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Post-traumatic stress disorder (PTSD) is an anxiety disorder arising from exposure to a traumatic event. Although primarily defined in terms of behavioral symptoms, the global neurophysiological effects of traumatic stress are increasingly recognized as a critical facet of the human PTSD phenotype. Here we use magnetoencephalographic recordings to investigate two aspects of information processing: inter-regional communication (measured by functional connectivity) and the dynamic range of neural activity (measured in terms of local signal variability). We find that both measures differentiate soldiers diagnosed with PTSD from soldiers without PTSD, from healthy civilians, and from civilians with mild traumatic brain injury, which is commonly comorbid with PTSD. Specifically, soldiers with PTSD display inter-regional hypersynchrony at high frequencies (80–150 Hz), as well as a concomitant decrease in signal variability. The two patterns are spatially correlated and most pronounced in a left temporal subnetwork, including the hippocampus and amygdala. We hypothesize that the observed hypersynchrony may effectively constrain the expression of local dynamics, resulting in less variable activity and a reduced dynamic repertoire. Thus, the re-experiencing phenomena and affective sequelae in combat-related PTSD may result from functional networks becoming “stuck” in configurations reflecting memories, emotions, and thoughts originating from the traumatizing experience.SIGNIFICANCE STATEMENTThe present study investigates the effects of post-traumatic stress disorder (PTSD) in combat-exposed soldiers. We find that soldiers with PTSD exhibit hypersynchrony in a circuit of temporal lobe areas associated with learning and memory function. This rigid functional architecture is associated with a decrease in signal variability in the same areas, suggesting that the observed hypersynchrony may constrain the expression of local dynamics, resulting in a reduced dynamic range. Our findings suggest that the re-experiencing of traumatic events in PTSD may result from functional networks becoming locked in configurations that reflect memories, emotions, and thoughts associated with the traumatic experience.

MEG somatosensory evoked fields (SEF) have been used in pre-surgical functional mapping to localize sensory cortex. Although the localization accuracy of the SEF has been compared to functional MRI, there have not been any direct comparisons between the SEF and sensory cortex identified by electrocorticography. In this retrospective study, we identified 9 children (5 males, 4 females; aged 4–17 yrs) who had pre-surgical functional mapping with MEG and then proceeded to epilepsy surgery with subdural grid recording. We compared the pre-operative localization of the MEG SEF with the location identified extra-operatively with subdural grid electrodes. We found 78% (7/9) concordance for gyral localization between pre-operative MEG and extra-operative grid recording. In the other two patients, MEG SEF was located in the central sulcus. We conclude that MEG demonstrates high accuracy in localizing sensory cortex and is a valuable tool in pre-surgical functional mapping.

Voice onset time (VOT) is a temporal acoustic parameter that reflects motor speech coordination skills. This study investigated the patterns of age and sex differences across development of voice onset time in a group of 70 English-speaking children, ranging in age from 4.1 to 18.4 years, and 12 young adults. The effect of the number of syllables on VOT patterns was also examined. Speech samples were elicited by producing syllables /pa/ and /pataka/. Results supported previous findings showing that younger children produce longer VOT values with higher levels of variability. Markedly higher VOT values and increased variability were found for boys at ages between 8 and 11 years, confirming sex differences in VOT patterns and patterns of variability. In addition, all participants consistently produced shorter VOT with higher variability for multisyllables than monosyllables, indicating an effect of syllable number. Possible explanations for these findings and clinical implications are discussed.

Theory of Mind (ToM) is the ability to understand the perspectives, mental states and beliefs of others in order to anticipate their behaviour and is therefore crucial to social interactions. Although fMRI has been widely used to establish the neural networks implicated in ToM, little is known about the timing of ToM-related brain activity. We used magnetoencephalography (MEG) to measure the neural processes underlying ToM, as MEG provides very accurate timing and excellent spatial localization of brain processes. We recorded MEG activity during a false belief task, a reliable measure of ToM, in twenty young adults (10 females). MEG data were recorded in a 151 sensor CTF system (MISL, Coquitlam, BC) and data were co-registered to each participant's MRI (Siemens 3T) for source reconstruction. We found stronger right temporoparietal junction (rTPJ) activations in the false belief condition from 150ms to 225ms, in the right precuneus from 275ms to 375ms, in the right inferior frontal gyrus from 200ms to 300ms and the superior frontal gyrus from 300ms to 400ms. Our findings extend the literature by demonstrating the timing and duration of neural activity in the main regions involved in the "mentalizing" network, showing that activations related to false belief in adults are predominantly right lateralized and onset around 100ms. The sensitivity of MEG will allow us to determine spatial and temporal differences in the brain processes in ToM in younger populations or those who demonstrate deficits in this ability.

