Impact of patent ductus arteriosus on non-invasive assessments of lung fluids in very preterm infants during the transitional period.

This prospective observational study aimed to evaluate whether lung fluids, assessed by lung ultrasonography and transthoracic electrical bioimpedance (TEB), may be influenced by the presence of a haemodynamically significant patent ductus arteriosus (hsPDA) in very preterm infants during the transitional period. Infants < 32 weeks of gestational age (GA) admitted to the neonatal intensive care units of IRCCS AOU Bologna and Niguarda Metropolitan Hospital of Milan (Italy) underwent a daily assessment of a lung ultrasound score (LUS) and of a TEB-derived index of thoracic fluid contents (TFC) during the first 72 h after birth. Echocardiographic scans were simultaneously performed to evaluate the concomitant ductal status (hsPDA vs. restrictive or closed duct). The correlation between LUS, TFC, and the ductal status was tested using generalized estimating equations. Forty-six infants (median GA: 29 [interquartile range, IQR: 27-31] weeks; median birth weight: 1099 [IQR: 880-1406] g) were included. At each daily evaluation, the presence of a hsPDA was associated with significantly higher LUS and TFC compared with a restrictive or closed ductus (p < 0.01 for all comparisons). These results were confirmed significant even after adjustment for GA and for the ongoing modality of respiratory support. Conclusion: Even during the first 72 h of life, the presence of a hsPDA determines a significant increase in pulmonary fluids which can be non-invasively detected and monitored over time using lung ultrasonography and TEB. What is Known: • Lung ultrasonography provides a non-invasive assessment of lung fluids and is widely used in neonatal settings. • In preterm infants, the persistence of a haemodynamically significant patent ductus arteriosus (hsPDA) over the first weeks can negatively affect pulmonary outcomes. What is New: • The presence of aan hsPDA is associated with increased lung fluids since early postnatal phases. • Lung ultrasonography and transthoracic electrical bioimpedance can effectively monitor lung fluid clearance in preterm infants with a hsPDA during the transitional period, with potential clinical implications.

Prediction of respiratory distress severity and bronchopulmonary dysplasia by lung ultrasounds and transthoracic electrical bioimpedance.

This study aims to evaluate whether the assessment of a lung ultrasound score (LUS) by lung ultrasonography and of thoracic fluid contents (TFC) by electrical cardiometry may predict RDS severity and the development of bronchopulmonary dysplasia (BPD) in preterm infants with respiratory distress (RDS). Infants ≤ 34 weeks' gestation admitted with RDS to two neonatal intensive care units were prospectively enrolled in this observational study. A simultaneous evaluation of LUS and TFC was performed during the first 72 h. The predictivity of LUS and TFC towards mechanical ventilation (MV) need after 24 h and BPD development was evaluated using receiver operating characteristic analysis. Sixty-four infants were included. The area under the curve (AUC) for the prediction of MV need was 0.851 (95%CI, 0.776-0.925, p < 0.001) for LUS and 0.793 (95%CI, 0.724-0.862, p < 0.001) for TFC, while an AUC of 0.876 (95%CI, 0.807-0.946, p < 0.001) was obtained for combined LUS and TFC evaluation. LUS and TFC AUC for BPD prediction were 0.769 (95%CI, 0.697-0.842, p < 0.001) and 0.836 (95%CI, 0.778-0.894, p < 0.001), respectively, whereas their combined assessment yielded an AUC of 0.867 (95%CI, 0.814-0.919, p < 0.001). LUS ≥ 11 and TFC ≥ 40 were identified as cut-off values for MV need prediction, whereas LUS ≥ 9 and TFC ≥ 41.4 best predicted BPD development.   Conclusion: A combined evaluation of LUS and TFC by lung ultrasonography and EC during the first 72 h may represent a useful predictive tool towards short- and medium-term pulmonary outcomes in preterm infants with RDS. What is Known: • Lung ultrasonography is largely used in neonatal intensive care and can contribute to RDS diagnosis in preterm infants. • Little is known on the diagnostic and predictive role of TFC, measured by transthoracic electrical bioimpedance, in neonatal RDS. What is New: • Combining lung ultrasonography and TFC evaluation during the first 72 h can improve the prediction of RDS severity and BPD development in preterm infants with RDS and may aid to establish tailored respiratory approaches to improve these outcomes.

