently shown that E2F2 activity facilitates the completion of liver regeneration after partial hepatectomy (PH) by regulating the expression of genes required for S-phase entry. Our study also revealed that E2F2 determines the duration of hepatectomy-induced hepatic steatosis. A transcriptomic analysis of normal adult liver identified "lipid metabolism regulation" as a major E2F2 functional target, suggesting that E2F2 has a role in lipid homeostasis. Here we use wild-type (E2F2(+/+)) and E2F2 deficient (E2F2(-/-)) mice to investigate the in vivo role of E2F2 in the composition of liver lipids and fatty acids in two metabolically different contexts: quiescence and 48-h post-PH, when cellular proliferation and anabolic demands are maximal. We show that liver regeneration is accompanied by large triglyceride and protein increases without changes in total phospholipids both in E2F2(+/+) and E2F2(-/-) mice. Remarkably, we found that the phenotype of quiescent liver tissue from E2F2(-/-) mice resembles the phenotype of proliferating E2F2(+/+) liver tissue, characterized by a decreased phosphatidylcholine to phosphatidylethanolamine ratio and a reprogramming of genes involved in generation of choline and ethanolamine derivatives. The diversity of fatty acids in total lipid, triglycerides and phospholipids was essentially preserved on E2F2 loss both in proliferating and non-proliferating liver tissue, although notable exceptions in inflammation-related fatty acids of defined phospholipid classes were detected. Overall, our results indicate that E2F2 activity sustains the hepatic homeostasis of major membrane glycerolipid components while it is dispensable for storage glycerolipid balance.

Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity

Background: Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological development. Therefore, apoptosis inhibition is still considered an unmet medical need. Methodology and Principal Findings: The interaction between Apaf-1 and the inhibitors was confirmed by NMR. Target specificity was evaluated in cellular models by siRNa based approaches. Cell recovery was confirmed by MTT, clonogenicity and flow cytometry assays. The efficiency of the compounds as antiapoptotic agents was tested in cellular and in vivo models of protection upon cisplatin induced ototoxicity in a zebrafish model and from hypoxia and reperfusion kidney damage in a rat model of hot ischemia. Conclusions: Apaf-1 inhibitors decreased Cytc release and apoptosome-mediated activation of procaspase-9 preventing cell and tissue damage in ex vivo experiments and in vivo animal models of apoptotic damage. Our results provide evidence that Apaf-1 pharmacological inhibition has therapeutic potential for the treatment of apoptosis-related diseases.

Feature Selection for Speech Emotion Recognition in Spanish and Basque: On the Use of Machine Learning to Improve Human-Computer Interaction

Study of emotions in human-computer interaction is a growing research area. This paper shows an attempt to select the most significant features for emotion recognition in spoken Basque and Spanish Languages using different methods for feature selection. RekEmozio database was used as the experimental data set. Several Machine Learning paradigms were used for the emotion classification task. Experiments were executed in three phases, using different sets of features as classification variables in each phase. Moreover, feature subset selection was applied at each phase in order to seek for the most relevant feature subset. The three phases approach was selected to check the validity of the proposed approach. Achieved results show that an instance-based learning algorithm using feature subset selection techniques based on evolutionary algorithms is the best Machine Learning paradigm in automatic emotion recognition, with all different feature sets, obtaining a mean of 80,05% emotion recognition rate in Basque and a 74,82% in Spanish. In order to check the goodness of the proposed process, a greedy searching approach (FSS-Forward) has been applied and a comparison between them is provided. Based on achieved results, a set of most relevant non-speaker dependent features is proposed for both languages and new perspectives are suggested.

In Vitro Surfactant and Perfluorocarbon Aerosol Deposition in a Neonatal Physical Model of the Upper Conducting Airways

