*3.3. Scanning Electronic Microscopy (SEM)*

SEM images of the catalyst were taken in order to corroborate the particle size. An FEI QUANTA 200 FEG (ESEM) was used at high-vacuum operation (<6 × 10−4 Pa (4.5 × 10−2 Torr)), electron landing energy of 5 keV and spot of 3.0.


**2.4 Statistical procedure**

The experimental design involved three treatments (CF, SS and CS) and nine replicates per plot. The data about spike weight (g), spike length (cm), number of grains per spike and total weight of the set of grains of that spike (g) were subjected to statistical processing by an analysis of variance. This was done to determine the factor or factors, and the possible interactions between them, which could affect any differences observed among the treatments.

All the statistical calculations were performed with Statgraphic Centurion XV. The ANOVA table decomposes the variability of the studied parameters (spike length, spike weight, number of grains per spike, total weight of grains per spike and yield) in contributions due to several factors. In the analysis, the sum of the type III squares was chosen. Thus, the contribution of each factor was measured by eliminating the effects of the other factors. P-values proved the statistical significance of all the factors, and those less than 0.05 indicated that these factors had a statistically significant effect on each parameter at the 95% confidence level.


**6. Conclusion**

The term IoT was coined in 1999 and it led to the evolution of IIoT enabled by other technologies that were being developed independently of each other. These technologies include such as: cyber-physical systems & cybersecurity; edge and cloud computing; mobile technologies; machine-to-machine communication; 3D printing; advanced robotics; big data; RFID technology; and AI. The SEPT Learning Factory is state-of-the art facility at McMaster University for the demonstration of integration of these technologies as well as development of educational/training material and resources, new technologies, and applied research.

Based on AI modeling the Fan Fault Detection and Diagnosis System described is able determine a fault state that was not included in training the AI model. The IIoT Vibration Demonstration Station using the neural networking model can detect the machine fault in real-time and publish the outcome on a dashboard connected via MQTT platform. The Machine Health Monitoring and Prediction Platform on the

#### *IoT Applications Computing*

other hand combines the best features of the last two models for advanced predictive maintenance learning concepts and real-time demonstrations. This station has been developed, with an embedded vibration sensor and other sensors, that analyses a system for faults and transmits information wirelessly. Students will be able to report errors such as general imbalances, mechanical failure, resonance, electrical faults, and critical speeds. It can be easily extended to further application demonstrations such as bearing faults, AI modeling using multiple sensor inputs and analysis.

In this chapter we have described IIoT machine health monitoring foundations, models and applications for education and training. We have also illustrated how these models can be extended for development of predictive maintenance using AI technology.


**Homocysteine in Red Blood Cells Metabolism – Pharmacological Approaches**

Filip Cristiana, Zamosteanu Nina and Albu Elena

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/47795


*Edited by Asma Salman and Muthanna G. Abdul Razzaq*

Accounting is both an art and science, which governs the communication and processing of the financial information in an organization. Technological advancement is helping the accountants to monitor financial performance in real time. This presents both opportunities and challenges for the current day organizations and accounting professionals alike. This book shows many different aspects to the same accounting principles but from a cross-cultural perspective. The diversity of the authors who contributed to this book signify the importance of accounting from various dimensions while ensuring that standards are adhered to, and principles are followed and applied. This book intends to feature the journey from the double-entry bookkeeping developed in medieval Europe to the changing dynamics of accounting. It is divided into five main sections: The Matching Principle, Ethics in Accounting, Insurance Contracts, Green Accounting, and Financial Instruments.

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Published in London, UK © 2018 IntechOpen © JDiamante / iStock


**6. Acknowledgment**

This chapter is based on several research performed at VTT and other research institutes and universities.

#### **7. References**

be between 2 and 2.5 times higher than that in Helsinki. In North Scandinavia it would be between 0.5 and 0.25, which will point out, the effect if climate on risk of decay development in outdoor structure varied vide within Europe. These coefficients can be used as one step to evaluate the effect of macroclimate conditions on service life of cladding and decking. Another way to evaluate the macroclimate conditions is presented by Thelandersson et al (2011) using Meteonorm climate data. By calculating the daily dose and accumulating the dose for one year a measure of the risk of decay is obtained. This is made for several sites, and the result in terms of dosedays can be compared between the different sites. To be able to compare different sites, the dose was transferred to a relative dose by dividing it by the dose for the "base-station" Helsinki. Due to the variation of climate across Europe, relative doses between 0.6 (northern Scandinavia) and 2.1 (Atlantic coast in Southern Europe) were

