Exchange-dependent relaxation in the rotating frame for slow and intermediate exchange - modeling off-resonant spin-lock and chemical exchange saturation transfer

Chemical exchange observed by NMR saturation transfer (CEST) and spin-lock (SL) experiments provide an MRI contrast by indirect detection of exchanging protons. The determination of the relative concentrations and exchange rates is commonly achieved by numerical integration of the Bloch-McConnell equations. We derive an analytical solution of the Bloch-McConnell equations that describes the magnetization of coupled spin populations under radiofrequency irradiation.As CEST and off-resonant SL are equivalent, their steady-state magnetization and dynamics can be predicted by the same single eigenvalue: the longitudinal relaxation rate in the rotating frame R1rho. For the case of slowly exchanging systems, e.g. amide protons, the saturation of the small proton pool is affected by transverse relaxation (R2b). It turns out, that R2b is also significant for intermediate exchange, such as amine- or hydroxyl-exchange or paramagnetic CEST agents, if pools are only partially saturated. We propose a solution for R1rho that includes R2 of the exchanging pool by extending existing approaches, and verify it by numerical simulations. With the appropriate projection factors, we obtain an analytical solution for CEST and SL for nonzero R2 of the exchanging pool, whilst considering the dilution by direct water saturation across the entire Z-spectra. This allows the optimization of irradiation parameters and the quantification of pH-dependent exchange rates and metabolite concentrations. In addition, we propose evaluation methods that correct for concomitant direct saturation effects. It is shown that existing theoretical treatments for CEST are special cases of this approach

Biologics for the treatment of chronic rhinosinusitis with nasal polyps : state of the art

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex upper airway disease affecting up to 11% of the population of Western Europe. In these western countries, 85% of the CRSwNP disease reveals a type 2 inflammatory pattern. In the last 15 years, several randomized double-blind studies on monoclonal antibodies in CRSwNP were performed. These studies demonstrated for the first time that biologics targeting type 2 immune reactions might be successful in nasal polyps. The target proteins, interleukin (IL)-4, IL-5, IL-13, and IgE were previously identified as key mediators in studies using nasal polyp tissues to measure and to interact in ex-vivo settings. No biomarkers have been identified to predict response to a specific biologic or to monitor treatment success. These studies were characterized by small numbers of patients and heterogeneous populations. They did, however, pave the way for currently performed and analyzed phase 3 studies, which will possibly lead to the registration of the first biologic drug with the indication CRSwNP. The studies already provide indications on the effects to be expected from those biologics; the results of phase-3 studies in larger populations will be decisive for the indications, patient selection, and finally the stopping rules for those drugs in subjects with severe nasal polyps, in whom the current standard of care including topical and oral glucocorticosteroids, antibiotics and surgical procedures failed to control the disease. We may expect that those biologics will open new perspectives for those patients with severe polyposis with, but also independent of asthma, allowing to avoid the possible adverse events resulting from systemic glucocorticosteroids and surgery

The IDEAL (Integrated Design and Engineering Analysis Languages) modeling methodology: Capabilities and Applications

The IDEAL (Integrated Design and Engineering Analysis Languages) modeling methodology has been formulated and applied over a five-year period. It has proven to be a unique, integrated approach utilizing a top-down, structured technique to define and document the system of interest; a knowledge engineering technique to collect and organize system descriptive information; a rapid prototyping technique to perform preliminary system performance analysis; and a sophisticated simulation technique to perform in-depth system performance analysis

IDEAL: A methology for developing information systems

As a result of improved capabilities obtained through current computer technologies, application programs and expert systems, Enterprises are being designed or upgraded to be highly integrated and automated information systems. To design or modify Enterprises, it is necessary to first define what functions are to be performed within the Enterprise, identify which functions are potential candidates for automation, and what automated or expert systems are available, or must be developed, to accomplish the selected function. Second, it is necessary to define and analyze the informational requirements for each function along with the informational relationships among the functions so that a database structure can be established to support the Enterprise. To perform this type of system design, an integrated set of analysis tools is required to support the information analysis process. The IDEAL (Integrated Design and Engineering Analysis Languages) methodology provides this integrated set of tools and is discussed

