Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer

Purpose: Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. Patients and Methods: Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. Results: Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients. Conclusion: Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC. © 2005 by American Society of Clinical Oncology.

Prognostic significance of platelet and microvessel counts in operable non-small cell lung cancer

Background: Microvessel density, an indirect measure of angiogenesis, has been shown to be an independent prognostic marker in many solid tumours including non-small cell lung cancer (NSCLC). Platelets transport and release angiogenic growth factors. Platelets are increasingly likely to adhere to tumour microvessels due to raised expression of platelet-binding proteins and stasis in blood-flow. Increased vascular permeability in tumour microvessels facilitates platelet extravasation into the extracellular matrix. Adherence and extravasation both lead to platelet activation and release of growth factors capable of instigating the angiogenic process. Methods: A total of 181 patients were identified who underwent resection of stage I-IIIa NSCLC with a post-operative survival >60 days. Patients were followed-up for a minimum of 24 months. Sections from the tumour periphery were stained for the endothelial marker CD34 (Novocastra NCL-END) using standard ABC immunohistochemistry. Chalkley counting was used to assess microvessel density. Results: A pre-operative platelet count greater than the median and above the normal range (>400) was associated with a poor outcome (P = 0.01 and P = 0.04, respectively). Tumours with an above median and high Chalkley count (upper tertile) had a worse prognosis (P = 0.007 and P = 0.0006, respectively). There was no association between platelet count and Chalkley count. Conclusions: Platelet and microvessel counts are both potential prognostic markers for NSCLC. The role of platelets in the angiogenic process needs to be further investigated. (C) 2000 Elsevier Science Ireland Ltd.

Platelet-derived endothelial cell growth factor (thymidine phosphorylase) expression in lung cancer

Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is an enzyme with angiogenic and cell motility properties. Moreover, it is involved in the transformation of fluoropyrimidines into active cytotoxic metabolites, In the present study, the expression of PD-ECGF in normal lung and lung cancer was immunohistochemically evaluated using the P-GF.44C monoclonal antibody. Alveolar and tumoural macrophages mere invariably stained and mere used as an internal control for assessment of the staining. Alveolar epithelium was always negative, whilst bronchiolar epithelium showed occasional positive reactivity. Normal lung and tumour endothelium was occasionally positive, Positive staining in more than 50 per cent of cells was observed in 23/71 squamous carcinomas (32 per cent), 16/38 (42 per cent) adenocarcinomas, and 2/6 (33 per cent) adenosquamous carcinomas. Differentiated areas and areas of squamous metaplasia mere more strongly positive than other tumour areas. All 22 small cell carcinomas and one carcinoid tumour were negative. The present study provides a baseline for future studies in non-small cell lung cancer to correlate PD-ECGF expression with tumour vascularization, prognosis, and response to chemotherapy.

A single institution experience of streptozocin/fluorouracil combination chemotherapy : a case series

Background The combination chemotherapy regimen of streptozocin and 5-fluorouracil (FU/STZ) has been used for the treatment of metastatic neuroendocrine tumours. Aim The aim of this study was to analyse the use of this regimen in a tertiary oncology referral centre over a 10-year period. Method We retrospectively analysed nine cases from February 2000 to May 2010. Patient demographics, chemotherapy schedule, toxicities, progression-free and overall survival were tabulated for each patient. Result The median progression-free survival was 17 months (range 3-48+ months), and overall survival 31 months (range 12-53+ months) with no toxicity related deaths. Conclusion FU/STZ was a well-tolerated regimen that produced significant benefit in the setting of metastatic and progressive disease. Our case series demonstrated comparable progression-free survival and overall survival in relation to randomized controlled studies and previous case series. © Royal Academy of Medicine in Ireland 2011.

