\r\n\tThe book primarily addresses the student's needs in the field of data assimilation. It is intended to provide the reader with a comprehensive overview of the subject, from basic principles to advanced state-of-the-art in the interdisciplinary field of data assimilation. It is compiled in a pedagogical way to become a reference book for researchers interested in the application of advanced analytical tools, deep learning, ANN in data assimilation implementation, data analytics, machine learning, and decision support systems.
",isbn:"978-1-83968-084-7",printIsbn:"978-1-83968-083-0",pdfIsbn:"978-1-83968-085-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"e7fde2a36354a2f5a4282fdf9c743380",bookSignature:"Dr. Dr. Dinesh G. Harkut",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9966.jpg",keywords:"Ensemble Kalman Filter, Machine Learning, Data Mining, Constraint Variational Methods, Markovian Processes Ensemble Filters, Convolutional Neural Network, Multilayer Perceptrons, Interpolation, Parameterization, Spatial Statistics, Bayesian Statistics, Probability Distribution Function",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 12th 2019",dateEndSecondStepPublish:"December 3rd 2019",dateEndThirdStepPublish:"February 1st 2020",dateEndFourthStepPublish:"April 21st 2020",dateEndFifthStepPublish:"June 20th 2020",remainingDaysToSecondStep:"4 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,editors:[{id:"216122",title:"Dr.",name:"Dr. Dinesh G.",middleName:null,surname:"Harkut",slug:"dr.-dinesh-g.-harkut",fullName:"Dr. Dinesh G. Harkut",profilePictureURL:"https://mts.intechopen.com/storage/users/216122/images/system/216122.png",biography:"Dinesh G. Harkut is currently working as an Associate Professor at PRMCEAM, Badnera, India in Computers Science & Engineering department. He has obtained his Bachelors, Masters of Engineering Degree (CSE) and his Ph.D. (CSE) from SGBAU Amravati University, Maharashtra, India. He has also obtained a Masters Degree and Ph.D. in Business Administration.\nHis primary research interests are in computer AI, Big Data, Analytics, Embedded Systems, e-commerce. He supervised around 18 Masters Degree and 24 Bachelors Degree Students. He has published 46 papers in refereed journals and published 05 books and 04 chapters with international publishers. He is having 02 patents filed and published in his name in India and has organized various Workshops, Sessions, Conferences, and Trainings. He is the principal investigator in setting the center of excellence of renowned technological giants like IBM, Oracle, Texas Instrument, and Huawei at PRMCEAM and establishing industry-funded laboratories from ARM, Cypress Semiconductor, Intel FPGA, Wind River, and Xilinx fetched a grant in the tune of Rs. 351.32 lacs.\nDr. Harkut is a Fellow member of the Institute of Electronics & Telecommunication Engineering (IETE), New Delhi, a Life member of Indian Society for Technical Education (ISTE), New Delhi, a Senior Member of Universal Association of Computer and Electronics Engineers (UACEE) USA, and a Professional member of the International Association of Engineers (IAENG), Hong Kong.",institutionString:"Sant Gadge Baba Amravati University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Sant Gadge Baba Amravati University",institutionURL:null,country:{name:"India"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"286446",firstName:"Sara",lastName:"Bacvarova",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/286446/images/8491_n.jpg",email:"sara.b@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"7795",title:"Artificial Intelligence",subtitle:"Scope and Limitations",isOpenForSubmission:!1,hash:"7e536b4fe8982ca9015228fe6f58c6ea",slug:"artificial-intelligence-scope-and-limitations",bookSignature:"Dinesh G. Harkut",coverURL:"https://cdn.intechopen.com/books/images_new/7795.jpg",editedByType:"Edited by",editors:[{id:"216122",title:"Dr.",name:"Dr. Dinesh G.",surname:"Harkut",slug:"dr.-dinesh-g.-harkut",fullName:"Dr. Dinesh G. 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Chan and Manoj Kumar Tiwari",coverURL:"https://cdn.intechopen.com/books/images_new/3794.jpg",editedByType:"Edited by",editors:[{id:"252210",title:"Dr.",name:"Felix",surname:"Chan",slug:"felix-chan",fullName:"Felix Chan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"57260",title:"Accurate and High Sensitivity Identification of PNH Clones by Flow Cytometry",doi:"10.5772/intechopen.71286",slug:"accurate-and-high-sensitivity-identification-of-pnh-clones-by-flow-cytometry",body:'\n
\n
1. Introduction
\n
Paroxysmal nocturnal hemoglobinuria is a rare, life-threatening acquired hematopoietic stem cell disorder resulting from the somatic mutation of the X-linked phosphatidylinositol glycan complementation Class A (PIG-A) gene [1]. PIG-A normally encodes an enzyme involved in the first stage of glycosylphosphatidylinositol (GPI) biosynthesis but in PNH, as a result of the mutation(s) in this gene, there is a partial or absolute inability to make GPI-anchored proteins, including complement defense structures such as CD55 and CD59 on red blood cells (RBCs) and white blood cells (WBCs) [2, 3]. Absence of CD59 in particular [4] and CD55 on RBCs is responsible for intravascular hemolysis associated with clinical PNH. Clonal expansion of the PNH population frequently occurs in patients with aplastic anemia in which normal hematopoiesis has failed, and with modern, high sensitivity assays, up to 70% of AA patients have detectable PNH clones [5]. Small populations of GPI-deficient PNH phenotypes have been reported in patients with early stage myelodysplastic syndrome (MDS) [6, 7]. Patients present with a wide range of clinical features, including intravascular hemolysis (that leads to hemoglobinuria), bone marrow failure and thrombosis, with the latter being a major cause of morbidity and mortality [5, 8]. As PNH is an acquired stem cell disease, it is important to demonstrate the loss of GPI-linked cell surface structures in at least two hematopoietic cell lineages, traditionally RBCs and neutrophils, although as more data have recently accumulated, monocytes should also be assessed as monocytes often exhibit a higher ‘clone size’ than is present in neutrophils. For true high-sensitivity assay design, it is critical to include carefully validated lineage-specific gating reagents such as CD235a (Glycophorin A) for RBC identification, CD15 for neutrophil identification and CD64 for monocyte identification. Examination of RBCs in the non-transfused PNH patient provides the most accurate assessment of the distribution of Type III PNH RBCs (complete CD59 deficiency), Type II PNH RBCs (partial CD59 deficiency) and normal Type I RBCs (normal CD59 expression). The distributions of these populations show a wide variation from patient to patient and delineation between the various types is not always clear-cut [9]. RBC analysis is important in PNH, as accurate determination of the distribution of Type II and III cells; patients with greater than 20% Type III RBCs almost always show clinical evidence of hemolysis [5]. While the loss of GPI-linked CD55 and CD59 was traditionally used to detect PNH RBCs [10, 11], ‘routine’ CD55 and/or CD59-based approaches are neither accurate nor sensitive below the 1–2% clone size, rendering them inadequate to detect small PNH clones typically found in PNH+ AA and MDS cases [5] or even in some heavily transfused PNH cases.
\n
\n
\n
2. Pre-analytical phase
\n
\n
2.1. Red blood cells
\n
\n
2.1.1. Sample and reagent requirements
\n
Freshly drawn EDTA (preferred) or heparin anti-coagulated whole peripheral blood is used for analysis. If samples are shipped or need to be stored prior to analysis, the blood sample should be kept at 4°C and should generally be used within 48 hours of sample draw. For high-sensitivity RBC analysis, the International Clinical Cytometry Society (ICCS) Guidelines recommended the use of CD235a (for RBC gating) and CD59 (to detect GPI-deficient cells) [12]. In the follow-up ‘Practical Guidelines’ [13], a large number of clones/conjugates to CD235a-FITC and CD59-PE were tested but only a few were found to have acceptable performance characteristics and further validated for a variety of instrument platforms (Table 1). Of note, even selected conjugates required extensive titration on an individual basis to minimize aggregation prior to premixing or ‘cocktailing’ for this assay. Only by performing extensive titrations, we were able to identify conjugates with the best performance characteristics for this specific assay. Premixing of reagents once adequately titrated is critically important in PNH assays as both RBC and WBC assays are designed to detect GPI-deficient phenotypes, i.e., cells unstained by the GPI-specific reagents. Given the very small volumes of reagents used for the RBC assay in particular, it is usually necessary to make a dilution of the RBC cocktail such that accurately pipettable volumes of reagent can be employed.
Recommended CD235a-FITC and CD59-PE conjugates for high-sensitivity PNH RBC assay.
\n
\n
\n
2.1.2. Staining procedure
\n
Blood samples are diluted 1:100 with fresh clean PBS and 100 μL is carefully pipetted using reverse pipetting techniques directly into the bottom of the staining tube taking care to avoid aerosols and blood trails on the inside of the tube. The appropriate volume of diluted CD235aFITC/CD59PE is then pipetted directly into the bottom of the tube and admixed with the diluted sample by gently up-and-down pipetting. After careful removal of the tip, the sample can be gently ‘swirled’ on a vortex set at a very low speed to avoid aerosol generation. After 20 minutes, the sample must be washed twice with clean phosphate buffered saline (PBS), resuspended in 1 ml of PBS and then ‘racked’ immediately before data acquisition to disrupt any RBC aggregates generated during the staining process [13].