Electrical cardiometry in monitoring percutaneous closure of ductus arteriosus in preterm infants: a case study on five patients.

Patent ductus arteriosus closure by catheter-based interventions has become the preferred therapeutic choice. However, hemodynamic perturbances associated to this procedure have not yet been investigated. This study sought to examine the on-site hemodynamic impact caused by the procedure in preterm neonates. In this study, hemodynamic monitoring was obtained in a non-invasive way using electrical cardiometry in five preterm infants who underwent percutaneous patent ductus arteriosus closing at ASST Grande Ospedale Metropolitano Niguarda of Milan. All five infants underwent successful transcatheter closures. All patients experienced immediate hemodynamic changes upon ductal closing. Significative modifications occurred mainly in heart contractility, cardiac output, and stroke volume. In three cases, there was also a significative increase of systemic vascular resistance which persisted for 4 h after closing. While in two cases they spontaneously reduced with an amelioration of cardiac output and contractility, in the other case they were persistently high, associated with an hypertensive crisis and a progressive reduction of cardiac functions. For these reasons, milrinone was started and hemodynamic parameters returned normal in about 3 h, so therapy was discontinued.   Conclusions: Our single-center, prospective, consecutive, case series demonstrated hemodynamic aberrations due to sudden closure of a patent ductus arteriosus. Moreover, post procedural hemodynamic monitoring is important to precociously detect possible cardiac impairment and start an adequate therapy. What is Known: • It has previously suggested a temporarily impairment in cardiac output following patent ductus arteriosus closing. • Little is known about the other hemodynamic parameters during the procedure and how they change in the next hours according to the new hemodynamic status. What is New: • The persistence of increased systemic vascular resistance after percutaneous closure of ductus arteriosus could suggest the occurrence of hemodynamic complications. • Electrical cardiometry was useful to early detect postoperative hemodynamic changes.

Neonatal Septic Shock and Hemodynamic Monitoring in Preterm Neonates in an NICU: Added Value of Electrical Cardiometry in Real-Time Tailoring of Management and Therapeutic Strategies.

OBJECTIVE: Electrical cardiometry is an impedance-based monitoring technique that provides data on several hemodynamic parameters in a noninvasive way. There is limited information on clinical utility of the application of this technique in neonates. STUDY DESIGN: In this study, we describe the case of a preterm neonate born at 302/7 weeks of gestational age who developed severe systemic infection with fluid refractory septic shock on day 2 of life. DISCUSSION: Electrical cardiometry was used and proved very helpful in real-time guiding the choice and the dosing of the most appropriate inotrope drugs in this patient. In addition, it promptly underlined an abrupt drop of systemic vascular resistances occurring after administration of the first dose of antibiotic, thus warning the attending neonatologist to institute appropriate treatment before the clinical conditions could further worsen. CONCLUSION: This case report suggests that electrical cardiometry could be a useful tool in assessing, monitoring, and guiding care of neonates who develop severe septic shock. We suggest that electrical cardiometry is a promising approach in the management strategies of such patients that warrants informative clinical trials. KEY POINTS: · Electrical cardiometry was helpful in real-time decision-making.. · Electrical cardiometry reported hemodynamic perturbations before worsening of clinical conditions.. · Electrical cardiometry should be included in the management of critical patients..

Noninvasive Cardiac Output Monitoring in Newborn with Hypoplastic Left Heart Syndrome.

OBJECTIVE: This study aimed to describe the first two cases of electrical cardiometry applied to newborn with hypoplastic left heart syndrome for hemodynamical assessment in the first days of life before surgical correction and see if this can help decision making process in these patients. STUDY DESIGN: We describe two case series of two full-term newborn with hypoplastic left heart syndrome in the Neonatal Intensive Care Unit, ASST Grande Ospedale Metropolitano Niguarda, between December 2019 and January 2020. RESULTS: Case 1 was persistently hemodynamically stable with prostaglandin E1 infusion at 0.01 mcg/kg/min, showing good capillary refill time, good diuresis, no difference between pre- and postductal values of oxygen saturation or blood pressure. Electrical cardiometry monitoring constantly showed cardiac output values higher than 300 mL/kg/min. Case 2 showed poor clinical condition needing prostaglandin E1 infusion up to 0.05 mcg/kg/min, intubation and septostomy associated with low cardiac output around 190 mL/kg/min. Once cardiac output has begun to rise and reached values constantly over 300 mL/kg/min, clinical condition improved with amelioration in oxygen saturation, diuresis, blood pressure, and blood gas analysis values. She was then extubated and finally clinically stable until surgery with minimal infusion of prostaglandin E1 at 0.01 mcg/kg/min. CONCLUSION: This case highlights how hemodynamic information provided by electrical cardiometry can be used to supplement the combined data from all monitors and the clinical situation to guide therapy in these newborns waiting surgery. KEY POINTS: · This is the first report of electrical cardiometry (EC) use in newborn with hypoplastic left heart syndrome (HLHS).. · In HLHS patients, it is impossible to measure cardiac output without being invasive.. · EC helps in guiding therapy in HLHS patients in a noninvasive way..

Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort.

OBJECTIVE: Combined pituitary hormonal deficiency (CPHD) can result from mutations within genes that encode transcription factors. This study evaluated the frequency of mutations in these genes in a cohort of 144 unrelated Italian patients with CPHD and estimated the overall prevalence of mutations across different populations using a systematic literature review. MATERIAL AND METHODS: A multicentre study of adult and paediatric patients with CPHD was performed. The PROP1, POU1F1, HESX1, LHX3 and LHX4 genes were analysed for the presence of mutations using direct sequencing. We systematically searched PubMed with no date restrictions for studies that reported genetic screening of CPHD cohorts. We only considered genetic screenings with at least 10 individuals. Data extraction was conducted in accordance with the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Global mutation frequency in Italian patients with CPHD was 2·9% (4/136) in sporadic cases and 12·5% (1/8) in familial cases. The worldwide mutation frequency for the five genes calculated from 21 studies was 12·4%, which ranged from 11·2% in sporadic to 63% in familial cases. PROP1 was the most frequently mutated gene in sporadic (6·7%) and familial cases (48·5%). CONCLUSION: The frequency of defects in genes encoding pituitary transcription factors is quite low in Italian patients with CPHD and other western European countries, especially in sporadic patients. The decision of which genes should be tested and in which order should be guided by hormonal and imaging phenotype, the presence of extrapituitary abnormalities and the frequency of mutation for each gene in the patient-referring population.

Synthesis and structure-activity relationship studies in serotonin 5-HT4 receptor ligands based on a benzo[de][2,6]naphthridine scaffold.

A small series of serotonin 5-HT4 receptor ligands has been designed from flexible 2-methoxyquinoline compounds 7a,b by applying the conformational constraint approach. Ligands 7a,b and the corresponding conformationally constrained analogues 8a-g were synthesized and their interactions with the 5-HT4 receptor were examined by measuring both binding affinity and the ability to promote or inhibit receptor-G protein coupling. Ester derivative 7a and conformationally constrained compound 8b were demonstrated to be the most interesting compounds showing a nanomolar 5-HT4R affinity similar to that shown by reference ligands cisapride (1) and RS-23,597-190 (4). The result was rationalized by docking studies in term of high similarity in the binding modalities of flexible 7a and conformationally constrained 8b. The intrinsic efficacy of some selected ligands was determined by evaluating the receptor-G protein coupling and the results obtained demonstrated that the nature and the position of substituents play a critical role in the interaction of these ligands with their receptor.

Exploring a potential palonosetron allosteric binding site in the 5-HT(3) receptor.

Palonosetron (Aloxi) is a potent second generation 5-HT(3) receptor antagonist whose mechanism of action is not yet fully understood. Palonosetron acts at the 5-HT(3) receptor binding site but recent computational studies indicated other possible sites of action in the extracellular domain. To test this hypothesis we mutated a series of residues in the 5-HT3A receptor subunit (Tyr(73), Phe(130), Ser(163), and Asp(165)) and in the 5-HT3B receptor subunit (His(73), Phe(130), Glu(170), and Tyr(143)) that were previously predicted by in silico docking studies to interact with palonosetron. Homomeric (5-HT(3)A) and heteromeric (5-HT(3)AB) receptors were then expressed in HEK293 cells to determine the potency of palonosetron using both fluorimetric and radioligand methods to test function and ligand binding, respectively. The data show that the substitutions have little or no effect on palonosetron inhibition of 5-HT-evoked responses or binding. In contrast, substitutions in the orthosteric binding site abolish palonosetron binding. Overall, the data support a binding site for palonosetron at the classic orthosteric binding pocket between two 5-HT3A receptor subunits but not at allosteric sites previously identified by in silico modelling and docking.