Advances in skin cancer early detection and diagnosis

OBJECTIVES: To provide an overview of 1) traditional methods of skin cancer early detection, 2) current technologies for skin cancer detection, and 3) evolving practice models of early detection. DATA SOURCES: Peer-reviewed databased articles and reviews, scholarly texts, and Web-based resources. CONCLUSION: Early detection of skin cancer through established methods or newer technologies is critical for reducing both skin cancer mortality and the overall skin cancer burden. IMPLICATIONS FOR NURSING PRACTICE: A basic knowledge of recommended skin examination guidelines and risk factors for skin cancer, traditional methods to further examine lesions that are suspicious for skin cancer and evolving detection technologies can guide patient education and skin inspection decisions.

Computer-assisted measurements of coronal knee joint laxity in vitro are related to low-stress behavior rather than structural properties of the collateral ligaments

The relationship between coronal knee laxity and the restraining properties of the collateral ligaments remains unknown. This study investigated correlations between the structural properties of the collateral ligaments and stress angles used in computer-assisted total knee arthroplasty (TKA), measured with an optically based navigation system. Ten fresh-frozen cadaveric knees (mean age: 81 ± 11 years) were dissected to leave the menisci, cruciate ligaments, posterior joint capsule and collateral ligaments. The resected femur and tibia were rigidly secured within a test system which permitted kinematic registration of the knee using a commercially available image-free navigation system. Frontal plane knee alignment and varus-valgus stress angles were acquired. The force applied during varus-valgus testing was quantified. Medial and lateral bone-collateral ligament-bone specimens were then prepared, mounted within a uni-axial materials testing machine, and extended to failure. Force and displacement data were used to calculate the principal structural properties of the ligaments. The mean varus laxity was 4 ± 1° and the mean valgus laxity was 4 ± 2°. The corresponding mean manual force applied was 10 ± 3 N and 11 ± 4 N, respectively. While measures of knee laxity were independent of the ultimate tensile strength and stiffness of the collateral ligaments, there was a significant correlation between the force applied during stress testing and the instantaneous stiffness of the medial (r = 0.91, p = 0.001) and lateral (r = 0.68, p = 0.04) collateral ligaments. These findings suggest that clinicians may perceive a rate of change of ligament stiffness as the end-point during assessment of collateral knee laxity.

Neoliberal issues in public education

We finished penning this special issue and sending it to press on martin Luther King Jr. Day. We take pause, honoring Martin Luther King's memory and we are dedicating this project to his profound vision as a public intellectual and world activist for whom two of his breakthrough ideas are particularly relevant to this collection. The guest editors, along with the contributors, are reinforcing his messages for the current and future eras that "leadership is the action of ideas to make change, through the agency of individuals" (p. 74) and that "Injustice anywhere is a threat to justice everywhere" (p. 75) (see Temes 1996).

Coexpression of epidermal growth factor receptor with related factors is associated with a poor prognosis in non-small-cell lung cancer

The epidermal growth factor receptor (EGFR) is commonly expressed in non-small-cell lung cancer (NSCLC) and promotes a host of mechanisms involved in tumorigenesis. However, EGFR expression does not reliably predict prognosis or response to EGFR-targeted therapies. The data from two previous studies of a series of 181 consecutive surgically resected stage I-IIIA NSCLC patients who had survived in excess of 60 days were explored. Of these patients, tissue was available for evaluation of EGFR in 179 patients, carbonic anhydrase (CA) IX in 177 patients and matrix metalloproteinase-9 (MMP-9) in 169 patients. We have previously reported an association between EGFR expression and MMP-9 expression. We have also reported that MMP-9 (P=0.001) and perinuclear (p)CA IX (P=0.03) but not EGFR expression were associated with a poor prognosis. Perinuclear CA IX expression was also associated with EGFR expression (P<0.001). Multivariate analysis demonstrated that coexpression of MMP-9 with EGFR conferred a worse prognosis than the expression of MMP-9 alone (P<0.001) and coexpression of EGFR and pCA IX conferred a worse prognosis than pCA IX alone (P=0.05). A model was then developed where the study population was divided into three groups: group 1 had expression of EGFR without coexpression of MMP-9 or pCA IX (number=21); group 2 had no expression of EGFR (number=75); and group 3 had coexpression of EGFR with pCA IX or MMP-9 or both (number=70). Group 3 had a worse prognosis than either groups 1 or 2 (P=0.0003 and 0.027, respectively) and group 1 had a better prognosis than group 2 (P=0.036). These data identify two cohorts of EGFR-positive patients with diametrically opposite prognoses. The group expressing either EGFR and or both MMP-9 and pCA IX may identify a group of patients with activated EGFR, which is of clinical relevance with the advent of EGFR-targeted therapies. © 2004 Cancer Research UK.

