Review of Pediatric Extraosseous Chordomas with a Unique, Illustrative Case.

INTRODUCTION: Chordoma is a rare, aggressive tumor that is believed to originate from notochord remnants. It can occur anywhere from the clivus to the sacrum and often recurs even after resection and radiotherapy. We present a unique case that initially suggested a different pathology based on imaging and presentation but was found to be a chordoma on gross and pathological analysis. CASE PRESENTATION: An 11-year-old girl presented outpatient for scoliosis evaluation and was found to have what appeared to be a right L4 peripheral nerve sheath tumor on MRI, causing dextroconvex scoliosis. She underwent a gross total resection via a retroperitoneal approach and was found to have what appeared to be an extraosseous, extradural, extra-spinal canal lumbar chordoma. Immunohistochemical features on surgical pathology were consistent with chordoma. The patient was referred to radiation oncology for adjuvant radiotherapy and pediatric hematology/oncology for recurrence monitoring. DISCUSSION: Our case is the first to present in such a manner, was shown to be external to the spinal canal, encasing the nerve root, and was the first such case in a pediatric patient. We reviewed the growing body of literature on spinal extraosseous chordomas and their characteristics within the pediatric patient population. We also reviewed chordoma pathogenesis theories as well as current and future treatment options.

Effect of Brief Training to Identify Autism Spectrum Disorder During Toddler Well-Child Care Visits.

OBJECTIVE: To examine the effect of a brief Enhanced training using the information-motivation-behavior (IMB) change model on improving providers' surveillance rates and accuracy of autism spectrum disorder (ASD) detection. METHOD: Toddlers (n = 5,672) were screened for ASD during their pediatric well-child visits. Pediatric providers (n = 120) were randomized to receive Enhanced (incorporating components of the IMB model) or Control training. Providers indicated whether they had an ASD concern at each well-child visit. Toddlers who were positive on any screener and/or whose provider indicated ASD concern were invited for a diagnostic evaluation. Differences in provider-indicated ASD concerns before and after training were evaluated using log-linear analyses. RESULTS: The Enhanced training did not have a significant effect on provider-endorsed ASD concerns (p = 0.615) or accuracy of endorsing concerns (p = 0.619). Providers in the Control training showed a significant reduction in indicating whether or not they had concerns after the training (from 71.9% to 64.3%), which did not occur in the Enhanced group. The Enhanced training led to more frequent endorsements of language (χ2 = 8.772, p = 0.003) and restricted and repetitive behavior (χ2 = 7.918, p = 0.005) concerns for children seen after training. CONCLUSION: Provider training had limited impact on ASD surveillance, indicating the importance of using formal screening instruments that rely on parent report during well-child visits to complement developmental surveillance. Future research should examine whether providers who indicate specific concerns are more likely to accurately refer children for ASD evaluations.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY): Molecular Profiling Confirms Frequent MAPK Pathway Activation.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5-52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.

A rare giant mixed germ cell tumor of the pineal region with immature elements: Case report and review of the literature.

The diagnosis and management of mixed intracranial germ cell tumors may be complicated by the diversity present within this tumor category. Mixed germ cell tumors demonstrate variable natural histories which may be altered by the inclusion of even the most minute immature histological components. We report the case of an 18-year-old male who presented with a 3-month history of progressive headache and nausea leading to lethargy. Imaging revealed a giant pineal region mass extending superiorly from the roof of the fourth ventricle into the lateral ventricle, with resultant obstructive hydrocephalus. No spinal lesions were noted. Following gross total resection, the patient experienced marked improvement. Pathologic analysis identified an uncommon tumor composition: mature teratoma (96%), immature teratoma (2%), and germinoma (2%). Guided by the immature component, chemotherapy and radiation were added post-operatively to provide this patient with the greatest chance of long-term survival. Intracranial pathology, including germ cell tumors, should be included in the differential for any young patient presenting with new and progressive headache and nausea. This case emphasizes the benefit of a multimodal approach to mixed germ cell tumors of the pineal region and the importance of careful pathologic review of all submitted material.

Early and Repeated Screening Detects Autism Spectrum Disorder.