Approaching the 5-HT3 receptor heterogeneity by computational studies of the transmembrane and intracellular domains.

5-hydroxytryptamine type-3 receptor (5-HT3), an important target of many neuroactive drugs, is a cation selective transmembrane pentamer whose functional stoichiometries and subunit arrangements are still debated, due to the extreme complexity of the system. The three dimensional structure of the 5-HT3R subunits has not been solved so far. Moreover, most of the available structural and functional data is related to the extracellular ligand-binding domain, whereas the transmembrane and the intracellular receptor domains are far less characterised, although they are crucial for receptor function. Here, for the first time, 3D homology models of the transmembrane and the intracellular receptor domains of all the known human 5-HT3 subunits have been built and assembled into homopentameric (5-HT(3A)R, 5-HT(3B)R, 5-HT(3C)R, 5-HT(3D)R and 5-HT(3E)R) and heteropentameric receptors (5-HT(3AB), 5-HT(3AC), 5-HT(3AD) and 5-HT(3AE)), on the basis of the known three-dimensional structures of the nicotinic-acetylcholine receptor and of the ligand gated channel from Erwinia chrysanthemi. The comparative analyses of sequences, modelled structures, and computed electrostatic properties of the single subunits and of the assembled pentamers shed new light both on the stoichiometric composition and on the physicochemical requirements of the functional receptors. In particular, it emerges that a favourable environment for the crossing of the pore at the transmembrane and intracellular C terminus domain levels by Ca²âº ions is granted by the maximum presence of two B subunits in the 5-HT3 pentamer.

Involvement of genes related to inflammation and cell cycle in idiopathic short stature.

Idiopathic Short Stature (ISS) defines a condition in which height is <-2SD compared to the mean of a reference population where systemic, endocrinological, nutritional or chromosomal disorders have not been identified and diagnosis is based on exclusion of any known causes of short stature. JAK/STAT pathway is triggered by GH binding to the GH receptor and promotes cellular growth through transcription of GH-responsive genes. In order to identify "candidate genes" differently expressed in ISS subjects with respect to control ones, we analyzed the expression of 84 genes related to JAK/STAT pathway by RT(2) Profiler PCR array approach in a total of 10 subjects. Then, we validated the observed data by Real Time PCR and ELISA assays in a major number of subjects. We found two genes that were differently expressed in ISS subjects with respect to the control group: CXCL9 and FCGR1A/CD64, both significantly up-regulated (fold change 2.17 and 1.70, respectively) and belonging to family of IFN-γ-inducible factors. Further, ISS subjects showed an increased gene expression of IFN-γ and IFI16, higher serum levels of IFN-γ but similar levels of CXCL9 when compared to healthy subjects. In addition, we showed a pubertal modulation of CXCL9 levels. These data suggest that inflammatory and regulatory factors of the cell cycle may be involved in the ISS condition, introducing a new perspective to its etiology.

A first step towards the understanding of the 5-HT3 receptor subunit heterogeneity from a computational point of view.

The functional serotonin type-3 receptor (5-HT(3)-R), which is the target of many neuroactive drugs, is known to be a homopentamer made of five identical subunits A (5-HT(3A)-R) or a binary heteropentamer made of subunits A and B (5-HT(3A/B)-R) with a still debated arrangement and stoichiometry. This complex picture has been recently further complicated by the discovery of additional 5-HT(3)-R subunits, C, D, and E, which, similarly to the B subunit, are apparently able to form functional receptors only if co-expressed with subunit A. Being the binding site for both serotonin and antagonists (i.e. drugs) located at the extracellular interface between two adjacent subunits, the large variability of the 5-HT(3)-R composition becomes a crucial issue, since it can originate many different interfaces providing non-equivalent ligand binding sites and complicating the pharmacological modulation. Here, the different 5-HT(3)-R interfaces are analysed, on the bases of the structural conformations of previously built 3D homology models and of the known subunit sequences, by addressing their physicochemical characterization. The results confirm the presence of an aromatic cluster located in the core of the A-A interface as a key determinant for having an interface both stable and functional. This is used as a discriminant to make hypotheses about the capability of all the other possible interfaces constituted by the known 5-HT(3)-R sequences A, B, C, D, and E to build active receptors.

