De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

Somatosensory evoked potential monitoring of peripheral nerves during external fixation for limb lengthening and correction of deformity in children.

We undertook a retrospective analysis of 306 procedures on 233 patients, with a mean age of 12 years (1 to 21), in order to evaluate the use of somatosensory evoked potential (SSEP) monitoring for the early detection of nerve compromise during external fixation procedures for limb lengthening and correction of deformity. Significant SSEP changes were identified during 58 procedures (19%). In 32 instances (10.5%) the changes were transient, and resolved once the surgical cause had been removed. The remaining 26 (8.5%) were analysed in two groups, depending on whether or not corrective action had been performed in response to critical changes in the SSEP recordings. In 16 cases in which no corrective action was taken, 13 (81.2%, 4.2% overall) developed a post-operative neurological deficit, six of which were permanent and seven temporary, persisting for five to 18 months. In the ten procedures in which corrective action was taken, four patients (40%, 1.3% overall) had a temporary (one to eight months) post-operative neuropathy and six had no deficit. After appropriate intervention in response to SSEP changes, the incidence and severity of neurological deficits were significantly reduced, with no cases of permanent neuropathy. SSEP monitoring showed 100% sensitivity and 91% specificity for the detection of nerve injury during external fixation. It is an excellent diagnostic technique for identifying nerve lesions when they are still highly reversible.

The nature of cationic adsorption sites in alkaline zeolites--single, dual and multiple cation sites.

Gas adsorption on zeolites constitutes the base of many technological applications of these versatile porous materials. Quite often, especially when dealing with small molecules, individual extra-framework (exchangeable) cations are considered to be the adsorption site on which molecules coming from a gas phase form the corresponding adsorption complex. Nonetheless, while that can be the case in some instances, recent research work that combines variable temperature infrared spectroscopy with periodic DFT calculations showed that some types of adsorption sites involve two or more cations, which constitute dual and multiple cation sites, respectively. Adsorption complexes formed on these cationic adsorption sites differ in both structure and stability from those formed on a single cation alone. Examples concerning CO, CO(2) and H(2) adsorption on alkali and alkaline-earth metal exchanged zeolites are reviewed, with the double purpose of clarifying concepts and highlighting their relevance to practical use of zeolites in such fields as gas separation and purification, gas storage and heterogeneous catalysis.

Trastorno de la imagen corporal en pacientesportadores de derivaciones urinarias / No disponible

A pesar de los avances en cirugía urológica que mejoran la salud física y psicológica de los pacientes, sigue habiendo pacientes con derivacionesurinarias heterotópicas no continentes que, además del problema físico que les reporta la intervención quirúrgica, tienen quereajustar su imagen mental que tienen de sí mismos.Se plantea como objetivo exponer los cuidados que presta el personal de enfermería para potenciar la imagen corporal del paciente.Se realizó estudio descriptivo transversal sobre la percepción de la imagen corporal de un total de 43 pacientes. Para estudio se utilizóla escala de Goldberg ansiedad-depresión relacionándolo con la imagen corporal.Con este estudio se pretende concienciar al personal de enfermería sobre la importancia del abordaje de la imagen corporal (AU)

In spite of the progress in urological surgery that improve both physical and psychological patients health, there keeps being patients withnon continent heterotopic urinary derivations that besides the physical problem that brings their the operation, they have to readjust theirmental self-image that they have about themselves.Exposing cares that nursing staff lends to promote the body image of the patient is suggested as goal.Transversal descriptive study on the perception of body image of a total of 43 patients was carried out. For the study, Goldberg scale ofanxiety was used - depression relating with body image. With this study it is intended to make nursing staff aware on the importance ofthe dealing with body image (AU)

Peripheral nerve repair through multi-luminal biosynthetic implants.

