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Most cortical neurons fire regularly when excited by a constant stimulus. In contrast, irregular-spiking (IS) interneurons are remarkable for the intrinsic variability of their spike timing, which can synchronize amongst IS cells via specific gap junctions. Here, we have studied the biophysical mechanisms of this irregular spiking in mice, and how IS cells fire in the context of synchronous network oscillations. Using patch-clamp recordings, artificial dynamic conductance injection, pharmacological analysis and computational modeling, we show that spike time irregularity is generated by a nonlinear dynamical interaction of voltage-dependent sodium and fast-inactivating potassium channels just below spike threshold, amplifying channel noise. This active irregularity may help IS cells synchronize with each other at gamma range frequencies, while resisting synchronization to lower input frequencies., Competing Interests: The authors declare that no competing interests exist.

Gamma oscillations (30-120 Hz) are thought to be important for various cognitive functions, including perception and working memory, and disruption of these oscillations has been implicated in brain disorders, such as schizophrenia and Alzheimer's disease. The cornu ammonis area 1 (CA1) of the hippocampus receives gamma frequency inputs from upstream regions (cornu ammonis area 3 and medial entorhinal cortex) and generates itself a faster gamma oscillation. The exact nature and origin of the intrinsic CA1 gamma oscillation is still under debate. Here, we expressed channel rhodopsin-2 under the CaMKIIα promoter in mice and prepared hippocampal slices to produce a model of intrinsic CA1 gamma oscillations. Sinusoidal optical stimulation of CA1 at theta frequency was found to induce robust theta-nested gamma oscillations with a temporal and spatial profile similar to CA1 gamma in vivo The results suggest the presence of a single gamma rhythm generator with a frequency range of 65-75 Hz at 32 °C. Pharmacological analysis found that the oscillations depended on both AMPA and GABAA receptors. Cell-attached and whole-cell recordings revealed that excitatory neuron firing slightly preceded interneuron firing within each gamma cycle, suggesting that this intrinsic CA1 gamma oscillation is generated with a pyramidal-interneuron circuit mechanism., Significance Statement: This study demonstrates that the cornu ammonis area 1 (CA1) is capable of generating intrinsic gamma oscillations in response to theta input. This gamma generator is independent of activity in the upstream regions, highlighting that CA1 can produce its own gamma oscillation in addition to inheriting activity from the upstream regions. This supports the theory that gamma oscillations predominantly function to achieve local synchrony, and that a local gamma generated in each area conducts the signal to the downstream region., (Copyright © 2016 Butler et al.)

Objective: To compare the effects of the neutral protamine Hagedorn (NPH) recombinant human insulin formulations Gansulin and Humulin N® on the glycemic control of patients with type 2 diabetes mellitus (T2DM)., Subjects and Methods: Prospective, double-blind, randomized, parallel, single-center study of 37 individuals with T2DM treated with NPH insulin formulations. The Tukey-Kramer test for multiple comparisons, the Wilcoxon paired comparison test and the Chi-Square test were used for the statistical analyses. The significance level was set at 5% (p < 0.05)., Results: The NPH insulin formulations Humulin and Gansulin similarly reduced the HbA1c levels observed at the end of the study compared with the values obtained at the beginning of the study. In the Humulin group, the initial HbA1c value of 7.91% was reduced to 6.56% (p < 0.001), whereas in the Gansulin group, the reduction was from 8.18% to 6.65% (p < 0.001). At the end of the study, there was no significant difference between the levels of glycated hemoglobin (p = 0.2410), fasting plasma glucose (FG; p = 0.9257) and bedtime plasma glucose (BG; p = 0.3906) between the two insulin formulations. There was no nt difference in the number of hypoglycemic events between the two insulin formulations, and no severe hyp episodes were recorded., Conclusion: This study demonstrated similar glycemic control by NPH insulin Gansulin compared with human insulin Humulin N® in patients with T2DM.

