Atypical attentional filtering of visual information in youth with chromosome 22q11.2 deletion syndrome as indexed by event-related potentials.

BACKGROUND: Youth with chromosome 22q11.2 deletion syndrome (22q) face one of the highest genetic risk factors for the development of schizophrenia. Previous research suggests impairments in attentional control and potential interactions with elevated anxiety and reduced adaptive functioning may increase the risk for developing psychosis in this population. Here, we examined how variations in attentional control relate to the presence or severity of psychosis-proneness symptoms in these individuals. METHODS: To achieve this, we measured attentional control in youth (12-18 years) with 22q (N = 35) compared to a typically developing group (N = 45), using a flanker task (the Distractor Target task) while measuring neural activity with event-related potentials. RESULTS: Similar to previous findings observed in people with schizophrenia, greater attentional capture by, and reduced suppression of, non-target flanker stimuli characterized participants with 22q and was indexed by the N2pc (N2-posterior-contralateral) and PD (distractor positivity) components. Although we observed no relationships between these components and measures of psychosis-proneness in youth with 22q, these individuals endorsed a relatively low incidence of positive symptoms overall. CONCLUSIONS: Our results provide neural evidence of an attentional control impairment in youth with 22q that suggests these individuals experience sustained attentional focus on irrelevant information and reduced suppression of distracting stimuli in their environment. Impairments in attentional control might be a valid biomarker of the potential to develop attenuated positive symptoms or frank psychosis in high-risk individuals long before the age at which such symptoms typically arise. The evaluation of such a hypothesis, and the preventive potential for the putative biomarker, should be the focus of future studies.

Compartmentalized dynamics of cytomegalovirus replication in treated congenital infection.

BACKGROUND: Cytomegalovirus (CMV) is the most prevalent congenital infection in developed countries. A significant number of infected infants develop long-term neurodevelopmental and hearing impairment irrespective of whether disease is detectable at birth. Studies of viral load and replication dynamics have informed the treatment of CMV in adult populations but no similar data exist in neonates. OBJECTIVES: To study CMV virus kinetics in different body fluids of babies treated for congenital infection. STUDY DESIGN: CMV virus load was sequentially analyzed in blood, urine and saliva in 17 babies treated for symptomatic congenital CMV infection. RESULTS: Virus was detectable in the urine and saliva of all babies at baseline but in only 15/17 in blood. At the end of 6 weeks of antiviral treatment CMV remained detectable in 9/14 blood samples, 9/12 urine samples and 4/7 salivary swabs. Median half-life (T1/2) of virus decline in blood was 2.4 days (IQR 1.9-3.3) and basic reproductive number (Ro) was 2.3. Although T1/2 values were similar in urine and saliva to those observed in blood, virus dynamics differed both during and after treatment. CONCLUSIONS: T1/2 and Ro in blood in this group of neonates were similar to values derived from studies of immunocompromised adults. The persistent viremia observed in treated neonates cannot therefore be adequately explained by the virus dynamics early in treatment. The different dynamics exhibited in blood and urine suggests that studying changes in distinct body compartments may assist in further understanding long-term manifestations of disease.

Clinically targeted screening for congenital CMV - potential for integration into the National Hearing Screening Programme.

UNLABELLED: Screening for a condition should only be undertaken if certain strict criteria are met. Congenital CMV (cCMV) is a leading cause of sensorineuronal hearing loss (SNHL) and meets many of these criteria, but is not currently screened for in the UK. Ganciclovir reduces CMV-induced progressive SNHL if treatment is begun in the first month of life. The Newborn Hearing Screening Programme (NHSP) has been shown to identify SNHL at the earliest possible age. The potential of integrating screening for cCMV into the NHSP is discussed to consolidate the link between screening, early diagnosis and management. CONCLUSION: The early diagnosis and treatment of cCMV may prevent a small proportion of late SNHL. In the absence of any screening programme, we provide evidence that clinically targeted screening through the NHSP is a potential option in the UK, enhancing the diagnostic pathway and enabling appropriate early treatment to reduce long-term morbidity.

The prevalence and natural history of pituitary hemorrhage in prolactinoma.

