**7. The atypical measles syndrome**

In contrast with the classic measles infection, the atypical measles syndrome occurs in older patients, often presenting with a heterogeneous rash, pulmonary infiltrates, hepatic dysfunction, and eosinophilia. The formation of immune complexes has been proposed as responsible for the manifestations of the syndrome [58]. This self-limiting disease, may show, however, long lasting, asymptomatic pulmonary nodules. An immune waning is suspected to occur in this disorder, though such an event has been refuted with measles virus infection at large. Officially, patients with this syndrome have been reported as recently as 2015 [59].

The atypical measles syndrome (AMS) stands out when compared with classic measles for the following reasons.

AMS presents at an older age, often with a high and prolonged fever. A polymorphic rash starts in the hands and feet. In the lungs, this disorder shows nodular infiltrates together with swollen hilar lymph nodes. These changes may regress suddenly. Liver function tests are often abnormal in AMS. Eosinophilia is frequent. This disease entity was first described in 1963, following the vaccination with the formalin inactivated measles virus (FIMV) vaccine. A subsequent exposure to the wild type MV has often been identified. The FIMV vaccine is said to have been withdrawn in 1967, but new cases of AMS were still reported in 2015 [59].

Clinically, the AMS does not resemble the classic MV disease and is usually mild. GPs have difficulties in making the diagnosis in real time. Anti-MV antibody titers are higher than 1:160, which is very unusual for classic measles. In AMS, Koplik spots are frequent and mostly will last 5–7 days, while they last rarely more than 2 days in the classic disease. Photophobia is rarely present in AMS. AMS is probably not contagious [60].

While most cases of AMS in the 1960s were associated with FIMV, the more recent occurrences have been associated with the live attenuated measles vaccine (LAV). Vaccination with FIMV had offered protection for a few months, after which the titers dropped suddenly [61]. We have suggested that this drop of antibody titers is most consistent with a humoral immunity waning. Cases of AMS with prior LAV vaccine have been reported, which are consistent with secondary vaccine failure. Such cases have been suggested to follow a prolonged exposure to an acute measles patient [62].

To confirm the ease by which the diagnosis of AMS is missed, 291 recruits were diagnosed with measles in 1987. They were young adults, with abdominal pain, diarrhea, and vomiting (33%); Koplik spots lasting a mean 7 days; and abnormal liver function tests (86%). The diagnosis of AMS was missed. Retrospectively, this was most certainly the diagnosis, although no anti-MV titers have been reported [63].

In 2015, Levine et al. reported on the status of the measles immunity, 20 years after the two-dose MMR vaccine was introduced. Of the cohort of recruits in 1996, 95.6% had shown positive anti-MV antibodies. In 2007, this positive data had dropped to 85%. Although the authors did not dare to make the statement, this reflected a state of waning immunity, to our opinion [64].

To summarize this issue, we have showed that the AMS differs from typical measles by various features. This is probably a disorder of immunologic nature, involving immune complexes. The AMS is presently rare, but to our opinion, this may be due to a notable under-diagnosis. The association between the AMS pathogenesis and immune waning should be confirmed. It is not excluded that this disorder be related with carcinogenesis as well [65, 66], as it has been proposed that a persistent viral infection is required for virus-associated carcinogenesis [67] and that a waning immunity might lead to a persistent MV infection.

**153**

**Acknowledgements**

*A Role for the Measles Virus in Oncology DOI: http://dx.doi.org/10.5772/intechopen.84342*

**8. Conclusions and prospects**

measles are described.

A relationship between MV expression and CHL was provisionally established on IHC [positive with two antigens or more in 82 of 154 CHL patients]; on RT-PCR [positive in 4 of 15 cases for HA-MV RNA; for 2 of 16 NP-MV RNA], and on *in situ* hybridization [for 2 of 7 CHL with HA-MV RNA; in 8 of 21 for NP-MV RNA], as well as with several other malignancies. When focusing on CHL, this association may even be causally linked: apoptosis regulation by the MV may be one of the supportive mechanisms. Our findings are probably sustained by an increasing CHL morbidity related with a progressing occurrence of measles in young adults, in Israel [68], in Quebec [69], and in Connecticut [70], in which frequent outbursts of

A clinicopathological correlation, based on the IHC results, was chosen, mainly due to the frequent results as compared with RT-PCR and *in situ* hybridization. In this part of our study, we confirmed an association between CHL and the MV. More females, NS-CHL cases, and more patients in the early stages of their disease were linked to the expression of MV in their tissues. In spite of these variables being, as a rule, correlated with a better prognosis, when they are associated with a positive

Regarding the refutation of our findings and conclusions by the German group, this might have been an occasion for further learning. However, the repercussions thereof, on our thesis and our findings, were such that no future was available for us in this domain. As a colleague described it, our position and our theory had been buried. Moreover, I never understood why it was done in that most unpleasant way. A chapter on the atypical measles syndrome was introduced at the end of the study. This disorder is related with measles and with the MV, but the link has not been clarified completely. Most of the AMS features, clinical, radiological, and biological, differ completely from those of measles. While measles is predominantly an infectious disease, and is highly contagious, AMS is probably not contagious, with its pathogenesis probably based on the formation of immune complexes. One of the highlights of the AMS is an anti-measles antibody titer of 1:160 or higher, much beyond that found in measles. Our interest, at this point, laid in evidence pointing toward immunity waning, as an essential component of AMS. Moreover, in the presence of a sharp drop in the titer, following mainly the FIMV vaccination, as well as occasionally that of the LAV vaccine, the subject might be submitted to the protracted exposition to an acute measles patient. So far, we are not aware of cancer developing in the context of AMS cases, but, since this disorder is often missed, it might be worthwhile looking for cases of cancer within such a context [60].