Small Groups: Growing in the Lutheran Church

The purpose of this major applied project is threefold. First, through a study of the Scriptures, the history and use of small groups will be traced, and the text will demonstrate that it is God\u27s will that His Church grow and be brought into a relationship with Himself. Secondly, the necessity and strategy for persons to be brought into a relationship with one another as they grow in discipleship will be emphasized and discussed in a chapter which reviews not only biblical data, but also provides a search of related literature from the fields of both theology and social psychology. Finally, specific concerns and tasks are suggested which must be identified as congregations intentionally pursue the task of disciple making. A Lutheran bias is reflected in the project with specific attention being drawn to the means of grace (Word and Sacrament) as the effective course for both church growth and growth in discipleship while also emphasizing the work of the social sciences in addressing the needs of people. Some of the present work in the area of small group ministry in the Lutheran Church-Missouri Synod is identified. A leadership manual is proposed in the final chapter for use in the training of leaders in a small group ministry within the Lutheran Church, a manual which is being used by the author

Family Support Caseloads--Determinants of Kentucky\u27s Division of Family Support Personnel Allocation

This paper is an examination of the determinants of Family Support employee allocation. Specifically, related to Kentucky, the goal of this research is to determine if public assistance caseloads are equitable across nine geographic regions. A review of relevant literature provides a larger context to this topic. Literature primarily suggests three mechanisms by which Family Support resources might be allocated: legal regulations, postcode lottery, and Tiebout migration. Supported by literature the larger context for this paper leads to the examination of five independent variables: (1) percent of Supplemental Nutrition Assistance Program recipients \, (2) total population, (3) percent of the population over 65, (4) percent population identified as white, and (5) percent below poverty. The dependent variable for this study is the number of Family Support personnel per region. Since the dependent variable was reported on a regional level an adjustment to the independent variable data. Level f aggregations of the 720 panel observations for the independent variables were collapsed into a regional level of 54 observations. The remaining 54 observations were then subjected to both fixed-effects and between effects regression analyses. The output of these analyses suggests that Family Support personnel were allocated to each region in a uniform standard. However, the primary factors in this allocation were more related to demographic variables than to the number of public assistance recipients. This means that the variation of Family Support personnel between the regions has a discriminatory effect as regions with younger populations will receive fewer resources

Chronic rhinosinusitis with nasal polyps in older adults : clinical presentation, pathophysiology, and comorbidity

Purpose of Review Chronic rhinosinusitis and nasal polyps (CRSwNP) is a common condition that significantly affects patients' life. This work aims to provide an up-to-date overview of CRSwNP in older adults, focusing on its aging-related clinical presentations, pathophysiology, and comorbidity associations including asthma. Recent Findings Recent large population-based studies using nasal endoscopy have shown that CRSwNP is a mostly late-onset disease. Age-related changes in physiologic functions, including nasal epithelial barrier dysfunction, may underlie the incidence and different clinical presentations of CRSwNP in older adults. However, there is still a paucity of evidence on the effect of aging on phenotypes and endotypes of CRSwNP. Meanwhile, late-onset asthma is a major comorbid condition in patients with CRSwNP; they frequently present with type 2 inflammatory signatures that are refractory to conventional treatments when they are comorbid. However, as they are more commonly non-atopic, causative factors other than classical atopic sensitization, such as Staphylococcus aureus specific IgE sensitization, are suggested to drive the type 2 inflammation. There are additional comorbidity associations in older patients with CRSwNP, including those with chronic otitis media and head and neck malignancy. Age is a major determinant for the incidence and clinical presentations of CRSwNP. Given the heterogeneity in phenotypes and endotypes, longitudinal investigations are warranted to elucidate the effects of aging on CRSwNP

Many faces of DAMPs in cancer therapy

A new concept of immunogenic cell death (ICD) has recently been proposed. The immunogenic characteristics of this cell death mode are mediated mainly by molecules called ‘damage-associated molecular patterns’ (DAMPs), most of which are recognized by pattern recognition receptors. Some DAMPs are actively emitted by cells undergoing ICD (e.g. calreticulin (CRT) and adenosine triphosphate (ATP)), whereas others are emitted passively (e.g. high-mobility group box 1 protein (HMGB1)). Recent studies have demonstrated that these DAMPs play a beneficial role in anti-cancer therapy by interacting with the immune system. The molecular pathways involved in translocation of CRT to the cell surface and secretion of ATP from tumor cells undergoing ICD are being elucidated. However, it has also been shown that the same DAMPs could contribute to progression of cancer and promote resistance to anticancer treatments. In this review, we will critically evaluate the beneficial and detrimental roles of DAMPs in cancer therapy, focusing mainly on CRT, ATP and HMGB1

LTD4 and TGF-β1 induce the expression of metalloproteinase-1 in chronic rhinosinusitis via a cysteinyl leukotriene receptor 1-related mechanism

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