Objective: Aerosol delivery holds potential to release surfactant or perfluorocarbon (PFC) to the lungs of neonates with respiratory distress syndrome with minimal airway manipulation. Nevertheless, lung deposition in neonates tends to be very low due to extremely low lung volumes, narrow airways and high respiratory rates. In the present study, the feasibility of enhancing lung deposition by intracorporeal delivery of aerosols was investigated using a physical model of neonatal conducting airways. Methods: The main characteristics of the surfactant and PFC aerosols produced by a nebulization system, including the distal air pressure and air flow rate, liquid flow rate and mass median aerodynamic diameter (MMAD), were measured at different driving pressures (4-7 bar). Then, a three-dimensional model of the upper conducting airways of a neonate was manufactured by rapid prototyping and a deposition study was conducted. Results: The nebulization system produced relatively large amounts of aerosol ranging between 0.3 +/- 0.0 ml/min for surfactant at a driving pressure of 4 bar, and 2.0 +/- 0.1 ml/min for distilled water (H(2)Od) at 6 bar, with MMADs between 2.61 +/- 0.1 mu m for PFD at 7 bar and 10.18 +/- 0.4 mu m for FC-75 at 6 bar. The deposition study showed that for surfactant and H(2)Od aerosols, the highest percentage of the aerosolized mass (similar to 65%) was collected beyond the third generation of branching in the airway model. The use of this delivery system in combination with continuous positive airway pressure set at 5 cmH(2)O only increased total airway pressure by 1.59 cmH(2)O at the highest driving pressure (7 bar). Conclusion: This aerosol generating system has the potential to deliver relatively large amounts of surfactant and PFC beyond the third generation of branching in a neonatal airway model with minimal alteration of pre-set respiratory support.

A Delphi Process to Optimize Quality and Performance of Drug Evaluation in Neonates

Background: Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. The objective of this work was to identify the major criteria considered necessary for selecting neonatal intensive care units that are able to perform drug evaluations competently. Methodology and Main Findings: This Delphi process was conducted with an international multidisciplinary panel of 25 experts from 13 countries, selected to be part of two committees (a scientific committee and an expert committee), in order to validate criteria required to perform drug evaluation in neonates. Eighty six items were initially selected and classified under 7 headings: "NICUs description - Level of care'' (21), "Ability to perform drug trials: NICU organization and processes (15), "Research Experience'' (12), "Scientific competencies and area of expertise'' (8), "Quality Management'' (16), "Training and educational capacity'' (8) and "Public involvement'' (6). Sixty-one items were retained and headings were rearranged after the first round, 34 were selected after the second round. A third round was required to validate 13 additional items. The final set includes 47 items divided under 5 headings. Conclusion: A set of 47 relevant criteria will help to NICUs that want to implement, conduct or participate in drug trials within a neonatal network identify important issues to be aware of. Summary Points: 1) Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. 2) The present Delphi study was conducted with an international multidisciplinary panel of 25 experts from 13 countries and aims to identify the major criteria considered necessary for selecting neonatal intensive care units (NICUs) that are able to perform drug evaluations competently. 3) Of the 86 items initially selected and classified under 7 headings - "NICUs description - Level of care'' (21), "Ability to perform drug trials: NICU organization and processes (15), "Research Experience'' (12), "Scientific competencies and area of expertise'' (8), "Quality Management'' (16), "Training and educational capacity'' (8) and "Public involvement'' (6) - 47 items were selected following a three rounds Delphi process. 4) The present consensus will help NICUs to implement, conduct or participate in drug trials within a neonatal network.

Birth Weight, Working Memory and Epigenetic Signatures in IGF2 and Related Genes: A MZ Twin Study

Neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of several phenotypes associated with neuropsychiatric diseases and cognitive dysfunctions. Importantly, it has been noticed that epigenetic processes occurring early in life may mediate these associations. Here, DNA methylation signatures at IGF2 (insulin-like growth factor 2) and IGF2BP1-3 (IGF2-binding proteins 1-3) were examined in a sample consisting of 34 adult monozygotic (MZ) twins informative for obstetric complications and cognitive performance. Multivariate linear regression analysis of twin data was implemented to test for associations between methylation levels and both birth weight (BW) and adult working memory (WM) performance. Familial and unique environmental factors underlying these potential relationships were evaluated. A link was detected between DNA methylation levels of two CpG sites in the IGF2BP1 gene and both BW and adult WM performance. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the WM-IGF2BP1 methylation relationship seemed mediated by both genes and environment. Our data is in agreement with previous evidence indicating that DNA methylation status may be related to prenatal stress and later neurocognitive phenotypes. While former reports independently detected associations between DNA methylation and either BW or WM, current results suggest that these relationships are not confounded by each other.