The prospects and suggestions for proceeding with our research include an epidemiologic study as well as the duplication of our basic investigation, but this once by scientists of good faith. The epidemiologic investigation should have 3 components: the first two, based on our CHL cohort, about half of which show IHC evidence of the MV. Of this population, we will attempt to identify, via the Israeli Ministry of Health Registry, patients who had contracted measles as well as those who had been vaccinated for MV, including vaccination details. The third will deal with AMS, based on the cohorts highlighted by Giladi M et al. [63], and Levine H et al. [64]. Confirmation in the first of the diagnosis of AMS, and research of patients with possibly MV-related

tumors and in the second, confirmation of the relevance to immune waning.

We thank Kibbutz Sde-Boker for their support.

measles expression, the net effect is a poor prognosis [3].


*2.4. Data Analysis*

Thematic analysis was the method chosen to support the analysis of the study's data. The Braun and Clarke [47] six-step proposition, which consists of eight discreet cycles, in conjunction with the QDA Training [48] material, formed the basis of the analysis technique. A practical iterative approach was adopted throughout the analysis where the data were formally arranged into discrete phases. The eight individual stages of analysis distributed over the six phases were designed to support a robust and rigorous analysis of the data. Table 4 below illustrates the stages and processes outlined and performed in NVivo and links this to the practical guidelines set out in Braun and Clarke [47]. Their six-step approach that supports the application of thematic analysis is shown in column one and the corresponding application in NVivo is shown in column two. The third column features the strategic elements of coding as the researcher moved from the initial participant-led descriptive coding, to the secondary coding which was more interpretative in nature indicating this phase of coding was both researcher- and participant-led. The final abstraction to themes was researcher informed only. This phase was designed to allow the researchers to engage the participant in direct dialogue with a wider arena such as literature and policy or strategy for example. The fourth and final column illustrates the more iterative nature of the coding, analysis and reporting of proceedings that terminate in a conclusion.

Phase 1 activity involves familiarizing oneself with the transcribed data. In this first phase, the data were loaded into NVivo. It was checked and re-read several times to ensure accuracy of the uploaded transcripts. At the end of the phase activity, initial codes were noted down and retained.

Generating initial codes (open coding: phase 2)—According to Lincoln and Guba [49] (p. 345), a data unit can be defined as the "smallest piece of information about something that can stand by itself, that is, it must be interpretable in the absence of any additional information other than a broad understanding of the context in which the inquiry is carried out". The open coding is intended to systemically organize the data and uncover the essential ideas found in the data [50]. Each discrete unit of data is labelled in line with the phenomenon it represents. The second phase required broad participant-driven open coding of the interview transcripts recorded during the data gathering step of the research study. Features of interest were coded in a systematic way across the complete dataset where data relevant to each code were collected. Clear labels were allocated to these codes and definitions to serve as rules for inclusion [26].

**Table 4.** Stages and Process Involved in Qualitative Analysis. Adapted from Braun and Clarke [47] and QDATRAINING Training [48] material.

A set of provisional categories was generated for the segmented data to be coded to. These categories were descriptions of concepts and themes in broad terms. They took two forms: researcher-driven and participant-driven. The former was derived from a theoretical framework underpinning the study and the latter from the knowledge gained of the participants' language and customs. Hammersley and Atkinson [51] (p.153) consider the importance of participant-driven categories: "the actual words people use can be of considerable analytic importance as the 'situated vocabularies' employed provide valuable information about the way in which members of a particular culture organize their perceptions of the world, and so engage in the social construction of reality".

Searching for themes—In phase 3, codes from phase 2 were collated into categories of codes by structuring all the data relevant to each potential category into a framework that could be used in support of further analysis. This phase also included distilling, re-labelling and merging common codes that were generated in phase 3 to ensure the labels and definitions for inclusion were an accurate reflection of the coded content. These first-round categories are best described as broad descriptions of concepts and themes. During the analytical process they underwent content and definition change and the existence of the two forms of category provides an important means of traversing between "natural" and "theoretical" discourses. Araujo [52] (p.68) suggests that "codes should be viewed in two ways: as part of the analyst's wider theoretical framework and as grounded in the data.; the process of coding data should be regarded as an important intermediary step in translating social actors' frames of meaning into the frame of theoretical discourse; coding frames therefore, mediate between the 'natural' everyday discourse and the theoretical discourses in social science".

Reviewing themes (coding on) in phase 4 required further decomposition of the study units of data identified in phase 1. This activity was intended to support a greater understanding of the highly qualitative elements and gain a deeper appreciation of the meanings contained within. It should be noted that not every task could be further broken down and this meant that the activity was performed only as required. Restructured codes were broken down into further sub-codes in order to augment a greater understanding of the meanings embedded within them. These distinctive aspects included communication with management, discovering latent issues, just culture, learning lessons, reporting, root causes and story of an incident.

