Resilience and corpus callosum microstructure in adolescence.

BACKGROUND: Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain's largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents. METHOD: Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. RESULTS: Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. CONCLUSION: High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure.

White-matter microstructure and gray-matter volumes in adolescents with subthreshold bipolar symptoms.

Abnormalities in white-matter (WM) microstructure, as lower fractional anisotropy (FA), have been reported in adolescent-onset bipolar disorder and in youth at familial risk for bipolarity. We sought to determine whether healthy adolescents with subthreshold bipolar symptoms (SBP) would have early WM microstructural alterations and whether those alterations would be associated with differences in gray-matter (GM) volumes. Forty-two adolescents with three core manic symptoms and no psychiatric diagnosis, and 126 adolescents matched by age and sex, with no psychiatric diagnosis or symptoms, were identified after screening the IMAGEN database of 2223 young adolescents recruited from the general population. After image quality control, voxel-wise statistics were performed on the diffusion parameters using tract-based spatial statistics in 25 SBP adolescents and 77 controls, and on GM and WM images using voxel-based morphometry in 30 SBP adolescents and 106 controls. As compared with healthy controls, adolescents with SBP displayed lower FA values in a number of WM tracts, particularly in the corpus callosum, cingulum, bilateral superior and inferior longitudinal fasciculi, uncinate fasciculi and corticospinal tracts. Radial diffusivity was mainly higher in posterior parts of bilateral superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi and right cingulum. As compared with controls, SBP adolescents had lower GM volume in the left anterior cingulate region. This is the first study to investigate WM microstructure and GM morphometric variations in adolescents with SBP. The widespread FA alterations in association and projection tracts, associated with GM changes in regions involved in mood disorders, suggest altered structural connectivity in those adolescents.

Cortical thickness of superior frontal cortex predicts impulsiveness and perceptual reasoning in adolescence.

Impulsiveness is a pivotal personality trait representing a core domain in all major personality inventories. Recently, impulsiveness has been identified as an important modulator of cognitive processing, particularly in tasks that require the processing of large amounts of information. Although brain imaging studies have implicated the prefrontal cortex to be a common underlying representation of impulsiveness and related cognitive functioning, to date a fine-grain and detailed morphometric analysis has not been carried out. On the basis of ahigh-resolution magnetic resonance scans acquired in 1620 healthy adolescents (IMAGEN), the individual cortical thickness (CT) was estimated. Correlations between Cloninger's impulsiveness and CT were studied in an entire cortex analysis. The cluster identified was tested for associations with performance in perceptual reasoning tasks of the Wechsler Intelligence Scale for Children (WISC IV). We observed a significant inverse correlation between trait impulsiveness and CT of the left superior frontal cortex (SFC; Monte Carlo Simulation P<0.01). CT within this cluster correlated with perceptual reasoning scores (Bonferroni corrected) of the WISC IV. On the basis of a large sample of adolescents, we identified an extended area in the SFC as a correlate of impulsiveness, which appears to be in line with the trait character of this prominent personality facet. The association of SFC thickness with perceptual reasoning argues for a common neurobiological basis of personality and specific cognitive domains comprising attention, spatial reasoning and response selection. The results may facilitate the understanding of the role of impulsiveness in several psychiatric disorders associated with prefrontal dysfunctions and cognitive deficits.

Orthognathic surgery for the complete rehabilitation of Moebius patients: principles, timing and our experience.

Moebius syndrome is a rare disorder found in approximately 1/100,000 neonates and the treatment of facial palsy is now well established worldwide and consists of free-muscle transplants reinnervated with motor nerves. Dentofacial deformities are often detected in Moebius patients, and different degrees of micrognathia are often present, particularly in patients with complete expressions of Moebius syndrome. However only two published reports have described the surgical treatment of such anomalies in these patients; in both cases, the suggested approach consisted of orthognathic surgery followed by soft-tissue management. In this paper we discuss the indications and correct timing of orthognathic surgery and suggest to perform facial animation at an early age and then to wait for the completion of maxillofacial skeletal growth before performing orthognathic surgery. Finally, facial animation should precede orthognathic surgery in adult patients to prevent lower lip deformities and to ensure more predictable and satisfactory results.

Boys do it the right way: sex-dependent amygdala lateralization during face processing in adolescents.