It is not an uncommon goal amongst policymakers to have a successful programme in one school be scaled up to more or even all schools in the system. However, the poetry of aspiration must be translated into the prose of implementation. Recent studies, such as those described in this book, have indicated that the scaling up of educational innovations across multiple settings requires a confluence of sociocultural factors. In this chapter, we describe a successful educational innovation in Singapore, the Strategies for English Language Learning and Reading (STELLAR) programme, and discuss the implementation approach and the critical success factors, which have contributed to its effective scaling up, at a system level.

Purpose In this prospective cross-sectional study on young premenopausal breast cancer patients, the objectives were to: determine the incidences of chemotherapy-related amenorrhea (CRA) and menopause (CRM); identify associated factors; and assess plasma levels of estradiol (E2) and follicular stimulating hormone (FSH) among patients who developed menopause. Methods Eligibility criteria include Chinese stage I-III breast cancer patients, premenopausal, age ≤45 at breast cancer diagnosis, having received adjuvant chemotherapy, within 3–10 years after breast cancer diagnosis. Detailed menstrual history prior to and after adjuvant treatment was taken at study entry. Patients’ background demographics, tumor characteristics and anti-cancer treatments were collected. The rates of CRA and CRM were determined. Analysis was conducted to identify factors associated with CRM. For postmenopausal patients, levels of E2 and FSH were analyzed. Results 286 patients were recruited; the median time from breast cancer diagnosis to study entry was 5.0 years. 255 patients (91.1%) developed CRA. Of these, 66.7% regained menstruation. At the time of study entry, 137 (48.9%) had developed CRM, amongst whom 84 were age ≤45. On multivariate analysis, age was the only associated factor. Among patients with CRM, the median FSH was 41.0 IU/L; this was significantly lower in those who were taking tamoxifen compared to those who were not (20.1 vs. 59.7 IU/L, p

We investigated whether malformations of cortical development yield a complex central cortex by studying nine children with malformations of cortical development and seven without malformations who underwent epilepsy surgery following extraoperative subdural somatosensory evoked potential and electrical stimulation to identify the sensorimotor cortex. We analyzed superficial structures of the central cortex, latency, amplitude, and location of N20 and P25. Sensorimotor responses in malformations of cortical development extended across the central sulcus in 1 to 4 of 3 to 12 electrodes (mean 32%) compared with 1 to 6 of 4 to 15 electrodes (mean 12%) in cases without malformations with a statistical significance (P < .05). N20 amplitudes were lower in epileptic than nonepileptic cortices (three with and three without malformations of cortical development) (P < .05). The central vein coursed partially along the central sulcus in eight cases of malformations of cortical development and five cases without malformations. We conclude that the sensorimotor cortex in malformations of cortical development is more complex than in cases without malformations, reduced N20 amplitude is indicative of epileptic sensorimotor cortex, and superficial veins do not indicate the sensory and motor cortical boundary. (J Child Neurol 2002;17:347-352).

Using comparative genomic hybridization (CGH) analysis, we, and others, have shown that there is a high and consistent incidence of chromosome 1q copy gain in human hepatocellular carcinoma (HCC). Chromosome 1 rearrangements, that involved peri-centromeric breakpoints, have also been frequently reported in karyotypic studies of HCC. Satellite DNA hypomethylation has been postulated as the mechanism underlying the induction of chromosome 1 peri-centromeric instability in many human cancers and in individuals with the rare recessive disorder ICF (immunodeficiency, centromeric heterochromatin instability, facial anomalies). In this study, we have investigated the role of DNA hypomethylation in 1q copy gain in HCC by examining the methylation status of chromosome 1 heterochromatin DNA (band 1q12). Thirty-six histologically confirmed samples of HCC were studied (24 paired tumor and adjacent nontumorous liver tissues, and 12 tumor only). Hypomethylation of satellite 2 (Sat2) DNA in 1q12 was analyzed by Southern blotting using methyl-sensitive enzyme digestion. In parallel, all cases were analyzed by CGH. A strong correlation between hypomethylated Sat2 sequences and 1q copy gain with a 1q12 breakpoint was found (P < 0.001). We postulate that such hypomethylation alters the interaction between the CpG-rich satellite DNA and chromatin proteins, resulting in heterochromatin decondensation, breakage and aberrant 1q formation. Spectral karyotyping further supported the presence of fragile 1q12 in HCC. Of particular interest was the finding of Sat2 DNA hypomethylation in 5 of 24 adjacent nontumorous liver tissues examined. These tissues showed no evidence of malignancy on histological examination nor did they display any CGH abnormalities. Our findings suggest a role for Sat2 demethylation in the early stages of the stepwise progression of liver carcinogenesis.