Defining and naming themes in phase 5 of the data analysis was concerned with analyzing the tentative categories identified in phase 2 for their properties and characteristics. This is a pre-cursor to drafting a propositional statement for each category. Developing analytical memos moves the process beyond identification and description of broad categories to a position of analyzing and fusing meanings in the data under each category. This progressed to drafting a statement that aspires to illustrate the concerted meaning of the segments of data coded to each category. Maykut and Morehouse [26] (p.140) defines a propositional statement as, "*a statement of fact the researcher tentatively proposes, based on data*". This phase in addition to further data analysis to refine the specifics for each theme, generated clear definitions and a name for each theme. It also involved data reduction by consolidating categories from all three cycles into a more abstract, philosophical and literature-based thematic framework and conceptually mapping and exploring their relationships with one another for reporting purposes.

Producing the report in phase 6 required analytical memos to be written against the higher-level themes to present an accurate summary of the content of each category and its codes and to also propose findings. The tasks associated with phase 6 included (i) generating analytical memos, (ii) testing and validating and (iii) synthesizing the memos coherently and cohesively, and were performed simultaneously. Writing the analytical memos against the higher-level codes (i.e., learning from incidents, learning process and learning product) required an accurate summary of each category and its codes and findings against categories. These memos considered a few key areas:

Testing, validating and revising analytical memos was performed in phase 7. The purpose of this was to provide a self-audit of the proposed findings by soliciting evidence in the data beyond just textual quotes in support of the recorded findings and to also expand on deeper meanings within the data. This required the data to be interrogated, not only relying on relationships across and between categories, but also a degree of cross tabulation with demographics, observations and the literature. The outcome of this phase was evidence-based findings as each proposed finding was validated by being rooted in the data themselves and was reliant on the creation of reports in support of substantiated findings.

The discipline of writing analytical memos was used during the data analysis process. Birks et al. [53] believe "memoing serves to assist the researcher in making conceptual leaps from raw data to those abstractions that explain research phenomena in the context of which it is examined". In general, memos were employed at the "ideation" stage when the researcher was developing thought processes and early in the data capture phase. As decisions were made, the early processes and rationale for final analysis iterations were recorded using this medium. Memos were further employed to preserve an objective closeness to the harvested data and to maintain the context of each semi-structured interview at the participating individuals' level. Developing ideas, reasons for considering possible category relationships and connections was also possible through the application of the analytical memo process. The rigorous support memoing o ffered served to guide the analysis of the data through di fferent levels of abstraction [54]. The rule of this activity served to ensure a high degree of continuity between the outputs of ideation and the evolving interpretation that were honed through the researchers' articulation, exploration and their iterations of the data. Overall, this drew out the meanings in the data through the increased sensitivity the researchers were o ffered by applying the memoing process [53].

In phase 8, the analytical memos were synthesized into a coherent and cohesive report with the findings well supported. The final phase involved the assembly of the narrative with the data extracts while appreciating the product of this amalgam in the context of the related literature. The example features the finding, clear links to the interview data and literature and an explanatory narrative in the form of a memo. This finally resulted in the compilation of the report which contained the results and discussion elements of the body of work.

In summary, this study adopted an interpretative approach pivoting on the fact that it was of an exploratory nature. The study performed thirty-four interviews in eight aircraft maintenance and management organizations based in Ireland. An analysis of various potential research methods and means of data collection resulted in the following research design being implemented. A thematic analysis approach was employed as a research methodology:

• Qualitative analysis based on the guidelines from Braun and Clarke [47] (thematic analysis) employing a six-phase approach was used in the study.


2.4.1. Weak-Form Tests

Weak-form tests are tests used to examine whether investors can earn abnormal profits from the past data on asset prices. If successive price changes are independent and then unpredictable, it is impossible for investors to earn more than buy-and-hold. In the literature, there is evidence of random walk and independence in the successive price changes in support of weak-form market efficiency (e.g., Alexander 1961; Fama 1965a, 1965b; Fama and Blume 1966). However, Fama (1970) documented some evidence of departures from random walk with non-zero serial correlations in successive price changes on stocks (e.g., Cootner 1964; Neiderho ffer and Osborne 1966). Nevertheless, Fama (1970) recognized that rejection of random-walk model does not imply market ine fficiency. The independence assumption is too restrictive and not a necessary condition for EMH because market efficiency only requires the martingale process of asset returns (Samuelson 1965) with zero expected profits to the investors.


Meet the editors

Cristiano Bellé is a researcher in the field of plant nematology and biological control at Phytus Institute, Brazil. He is also a researcher at the Universidad Nacional de San Agustín de Arequipa (UNSA), Peru. He obtained a master's degree in Agronomy from the Federal University of Santa Maria, Brazil, in 2014, a doctorate degree in Crop Protection from the Federal University of Pelotas, Brazil, in 2018, and a post-doctorate degree in Soil

Biology and Microbiology from the Federal University of Santa Maria in 2019. He has experience in the field of agronomy with an emphasis on plant pathology and plant nematology. His work is related to the etiology and diagnosis of plant diseases caused by nematodes and fungi, pathogenicity and host-parasite relationships of plant-parasitic nematode diseases, the interaction between plant-parasitic nematodes and soilborne fungi in plants, and biological, cultural, and chemical control of plant-parasitic nematodes.

Dr. Tiago Kaspary obtained a Ph.D. in Weed Science from Universidade Federal do Rio Grande do Sul (UFRGS), Brazil, and a sandwich Ph.D. from the University of Arkansas, USA. He is currently a weed science researcher at the Instituto Nacional de Investigación Agropecuaria (INIA), La Estanzuela, Uruguay (SNI - I). He has experience in the field of agronomy with an emphasis on weed science. His works are related to biology and

weed management, the interaction of weeds with pathogens and nematodes, the resistance of weeds to herbicides, and molecular biology applied to weed science.