There are several factors involved with the bio-deterioration of materials and buildings, and mathematic modelling that may help us to understand the complicated interaction of many factors. The presented numerical mould growth and decay development models are based on experimental results from several research projects. It is suitable for post-processing temperature and humidity data from any numerical simulation of hygrothermal conditions in building constructions. However, it must be kept in mind when performing the assessment that there is a great uncertainty coupled to this kind of analysis: the variation of the material sensitivities is high, estimation of a product sensitivity class is difficult without testing, the surface treatments may enhance or reduce growth potential, different mould species have different requirements for growth and the evaluation of the actual conditions in the critical material layers may include uncertainties. The best way to use the predicted mould growth and decay development as an assessment tool is to compare different solutions with each others: The solution with the lowest risk for the mould growth or decay

development would most probably also have least other moisture related problems

This chapter is based on several research performed at VTT and other research institutes

Adan, O.C.G. 1994. On the fungal defacement of interior finishes. Eindhoven University of

Ayerst, G. 1969. The effects of moisture and temperature on growth and spore germination

Clarke, J.A. Johnstone, C.M. Kelly, N.J. Mclean, R.C. Anderson, J.A., Rowan N.J. and Smith,

Grant, C., Hunter, C.A., Flannigan, B. and Bravery, A.F. 1989. The moisture requirements of moulds isolated from domestic dwellings. Internat. Biodet. 25:259-284.

J.E. 1998. A technique for prediction of the conditions leading to mould growth in

Technology. Thesis. Eindhoven, pp. 83-185.

in some fungi. J. Stored Prod. Res. 5:127-141.

buildings. Building and Environment 34 pp 515-521.

obtained.

**5. Conclusion**

**6. Acknowledgment**

and universities.

**7. References**

**26**

**The Release of**

*Technical University of Lodz*

Marek Solecki

*Poland*

**Compounds from Microbial Cells**

Compounds present in the microbial cells are of great commercial value. Their separation requires disintegration of cell walls and cytoplasmic membranes. The disintegration of microorganisms on an industrial scale is carried out, among the others, in bead mills (Chisti & Moo-Young, 1986; Geciowa et al., 2002; Hatti-Kaul & Mattiasson, 2003). A bead mill is a container filled with beads that are set in circular motion by a rotating stirrer. Microorganisms dispersed in the liquid are disrupted due to the impact of beads. The mechanism of cell destruction is a result of combined action of normal and tangential forces. There are three basic types of this mechanism: collisions of beads, grinding and rolling performed by the beads. Disintegration is a very complex process. In this process, cell walls of microorganisms are disrupted, intracellular compounds are released and dissolved in the continuous phase, cell walls are subjected to microgrinding, the released macromolecular compounds are cut and the released enzymes interact. Rheological properties of the

Currie et al. (1974) described disintegration kinetics of microorganisms in the bead mill. The authors developed a linear model by comparing experimental data with results obtained during the disintegration process carried out in a high-pressure homogenizer (Hetherington et al., 1971). A logical model based on the analogy to the theory of gas kinetics was proposed by Melendres et al. (1998). They presumed that microorganisms could be destroyed due to collisions of dispersed beads of the packing. A phenomenological model based on the flow of suspension between two volumes was developed by Heim & Solecki (1998). The authors assumed that cells were disrupted while moving from a safe volume to the one in which no living microorganisms could exist. Basing on the sequence of events: cell disruption – the release of intracellular compounds, Melendres et al. (1993) developed a nonlinear model of the release of selected intracellular enzymes. Heim et al. (2007) described nonlinearity of the kinetics caused by changes in the disintegration conditions which was a result of the process run. Nonlinearity of the disintegration process resulting from subsequent decline of the biggest fractions of yeast cells was observed by Solecki (2009). Earlier, Whitworth (1974) described nonlinearity of cell disintegration kinetics in a suspension containing microorganisms (*Candida lipolytica*) which belonged to the same species and occurred in two morphological forms. The recently developed theory of random transformations of dispersed matter makes it possible to include in the description the fundamental phenomena observed during the process (Solecki, 2011). The aim of the study was to

**1. Introduction**

suspension and its continuous phase are changed.