OBJECTIVE: To evaluate timing and accuracy of early and repeated screening for autism spectrum disorder (ASD) during well-child visits. STUDY DESIGN: Using a longitudinal study design, toddlers (n = 5784) were initially screened at 12 (n = 1504), 15 (n = 1228), or 18 (n = 3052) months during well-child visits, and rescreened at 18, 24, and 36 months. Of those screened, 368 toddlers attended an ASD evaluation after a positive screen and/or a provider concern for ASD at any visit. RESULTS: Screens initiated at 12 months yielded an ASD diagnosis significantly earlier than at 15 months (P = .003, d = 0.99) and 18 months (P < .001, d = 0.97). Cross-group overall sensitivity of the initial screen was .715 and specificity was .959. Repeat screening improves sensitivity (82.1%), without notably decreasing specificity (all >93.5%). Screening at 18 months resulted in significantly higher positive predictive value than at 12 months (X2 (1, n = 221) = 9.87, P = .002, OR = 2.60) and 15 months (X2 (1, n = 208) = 14.57, P < .001, OR = 3.67). With repeat screening, positive predictive value increased for all screen groups, but the increase was not significant. CONCLUSIONS: Screening as early as 12 months effectively identifies many children at risk for ASD. Children screened at 12 months receive a diagnosis of ASD significantly earlier than peers who are first screened at later ages, facilitating earlier intervention. However, as the sensitivity is lower for a single screen, screening needs to be repeated.

Zinc-Dependent Regulation of ZEB1 and YAP1 Coactivation Promotes Epithelial-Mesenchymal Transition Plasticity and Metastasis in Pancreatic Cancer.

BACKGROUND: Pancreatic cancer is characterized by extensive metastasis. Epithelial-mesenchymal transition (EMT) plasticity plays a critical role in tumor progression and metastasis by maintaining the transition between EMT and mesenchymal-epithelial transition states. Our aim is to understand the molecular events regulating metastasis and EMT plasticity in pancreatic cancer. METHODS: The interactions between a cancer-promoting zinc transporter ZIP4, a zinc-dependent EMT transcriptional factor ZEB1, a coactivator YAP1, and integrin α3 (ITGA3) were examined in human pancreatic cancer cells, clinical specimens, spontaneous mouse models (KPC and KPCZ) and orthotopic xenografts, and 3-dimensional spheroid and organoid models. Correlations between ZIP4, miR-373, and its downstream targets were assessed by RNA in situ hybridization and immunohistochemical staining. The transcriptional regulation of ZEB1, YAP1, and ITGA3 by ZIP4 was determined by chromatin immunoprecipitation, co-immunoprecipitation, and luciferase reporter assays. RESULTS: The Hippo pathway effector YAP1 is a potent transcriptional coactivator and forms a complex with ZEB1 to activate ITGA3 transcription through the YAP1/transcriptional enhanced associate domain (TEAD) binding sites in human pancreatic cancer cells and KPC-derived mouse cells. ZIP4 upregulated YAP1 expression via activation of miR-373 and inhibition of the YAP1 repressor large tumor suppressor 2 kinase (LATS2). Furthermore, upregulation of ZIP4 promoted EMT plasticity, cell adhesion, spheroid formation, and organogenesis both in human pancreatic cancer cells, 3-dimensional spheroid model, xenograft model, and spontaneous mouse models (KPC and KPCZ) through ZEB1/YAP1-ITGA3 signaling axis. CONCLUSION: We demonstrated that ZIP4 activates ZEB1 and YAP1 through distinct mechanisms. The ZIP4-miR-373-LATS2-ZEB1/YAP1-ITGA3 signaling axis has a significant impact on pancreatic cancer metastasis and EMT plasticity.

Realising the electrochemical stability of graphene: scalable synthesis of an ultra-durable platinum catalyst for the oxygen reduction reaction.