## Contents


**8.4. Bortezomib**

**8.2. Rituximab**

430 Current Issues and Future Direction in Kidney Transplantation

Rituximab, a chimeric monoclonal anti-CD20 antibody directed against B cells, prevents new antibody production by depletion of B cells as precursors of mature plasma cells in the circulation and the lymphoid tissue {although, some recent reports demonstrated that depletion in secondary and tertiary lymphoid structures is far less efficient and may not affect an ongoing localized humoral immune response (Genberg et al., 2006; Thaunat et al., 2008)}, prevention of B-cell proliferation, and induction of apoptosis and lysis of B cells through complement-dependent and -independent mechanisms (Salama & Pusey, 2006). Rituximab binds CD20 at the surface of precursor and mature B cells and leads to transient B-cell depletion, with typical B-cell recovery after 6–12 months in more than 80% of patients, although the degree of depletion is highly variable and is observed for up to 24 months in some individuals (Sureshkumar et al., 2007).An additional potential mechanism of action of rituximab is the direct targeting of CD20-positive cells that infiltrate the graft (Steinmetz et al., 2007). Preliminary studies indicate that rituximab decreases the concentration of pre-existing and post-transplantation antibodies (Gloor et al., 2003; Vieira et al., 2004). Conclusions and extrapolations from these studies are limited, because rituximab is usually combined with other therapies in these small and uncontrolled trials. The risk of bacterial infection as a result of immunoglobulin deficiency is also an important consideration. Based on the pathophysio‐ logic condition of this rejection process and efficacy of rituximab in B cells and antibodymediated autoimmune diseases (Eisenberg & Albert, 2006; Levesque & St Clair, 2008), a

combination treatment with rituximab/IVIG represents a logical approach.

In a multicenter study, MMF in combination with cyclosporine resulted in significantly lower frequencies of HLA antibodies when compared with azathioprine and cyclosporine treatment (Terasaki & Ozawa, 2004). Moreover, MMF was described to be effective in inhibiting primary antigen-specific antibody responses in renal transplant patients (Rentenaar et al., 2002). Heidt et al (Heidt et al., 2008) stimulated purified human B cells devoid of T cells with CD40L expressing L cells, or by anti-CD40mAb with or without Toll-like receptor triggering, all in the presence of B-cell activating cytokines. These three protocols resulted in various degrees of Bcell stimulation. Then, they added four commonly used immunosuppressive drugs (tacroli‐ mus, cyclosporin, mycophenolic acid [MPA], and rapamycin) to these cultures and tested a variety of parameters of B-cell activity including proliferation, apoptosis induction, and both IgM and IgG production. They found that MPA was extremely potent in inhibiting both proliferation and immunoglobulin production. Moreover, these effects persisted when MPA was added to already activated B cells, implying that an ongoing B-cell response may be dampened by MPA, whereas calcineurin inhibitors are ineffective. MPA levels used are lower

In the same in vitro experiments, rapamycin, like MMF, was described to be extremely potent in inhibiting humoral responses. Rapamycin was the most effective drug tested, as it inhibited not only B-cell proliferation and immunoglobulin production, but also inhibited the number of immunoglobulin producing cells. None of the other drugs tested were capable of decreasing

**8.3. Mycophenolic acid and sirolimus**

than levels that are usually achieved physiologically.

While the B cell-depleting anti-CD20 antibody rituximab is increasingly incorporated in treatment protocols of humoral rejection (Faguer et al., 2007), this reagent is neither effective in eliminating antibody-producing plasma cells (PC) – either newly created from memory or naıïve B cells or from those that existed prior to transplant- nor does it decrease circulating antibody titers (Singh et al., 2009). For an effective blockade of alloantibody formation, a specific PC-depleting reagent would be desirable. Bortezomib (BZ), a selective inhibitor of the 26S proteasome, has been approved by FDA for the treatment of relapsed multiple myeloma. Mechanisms of BZ action include inhibition of NF-κ B and cytokine expression as well as induction of apoptosis as a result of activation of the terminal unfolded protein response (Meister et al., 2007). Susceptibility to BZ-induced apoptosis is related to the high immuno‐ globulin synthesis rate of PCs associated with accumulation of unfolded proteins/DRiPs inducing endoplasmatic reticulum stress (Meister et al., 2007). Moreover, BZ not only acted on the humoral response but also effectively inhibited the influx of MHC class II+ cells, mono‐ cytes/macrophages, CD8+ as well as CD4+ T cells. In animal models, Vogelbacher and colleagues (Vogelbacher et al., 2010) found that combination of Bortezomib and sirolimus inhibit the chronic active antibody-mediated rejection in experimental renal transplantation in the rat. In humans, data are lacking. In one case report, Bortezomib failed to treat CAMR even after treatment with rituximab and IVIG.

