Putting Photomechanical Switches to Work: An Ab Initio Multiple Spawning Study of Donor-Acceptor Stenhouse Adducts.

Photomechanical switches are light sensitive molecules capable of transducing the energy of a photon into mechanical work via photodynamics. In this Letter, we present the first atomistic investigation of the photodynamics of a novel class of photochromes called donor-acceptor Stenhouse adducts (DASA) using state-of-the-art ab initio multiple spawning interfaced with state-averaged complete active-space self-consistent field theory. Understanding the Z/E photoisomerization mechanism in DASAs at the molecular level is crucial in designing new derivatives with improved photoswitching capabilities. Our dynamics simulations show that the actinic step consists of competing nonradiative relaxation pathways that collectively contribute to DASAs' low (21% in toluene) photoisomerization quantum yield. Furthermore, we highlight the important role the intramolecular hydrogen bond plays in the selectivity of photoisomerization in DASAs, identifying it as a possible structural element to tune DASA properties. Our fully ab initio simulations reveal the key degrees of freedom involved in the actinic step, paving the way for the rational design of new generations of DASAs with improved quantum yield and efficiency.

Primary headache in childhood associated with psychiatric disturbances: an update.

OBJECTIVE: Primary headache disorders in children are one of the most prominent topics in the pediatric neurology literature. However, there are many unsolved aspects, including the conditions associated with migraine. The present study aims to report on the frequency of behavioral comorbidities in the setting of primary headache in childhood. PATIENTS AND METHODS: In this study, we enlisted 475 children (290 males and 185 females; ratio 1.6:1), aged 4 to 14 years, who were affected by primary headache. In direct interviews, children and parents gave information on the association of their headache with, attention-deficit/hyperactivity disorder, learning disabilities, tics, anxiety, depression, and obsessive-compulsive disorder. Other 475 children with no history of headache or recognized neurological conditions were matched for age, sex, race, and socioeconomic status and were used as controls. RESULTS: A significant association of primary headache was found with anxiety and depression (p-value <0.001); overall, behavioral disorders were more common in children who experienced headache than in controls (p-value <0.001). CONCLUSIONS: Primary headache in children is not associated with most of the common behavioral conditions. On the contrary, there was a significant association with anxiety and depression, as reported in adults.

Elevated serum ALT in children presenting to the emergency unit: Relationship with NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease, ranging from hepatic steatosis to necro-inflammation with or without fibrosis (non-alcoholic steatohepatitis), is a growing clinical liver disorder in children. AIM: The goals of this study were to characterize liver disorders associated with elevated aminotransferases and establish the non-alcoholic fatty liver disease/non-alcoholic steatohepatitis prevalence in hypertransaminasemic children admitted to the emergency room. METHODS: The medical records of 3280 children (2-17 years of age) admitted to the emergency room of Bambino Gesù Children's Hospital of Rome, and presenting with hypertransaminasemia were analysed retrospectively. RESULTS: Elevation of serum alanine aminotransferases was present in 897 patients. Of these, 520 (58%) spontaneously normalized alanine aminotransferases, and 179/897 (20%) maintained persistently elevated alanine aminotransferases levels. Twenty-one patients were excluded because of medication or alcohol use. In the remaining 157 patients with elevated alanine aminotransferases, obesity was found in 87 (55%), viral infections in 52 (33%) and genetic diseases in 14 (9%). Obesity-related alanine aminotransferases elevation was associated with a histological diagnosis of non-alcoholic fatty liver disease in 85% of patients. In particular, steatosis was histologically confirmed in 74 patients; 43/74 (58%) had steatohepatitis, and 12/74 (16%) had fibrosis. CONCLUSIONS: Twenty percent of children with elevated aminotransferases on routine testing may hide non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. A careful diagnostic workup of persistent hypertransaminasemia in all obese subjects is warranted in the paediatric setting.