Creating effective and stable catalyst nanoparticle-coated electrodes that can withstand extensive cycling is a current roadblock in realising the potential of polymer electrolyte membrane fuel cells. Graphene has been proposed as an ideal electrode support material due to its corrosion resistance, high surface area and high conductivity. However, to date, graphene-based electrodes suffer from high defect concentrations and non-uniform nanoparticle coverage that negatively affects performance; moreover, production methods are difficult to scale. Herein we describe a scalable synthesis for Pt nanoparticle-coated graphene whereby PtCl2 is reduced directly by negatively charged single layer graphene sheets in solution. The resultant nanoparticles are of optimal dimensions and can be uniformly dispersed, yielding high catalytic activity, remarkable stability, and showing a much smaller decrease in electrochemical surface area compared with an optimised commercial catalyst over 30 000 cycles. The stability is rationalised by identical location TEM which shows minimal nanoparticle agglomeration and no nanoparticle detachment.

ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3ß1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells.

BACKGROUND & AIMS: Pancreatic tumors undergo rapid growth and progression, become resistant to chemotherapy, and recur after surgery. We studied the functions of the solute carrier family 39 member 4 (SLC39A4, also called ZIP4), which regulates concentrations of intracellular zinc and is increased in pancreatic cancer cells, in cell lines and mice. METHODS: We obtained 93 pancreatic cancer specimens (tumor and adjacent nontumor tissues) from patients who underwent surgery and gemcitabine chemotherapy and analyzed them by immunohistochemistry. ZIP4 and/or ITGA3 or ITGB1 were overexpressed or knocked down with short hairpin RNAs in AsPC-1 and MIA PaCa-2 pancreatic cancer cells lines, and in pancreatic cells from KPC and KPC-ZEB1-knockout mice, and pancreatic spheroids were established; cells and spheroids were analyzed by immunoblots, reverse transcription polymerase chain reaction, and liquid chromatography tandem mass spectrometry. We studied transcriptional regulation of ZEB1, ITGA3, ITGB1, JNK, and ENT1 by ZIP4 using chromatin precipitation and luciferase reporter assays. Nude mice were given injections of genetically manipulated AsPC-1 and MIA PaCa-2 cells, and growth of xenograft tumors and metastases was measured. RESULTS: In pancreatic cancer specimens from patients, increased levels of ZIP4 were associated with shorter survival times. MIA PaCa-2 cells that overexpressed ZIP4 had increased resistance to gemcitabine, 5-fluorouracil, and cisplatin, whereas AsPC-1 cells with ZIP4 knockdown had increased sensitivity to these drugs. In mice, xenograft tumors grown from AsPC-1 cells with ZIP4 knockdown were smaller and more sensitive to gemcitabine. ZIP4 overexpression significantly reduced accumulation of gemcitabine in pancreatic cancer cells, increased growth of xenograft tumors in mice, and increased expression of the integrin subunits ITGA3 and ITGB1; expression levels of ITGA3 and ITGB1 were reduced in cells with ZIP4 knockdown. Pancreatic cancer cells with ITGA3 or ITGB1 knockdown had reduced proliferation and formed smaller tumors in mice, despite overexpression of ZIP4; spheroids established from these cells had increased sensitivity to gemcitabine. We found ZIP4 to activate STAT3 to induce expression of ZEB1, which induced expression of ITGA3 and ITGB1 in KPC cells. Increased ITGA3 and ITGB1 expression and subsequent integrin α3ß1 signaling, via c-Jun-N-terminal kinase (JNK), inhibited expression of the gemcitabine transporter ENT1, which reduced gemcitabine uptake by pancreatic cancer cells. ZEB1-knockdown cells had increased sensitivity to gemcitabine. CONCLUSIONS: In studies of pancreatic cancer cell lines and mice, we found that ZIP4 increases expression of the transcription factor ZEB1, which activates expression of ITGA3 and ITGB1. The subsequent increase in integrin α3ß1 signaling, via JNK, inhibits expression of the gemcitabine transporter ENT1, so that cells take up smaller amounts of the drug. Activation of this pathway might help mediate resistance of pancreatic tumors to chemotherapeutic agents.