Peripheral nerve damage is routinely repaired by autogenic nerve grafting, often leading to less than optimal functional recovery at the expense of healthy donor nerves. Alternative repair strategies use tubular scaffolds to guide the regeneration of damaged nerves, but despite the progress made on improved structural materials for the nerve tubes, functional recovery remains incomplete. We developed a biosynthetic nerve implant (BNI) consisting of a hydrogel-based transparent multichannel scaffold with luminar collagen matrix as a 3-D substrate for nerve repair. Using a rat sciatic nerve injury model we showed axonal regeneration through the BNI to be histologically comparable to the autologous nerve repair. At 10 weeks post-injury, nerve defects repaired with collagen-filled, single lumen tubes formed single nerve cables, while animals that received the multi-luminal BNIs showed multiple nerve cables and the formation of a perineurial-like layer within the available microchannels. Total numbers of myelinated and unmyelinated axons in the BNI were increased 3-fold and 30%, respectively, compared to collagen tubes. The recovery of reflexive movement confirmed the functional regeneration of both motor and sensory neurons. This study supports the use of multi-luminal BNIs as a viable alternative to autografts in the repair of nerve gap injuries.

Practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.

OBJECTIVE: To evaluate published evidence of efficacy and safety of pharmacologic treatments for childhood spasticity due to cerebral palsy. METHODS: A multidisciplinary panel systematically reviewed relevant literature from 1966 to July 2008. RESULTS: For localized/segmental spasticity, botulinum toxin type A is established as an effective treatment to reduce spasticity in the upper and lower extremities. There is conflicting evidence regarding functional improvement. Botulinum toxin type A was found to be generally safe in children with cerebral palsy; however, the Food and Drug Administration is presently investigating isolated cases of generalized weakness resulting in poor outcomes. No studies that met criteria are available on the use of phenol, alcohol, or botulinum toxin type B injections. For generalized spasticity, diazepam is probably effective in reducing spasticity, but there are insufficient data on its effect on motor function and its side-effect profile. Tizanidine is possibly effective, but there are insufficient data on its effect on function and its side-effect profile. There were insufficient data on the use of dantrolene, oral baclofen, and intrathecal baclofen, and toxicity was frequently reported. RECOMMENDATIONS: For localized/segmental spasticity that warrants treatment, botulinum toxin type A should be offered as an effective and generally safe treatment (Level A). There are insufficient data to support or refute the use of phenol, alcohol, or botulinum toxin type B (Level U). For generalized spasticity that warrants treatment, diazepam should be considered for short-term treatment, with caution regarding toxicity (Level B), and tizanidine may be considered (Level C). There are insufficient data to support or refute use of dantrolene, oral baclofen, or continuous intrathecal baclofen (Level U).

TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype.

Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-ß signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1-2% of patients with non-syndromic, non-chromosomal HPE. We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (χ(2) ((2)) = 6.97, p(permutated) = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients.

Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function.

BACKGROUND: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. OBJECTIVE: To characterise genetic and clinical findings in patients with SIX3 mutations. METHODS: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. RESULTS: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. CONCLUSIONS: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.

Computational and FTIR spectroscopic studies on carbon monoxide and dinitrogen adsorption on a high-silica H-FER zeolite.

Adsorption (at a low temperature) of carbon monoxide and dinitrogen on a high-silica ferrierite-type zeolite (H-FER, Si : Al = 27.5 : 1) was investigated by means of variable temperature infrared spectroscopy and theoretical calculations at the periodic DFT level. This combined experimental and computational approach led to detailed characterization of several types of hydrogen-bonded OHCO and OHN(2) complexes, formed by interaction between the adsorbed molecules and the Brønsted acid OH groups of the zeolite. CO or N(2), forming linear complexes with OH groups pointing towards a sufficiently ample void space, show the largest adsorption enthalpy which was found to be in the (approximate) range of -25 to -29 kJ mol(-1) for CO and -15 to -19 kJ mol(-1) for N(2). Less stable OHCO or OHN(2) complexes can be formed when either the Brønsted acid OH group is involved in intra-zeolite hydrogen bonding or when the free space available is too small to allow formation of linear complexes without previous re-location of the proton of the OH group involved. The details of experimental IR spectra in the O-H, C-O, and N-N stretching regions could be interpreted on the basis of good agreement between experimental and calculated results.