\n
\n
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2.2. White blood cells
\n
\n
2.2.1. Sample and reagent requirements
\n
For high-sensitivity WBC analysis using a single tube approach, CD45 is employed for pattern recognition and to exclude unlysed RBCs, other debris not excluded by light scatter thresholding. Thereafter, carefully selected/validated conjugates of CD15 and CD64 are used to accurately delineate/‘gate’ neutrophils and monocytes, respectively. To detect GPI-deficient CD15-gated neutrophils, FLAER is used in combination with either carefully selected/validated CD24 or CD157 conjugates, and to detect GPI-deficient CD64-gated monocytes, FLAER is used in combination with either carefully selected/validated CD14 or CD157 conjugates (Table 2 and 3) [13, 14, 15, 16].
Recommended clones/conjugates for high-sensitivity detection of PNH WBC on Becton Dickinson Cytometers.
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\n
\n
2.2.2. Staining procedure
\n
Undiluted anti-coagulated whole blood is the preferred sample source for the analysis of PNH phenotypes in WBCs. Reverse pipetting is used to dispense 100 μL of sample into the staining tube, taking all the precautions noted above for the RBC assay to avoid aerosols and ensure that the sample is not left on the wall of the tube. The reagent set in use should be cocktailed, once optimal volumes of each reagent have been determined by titrations. The appropriate volume of cocktail is added directly into the blood sample at the bottom of the tube and gently admixed by up-and-down pipetting. After gentle swirling to avoid aerosols, the sample is incubated in the dark for 20–30 minutes at room temperature before RBC lysis. There are a variety of commercial lysing agents available such as Versalyse, FACSLyse and Immunoprep and most do a very good job. After lysis following manufacturers’ recommendations, the sample is centrifuged and washed with PBS supplemented with 1% serum albumin. The sample is resuspended in 0.5–1 ml of PBS and acquired.
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\n
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\n
3. Analytical phase and data reporting
\n
\n
3.1. Instrument setup and standardization
\n
Optimal instrument setup and standardization is a prerequisite for reproducible results over time and among laboratories. For the analysis of RBCs, the forward scatter (FS) and side scatter (SS) voltages are set in logarithmic mode and voltages adjusted to bring all unstained RBCs into the middle of the plot and above any FS threshold/discriminator. For WBCs, light scatter voltages are set in linear mode at such values that all unstained leukocyte subsets including lymphocytes scatter above the FS threshold and are clearly clustered on scale. Photomultiplier tube (PMT) voltage optimization, standardization and computer-assisted spectral overlap compensation are mandatory steps for instrument standardization of multi-parameter assays and can be performed using an instrument platform-based approach (BD Biosciences, Beckman Coulter) or interplatform-based approach [17, 18, 19, 20].
\n
\n
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3.2. Data acquisition and analysis
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\n
3.2.1. Red blood cells
\n
For high-sensitivity RBC analysis, the ICCS Guidelines recommended the use of CD235a (for RBC gating) and CD59 (to detect GPI-deficient cells) [9]. Based on subsequent publications that included rigorous testing and validation of various CD235a and CD59 clones and conjugates, optimal reagent combinations of CD235a-FITC and CD59-PE were identified [13]. Once extensively titrated, these reagents in combination did not cause major aggregation of RBCs while still maintaining a good signal-to-noise ratio and the ability to adequately separate Type II and Type III PNH RBCs from normal (Type I) RBCs [13, 14, 15]. Red blood cells are analyzed by a series of gating dot plots beginning with TIME versus SS, FS versus SS with detectors set in logarithmic mode, and CD235a-FITC versus FS to gate singlet RBCs and to quantify and exclude any remaining RBC aggregates (Figure 1). TIME is collected as a parameter and monitored during acquisition so that if fluidics problems are encountered, the sample can be reacquired if possible, or if not, data acquired prior to the fluidics hiatus can be ‘gated’ and only that portion of the data file subsequently analyzed. It is important to adjust the threshold (discriminator) for the FS so that no RBCs are excluded from acquisition. The diagnostic plots include a bivariate CD59 versus CD235a dot plot, a bivariate CD59 versus CD235a density plot and a single parameter histogram of CD59 staining (Figure 1). Bivariate dot plots and/or density plots are recommended over single-parameter histograms, especially for samples containing small numbers of PNH phenotypes, for identifying poorly stained samples that need to be re-stained and for detecting media contamination and troubleshooting instrumentation issues [13]. However, while data regarding clone sizes come predominantly from the two-dimensional plots, in which the gating regions are linked across the dot plot and density plots, the single parameter histogram can also be useful in some situations. All three plots work in concert for optimal adjustment of the regions for Type III PNH cells and Type II PNH cells. An additional utility of the single parameter histogram is in comparing old versus new plots of CD235a-FITC/CD59-PE cocktails when tested on non-PNH samples.
\n
Figure 1.
Sequence of bivariate gating and diagnostic dot-plots for analysis of PNH RBCs.
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\n
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3.2.2. White blood cells
\n
High-sensitivity methodologies to detect PNH phenotypes in neutrophils and monocytes have been published previously. These methods were initially based on two separate 4-color neutrophil (FLAER, CD24, CD15 and CD45) and monocyte (FLAER, CD14, CD64 and CD45) tubes. In this earlier setting, samples were stained first with the RBC and neutrophil cocktails and if PNH phenotypes were detected, the ‘reflex’ monocyte tube was thereafter set up. The current document uses the same gating strategy used in earlier assays but discuss the more modern single tube assays on newer flow cytometers with 5, 6, or more PMTs that allow the simultaneous detection and quantification of both neutrophils and monocytes.
\n
\n
3.2.2.1. FLAER/CD24/CD14-based assay
\n
For laboratories equipped with modern cytometers with 6-, 8- or 10 PMTs (Canto, Canto II and Navios), it is possible to configure 6-color cocktails based on FLAER, CD24 and CD14 (Tables 2 and 3). Figure 2 shows the sequence of bivariate gating and diagnostic dot-plots from a Navios-specific reagent set comprising FLAER-Alexa488, CD24-PE (clone ALB9), CD15-PC5 (clone 80H5), CD64-PC7 (clone 22), CD14-APCA700 (clone RMO52) and CD45-KO (clone J33). The FS versus SS plot is gated from TIME versus SS plot (not shown) and light scatter voltages are set so that all WBC subsets are clearly visible and optimally separated; the threshold/discriminator is set to ensure that no lymphocytes are excluded. A debris exclusion gate (or WBC inclusion gate) can then be established to exclude any debris above the threshold/discriminator but below the smallest lymphocytes. The CD45 versus SS plot is then gated through Boolean gating on Time and “not debris” with a gate drawn around the CD45+ cells. The CD45 versus SS plot is useful not only for pattern recognition but also for excluding any unlysed RBCs and other debris not removed by the debris exclusion gate. The CD15 versus SS plot is gated on the CD45+ populations and includes a gate drawn around the CD15++ neutrophils excluding as well as possible the CD15 dim + eosinophils visible to the left of the neutrophil/granulocyte population. The diagnostic FLAER/CD24 plot is gated on the CD15++ neutrophils and a region is drawn to encompass the FLAER-negative/CD24-negative cells, which represent the PNH neutrophils. The CD64 versus SS plot is also gated on the CD45+ cells and a region is drawn around the CD64++ monocytes. The FLAER versus CD14 dot plot is gated on the CD64++ monocytes and a region is drawn to delineate the FLAER-negative/CD14-negative cells, which represent the PNH monocytes. The lymphocytes gated on the CD64-negative/low SS plot are not a suitable target population for the PNH clone quantification due to their long lifespan. However, they serve as internal controls for verification of antigen expression and compensation settings. Plotting FLAER versus CD24, CD14, CD15 and CD64 verifies the instrument voltage and compensation settings as visible and clustered populations in the “correct” location. Plot FLAER versus CD24 shows B-cells (FLAER+/CD24+) verifying that both reagents were added, FLAER+/CD24-negative NK and T-cells and no dual-negative cells as this is a PNH-negative sample.
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Figure 2.
Sequence of bivariate gating and diagnostic dot-plots for FLAER/CD24/CD14- based analysis of PNH neutrophils and monocytes.
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3.2.2.2. FLAER/CD157-based assay
\n
ADP-ribosyl cyclase 2 (CD157) is a GPI-anchored cell surface enzyme encoded by the bone marrow stromal cell antigen-1 gene, which plays a role in pre-B cell growth [21]. Within the hematopoietic system, CD157 is highly expressed on both mature neutrophils and monocytes [22] leading to the possibility that CD157 could replace both CD24 and CD14, allowing the development of a single tube, high sensitivity 5C assay to identify and quantify both PNH neutrophils and PNH monocytes on cytometers with five or more PMTs [14, 15, 16]. The ability to perform simultaneous evaluation of both PNH neutrophils and PNH monocytes is particularly attractive to laboratories equipped with 5-C instruments such as the FC500 due to the major cost and time savings involved over running two separate 4-color assays for neutrophils and monocytes [14, 15, 16]. The gating and analysis strategies are similar to the ones used for the above described single-tube 6-color assay, except for the diagnostic FLAER/CD157 dot plots gated on CD15++ neutrophils and CD64++ monocytes (Figure 3). Three control lymphocyte plots (FLAER/CD15, FLAER/CD64 and FLAER/CD157) are also shown to monitor instrument setup and compensation.