Clinical features of hemophagocytic syndrome in children and significance of gene detection / 中华实用儿科临床杂志

Objective To explore the clinical features of hemophagocytic syndrome in children and the signifi﹣cance of gene detection. Methods TWenty－tWo pediatric patients diagnosed as hemophagocytic syndrome since 2004 clinical and laboratory criteria Were enrolled in Children＇s Hospital Affiliated to Zhengzhou University from January 2014 to January 2016. The clinical data of patients Were analyzed,and the genes associated With hemophagocytic syn﹣drome Were detected. The clinical biochemical indicators Were compared betWeen mutation group and non －mutation group. Results TWenty－tWo cases of patients(3 months to 12 years)Were enrolled,including 10 males and 12 fe﹣males,and the proportion of children over 5 years old accounted for the highest proportion,accounting for 50%,and all of them had fever,liver,spleen and lymph node enlargement. The main test results Were as folloWs:peripheral blood cells decreased in 6 cases( 27. 27%),hemophagocytic phenomena presented in bone marroW smears in 12 cases (54. 55%),abnormal liver function in 18 cases(81. 82%),and loW serum albumin in 22 cases(100. 00%). High serum ferritin levels Were detected in 20 cases(90. 91%);the detection of natural killer(NK)cell activity shoWed nor﹣mal activity( active ＞ 15%) in 7 cases( 31. 82%),and decreased activity( activity ≤ 15%) in 15 cases (68. 18%). The genes associated With hemophagocytic syndrome Were detected in 22 cases of patients,and 12 of them Were associated With mutations related to hemophagocytic syndrome,accounting for 54. 55%. LYST,ITK and UNC13D gene Were common. There Was no statistical difference in Which ages of onset,symptoms of the nervous system,and labo﹣ratory data of leukocyte count,red blood cell count,hemoglobin,platelet count,NK cell activities,prognosis,hemophago﹣cytic phenomena shoWed in bone marroW smears,alanine aminotransferase,albumin,triglyceride,ferritin and fibrinogen betWeen mutation group and non－mutation group(all P＞0. 05). Conclusions Pediatric hemophagocytic syndrome is mostly accompanied by fever,liver,spleen and lymph node enlargement,and most of them are accompanied by gene mu﹣tations. LYST,ITK and UNC13D gene are commonly seen. But there is no significant correlation betWeen gene mutation and general condition,biochemical index and severity of the disease.

Assessment of mouse strain differences in baseline esterase activities and toxic response to sarin.

Genetics likely play a role in various responses to nerve agent (NA) exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses. This study uses different mouse strains to identify if mouse strain differences in sarin exposure exist. In Experiment 1, basal levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CE) were measured in different strains of naïve mice to account for potential pharmacokinetic determinants of individual differences. In Experiment 2, median lethal dose (MLD) levels were estimated in 8 inbred mouse strains following subcutaneous (s.c.) administration of sarin. Few strain or sex differences in esterase activity levels were observed, with the exception of erythrocyte AChE activity in the C57BL/6J strain. Both sex and strain differences in toxicity were observed, with the most resistant strains being the BALB/cByJ and FVB/NJ strains and the most sensitive strain being the DBA/2J strain. These findings can be expanded to explore pathways involved in NA response, which may provide an avenue to develop therapeutics for preventing and treating the damaging effects of NA exposure.

Human immunodeficiency virus Tat-TIP30 interaction promotes metastasis by enhancing the nuclear translocation of Snail in lung cancer cell lines.

Lung cancer patients with human immunodeficiency virus (HIV) have a poorer prognosis than do patients without HIV infection. HIV1 Tat is a secreted viral protein that penetrates the plasma membrane and interacts with a number of proteins in non-HIV-infected cells. The loss of function of Tat-interacting protein 30 (TIP30) has been linked to metastasis in non-small cell lung cancer (NSCLC). However, it is unknown how the interaction of HIV1 Tat with TIP30 regulates the metastasis of NSCLC cells. In this study, the overexpression of TIP30 decreased tumor growth factor-ß-induced epithelial-to-mesenchymal transition (EMT) and invasion of NSCLC cells, whereas the knockdown of TIP30 promoted EMT, invasion and stemness. Exposure to recombinant HIV1 Tat proteins promoted EMT and invasion. A mechanistic study showed that the interaction of HIV1 Tat with TIP30 blocked the binding of TIP30 to importin-ß, which is required for the nuclear translocation of Snail. Indeed, the loss of TIP30 promoted the nuclear translocation of Snail. In vivo studies demonstrated that the overexpression of TIP30 inhibited the metastasis of NSCLC cells. In contrast, the coexpression of HIV1 Tat and TIP30 diminished the inhibitory effect of TIP30 on metastasis. Immunohistochemistry confirmed that TIP30 overexpression reduced the nuclear localization of Snail, whereas the coexpression of HIV1 Tat and TIP30 increased nuclear Snail in metastatic tumors. In conclusion, the binding of HIV1 Tat to TIP30 enhanced EMT and metastasis by regulating the nuclear translocation of Snail. Targeting Tat-interacting proteins may be a potential therapeutic strategy to prevent metastasis in NSCLC patients with HIV infection.