Self-Organized Criticality, Plasticity and Sensorimotor Coupling. Explorations with a Neurorobotic Model in a Behavioural Preference Task

During the last two decades, analysis of 1/f noise in cognitive science has led to a considerable progress in the way we understand the organization of our mental life. However, there is still a lack of specific models providing explanations of how 1/f noise is generated in coupled brain-body-environment systems, since existing models and experiments typically target either externally observable behaviour or isolated neuronal systems but do not address the interplay between neuronal mechanisms and sensorimotor dynamics. We present a conceptual model of a minimal neurorobotic agent solving a behavioural task that makes it possible to relate mechanistic (neurodynamic) and behavioural levels of description. The model consists of a simulated robot controlled by a network of Kuramoto oscillators with homeostatic plasticity and the ability to develop behavioural preferences mediated by sensorimotor patterns. With only three oscillators, this simple model displays self-organized criticality in the form of robust 1/f noise and a wide multifractal spectrum. We show that the emergence of self-organized criticality and 1/f noise in our model is the result of three simultaneous conditions: a) non-linear interaction dynamics capable of generating stable collective patterns, b) internal plastic mechanisms modulating the sensorimotor flows, and c) strong sensorimotor coupling with the environment that induces transient metastable neurodynamic regimes. We carry out a number of experiments to show that both synaptic plasticity and strong sensorimotor coupling play a necessary role, as constituents of self-organized criticality, in the generation of 1/f noise. The experiments also shown to be useful to test the robustness of 1/f scaling comparing the results of different techniques. We finally discuss the role of conceptual models as mediators between nomothetic and mechanistic models and how they can inform future experimental research where self-organized critically includes sensorimotor coupling among the essential interaction-dominant process giving rise to 1/f noise.

The Interplay between Natural Selection and Susceptibility to Melanoma on Allele 374F of SLC45A2 Gene in a South European Population

We aimed to study the selective pressures interacting on SLC45A2 to investigate the interplay between selection and susceptibility to disease. Thus, we enrolled 500 volunteers from a geographically limited population (Basques from the North of Spain) and by resequencing the whole coding region and intron 5 of the 34 most and the 34 least pigmented individuals according to the reflectance distribution, we observed that the polymorphism Leu374Phe (L374F, rs16891982) was statistically associated with skin color variability within this sample. In particular, allele 374F was significantly more frequent among the individuals with lighter skin. Further genotyping an independent set of 558 individuals of a geographically wider population with known ancestry in the Spanish population also revealed that the frequency of L374F was significantly correlated with the incident UV radiation intensity. Selection tests suggest that allele 374F is being positively selected in South Europeans, thus indicating that depigmentation is an adaptive process. Interestingly, by genotyping 119 melanoma samples, we show that this variant is also associated with an increased susceptibility to melanoma in our populations. The ultimate driving force for this adaptation is unknown, but it is compatible with the vitamin D hypothesis. This shows that molecular evolution analysis can be used as a useful technology to predict phenotypic and biomedical consequences in humans.

Incidental Memory of Younger and Older Adults for Objects Encountered in a Real World Context

Effects of context on the perception of, and incidental memory for, real-world objects have predominantly been investigated in younger individuals, under conditions involving a single static viewpoint. We examined the effects of prior object context and object familiarity on both older and younger adults' incidental memory for real objects encountered while they traversed a conference room. Recognition memory for context-typical and context-atypical objects was compared with a third group of unfamiliar objects that were not readily named and that had no strongly associated context. Both older and younger adults demonstrated a typicality effect, showing significantly lower 2-alternative-forced-choice recognition of context-typical than context-atypical objects; for these objects, the recognition of older adults either significantly exceeded, or numerically surpassed, that of younger adults. Testing-awareness elevated recognition but did not interact with age or with object type. Older adults showed significantly higher recognition for context-atypical objects than for unfamiliar objects that had no prior strongly associated context. The observation of a typicality effect in both age groups is consistent with preserved semantic schemata processing in aging. The incidental recognition advantage of older over younger adults for the context-typical and context-atypical objects may reflect aging-related differences in goal-related processing, with older adults under comparatively more novel circumstances being more likely to direct their attention to the external environment, or age-related differences in top-down effortful distraction regulation, with older individuals' attention more readily captured by salient objects in the environment. Older adults' reduced recognition of unfamiliar objects compared to context-atypical objects may reflect possible age differences in contextually driven expectancy violations. The latter finding underscores the theoretical and methodological value of including a third type of objects-that are comparatively neutral with respect to their contextual associations-to help differentiate between contextual integration effects (for schema-consistent objects) and expectancy violations (for schema-inconsistent objects).

Seasonal Blowfly Distribution and Abundance in Fragmented Landscapes. Is It Useful in Forensic Inference about Where a Corpse Has Been Decaying?