Assessing the severity of liver fibrosis has direct clinical implications for patient diagnosis and treatment. Liver biopsy, typically considered the gold standard, has limited clinical utility due to its invasiveness. Therefore, several imaging-based techniques for staging liver fibrosis have emerged, such as magnetic resonance elastography (MRE) and ultrasound elastography (USE), but they face challenges that include limited availability, high cost, poor patient compliance, low repeatability, and inaccuracy. Computed tomography (CT) can address many of these limitations, but is still hampered by inaccuracy in the presence of confounding factors, such as liver fat. Dual-energy CT (DECT), with its ability to discriminate between different tissue types, may offer a viable alternative to these methods. By combining the "multi-material decomposition" (MMD) algorithm with a biologically driven hypothesis we developed a method for assessing liver fibrosis from DECT images. On a twelve-patient cohort the method produced quantitative maps showing the spatial distribution of liver fibrosis, as well as a fibrosis score for each patient with statistically significant correlation with the severity of fibrosis across a wide range of disease severities. A preliminary comparison of the proposed algorithm against MRE showed good agreement between the two methods. Finally, the application of the algorithm to longitudinal DECT scans of the cohort produced highly repeatable results. We conclude that our algorithm can successfully stratify patients with liver fibrosis and can serve to supplement and augment current clinical practice and the role of DECT imaging in staging liver fibrosis.

Objective: To determine the validity of alpha-1-acid glycoprotein as a novel biomarker for mortality in patients with severe sepsis., Methods: We prospectively included patients with severe sepsis or septic shock at the emergency department at a single tertiary referral teaching hospital. All of the patients were enrolled within the first 24 hours of emergency department admission, and clinical data and blood samples were obtained. As the primary outcome, we investigated the association of serum levels of alpha-1-acid glycoprotein and 96-hour mortality with logistic regression analysis and generalized estimating equations adjusted for age, sex, shock status and Acute Physiology and Chronic Health Evaluation II score., Results: Patients with septic shock had lower alpha-1-acid glycoprotein levels at the time of emergency department admission compared to patients without shock (respectively, 149.1 ±42.7 vs. 189.8 ±68.6; p = 0.005). Similarly, non-survivors in the first 96 hours were also characterized by lower levels of alpha-1-acid glycoprotein at the time of emergency department admission compared to survivors (respectively, 132.18 ±50.2 vs. 179.8 ±61.4; p = 0.01). In an adjusted analysis, alpha-1-acid glycoprotein levels ≤120 mg/dL were significantly associated with 96-hour mortality (odds ratio = 14.37; 95% confidence interval = 1.58 to 130.21)., Conclusion: Septic shock patients exhibited lower circulating alpha-1-acid glycoprotein levels than patients without shock. Alpha-1-acid glycoprotein levels were independently associated with 96-hour mortality in individuals with severe sepsis.

The diagnosis and treatment of fatty liver disease requires accurate quantification of the amount of fat in the liver. Image-based methods for quantification of liver fat are of increasing interest due to the high sampling error and invasiveness associated with liver biopsy, which despite these difficulties remains the gold standard. Current computed tomography (CT) methods for liver-fat quantification are only semi-quantitative and infer the concentration of liver fat heuristically. Furthermore, these techniques are only applicable to images acquired without the use of contrast agent, even though contrast-enhanced CT imaging is more prevalent in clinical practice. In this paper, we introduce a method that allows for direct quantification of liver fat for both contrast-free and contrast- enhanced CT images. Phantom and patient data are used for validation, and we conclude that our algorithm allows for highly accurate and repeatable quantification of liver fat for spectral CT.

This paper describes a system for detecting pulmonary nodules in CT images. It aims to label individual image voxels in accordance to one of a number of anatomical (pulmonary vessels or junctions), pathological (nodules), or spurious (noise) events. The approach is orthodoxly Bayesian, with particular care taken in the objective establishment of prior probabilities and the incorporation of relevant medical knowledge. We provide, under explicit modeling assumptions, closed-form expressions for all the probability distributions involved. The technique is applied to real data, and we present a discussion of its performance.