AIDS incidence trends at presentation and during follow-up among HIV-at-risk populations: a 15-year nationwide cohort study in Taiwan.

BACKGROUND: Although Taiwan has implemented several important interventions for various HIV-at-risk populations to combat the HIV epidemic, little is known regarding AIDS incidence at presentation and during follow-up among the various HIV-at-risk populations in Taiwan. A better understanding of AIDS incidence trends would help improve patient care and optimize public health strategies aimed at further decreasing HIV-related morbidity and mortality. METHODS: Data from Taiwan Centers for Disease Control-operated Notifiable Diseases Surveillance System and Taiwan National Health Insurance Research Database (1998-2012) was divided into five cohort periods (consecutive 3-year groups). Logistic regression was employed to identify factors associated with AIDS incidence at presentation. Time-dependent Cox regression was used to identify factors associated with AIDS incidence during the follow-up period. RESULTS: Of 22,665 patients [mean age: 32 years; male (93.03%)], 6210 (27.4%) had AIDS incidence over 2 (1.16) [median (interquartile range)] years of follow-up. AIDS developed in ≤3 months of HIV diagnosis in 73.6% AIDS patients. AIDS incidence trends at presentation and during follow-up differed according to HIV transmission routes over the five periods: AIDS at presentation increased in the sexual contact groups (P < 0.001 for homosexuals/heterosexuals; 0.648 for bisexuals) but decreased to a nadir in period 3 and then increased slightly in period 5 (P < 0.001) in people who injected drugs (PWIDs). AIDS incidence during the follow-up period increased from period 1 to a peak in period 3 or 4, before declining slightly in period 5, in the sexual contact groups (P < 0.001 for homosexuals/heterosexuals; 0.549 for bisexuals). However, it increased throughout the five periods in PWIDs (P < 0.001). Older age, sexual contact group versus PWIDs, high versus low income level, cohort periods, and HIV diagnosis regions helped predict AIDS at presentation and during follow-up. CONCLUSIONS: Disparities in AIDS incidence trends in various HIV-at-risk populations reflect different sociodemographic variables of HIV exposure and the adopted HIV prevention strategies. This study suggests the urgent need for tailored strategies aimed at specific populations at presentation and during follow-up.

1,2,3,4,6-Penta-O-Galloyl-Beta-D-Glucopyranoside Inhibits Proliferation of Multiple Myeloma Cells Accompanied with Suppression of MYC Expression.

Multiple myeloma (MM) still remains an incurable disease, therefore discovery of novel drugs boosts the therapeutics for MM. The natural compound 1,2,3,4,6-Penta-O-galloyl-beta-D-glucopyranoside (PGG) has been shown to exhibit antitumor activities against various cancer cells. Here, we aim to evaluate antitumor effects of PGG on MM cell lines. PGG inhibited the growth of three different MM cell lines in a dose- and time-dependent manner. Cell cycle analysis revealed that PGG treatment caused cell cycle arrest in G1 phase. It also induced apoptosis which was indicated by significant increases of Annexin V positive cells, caspase 3/7 activity, and cleaved caspase 3 expression in PGG treated MM cell. Since MYC is frequently hyperactivated in MM and inhibition of MYC leads to MM cell death. We further demonstrated that PGG decreased MYC expression in protein and mRNA levels and reversed the mRNA expression of MYC target genes such as p21, p27, and cyclin D2. In addition, PGG also reduced protein expression of DEPTOR which is commonly overexpressed in MM. Unexpectedly, PGG antagonized the cytotoxic effect of bortezomib in the combination treatment. However, PGG treatment sensitized MM cells to another proteasome inhibitor MG132 induced cytotoxicity. Moreover, MYC inhibitor JQ1 enhanced the cytotoxic effect of bortezomib on MM cells. Our findings raised concerns about the combinatory use of bortezomib with particular types of chemicals. The evidence also provide useful insights into the combination of MYC and proteasome-inhibitors for MM therapy. Finally, PGG has a therapeutic potential for treatment of MM and further development is mandatory.