**1. Introduction**

The 5xxx series Al-Mg alloys are widely used materials in the automotive industry due to their high strength-to-weight ratios, weldability, and good corrosion resistance [1–3]. Strength and ductility can be improved by adding solute Mg to the alloys because of the solid solution strengthening mechanism [4,5]. Nevertheless, as the amount of Mg increases, a selective oxidation prevails and causes a formation of oxide inclusions at elevated temperatures [6]. The rapid oxidation of magnesium alloys can be suppressed by additions of Ca [7]. With this background, a new alloying strategy has been developed. The strategy uses an Mg + Al2Ca master alloy instead of pure Mg during casting. The Mg + Al2Ca master alloy improves the oxidation resistance of Al-Mg alloys by forming a protective CaO/MgO mixed layer on the surface [8,9]

Previous studies have shown that anodic β-phase (β-Mg2Al3) precipitation along grain boundaries is an important factor affecting the intergranular corrosion (IGC) susceptibility of Al-Mg alloy [6–8]. The Mg segregation leads to anodic β-phase formation at 50–200 ◦C. The β-phase precipitation is referred to as sensitization [10–13]. The β-phase formation is usually observed at grain boundaries (GB), sub-grains, intermetallics, dislocations and other defects. Generally, the sequences of β precipitation have been reported as follows [14–16]:

Solid solution α → Guinier–Peston zones → β" → β' → β precipitation The β phases are electrochemically active compared to the Al matrix which leads to galvanic corrosion. The distribution and morphology of β precipitates affect the susceptibility of the alloy to IGC. To evaluate the IGC susceptibility, a nitric acid mass-loss test (NAMLT, ASTM G67) can be used to measure the corrosion rate.

**Citation:** Choi, K.-H.; Kim, B.-H.; Lee, D.-B.; Yang, S.-Y.; Kim, N.-S.; Ha, S.-H.; Yoon, Y.-O.; Lim, H.-K.; Kim, S.-K. Intergranular Corrosion and Microstructural Evolution in a Newly Designed Al-6Mg Alloy. *Materials* **2021**, *14*, 3314. https://doi.org/ 10.3390/ma14123314

Academic Editor: Marián Palcut

Received: 11 May 2021 Accepted: 9 June 2021 Published: 15 June 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

In this research, the IGC susceptibility of sensitized Al-6Mg alloy with two different cold rolling conditions was studied. It is not yet clearly understood how the cold rolling process affects the corrosion behavior [17]. D'Antuono et al. observed that an increased rolling reduction increased the growth rate of β precipitation due to lowering nucleation temperature [18]. Additionally, an initial β precipitation was observed preferentially at low-angle grain boundaries rather than high-angle grain boundaries [19]. On the contrary, Wang et al. found that the maximum corrosion depth decreases with increasing cold rolling reduction ratio. They also stated that larger thickness reductions are attributable to an increased number of small-sized grains formed at the grain boundary, which can eventually break off the continuity of corrosion.

This paper aims to figure out the effect of cold rolling and sensitization treatment on the IGC susceptibility of a newly designed Al-6Mg alloy. In this study, a microstructure evolution of the alloy was analyzed by electron backscattered diffraction (EBSD). The continuity of β-phase precipitation at grain boundary was studied by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The effects of the cold rolling reduction ratio and sensitization heat treatment on the IGC susceptibility are discussed.


#### *3.2. Framework of RUL Prediction Method*

The integrated framework for the life prediction approach is described in Figure 8 and divided into offline training and online prediction. In the offline stage, first, the IC curve is calculated in the CC charging phase, in which the two HIs that inflection point height and position are extracted, with the curve smoothing method derived from the KF algorithm. Combined with the charging capacity in the CV phase of every cycle, all three HIs effectively characterize the battery aging of the entire charging process. Then, a novel AutoML model is established with Auto-sklearn architecture, to realize the automatic design of the pipeline. The model hyperparameters are tuned and the search is optimized in the training stage. In the online stage, the extracted three features are directly applied to predict the battery RUL based on the trained AutoML model.