The obesity epidemic : both energy intake and physical activity contribute

Recent data from Australia, the United States and Europe show increased self-reported energy intake associated with obesity, in contrast to earlier suggestions that the obesity epidemic has occurred despite minimal or no increase in per capita energy intake from food. The effect of increased energy intake is compounded by sedentary lifestyles. Both physical activity and nutrition must be addressed to reduce the prevalence of obesity and improve the health of Australians.

Stress, lifestyle and quality of life in midlife and older Australian women : results from the stress and the health of women study

Background Chronic psychological stress may pose a serious threat to health, although the mechanisms are not fully understood. This study examines the impact of stress on modifiable lifestyle factors, depressive symptoms, health-related quality of life (HRQOL) and chronic illness in older Australian women. Methods Cross-sectional data were collected from a random sample of 181 older adults aged 60-70 years from rural and urban areas of South-East Queensland, Australia. We used structural equation modelling to examine associations between stress, modifiable lifestyle factors, HRQoL, and chronic illness. Findings Parameter estimates show that older women who reported life stressors where they felt helpless and feared for their life (high magnitude stressors) also reported higher body mass index (p = 0.03) and more chronic illness (p <0.01). In contrast, duration of exposure to life stressors was associated with higher depressive symptom scores (CES-D, p = 0.02) and sleep disturbance scores (p <0.01). Conclusions Our findings support the link between traumatic personal histories (exposure to high magnitude stressors) and unhealthy lifestyle factors. Findings highlight the need for more research on how stress reduction healthy lifestyle and positive coping strategies can be used to reduce the effects of high magnitude stress on health-related quality of life and chronic illness.

Hydroxyl radical formation in the gas phase oxidation of distonic 2-methylphenyl radical cations

The reactions of distonic 4-(N, N, N-trimethylammonium)-2-methylphenyl and 5-(N, N, N-trimethylammonium)-2-methylphenyl radical cations (m/z 149) with O-2 are studied in the gas phase using ion-trap mass spectrometry. Photodissociation (PD) of halogenated precursors gives rise to the target distonic charge-tagged methylphenyl radical whereas collision-induced dissociation (CID) is found to produce unreactive radical ions. The PD generated distonic radicals, however, react rapidly with O-2 to form \[M + O2](center dot+) and \[M + O-2 - OH](center dot+) ions, detected at m/z 181 and m/z 164, respectively. Quantum chemical calculations using G3SX(MP3) and M06-2X theories are deployed to examine key decomposition pathways of the 5-(N, N, N-trimethylammonium)-2-methylphenylperoxyl radical and rationalise the observed product ions. The prevailing product mechanism involves a 1,5- H shift in the peroxyl radical forming a QOOH-type intermediate that subsequently eliminates (OH)-O-center dot to yield charge-tagged 2-quinone methide. Our study suggests that the analogous process should occur for the neutral methylphenyl + O-2 reaction, thus serving as a plausible source of (OH)-O-center dot radicals in combustion environments. Grants: ARC/DP0986738, ARC/DP130100862

Evoking gesture in interactive art

In this paper, we describe an interactive artwork that uses large body gestures as its primary interactive mode. The artist intends the work to provoke active reflection in the audience by way of gesture and content. The technology is not the focus, rather the aim is to provoke memory, to elicit feelings of connective human experiences in a required-to-participate audience. We find the work provokes a diverse and contradictory set of responses. The methods used to understand this include qualitative methods common to evaluating interactive art works, as well as in-depth discussions with the artist herself. This paper is relevant to the Human - Centered Computing track because in all stages of the design of the work - as well as the evaluation - the focus is on the human aspect; the computing is designed to enable all-too-human responses.