\n
Figure 3.
Sequence of bivariate gating and diagnostic dot-plots for FLAER/CD157- based analysis of PNH neutrophils and monocytes.
\n
It is important to note that several CD157-negative, non-PNH cases have been observed in the authors’ laboratories (unpublished data). For these rare cases, the inclusion of the second GPI reagent (FLAER) as part of the built-in robustness of the assay prevents the misinterpretation of the data as a PNH clone-containing sample. Furthermore, in keeping with current state-of-the-art guidelines [12, 13], the RBC lineage should also be analyzed on every sample tested for the presence of PNH WBCs. As these rare CD157-negative non-PNH samples only contain normal (Type I) RBCs, there is even less chance of misinterpretation. An example of a CD157-negative case is shown in Figure 4. The sample was stained with a 7-color combination of FLAER, CD157, CD24, CD14, CD15, CD64 and CD45. While the CD157 failed to stain normal neutrophils in this sample, FLAER and CD24 stained the neutrophils in the expected manner. Similarly, while CD157 failed to stain normal monocytes in this sample, FLAER and CD14 stained monocytes in the expected manner.
\n
Figure 4.
Example of CD157-negative, non-PNH case, 7-color FLAER/CD24/CD14/CD157-based protocol.
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\n
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3.3. Reporting
\n
The following components are recommended for a PNH report:
\n
The presence or absence of PNH clones. It is important to be clear and to avoid potentially misleading ambiguous terminology. A report stating that a CD59 test is negative may imply to some providers that the target population is negative for the GPI marker CD59 (thus indicating a PNH clone) or that absence of CD59 is not seen (thus indicating the absence of a PNH clone).
PNH clone size in the RBCs (total PNH clone size as well as the percentages for Type II and Type III PNH populations). There is a clinical significance associated for Type II and Type III RBCs. Type I RBCs are normal red blood cells with bright CD59 expression and a lifespan of approximately 120 days. Type III PNH RBCs have complete CD59 deficiency, which results in no protection from complement-mediated lysis and a shortened lifespan of 10–15 days. Type II PNH RBCs have partial CD59 deficiency resulting in partial protection from complement-mediated lysis. Just as the expression of CD59 on Type II RBCs varies considerably from patient to patient, the lifespan of Type II cells reflects this being intermediate between Type I normal RBCs and Type III PNH RBCs. Since the clinical significance of Type II PNH RBCs and Type III PNH RBCs is well established, it is recommended to report them separately and combined as the total PNH RBC clone.
PNH clone size in both lineages for the WBCs (neutrophils and monocytes). The PNH monocyte clone is often larger than the neutrophil PNH clone and reporting only the PNH neutrophil/granulocyte clone may underestimate the PNH clone size in the WBCs. Neutrophils and monocytes may also show the presence of Type II populations but the clinical and biological significance of these populations has not been established at this time. It is therefore recommended to report only the total PNH clone size in the neutrophils and monocytes.
Interpretive terminology of reporting PNH clones based on CSLI H52-A2 [23]:
PNH population > 1%: “PNH clone.”
PNH population 0.1–1%: “minor population of PNH cells” or “minor PNH clone.”
PNH population < 0.1%: “rare cells with GPI deficiency” or “rare cells with PNH phenotype.
List of all gating and diagnostic markers used for the PNH assay.
Levels of the limit of quantification (LOQ) for the neutrophil assay and the RBC assay, stating the recommended LOQ of 0.05% or better for RBCs (100,000 gated cells) and 0.1% or better for neutrophils (50,000 gated cells). It is important to include this information to the provider as an LOQ of 1% means that the possibility of a minor clone (less than 1%) cannot be excluded based on this LOQ.
Histograms or dot plots if possible because the dot plots may provide powerful visual supportive evidence of the PNH clone and also provide evidence of the quality of the assay.
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4. Post-analytical phase and assay validation
\n
The results of PNH testing by flow cytometry are usually reported as percentage of type II and III PNH cells from the total gated neutrophils, monocytes and red blood cells. Assays reporting numeric data are considered as semi-quantitative, therefore the post-analytical validation process should comprise confirmation of accuracy, specificity, sensitivity, repeatability, reproducibility and stability [24, 25].
\n
\n
4.1. Accuracy of PNH assays
\n
The accuracy of a measurement is described by its trueness, which refers to the closeness of agreement between the average value of a large number of test results and the true or accepted reference value [25]. For PNH assays, we do not have cellular reference standard, therefore accuracy cannot be determined directly. Alternatively, interlaboratory comparison and/or external quality assessment represent the only available option for assay validation and mandatory step for ISO accreditation [26].
\n
\n
\n
4.2. Specificity of PNH assays
\n
\n
4.2.1. Analytical specificity
\n
The analytical specificity of PNH testing assays reflects the choice and validation of all antibodies/reagents and corresponding fluorochromes (Tables 1–3).
\n
\n
\n
4.2.2. Clinical specificity
\n
The clinical specificity or the ability to exclude abnormal specimen defined by true negatives/true negatives + false positives should be determined by assay of a series of samples and scoring for abnormality in comparison to a suitable reference method, such as clinical diagnosis [27]. The clinical specificity of well-established PNH assays is usually >99%.
\n
\n
\n
\n
4.3. Sensitivity of PNH assays
\n
\n
4.3.1. Analytical sensitivity
\n
The analytical sensitivity of PNH assays is determined by the limit of blank (LoB) defined by the highest apparent signal detected in replicates of a sample containing no measurand and the limit of detection (LoD) defined by the lowest level of measurand that can be reliably distinguished from the LoB [28]. LoB for PNH assays could be determined by measuring a few replicates of a few negative specimens run over a few separate days and calculating the mean and standard deviation (SD) according to: LoB = mean of blank +1.645 SD of blank, assuming that 95% of negative values will be below this limit. Typically, the LoB for well-established PNH assays is <0.001% (<10 PNH phenotypes out of 1,000,000 acquired events). LoD for PNH assays is closely related but usually greater than LoB and could be determined by measuring a few replicates of a few negative specimens run over a few separate days and calculating the mean and SD according to: LoD = mean of blank + 2SD (3SD) of blank or by measuring a few replicates of a few low positive specimens run over a few separate days and calculating the SD according to: LoD = LoB + 1.645 SD of low positive. Alternatively, target LoD could be estimated by measuring a few replicates of a few low positive specimens run over a few separate days and calculating the reproducibility (inter-assay imprecision) expressed as coefficient of variation (CV%) or by confirming that no more than 5% of the values for a target LoD fall beyond the LoB. The generally accepted smallest number of events required to reproducibly detect a PNH population and determine LoD is 20 PNH events, lower levels should be validated in each laboratory.
\n
\n
\n
4.3.2. Functional sensitivity
\n
The functional sensitivity of PNH assays is determined by the limit of quantification (LoQ), which is the lowest level of measurand that can be reliably detected at predefined levels of bias and imprecision [28]. LoQ is usually greater than LOD and for PNH assays could be determined by measuring a few replicates of a few positive (near the expected LoQ) specimens run over a few separate days and calculating the reproducibility (inter-assay imprecision) expressed as CV%, which should be acceptable at levels below 10%. The generally accepted smallest number of events required to reproducibly quantify a PNH population and determine LoQ is 50 PNH events, lower levels should be validated in each laboratory.
\n
\n
\n
4.3.3. Clinical sensitivity
\n
The clinical sensitivity or the ability to detect an abnormal specimen and distinguish from normal specimens defined by true positive/true positive + false negative should be determined by assay of a series of abnormal samples and scoring for abnormality in comparison to a suitable reference method, such as clinical findings [27]. The values for clinical sensitivity of well-established PNH assays is usually >99%.
\n
\n
\n
\n
4.4. Repeatability and reproducibility
\n
The validation of assay performance characteristics comprises the determination of repeatability (intra-assay imprecision) and reproducibility (inter-assay imprecision). It is generally recommended to assay a few replicates from at least five samples within a single analytical run for repeatability and a few replicates from at least five samples in separate analytical runs for reproducibility [29]. For confirmation of good performance characteristics, CV% below 10% should be obtained for samples with more than 1% target PNH cells and below 20% for samples with minor clones (<1%).
\n
\n
\n
4.5. Stability
\n
The validation of specimen, processed specimen and reagent stability has been reviewed in Section 2 [13, 16, 23].
\n
\n
\n
\n
5. Accreditation
\n
Flow cytometry is a highly versatile and complex technology, which is routinely applied in clinical diagnostic laboratories. The vast majority of assays are laboratory developed tests based on publications, without any gold standard reference [30] mostly with poor validation. For the purpose the ICSH/ICCS workgroup published in 2013 the practice guidelines for validation of cell-based fluorescence assays [31], subsequently several relevant publications addressed various aspects of the validation of PNH testing by flow cytometry [12, 13, 32]. Each laboratory applying for ISO 15189 accreditation should confirm optimal validation of instrument setup, assay performance characteristics, laboratory information system and result reporting [33].