The extracellular subunit interface of the 5-HT3 receptors: a computational alanine scanning mutagenesis study.

The functional serotonin 5-HT type-3 (5-HT(3)) receptor, the target of many neuroactive drugs, is known to be a pseudo-symmetric pentamer made either of five identical subunits A (homomeric 5-HT(3A)-R) or of subunits A and B (heteromeric 5-HT(3A/B)-R) in a still debated arrangement. The serotonin binding site is located in the extracellular region, at the interface between two monomers, called the principal and the complementary subunits. The results of molecular dynamics simulations and computational alanine scanning mutagenesis studies applied here to the homomeric human 5-HT(3A)-R disclose an aromatic "hot" cluster in the centre of the interface formed by residues W178 (principal subunit), Y68, Y83, W85 and Y148 (complementary subunit). Moreover, investigation of the coupling of agonist/antagonist binding to channel activation/inactivation points out the presence of two putative functional pathways at the subunit interface: W116-H180-L179-W178-E124-F125 (principal subunit) and Y136-Y138-Y148-W85-(P150) (complementary subunit), where W178 and Y148 appear to be critical residues for the binding/activation mechanism. Finally, direct comparison of the main features shown by the AA interface in the human 5-HT(3A)-R with those of the BB interface in the homopentameric human 5-HT(3B)-R provides interesting clues about the possible reasons that cause the 5-HT(3B)-R not to be functional.

Computational Insights into ADAMTS4, ADAMTS5 and MMP13 Inhibitor Selectivity.

The results obtained by means of Molecular Dynamics simulations and Multiway Explorative Data Analysis on ADAMTS4, ADAMTS5 and MMP13 complexed with Marimastat and two cis-1(S)2(R)-amino-2-indanol ligands suggest that determinant characteristics for ligand binding and selectivity among the three enzymes are to be found in the different protein conformation flexibility. Moreover, the role of the TS-domain in the inhibitor binding to ADAMTS enzymes has been investigated for the first time in this work. The results obtained suggest that the influence of the TS-domain on the S1' loop fluctuations of ADAMTS4 and ADAMTS5 could be exploited for the design of therapeutics for chronic osteoarthritis diseases.

Bivalent Ligands for the Serotonin 5-HT3 Receptor.

The serotonin 5-HT3 receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, can be considered to be an intriguing example of intrinsically multivalent biological receptors. This paper describes a general design approach to the study of multivalency in this multimeric ion channel. Bivalent ligands for 5-HT3 receptor have been designed by linking an arylpiperazine moiety to probes showing different functional features. Both homobivalent and heterobivalent ligands have shown 5-HT3 receptor affinity in the nanomolar range, providing evidence for the viability of our design approach. Moreover, the high affinity shown by homobivalent ligands suggests that bivalency is a promising approach in 5-HT3 receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 receptor function.

Computational analysis of ligand recognition sites of homo- and heteropentameric 5-HT3 receptors.

Inhibition of the 5-hydroxytryptamine receptor (5-HT(3)R), a member of the Cys-loop superfamily of Ligand-Gated Ion Channels (LGICs), has been recognized to have important antiemetic effects. With respect to the many other drugs already in use, such as the first generation 5-HT(3)R antagonist granisetron, palonosetron, a second generation antagonist, clearly demonstrates superior inhibition potency towards the 5-HT(3)Rs. Five different receptor monomers, the 5-HT(3)R A-E, have been identified although the A and B subunits are the only known to build functional receptors, the homopentameric 5-HT(3A)R and the heteropentameric 5-HT(3B-A)R (with BBABA subunit arrangement). At present, however, no three-dimensional structure has been reported for any of the 5-HT(3)R subunits. To understand the binding properties of agonists and antagonists, models of the extracellular portion of the 5-HT(3)R A and B subunits are built and assembled into the receptor (homo- and hetero-) pentameric structure on the basis of the known three-dimensional structure of the nicotinic-acetylcholine receptor (nACh-R). The results of docking studies of the natural agonist serotonin and the antagonists palonosetron and granisetron into the modelled homomeric and heteromeric 5-HT(3)R binding interfaces, provide a possible rationalization both of the higher potency of palonosetron with respect to other antagonists, and of its previously reported allosteric binding and positive cooperativity properties.