**Figure 8.** Framework of RUL prediction based AutoML.

#### **4. Results and Discussion**

#### *4.1. Evaluation Criteria*

In this study, root mean square error (RMSE) and mean absolute error (MAE) indexes are applied to evaluate the performance of the prediction method. The formulae for calculating are as follows:

$$\text{RMSE} = \sqrt{\frac{\sum\_{i=1}^{n} (\mathbb{C}\_{real}(n) - \mathbb{C}\_{prd}(n))^2}{n}} \tag{12}$$

$$\text{MAE} = \frac{1}{n} \sum\_{i=1}^{n} \left| \mathbb{C}\_{real}(n) - \mathbb{C}\_{prd}(n) \right| \tag{13}$$

where *n* is the number of cycles, *Creal* is the real capacity, and *Cprd* is the predicted capacity.

In most experiment settings in data-driven methods, the training set and validation set are usually divided on the same single battery, which can implement the online prediction. In the driving scenario, unlike in the bench test, the BMS cannot predict online capacity without the first 60% to 80% battery running data, so the goal of online prediction for the entire battery aging cycle is hard to achieve. To tackle this, we use the leave-one-out evaluation as Chen et al. [45] applied to evaluate their model: one battery is sampled for validation, and the other three batteries are used for training. A total of four trials are conducted and hyperparameters of the model as well as the average evaluating index over all batteries are determined.

#### *4.2. Prediction Results and Analysis*

As the framework showed in Figure 8, the HIs F1, F2, and F3 calculated by raw voltage and current data are used as input of the AutoML model, and the training set and validation set are divided by leave-one-out evaluation.

By means of searching and evaluating, the three methods, poly, rbf, and sigmoid, are used for feature preprocessing, and the five classifiers are selected in the AutoML model, and the classifiers' type and ensembled weight are listed in Table 2. In Table 3 we show the hyperparameters used in this study.

**Table 2.** The classifiers type and ensembled weight in the AutoML model.

**Table 3.** Hyperparameters used in verification.

The capacity prediction and relative error of B05, B06, B07, and B18 are depicted in Figure 9. The red predicted capacity curve approximates the yellow real capacity curve with most prediction errors controlled within 7% in the validation of four batteries, indicating high accuracy and robustness.

**Figure 9.** Capacity prediction results and errors of (**a**) B05, (**b**) B06, (**c**) B07, and (**d**) B18.

Compared to the RMSE value in Table 4, the lowest prediction accuracy among the four batteries is B18. Although it is not as good as other batteries, the MAE of B18 is 0.0479, indicating the test accuracy rate reached more than 95%. According to the development requirements of batteries in EVs, the fault threshold is set to 80% of initial capacity, and the life value can also be predicted. The predicted error is 1 and 8 cycles for B06 and B18 respectively. All of the above illustrates that the proposed online prediction method has high accuracy and reliability.

**Table 4.** Prediction results of four batteries.

We conducted the same training and validation for NASA's data and average evaluation index as in Ref. [45], so we can perform a valid benchmark comparison. Table 5 summarizes the RUL prediction results from various methods, and it is obvious that the proposed method achieves a better performance than other methods, which is presented in Ref. [45]. It is obvious that the prediction based on AutoML is more accurate using the same data set and training method, with the MAE increased by 52.8% and RMSE increased by 48.3% than DeTransformer.

**Table 5.** Comparison of prediction results of AutoML with other ML methods.

#### **5. Conclusions**

In this study, according to our knowledge, we are the first to propose the AutoML model applied in the RUL prediction of LIBs, with the HIs extracted by IC analysis. A smoothing IC curve based on the KF algorithm is employed for HIs extraction and three HIs have been verified to characterize the aging phenomenon in the entire charging process including the CC and CV phases. We proposed a prediction method based on AutoML running in the Auto-sklearn architecture, which can customize the pipeline for specific datasets automatically, overcoming the problem of redundant model information and high computational cost. Then the experiment on NASA's LIBs cycle life dataset verifies the accuracy and robustness. As a next step, we plan to keep on further studies on neural networks in the AutoML model, using neural architecture search to improve pipeline, as well as investigating effective dimensionality optimization techniques for the HIs extraction by IC analysis.