\n
\n
\n
6. Conclusion
\n
Highly sensitive and specific PNH testing of all three lineages (RBC, neutrophils and monocytes) has become the standard of care for patients with suspected PNH. This is a rare disease and therefore often overlooked as a diagnostic possibility. It is important for the ordering physician to test the high-risk patients for PNH [12] and also to receive informational reports as an important part for best patient management. The laboratories are challenged with the validation of multiple steps, including instrument optimization, selection of best antibody clones/conjugates, panel design and targeted acquisition and interpretation of data. Developing competency in PNH testing and reporting is critical for laboratories and is directly related to awareness of best practices, following guidelines which are developed by experts based on extensive evaluation of various approaches. Standardized reporting based on currently available guidelines is important to communicate to the physician the size of the PNH clone, which aids him/her in the decision-making for optimal treatment of the patient.
\n
\n\n',keywords:"PNH, flow cytometry, high sensitivity assay, validation, standardization",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/57260.pdf",chapterXML:"https://mts.intechopen.com/source/xml/57260.xml",downloadPdfUrl:"/chapter/pdf-download/57260",previewPdfUrl:"/chapter/pdf-preview/57260",totalDownloads:318,totalViews:229,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"May 8th 2017",dateReviewed:"September 26th 2017",datePrePublished:"December 20th 2017",datePublished:"June 27th 2018",readingETA:"0",abstract:"Flow cytometry performs a key role in the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). Careful selection and validation of antibody conjugates have allowed the development of reagent cocktails suitable for the high sensitivity detection of PNH red blood cells (RBCs) and white blood cells (WBCs) in PNH and related diseases such as aplastic anemia (AA) and some subsets of myelodysplastic syndromes (MDS). A CD235a-FITC/CD59-PE assay was developed capable of detecting Type III PNH RBCs at a limit of quantification (LOQ) of 0.01% or better. While separate 4-color Fluorescent Aerolysin (FLAER), CD24, CD15 and CD45-based neutrophil and FLAER, CD14, CD64 and CD45-based monocyte assays were developed to detect PNH WBC phenotypes, 5-, 6- and 7-color assays have subsequently been developed for more modern cytometers equipped with five or more fluorescence detectors. For instrumentation with five detectors, a single tube 5-color FLAER, CD157, CD15, CD64 and CD45-based assay to simultaneously detect PNH neutrophils and monocytes has been developed. For instruments with six or more detectors and multiple lasers, a variety of 5-, 6- and 7-color assays have been developed using combinations of FLAER, CD24, CD14 and CD157. All WBC assays have a limit of quantification (LOQ) of 0.1% or better. Using these standardized approaches, results have demonstrated good intra- and inter-laboratory performance characteristics even in laboratories with little prior experience performing PNH testing.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/57260",risUrl:"/chapter/ris/57260",book:{slug:"multidimensional-flow-cytometry-techniques-for-novel-highly-informative-assays"},signatures:"Iuri Marinov, Andrea Illingworth and D. Robert Sutherland",authors:[{id:"210629",title:"Associate Prof.",name:"Iuri",middleName:null,surname:"Marinov",fullName:"Iuri Marinov",slug:"iuri-marinov",email:"iuri.marinov@uhkt.cz",position:null,institution:{name:"Charles University",institutionURL:null,country:{name:"Czech Republic"}}},{id:"221041",title:"MSc.",name:"Andrea",middleName:null,surname:"Illingworth",fullName:"Andrea Illingworth",slug:"andrea-illingworth",email:"AIllingworth@dahlchase.com",position:null,institution:null},{id:"221042",title:"Prof.",name:"D. Robert",middleName:null,surname:"Sutherland",fullName:"D. Robert Sutherland",slug:"d.-robert-sutherland",email:"rob.sutherland@utoronto.ca",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Pre-analytical phase",level:"1"},{id:"sec_2_2",title:"2.1. Red blood cells",level:"2"},{id:"sec_2_3",title:"Table 1.",level:"3"},{id:"sec_3_3",title:"2.1.2. Staining procedure",level:"3"},{id:"sec_5_2",title:"2.2. White blood cells",level:"2"},{id:"sec_5_3",title:"Table 2.",level:"3"},{id:"sec_6_3",title:"2.2.2. Staining procedure",level:"3"},{id:"sec_9",title:"3. Analytical phase and data reporting",level:"1"},{id:"sec_9_2",title:"3.1. Instrument setup and standardization",level:"2"},{id:"sec_10_2",title:"3.2. Data acquisition and analysis",level:"2"},{id:"sec_10_3",title:"3.2.1. Red blood cells",level:"3"},{id:"sec_11_3",title:"3.2.2. White blood cells",level:"3"},{id:"sec_11_4",title:"3.2.2.1. FLAER/CD24/CD14-based assay",level:"4"},{id:"sec_12_4",title:"3.2.2.2. FLAER/CD157-based assay",level:"4"},{id:"sec_15_2",title:"3.3. Reporting",level:"2"},{id:"sec_17",title:"4. Post-analytical phase and assay validation",level:"1"},{id:"sec_17_2",title:"4.1. Accuracy of PNH assays",level:"2"},{id:"sec_18_2",title:"4.2. Specificity of PNH assays",level:"2"},{id:"sec_18_3",title:"4.2.1. Analytical specificity",level:"3"},{id:"sec_19_3",title:"4.2.2. Clinical specificity",level:"3"},{id:"sec_21_2",title:"4.3. Sensitivity of PNH assays",level:"2"},{id:"sec_21_3",title:"4.3.1. Analytical sensitivity",level:"3"},{id:"sec_22_3",title:"4.3.2. Functional sensitivity",level:"3"},{id:"sec_23_3",title:"4.3.3. Clinical sensitivity",level:"3"},{id:"sec_25_2",title:"4.4. Repeatability and reproducibility",level:"2"},{id:"sec_26_2",title:"4.5. Stability",level:"2"},{id:"sec_28",title:"5. Accreditation",level:"1"},{id:"sec_29",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T, Takahashi M, Kitani T, Kinoshita T. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993;73:703-711. DOI: 10.1016/0092-8674(93)90250-T\n'},{id:"B2",body:'Nicholson-Weller A, March JP, Rosenfeld SI, Austen KF. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay acceleration factor. Proceedings of the National Academy of Sciences of the United States of America. 1983;80:5066-5070. DOI: 10.1073/pnas.80.16.5066\n'},{id:"B3",body:'Holguin MH, Frederick LR, Bernshaw NJ, Wilcox LA, Parker CJ. Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria. The Journal of Clinical Investigation. 1989;84:7-17. 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Deficiency of glycosyl-phosphatidylinositol-linked membrane glycoproteins of leukocytes in paroxysmal nocturnal hemoglobinuria, description of a new diagnostic cytofluorometric assay. Blood. 1990;76:1853-1859 PMD: 2145990\n'},{id:"B11",body:'Hall SE, Rosse WF. The use of monoclonal antibodies and flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria. Blood. 1996;87:5332-5340 PMD: 8652849\n'},{id:"B12",body:'Borowitz MJ, Craig FE, DiGiuseppe JA, Illingworth AJ, Rosse W, Sutherland DR, Wittwer CT, Richards SJ, On Behalf of the Clinical Cytometry Society. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry. Part B. 2010;78B:211-230. DOI: 10.1002/cyto.b.20525\n'},{id:"B13",body:'Sutherland DR, Keeney M, Illingworth A. Practical guidelines for the high-sensitivity detection and monitoring of paroxysmal nocturnal hemoglobinuria clones by flow cytometry. Cytometry. Part B. 2012;82B:195-208. 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DOI: http://dx.doi.org/10.1002/cyto.a.22404\n\n'},{id:"B19",body:'Lacombe F, Bernal E, Bloxham D, Couzens S, Porta MG, Johansson U, Kern W, Macey M, Matthes T, Morilla R, Paiva A, Palacio C, Preijers F, Ratei R, Siitonen S, Allou K, Porwit A, Béné MC. Harmonemia: A universal strategy for flow cytometry immunophenotyping-A European LeukemiaNet WP10 study. Leukemia 2016;8:1769-1772. DOI: http://dx.doi.org/10.1038/leu.2016.44\n\n'},{id:"B20",body:'Byrd T, Carr KD, Norman JC, Huye L, Hegde M, Ahmed N. Polystyrene microspheres enable 10-color compensation for immunophenotyping of primary human leukocytes. Cytometry. Part A 2015;87:1038-1046. DOI: http://dx.doi.org/10.1002/cyto.a.22717\n\n'},{id:"B21",body:'Kajimoto Y, Miyagawa J, Ishihara K, Okuyama Y, Fujitani Y, Itoh M, Kaisiho T, Mtsuoka T, Watada H, Hanafusa T, Yamasaki Y, Kamada T, Matsuzawa Y, Hirano T. Pancreatic islet cells express BS-1, a CD38-like surface molecule having ADP-ribosyl cyclase activity. Biochemical and Biophysical Research Communications 1996; 219:941-946. DOI: http://dx.doi.org/10.1006/bbrc.1996.0327\n\n'},{id:"B22",body:'Hernandez-Campo PM, Almeida J, Sanchez ML, Malvezzi M, Orfao A. Normal patterns of expression of glycosylphosphatidylinositol-anchored proteins on different subsets of peripheral blood cells: A frame of reference for the diagnosis of paroxysmal nocturnal hemoglobinuria. Cytometry. Part B, DOI. 2006;70B:71-81. http://dx.doi.org/10.1002/cyto.b.20087\n\n'},{id:"B23",body:'Davis BH, Keeney M, Brown R, Illingworth AJ, King MJ, Kumpel B, Meier ER, Sandler SG, Shaz BH, Sutherland DR. CLSI H52-A2 Red Blood Cell Diagnostic Testing Using Flow Cytometry; Approved Guideline, 2nd ed. Wayne, PA: Clinical and Laboratory Standards Institute. 2014. ISBN: 1-56238-957-2\n'},{id:"B24",body:'Owens MA, Vall HG, Hurley AA, Wormsley SB. Validation and quality control of immunophenotyping in clinical flow cytometry. Journal of Immunological Methods. 2000;243:33-50. DOI: 10.1016/S0022-1759(00)00226-X\n'},{id:"B25",body:'ISO 3534-1:2006. Statistics-Vocabulary and Symbols. General Statistical Terms and Terms Used in Probability. Geneva: ISO; 2006\n'},{id:"B26",body:'Libeer J-C. Role of external quality assurance schemes in assessing and improving quality in medical laboratories. Clinica Chimica Acta. 2001;309:173-177. DOI: 10.1016/S0009-8981(01)00518-6\n'},{id:"B27",body:'CLSI EP12-A2: User Protocol for Evaluation of Qualitative Test Performance—Second Edition—Approved Guideline. Wayne, PA: National Committee for Clinical Laboratory Standards, 2008. ISBN 1-56238-468-6\n'},{id:"B28",body:'NCCLS. Protocols for Determination of Limits of Detection and Limits of Quantitation Approved Guideline. NCCLS document EP17-A. 2004. ISBN 1-56238-551-8\n'},{id:"B29",body:'CLSI EP06-A: Evaluation of the Linearity of Quantitative Measurement Procedures—Аpproved Guideline. Wayne, PA: National Committee for Clinical Laboratory Standards, 2003. ISBN 1-56238-498-8\n'},{id:"B30",body:'Spitzenberger F, Edelhaeuser R. Accreditation of medical laboratories in Europe: Statutory framework, current situation and perspectives. Transfusion Medicine and Hemotherapy. 2006;33:384-392. DOI: 10.1159/000094738\n'},{id:"B31",body:'Validation of cell-based fluorescence assays: practice guidelines from the international council for standardization of haematology and international clinical cytometry society. Cytometry, Part B (Clinical Cytometry). 2013;84B:Special Issue. ISSN: 1552/4949\n'},{id:"B32",body:'Marinov I, Kohoutová M, Tkáčová V, Pešek A, Pešek A, Čermák J, Cetkovský P. Performance characteristics of consensus approaches for small and minor paroxysmal nocturnal hemoglobinuria clone determination by flow cytometry. Clinical Chemistry and Laboratory Medicine. 2013;(11):2133-2139. DOI: 10.1515/cclm-2013-0251\n'},{id:"B33",body:'ISO 15189-1012. Medical Laboratories—Requirements for Quality and Competence. Geneva: ISO; 2012\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Iuri Marinov",address:"iuri.marinov@uhkt.cz",affiliation:'