Evaluación no invasiva del status volémico. Confrontación entre indicadores radiográficos y volumétricos / Not invasive evaluation of the status volémico. Confrontation between warning radiográficos and volumetric

La finalidad de nuestro estudio ha sido la de evaluar la existencia de posibles correlaciones entre los principales indicadores volumétricos de carga previa y de función cardiaca, obtenida mediante el sistema PiCCO® (Pulsion Medical Systems, Munich, Alemania), con todos los datos derivados del análisis sistemático de la radiografía de tórax en proyección antero posterior, así como el pedúnculo vascular (VPW) y el índice cardiotorácico (RCT). Materiales y Métodos: Hemos incluido 15 pacientes y analizado conjuntamente 79 radiografías de pacientes electivos. Todos fueron sometidos a monitorización hemodinámica mediante PiCCO y al estudio de los parámetros radiográficos obtenidos (VPW, RCT). El análisis: cálculo de la media y desviación estándar; un análisis de la correlación para las siguientes parejas de parámetros: volumen de sangre intratorácica (ITBVI)-RCT, ITBVI-VPW, agua extravascular (EVLWI )-RCT, EVLWI-VPW . Resultados. Las parejas de los valores estudiados han evidenciado una correlación linear con R igual a 0.54 entre EVLWI-RCT. Discusión. Aunque es un estudio preliminar, los hallazgos más significativos se ven en las variaciones de RCT, que presentan una correspondencia con el edema intersticial antes de que aparezca un incremento crítico de la rata de líquido alveolar. En nuestra experiencia no hemos evidenciado una fuerte correlación entre VPW y los normales indicadores volumétricos de precarga. De acuerdo con los datos en literatura y también en la experiencia pediátrica, estos instrumentos presentan límites que aún no consienten sustituir completamente a la correcta cuantificación de la rata de agua extravascular, en respuesta al incremento volémico. Palabras Claves: Monitorización Hemodinámica, Monitor de PiCCO, Volemia, pedúnculo vascular, índice cardiotorácico, Volumen de sangre intratorácica, Volumen de agua extravascular intrapulmonar, Índice de función cardiaca...

Monitoring of intrathoracic volemia and cardiac output in critically ill children.

AIM: Hemodynamic monitoring is an important step in the management of critically ill children despite the difficulty in measuring preload indices continuously. The aim of the study was to analyze cardiac output parameters and preload indices after acute changes in mean airway pressure and volemia. METHODS: Twenty-three children treated at our unit were enrolled in a prospective non randomized cohort study. Respiration was supported by controlled mechanical ventilation with positive expiratory-end pressure (PEEP), peak inspiratory pressure <20 cm H(2)O and mean airway pressure <10 cm H(2)O, and hemodynamic monitoring using the PiCCO system. Hemodynamic parameters were measured at T0 (base line), T(1) (after an increase in PEEP of 5 cm H(2)O for 10 min), and T(2) (after fluid challenge). The statistical analysis (BMPD New System software package) comprised comparison of changes at T(0) vs T(1), T(1) vs T(2) and T(0) vs T(2), construction of 3 correlation matrices and multiple linear regression analysis. RESULTS: Sixty-nine hemodynamic parameters were measured in the 23 patients. A comparison between T(0) and T(1) showed no significant changes; differences between T(0) and T(2) were found for cardiac index (CI), (p=0.003); between T(0) and T(2) significant differences were found for CI (p=0.0015), intrathoracic blood volume index (ITBVI) (p=0.04) and stroke volume index (SVI) (p=0.06). The analysis of the correlation matrices yielded ITBVI with CI (p=0.0006), ITBVI with SVI (p=1 x 10(-5)), CI with SVI (p=0.002); a significant correlation between CI and extravascular lung water index (EVLWI) was found only at T(1). Multiple linear regression analysis showed that ITBVI and SVI were predictive for variance of CI at each time point. CONCLUSION: ITBVI measured by a volumetric monitoring system such as the PiCCO may be considered a sensitive preload indicator also in critically ill children.

Functional neuroradiologic investigations in band heterotopia.

Band heterotopias are an example of genetic generalized neuronal migration disorders that may be present in patients with mild epilepsy and normal or slightly impaired intellect, as well as in patients with intractable epilepsy and mental retardation. The case of a 17-year-old left-handed female patient with epilepsy and normal cognitive development is reported in whom single-photon emission computed tomography (SPECT), proton magnetic resonance spectroscopy, and functional magnetic resonance imaging (fMRI) were performed. MRI revealed the presence of bilateral asymmetric band heterotopia. SPECT revealed a left frontoparietal and occipital hypoperfusion, demonstrating a good correlation with the electroencephalogram abnormalities. Because of the appearance of new types of seizures, the patient underwent a second MRI investigation together with a proton magnetic resonance spectroscopy (MRS) study. MRI confirmed bilateral band heterotopia characterized by greater thickness in the left hemisphere at the frontal and occipital level. MRI and SPECT findings were in agreement with left occipital electroencephalogram abnormalities and with occipital seizure type. Qualitative results of proton MRS revealed normal spectra profiles in the examined left frontal and occipital heterotopic area and in the normal overlying cortex. Later, fMRI was performed. The finger-tapping test of the right hand yielded the activation of both normal left sensory-motor cortex and the facing band heterotopia. In the right hemisphere, only the activation of the sensory-motor neocortex was observed; no involvement of the right misplaced brain tissue was present. This functional behavior could be considered the consequence of poor neuronal representation. On the contrary, the involvement of both band heterotopia and normal cortex observed in the left hemisphere could be the result of many synaptic interconnections. Functional investigations may have an important role in defining the activity of band heterotopia per se and in relation to the overlying neocortex.