Blowflies are insects of forensic interest as they may indicate characteristics of the environment where a body has been laying prior to the discovery. In order to estimate changes in community related to landscape and to assess if blowfly species can be used as indicators of the landscape where a corpse has been decaying, we studied the blowfly community and how it is affected by landscape in a 7,000 km(2) region during a whole year. Using baited traps deployed monthly we collected 28,507 individuals of 10 calliphorid species, 7 of them well represented and distributed in the study area. Multiple Analysis of Variance found changes in abundance between seasons in the 7 analyzed species, and changes related to land use in 4 of them (Calliphora vomitoria, Lucilia ampullacea, L. caesar and L. illustris). Generalised Linear Model analyses of abundance of these species compared with landscape descriptors at different scales found only a clear significant relationship between summer abundance of C. vomitoria and distance to urban areas and degree of urbanisation. This relationship explained more deviance when considering the landscape composition at larger geographical scales (up to 2,500 m around sampling site). For the other species, no clear relationship between land uses and abundance was found, and therefore observed changes in their abundance patterns could be the result of other variables, probably small changes in temperature. Our results suggest that blowfly community composition cannot be used to infer in what kind of landscape a corpse has decayed, at least in highly fragmented habitats, the only exception being the summer abundance of C. vomitoria.

Genotypes, Recombinant Forms, and Variants of Norovirus GII.4 in Gipuzkoa (Basque Country, Spain), 2009-2012

Background: Noroviruses (NoVs) are genetically diverse, with genogroup II-and within it-genotype 4 (GII.4) being the most prevalent cause of acute gastroenteritis worldwide. The aim of this study was to characterize genogroup II NoV causing acute gastroenteritis in the Basque Country (northern Spain) from 2009-2012. Methods: The presence of NoV RNA was investigated by reverse transcriptase-polymerase chain reaction (RT-PCR) in stool specimens from children younger than 15 years old with community-acquired acute gastroenteritis, and from hospitalized adults or elderly residents of nursing homes with acute gastroenteritis. For genotyping, the open reading frames ORF1 (encoding the polymerase) and ORF2 (encoding the major capsid protein) were partially amplified and sequenced. Recombinant strains were confirmed by PCR of the ORF1/ORF2 junction region. Results: NoV was detected in 16.0% (453/2826) of acute gastroenteritis episodes in children younger than 2 years, 9.9% (139/1407) in children from 2 to 14 years, and 35.8% (122/341) in adults. Of 317 NoVs characterized, 313 were genogroup II and four were genogroup I. The GII.4 variants Den Haag-2006b and New Orleans-2009 predominated in 2009 and 2010-2011, respectively. In 2012, the New Orleans-2009 variant was partially replaced by the Sydney-2012 variant (GII.Pe/GII.4) and New Orleans-2009/Sydney-2012 recombinant strains. The predominant capsid genotype in all age groups was GII.4, which was the only genotype detected in outbreaks. The second most frequent genotype was GII.3 (including the recently described recombination GII.P16/GII.3), which was detected almost exclusively in children. Conclusion: Nine different genotypes of NoV genogroup II were detected; among these, intergenotype recombinant strains represented an important part, highlighting the role of recombination in the evolution of NoVs. Detection of new NoV strains, not only GII.4 strains, shortly after their first detection in other parts of the world shows that many NoV strains can spread rapidly.

Dobutamine in Paediatric Population: A Systematic Review in Juvenile Animal Models

Objective: Although dobutamine is widely used in neonatal clinical practice, the evidence for its use in this specific population is not clear. We conducted a systematic review of the use of dobutamine in juvenile animals to determine whether the evidence from juvenile animal experiments with dobutamine supported the design of clinical trials in neonatal/ paediatric population. Methods: Studies were identified by searching MEDLINE (1946-2012) and EMBASE (1974-2012). Articles retrieved were independently reviewed by three authors and only those concerning efficacy and safety of the drug in juvenile animals were included. Only original articles published in English and Spanish were included. Results: Following our literature search, 265 articles were retrieved and 24 studies were included in the review: 17 focused on neonatal models and 7 on young animal models. Although the aims and design of these studies, as well as the doses and ages analysed, were quite heterogeneous, the majority of authors agree that dobutamine infusion improves cardiac output in a dose dependent manner. Moreover, the cardiovascular effects of dobutamine are influenced by postnatal age, as well as by the dose used and the duration of the therapy. There is inadequate information about the effects of dobutamine on cerebral perfusion to draw conclusions. Conclusion: There is enough preclinical evidence to ensure that dobutamine improves cardiac output, however to better understand its effects in peripheral organs, such as the brain, more specific and well designed studies are required to provide additional data to support the design of clinical trials in a paediatric population.