Long-range gamma phase synchronization as a compensatory strategy during working memory in high-performing patients with schizophrenia.

Working memory deficits in schizophrenia may be associated with impairments in the integration of neural activity across a distributed network of cortical areas. However, evaluation of the contribution of this integration to working memory impairments in patients is severely confounded by behavioral performance. In the present multidimensional-neuroimaging study, measures of neural oscillations at baseline and during a working memory task, baseline gamma-aminobutyric acid (GABA) level in the left dorsolateral prefrontal cortex (DLPFC), and behavioral performance were obtained. Controlling behavioral performance by recruiting only "high-performing" patients with schizophrenia, we investigated whether the strength of cross-area communications differs between patients with schizophrenia and healthy participants under accurate and equivalent behavioral performance. Results of phase-locking value indicated that these high-performing patients recruited significantly more between frontal and occipital regions in the left hemisphere, t(13) = -2.16, p = .05, Cohen's d = -1.20, and between frontal and temporal regions in the right hemisphere, t(13) = -2.63, p = .02, Cohen's d = -1.46. These cross-area communication patterns may be associated with visuoverbal and visuospatial working memory networks of the left and right hemispheres, respectively. Moreover, correlations of patient's cross-area communication with in vivo GABA levels of the left DLPFC revealed a significant positive relationship (r = .77, p = .04), demonstrating that the critical role of GABA functions in gamma band oscillations may go beyond local neuronal assemblies in the left DLPFC. Altogether, these exploratory findings point to the heterogeneity among schizophrenia patients and highlight the notion that high-performing patients may engage in potential compensatory mechanisms and may represent a subgroup of patients that may be categorically or dimensionally divergent in psychopathology.

Effects of chronic ketamine on hippocampal cross-frequency coupling: implications for schizophrenia pathophysiology.

Disrupted neuronal oscillations have been identified as a potentially important biomarker for the perceptual and cognitive symptoms of schizophrenia. Emerging evidences suggest that interactions between different frequency bands, cross-frequency coupling (CFC), serve an important role in integrating sensory and cognitive information and may contribute to disease pathophysiology. In this study, we investigated the effects of 14-day consecutive administration of ketamine (30 mg/kg i.p.) vs. saline on alterations in amplitude and changes in the coupling of low-frequency (0-30 Hz) phase and high-frequency (30-115 Hz) amplitude in the CA1 hippocampus of Long Evans rats. Intracranial electrode recordings were conducted pre- and post-injection while the animals performed a foraging task on a four-arm rectangular maze. Permutation analysis of frequency band-specific change in amplitudes revealed between-group differences in theta (6-12 Hz) and slow gamma (25-50 Hz) but not fast gamma (65-100 Hz) bands at both slow and fast speeds. Chronic ketamine challenge resulted in decreased coupling (pre to post) at slow speeds but increased coupling at faster speeds, compared to either no or modest increased coupling in the saline group. These results demonstrate that chronic ketamine administration alters the interaction of low-frequency phase and high-frequency oscillations chronically and that such coupling varies as a function of locomotive speed. These findings provide evidence for the potential relevance of CFC to the pathophysiology of schizophrenia.

Indigenous Wildlife Rabies in Taiwan: Ferret Badgers, a Long Term Terrestrial Reservoir.