Extending animal models of fear conditioning to humans.

A goal of fear and anxiety research is to understand how to treat the potentially devastating effects of anxiety disorders in humans. Much of this research utilizes classical fear conditioning, a simple paradigm that has been extensively investigated in animals, helping outline a brain circuitry thought to be responsible for the acquisition, expression and extinction of fear. The findings from non-human animal research have more recently been substantiated and extended in humans, using neuropsychological and neuroimaging methodologies. Research across species concur that the neural correlates of fear conditioning include involvement of the amygdala during all stages of fear learning, and prefrontal areas during the extinction phase. This manuscript reviews how animal models of fear are translated to human behavior, and how some fears are more easily acquired in humans (i.e., social-cultural). Finally, using the knowledge provided by a rich animal literature, we attempt to extend these findings to human models targeted to helping facilitate extinction or abolishment of fears, a trademark of anxiety disorders, by discussing efficacy in modulating the brain circuitry involved in fear conditioning via pharmacological treatments or emotion regulation cognitive strategies.

Fear of losing money? Aversive conditioning with secondary reinforcers.

Money is a secondary reinforcer that acquires its value through social communication and interaction. In everyday human behavior and laboratory studies, money has been shown to influence appetitive or reward learning. It is unclear, however, if money has a similar impact on aversive learning. The goal of this study was to investigate the efficacy of money in aversive learning, comparing it with primary reinforcers that are traditionally used in fear conditioning paradigms. A series of experiments were conducted in which participants initially played a gambling game that led to a monetary gain. They were then presented with an aversive conditioning paradigm, with either shock (primary reinforcer) or loss of money (secondary reinforcer) as the unconditioned stimulus. Skin conductance responses and subjective ratings indicated that potential monetary loss modulated the conditioned response. Depending on the presentation context, the secondary reinforcer was as effective as the primary reinforcer during aversive conditioning. These results suggest that stimuli that acquire reinforcing properties through social communication and interaction, such as money, can effectively influence aversive learning.

Perceptions of moral character modulate the neural systems of reward during the trust game.

Studies of reward learning have implicated the striatum as part of a neural circuit that guides and adjusts future behavior on the basis of reward feedback. Here we investigate whether prior social and moral information about potential trading partners affects this neural circuitry. Participants made risky choices about whether to trust hypothetical trading partners after having read vivid descriptions of life events indicating praiseworthy, neutral or suspect moral character. Despite equivalent reinforcement rates for all partners, participants were persistently more likely to make risky choices with the 'good' partner. As expected from previous studies, activation of the caudate nucleus differentiated between positive and negative feedback, but only for the 'neutral' partner. Notably, it did not do so for the 'good' partner and did so only weakly for the 'bad' partner, suggesting that prior social and moral perceptions can diminish reliance on feedback mechanisms in the neural circuitry of trial-and-error reward learning.

An fMRI study of reward-related probability learning.

The human striatum has been implicated in processing reward-related information. More recently, activity in the striatum, particularly the caudate nucleus, has been observed when a contingency between behavior and reward exists, suggesting a role for the caudate in reinforcement-based learning. Using a gambling paradigm, in which affective feedback (reward and punishment) followed simple, random guesses on a trial by trial basis, we sought to investigate the role of the caudate nucleus as reward-related learning progressed. Participants were instructed to make a guess regarding the value of a presented card (if the value of the card was higher or lower than 5). They were told that five different cues would be presented prior to making a guess, and that each cue indicated the probability that the card would be high or low. The goal was to learn the contingencies and maximize the reward attained. Accuracy, as measured by participant's choices, improved throughout the experiment for cues that strongly predicted reward, while no change was observed for unpredictable cues. Event-related fMRI revealed that activity in the caudate nucleus was more robust during the early phases of learning, irrespective of contingencies, suggesting involvement of this region during the initial stages of trial and error learning. Further, the reward feedback signal in the caudate nucleus for well-learned cues decreased as learning progressed, suggesting an evolving adaptation of reward feedback expectancy as a behavior-outcome contingency becomes more predictable.