CONTEXT: Incidental pituitary hemorrhage, without full pituitary apoplexy, is a recognized radiological finding, but little information exists on its clinical behavior, with most reports describing surgically treated macroprolactinoma or nonfunctioning adenoma. OBJECTIVE: Our aim was to characterize the prevalence, natural history, and risk factors associated with pituitary hemorrhage in a large clinic prolactinoma population. DESIGN: The design consisted of a retrospective analysis of a clinic population. SETTING: The setting was a tertiary endocrine center in a large teaching hospital. PATIENTS: We studied three hundred sixty-eight patients with prolactinoma. The presence of hemorrhage was documented on magnetic resonance imaging. MAIN OUTCOME MEASURE: The main outcome measures were the prevalence, risk factors, and natural history of pituitary hemorrhage. RESULTS: Pituitary hemorrhage was found in 25 patients, giving an overall prevalence of 6.8%, and was significantly higher in macroprolactinoma (20.3%) compared to microprolactinoma (3.1%, P < .0001). Three patients had classical pituitary apoplexy. The majority of patients in the hemorrhage group had macroprolactinomas (16/25 [64%]) and were women (22/25 [88%]). The proportion of women with macroprolactinoma was higher in the hemorrhage group (14/16 macroprolactinomas [87.5%]) than in the nonhemorrhage group (36/63 macroprolactinomas [57.1%], P = .02). The majority of pituitary hemorrhages (92%) were treated conservatively with dopamine agonist therapy for hyperprolactinemia. Eighty-seven percent of patients had complete resolution of their hemorrhage within 26.6 ± 23.3 (mean ± SD) months. The presence of macroprolactinoma (odds ratio 9.00 [95%CI 3.79-23.88], P < .001) and being female (odds ratio 8.03 [95%confidence interval 1.22-52.95], P = .03) were independently associated with hemorrhage. CONCLUSIONS: These data show that incidental hemorrhage in prolactinoma is not uncommon. It is more likely to occur in macroprolactinoma, where 1 in 5 develop hemorrhage, and is particularly common in women with macroprolactinoma. The majority are asymptomatic and resolve spontaneously.

Evidence based management guidelines for the detection and treatment of congenital CMV.

CMV is the most common congenital infection in newborns worldwide. Congenital CMV causes sensorineural hearing loss in a significant proportion of infected newborns, while the majority of newborns are asymptomatic. In the last three years there have been significant advances in the diagnosis and treatment of congenital CMV. We have developed practical evidence based guidelines for the management of congenital CMV.

Deregulated apoptosis signaling in core-binding factor leukemia differentiates clinically relevant, molecular marker-independent subgroups.

Core-binding factor (CBF) leukemias, characterized by translocations t(8;21) or inv(16)/t(16;16) targeting the CBF, constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, about 40% of patients relapse and the current classification system does not fully reflect this clinical heterogeneity. Previously, gene expression profiling (GEP) revealed two distinct CBF leukemia subgroups displaying significant outcome differences and identified apoptotic signaling, MAPKinase signaling and chemotherapy-resistance mechanisms among the most significant differentially regulated pathways. We now tested different inhibitors of the respective pathways in a cell line model (six cell lines reflecting the CBF subgroup-specific gene expression alterations), and found apoptotic signaling to be differentiating between the CBF subgroup models. In accordance, primary samples from newly diagnosed CBF AML patients (n=23) also showed differential sensitivity to in vitro treatment with a Smac mimetic such as BV6, an antagonist of inhibitor of apoptosis (IAP) proteins, and ABT-737, a BCL2 inhibitor. Furthermore, GEP revealed the BV6-resistant cases to resemble the previously identified unfavorable CBF subgroup. Thus, our current findings show deregulated IAP expression and apoptotic signaling to differentiate clinically relevant CBF subgroups, which were independent of known molecular markers, thereby providing a starting point for novel therapeutic approaches.

Volumetry of fetal hearts using 3D real-time matrix echocardiography - in vitro validation experiments and 3D echocardiographic studies in fetuses.