Visual field constriction in children with epilepsy on vigabatrin treatment.

Vigabatrin is considered the drug of choice for infantile spasms and simple and complex partial epilepsy in childhood. Its mechanism of action relies on the irreversible inhibition of gamma-aminobutyric acid (GABA) transaminase. Since June 1997 several articles have been published reporting visual field constriction in adult patients on vigabatrin therapy. Recently, 7 pediatric patients, 1 on vigabatrin monotherapy and 6 on add-on therapy with visual field constriction have been described. We have observed 30 pediatric patients with epilepsy (14 boys and 16 girls), ages ranging from 4 to 20 years (mean: 11 years and 2 months) treated with vigabatrin for infantile spasms, simple and complex partial epilepsy, who had never complained of ophthalmologic disturbances. Twenty-one patients underwent complete routine ophthalmologic examination (fundus oculi, visual acuity, intraocular pressure, and visual field tests); 9 children (<6 years old) underwent only fundus examination, because collaboration was lacking. We report on 4 children showing constriction of visual field, prevailing in nasal hemifield. In 1 child, visual abnormalities were stable even 10 months after vigabatrin discontinuation, while in another a greater improvement was observed 5 months after discontinuation. The possible mechanisms have been discussed and the cone dysfunction, connected with GABA augmentation in the outer retina, has been outlined. We suggest a possible protocol to control visual abnormalities in epileptic children.

Lamotrigine hypersensitivity in childhood epilepsy.

PURPOSE: To evaluate the effect of lamotrigine (LTG) on several humoral and cellular immune functions in children with epilepsy and the change in immunological status in patients with LTG-induced rash. METHODS: Sixteen children with epilepsy of unknown origin or secondary to various etiologies undergoing treatment with LTG participated in the humoral and cellular immunological study. Of these, 2 patients developed a rash during LTG treatment and are described in detail. RESULTS: No modifications of humoral or cellular immunity (measured at 1 and 3 months) were noted in 14 of the 16 patients during this treatment. In the 2 children who manifested rash, basal immune function was normal. In both, immediately after the skin rash appeared, there was a high increase in the percentage of activated T-helper lymphocytes (CD4-DR) and activated T-suppressor lymphocytes (CD8-DR), a slight increase in percentage of B lymphocytes (CD19), and a greater increase in serum concentration of IgE. In 1 of the 2 patients, reevaluation of immunity 20 days after the rash appeared and after LTG suspension showed normal percentages of CD4-DR, CD8-DR, and CD19, whereas the serum concentration of IgE had decreased. CONCLUSIONS: The observed immunological results indicate that LTG-induced rash may be considered an immune-mediated hypersensitivity reaction.

Gelastic epilepsy: video-EEG, MRI and SPECT characteristics.

Gelastic epilepsy, or ictal laughter, is a relatively uncommon type of seizure which may occur singly or, more frequently, with other types of convulsions. Gelastic seizures have been observed to be associated with many different conditions, mainly hypothalamic hamartomas. We report on a patient whose ictal laughter was the only neurologic disturbance. Ictal video-EEG demonstrated seizure arising from the left frontal region with subsequent involvement of the contralateral homologous area and secondary generalization. MRI showed an enlarged left frontal horn of the lateral ventricle. Postictal SPECT, performed 6 min after the seizure had ended, showed hypoperfusion in the bilateral frontoparietal region and in both cerebellar hemispheres; the presence of this abnormality may be due to the spreading of the cortical epileptogenic focus and to the complex intercommunication between the frontal cortex and the cerebellar hemispheres. Interictal SPECT, in accordance with MRI features, demonstrated a left frontoparietal hypoperfusion. The neurofunctional features observed in the reported child could suggest that gelastic epilepsy originates in the frontal cortex. However, further studies are undoubtedly needed to define the pathogenetic mechanisms of ictal laughter.