Previous studies have observed a sex-dependent lateralization of amygdala activation related to emotional memory. Specifically, it was shown that the activity of the right amygdala correlates significantly stronger with memory for images judged as arousing in men than in women, and that there is a significantly stronger relationship in women than in men between activity of the left amygdala and memory for arousing images. Using a large sample of 235 male adolescents and 235 females matched for age and handedness, we investigated the sex-specific lateralization of amygdala activation during an emotional face perception fMRI task. Performing a formal sex by hemisphere analysis, we observed in males a significantly stronger right amygdala activation as compared to females. Our results indicate that adolescents display a sex-dependent lateralization of amygdala activation that is also present in basic processes of emotional perception. This finding suggests a sex-dependent development of human emotion processing and may further implicate possible etiological pathways for mental disorders most frequent in adolescent males (i.e., conduct disorder).

The neural basis of video gaming.

Video game playing is a frequent recreational activity. Previous studies have reported an involvement of dopamine-related ventral striatum. However, structural brain correlates of video game playing have not been investigated. On magnetic resonance imaging scans of 154 14-year-olds, we computed voxel-based morphometry to explore differences between frequent and infrequent video game players. Moreover, we assessed the Monetary Incentive Delay (MID) task during functional magnetic resonance imaging and the Cambridge Gambling Task (CGT). We found higher left striatal grey matter volume when comparing frequent against infrequent video game players that was negatively correlated with deliberation time in CGT. Within the same region, we found an activity difference in MID task: frequent compared with infrequent video game players showed enhanced activity during feedback of loss compared with no loss. This activity was likewise negatively correlated with deliberation time. The association of video game playing with higher left ventral striatum volume could reflect altered reward processing and represent adaptive neural plasticity.

The IMAGEN study: reinforcement-related behaviour in normal brain function and psychopathology.

A fundamental function of the brain is to evaluate the emotional and motivational significance of stimuli and to adapt behaviour accordingly. The IMAGEN study is the first multicentre genetic-neuroimaging study aimed at identifying the genetic and neurobiological basis of individual variability in impulsivity, reinforcer sensitivity and emotional reactivity, and determining their predictive value for the development of frequent psychiatric disorders. Comprehensive behavioural and neuropsychological characterization, functional and structural neuroimaging and genome-wide association analyses of 2000 14-year-old adolescents are combined with functional genetics in animal and human models. Results will be validated in 1000 adolescents from the Canadian Saguenay Youth Study. The sample will be followed up longitudinally at the age of 16 years to investigate the predictive value of genetics and intermediate phenotypes for the development of frequent psychiatric disorders. This review describes the strategies the IMAGEN consortium used to meet the challenges posed by large-scale multicentre imaging-genomics investigations. We provide detailed methods and Standard Operating Procedures that we hope will be helpful for the design of future studies. These include standardization of the clinical, psychometric and neuroimaging-acquisition protocols, development of a central database for efficient analyses of large multimodal data sets and new analytic approaches to large-scale genetic neuroimaging analyses.

Pharmacokinetics and pharmacodynamics of sequential intravenous and subcutaneous teicoplanin in critically ill patients without vasopressors.

OBJECTIVE: To compare the pharmacokinetic parameters of sequential intravenous and subcutaneous teicoplanin in the plasma of surgical intensive care unit patients. DESIGN AND SETTING: Prospective, randomized, crossover study in the surgical ICU of a university hospital. PATIENTS: Twelve patients with a suspected nosocomial infection, a serum albumin level higher than 10 g/l, body mass index less than 28 kg/m(2), and estimated creatinine clearance higher than 70 ml/min. INTERVENTIONS: Teicoplanin was first administered intravenously as a loading dose of 6 mg/kg per 12 h for 48 h and then continued at a daily dose of 6 mg/kg. On the fourth day patients were randomized in two groups according to the order of the pharmacokinetic studies. MEASUREMENTS AND RESULTS: Serial plasma samples were obtained to measure teicoplanin levels. Compared with a 30-min intravenous infusion the peak concentration of teicoplanin after a 30-min subcutaneous administration occurred later (median 7 h, range 5-18) and was lower (16 micro g/ml, 9-31; vs. 73, 53-106). Despite large and unpredictable interindividual differences no significant differences between subcutaneous and intravenous administration were observed in: trough antibiotic concentrations (10 micro g/ml, 6-24; vs. 9, 5-30), the area under the teicoplanin plasma concentration vs. time curves from 0 to 24 h (AUC(0-24h); 309 micro g/ml per minute, 180-640; vs. 369, 171-955), the proportion of the dosing interval during which the plasma teicoplanin concentration exceeded 10 micro g/ml (96%, 0-100%; vs. 79%, 13-100%), and the ratio of AUC(0-24h) to 10 (77, 45-160; vs. 92, 43-239). CONCLUSIONS: In critically ill patients without vasopressors a switch to the subcutaneous teicoplanin after an initial intravenous therapy seems to give comparable pharmacodynamic indexes of therapeutic success.