PURPOSE: The aim of this study was to assess the feasibility, accuracy and reliability of 3D real-time echocardiography for fetal heart volumetry. MATERIALS AND METHODS: Fifty unselected and consecutive fetuses, including 14 with cardiac malformations, were scanned prospectively using real-time 3D matrix technology and 2D echocardiography to determine ventricular volumes. Small phantoms as well as modified balloons (0.5 - 20 ml) were used to assess the validity of 2D and 3D distance, area and volume calculations and to study potential sources of error during data acquisition and analysis. The data was evaluated by two blinded observers. RESULTS: In vitro, real-time 3D and 2D underestimated the actual volumes by -5.49 % (3D) and -6.86 % (2D). The intraobserver and interobserver variability were excellent. In vivo, real-time 3D was superior to 2D with regard to intraobserver and interobserver variability (mean coefficient of variation 8.28 % (3D) versus 13.96 % (2D), and mean intraclass correlation coefficient 0.997 (3D) versus 0.885 (2D) for left ventricular volumes). Similar to in vitro, in vivo 2D volumes were calculated smaller than 3D volumes (mean difference -0.39 to -0.94 ml). The ventricular volumes and stroke volumes increased exponentially with gestation. Secondary to poor imaging windows in advanced gestation or inadequate delineation of endocardial borders in small hearts at less than 19 weeks, 3D data could not be analyzed sufficiently in 6 / 50 fetuses. CONCLUSION: Real-time 3D using a matrix transducer is a feasible, reliable and valid method for volume determination in the fetus beyond 19 weeks of gestation. If compared to 2D, real-time 3D echocardiography provides improved accuracy of cardiac volumetry, decreases intraobserver and interobserver variability and is a promising tool for the accurate assessment of cardiac size and function.

Three-dimensional analysis of intermediate filament networks using SEM tomography.

We identified tomographic reconstruction of a scanning electron microscopy tilt series recording the secondary electron signal as a well-suited method to generate high-contrast three-dimensional data of intermediate filament (IF) networks in pancreatic cancer cells. Although the tilt series does not strictly conform to the projection requirement of tomographic reconstruction, this approach is possible due to specific properties of the detergent-extracted samples. We introduce an algorithm to extract the graph structure of the IF networks from the tomograms based on image analysis tools. This allows a high-resolution analysis of network morphology, which is known to control the mechanical response of the cells to large-scale deformations. Statistical analysis of the extracted network graphs is used to investigate principles of structural network organization which can be linked to the regulation of cell elasticity.

Hazardous complications of multiple ingested magnets: report of four cases.

Foreign body ingestion is a common occurrence in the pediatric population. Frequent culprits include coins, toys, sharp objects and bones, which most often pass spontaneously. Magnet ingestion, however, can be a serious matter, especially when more than one is taken in. The extremely strong magnetic force between multiple magnets may result in numerous complications including bowel necrosis, perforation, obstruction, fistula formation, volvulus and death. We present the largest series reported to date, with four cases of multiple magnet ingestion at our institution with varied presentations and findings. We review the literature, and discuss the importance of having a high index of suspicion.

Postnatal cytomegalovirus: innocent bystander or hidden problem?

Cytomegalovirus (CMV) is a common pathogen, associated with mild illness in most immunocompetent people. Historically, research on CMV infection in the relatively immunocompromised premature and small-for-gestational age neonatal population has been neglected. Recent studies have not only defined factors important in the transmission of CMV, but also led to the suggestion of serious morbidity related to postnatal acquisition. The burden of postnatal CMV disease and the risk-benefit of screening and prevention strategies are all still unclear.

Direct neurophysiological evidence for spatial suppression surrounding the focus of attention in vision.

The spatial focus of attention has traditionally been envisioned as a simple spatial gradient of enhanced activity that falls off monotonically with increasing distance. Here, we show with high-density magnetoencephalographic recordings in human observers that the focus of attention is not a simple monotonic gradient but instead contains an excitatory peak surrounded by a narrow inhibitory region. To demonstrate this center-surround profile, we asked subjects to focus attention onto a color pop-out target and then presented probe stimuli at various distances from the target. We observed that the electromagnetic response to the probe was enhanced when the probe was presented at the location of the target, but the probe response was suppressed in a narrow zone surrounding the target and then recovered at more distant locations. Withdrawing attention from the pop-out target by engaging observers in a demanding foveal task eliminated this pattern, confirming a truly attention-driven effect. These results indicate that neural enhancement and suppression coexist in a spatially structured manner that is optimal to attenuate the most deleterious noise during visual object identification.

How does attention attenuate target-distractor interference in vision?. Evidence from magnetoencephalographic recordings.

This study used magnetoencephalographic and electroencephalographic recordings to investigate the neural mechanisms that underlie the attentional resolution of ambiguous feature coding in visual search. We addressed this issue by comparing neural activity related to target discrimination under conditions of more versus less feature overlap between the target and distractor items. The results show that increasing feature overlap leads to a focal enhancement of neural activity in ventral occipito-temporal areas, consistent with the larger need to attenuate distractor interference. Furthermore, the results suggest that distractor attenuation proceeds as a stepwise operation, with different spatial locations containing interfering features being suppressed successively. These findings support theories of visual search that emphasize location-based attentional selection as a key mechanism in resolving ambiguous feature coding in vision.