The current paucity of cytogenetic information on hepatocellular carcinoma (HCC) reflects the difficulties in culturing hepatocytes in vitro. Here, we report on the successful culture of 15 HCC cases. Chromosome aneuploidy ranging from a near-diploid to hyperhexaploid karyotype was found, but their complete karyotypic interpretations were hampered by the presence of many unidentifiable rearrangements. Spectral karyotyping (SKY) was used to elucidate structural changes in these HCC samples and 3 liver cancer cell lines (PLC/PRF/5, Hep3B, and HepG2). Frequent structural abnormalities were found on chromosomes 1 (13 of 15 cases; 3 of 3 cell lines), 8 (10 of 15 cases; 2 of 3 cell lines), 17 (9 of 15 cases; 3 of 3 cell lines), and 19 (9 of 15 cases; 1 of 3 cell lines). In particular, the chromosome regions 1p13-q21, 8p12-q21, 17p11-q12, 17q22, and 19p10-q13.1 were involved in multiple rearrangements. SKY analysis also suggested several previously undescribed breakpoints in HCC. These breakpoints, predominantly pericentromeric, clustered around the chromosome bands 2q33-q34, 3p13-q12, 4p14-q12, 5p10-q11, 7p12-q11, 10q10-q11, 11q10, 11q13-q21, 12q10-q13, 12q22-q23, 13q10-q14, 15q10, 16q10-q13, 18p11-q11, 20p11-q13.1, 21q10, and 22q10. When tumor sizes were compared, a significantly higher number of structural abnormalities was found in tumors larger than 4 cm (P =.007). Rearrangements such as t(1;8), t(1;11), t(1;19), and t(17;21) that were identified in both primary tumors and cell lines might represent markers that reflect proliferative advantages. Although SKY analysis did not indicate consistent translocations, it suggested nonrandom breakpoints, predominantly in the pericentromeric region, on a number of chromosomes. These breakpoint clusters may thus prove to be more important in the liver carcinogenesis and targets for further molecular investigations.

Hepatocellular carcinoma (HCC) is a common and highly malignant tumor that is prevalent in Southeast Asia. Although the etiological factors associated are now well recognized, the interactions between individual factors and the molecular mechanisms by which they lead to cancer remain unclear. Cytogenetic analysis on HCC has been limited because of poor hepatocyte growth in vitro. The recently developed technique of comparative genomic hybridization (CGH), however, permits screening of the entire genome without the need of cell culture. CGH was applied to the study of genomic aberrations in 67 surgically resected samples of HCC, 3 of adenomatous hyperplasia (AH), and 12 of nontumorous cirrhotic liver surrounding the tumors. All samples were from patients of a racially and etiologically homogeneous population in Southern China, where chronic hepatitis B virus infection is the main etiological factor. CGH analysis of the HCC samples revealed frequent copy number gain of 1q (48/67 cases, 72%), 8q (32/67 cases, 48%), 17q (20/67 cases, 30%), and 20q (25/67 cases, 37%) and common losses on 4q (29/67 cases, 43%), 8p (25/67 cases, 37%), 13q (25/67 cases, 37%), and 16q (20/67 cases, 30%). Our finding of a high incidence of 1q gain strongly suggested this aberration was associated with the development of HCC. Genomic abnormalities were detected in 1 of the 3 AH specimens but absent in all 12 cirrhotic tissues surrounding the tumor. Clinical staging classified 3/67 HCC cases as T1, 53 cases as T2, and 11 cases as T3. No significant difference in the pattern of genomic imbalances was detected between stages T2 and T3. A significant copy number loss of 4q11-q23 was, however, identified in those tumors larger than 3 cm in diameter. Of particular interest was the identification of 8q copy number gain in all 12 cases of HCC that arose in a noncirrhotic liver, compared with only 20/55 cases in HCC arising in a cirrhotic liver. We suggest that 8q over-representation is likely associated with a growth advantage and proliferative stimulation that have encouraged malignant changes in the noncirrhotic human liver.

Studies of first (L1) and second (L2) language representation in the brain have not identified the timing and locations of neural regions involved in L1 and L2 processing. Magnetoencephalography offers high spatial and temporal resolution and can be employed to disentangle subtle timing and neural control differences between L1 and L2 use. We tested bilingual adults in the MEG as they completed a picture verb generation task in L1 and L2. We found the expected progression of activation from occipital to temporal to inferior frontal areas. We also observed the following differences. A sustained insula and early cingulate event-related desynchrony was observed only with L2; the fMRI literature suggests that the former reflects an activation, and the latter an inhibition, sub-process for language selection. L2 processes exhibited a lag and were bilateral compared to L1 processes. Finally, L1 and L2 activated adjacent language control in dorsolateral pre-frontal cortex.