Speech recognition in elderly cochlear implant recipients.

The benefits of cochlear implantation in the adult and paediatric populations are well established. Cochlear implantation in the geriatric population still remains controversial because of the misconception that elderly patients might perform poorly. The purpose of this study was to report the speech performance of 16 patients over 65 years of age implanted with a Nucleus multichannel cochlear implant and to compare it with that of a control group of 14 adults aged between 41 and 59 years. At the 12 months postoperative evaluation, no significant differences were detected on speech performances between the elderly patients and the control group. The mean word recognition scores were 72.5% for the elderly group and 82% for the control group. The mean everyday sentence recognition scores were 72.5% for the elderly group and 85.7% for the control group. Overall, the results are encouraging and demonstrate that the elderly population with profound hearing loss obtain significant benefits from cochlear implantation despite the age-related auditory processing problems.

[Multi-channel cochlear implant in cochlear ossification]. / L'impianto cocleare multicanale nelle ossificazioni cocleari.

Cochlear ossification, considered until only a few years ago as a contraindication for cochlear implants (C.I.), may now be managed by means of a wide variety of surgical techniques. In cases with massive ossification, the drill-out circummodiolar technique described by Gantz et al. in 1988 and successively modified by Balkany et al. in 1997 may be adopted. The technique of electrode insertion in the scala vestibuli, perfected by Steenerson et al. in 1990, may be used when cochlear ossification has spread no further than the scala tympani. Other methods call for a groove to be drilled along the proximal tip of the basal turn of the cochlea (Cohen and Waltzman, 1993), the insertion of electrodes through the middle cranial fossa (Colletti et al., 2000), or the utilization of a double electrode array (Bredberg et al., 1997, Lenarz et al., 2001). This study reports the experience conducted at the Cochlear Implants Centre of the Otorhinolaryngoiatrics, Otological and Otoneurological Microsurgery Section of the University of Parma in a group of 15 patients who underwent C.I. in the presence of varying degrees of ossification. In 3 cases the ossification was limited to the region of the round window and a few millimetres of the scala tympani; cochleostomy was performed anteriorly and inferiorly to the anterior niche of the round window. In 11 cases (of which 3 of pediatric age), the ossification had spread to the horizontal portion of the scala tympani; in these cases, the electrodes were inserted in the scala vestibuli. The scala vestibuli was opened by drilling anteriorly to the round window and superiorly to the spiral ligament. In the only case of massively ossified cochlea, it was possible to partially insert the electrodes in a circum-modiolar tunnel. In the 12-month follow-up hearing test, the 3 patients with ossification of the round window region and the first millimetres of the scala tympani respectively averaged 61.6% in recognizing 2-syllable words and 59% in recognizing words embedded in phrases. The averages on the 12-month follow-up hearing test in the 8 adult patients who received the implant in the scala vestibuli were 80.6% in recognizing 2-syllable words and 89.1% in recognizing words in phrases. The 3 pediatric patients were classified on the Geers and Moog scale, which situated 2 of them in the 6th category of perception and 1 of them in the 4th category of perception. As regards the only case of massive cochlear ossification, the patient underwent surgery recently, and the sole follow-up available is the one conducted after only 3 months; the vowel identification average was 55%; the average on the VCV test was 31%; and the 2-syllable word recognition average was 20%.

Stabilization of recombinant adenovirus: site-directed mutagenesis of key asparagine residues in the hexon protein.

