Defective glucose-stimulated insulin release in the diabetic Goto-Kakizaki (GK) rat coincides with reduced activity of the islet carbon monoxide signaling pathway

The Goto-Kakizaki (GK) rat displays a markedly reduced insulin response to glucose, a defect that is thought to be coupled to an impaired glucose signaling in the beta-cell. We have examined whether carbon monoxide (CO), derived from beta-cell heme oxygenase (HO), might be involved in the secretory dysfunction. Immunocytochemical labeling of constitutive HO (HO-2) showed no overt difference in fluorescence pattern in islets from GK vs. Wistar controls. However, isolated islets from GK rats displayed a markedly impaired HO activity measured as CO production (-50%), and immunoblotting revealed an approximately 50% reduction of HO-2 protein expression compared with Wistar controls. Furthermore, there was a prominent expression of inducible HO (HO-1) in GK islets. Incubation of isolated islets showed that the glucose-stimulated CO production and the glucose-stimulated insulin response were considerably reduced in GK islets compared with Wistar islets. Addition of the HO activator hemin or gaseous CO to the incubation media brought about a similar amplification of glucose-stimulated insulin release in GK and Wistar islets, suggesting that distal steps in the HO-CO signaling pathway were not appreciably affected. We conclude that the defective insulin response to glucose in the GK rat can be explained, at least in part, by a marked impairment of the glucose-HO-CO signaling pathway as manifested by a prominent decrease in glucose stimulation of islet CO production and a reduced expression of HO-2. A possible role of HO-1 expression as a compensatory mechanism in the GK islets is presently unclear.     

Diagnostic methods and treatment options for focal cortical dysplasia

Our inability to adequately treat many patients with refractory epilepsy caused by focal cortical dysplasia (FCD), surgical inaccessibility and failures are significant clinical drawbacks. The targeting of physiologic features of epileptogenesis in FCD and colocalizing functionality has enhanced completeness of surgical resection, the main determinant of outcome. Electroencephalography (EEG)–functional magnetic resonance imaging (fMRI) and magnetoencephalography are helpful in guiding electrode implantation and surgical treatment, and high‐frequency oscillations help defining the extent of the epileptogenic dysplasia. Ultra high‐field MRI has a role in understanding the laminar organization of the cortex, and fluorodeoxyglucose–positron emission tomography (FDG‐PET) is highly sensitive for detecting FCD in MRI‐negative cases. Multimodal imaging is clinically valuable, either by improving the rate of postoperative seizure freedom or by reducing postoperative deficits. However, there is no level 1 evidence that it improves outcomes. Proof for a specific effect of antiepileptic drugs (AEDs) in FCD is lacking. Pathogenic mutations recently described in mammalian target of rapamycin (mTOR) genes in FCD have yielded important insights into novel treatment options with mTOR inhibitors, which might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease. The ketogenic diet (KD) has been demonstrated to be particularly effective in children with epilepsy caused by structural abnormalities, especially FCD. It attenuates epigenetic chromatin modifications, a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression. This could imply lasting benefit of dietary manipulation. Neurostimulation techniques have produced variable clinical outcomes in FCD. In widespread dysplasias, vagus nerve stimulation (VNS) has achieved responder rates >50%; however, the efficacy of noninvasive cranial nerve stimulation modalities such as transcutaneous VNS (tVNS) and noninvasive (nVNS) requires further study. Although review of current strategies underscores the serious shortcomings of treatment‐resistant cases, initial evidence from novel approaches suggests that future success is possible.     

Validation of the cocaine versions of the Obsessive Compulsive Drug Use Scale and the Desires for Drug Questionnaire

Background: The Obsessive Compulsive Drug Use Scale (OCDUS) and the Desires for Drug Questionnaire (DDQ) are two frequently used drug craving questionnaires. Although both heroin and cocaine versions of the questionnaires exist, only the heroin versions have been psychometrically evaluated. The present study was conducted to evaluate the psychometric qualities of the cocaine versions of the OCDUS (OCDUS-C) and DDQ (DDQ-C). Methods: Cocaine-dependent inpatients (n?=?101) completed both scales as well as a Visual Analogue Craving Scale (VACS), an alternative, one-item index for assessing momentary craving. We examined the reliability (internal consistency), construct validity (factor structure), and concurrent validity (correlations among both questionnaires, the VACS, and indicators of severity of dependence). A subsample also completed the OCDUS-C and DDQ-C for a second time, one week after the initial administration to obtain a preliminary investigation of the test-retest reliability. Results: In general, both questionnaires displayed good internal consistency, test-retest reliability, and concurrent validity. Further, the construct validity of both the DDQ and OCDUS was demonstrated by means of confirmatory factor analyses showing the expected three-factor models. Conclusion: Our results indicate that the OCDUS and DDQ for cocaine are both easy to administer and reliable instruments to assist the clinical practitioner or researcher to measure craving in cocaine dependent subjects. Moreover, the factor structure for the cocaine versions were similar to the heroin versions, indicating the OCDUS and the DDQ can be reliably used to measure craving for both substances, enabling a direct comparison between heroin and cocaine craving.     