Ferric dicitrate transport system (Fec) of Shigella flexneri 2a YSH6000 is encoded on a novel pathogenicity island carrying multiple antibiotic resistance genes.

Iron uptake systems which are critical for bacterial survival and which may play important roles in bacterial virulence are often carried on mobile elements, such as plasmids and pathogenicity islands (PAIs). In the present study, we identified and characterized a ferric dicitrate uptake system (Fec) in Shigella flexneri serotype 2a that is encoded by a novel PAI termed the Shigella resistance locus (SRL) PAI. The fec genes are transcribed in S. flexneri, and complementation of a fec deletion in Escherichia coli demonstrated that they are functional. However, insertional inactivation of fecI, leading to a loss in fec gene expression, did not impair the growth of the parent strain of S. flexneri in iron-limited culture media, suggesting that S. flexneri carries additional iron uptake systems capable of compensating for the loss of Fec-mediated iron uptake. DNA sequence analysis showed that the fec genes are linked to a cluster of multiple antibiotic resistance determinants, designated the SRL, on the chromosome of S. flexneri 2a. Both the SRL and fec loci are carried on the 66,257-bp SRL PAI, which has integrated into the serX tRNA gene and which carries at least 22 prophage-related open reading frames, including one for a P4-like integrase. This is the first example of a PAI that carries genes encoding antibiotic resistance and the first report of a ferric dicitrate uptake system in Shigella.

Nested deletions of the SRL pathogenicity island of Shigella flexneri 2a.

In this study, we determined the boundaries of a 99-kb deletable element of Shigella flexneri 2a strain YSH6000. The element, designated the multiple-antibiotic resistance deletable element (MRDE), had recently been found to contain a 66-kb pathogenicity island (PAI)-like element (designated the SRL PAI) which carries the Shigella resistance locus (SRL), encoding resistance determinants to streptomycin, ampicillin, chloramphenicol, and tetracycline. The YSH6000 MRDE was found to be flanked by two identical IS91 elements present at the S. flexneri homologs of the Escherichia coli genes putA and mdoA on NotI fragment D. Sequence data from two YSH6000-derived MRDE deletants, YSH6000T and S2430, revealed that deletion of the MRDE occurred between the two flanking IS91 elements, resulting in a single IS91 element spanning the two original IS91 loci. Selection for the loss of tetracycline resistance confirmed that the MRDE deletion occurred reproducibly from the same chromosomal site and also showed that the SRL PAI and the SRL itself were capable of independent deletion from the chromosome, thus revealing a unique set of nested deletions. The excision frequency of the SRL PAI was estimated to be 10(-5) per cell in the wild type, and mutation of a P4-like integrase gene (int) at the left end of the SRL PAI revealed that int mediates precise deletion of the PAI.

Visual search remains efficient when visual working memory is full.

Many theories of attention have proposed that visual working memory plays an important role in visual search tasks. The present study examined the involvement of visual working memory in search using a dual-task paradigm in which participants performed a visual search task while maintaining no, two, or four objects in visual working memory. The presence of a working memory load added a constant delay to the visual search reaction times, irrespective of the number of items in the visual search array. That is, there was no change in the slope of the function relating reaction time to the number of items in the search array, indicating that the search process itself was not slowed by the memory load. Moreover, the search task did not substantially impair the maintenance of information in visual working memory. These results suggest that visual search requires minimal visual working memory resources, a conclusion that is inconsistent with theories that propose a close link between attention and working memory.

Storage of features, conjunctions and objects in visual working memory.

Working memory can be divided into separate subsystems for verbal and visual information. Although the verbal system has been well characterized, the storage capacity of visual working memory has not yet been established for simple features or for conjunctions of features. The authors demonstrate that it is possible to retain information about only 3-4 colors or orientations in visual working memory at one time. Observers are also able to retain both the color and the orientation of 3-4 objects, indicating that visual working memory stores integrated objects rather than individual features. Indeed, objects defined by a conjunction of four features can be retained in working memory just as well as single-feature objects, allowing many individual features to be retained when distributed across a small number of objects. Thus, the capacity of visual working memory must be understood in terms of integrated objects rather than individual features.