Institute of Hematology and Blood Transfusion, Czech Republic
'},{corresp:null,contributorFullName:"D. Robert Sutherland",address:null,affiliation:'
University Health Network/Toronto General Hospital, Canada
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Management of Constipation: Current Status and Future Prospects",doi:"10.5772/intechopen.83467",slug:"the-management-of-constipation-current-status-and-future-prospects",body:'\n
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1. Introduction
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Many reports describe a high prevalence of constipation worldwide. For example, a survey conducted in North America by Higgins et al. reported prevalence rates of 12–19%, particularly among older populations [1]. Generally, research suggests that constipation reduces the patient’s quality of life (QOL) to a level comparable with the negative effects of allergy or inflammatory bowel disease [2]. Despite these negative characteristics, however, a clear overview of chronic constipation has not yet been established.
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The Rome IV diagnostic criteria, which were revised in 2016, are often used to evaluate functional constipation. However, these diagnostic criteria exclude irritable bowel syndrome (IBS), a prevalent condition (7–21%) that exists on a continuous spectrum with functional constipation. Notably, IBS and functional constipation may be associated with predominant symptoms such as abdominal pain or bloating, which are not necessarily predominant in all cases of constipation [3]. This suggests that IBS and functional constipation often overlap in real-world scenarios [4]. Furthermore, the diagnosis of chronic constipation, which often involves the appraisal of symptoms (including QOL measures), and associated therapies appear to be incomplete.
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In addition to the lack of diagnostic and treatment methodology, the Japan Collaborative Cohort Study found evidence suggesting that a low bowel movement frequency increases the risks of cardiovascular disease (CVD), such as stroke and ischemic myocardial infarction, and of related mortality. The same study also found a high incidence of CVD among laxative users in Japan [5, 6]. Therefore, the effect of constipation indicates an increasingly poor prognosis. In this chapter, we review the present clinical practices targeting constipation and discuss newly introduced therapeutic drugs for constipation, such as secretagogues, which have recently yielded medical advances. With this review, we aim to prevent a perspective on the future treatment of chronic constipation.
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2. Definition of constipation
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Individual bowel movement patterns (including constipation) vary widely and are easily affected by many factors, including changes in the diet, living environment, mental status, and time course [7, 8]. Additionally, physicians and patients may hold different understandings of constipation. Consequently, the term “constipation” may encompass a broad spectrum of symptoms and situations. Despite these differences, constipation can be adequately defined as a status in which comfortable defecation is impossible, in accordance with many international clinical practice guidelines and review articles, as well as the Rome IV criteria [4, 9, 10].
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3. Chronic constipation, including chronic functional constipation and IBS
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Constipation can be roughly classified as acute or chronic, each of which can be further divided according to an organized or functional pathogenic mechanism. However, this chapter will discuss specifically chronic functional constipation in adult patients and its deleterious effects on the long-term QOL. Previously, the Rome III criteria were used to diagnose chronic functional constipation when a stringent definition is required for research purposes. In May 2016, however, the revised Rome IV criteria were published [10] (Table 1). Notably, these updated criteria include the requirement of other symptoms associated with difficulty of defecation and incompleteness of evacuation, as well as symptoms associated with constipation, and do not diagnose chronic functional constipation based on the frequency of bowel movements alone. Of note, these criteria require the exclusion of IBS prior to a diagnosis of chronic functional constipation (Table 2). However, this condition overlaps with IBS in many clinical cases. Accordingly, we recommend that in actual clinical settings, cases in which a patient’s continued inability to defecate comfortably that has deleterious effects on daily life should be managed as chronic constipation, even if the Rome IV criteria are not fulfilled [4]. Later, we discuss the diagnosis and management of chronic constipation, including chronic functional constipation and IBS.
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Diagnostic criteriaa for functional constipation (FC)
Straining during more than one-fourth (25%) of defecations
Lumpy or hard stools (Bristol Stool Form Scale: BSFS 1-2) more than one-fourth (25%) of defecations
Sensation of incomplete evacuation more than one-fourth (25%) of defecations
Sensation of anorectal obstruction/blockage more than one-fourth (25%) of defecations
Manual maneuvers to facilitate more than one fourth (25%) of defecations (e.g., digital evacuation, support of the pelvic floor)
Fewer than 3 spontaneous bowel movements per week
Loose stools are rarely present without the use of laxatives
Insufficient criteria for irritable bowel syndrome
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Table 1.
The diagnostic criteria for functional constipation: This criteria is cited from “Mearin et al. [10]”.
Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.
For research studies, patients meeting criteria for Opioid-Induced Constipation (OIC) should not be given a diagnosis of FC because it is difficult to distinguish between opioid side effects and other causes of constipation. However, clinicians recognize that these 2 conditions might overlap.
Recurrent abdominal pain, on average, at least a day per week in the last 3 months, associated with 2 or more of the following criteria: \n
Related to defecation
Associated with a change in frequency of stool
Associated with a change in form (appearance) of stool
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Table 2.
The diagnostic criteria for irritable bowel syndrome: This criteria is cited from “Mearin, et al. [10]”.
Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.
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3.1. Alarming symptoms associated with chronic constipation
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Particular attention should be given to the management of constipation associated with alarming symptoms, which may correlate with a poor outcome due to the required therapy for an underlying disease or surgically treated condition. Patients with alarming symptoms should be further scrutinized and subjected to additional diagnostic testing before treatment is administered for constipation. Potentially alarming symptoms may include a change in stool caliber, heme-positive stool, iron-deficiency anemia, obstructive symptoms, an age of >50 years with no history of colon cancer screening, recent onset of constipation, rectal bleeding, rectal prolapse, and weight loss [9, 10, 11]. Such symptoms should be considered an indication for colonoscopy.
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3.2. Secondary constipation
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Secondary constipation should be excluded prior to a diagnosis of functional or chronic constipation due to IBS, as underlying high-risk diseases and etiologies must be identified [4, 10, 11]. Secondary constipation can be subdivided coarsely into drug-induced and symptomatic cases. Consequently, a diagnostic interview for chronic constipation should inquire about the time of onset, duration of disease, frequency of bowel movements, consistency of stool, symptoms associated with constipation, and the presence of concrete situations of dyschezia (e.g., abdominal pain and/or bloating, sensation of incomplete evacuation, need for manual maneuvers to facilitate defecation, and evacuation time). A clinical history, including lifestyle factors and dietary fiber and fluid intake, should also be taken. A systemic physical examination that includes a digital rectal examination (palpation for gastrointestinal mass, anorectal inspection to assess fecal impaction, stricture, rectal prolapse, rectocele, paradoxical or nonrelaxing puborectalis activity, and rectal mass), laboratory analyses (complete blood counts, biochemical profile, calcium and glucose levels, and thyroid function tests) and colonoscopy is also required to exclude secondary constipation. In summary, underlying diseases and drug-affected constipation should be considered in an evaluation of chronic constipation.