Insights into MAPK p38alpha DFG flip mechanism by accelerated molecular dynamics.

The DFG motif at the beginning of the activation loop of the MAPK p38alpha undergoes a local structural reorganization upon binding of allosteric type-II and type-III inhibitors, which causes the residue F169 to move from a buried conformation (defined as DFG-in) to a solvent exposed conformation (defined as DFG-out). Although both experimental and computer simulation studies had been performed with the aim of unveiling the details of the DFG-in to DFG-out transition, the molecular mechanism is still far from being unequivocally depicted. Here, the accelerated molecular dynamics (AMD) technique has been applied to model the active loop flexibility of p38alpha and sample special protein conformations which can be accessible only in some conditions or time periods. Starting from the assumption of an experimentally known initial and final state of the protein, the study allowed the description of the interaction network and the structural intermediates which lead the protein to change its loop conformation and active site accessibility. Besides a few important hydrogen bond interactions, a primary role seems to be played by cation-pi interactions, involving the DFG-loop residue F(169), which participate in the stabilization of an intermediate conformation and in its consequent transition to the DFG-out conformation. From this study, insights which may prove useful for inhibitor design and/or site directed mutagenesis studies are derived.

Disruption of the H-bond network in the main access channel of catalase-peroxidase modulates enthalpy and entropy of Fe(III) reduction.

Catalase-peroxidases are the only heme peroxidases with substantial hydrogen peroxide dismutation activity. In order to understand the role of the redox chemistry in their bifunctional activity, catalatically-active and inactive mutant proteins have been probed in spectroelectrochemical experiments. In detail, wild-type KatG from Synechocystis has been compared with variants with (i) disrupted KatG-typical adduct (Trp122-Tyr249-Met275), (ii) mutation of the catalytic distal His123-Arg119 pair, and (iii) altered accessibility to the heme cavity (Asp152, Ser335) and modified charge at the substrate channel entrance (Glu253). A valuable insight into the mechanism of reduction potential (E degrees ') modulation in KatG has been obtained from the parameterization of the corresponding enthalpic and entropic components, determined from the analysis of the temperature dependence of E degrees '. Moreover, model structures of ferric and ferrous Synechocystis KatG have been computed and used as reference to analyze and discuss the experimental data. The results, discussed by reference to published resonance Raman data on the strength of the proximal iron-imidazole bond and catalytic properties, demonstrate that E degrees ' of the Fe(III)/Fe(II) couple is not strongly correlated with the bifunctional activity. Besides the importance of an intact Trp-Tyr-Met adduct, it is the architecture of the long and constricted main channel that distinguishes KatGs from monofunctional peroxidases. An ordered matrix of oriented water dipoles is important for H(2)O(2) oxidation. Its disruption results in modification of enthalpic and entropic contributions to E degrees ' that reflect reduction-induced changes in polarity, electrostatics, continuity and accessibility of solvent to the metal center as well as alterations in solvent reorganization.

Protein-surface interactions: challenging experiments and computations.

Protein-surface interactions are fundamental in natural processes, and have great potential for applications ranging from nanotechnology to medicine. A recent workshop highlighted the current achievements and the main challenges in the field.

Ghrelin levels are reduced in prepubertal epileptic children under treatment with carbamazepine or valproic acid.

A relationship between ghrelin and epilepsy has been already shown in humans, although the results are controversial. Ghrelin levels are reduced in obesity. Epileptic patients progressively develop a therapy-linked weight gain; however, the mechanisms for this have not been fully explained. The aim of our study is to evaluate if ghrelin secretion is modulated by treatment with carbamazepine or valproic acid in young prepubertal epileptic children. Ghrelin levels were reduced in normal-weight young epileptic prepubertal children under treatment with carbamazepine (p < 0.0001) or valproic acid (p < 0.006) compared to healthy age- and weight-matched subjects. Ghrelin was also lower in children under carbamazepine when compared to those under valproic acid (p < 0.01). A derangement in ghrelin secretion in epilepsy during specific pharmacologic therapies and independent of weight gain could be hypothesized.