Perry and colleagues (Perry et al., 2009) described two sensitized patients with AMR treated in February 2007 using a combination of bortezomib and multiple plasmapheresis. Both patients had resolution of AMR and decreased serum DSA levels months after treatment. Neither developed transplant glomerulopathy. In a slightly different clinical setting, Everly and colleagues (Everly et al., 2008) used bortezomib to treat six patients who had combined AMR and cellular rejection occurring from 3 months to 7.5 years after transplant. All six patients showed resolution of AMR with a decrease in DSA levels after treatment. Unfortu‐ nately, three of the six patients developed transplant glomerulopathy. Flechner and coworkers (Flechner et al., 2010) treated 20 cases (16 kidney-only and 4 kidney-combined organ recipients) with AMR 19.8 months (range 1-71 months) posttransplant using a combined regimen of intravenous corticosteroids followed by a 2-week cycle on days 1-4-8-11 of plasmapheresis and 1.3 mg/m2 bortezomib; then 0.5 mg/kg intravenous immunoglobulin four times. They found that the bortezomib-containing regimen demonstrated activity in AMR but seems to be most effective before the onset of significant renal dysfunction (serum creatinine <3 mg/dL) or proteinuria (<1 g/day).

Compared to rituximab, Waiser and colleagues (Waiser et al., 2012) found that patients with AMR treated with bortezomib had better graft survival At 18 months after treatment (P = 0.071) and renal function at 9 months was superior in patients treated with bortezomib as compared to rituximab-treated patients (P= 0.008). Whereas these early clinical experiences with protea‐ some inhibition are encouraging, the lack of controls is a major limitation in assessing true efficacy. In addition, since even successfully treated AMR can still result in the development of chronic transplant glomerulopathy, the prevention of AMR might be a more important goal of these types of therapies.

These cell-surface markers might be useful targets to prevent the development of B cells into

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Normal plasma cells express little or no CD20 and are therefore resistant to rituximabmediated depletion. Several cell-surface molecules that are expressed by plasma cells might be considered as drug targets — syndecan-1 (CD138), CD38, α4β1-integrin (CD49d–CD29) and CXC-chemokine receptor 4 (CXCR4) — although none of these is en‐ tirely plasma-cell specific. Plasma-cell longevity is thought to be an extrinsic phenomen‐ on that is mediated by survival signals delivered by bone-marrow stromal cells (Colvin & Smith, 2005). Because the transcription factors BLIMP1 (B-lymphocyte-induced matura‐ tion protein 1) and XBP1 (X-box-binding protein 1) (as well as the repression of PAX5, paired box gene 5) are required to maintain plasma-cell function, their inhibition might

Complement antagonists could prevent the acute pathological effects of complement activa‐ tion. For example, soluble CR1 delays antibody-mediated rejection in xenograft models but is insufficient to prevent graft rejection completely (Azimzadeh et al., 2003). Other complement antagonists, such as C5-specific antibody, which blocks activation of C5 and formation of both C5a and the MAC, are in ongoing evaluation. Transgenic expression of human complementregulatory proteins (DAF and CD59) in pigs has shown potency for preventing xenograft rejection (Menoret et al., 2004), but the relevance of these studies to allografts needs to be

Immunologic barriers once considered insurmountable are now consistently overcome to enable more patients to undergo organ transplantation. Alloantibodies are a substantial obstacle to short- and long-term graft survival. To prevent or reduce alloantibody titres, more insights are needed to improve our understanding of the regulation of B cells and the devel‐

Several important issues regarding AMR remain. First, the immunologic mechanisms respon‐ sible for the development of high levels of DSA are still unclear. The contribution of memory B cells versus the role of pre-existing PCs has important therapeutic implications since each

Whereas several new therapeutic approaches have emerged, more extensive study and followup are needed to determine if these apparent advances will improve the outcomes of AMR.

opmental and differentiation pathways of memory B cells and plasma cells.

may have a differential sensitivity to various agents.

result in the loss of plasma-cell function (Shapiro-Shelef & Calame, 2005).

plasma cells.

*8.6.2. Plasma cells*

*8.6.3. Complement antagonists*

extended and tested.

**9. Summary**


**4. Doppler waveform of ureteric jet**

### **4.1. Pattern of the ureteric jet**

*Parameters of the jet*

116 Recent Advances in the Field of Urinary Tract Infections

(Matsuda & Saitoh, 1995).

*3.2.2. Clinical implication of ureteric jet*

Summers et al., 1992; Wachsberg, 1998)

**3.3. Previous work on the ureteric jet on animals**

The extension of jet varies from 1 to 5 cm into the bladder but sometimes extended more than 5 cm or less than 1 cm (Dubbins et al., 1981; Elejalde & de Elejalde, 1983; Kremer et al., 1982).

The mean jet velocity in the paediatric group varies between 18 to 31.6 cm/s (from 26 days to 17 years old) while in the adults it varies from 32.1 to 60 cm/s (from 18 to 49 years old (Cox et al., 1992; Jequier et al., 1990; Marshall, 1990; Matsuda et al., 1995; Matsuda& Saitoh, 1995; Sperandeo et al., 1994;). The duration of jet ranges from 0.6 to 7.5 s (Jequier et al., 1990) in paediatric and from 3.5 to 15 s in adult (Catalano et al., 1998; Cox et al., 1992; Kremer et al., 1982; Matsuda et al., 1995). The frequency of jet ranges from 2.4 to 5.4 jets/min in adult (Burge et al., 1991; Catalano et al., 1998; Kremer et al., 1982; Matsuda & Saitoh, 1995). The

Adult subjects have a higher velocity (20 vs. 16 cm/s), duration (2.5 vs. 1.8 s) and frequency

There is symmetry in jet frequency, jet parameters of velocity and duration between right and left side in healthy subjects (Burge et al., 1991; Cox et al., 1992; Matsuda & Saitoh, 1995).