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3.2.1. Underlying diseases
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The diagnosis and treatment of underlying diseases is very important in the management of chronic constipation. Underlying diseases that may cause chronic constipation are listed below [9]:
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Mechanical obstruction: colorectal tumor, diverticulosis, stricture, external compression from tumor/other structures, large rectocele, megacolon, postoperative abnormalities, and anal fissure.
Other causes: cardiac disease, degenerative joint disease, and immobility.
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3.2.2. Drug-induced constipation
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When evaluating a case of chronic constipation, the patient’s current profile of medicine use must be understood precisely and considered during further treatment. A list of drugs that may cause chronic constipation is provided below [9].
Self-medication (i.e., over-the-counter drugs): antacids (containing aluminum and calcium), antidiarrheal agents, calcium and iron supplements, and nonsteroidal anti-inflammatory drugs.
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4. Diagnostic approaches to the treatment of chronic constipation
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An interview based on the diagnostic criteria (Table 1) for functional constipation is useful when planning treatment for chronic constipation. The simple and objective Bristol stool form scale, which is used worldwide, is particularly useful for enabling an evaluation and record of the stool form and thus elucidating an individual patient’s defecation status [12, 13]. When possible, the patient should maintain a stool diary that includes the number of bowel movements per day and stool consistency (Bristol stool form types 1–7, Figure 1) for approximately 1 week. This record is also useful for evaluating symptoms and sensations (e.g., sensation of incomplete evacuation, abdominal pain, and/or bloating) after evacuation [4].
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Figure 1.
The Bristol Stool Form Scale: This scale is a useful tool to evaluate stool and can evaluate colonic transit time.
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The Bristol scale can also be used to estimate the colonic transit time. Currently, cases of functional constipation are categorized as normal-transit, slow-transit, or defecatory rectal evacuation disorder [10]. A previous histological analysis reported that slow-transit constipation results from a reduction in Cajal cells [14], suggesting that this type is caused by a decrease in the statuses of lower postprandial phasic responses (e.g., the disappearance of bowel peristalsis) [15]. Other research indicates that defecatory rectal evacuation disorders are caused by functional failures (e.g., pelvic floor line coordination disturbance) [16]. Although Bristol stool form types 1 and 2 can be attributed to slower transit constipation and types 6 and 7 are characteristic of rapid transit constipation [17], patients who meet the diagnostic criteria for functional constipation often exhibit characteristics of slow colonic transit constipation [18]. Still, the diagnosis of defecatory rectal evacuation disorders does not require diagnostic colonic and anorectal testing [19].
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An improved QOL is among the most important goals of treatment for chronic constipation. Accordingly, various questionnaires are useful during the processes of diagnosis and treatment (see Section 5). If initial conservative medical management does not cure chronic constipation, additional measures such as the balloon expulsion test [8, 20, 21], manometric assessment [20], defecography [22], and radio-opaque marker testing of the whole-gut transit time should be considered [23]. Additional tests may also be performed, although the availability may be limited to certain medical centers or countries. Accordingly, interinstitutional cooperation is important.
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5. Self-reported questionnaires for diagnostic purposes
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Questionnaire-based self-report measures can be classified by the type of QOL evaluation and type of constipation severity quantitation. Various methods are currently advocated, although further progress in this area is needed [24]. The questionnaires most frequently mentioned in a literature search via the PubMed database are shown below.
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5.1. Evaluation of severity of constipation
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Constipation scoring system (CSS) [25]. The CSS comprises eight questionnaire items to assess the frequency of bowel movements, difficult or painful evacuation, completeness of evacuation, abdominal pain, time per attempt, type of assistance (including laxatives, digitation, or enemas), number of unsuccessful attempts at evacuation in a 24-h period, and duration of constipation. All but one item are scored on a 5-point Likert scale (range: 0–4); the type of assistance, including laxatives, is scored on a 3-point scale (range: 0–2). A cutoff score of 15 is used to indicate constipation.
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Patient assessment of constipation symptoms (PAC-SYM) [26]. The PAC-SYM was validated for the assessment of chronic functional constipation in 216 adult patients in the USA. This tool includes 12 items to assess abdominal, rectal, and stool factors. The items are scored on a 5-point Likert scale (range: 0–4), with a score of 4 indicating the worst symptom severity. The total possible scores for the PAC-SYM range from 0 to 48, and no diagnostic cutoff score has been reported. This questionnaire has a 7-point Likert scale for four items of abdominal symptoms and three items of rectal symptoms (e.g., abdominal pain, bloating, and rectal burning) from no discomfort to very severe discomfort.
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5.2. QOL evaluation tool
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Gastrointestinal symptom rating scale (GSRS) [27]. The GSRS is a questionnaire comprising 15 items intended to address common gastrointestinal symptoms. The scale can be completed by the patient within approximately 5 min, and the items are scored on a 7-point Likert scale ranging from no discomfort to very severe discomfort. For evaluation purposes, a mean scale score is calculated for the equivalent of items (e.g., heart burn, nausea, and abdominal pain), and a high score indicates more severe symptoms.
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Patient assessment of constipation quality of life (PAC-QOL) [28]. The PAC-QOL is a simple self-reported questionnaire used to measure the patient’s QOL associated with constipation, including daily behavioral and therapeutic aspects relevant to constipation during the previous 2 week period. The PAC-QOL comprises 28 items divided into four subscales that address the patient’s worries/concerns relevant to constipation, physical discomfort, psychosocial discomfort, and satisfaction. The items are scored on a 5-point scale, and a higher score indicates a lower QOL. The original edition was developed in English and has since been translated into many languages.
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6. Practical treatment
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In this section, we aim to provide an overview of the various available treatments for chronic constipation for which the details have been published. Patient education is a very important first step in the therapeutic management of chronic constipation [3]. Patients should be instructed to consume an adequate quantity of dietary fiber (total fiber intake: 20–30 g/day), set a routine of regular toilet time after mealtimes, and take an on-defecation position involving elevation of the lower limbs. If such measures are ineffective, an oral fiber supplement, such as psyllium (up to 30 mg/day in divided doses) may be attempted [29].
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Drug therapy should be initiated if the above-described lifestyle modifications fail to treat chronic constipation, and this should be accompanied by an assessment of bowel movements every 2–4 weeks to determine the therapeutic effects. Generally, osmotic laxatives (e.g., lactulose, lactitol, mannitol, and sorbitol) are administered initially as these are cost-effective and have few adverse effects [18, 30]. Although saline laxatives (e.g., magnesium sulfate) are frequently administered in Japan, these drugs are not widely accepted worldwide and have only been evaluated clinically in small-scale randomized controlled trials (RCTs) [31]. Furthermore, patients with renal failure face the risk of serious hypermagnesemia consequent to the use of magnesium sulfate [32]. However, this drug should be considered, given its low cost and abundant use in Japan. Polyethylene glycol laxatives (17–34 g/day) should also be considered, as many RCTs have indicated that these agents are more effective than lactulose [33, 34].
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If chronic constipation remains unresolved by the above therapies, newer medicines should be considered. Recent years have seen the rapid development of novel agents such as secretagogues (e.g., lubiprostone and linaclotide). However, as the availability and indications of these new drugs for chronic constipation vary among countries, all medical treatment for chronic constipation should comply with national clinical practice guidelines or guiding principle. Finally, surgical or biofeedback treatment should be considered for cases of chronic constipation that cannot be resolved with medication and patients with defecatory rectal evacuation disorders [35, 36].
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7. New therapeutic drugs for chronic constipation
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The extensive development of novel drugs for chronic constipation has led to variability in the potential applications among countries. For example, neither secretagogues (e.g., plecanatide) nor serotonergic enterokinetic agents (e.g., prucalopride and selective 5-hydroxytryptamine receptor agonists) have been approved for use in Japan. Below, we comment mainly on the new therapeutic drugs for chronic constipation that have been authorized for use in Japan.
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7.1. Lubiprostone
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Various studies have analyzed lubiprostone, the most well-developed one of the newer class of drugs. The mechanism of action of this constipation-targeting drug is interesting. Lubiprostone is a selective type-2 chloride channel (ClC-2 channel) activator. This biogenic bicyclic fatty acid was developed by Cuppoletti and Ueno for the treatment of chronic constipation and has been approved for use worldwide after the initial authorization for manufacturing and marketing in the US and Japan. [37, 38] Lubiprostone is the first clinically applied secretagogue, and accordingly, a broad range of clinical experience is associated with this drug. Moreover, the mechanism of action of this drug has been analyzed in much greater detail relative to secretagogues introduced subsequently. Specifically, this drug activates ClC-2 channels expressed in the apical membranes of intestinal epithelial cells and exerts its laxative function by inducing the secretion of intestinal fluids. The ability of lubiprostone to improve constipation symptoms has been validated through RCTs [39], which reported the maintenance of efficacy throughout a 48-week administration period with no significant side effects [40].