The emerging disease of rabies was confirmed in Taiwan ferret badgers (FBs) and reported to the World Organization for Animal Health (OIE) on July 17, 2013. The spread of wildlife rabies can be related to neighborhood countries in Asia. The phylogenetic analysis was conducted by maximum likelihood (ML) methods and the Bayesian coalescent approach based on the glycoprotein (G) and nucleoprotein (N) genes. The phylogeographic and spatial temporal dynamics of viral transmission were determined by using SPREAD, QGIS. Therefore, the origin and the change with time of the viruses can be identified. Results showed the rabies virus of FB strains in Taiwan is a unique clade among other strains in Asia. According to the phylogeographic coalescent tree, three major genotypes of the FB rabies virus have circulated in three different geographical areas in Taiwan. Two genotypes have distributed into central and southern Taiwan between two ecological river barriers. The third genotype has been limited in southeastern Taiwan by the natural mountain barrier. The diversity of FB rabies viruses indicates that the biological profile of FBs could vary in different geographical areas in Taiwan. An enhanced surveillance system needs to be established near the currently identified natural barriers for early warnings of the rabies virus outbreak in Taiwan.

Mortality in tongue cancer patients treated by curative surgery: a retrospective cohort study from CGRD.

BACKGROUND: Our study aimed to compare the outcomes of surgical treatment of tongue cancer patients in three different age groups. METHODS: From 2004 to 2013, we retrospectively analyzed the clinical data of 1,712 patients who were treated in the four institutions constituting the Chang Gung Memorial Hospitals (CGMH). We divided and studied the patients in three age groups: Group 1, younger (<65 years); Group 2, young old (65 to <75); and Group 3, older old patients (≥75 years). RESULTS: Multivariate analyses determined the unfavorable, independent prognostic factors of overall survival to be male sex, older age, advanced stage, advanced T, N classifications, and surgery plus chemotherapy. No significant differences were found in adjusted hazard ratios (HR) of death in early-stage disease (stage I-II) among Group 1 (HR 1.0), Group 2 (HR 1.43, 95% confidence interval (CI) [0.87-2.34], p = 0.158), and Group 3 (HR 1.22, 95% CI [0.49-3.03], p = 0.664) patients. However, amongst advanced-stage patients (stage (III-IV)), Group 3 (HR 2.53, 95% CI [1.46-4.38], p  = 0.001) showed significantly worse survival than the other two groups after other variables were adjusted for. Fourteen out of 21 older old, advanced-staged patients finally died, and most of the mortalities were non-cancerogenic (9/14, 64.3%), and mostly occurred within one year (12/14, 85%) after cancer diagnosis. These non-cancer cause of death included underlying diseases in combination with infection, pneumonia, poor nutrition status, and trauma. CONCLUSIONS: Our study showed that advanced T classification (T3-4), positive nodal metastasis (N1-3) and poorly differentiated tumor predicted poor survival for all patients. Outcome of early-stage patients (stage I-II) among three age groups were not significantly different. However, for advanced-stage patients (stage III-IV), the older old patients (≥75) had significantly worse survival than the other two patient groups. Therefore, for early-stage patients, age should not deny them to receive optimal treatments. However, older old patients (≥75) with advanced cancer should be comprehensively assessed by geriatric tools before surgical treatment and combined with intensive postoperative care to improve outcome, especially the unfavorable non-cancerogenic mortalities within one year after cancer diagnosis.

Machine learning identification of EEG features predicting working memory performance in schizophrenia and healthy adults.

BACKGROUND: With millisecond-level resolution, electroencephalographic (EEG) recording provides a sensitive tool to assay neural dynamics of human cognition. However, selection of EEG features used to answer experimental questions is typically determined a priori. The utility of machine learning was investigated as a computational framework for extracting the most relevant features from EEG data empirically. METHODS: Schizophrenia (SZ; n = 40) and healthy community (HC; n = 12) subjects completed a Sternberg Working Memory Task (SWMT) during EEG recording. EEG was analyzed to extract 5 frequency components (theta1, theta2, alpha, beta, gamma) at 4 processing stages (baseline, encoding, retention, retrieval) and 3 scalp sites (frontal-Fz, central-Cz, occipital-Oz) separately for correctly and incorrectly answered trials. The 1-norm support vector machine (SVM) method was used to build EEG classifiers of SWMT trial accuracy (correct vs. incorrect; Model 1) and diagnosis (HC vs. SZ; Model 2). External validity of SVM models was examined in relation to neuropsychological test performance and diagnostic classification using conventional regression-based analyses. RESULTS: SWMT performance was significantly reduced in SZ (p < .001). Model 1 correctly classified trial accuracy at 84 % in HC, and at 74 % when cross-validated in SZ data. Frontal gamma at encoding and central theta at retention provided highest weightings, accounting for 76 % of variance in SWMT scores and 42 % variance in neuropsychological test performance across samples. Model 2 identified frontal theta at baseline and frontal alpha during retrieval as primary classifiers of diagnosis, providing 87 % classification accuracy as a discriminant function. CONCLUSIONS: EEG features derived by SVM are consistent with literature reports of gamma's role in memory encoding, engagement of theta during memory retention, and elevated resting low-frequency activity in schizophrenia. Tests of model performance and cross-validation support the stability and generalizability of results, and utility of SVM as an analytic approach for EEG feature selection.