To characterize the developmental trajectory for expressive language representation and to test competing explanations for the relative neuroplasticity of language in childhood, we studied 28 healthy children and adolescents (aged 5-19 years) participating in a covert verb generation task in magnetoencephalography. Lateralization of neuromagnetic responses in the frontal lobe was quantified using a bootstrap statistical thresholding procedure for differential beamformer analyses. We observed a significant positive correlation between left hemisphere lateralization and age. Findings suggest that adult-typical left hemisphere lateralization emerges from an early bilateral language network, which may explain the pediatric advantage for interhemispheric plasticity of language.

Ten subjects breathed experimental mixtures of 20% and 35% nitrous oxide (N2O) balanced with oxygen and then aligned a pointer with a target using vision, kinesthesis, or combinations of these senses. In a prior session the subjects had been trained on the task with feedback while breathing N2O. The results showed that N2O did not influence variable error (VE), constant error, (CE), or absolute CE, but perceptual conditions influenced VE and absolute CE. These results suggest that the demonstration by Legge (1965) of changes in the variability and accuracy of matching on this task under N2O are indicative of changes in response bias and/or attention rather than perceptual sensitivity. It is argued that narcosis slows rather than distorts information processing. Slowing is accompanied by strategic changes that may be maladaptive. This suggests that, contrary to conventional wisdom, the safety and efficiency of divers exposed to narcosis could be improved with training.

Post-traumatic stress disorder (PTSD) is a mental health injury characterised by re-experiencing, avoidance, numbing and hyperarousal. Whilst the aetiology of the disorder is relatively well understood, there is debate about the prevalence of cognitive sequelae that manifest in PTSD. In particular, there are conflicting reports about deficits in executive function and mental flexibility. Even less is known about the neural changes that underlie such deficits. Here, we used magnetoencephalography to study differences in functional connectivity during a mental flexibility task in combat-related PTSD (all males, mean age = 37.4, n = 18) versus a military control (all males, mean age = 33.05, n = 19) group. We observed large-scale increases in theta connectivity in the PTSD group compared to controls. The PTSD group performance was compromised in the more attentionally-demanding task and this was characterised by 'late-stage' theta hyperconnectivity, concentrated in network connections involving right parietal cortex. Furthermore, we observed significant correlations with the connectivity strength in this region with a number of cognitive-behavioural outcomes, including measures of attention, depression and anxiety. These findings suggest atypical coordination of neural synchronisation in large scale networks contributes to deficits in mental flexibility for PTSD populations in timed, attentionally-demanding tasks, and this propensity toward network hyperconnectivity may play a more general role in the cognitive sequelae evident in this disorder.

P087 Endocrine sensitivity is decisive for patient outcome in small PN0 breast cancers (PT1A,b) T. Kolben, R. Wuerstlein *, N. Harbeck, G. Schubert-Fritschle, I. Bauerfeind, S. Schrodi, J. Engel. Breast Center, University Hospital Munich – Grosshadern, Munich, Germany, Medical Informatics, Biometry and Epidemiology, Munich Cancer Registry of the Munich Cancer Center, Munich, Germany, Head of The Project Group “breast Cancer” of The Munich Tumorcenter, Klinikum Landshut, Germany, Landshut, Germany

Magnetoencephalography (MEG) and magnetic source imaging (MSI) together represent a uniquely powerful functional imaging modality because of their capabilities of directly observing the electrophysiologic activity of neurons with exquisite temporal detail and accurately localizing corresponding neuromagnetic field sources onto high-resolution MR images. These features have and should continue to advance our understanding of the complex spatiotemporal basis of normal and abnormal brain function and development in children. By more clearly delineating and characterizing epileptogenic foci and their relation to eloquent cortex, MSI enables earlier and more effective neurosurgery to be performed, thus resulting in improved seizure outcomes. Although MEG and MSI cannot replace scalp electroencephalography, neuropsychologic testing, and the need for meticulous intraoperative cortical mapping in patients undergoing excision of epileptogenic lesions, their increasing availability should ultimately persuade many clinicians of their key, if not essential, role in the evaluation and treatment of children with epilepsy.

We define specific neurophysiologic characteristics for focal cortical dysplasia, a neuronal migration disorder. We reviewed data from published reports and our patients with focal cortical dysplasia. Our patients underwent preoperative scalp video-electroencephalography (EEG), magnetic resonance imaging (MRI), magnetoencephalography, and intraoperative or extraoperative electrocorticography monitoring. Scalp EEG showed trains of rhythmic epileptiform spike or sharp waves. Positive spikes correlated with early seizure onset, MRI lesion around the rolandic fissure, hemiparesis, and a less favorable outcome. Interictal electrocorticography showed continuous epileptogenic discharges: repetitive electrographic seizures and bursting discharges or continuous or quasicontinuous rhythmic spiking. Ictal electrocorticography showed paroxysmal fast and/or repetitive spiking. Magnetoencephalography showed clustered spike sources within and extending from the lesion. Cortical stimulation gave more frequent, lower-threshold afterdischarges and higher-threshold primary motor function. Focal cortical dysplasias are highly and intrinsically epileptogenic. For surgical seizure control, EEG, electrocorticography, and magnetoencephalography must delineate the intrinsic epileptogenic zone within and extending from the focal cortical dysplasia identified by MRI. ( J Child Neurol 2005;20:357—363).