Talk2Me : engaging interactive installation environments

In this research I explore what elements there may be in common between tangible interactive-technology works that successfully engage their participants. An exploration of existing methods for obtaining useful evaluations for non-use and ambiguous environments forms a part of the discussion.

Understanding the abnormal brain activity in epilepsy as a potential predictor of the onset of an epileptic seizure

The Brain Research Institute (BRI) uses various types of indirect measurements, including EEG and fMRI, to understand and assess brain activity and function. As well as the recovery of generic information about brain function, research also focuses on the utilisation of such data and understanding to study the initiation, dynamics, spread and suppression of epileptic seizures. To assist with the future focussing of this aspect of their research, the BRI asked the MISG 2010 participants to examine how the available EEG and fMRI data and current knowledge about epilepsy should be analysed and interpreted to yield an enhanced understanding about brain activity occurring before, at commencement of, during, and after a seizure. Though the deliberations of the study group were wide ranging in terms of the related matters considered and discussed, considerable progress was made with the following three aspects. (1) The science behind brain activity investigations depends crucially on the quality of the analysis and interpretation of, as well as the recovery of information from, EEG and fMRI measurements. A number of specific methodologies were discussed and formalised, including independent component analysis, principal component analysis, profile monitoring and change point analysis (hidden Markov modelling, time series analysis, discontinuity identification). (2) Even though EEG measurements accurately and very sensitively record the onset of an epileptic event or seizure, they are, from the perspective of understanding the internal initiation and localisation, of limited utility. They only record neuronal activity in the cortical (surface layer) neurons of the brain, which is a direct reflection of the type of electrical activity they have been designed to record. Because fMRI records, through the monitoring of blood flow activity, the location of localised brain activity within the brain, the possibility of combining fMRI measurements with EEG, as a joint inversion activity, was discussed and examined in detail. (3) A major goal for the BRI is to improve understanding about ``when'' (at what time) an epileptic seizure actually commenced before it is identified on an eeg recording, ``where'' the source of this initiation is located in the brain, and ``what'' is the initiator. Because of the general agreement in the literature that, in one way or another, epileptic events and seizures represent abnormal synchronisations of localised and/or global brain activity the modelling of synchronisations was examined in some detail. References C. M. Michel, G. Thut, S. Morand, A. Khateb, A. J. Pegna, R. Grave de Peralta, S. Gonzalez, M. Seeck and T. Landis, Electric source imaging of human brain functions, Brain Res. Rev. , 36 (2--3), 2001, 108--118. doi:10.1016/S0165-0173(01)00086-8 S. Ogawa, R. S. Menon, S. G. Kim and K. Ugurbil, On the characteristics of