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Lubiprostone promotes the secretion of intestinal fluid by activating ClC-2 channels. Upon absorption from the small intestine, lubiprostone is degraded immediately to an inactive metabolite. Therefore, the effects of this drug are tissue selective, and few side effects have been observed. In the small intestine, lubiprostone activates the ClC-2 channels expressed on mucosal epithelial cells to promote the transport of chloride ions from the visceral lumen and concomitant countertransport of cations into the lumen. This activity induces a difference in the local osmotic pressure across the epithelial cell membrane, and the resulting secretion of intestinal fluid expedites defecation [41, 42]. As the expression of the ClC-2 channel is not expected to vary according to age, sex, or race, lubiprostone may be effective in elderly patients with constipation.
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Clinical usefulness of lubiprostone for chronic constipation. As mentioned above, multiple RCTs have validated the effectiveness of lubiprostone for chronic constipation [39] and demonstrated a both sustained efficacy and a lack of serious adverse effects during a 48-week period of administration. The most common side effects of this drug include nausea (frequency: 19.8%), diarrhea (9.7%), abdominal distension (6.9%), headache (6.9%), and abdominal pain (5.2%) [40]. Recently, the mechanism of action of lubiprostone as a therapeutic drug for constipation was investigated in detail (see below.) Notably, a study based on a questionnaire regarding QOL, work productivity, and lifestyle impairment found that lubiprostone improved both symptoms related to chronic constipation and the patients’ QOL [43]. In a phase 3 trial, Fukudo et al. found that long-term lubiprostone administration was associated with an average increase in the average spontaneous bowel movement (SBM) number per week and an improved QOL among Japanese patients with chronic idiopathic constipation [44]. In a randomized, double-blind, placebo-controlled trial of the effects of lubiprostone on chronic idiopathic constipation in diabetic patients, Christie et al. found that this drug reduced the colon transit time and increased the SBM number safely and effectively [45].
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Parkinson’s disease: Parkinson’s disease is a very common neurodegenerative disorder characterized by motility disturbances. Constipation occurs very frequently in affected patients and is a predictor of the onset of movement disorder. Constipation appears as a symptom prior to more obvious signs of parkinsonism before disappearance of dopamine cells in substantia nigra. Accordingly, clinicians should consider the early detection of a movement disorder when evaluating cases of constipation. In a double-blind RCT of the efficacy and tolerability of lubiprostone in patients with Parkinson’s disease with constipation, Ondo et al. concluded that the drug was well tolerated and effective when administered for a short duration [46].
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Efficacy of lubiprostone for CKD: Mishima et al. demonstrated clearly that lubiprostone could inhibit an exacerbation of adenine-induced CKD by altering the intestinal environment or intestinal flora. That study suggested that in a patient with CKD, the intestinal tract acts as a conduit for uremic toxin excretion that is comparable with hemodialysis and urine. Lubiprostone may, therefore, be a novel therapeutic drug for CKD [47].
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Protective effects on the small intestine and “leaky gut syndrome.” The small intestine serves as a barrier for the selective transport of molecules in and out of the gastrointestinal tract. Failure of this barrier function renders the patient unable to absorb the nutrient for use as energy and can enable the transport of microbial pathogens and harmful chemical substances into the interior of the body. This state is known as the “leaky gut syndrome” and is thought to induce various diseases, including gastrointestinal diseases (e.g., inflammatory bowel disease), allergies, diabetes, connective tissue diseases, and liver diseases [48]. Therefore, the prevention of leaky gut syndrome would be therapeutically valuable.
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No currently available therapeutic drug can improve abnormal intestinal tract permeability in humans. However, Moeser et al. revealed that lubiprostone not only promotes the secretion of intestinal fluid by activating ClC-2 channels but also protects and restores injured small intestinal mucosa [49]. The mechanism underlying the restoration of tight junctions in the mucosa remains unknown, although the ClC-2 channel was found to play an important role in restoring the tight-junction structure and barrier function in a mouse model of colitis [48]. Furthermore, Kato et al. demonstrated that lubiprostone could improve intestinal permeability in humans [50]. Although these research findings require validation, lubiprostone appears to be a promising treatment for leaky gut syndrome.
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Anti-inflammatory effect. Experimentally, lubiprostone was shown to prevent indomethacin-induced intestinal disease through a mechanism dependent on the prostaglandin EP4 receptor subtype in male Sprague-Dawley rats. This effect might suppress excessive intestinal motility and promote intestinal fluid secretion, while controlling bacterial invasion and inducible nitric-oxide synthase/tumor necrosis factor alpha expression, the main pathological events of intestinal disease. However, it is difficult to understand how the protective effect of lubiprostone would rely on the direct activation of the cystic fibrosis transmembrane regulator/ClC-2 channel [51].
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Promotion of mucin secretion. Lubiprostone has been shown to promote mucin secretion in the small intestinal mucosa via a prostaglandin-like action and thus maintain digestive function [51]. Lubiprostone might also promote the intestinal transit of feces by providing lubrication and could thus improve the likelihood of comfortable defecation [52, 53].
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Lubiprostone in clinic. A previous report indicated a correlation of Munchausen syndrome with the overuse of stimulant laxatives [54], which presents a challenge regarding dependence on these drugs. We, therefore, investigated whether lubiprostone administration would facilitate a reduction in the dose of a continuously administered stimulant laxative. In real clinics, we have shown the successful reduction or cessation of the stimulant laxative (e.g., sodium picosulfate, senna) in more than 50% of cases (n = 21) within 6 months of administering lubiprostone (manuscript in preparation). Notably, no further medications were needed in these cases. These clinical experiences suggested us that the lubiprostone may be useful not only for the symptom itself but also for the reduction of stimulant laxatives leading to the safe and cost effective treatment of constipation.
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7.2. Linaclotide
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Linaclotide is a newly developed therapeutic drug for chronic constipation and constipation-predominant IBS. This drug is absorbed at low levels and has few adverse effects, of which the main complaint is diarrhea [55]. This peptide drug comprises 14 amino acids and acts by binding to the guanylate cyclase C (GC-C) receptor expressed on intestinal epithelial cells, which promotes the secretion of fluids into the intestinal lumen. The GC-C receptor is associated with bodily fluid and ionic homeostasis, bowel movements, and relief from afferent pain signaling and is thus considered a therapeutic target for chronic constipation and constipation-predominant IBS [56].
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When compared with placebo, linaclotide yielded excellent results in terms of the reduction in abdominal pain and increase in complete SBMs at 12 weeks after the initial first administration [57]. Furthermore, linaclotide was associated with a significant increase in the average QOL score relative to placebo in a questionnaire-based survey [58]. A cost-effectiveness analysis study revealed that the less expensive linaclotide yielded equivalent patient satisfaction to that achieved with lubiprostone [59]. As chronic constipation overlaps partially with constipation-predominant IBS, linaclotide may greatly expand the treatment options for constipation. Although linaclotide has been prescribed widely at our hospital at an appropriate once-daily dosage of 0.5 mg, we presume that many physicians may initiate this drug at a daily dosage of 0.25 mg to avoid adverse effects.
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7.3. Elobixibat
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Bile acids are synthesized from cholesterol in the liver and secreted to the duodenum, where they play an essential role in lipid digestion and absorption. Upon reaching the terminal ileum, bile acids are absorbed solely by the ileal bile acid transporter (IBAT) expressed only in the terminal ileum [60]. Here, 95% of the bile acids are reabsorbed through the portal system and are reconjugated and reexcreted into bile by hepatocytes in an enterohepatic cycle that occurs 2–15 times daily. Unabsorbed bile acids are transported to the colon, where they encourage the secretion of water into the large bowel lumen and thus promote large bowel movement [61, 62]. Accordingly, the administration of ursodeoxycholic acid or the occurrence of ileal diseases that enable the transport of excess amounts of bile acids to the large bowel can cause diarrhea [60].
\n
The drug elobixibat specifically inhibits the IBAT required for bile acid reabsorption and is thus commercially available as the first IBAT inhibitor. Through its inhibitory actions, elobixibat increases the entry of bile acids into the large bowel and thus promotes evacuation. When administered orally, this drug is absorbed at low levels; accordingly, it has few adverse effects and is considered safe [63]. In Japan, elobixibat is administered orally at a once-daily dosage of 10 mg before a meal. However, the usage of this drug may vary among countries and should be confirmed carefully. To date, elobixibat has been used in only seven cases at our hospital in the short time since it has been licensed. Although only two patients have used this drug continuously for at least 2 months, all treated patients have achieved complete SBM. Elobixbat appears to act simultaneously as a stool softener and laxative stimulant. We expect that the use of this drug will increase.
\n
\n
\n
7.4. Naldemedine
\n
Naldemedine, a peripherally acting μ-opioid receptor antagonist, was developed as a therapeutic drug for opioid-induced constipation and is approved in the US and Japan [64]. This new class medication showed important therapeutic effect in improving opioid-induced constipation without reducing the efficacy of opioid drugs because it selectively targets the peripheral μ-opioid receptor as demonstrated in two-phase 3 trials [65, 66]. Therefore, although opioid-induced constipation has been initially treated with conventional laxatives, however, based on these evidences, naldemedine is expected to become a leading therapy for cases using opioids. Recently, we are switching to naldemedine to manage the constipation in cases using opioid, and approximately one-third of patients using opioids have been treated with naldemedine and showed the safe and effective bowel movement (manuscript in preparation).