We present the first case of a thoracic ranula which originated from the left submandibular area extending into the subcutaneous tissue planes of the anterior chest wall. The patient had a history of surgery for a previous benign left salivary gland cyst, and presented with an enlarging mass in the anterior chest wall. This was a recurrence of a ranula, with an extension into the anterior thoracic wall. The thoracic ranula was excised, together with ipsilateral sublingual and submandibular glands, via a transcervical approach. No recurrence was detected over a 3-year post-operative follow up.

OBJECTIVE: To determine the role of reconstructing three-dimensional magnetic source imaging (MSI) data on cortical resections for children undergoing epilepsy surgery using neuronavigation. METHODS: Magnetoencephalographic recordings were analyzed in 16 children under 18 years of age with intractable epilepsy. The data were transferred to the neuronavigation workstation for intraoperative localization of MSI spike sources in selected patients. With the aid of neuronavigation, the MSI spike sources were resected. Intraoperative electrocorticography was then used to survey the surrounding field for residual epileptiform activity. RESULTS: MSI spike sources were obtained in 13 of 16 patients. MSI spike sources localized the cortical and subcortical discharges before intraoperative electrocorticography in nine patients and before extraoperative subdural grid electroencephalographic monitoring in four patients. The localization of MSI spikes sources was characterized by clustered spike sources in 10 patients. By use of neuronavigation, the clustered spike sources were correlated to the interictal zone indicated by intraoperative electrocorticography in six patients and to the ictal onset zone shown on extraoperative subdural grid electroencephalography in three patients. Cortical excision of the spike cluster focus was then performed in these six patients. The technique used here to resect MSI spike source clusters that correlate with the ictal onset zone by invasive subdural grid monitoring is illustrated in one patient who underwent cortical resection for epilepsy surgery. CONCLUSION: Three-dimensional reconstruction of MSI data linked to neuronavigation is a promising technique to facilitate resections around eloquent cortex in children with epilepsy.

Administration of doxorubicin has been shown to prolong survival of patients with hepatocellular carcinoma (HCC). However, treatment regimen is often complicated by the emergence of drug resistance. The goal of our study is to enhance our understanding on the genetic changes that confer cellular chemoresistance to doxorubicin. To model this insensitive response, we established five doxorubicin-resistant (DOR) sublines through repeated exposure of escalating doses of doxorubicin to HCC cell lines (HKCI-2, -3, -4, -C1 and -C2). The DOR sublines developed displayed an average approximately 17-fold higher IC(50) value than their sensitive parental cell lines. The resistant phenotype displayed was investigated by the genome-wide analyses of comparative genomic hybridization (CGH) and complementary DNA microarray for the affected genomic anomalies and deregulated genes expressed, respectively. Over-representations of regional chr. 7q11-q21, 8q22-q23 and 10p13-pter were indicated in the DOR sublines from CGH analysis. Of particular interest was the finding of amplicon augmentations from regional or whole chromosome gains during the clonal expansion of resistant sublines. Most notably, recurring amplicon 7q11.2-q21 identified coincided with the location of the multi-drug-resistant gene, MDR1. The potential involvement of MDR1 was examined by quantitative reverse transcription-polymerase chain reaction RT-PCR (qRT-PCR), which indicated an upregulation in all DOR sublines (P=0.015). Consistent overexpression of the translated MDR1 gene, P-glycoprotein, in all five DOR sublines was further confirmed in Western blot analysis. Two distinct cluster dendrograms were achieved between the DOR sublines and their sensitive parental counterparts in expression profiling. Within the doxorubicin-resistant group, distinct features of candidate genes overexpressions including ABC transporting proteins, solute carriers and TOP2A were suggested. Further assessment of TOP2A messenger RNA levels by qRT-PCR confirmed array findings and pinpointed to a common up-regulation of TOP2A in DOR sublines. Our present study highlighted areas of genomic imbalances and candidate genes in the acquired doxorubicin-resistance behavior of HCC cells.