functional magnetic resonance imaging of the brain, Annu. Rev. Bioph. Biom. , 27 , 1998, 447--474. doi:10.1146/annurev.biophys.27.1.447 C. D. Binnie and H. Stefan, Modern electroencephalography: its role in epilepsy management, Clin. Neurophysiol. , 110 (10), 1999, 1671--1697. doi:10.1016/S1388-2457(99)00125-X J. X. Tao, A. Ray, S. Hawes-Ebersole and J. S. Ebersole, Intracranial eeg substrates of scalp eeg interictal spikes, Epilepsia , 46 (5), 2005, 669--76. doi:10.1111/j.1528-1167.2005.11404.x S. Ogawa, D. W. Tank, R. Menon, J. M. Ellermann, S. G. Kim, H. Merkle and K. Ugurbil, Intrinsic signal changes accompanying sensory stimulation: Functional brain mapping with magnetic resonance imaging, P. Natl. Acad. Sci. USA , 89 (13), 1992, 5951--5955. doi:10.1073/pnas.89.13.5951 J. Engel Jr., Report of the ilae classification core group, Epilepsia , 47 (9), 2006, 1558--1568. doi:10.1111/j.1528-1167.2006.00215.x L. Lemieux, A. Salek-Haddadi, O. Josephs, P. Allen, N. Toms, C. Scott, K. Krakow, R. Turner and D. R. Fish, Event-related fmri with simultaneous and continuous eeg: description of the method and initial case r port, NeuroImage , 14 (3), 2001, 780--7. doi:10.1006/nimg.2001.0853 P. Federico, D. F. Abbott, R. S. Briellmann, A. S. Harvey and G. D. Jackson, Functional mri of the pre-ictal state, Brain , 128 (8), 2005, 1811-7. doi:10.1093/brain/awh533 C. S. Hawco, A. P. Bagshaw, Y. Lu, F. Dubeau and J. Gotman, bold changes occur prior to epileptic spikes seen on scalp eeg, NeuroImage , 35 (4), 2007, 1450--1458. doi:10.1016/j.neuroimage.2006.12.042 F. Moeller, H. R. Siebner, S. Wolff, H. Muhle, R. Boor, O. Granert, O. Jansen, U. Stephani and M. Siniatchkin, Changes in activity of striato-thalamo-cortical network precede generalized spike wave discharges, NeuroImage , 39 (4), 2008, 1839--1849. doi:10.1016/j.neuroimage.2007.10.058 V. Osharina, E. Ponchel, A. Aarabi, R. Grebe and F. Wallois, Local haemodynamic changes preceding interictal spikes: A simultaneous electrocorticography (ecog) and near-infrared spectroscopy (nirs) analysis in rats, NeuroImage , 50 (2), 2010, 600--607. doi:10.1016/j.neuroimage.2010.01.009 R. S. Fisher, W. Boas, W. Blume, C. Elger, P. Genton, P. Lee and J. Engel, Epileptic seizures and epilepsy: Definitions proposed by the international league against epilepsy (ilae) and the international bureau for epilepsy (ibe), Epilepsia , 46 (4), 2005, 470--472. doi:10.1111/j.0013-9580.2005.66104.x H. Berger, Electroencephalogram in humans, Arch. Psychiat. Nerven. , 87 , 1929, 527--570. C. M. Michel, M. M. Murray, G. Lantz, S. Gonzalez, L. Spinelli and R. G. de Peralta, eeg source imaging, Clin. Neurophysiol. , 115 (10), 2004, 2195--2222. doi:10.1016/j.clinph.2004.06.001 P. L. Nunez and R. B. Silberstein, On the relationship of synaptic activity to macroscopic measurements: Does co-registration of eeg with fmri make sense?, Brain Topogr. , 13 (2), 2000, 79--96. doi:10.1023/A:1026683200895 S. Ogawa, T. M. Lee, A. R. Kay and D. W. Tank, Brain magnetic resonance imaging with contrast dependent on blood oxygenation, P. Natl. Acad. Sci. USA , 87 (24), 1990, 9868--9872. doi:10.1073/pnas.87.24.9868 J. S. Gati, R. S. Menon, K. Ugurbil and B. K. Rutt, Experimental determination of the bold field strength dependence in vessels and tissue, Magn. Reson. Med. , 38 (2), 1997, 296--302. doi:10.1002/mrm.1910380220 