Under the condition of forced diuresis, the jet hasa higher velocity (32.1 vs. 20 cm/s), dura‐ tion (6.7 vs. 2.5 s) and frequency (2.4 vs. 1.2 jets/min) than in the normal physiological state

It has previously been suggested that the presence of ureteric jet implies concurrenturinary tract infection (UTI) (Kalmon et al., 1955; Nevin et al., 1962) and absence of vesicoureteric reflux (VUR) (Kuhns, 1977). Subsequent studies prove that the presence of ureteric jet is just a normal physiologic phenomenon and cannot be used to diagnosis UTI or exclude VUR (Eklöf & Johan‐

However, the presence of jet could be used to exclude ureteric obstruction. The complete ab‐ sence of jet or a continuous low-level waveform is diagnostic for high-grade obstruction from ureteric calculi (Abulafia et al., 1997; Burge et al., 1991; Catalano et al., 1998; Elejalde & de Elejalde, 1983; Laing et al., 1994; Tal et al., 1994; Timor-Tritsch et al., 1997; Wu et al., 1995; Yoon et al., 2000).The difference in jet velocity has been used to study the effect of drug treatment on benign prostatic hyperplasia (Sperandeo et al., 1994, 1996) and to study the physiology of the kidney and ureter, includingthe glomerular filtration rate (Blomley et al., 1997; Burke & Washowich, 1998; Chiu et al., 1999; Han et al., 1996, 1997; Patel et al., 1996;

Lamb et al has found that ureteric jet can be consistently visualized in the dogs. The ureteric jets show variable frequency and duration. Lamb has suggested that the non-visualization of the ureteric jet might be helpful in diagnosing ectopic ureter (Lamb & Gregory, 1994).

son, 1980; Gothlin, 1964; Gudinchet et al., 1997; Jequier et al., 1990; Marshall et al., 1990).

interjet interval ranges from 2 to 150 seconds (Catalano et al., 1998; Cox et al., 1992).

(1.2 vs1 jets/min) than children (Matsuda & Saitoh., 1995).

Ureteric jets areclassified according to the number of peaks within that particular Doppler waveform. Six basic patterns are identified: monophasic (with only one peak), biphasic (two peaks), triphasic (three peaks), polyphasic (number of peaks exceeding three), "square" (a plateau waveform in which no distinct peak be identified but of average duration); and "continuous" when the waveform lasts longer than 20 seconds which can be either polypha‐ sic or plateau form. These waveforms are further classified as three categories. Monophasic jet is classifies as the first category of simple and immature pattern (Fig. 4).

**Figure 4.** The simple, immature monophasic pattern of the ureteric jet

The bi, tri- and polyphasic patterns are classified as the complex and mature pattern (Fig 5).

The last two patterns are the square and continuous forms. These are modified waveform under the state of forced diuresis. They are classified as the diuretic pattern (Fig. 6).

**Figure 5.** The complex and mature pattern of the ureteric jet: bi (a), tri (b), polyphasic (c)

**Figure 7.** Doppler measurement of the ureteric jet: peak velocity (a), duration (b) and initial slope (c)

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Multispike pattern is defined as the pulsation in the jet pattern as a result of the pulsation transmitted from the adjacent arteries (Fig 9). This pattern is more commonly observed when bladder is maximally full and the incidence is found to be 1.9% of the study popula‐

Change in angle of the jet meant there was a change in the direction of the jet at the begin‐ ning and at the end (Fig. 10). This pattern could be observed at any diuresis status. The inci‐

dence is found to be 4.3% of the study population (Leung et al., 2007b).

**Figure 8.** Presence of break (arrow) within the ureteric jet

tion (Leung et al., 2007b).

**Figure 6.** The diuretic pattern of the ureteric jet: square (a), continuous (b)

### **4.2. Measurement of ureteric jet**

On the Doppler waveform, the maximum velocity (peak velocity), jet duration and initial slope can be measured (Fig 7).

### **4.3. Uncommon modification of the jet**

There are three uncommon but interesting modifications of the jet. They are: presence of breaks, multispike pattern and change in direction of the jet. These patterns are relatively uncommon in the normal population but they provide indirect supportive evidence for the hypothesis of functional sphincter action at the VUJ.

Presence of breaks meant there is a total absence of signal between peaks within the dura‐ tion of that particular wave (Fig 8). Most of the breaks are observed in the maximally full bladder and the incidence is found to be 5.7% of the study population (Leung et al., 2007b).

Functional Anatomy of the Vesicoureteric Junction: Implication on the Management of VUR/ UTI http://dx.doi.org/10.5772/52168 119

**Figure 7.** Doppler measurement of the ureteric jet: peak velocity (a), duration (b) and initial slope (c)

**Figure 8.** Presence of break (arrow) within the ureteric jet

**Figure 5.** The complex and mature pattern of the ureteric jet: bi (a), tri (b), polyphasic (c)

**Figure 6.** The diuretic pattern of the ureteric jet: square (a), continuous (b)

On the Doppler waveform, the maximum velocity (peak velocity), jet duration and initial

There are three uncommon but interesting modifications of the jet. They are: presence of breaks, multispike pattern and change in direction of the jet. These patterns are relatively uncommon in the normal population but they provide indirect supportive evidence for the

Presence of breaks meant there is a total absence of signal between peaks within the dura‐ tion of that particular wave (Fig 8). Most of the breaks are observed in the maximally full bladder and the incidence is found to be 5.7% of the study population (Leung et al., 2007b).

**4.2. Measurement of ureteric jet**

118 Recent Advances in the Field of Urinary Tract Infections

slope can be measured (Fig 7).