This paper presents a model-based technique for lesion detection in colon CT scans that uses analytical shape models to map the local shape curvature at individual voxels to anatomical labels. Local intensity profiles and curvature information have been previously used for discriminating between simple geometric shapes such as spherical and cylindrical structures. This paper introduces novel analytical shape models for colon-specific anatomy, viz. folds and polyps, built by combining parts with simpler geometric shapes. The models better approximate the actual shapes of relevant anatomical structures while allowing the application of model-based analysis on the simpler model parts. All parameters are derived from the analytical models, resulting in a simple voxel labeling scheme for classifying individual voxels in a CT volume. The algorithm's performance is evaluated against expert-determined ground truth on a database of 42 scans and performance is quantified by free-response receiver-operator curves.

Emphysema is characterized by the destruction and over distension of lung tissue, which manifest on high resolution computer tomography (CT) images as regions of low attenuation. Typically, it is diagnosed by clinical symptoms, physical examination, pulmonary function tests, and X-ray and CT imaging. In this paper we discuss a quantitative imaging approach to analyze emphysema which employs low-level segmentations of CT images that partition the data into perceptually relevant regions. We constructed multi-dimensional histograms of feature values computed over the image segmentation. For each region in the segmentation, we derive a rich set of feature measurements. While we can use any combination of physical and geometric features, we found that limiting the scope to two features - the mean attenuation across a region and the region area - is effective. The subject histogram is compared to a set of canonical histograms representative of various stages of emphysema using the Earth Mover's Distance metric. Disease severity is assigned based on which canonical histogram is most similar to the subject histogram. Experimental results with 81 cases of emphysema at different stages of disease progression show good agreement against the reading of an expert radiologist.

Thin-slice computer tomography provides high-resolution images that facilitate the diagnosis of early-stage lung cancer. However, the sheer size of the CT volumes introduces variability in radiological readings, driving the need for automated detection systems. The main contribution of this paper is a technique for combining geometric and intensity models with the analysis of local curvature for detecting pulmonary lesions in CT. The local shape at each voxel is represented via the principal curvatures of its associated isosurface without explicitly extracting the isosurface. The comparison of these curvatures to values derived from analytical shape models is then used to label the voxel as belonging to particular anatomical structures, e.g., nodules or vessels. The algorithm was evaluated on 242 CT exams with expert-determined ground truth. The performance of the algorithm is quantified by free-response receiver-operator characteristic curves, as well as by its potential for improvement in radiologist sensitivity.

Rationale and Objectives: In this study, we developed a prototype model-based computer aided detection (CAD) system designed to automatically detect both solid and subsolid pulmonary nodules in computed tomography (CT) images. By using this CAD algorithm, along with the radiologist's initial interpretation, we aim to improve the sensitivity of radiologic readings of CT lung exams., Materials and Methods: We have developed a model-based CAD algorithm through the use of precise mathematic models that capture scanner physics and anatomic information. Our model-based CAD algorithm uses multiple segmentation algorithms to extract noteworthy structures in the lungs and a Bayesian statistical model selection framework to determine the probability of various anatomical events throughout the lung. We tested this algorithm on 50 low-dose CT lung cancer screening cases in which ground truth was produced through readings by three expert chest radiologists., Results: Using this model-based CAD algorithm on 50 low-dose CT cases, we measured potential sensitivity improvements of 7% and 5% in two radiologists with respect to all noncalcified nodules, solid and subsolid, greater than 5 mm in diameter. The third radiologist did not miss any nodules in the ground truth set. The CAD algorithm produced 8.3 false positives per case., Conclusion: Our prototype CAD system demonstrates promising results as a tool to improve the quality of radiologic readings by increasing radiologist sensitivity. A significant advantage of this model-based approach is that it can be easily extended to support additional anatomic models as clinical understanding and scanning practices improve.