Despite a prolongation of patient survival, the overall response of doxorubicin (DX) treatment on patients with hepatocellular carcinoma (HCC) remains modest. This is largely attributed to the development of tumor drug resistance either at the onset or during the course of treatment. To investigate the genetic changes associated with DX chemo-resistance, we examined the cytotoxic effect of DX on a panel of 9 HCC cell lines (HepG2, Hep3B, PLC/PRF/5, and six in-house established, HKCI-1, 2, 3 and 4, C1 and C2). The karyotypic abnormalities were examined by spectral karyotyping (SKY) and the chromosome loci defined were investigated for underlying deregulated genes by positional expression profiling. Quantitative RT-PCR was employed to verify the profiling findings, and also used to examine a number of drug resistance-related candidate genes (MDR1, MRP1, MGMT, PTEN, BCL2, BAX, TP53 and P21). Our results indicated that the cytotoxic effect of DX in cell lines exhibited IC50 values that ranged from sensitive to resistant (0.07 to 3.55 microM). While the overall chromosome aneuploidy did not correlate with DX resistance, aberrations on chromosome 10 demonstrated significant correlation with increasing IC50 (p=0.007). Positional profiling further suggested the consistent down-regulation of CGI-18 and ECHS1 on chromosome 10q. The array findings were substantiated by quantitative RT-PCR, which further pointed to a repressed ECHS1 expression in correlation with DX resistance (p=0.021). Among the candidate genes studied, an inverse relationship of P21 (p=0.034) and BAX (p=0.002) expression with DX resistance was also indicated. Our present study highlights the usefulness of multimodality approaches in identifying genetic markers, and further describes the novel finding of ECHS1 down-regulation in the DX chemo-resistance of HCC.

Squamous cell carcinoma (SqC) and adenocarcinoma (AdC) are the two most common subtypes of non-small cell lung cancer (NSCLC). Cumulative information suggests that the SqC and AdC subtypes progress through different carcinogenic pathways, but the genetic aberrations promoting such differences remain unclear. Here we have assessed the overall genomic imbalances and structural abnormalities in SqC and AdC. By parallel analyses with comparative genomic hybridisation (CGH) on tumorous lung tissues and spectral karyotyping (SKY) on short-term cultured primary tumours, genome-wide characterisation was carried out on 69 NSCLC (35 SqC, 34 AdC). Molecular cytogenetic characterisation indicated common and distinct genetic changes in SqC and AdC. Common events of +1q21-q24, +5p15-p14, and +8q22-q24.1, and -17p13-p12 were found in both groups, although hierarchical clustering simulation on CGH findings depicted +2p13-p11.2, +3q25-q29, +9q13-q34, +12p, +12q12-q15 and +17q21, and -8p in preferential association with SqC pathogenesis (P

Adenocarcinoma (AdC) of the lung represents a common histologic subtype of non–small cell lung cancer. While there is a rising incidence of AdC in nonsmoking women, information on the cytogenetic changes involved has been minimal to date. In the present study, spectral karyotyping analysis uncovered the genome-wide chromosomal aberrations in two AdC tumors derived from women who were lifelong nonsmokers. Simple and complex structural rearrangements were indicated. A ploidy status of hypertetraploidy was suggested in both cases, with recurring derivative translocations involving chromosome arms 3q, 8q, 12q, 15q, 22q, and Xq.

Nasopharyngeal carcinoma (NPC) cell lines and xenografts represent valuable models for functional and therapeutic studies on this common malignancy in Southeast Asia. The karyotypic information in most NPC cell lines and xenografts, however, remains largely unclear to date. We have characterized the chromosomal aberrations in six commonly used human NPC cell lines and xenografts using the molecular cytogenetic technique of comparative genomic hybridization (CGH). Genomic imbalances identified in cell lines were further correlated with structural abnormalities indicated from spectral karyotyping (SKY) analysis. CGH revealed consistent overrepresentations of 8q (six out of six cases) with a smallest overlapping region identified on 8q21.1 approximately q22. Other common gains included 7p (4/6 cases), 7q (4/6 cases), 12q (4/6), and 20q (4/6 cases), where minimal overlapping regions were suggested on 7p15 approximately p14, 7q11.2 approximately q21, and 12q22 approximately q24.1. Common losses were detected on 3p12 approximately p21 (4/6 cases) and 11q14 approximately qter (4/6 cases). Although SKY analysis on cell lines revealed predominantly unbalanced rearrangements, reciprocal translocations that involved chromosome 2 [i.e., t(1;2), t(2;3), and t(2;4)] were suggested. Furthermore, SKY examination illustrated additional breakpoints on a number of apparently balanced chromosomes. These breakpoints included 3p21, 3q26, 5q31, 6p21.1 approximately p25, 7p14 approximately p22, and 8q22. Our finding of regional gains and losses and breakpoints represents information that may contribute to NPC studies in vitro.