P. A. Bandettini, E. C. Wong, R. S. Hinks, R. S. Tikofsky and J. S. Hyde, Time course EPI of human brain function during task activation, Magn. Reson. Med. , 25 (2), 1992, 390--397. K. K. Kwong, J. W. Belliveau, D. A. Chesler, I. E. Goldberg, R. M. Weisskoff, B. P. Poncelet, D. N. Kennedy, B. E. Hoppelm, M. S. Cohen and R. Turner, Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation, P. Natl. Acad. Sci. USA , 89 (12), 1992, 5675--5679. doi:10.1073/pnas.89.12.5675 J. Frahm, K. D. Merboldt and W. Hnicke, Functional mri of human brain activation at high spatial resolution, Magn. Reson. Med. , 29 (1), 1993, 139--144. P. A. Bandettini, A. Jesmanowicz, E. C. Wong and J. S. Hyde, Processing strategies for time-course data sets in functional MRI of the human brain, Magn. Reson. Med. , 30 (2), 1993, 161--173. K. J. Friston, P. Jezzard and R. Turner, Analysis of functional MRI time-series, Hum. Brain Mapp. , 1 (2), 1994, 153--171. B. Biswal, F. Z. Yetkin, V. M. Haughton and J. S. Hyde, Functional connectivity in the motor cortex of resting human brain using echo-planar mri, Mag. Reson. Med. , 34 (4), 1995, 537--541. doi:10.1002/mrm.1910340409 K. J. Friston, J. Ashburner, C. D. Frith, J. Poline, J. D. Heather and R. S. J. Frackowiak, Spatial registration and normalization of images, Hum. Brain Mapp. , 3 (3), 1995, 165--189. K. J. Friston, S. Williams, R. Howard, R. S. Frackowiak and R. Turner, Movement-related effects in fmri time-series, Magn. Reson. Med. , 35 (3), 1996, 346--355. G. H. Glover, T. Q. Li and D. Ress, Image-based method for retrospective correction of physiological motion effects in fmri: Retroicor, Magn. Reson. Med. , 44 (1), 2000, 162--167. doi:10.1002/1522-2594(200007)44:13.0.CO;2-E K. J. Friston, O. Josephs, G. Rees and R. Turner, Nonlinear event-related responses in fmri, Magn. Reson. Med. , 39 (1), 1998, 41--52. doi:10.1002/mrm.1910390109 K. Ugurbil, L. Toth and D. Kim, How accurate is magnetic resonance imaging of brain function?, Trends Neurosci. , 26 (2), 2003, 108--114. doi:10.1016/S0166-2236(02)00039-5 D. S. Kim, I. Ronen, C. Olman, S. G. Kim, K. Ugurbil and L. J. Toth, Spatial relationship between neuronal activity and bold functional mri, NeuroImage , 21 (3), 2004, 876--885. doi:10.1016/j.neuroimage.2003.10.018 A. Connelly, G. D. Jackson, R. S. Frackowiak, J. W. Belliveau, F. Vargha-Khadem and D. G. Gadian, Functional mapping of activated human primary cortex with a clinical mr imaging system, Radiology , 188 (1), 1993, 125--130. L. Allison, Hidden Markov Models, Technical Report , School of Computer and Software Engineering, Monash University, 2000. R. J. Elliott, L. Aggoun and J.B. Moore, Hidden Markov Models: Estimation and Control, Appl. Math.-Czech. , 2004. B. Bhavnagri, Discontinuities of plane functions projected from a surface with methods for finding these , Technical Report, 2009. B. Bhavnagri, Computer Vision using Shape Spaces , Technical Report,1996, University of Adelaide. B. Bhavnagri, A method for representing shape based on an equivalence relation on polygons, Pattern Recogn. , 27 (2), 1994, 247--260. doi:10.1016/0031-3203(94)90057-4 D. F. Abbott, A. B. Waites, A. S. Harvey and G. D. Jackson, Exploring epileptic seizure onset with fmri, NeuroImage , 36(S1) (344TH-PM), 2007. M. C. Mackey and L. Glass, Oscillation and chaos in physiological control systems, Science , 197 , 1977, 287--289. S. H. Strogatz, SYNC - The Emerging Science of Spontaneous Order , Theia, New York, 2003. J. W. Kim, J. A. Roberts and P. A. Robinson, Dynamics of epileptic seizures: Evolution, spreading, and suppression, J. Theor. Biol. , 257 (4), 2009, 527--532. doi:10.1016/j.jtbi.2008.12.009 Y. Kuramoto, T. Aoyagi, I. Nishikawa, T. Chawanya T and K. Okuda, Neural network model carrying phase information with application to collective dynamics, J. Theor. Phys. , 87 (5), 1992, 1119--1126. V. B. Mountcastle, The columnar organization of the neocortex, Brain , 120 (4), 1997, 701. doi:10.1093/brain/120.4.701 F. L. Silva, W. Blanes, S. N. Kalitzin, J. Parra, P. Suffczynski and D. N. Velis, Epilepsies as dynamical diseases of brain systems: Basic models of the transition between normal and epileptic activity, Epilepsia , 44 (12), 2003, 72--83. F. H. Lopes da Silva, W. Blanes, S. N. Kalitzin, J. Parra, P. Suffczynski and D. N. Velis, Dynamical diseases of brain systems: different routes to epileptic seizures, ieee T. Bio-Med. Eng. , 50 (5), 2003, 540. L.D. Iasemidis, Epileptic seizure prediction and control, ieee T. Bio-Med. Eng. , 50 (5), 2003, 549--558. L. D. Iasemidis, D. S. Shiau, W. Chaovalitwongse, J. C. Sackellares, P. M. Pardalos, J. C. Principe, P. R. Carney, A. Prasad, B. Veeramani, and K. Tsakalis, Adaptive epileptic seizure prediction system, ieee T. Bio-Med. Eng. , 50 (5), 2003, 616--627. K. Lehnertz, F. Mormann, T. Kreuz, R.G. Andrzejak, C. Rieke, P. David and C. E. Elger, Seizure prediction by nonlinear eeg analysis, ieee Eng. Med. Biol. , 22 (1), 2003, 57--63. doi:10.1109/MEMB.2003.1191451 K. Lehnertz, R. G. Andrzejak, J. Arnhold, T. Kreuz, F. Mormann, C. Rieke, G. Widman and C. E. Elger, Nonlinear eeg analysis in epilepsy: Its possible use for interictal focus localization, seizure anticipation, and prevention, J. Clin. Neurophysiol. , 18 (3), 2001, 209. B. Litt and K. Lehnertz, Seizure prediction and the preseizure period, Curr. Opin. Neurol. , 15 (2), 2002, 173. doi:10.1097/00019052-200204000-00008 B. Litt and J. Echauz, Prediction of epileptic seizures, Lancet Neurol. , 1 (1), 2002, 22--30. doi:10.1016/S1474-4422(02)00003-0 M. M{a}kiranta, J. Ruohonen, K Suominen, J. Niinim{a}ki, E. Sonkaj{a}rvi, V. Kiviniemi, T. Sepp{a}nen, S. Alahuhta, V. J{a}ntti and O. Tervonen, {bold} signal increase preceeds eeg spike activity--a dynamic penicillin induced focal epilepsy in deep anesthesia, NeuroImage , 27 (4), 2005, 715--724. doi:10.1016/j.neuroimage.2005.05.025 K. Lehnertz, F. Mormann, H. Osterhage, A. M{u}ller, J. Prusseit, A. Chernihovskyi, M. Staniek, D. Krug, S. Bialonski and C. E. Elger, State-of-the-art of seizure prediction, J. Clin. Neurophysiol. , 24 (2), 2007, 147. doi:10.1097/WNP.0b013e3180336f16 F. Mormann, T. Kreuz, C. Rieke, R. G. Andrzejak, A. Kraskov, P. David, C. E. Elger and K. Lehnertz, On the predictability of epileptic seizures, Clin. Neurophysiol. , 116 (3), 2005, 569--587. doi:10.1016/j.clinph.2004.08.025 F. Mormann, R. G. Andrzejak, C. E. Elger and K. Lehnertz, Seizure prediction: the long and winding road, Brain , 130 (2), 2007, 314--333. doi:10.1093/brain/awl241 Z. Rogowski, I. Gath and E. Bental, On the prediction of epileptic seizures, Biol. Cybern. , 42 (1), 1981, 9--15. Y. Salant, I. Gath, O. Henriksen, Prediction of epileptic seizures from two-channel