Motivation-dependent responses in the human caudate nucleus.

Motivation is a complex process that leads to completion or avoidance of a behavior. Past research strongly implicates the basal ganglia in a circuit integral for the control of motivation. Specifically, the human striatum has been shown to process reward information, differentiating between monetary rewards and punishments in recent neuroimaging experiments. It is unclear, however, how the dorsal striatum, particularly the caudate nucleus, responds to changes in the motivational context of a task. Using an event-related design, where participants were given positive and negative feedback upon guessing the value of an unknown card, we manipulated the motivational context of the task by dividing trials into periods of high incentive (where visual feedback indicated monetary rewards and punishments) and low incentive (where visual feedback indicated only accuracy). We found that activity in the caudate nucleus was strongly influenced by the different incentive periods. The hemodynamic response was characterized by a larger rise at the onset of trials and larger differences between positive and negative feedback during periods of high incentive. These results suggest that changes in motivation are capable of modulating basal ganglia activity, and further support an important role for the caudate nucleus in affective processing.

Dorsal striatum responses to reward and punishment: effects of valence and magnitude manipulations.

The goal of this research was to further our understanding of how the striatum responds to the delivery of affective feedback. Previously, we had found that the striatum showed a pattern of sustained activation after presentation of a monetary reward, in contrast to a decrease in the hemodynamic response after a punishment. In this study, we tested whether the activity of the striatum could be modulated by parametric variations in the amount of financial reward or punishment. We used an event-related fMRI design in which participants received large or small monetary rewards or punishments after performance in a gambling task. A parametric ordering of conditions was observed in the dorsal striatum according to both magnitude and valence. In addition, an early response to the presentation of feedback was observed and replicated in a second experiment with increased temporal resolution. This study further implicates the dorsal striatum as an integral component of a reward circuitry responsible for the control of motivated behavior, serving to code for such feedback properties as valence and magnitude.

Middle interhemispheric variant of holoprosencephaly: a distinct cliniconeuroradiologic subtype.

BACKGROUND: The middle interhemispheric variant (MIH) is a subtype of holoprosencephaly (HPE) in which the posterior frontal and parietal areas lack midline separation, whereas more polar areas of the cerebrum are fully cleaved. While the neuroradiologic features of this subtype have been recently detailed, the clinical features are largely unknown. OBJECTIVE: To present the clinical manifestations of MIH and to compare them with classic subtypes (alobar, semilobar, and lobar) of HPE. METHODS: The authors evaluated 15 patients with MIH in a multicenter study. Neuroimaging and clinical data were collected and correlated. They compared the data with those of 68 patients who had classic HPE. RESULTS: The frequency of endocrinopathy in MIH (0%) was lower compared with the classic subtypes (72%) (p < 0.0001). This correlated with the lack of hypothalamic abnormalities. The percentage of patients with seizures (40%) did not significantly differ from classic HPE. Spasticity was the most common motor abnormality, seen in 86% of MIH patients, similar to other subtypes. The frequency of choreoathetosis in MIH (0%) was lower than that for semilobar HPE (41%) (p < 0.0039). This correlated with the lack of caudate and lentiform nuclei abnormalities. Developmental functions, including mobility, upper-extremity function, and language, of the MIH group were similar to the least severe classic type, lobar HPE. CONCLUSION: MIH is a recognizable variant of HPE with differing clinical prognosis. Similar to the lobar subtype by functional measures, MIH differs from classic HPE by the absence of endocrine dysfunction and choreoathetosis.

Neuroanatomy of holoprosencephaly as predictor of function: beyond the face predicting the brain.