**4.3. Uncommon modification of the jet**

hypothesis of functional sphincter action at the VUJ.

Multispike pattern is defined as the pulsation in the jet pattern as a result of the pulsation transmitted from the adjacent arteries (Fig 9). This pattern is more commonly observed when bladder is maximally full and the incidence is found to be 1.9% of the study popula‐ tion (Leung et al., 2007b).

Change in angle of the jet meant there was a change in the direction of the jet at the begin‐ ning and at the end (Fig. 10). This pattern could be observed at any diuresis status. The inci‐ dence is found to be 4.3% of the study population (Leung et al., 2007b).

*5.1.1. General properties of jet*

**Incidence (%)**

dren (22%) than in adult (1.9%) (Table 2).

**Children**

P < 0.01

**Table 2.** Incidence of monophasic jet in children and adult.

78.89 cm/s for the complex pattern.

complex pattern.

**Number Incidence (%)**

**Monophasic Biphasic Triphasic Polyphasic**

0-9.9 30 30.6 23.3 16.1

10-19.9 3.3 28.7 41.1 26.9

20-29.9 0 35.6 40.7 23.7

30-39.9 2.0 35.6 35.1 27.3

40-49.9 2.5 34.1 32.7 30.7

50-59.9 3.8 38.7 30.8 26.7

60-69.9 0 38.0 35.5 26.4

70-79.9 4.7 37.2 37.2 20.9

In the normal population, there is strikingly larger number of monophasic patterns in chil‐

For the mean velocity, it is 34.03 cm/s for the monophasic jet and 61.82 cm/s for the complex pattern in children. While in adult, the mean velocity of the monophasic jet is 57.65 cm/s and

For the mean jet duration, it is 1.17 s for children with monophasic pattern and 5.26 s for the complex pattern. In adults, the mean jet duration is 1.91 s for monophasic jet and 6.9 s for

**Adult**

**Number Incidence (%)**

**Table 1.** Incidence of the four patterns in different age groups of the normal population.

Monophasic 83 22 18 1.9

patterns prevail.

**Age (year)**

In the normal population, four common patterns can be identified: monophasic, biphasic, triphasic and polyphasic (Table 1). The square and continuous patterns occur under force di‐ eresis, which contributes only 1.5% of cases in the normal population. With increasing age from infancy, the proportion of monophasic waveform decreases while the more complex

Functional Anatomy of the Vesicoureteric Junction: Implication on the Management of VUR/ UTI

http://dx.doi.org/10.5772/52168

121

**Figure 9.** Multispike pattern (arrows) of the ureteric jet.

**Figure 10.** Changing of angle in the ureteric jet: from vertical at the beginning (a) to slightly inclined at the end (b) of the jet.


**Abstract**

Finding successful therapies for the treatment of Alzheimer's disease (AD) is one of the most challenging tasks existing for human health. Several drugs have been found and validated in preclinical studies with some success, but not with the desired breakthroughs in the following clinical development phases. AD causes multiple brain dysfunctions that can be described as a brain organ failure, resulting in significant cognitive decline. Aggregation of amyloid proteins and neuronal loss are the hallmarks of AD. Thus, one of the strategies to treat AD is to find a multifunctional drug that may combine both anti-aggregation and neuroprotective properties. Such a candidate could be chemically modified dendrimers. Dendrimers are branched, nonlinear molecules with multiple reactive groups located on their surface. Chemical modification of reactive surface groups defines the property of the dendrimers. In this chapter, I will discuss poly(propylene imine) dendrimers with the surface functionalized with histidine and maltose as an example of a multifunctional therapeutic drug candidate able to protect the memory of AD transgenic model mice.

**Keywords:** dendrimer, histidine, aggregation, synapse, memory, Alzheimer's disease


With the impact of changing market dynamics, celebrity endorsement has become one of the most frequently used communication strategy in marketing of housings; however, this strategy that is being widely used in marketing of housings has not been investigated yet at a scientific level. In this respect, this study accomplishes a first, but at the same time it has specific limitations. First, this study examined the celebrity endorsement issues mostly over the newspaper advertisements, which is one of the traditional marketing communication tools. However today, it is known that, just like it is true for other sectors, digital marketing communication tools (facebook, twitter, instagram and similar social networks, web sites, etc.) are being used in this sector along with traditional marketing communication tools [34]. For this reason, it seems important to include digital marketing communication tools alongside the traditional marketing communication tools in the future researches that will examine the celebrity endorsement. This way it will become possible to examine the issue on a more extensive set of samples and it may even be possible to compare the celebrity endorsement strategies used in traditional marketing communication tools (newspaper, journals, TV, radio, etc.) with the ones used in digital marketing communication tools.

A similar suggestion is mentioned in the study of Bergkvist and Zhou [35], which is one of the most recent studies carried out regarding celebrity endorsement. Writers have examined 10 marketing journal and 5 advertising journal and reviewed the literature in celebrity endorsement fields over 126 articles published after 2013. The most significant finding determined as the result of this literature review was that all publications they reviewed still used the "celebrity endorsement" definition made by McCracken [1] in 1989. Writers claim that this definition is outdated. Because celebrity endorsement strategy today is being used in other social media platforms besides advertisements. Also celebrities no longer endorse just consumption goods but they also endorse business to business products and service, consumer services, noncommercial entities like political parties, etc. In the light of changing conditions, Bergkvist and Zhou [35], p. 644] makes a new definition of celebrity endorsement: "*A celebrity endorsement is an agreement between an individual who enjoys public recognition (a celebrity) and an entity (e.g., a brand) to use the celebrity for the purpose of promoting the entity.*" It will make sense to discuss in future researches, the celebrity endorsement strategy as part of the changing conditions specifically in the housing market.