Primary CNS demyelinating diseases in childhood: multiple sclerosis.

We report on five children (three female and two male, age span 11-16 years) with laboratory-supported definite multiple sclerosis or clinically definite multiple sclerosis, diagnosed on the basis of Poser and Paty criteria. All patients were subjected to serial clinical examinations, magnetic resonance investigations, CSF biochemical and immunological studies, and neurophysiological and neuropsychological assessments. Four of the five examined subjects underwent steroid treatment. Over a period of 3 years relapses have been observed in three of them. The first symptoms and signs of multiple sclerosis may be subtle and misleading; careful assessment of them may be crucial for an early diagnosis of the disease.

Myoclonic epilepsy, neuroblast migration disorders, and maternally derived partial duplication 14q/deletion 15q.

A large maternally inherited duplication of 14q and deletion of proximal 15q was observed in a child with myoclonic epilepsy, mental retardation and neuroblast migration disorders (NMDs) detected by MRI. Genetic syndromes associated with NMDs have previously been described. In additional our observations support the connection between major chromosomal imbalances, developmental brain disorders and epilepsy. Thus, in patients with these combinations of symptoms, careful chromosome investigations are recommended.

Clonazepam prophylaxis and busulfan-related myoclonic epilepsy in autografted acute leukemia patients.

A prospective neurological and electroencephalographic (EEG) study was performed in sixteen leukemia patients receiving busulfan (BU) and cyclophosphamide before autologous bone marrow transplantation. All patients were given anticonvulsant prophylaxis with a combination of phenobarbital (PB) and clonazepam (CLZ). Neurological examination and EEG were performed prior to and soon after completion of BU treatment and were repeated two months later. No tonic-clonic and/or myoclonic convulsions were observed. In two patients, comparison of EEG recorded before and upon completion of BU administration revealed modification of features. EEG re-evaluated two months after BU showed normalization in one of the two patients. BU may trigger both generalized and myoclonic seizures together with EEG abnormalities; PB combined with CLZ may be useful prophylactic treatment.

Immunologic aspects of vigabatrin treatment in epileptic children.

Vigabatrin (VGB) is an antiepileptic drug (AED) that acts by irreversibly inhibiting gamma-aminobutyric acid transaminase (GABA-T). To evaluate immune responses to GVG, we studied 29 idiopathic or symptomatic epileptic children and also examined a control group (n = 15). Epileptic children were tested before and after 1 and 3 months of VGB treatment. Whole blood was used to connect subsets with commercial monoclonal antibodies. Peripheral blood mononuclear cells (PBMC) were used to assess natural killer (NK) cell activity and lymphocyte response to phytohemagglutinin (PHA) and concavalin A (Con A). Immunoglobulin (Ig) levels were tested in serum. At baseline, no immunologic abnormalities were observed in either control or treated patients. During treatment, the percentage and absolute number of B lymphocytes, serum concentration of Ig, number of T total mature lymphocytes (CD3), T-rosetting lymphocytes (CD11), T-helper cells (CD4), and mitogenic response of lymphocytes remained unchanged. Several other immunologic responses showed a statistically significant increase after 1 and 3 months of VGB treatment, however, including the percentage and absolute number of T-suppressor cells (CD8) and NK cells and NK cell activity. The correlation between number of NK cells and NK cell activity was significant. Data obtained demonstrated that VGB may interfere with the modulation of the immune system, especially cytotoxic cell populations.

[New drugs in the treatment of childhood epilepsy: vigabatrin (study of 61 subjects)]. / Nuovi farmaci nella terapia dell'epilessia dell'infanzia: vigabatrin (studio di 61 soggetti).

This study was conducted to determine the efficacy of vigabatrin in children with epilepsy. Sixty-one children with various types of severe epilepsy were studied. In 12 children vigabatrin was introduced as monotherapy, while in 49 it was added to other antiepileptic drugs. Following the introduction of vigabatrin, 17 patients became seizure free, and 19 responded with a greater than 50% reduction in seizure frequency. The following types of epilepsy responded favorably to treatment (in order of decreasing efficacy): West syndrome, especially if secondary to Tuberous Sclerosis; cryptogenic and symptomatic partial epilepsy; Lennox-Gastaut syndrome, and other symptomatic generalized epilepsy. Optimal responses were found with vigabatrin doses of 30 to 50 mg/kg/day. Forty-one responders continued on vigabatrin, with generally good efficacy. Vigabatrin tolerability was good; in only 6 children was treatment discontinued because of side-effects such as somnolence, irritability, weight gain, and cutaneous rash. This study shows that vigabatrin is effective in the treatment of refractory epilepsy, especially in West syndrome secondary to Tuberous Sclerosis, partial epilepsy, and Lennox-Gastaut syndrome. Further studies are needed to analyze the increased frequency of seizures and the appearance of new seizure types associated with vigabatrin treatment.