**Author Contributions:** Conceptualization, C.L. and Z.Z.; methodology, C.L. and D.Q.; software, C.L. and Y.L.; validation, C.L. and Y.L.; formal analysis, C.L. and D.Q.; investigation, C.L.; resources, C.L.; data curation, C.L. and D.Q.; writing—original draft preparation, C.L.; writing—review and editing, C.L.; visualization, C.L.; supervision, Z.Z. and X.L.; project administration, C.L. and S.W.; funding acquisition, Z.Z. and X.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the National Natural Science Foundation of China, grant number 51977131.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


**5. Conclusions and Future Prospects**

By analyzing the internal relationship between ecological civilization, beautiful China, and PLES, as well as the scientific connotations of PLES, this paper systematically organized the optimization theory, methods, and practices for PLES around territorial spatial planning, with the overall planning of PLES as the goal, and the promotion of ecological civilization construction as the starting point. We also proposed an optimization approach for PLES. Based on the analysis and summary, the main research directions for the overall optimization of PLES in the future should include the following:

(1) Research on the main regional types and differentiation rules of PLES: This paper studied the distribution characteristics of the functional spatial patterns of PLES at multiple scales. In this way, the scale differences and functional complexities of PLES under different spatial scales were clarified. Moreover, classification and identification systems for PLES under different scales and different regional types were established.

(2) Analysis and research on the evolution process, structural characteristics, and development trends of PLES: The dynamic spatial and temporal evolution characteristics of the structural proportion and spatial scale of PLES were analyzed, including regional suitability and carrying capacity evaluation, regional differences in space, and development over time. Moreover, the coupling coordination degree and conflict mechanism in the evolutionary process of PLES were revealed.

(3) Analysis of the internal nonlinear mechanism for the PLES System: Guided by the theory of the human–Earth system, we revealed the competition and synergistic interactions and positive feedback mechanisms between population, resources, ecology, environment, and economic and social development in the PLES system, and identified the nonlinear dynamic effects among subsystems and elements in the system.

(4) Analysis of the mechanism for matter and energy transfer in the overall optimization system of PLES: Based on the regional resource metabolism theory and the geographical patterns of PLES, we deeply analyzed the transfer path, flow process, and metabolic mechanisms of key elements, such as water, soil, energy, and carbon, in the co-evolution process of PLES.

(5) Development and application of a simulation model and multi-objective optimization model for the overall optimization system of PLES: Studies should make full use of the research results for the nonlinear dynamic mechanisms, transmission paths, and flow processes of key elements in the PLES system, and carry out research on overall optimization strategies and scenario predictions for PLES in different regions, at different scales, and for different types.

(6) Research, development, and application of the overall optimization and decision support platform for PLES: A visual support platform was developed with integrated functions for data processing, spatio-temporal analysis, scenario simulation, result output, problem diagnosis, and early warning and control. This platform can help coordinate the government at all levels, and between different departments and different areas of the target demand, to facilitate population migration, urban and rural construction and industrial development, resource development, ecological construction, environmental protection, infrastructure construction, public services and disaster prevention, and mitigation-system spatial deployment as components of unified and consensus development goals and plans.

**Author Contributions:** G.L. and J.F. contributed to all aspects of this work; D.J. conducted data analysis; and G.L. and Y.Z. wrote the main manuscript text. All authors reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDA19040305), Youth Innovation Promotion Association (Grant No. 2018068), and Institute of Geographical Sciences and Natural Resources Research, Chinese Academy of Sciences (Grant No. E0V00112YZ).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available on request from the author.

**Conflicts of Interest:** The authors declare no conflict of interest.


**Author details**

Mihaela Violeta Ghica, Cristina Elena Dinu-Pîrvu\*, Lăcrămioara Popa, Elena-Emilia Tudoroiu, Diana-Georgiana Ionescu and Claudia-Maria Benga Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy Bucharest, Romania

\*Address all correspondence to<EMAIL_ADDRESS>and<EMAIL_ADDRESS>
© 2022 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.

*Promising Hydrogels-Based Dressings for Optimal Treatment of Cutaneous Lesions DOI: http://dx.doi.org/10.5772/intechopen.105825*


**8.2 Clinical data**

40 Basic Nephrology and Acute Kidney Injury

important because it is the most used marker in USA. For example, iothalamate has been