Cancer cell lines represent an invaluable resource for isolation of novel genes relevant to tumor pathogenesis and as in vitro models. In this study, we report on the successful establishment of four cell lines from hepatocellular carcinoma tissue. These cell lines, designated HKCI-1, HKCI-2, HKCI-3, and HKCI-4, have been growing continuously for more than 24 months and have been passaged more than 50 times. A comprehensive cytogenetic characterization on the primary tumors and the derived cell lines was achieved by the combined approach of spectral karyotyping and comparative genomic hybridization. Chromosomal imbalances from the primary tumors were also maintained in the cell lines and included gains of 1q, 6p, 7, 10p, 17q, and 20 and loss of 4q. Recurring translocations included t(X;11), t(1;10), t(4;16), i(5)(p10), t(7;21), t(8;17), t(9;22), i(10)(p10), t(14;20), t(16;22), and t(17;19). It was noteworthy that consistent chromosome 10 aberrations, in particular t(1;10)(q10;p10), were detected in all four cell lines. Furthermore, microsatellite analysis on primary tumor and derived cell lines indicated a common deleted region of 10q23-q26. The functional importance of chromosome 10 aberrations in relation to the pathogenesis of HCC is unknown; however, the high frequency with which such aberrations were maintained in the cell lines suggests proliferative advantages of 10q loss or 10p gain in the multistep development of hepatic neoplasia.

A new human esophageal cancer cell line, named SLMT-1, was established from a nude-mouse xenograft of a well-differentiated esophageal squamous cell carcinoma (ESCC) of the lower esophagus from a male Hong Kong Chinese patient. SLMT-1, passaged over 34 times and with a doubling time of 31 hours, has the microscopic features of epithelial cells with adherent growth as a monolayer. The general biologic properties of SLMT-1 cells were characterized by (1) a positive test of tumorigenicity obtained by injecting cells subcutaneously into athymic nude mice and observing their development into well-differentiated squamous cell carcinoma; (2) immunohistochemical staining using antibodies (AE1/AE3, CAM5.2 and MAK 6) which show the presence of cytokeratin intermediate filaments; and (3) electron microscopy demonstrating the morphologic features of epithelial cells with the presence of desmosomes. The cytogenetic abnormalities found in both the primary culture and SLMT-1 included der(1;14)(q10;q10), add(1)(p1?), +1, +2, del(3)(q11), +6, +7, i(8)(q10), +8, +10, +11, −13, −15, +16, +17, −18, −19, −Y and marker chromosomes. Additional changes observed in the 34th passage included gains as well as losses of both numerical and structural abnormalities. Comparative genomic hybridization (CGH) indicated copy number gains on chromosomal regions 3q32–qter, 5p, 8p12–p11.2, 11q13–q22 and 13q22–qter, and loss of the Y. The gains of 8p12–p11.2 in SLMT-1 cells are novel to ESCC. Based on its distinct and common characteristics, the SLMT-1 cell line serves as a useful tool for studying the molecular and genetic basis of the pathogenesis of ESCC.

A continuously growing human hepatocellular carcinoma (HCC) cell line was established from a Chinese male, carrier of the hepatitis B virus (HBV). This cell line, designated HKCI-1, grows as an adhering monolayer of polygonal epithelial cells that embody one or more nuclei. HKCI-1 secretes α -fetoprotein but shows no evidence of HBV carriage. Conventional banding analysis of the short-term cultured primary tumor and the propagated HKCI-1 revealed a chromosome modal number of near-triploidy. It was, however, impossible to derive their complete karyotype due to the complex nature of chromosomal rearrangements and many marker chromosomes of uncertain origin. Spectral karyotyping (SKY) is a newly developed molecular cytogenetic technique that allows the unprecedented discernment of chromosomal abnormalities. Spectral karyotyping analysis on HKCI-1 and the primary tumor elucidated all aberrant chromosomes and revealed complex karyograms. Recurring aberrations detected in both primary tumor and HKCI-1 included der(X)t(X;11)(q10;p10), der(1)t(1;10)(q10;?pq), der(4)t(4;16)(p10;q10), i(5p), del(5)(q13), der(7)t(7;21)(q32q10::q10), der(8)t(8;17)(q10;p10), and der(9)t(9;22)(q34;?pq). Comparative genomic hybridization (CGH) was employed to monitor the culture evolution in vitro. Genomic imbalances in HKCI-1 involved chromosomal losses on 4q, 5q13–qter, 8p, 9pter–q33, 10q, 11q, 13q, 16q, 17q12–qter, and 22, and low-level gains on 6pter–q22, 7p, 8q, 9q34, 10p, 11p, 12, 17pter–q11.2, 18, 19, 20, 21, and Y. High-level amplifications were also detected on 5pter–q12, 7q11.2–qter, and Xq. The corresponding CGH finding on the primary tumor indicated similar imbalances. TP53 mutational analysis showed that both HKCI-1 and the primary tumor had the aflatoxin-associated mutation in codon 249 and an additional TP53 polymorphism in codon 72. Our present study demonstrates the value of combined SKY and CGH study in defining complex rearrangements and identifying cryptic translocations, and provides a comprehensive analysis on the chromosomal abnormalities in HKCI-1.