\n
\n
\n
\n
8. Conclusion
\n
To improve the QOL in the cases suffered with chronic constipation, the appropriate therapeutic intervention is essential. With the rise in the therapeutic options and its real world data, and the objective assessment methods, its treatment is dramatically changing. It is obvious that the correct diagnosis excluding the emergent situation is essential; however, the physicians need to update the information for these newly developed medicines useful for constipation and switch from the conventional agents for better QOL.
\n
As the appropriate use of these new agents under various conditions remains uncertain, therefore, the accumulation of the clinical information, real-world data are necessary. For this purpose, this review overviewed the symptoms, diagnosis, and medicines available to date. We hope that these informations are useful for physicians treating patients and that various pathophysiological studies will elucidate the correct use of these new anticonstipation agents.
\n
Furthermore, we hope that the development of a more ideal questionnaire will enable effective decisions regarding the most effective treatment for chronic constipation.
\n
\n
Conflict of interest
The authors declare that they have no current financial arrangement or affiliation with any organization that may have a direct influence on their work.
\n',keywords:"chronic constipation, Rome IV diagnostic criteria, secretagogues, lubiprostone",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65080.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65080.xml",downloadPdfUrl:"/chapter/pdf-download/65080",previewPdfUrl:"/chapter/pdf-preview/65080",totalDownloads:571,totalViews:0,totalCrossrefCites:1,dateSubmitted:"August 30th 2018",dateReviewed:"December 11th 2018",datePrePublished:"January 9th 2019",datePublished:"October 2nd 2019",readingETA:"0",abstract:"Chronic constipation, a common condition, can have remarkably negative effects on a patient’s quality of life. Recent research has identified factors that may influence the prognosis of chronic constipation and suggests the need for adequate therapy. However, the major obstacles in this field were: (1) a small number of therapeutic options, (2) no clear diagnostic criteria, and (3) no effective method to collect information form the patients. These were due to the fact that bowel movement patterns vary widely among individuals, and also the functional constipation, including irritable bowel syndrome, is difficult to be distinguished from the chronic constipation. Recently, it has been demonstrated that the Rome IV diagnostic criteria of functional constipation and the Bristol stool form scale are useful for the objective evaluation and recording of stool. Based on these developments, and the increase of newly developed medicines the therapy for the constipation is significantly changing and therefore, if conventional therapy for chronic constipation is ineffective, switching of medicines is possible. Therefore, clinicians should update the information of these newly developed drugs available in clinics and diagnostic criteria. For this purpose, in this chapter, we have summarized the perspective on the current paradigm of treatment for chronic constipation focusing on recently introduced therapeutic drugs.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65080",risUrl:"/chapter/ris/65080",signatures:"Masaki Maruyama, Kenya Kamimura, Moeno Sugita, Nao Nakajima, Yoshifumi Takahashi, Osamu Isokawa and Shuji Terai",book:{id:"7103",title:"Constipation",subtitle:null,fullTitle:"Constipation",slug:"constipation",publishedDate:"October 2nd 2019",bookSignature:"Gyula Mózsik",coverURL:"https://cdn.intechopen.com/books/images_new/7103.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"51900",title:"Dr.",name:"Kenya",middleName:null,surname:"Kamimura",fullName:"Kenya Kamimura",slug:"kenya-kamimura",email:"kenya-k@med.niigata-u.ac.jp",position:null,institution:null},{id:"272130",title:"Dr.",name:"Masaki",middleName:null,surname:"Maruyama",fullName:"Masaki Maruyama",slug:"masaki-maruyama",email:"gontax@nifty.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Definition of constipation",level:"1"},{id:"sec_3",title:"3. Chronic constipation, including chronic functional constipation and IBS",level:"1"},{id:"sec_3_2",title:"3.1. Alarming symptoms associated with chronic constipation",level:"2"},{id:"sec_4_2",title:"3.2. Secondary constipation",level:"2"},{id:"sec_4_3",title:"3.2.1. Underlying diseases",level:"3"},{id:"sec_5_3",title:"3.2.2. Drug-induced constipation",level:"3"},{id:"sec_8",title:"4. Diagnostic approaches to the treatment of chronic constipation",level:"1"},{id:"sec_9",title:"5. Self-reported questionnaires for diagnostic purposes",level:"1"},{id:"sec_9_2",title:"5.1. Evaluation of severity of constipation",level:"2"},{id:"sec_10_2",title:"5.2. QOL evaluation tool",level:"2"},{id:"sec_12",title:"6. Practical treatment",level:"1"},{id:"sec_13",title:"7. New therapeutic drugs for chronic constipation",level:"1"},{id:"sec_13_2",title:"7.1. Lubiprostone",level:"2"},{id:"sec_14_2",title:"7.2. Linaclotide",level:"2"},{id:"sec_15_2",title:"7.3. Elobixibat",level:"2"},{id:"sec_16_2",title:"7.4. Naldemedine",level:"2"},{id:"sec_18",title:"8. Conclusion",level:"1"},{id:"sec_22",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Higgins PD, Johanson JF. Epidemiology of constipation in North America: A systematic review. The American Journal of Gastroenterology. 2004;99:750-759. DOI: 10.1111/j.1572-0241.2004.04114.x\n'},{id:"B2",body:'Belsey J, Greenfield S, Candy D, Geraint M. Systematic review: Impact of constipation on quality of life in adults and children. Alimentary Pharmacology & Therapeutics. 2010;31:938-949. DOI: 10.1111/j.1365-2036.2010.04273.x\n'},{id:"B3",body:'Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: A clinical review. Journal of the American Medical Association. 2015;313:949-958. DOI: 10.1001/jama.2015.0954\n'},{id:"B4",body:'Rao SS, Rattanakovit K, Patcharatrakul T. 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DOI: 10.1172/JCI106644\n'},{id:"B62",body:'Bampton PA, Dinning PG, Kennedy ML, Lubowski DZ, Cook IJ. The proximal colonic motor response to rectal mechanical and chemical stimulation. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2002;282:G443-G449. DOI: 10.1152/ajpgi.00194.2001\n'},{id:"B63",body:'Acosta A, Camilleri M. Elobixibat and its potential role in chronic idiopathic constipation. Therapeutic Advances in Gastroenterology. 2014;7:167-175. DOI: 10.1177/1756283X14528269\n'},{id:"B64",body:'Markham A. Naldemedine: First global approval. Drugs. 2017;77:923-927. DOI: 10.1007/s40265-017-0750-0\n'},{id:"B65",body:'Hale M, Wild J, Reddy J, Yamada T, Arjona Ferreira JC. Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): Two multicentre, phase 3, double-blind, randomised, parallel-group trials. The Lancet Gastroenterology & Hepatology. 2017;2:555-564. DOI: 10.1016/S2468-1253(17)30105-X\n'},{id:"B66",body:'Katakami N, Harada T, Murata T, Shinozaki K, Tsutsumi M, Yokota T, et al. Randomized phase III and extension studies of naldemedine in patients with opioid-induced constipation and cancer. Journal of Clinical Oncology. 2017;35:3859-3866. DOI: 10.1200/JCO.2017.73.0853\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Masaki Maruyama",address:null,affiliation:'
Department of Gastroenterology, Kashiwazaki General Hospital and Medical Center, Japan
Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
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She received her PhD degree in 1994 from the School of Physiology and Pharmacology, Faculty of Medicine, UNSW, followed by Post doc at the Allegheny University of Health Sciences, Philadelphia, USA. \r\n\r\nShe is an academic with medical background along with more than thirty years of experience in teaching Medical and Health Sciences, to medical, dental, and science students at the postgraduate, graduate and undergraduate levels in various universities. Recently, she have started a company named "Shad Diagnostics" for developing a diagnostic tool "Stroke Meter". \r\n\r\nShe has supervised thirty five postgraduate students. At present she is a visiting professor and casual academic of University Technology of Sydney, and Australian Catholic University teaching under graduates and supervising graduates.',institutionString:"University of Technology Sydney",institution:{name:"University of Technology Sydney",institutionURL:null,country:{name:"Australia"}}},{id:"34340",title:"Ms",name:"Sarah",surname:"Heron",slug:"sarah-heron",fullName:"Sarah Heron",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"37955",title:"Mr.",name:"Faisal",surname:"Khan",slug:"faisal-khan",fullName:"Faisal Khan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/37955/images/3903_n.jpg",biography:null,institutionString:null,institution:{name:"University of Karachi",institutionURL:null,country:{name:"Pakistan"}}},{id:"43722",title:"Prof.",name:"Bjoern",surname:"Bauer",slug:"bjoern-bauer",fullName:"Bjoern Bauer",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Minnesota",institutionURL:null,country:{name:"United States of America"}}},{id:"45581",title:"Dr.",name:"Martine",surname:"Mirrione",slug:"martine-mirrione",fullName:"Martine Mirrione",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"53387",title:"Prof.",name:"Anika",surname:"Hartz",slug:"anika-hartz",fullName:"Anika Hartz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"53388",title:"Dr.",name:"Juli",surname:"Schlichtiger",slug:"juli-schlichtiger",fullName:"Juli Schlichtiger",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"53389",title:"Dr.",name:"Anton",surname:"Pekcec",slug:"anton-pekcec",fullName:"Anton Pekcec",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"our-story",title:"Our story",intro:"
The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:null},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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