Benign epilepsy of childhood with centrotemporal spikes and unilateral developmental opercular dysplasia.

The case of a 15-year-old right-handed girl with developmental delay, mild retardation, astereognosis, and tactile discrimination impairment in the left arm, is reported. During sleep, right partial simple motor seizures with sialorrhea and saliva pooling were present, sometimes followed by secondary generalization. Absences and drop attacks were also observed. Electroencephalography revealed left centrotemporal spike waves spreading to the homologous contralateral region, generalized 3-Hz spike-and-wave complexes enhanced by hyperventilation, and generalized polyspike-and-wave discharges during drowsiness. Magnetic resonance imaging showed right perisylvian (opercular) malformation. Benign epilepsy of childhood with centrotemporal spikes (BECCTS) is a focal idiopathic epilepsy presumed to be of genetic origin. Although brain damage is not expected, structural lesions including opercular macrogyria have been reported. This coexistence has been considered mainly causal and only exceptionally causal. The Foix-Chavany-Marie syndrome or operculum syndrome is the result of bilateral opercular damage. In our child the right structural and the left functional lesions appeared mutually activated, yielding a transient opercular syndrome. The concomitance of BECCTS and developmental opercular dysplasia is suggestive of a common genetic substratum.

Neuronal migrational disorders: diffuse cortical dysplasia or the "double cortex" syndrome.

We report a 10-year-old girl who presented with a single episode of partial complex seizure. Neurological examination and psychological evaluation were normal. Electroencephalogram showed abnormalities in the left temporo-occipital region. Magnetic resonance imaging revealed a bilateral layer of tissue iso-intense with gray matter, between the wall of the lateral ventricle and the cortex, extending from the frontal to the occipital region, and enlarged left lateral ventricle. The images indicated diffuse cortical dysplasia, also known as band heterotopia or "double cortex", and left cortical hemiatrophy.

Gelastic epilepsy. A clinical contribution.

Gelastic (laughing) epilepsy, relatively uncommon, is usually associated with hypothalamic hamartomas, pituitary tumors, astrocytomas of the mammillary bodies, and dysraphic conditions. Cases of unknown etiology are rare. In three of the four cases reported here, the diagnoses were hamartoma of the tuber cinereum; lobar holoprosencephaly; and lissencephaly type I, grade 2. In the fourth, radiographic investigation gave a normal result; a genetic etiology was suggested because of bilateral familial idiopathic epilepsy. In all patients, EEGs showed both focal spikes and generalized spike-and-wave discharges. The primary underlying neurophysiologic disorder may be provoked by the diffuse hyperexcitability of the cortex and subsequent firing of the thalamocortical networks with which the cortical brain is reciprocally interlinked.

Pretransplant conditioning with busulfan and cyclophosphamide in acute leukemia patients: neurological and electroencephalographic prospective study.

A neurological and electroencephalographic (EEG) prospective study was performed in 34 leukemic patients receiving busulfan (BU) plus cyclophosphamide (CY) before bone marrow autologous transplant. During BU treatment and briefly thereafter, all patients were given anticonvulsant prophylaxis with phenobarbital. Neurological evaluations were performed daily and EEGs, recorded one week before and soon after the end of the BU regimen, were re-evaluated two months later. Basal EEGs were normal in 23 of the 34 patients, focal abnormalities were detected in 9 cases, and generalized epileptic discharges were present in one (one subject was not studied). EEGs performed at the end of BU administration showed generalized spike/polyspike-and-wave discharges in 21 of the 34 patients, with associated myoclonic epilepsy in 10 subjects appearing on the 3rd or 4th day of treatment. Focal abnormalities were present in 6 patients and constant EEG normality in 7. It is known that myoclonic epilepsy can be induced by drugs. Oral administration of high-dose BU is followed by a high-dose cerebrospinal fluid concentration of the drug. Therefore, myoclonic epilepsy and/or paroxysmal epileptiform EEG discharges may be observed in leukemic patients undergoing high-dose BU therapy.