Air-ambulance services are extremely expensive to operate and maintain. The value of their existence has been questioned in this era of rationalization and downsizing. We examined the cost, safety, flight crew composition, types of trauma, and effectiveness of our air-ambulance program at the Children's Hospital of Eastern Ontario (CHEO) over a 3-year period, 1994-1997. During this time, 392 children were aeroevacuated to CHEO, 113 surgical (29%), 136 medical (35%), and 143 neonates (36%). Of the surgical cases, 43% were transferred for orthopaedic trauma, the commonest being fractured femur, 23% for general surgical cases, most common being thoracoabdominal trauma, and 22% for neurosurgical reasons, most commonly basilar skull fractures. The average response time (time from which the call was received to the time when the helicopter reached the patient site) for all of the cases was 46 min. The average travel time (time from departure of patient site to arrival at CHEO) for these same cases was 25.59 min. The air-ambulance program for children in the Ottawa-Carleton Eastern Ontario areas, was found to be safe, effective, and allowed earlier specialized medical care to be provided.

The periosteum in children and especially infants has significant osteogenic potential. To determine the efficacy of periosteal flaps to assist in improving acetabular coverage in children with acetabular dysplasia, a series of experiments were designed using young rabbits. Three groups of five rabbits each had periosteal flaps fashioned and brought down from the anterolateral aspect of the innominate bone superior to the acetabulum and sutured to the capsule of the hip. The study was designed to examine the effects of the periosteal cambium layer in the formation of new bone to augment the acetabulum and to determine the effects of a periosteal flap plus cancellous bone graft. A control group of five rabbits underwent a sham operation of an open arthrotomy of the hip. Radiographic and histologic examination at 12 weeks revealed augmentation of the acetabulum with periosteal flaps that resulted in an average improvement of the acetabular index of 3.5 degrees and 6.6 degrees, without and with bone graft, respectively. New bone formation from the rim of the acetabulum averaged 3.9 mm with periosteal flaps alone and 4.6 mm with bone graft added. Periosteal augmentation of the acetabulum in conjunction with established procedures for augmenting acetabular coverage would appear to be a useful procedure for improving coverage of the femoral head in children with acetabular dysplasia.

Prostaglandins are being commonly used to maintain the patency of the ductus arteriosus in infants with congenital ductal-dependent heart disease. A significant and unusual side effect of this drug treatment is the symmetrical development of periostitis of the long bones. A review of neonates with congenital heart disease requiring prostaglandin treatment at the Children's Hospital of Eastern Ontario revealed five infants who developed periostitis, the earliest onset being after 14 days of prostaglandin infusion. The drug dosage varied in these infants from 0.02 to 0.10 micrograms/kg/min. The periostitis was associated with limb pain and considerable swelling of the extremities in all children. The periostitis improved on cessation of the prostaglandin infusion, and by 6 weeks after the cessation of the drug, the periostitis had decreased significantly. Periostitis seemed more dependent on the duration of administration of the prostaglandin than on the dosage of prostaglandin administered. Awareness of this entity is essential not only for the treatment team caring for these infants but also for consultant pediatric orthopaedists to avoid excessive investigation for infection, metabolic disease, or vitamin deficiencies that resemble prostaglandin-induced periostitis.

Background Post-traumatic stress disorder (PTSD) is associated with atypical responses to emotional face stimuli with preferential processing given to threat-related facial expressions via hyperactive amygdalae disengaged from medial prefrontal modulation. Method We examined implicit emotional face perception in soldiers with (n = 20) and without (n = 25) PTSD using magnetoencephalography to define spatiotemporal network interactions, and a subsequent region-of-interest analysis to characterize the network role of the right amygdala and medial prefrontal cortex in threatening face perception. Results Contrasts of network interactions revealed the PTSD group were hyperconnected compared to controls in the phase-locking response in the 2–24 Hz range for angry faces, but not for happy faces when contrasting groups. Hyperconnectivity in PTSD was greatest in the posterior cingulate, right ventromedial prefrontal cortex, right parietal regions and the right temporal pole, as well as the right amygdala. Graph measures of right amygdala and medial prefrontal connectivity revealed increases in node strength and clustering in PTSD, but not inter-node connectivity. Additionally, these measures were found to correlate with anxiety and depression. Conclusions In line with prior studies, amygdala hyperconnectivity was observed in PTSD in relation to threatening faces, but the medial prefrontal cortex also displayed enhanced connectivity in our network-based approach. Overall, these results support preferential neurophysiological encoding of threat-related facial expressions in those with PTSD.