Origin of information-limiting noise correlations

The ability to discriminate between similar sensory stimuli relies on the amount of information encoded in sensory neuronal populations. Such information can be substantially reduced by correlated trial-to-trial variability. Noise correlations have been measured across a wide range of areas in the brain, but their origin is still far from clear. Here we show analytically and with simulations that optimal computation on inputs with limited information creates patterns of noise correlations that account for a broad range of experimental observations while at same time causing information to saturate in large neural populations. With the example of a network of V1 neurons extracting orientation from a noisy image, we illustrate to our knowledge the first generative model of noise correlations that is consistent both with neurophysiology and with behavioral thresholds, without invoking suboptimal encoding or decoding or internal sources of variability such as stochastic network dynamics or cortical state fluctuations. We further show that when information is limited at the input, both suboptimal connectivity and internal fluctuations could similarly reduce the asymptotic information, but they have qualitatively different effects on correlations leading to specific experimental predictions. Our study indicates that noise at the sensory periphery could have a major effect on cortical representations in widely studied discrimination tasks. It also provides an analytical framework to understand the functional relevance of different sources of experimentally measured correlations.The response of cortical neurons to an identical stimulus varies from trial to trial. Moreover, this variability tends to be correlated among pairs of nearby neurons. These correlations, known as noise correlations, have been the subject of numerous experimental as well as theoretical studies because they can have a profound impact on behavioral performance (1–7). Indeed, behavioral performance in discrimination tasks is inversely proportional to the Fisher information available in the neural responses, which itself is strongly dependent on the pattern of correlations. In particular, correlations can strongly limit information in the sense that some patterns of correlations can lead information to saturate to a finite value in large populations, in sharp contrast to the case of independent neurons for which information grows proportionally to the number of neurons. However, the saturation is observed for only one type of correlations known as differential correlations. If the correlation pattern slightly deviates from differential correlations, information typically scales with the number of neurons, just like it does for independent neurons (7). These previous results clarify how correlations impact information and consequently behavioral performance but fail to address another fundamental question, namely, Where do noise correlations, and in particular information-limiting differential correlation, come from? Understanding the origin of information-limiting correlation is a key step toward understanding how neural circuits can increase information transfer, thereby improving behavioral performance, via either perceptual learning or attentional selection.Several groups have started to investigate sources of noise correlations such as shared connectivity (2), feedback signals (8), internal dynamics (9–11), or global fluctuations in the excitability of cortical circuits (12–16). Global fluctuations have received a lot of attention recently as they appear to account for a large fraction of the measured correlations in the primary visual cortex. Correlations induced by global fluctuations, however, do not limit information in most discrimination tasks (with the possible exception of contrast discrimination for visual stimuli). Therefore, if cortex indeed operates at information saturation, the source of information-limiting correlations is still very much unclear.In this paper, we focus on correlations induced by feedforward processing of stimuli whose information content is small compared with the information capacity of neural circuits. Using orientation selectivity as a case study, we find that feedforward processing induces correlations that share many properties of the correlations observed in vivo. Moreover, we also show feedforward processing leads to information-limiting correlations as a direct consequence of the data processing inequality. Interestingly, these information-limiting correlations represent only a small fraction of the overall correlations induced by feedforward processing, making them difficult to detect through direct measurements of correlations. Finally, we demonstrate that correlations induced by global fluctuations cannot limit information on their own, but can reduce the level at which information saturates in the presence of information-limiting correlations. Despite our focus on orientation selectivity, our results can be generalized to other modalities, stimuli, and brain areas.In summary, this work identifies a major source of noise correlations and, importantly, a source of information-limiting noise correlations, while clarifying the interactions between information-limiting correlations and correlations induced by global fluctuations.     

Multiphasic presentation of Rasmussen's encephalitis

Rasmussen's encephalitis is a rare, chronic inflammatory disorder of unknown cause, characterised by drug‐resistant focal epilepsy that may rarely present in adolescence or adulthood. We present a case of Rasmussen's encephalitis with prominent recurrent fluctuation in symptoms and well‐documented fluctuating changes on MRI, adding to the spectrum of diversity of Rasmussen's encephalitis.     

The Prognostic Role of Optimal Cytoreduction in Advanced,Bowel Infiltrating Ovarian Cancer

Aim: In locally advanced ovarian cancer with bowel involvement appropriate surgical treatment is still controversial. Objective was to delineate factors to select those most likely to benefit from radical surgery in patients with locally advanced ovarian cancer. Methods: Therefore, we retrospectively evaluated 207 consecutive patients with primary stage IIB-IV ovarian cancer who underwent primary surgery between 2000 and 2007. Every patient received stage-related surgery and adjuvant platinum-based chemotherapy. Median follow-up was 53.5 months. Data collected included stage, histology, extent of cytoreduction and type of bowel resection. Univariate survival analyses were performed to investigate variables associated with outcome. Results: Optimal cytoreduction (OCR) (R ≤ 1 cm) was achieved in 76.8%. Most patients presented histologic grade 2/3 (96.6%), serous ovarian cancers (84.1%) and lymph node involvement (52.2%). Complete cytoreduction (R = 0 mm) has significant best prognostic impact in FIGO IIB–IV (p = .026). Regarding bowel involvement, bowel resection was performed in 82 patients (39.6%). In this subgroup of patients complete cytoreduction led to significant better overall survival than R > 0 mm–1 cm, even in FIGO IIIC–IV patients (p = .027); this fact is independent of bowel resection. Noticeably, for survival bowel resection achieving residual tumor mass below 1 cm was also one main prognostic factor and even recurrence rate was associated with residual tumor mass. Conclusion: Our findings suggest that the major prognostic factor in patients with advanced ovarian cancer needing colorectal resection is completeness of cytoreduction. Therefore, in advanced ovarian cancer patients, multivisceral surgery is indicated to achieve OCR (R ≤ 1 cm) with or without bowel resection with best prognostic impact.