Second, this study reviews a qualitative research carried out about celebrity endorsement. Future researches may be built on evaluating the impact of celebrity endorsement strategy used in housing market, on consumers via methods like surveys, etc. Accordingly the contribution of celebrity endorsement to the perception of brand image and its impact on purchasing behavior of consumers may be interpreted in more detail.

And third, it is anticipated that actors like investors, designers, marketing experts, etc., who play a role in housing production process are included within the scope of the research in order to discuss the issue more extensively. Actors that take a part in production and marketing of housings may be interviewed and positive and negative results arising from use of these strategies may be discussed and even compared with other sectors. The issue of popularization in the housing production is very different from other sectors. And the main reason for this is that the housing is a location-dependent product and is redesigned every time according to the quality of the land it is built on. In this context, it is believed that the results are much different than the results obtained in cosmetics industry, automotive industry and similar industries where celebrity endorsement is studied profoundly.

## **Author details**

has specific limitations. First, this study examined the celebrity endorsement issues mostly over the newspaper advertisements, which is one of the traditional marketing communication tools. However today, it is known that, just like it is true for other sectors, digital marketing communication tools (facebook, twitter, instagram and similar social networks, web sites, etc.) are being used in this sector along with traditional marketing communication tools [34]. For this reason, it seems important to include digital marketing communication tools alongside the traditional marketing communication tools in the future researches that will examine the celebrity endorsement. This way it will become possible to examine the issue on a more extensive set of samples and it may even be possible to compare the celebrity endorsement strategies used in traditional marketing communication tools (newspaper, journals, TV, radio,

A similar suggestion is mentioned in the study of Bergkvist and Zhou [35], which is one of the most recent studies carried out regarding celebrity endorsement. Writers have examined 10 marketing journal and 5 advertising journal and reviewed the literature in celebrity endorsement fields over 126 articles published after 2013. The most significant finding determined as the result of this literature review was that all publications they reviewed still used the "celebrity endorsement" definition made by McCracken [1] in 1989. Writers claim that this definition is outdated. Because celebrity endorsement strategy today is being used in other social media platforms besides advertisements. Also celebrities no longer endorse just consumption goods but they also endorse business to business products and service, consumer services, noncommercial entities like political parties, etc. In the light of changing conditions, Bergkvist and Zhou [35], p. 644] makes a new definition of celebrity endorsement: "*A celebrity endorsement is an agreement between an individual who enjoys public recognition (a celebrity) and an entity (e.g., a brand) to use the celebrity for the purpose of promoting the entity.*" It will make sense to discuss in future researches, the celebrity endorsement strategy as part of the changing

Second, this study reviews a qualitative research carried out about celebrity endorsement. Future researches may be built on evaluating the impact of celebrity endorsement strategy used in housing market, on consumers via methods like surveys, etc. Accordingly the contribution of celebrity endorsement to the perception of brand image and its impact on

And third, it is anticipated that actors like investors, designers, marketing experts, etc., who play a role in housing production process are included within the scope of the research in order to discuss the issue more extensively. Actors that take a part in production and marketing of housings may be interviewed and positive and negative results arising from use of these strategies may be discussed and even compared with other sectors. The issue of popularization in the housing production is very different from other sectors. And the main reason for this is that the housing is a location-dependent product and is redesigned every time according to the quality of the land it is built on. In this context, it is believed that the results are much different than the results obtained in cosmetics industry, automotive industry and

purchasing behavior of consumers may be interpreted in more detail.

similar industries where celebrity endorsement is studied profoundly.

etc.) with the ones used in digital marketing communication tools.

conditions specifically in the housing market.

194 Advancing Insights on Brand Management

Füsun Çizmeci Yöreş

Address all correspondence to<EMAIL_ADDRESS>
Department of Architecture, Yildiz Technical University, Beşiktaş, İstanbul, Turkey

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## *Edited by Paolo Popoli*

This book is an original, high-quality collection of chapters about highly topical and important brand management issues, and it shows both theoretical and empiric analysis. The 10 selected chapters are referred, with original contents and rigorous research methodologies, to some important challenges the brand management has to face in the current competitive contexts, characterized by the dominance of the intangible resources and the new information and communication technologies.

Written by leading academics, this book is dedicated not only to marketing and management scholars but also to students wanting to investigate the knowledge concerning special fields and special brand management themes. As well to the practitioners who can find a wide reference also to the managerial implication from the strategic and operative perspectives.

Advancing Insights on Brand Management

Advancing Insights on

Brand Management

*Edited by Paolo Popoli*

Photo by ktsimage / iStock


Author details

Mauricio Díaz-Muñoz, Anaí Campos-Contreras, Patricia Juárez-Mercado, Erandi Velázquez-Miranda and Francisco G. Vázquez-Cuevas\* Department of Cellular and Molecular Neurobiology, Neurobiology Institute, National Autonomous University of México, Mexico

\*Address all correspondence to<EMAIL_ADDRESS>
© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


# **Future Trends in Advanced Materials and Processes**

Edited by Petrica Vizureanu Printed Edition of the Special Issue Published in *Materials*

www.mdpi.com/journal/materials

## **Future Trends in Advanced Materials and Processes**