Iohexol is a non-ionic contrast product, mainly used for myelography. Its molecular weight is 821 Da (Olsson et al., 1983; Schwartz et al., 2006). Iohexol is chronologically the last marker proposed for measuring GFR. Actually, the first human was receiving iohexol in 1980 (Aakhus et al., 1980). In this study, it was shown that the substance was safe and fully excreted by the kidneys (this assertion will be criticized thereafter, see below). However, these authors also describe (but data are not available) a higher urinary clearance of iohexol than 51Cr-EDTA (Aakhus et al., 1980). The details of these comparison studies were published three years after (see clinical data)(Olsson et al., 1983). In the same study, the authors confirm that iohexol is distributed through the extracellular volume, which will be confirmed by other authors (including in CKD patients and in obese subjects) (Friedman et al., 2010; Nossen et al., 1995; Edelson et al., 1984; Back et al., 1988b; Olsson et al., 1983). Iohexol has not effect *per se* on GFR (Olofsson et al., 1996). Binding to protein seems very limited for iohexol. The first study described a binding to protein of only 1.5% (Mutzel et al., 1980). This will be thereafter confirmed (Back et al., 1988b; Krutzen et al., 1984). Physical properties of iohexol make it a good candidate to be used in simplified protocols like plasma clearance (Thomsen & Hvid-Jacobsen, 1991; Gaspari et al., 1995; Edelson et al., 1984). Contrary to the prior studies (Aakhus et al., 1980), several authors have shown that extrarenal clearance of iohexol is limited but not null (Arvidsson & Hedman, 1990; Krutzen et al., 1984). Back calculated at 6.2 mL/min the difference between total and urinary clearance of iohexol in healthy subjects (Back et al., 1988b). Frennby observed an extra-renal clearance lower than 2 mL/min in 6 anuric dialysis patients (Frennby et al., 1994; Frennby et al., 1995). These last very low results were also found by Nossen in 16 patients with severe CKD. Their mean measured GFR was 14 mL/min and the extra-renal clearance was estimated at 10% (Nossen et al., 1995). In 16 healthy subjects, Edelson estimated the extrarenal clearance of iohexol at 5% (Edelson et al., 1984). Contrary to iothalamate, there are very

used in trials having built the new creatinine-based equations (Levey et al., 1999).

few physiological studies on the renal tubular handling of iohexol.

As for iothalamate, iohexol can be measured by several different techniques. Among these, HPLC and XRF are the most used ones. HPLC was historically the first method used (Aakhus et al., 1980) and described (Krutzen et al., 1984). As we have shown, iohexol measurements by HPLC are sensitive, specific and reproducible (Back et al., 1988c; Farthing et al., 2005; Cavalier et al., 2008). The high performance of such dosage notably enables the use of iohexol low doses and the measurement on finger-prick samples (Krutzen et al., 1990; Niculescu-Duvaz et al., 2006; Mafham et al., 2007; Cavalier et al., 2008; Aurell, 1994). Iohexol measurement is also pretty stable at room temperature and at -20°C(Krutzen et al., 1984; O'Reilly et al., 1988).  We will not discuss into details the other methods for measuring iohexol: capillary electrophoresis (Shihabi & Constantinescu, 1992) and mass spectrometry (Lee et al., 2006; Annesley & Clayton, 2009; Denis et al., 2008; Stolz et al., 2010). The safety of iohexol is now confirmed (Heron et al., 1984; Aurell, 1994), notably by the largest series of iohexol

**8. Iohexol**

**8.1 Physiological and analytical data**

The results of the first clinical study on iohexol as a reference GFR marker will be published in 1983 (Olsson et al., 1983). Actually, GFR was measured in 10 healthy subjects with urinary clearances of iohexol and 51Cr-EDTA. In this study, the iohexol clearance was significantly higher than the 51Cr-EDTA clearance (110 versus 96 mL/min). In this first study, large dose of iohexol was injected to the patient (from 375 to 500 mg I/kg)(Olsson et al., 1983). Thereafter, the doses of iohexol used will be drastically reduced but it has been well described that the physiologic handling of iohexol was identical if different dosages are used (Back et al., 1988a). In table 5, we resumed the study results having compared the performance of iohexol to inulin in adult subjects. To the best of our knowledge, only two studies have compared urinary clearances of iohexol and inulin. The results seem excellent but Bland and Altman analysis have not been realized (Brown & O'Reilly, 1991; Perrone et al., 1990). Contrary to other markers, iohexol plasmatic clearances have been the most studied. The relatively worst results obtained by Erley are explained by the patients included (Erley et al., 2001). Actually, the patients hospitalized in intensive care are prone to develop edema and, in this situation, plasmatic clearances are not accurate, whatever the marker (Skluzacek et al., 2003). The study published by Gaspari demonstrated a good performance of iohexol plasma clearance compared to inulin but the number of samples was high and these samples were drawn lately (after 10h)(Gaspari et al., 1995).