The quality and stability of recombinant adenovirus preparations for gene therapy trials are currently analyzed by anion-exchange HPLC. It was shown that the retention time of the adenovirus peak increased over the course of time upon storage in current liquid formulations. The number of isoaspartate residues at the outer surface of the particles also increased in parallel in these preparations. A recombinant adenovirus AV3760 was constructed with a modified hexon protein in which all four accessible Asn residues engaged in Asn-Gly pairs were changed into Leu (Asn244, Asn255, Asn437) or Ala (Asn276). The retention time of AV3760, as measured by HPLC, was unchanged after 2 months at +20 degrees C as opposed to the control adenovirus. This demonstrates that the shift in retention time is caused by an increase in carboxyl groups on the outer surface of the virion due to deamidation of the above Asn residues. The modifications introduced in the hexon protein reduced the rate of Asn deamidation, without adverse effects on the infectivity of the virions. By reducing microheterogeneity in recombinant adenovirus, this work represents a significant advance in the development of a stable pharmaceutical vector for gene therapy.

Polypeptide composition of an adenovirus type 5 used in cancer gene therapy.

For cancer gene therapy, a recombinant adenovirus serotype 5 named RPR/INGN201 has been constructed by susbtitution of the E1 region with human tumor suppressor gene p53. The protein components of RPR/INGN201 virions were separated by reversed-phase HPLC and were individually identified by electrospray time-of-flight mass spectrometry and N-terminal sequencing, both on intact proteins and on their proteolytic fragments after trypsin digestion. Twenty-five peptide components of the proteome (including fiber) with greater than 0.25-0.5% contribution to the protein content of the virus were identified and characterized. Fiber was confirmed to be partially glycosylated (both the non-glycosylated and the monoglycosylated states were identified), and two proteins were isolated and identified as phosphorylation derivatives, namely protein V (non-phosphorylated and monophosphorylated) and protein IIIa (mono- and diphosphorylated). This new analytical tool proved to be very useful not only for refining our current knowledge of the polypeptide repertoire of purified infectious virions but also for monitoring and very rapidly identifying structural modifications resulting from changes in the manufacturing process. It was also used successfully for the characterization of various adenoviral constructs.

An improved anion-exchange HPLC method for the detection and purification of adenoviral particles.

We have developed an anion-exchange high-performance liquid chromatography (HPLC) method using Q Sepharose XL (Amersham Pharmacia Biotech) as adsorbent to analyze samples containing adenovirus. This method has several major advantages over the HPLC method previously described for quantitating particles, namely (1) a >10-fold improvement in the detection limit of adenovirus in crude preparations; (2) absence of interferences originating from nucleic acids and proteins which usually contaminate crude samples; (3) unprecedented sharpness and symmetry of adenovirus peak, rendering the identification of the viral peak unambiguous, even in extremely crude and dilute preparations; and (4) no enzymatic treatment required even for crude samples. This assay was used to quantitate particles in samples taken at the transfection and amplification stages of production of various recombinant adenovirus, and in cultures of wild-type adenovirus of different serotypes. A modification of this analytical method was also developed for the purification of infectious adenovirus particles, including fiber-modified and third-generation recombinant viruses, giving highly purified preparations from low-titer crude lysates with an excellent overall recovery (50-74%).

Prognostic value of response after three MOPP cycles in Hodgkin's disease--stage III and IV.

Sixty-eight patients with Hodgkin's disease stage III and IV were evaluated after three out of six MOPP cycles. At that time, 46 (68%) were classified as early responders and 22 as slow responders. The criteria of response were: disappearance of B symptoms, decrease in the size of the largest lymph nodes (by more than 50%) and significant reduction (more than 20%) of mediastinal enlargement. Out of 43 early responders, 38 were in complete remission after six MOPP cycles and only five out of 22 slow responders. Such an early response is only related to the absence of B symptoms at the time of diagnosis (p less than 0.05). The survival curves of early responders and slow responders were significantly different (p less than 0.02). A rapid erythrocyte sedimentation rate (ESR) (greater than 50 mm) was the most frequently abnormal sign found in the group not responding after three MOPP cycles (p less than 0.0001). Such a significant prognostic value of early response is observed for stage III but not for stage IV patients. We conclude that early clinical response after three MOPP cycles is a good prognostic factor which must be kept in mind in the formulation of the therapeutic regimen for Hodgkin's disease stage III and IV.