BACKGROUND: Despite advances in neuroimaging and molecular genetics of holoprosencephaly (HPE), the clinical spectrum of HPE has remained inadequately described. OBJECTIVE: To better characterize the clinical features of HPE and identify specific neuroanatomic abnormalities that may be useful predictors of neurodevelopmental function. METHODS: The authors evaluated 68 children with HPE in a multicenter, prospective study. Neuroimaging studies were assessed for the grade of HPE (lobar, semilobar, and alobar), the degree of nonseparation of the deep gray nuclei, and presence of dorsal cyst or cortical malformation. RESULTS: In general, the severity of clinical problems and neurologic dysfunctions correlated with the degree of hemispheric nonseparation (grade of HPE). Nearly three-quarters of the patients had endocrinopathies, with all having at least diabetes insipidus. The severity of endocrine abnormalities correlated with the degree of hypothalamic nonseparation (p = 0.029). Seizures occurred in approximately half of the children with HPE. The presence of cortical malformations was associated with difficult-to-control seizures. The presence and degree of dystonia correlated with the degree of nonseparation of the caudate and lentiform nuclei and the grade of HPE (p < 0.05). Hypotonia correlated with the grade of HPE (p < 0.05). Mobility, upper extremity function, and language correlated with the degree of nonseparation of the caudate, lentiform and thalamic nuclei, and grade of HPE (p < 0.01). CONCLUSIONS: Patients with HPE manifest a wide spectrum of clinical problems and neurologic dysfunction. The nature and severity of many of these problems can be predicted by specific neuroanatomic abnormalities found in HPE.

Use of botulinum toxin type A in pediatric patients with cerebral palsy: a three-center retrospective chart review.

Over the last several years, botulinum toxin type A has gained widespread use for the management of focal spasticity in children with cerebral palsy. To assess the current patterns of botulinum toxin type A use in the clinical setting, the dose, muscles injected, age at injection, and interval between injections of botulinum toxin type A treatments were examined in a retrospective chart review of children with cerebral palsy (N = 270) over a 2-year period at three major treatment centers. The average dose of botulinum toxin type A across the three centers ranged from 7.7 to 10.8 U/kg body weight, and the average total amount of botulinum toxin type A injected at a single visit ranged from 154 to 205 U. The majority of botulinum toxin type A injections were to the muscles to the lower limbs. The average age at first injection was 6.2 years, and the average interval between injections ranged from 134 to 199 days.

Tracking the hemodynamic responses to reward and punishment in the striatum.

Research suggests that the basal ganglia complex is a major component of the neural circuitry that mediates reward-related processing. However, human studies have not yet characterized the response of the basal ganglia to an isolated reward, as has been done in animals. We developed an event-related functional magnetic resonance imaging paradigm to identify brain areas that are activated after presentation of a reward. Subjects guessed whether the value of a card was higher or lower than the number 5, with monetary rewards as an incentive for correct guesses. They received reward, punishment, or neutral feedback on different trials. Regions in the dorsal and ventral striatum were activated by the paradigm, showing differential responses to reward and punishment. Activation was sustained following a reward feedback, but decreased below baseline following a punishment feedback.

Abnormal sudomotor function in the hypomelanotic macules of tuberous sclerosis complex.

To investigate the integrity of sympathetic innervation in the hypomelanotic macules of tuberous sclerosis complex, we studied sudomotor function in nine patients with tuberous sclerosis complex. Postganglionic sudomotor function was assessed using the Silastic imprint test in nine patients with tuberous sclerosis complex who have at least one hypomelanotic macule greater than 2 cm in diameter. Sweating was induced by iontophoresis with 0.5% pilocarpine nitrate and sweat droplets were counted under a microscope using a 1 x 1 cm grid. Silastic imprint testing of an analogous skin area contralateral to the hypomelanotic macule was measured as a control. Sweat volume quantitation using sweat collectors was performed in five of the subjects. The sweat volume collected from the hypomelanotic macule was reduced compared to the control skin in four of the five subjects. Sweat droplet counts from the hypomelanotic macule were significantly reduced in only one of nine subjects. These data suggest that, although there is no difference in the number of functioning sweat glands in most hypomelanotic macules, the sweat glands produce less sweat (ie, decreased sweat volume) than in normal skin. We hypothesize that focal abnormalities of sympathetic innervation might be responsible for the hypomelanotic macules of tuberous sclerosis complex.