Isolating dividing neural and brain tumour cells for gene expression profiling.

BACKGROUND: The characterisation of dividing brain cells is fundamental for studies ranging from developmental and stem cell biology, to brain cancers. Whilst there is extensive anatomical data on these dividing cells, limited gene transcription data is available due to technical constraints. NEW METHOD: We focally isolated dividing cells whilst conserving RNA, from culture, primary neural tissue and xenografted glioma tumours, using a thymidine analogue that enables gene transcription analysis. RESULTS: 5-ethynyl-2-deoxyuridine labels the replicating DNA of dividing cells. Once labelled, cultured cells and tissues were dissociated, fluorescently tagged with a revised click chemistry technique and the dividing cells isolated using fluorescence-assisted cell sorting. RNA was extracted and analysed using real time PCR. Proliferation and maturation related gene expression in neurogenic tissues was demonstrated in acutely and 3 day old labelled cells, respectively. An elevated expression of marker and pathway genes was demonstrated in the dividing cells of xenografted brain tumours, with the non-dividing cells showing relatively low levels of expression. COMPARISON WITH EXISTING METHOD: BrdU "immune-labelling", the most frequently used protocol for detecting cell proliferation, causes complete denaturation of RNA, precluding gene transcription analysis. This EdU labelling technique, maintained cell integrity during dissociation, minimized copper exposure during labelling and used a cell isolation protocol that avoided cell lysis, thus conserving RNA. CONCLUSIONS: The technique conserves RNA, enabling the definition of cell proliferation-related changes in gene transcription of neural and pathological brain cells in cells harvested immediately after division, or following a period of maturation.

Risk group characteristics and viral transmission clusters in South-East Asian patients infected with human immunodeficiency virus-1 (HIV-1) circulating recombinant form (CRF) 01_AE and subtype B.

Human immunodeficiency virus (HIV)-1 epidemics in Asian countries are driven by varying exposures. The epidemiology of the regional pandemic has been changing with the spread of HIV-1 to lower-risk populations through sexual transmission. Common HIV-1 genotypes include subtype B and circulating recombinant form (CRF) 01_AE. Our objective was to use HIV-1 genotypic data to better quantify local epidemics. TASER-M is a multicenter prospective cohort of HIV-infected patients. Associations between HIV exposure, patient sex, country of sample origin and HIV-1 genotype were evaluated by multivariate logistic regression. Phylogenetic methods were used on genotypic data to investigate transmission relationships. A total of 1086 patients from Thailand, Hong Kong, Malaysia and the Philippines were included in analyses. Proportions of male patients within countries varied (Thailand: 55.6%, Hong Kong: 86.1%, Malaysia: 81.4%, Philippines: 93.8%; p < 0.001) as did HIV exposures (heterosexual contact: Thailand: 85.7%, Hong Kong, 46.2%, Malaysia: 47.8%, Philippines: 25.0%; p < 0.001). After adjustment, we found increased subtype B infection among men who have sex with men, relative to heterosexual-reported exposures (odds ratio = 2.4, p < 0.001). We further describe four transmission clusters of eight to 15 treatment naïve, predominantly symptomatic patients (two each for subtype B and CRF01_AE). Risk-group subpopulations differed with respect to the infecting HIV-1 genotype. Homosexual exposure patients had higher odds of being infected with subtype B. Where HIV-1 genotypes circulate within countries or patient risk-groups, local monitoring of genotype-specific transmissions may play a role in focusing public health prevention strategies. Phylogenetic evaluations provide complementary information for surveillance and monitoring of viruses with high mutation rates such as HIV-1 and Ebola.