eeg, Med. Biol. Eng. Comput. , 36 (5), 1998, 549--556. doi:10.1007/BF02524422 J. Gotman and D.J. Koffler, Interictal spiking increases after seizures but does not after decrease in medication, Evoked Potential , 72 (1), 1989, 7--15. J. Gotman and M. G. Marciani, Electroencephalographic spiking activity, drug levels, and seizure occurence in epileptic patients, Ann. Neurol. , 17 (6), 1985, 59--603. A. Katz, D. A. Marks, G. McCarthy and S. S. Spencer, Does interictal spiking change prior to seizures?, Electroen. Clin. Neuro. , 79 (2), 1991, 153--156. A. Granada, R. M. Hennig, B. Ronacher, A. Kramer and H. Herzel, Phase Response Curves: Elucidating the dynamics of couples oscillators, Method Enzymol. , 454 (A), 2009, 1--27. doi:10.1016/S0076-6879(08)03801-9 doi:10.1016/S0076-6879(08)03801-9 H. Kantz and T. Schreiber, Nonlinear time series analysis , 2004, Cambridge Univ Press. M. V. L. Bennett and R. S Zukin, Electrical coupling and neuronal synchronization in the mammalian brain, Neuron , 41 (4), 2004, 495 --511. doi:10.1016/S0896-6273(04)00043-1 L.D. Iasemidis, J. Chris Sackellares, H. P. Zaveri and W. J. Williams, Phase space topography and the Lyapunov exponent of electrocorticograms in partial seizures, Brain Topogr. , 2 (3), 1990, 187--201. doi:10.1007/BF01140588 M. Le Van Quyen, J. Martinerie, V. Navarro, M. Baulac and F. J. Varela, Characterizing neurodynamic changes before seizures, J. Clin. Neurophysiol. , 18 (3), 2001, 191. J. Martinerie, C. Adam, M. Le Van Quyen, M. Baulac, S. Clemenceau, B. Renault and F. J. Varela, Epileptic seizures can be anticipated by non-linear analysis, Nat. Med. , 4 (10), 1998, 1173--1176. doi:10.1038/2667 A. Pikovsky, M. Rosenblum, J. Kurths and R. C. Hilborn, Synchronization: A universal concept in nonlinear science, Amer. J. Phys. , 70 , 2002, 655. H. R. Wilson and J. D. Cowan, Excitatory and inhibitory interactions in localized populations of model neurons, Biophys. J. , 12 (1), 1972, 1--24. D. Cumin and C. P. Unsworth, Generalising the Kuramoto model for the study of neuronal synchronisation in the brain, Physica D , 226 (2), 2007, 181--196. doi:10.1016/j.physd.2006.12.004 F. K. Skinner, H. Bazzazi and S. A. Campbell, Two-cell to N-cell heterogeneous, inhibitory networks: Precise linking of multistable and coherent properties, J. Comput. Neurosci. , 18 (3), 2005, 343--352. doi:10.1007/s10827-005-0331-1 W. W. Lytton, Computer modelling of epilepsy, Nat. Rev. Neurosci. , 9 (8), 2008, 626--637. doi:10.1038/nrn2416 R. D. Traub, A. Bibbig, F. E. N. LeBeau, E. H. Buhl and M. A. Whittington, Cellular mechanisms of neuronal population oscillations in the hippocampus in vitro, Ann. Rev. , 2004. R. D. Traub, A. Draguhn, M. A. Whittington, T. Baldeweg, A. Bibbig, E. H. Buhl and D. Schmitz, Axonal gap junc ions between principal neurons: A novel source of network oscillations, and perhaps epileptogenesis., Rev. Neuroscience , 13 (1), 2002, 1. doi:10.1146/annurev.neuro.27.070203.144303 M. Scheffer, J. Bascompte, W. A. Brock, V. Brovkin, S. R. Carpenter, V. Dakos, H. Held, E. H. van Nes, M. Rietkerk and G. Sugihara, Early-warning signals for critical transitions, Nature , 461 (7260), 2009, 53--59. doi:10.1038/nature08227 K. Murphy, A Brief Introduction to Graphical Models and Bayesian Networks , 2008, http://www.cs.ubc.ca/murphyk/Bayes/bnintro.html . R. C. Bradley, An elementary