How Measuring Glomerular Filtration Rate? Comparison of Reference Methods 43

data). The limitations of iohexol are the lack of strong physiological data (notably regarding the tubular handling of the marker) and the relatively few studies having compared iohexol

In Table 6, we resumed the results of studies comparing reference markers (other than inulin). We selected studies in adults. We focused on studies having used the best statistical methods to analyze the results, i.e. the Bland and Altman analysis. It is difficult to interpret results from studies having compared different markers but also different methods (for example, plasmatic clearance of iothalamate with urinary clearance of 51Cr-EDTA) because it is impossible to affirm that potential differences are due to difference in markers or to difference in methods. Another limitation of several studies is the relatively small sample of subjects included. If we take into account these two limitations, we can stress on some interesting results showing good concordance (bias±SD) between plasma clearances of 51Cr-EDTA and 99Tc-DTPA (1.91±6.1 mL/min), and between plasma clearances of 51Cr-EDTA and iohexol (-0.16±6.17 mL/min in (Brandstrom et al., 1998), 4±7.9 mL/min in (Bird et al., 2009), 2±9.2 (Lundqvist et al., 1997), and -0.6±3.6 mL/min in

> **(mL/min/1.73 m²)**

16 NA 21 to 156 Cu 125It: Cu

15 urography 22 to 110 Cp of Io

**GFR methods**

125It: samples at 180, 210 and 240 min + BM correction

Io (XRF): samples at 3 and 4 h after bolus

after bolus IV and infusion Cp of Dt: samples at 60 and 180 min+ BM correction

(XRF), Cr and Dt : samples at 0, 10, 20, 30, 120, 180, 240 and 300 min

37 to 137 Cp of Cr and

10 to 117 Cu of Dt and

**Statistics Results**

It higher (p<0.001) 1.13 12±7.5

0.89 Io=0.89Dt+6.5 1.08±0.06 -0.7±14.8

> 0.99 3.2±6.1

Io=0.97Dt-11 0.96 Io=1.01Cr+8 0.95 -10.8±7.9 -9.4±6.9 -0.7±10.4

Wilcoxon

Ratio It/Cr BAr It-Cr

Correlation Regression Ratio BAr Dt-Io

Correlation BAr Io-Dt

Regression Correlation

BA : Cr-Io Dt-Io Cr-Dt

with inulin. More studies have actually compared iohexol with other GFR markers.

**9. Studies comparing reference methods**

**References Sample Population GFR range**

11 Nephrectomy

29 10 heart grafted 11 renal grafted 10 donors

and CKD

(Pucci et al., 2001)).

 Studies comparing iohexol with inulin. NA: not available, CKD: chronic kidney disease subjects, BA: Bland and Altman analysis, BAr: Bland and Altman analysis recalculated by us, BM: Brochner-Mortensen, HPLC: high pressure liquid chromatography, Io: iohexol, SC: subcutaneous, XRF: X ray fluorescence.


*5.5. The Dependence of the Time of the Heating Season on the Thickness of the Insulation*

The dependence of the length of the heating season on the insulation thickness is shown in Figure 14.

**Figure 14.** Variability of the duration of the heating season as a function of insulation thickness.

The diagram in Figure 14 clearly shows the dependence of the heating season on the "insulation" of external walls. Increasing the thickness of the insulation shortens the heating season, which contributes to reducing the annual heat consumption for heating purposes. For comparison, the graph also shows (red) the time determined on the basis of the annual variability of the outside air temperature. This time is approximately in line with the calculation method adopted for the wall without external insulation (x = 0). This confirms the correctness of the adopted calculation methodology and the correctness of the performed calculations.


**2. Clinical entities**

#### **2.1. Aicardi syndrome**

#### *2.1.1. Overview*

Aicardi syndrome (MIM: 304050) is a congenital disorder characterized by a triad of signs, including corpus callosum agenesis, severe epilepsy, and chorioretinal lacunae (Aicardi et al., 1965; Dennis & Bower, 1972).

#### *2.1.2. History*

In 1965, Aicardi et al. reported eight female infants with spasms in flexion, callosal agenesis and various ocular abnormalities. In 1972, Dennis & Bower also reported a female patient and established the Aicardi Syndrome.

#### *2.1.3. Genetics*

The Aicardi syndrome is believed to an X-linked dominant disorder lethal to males and the cases of Aicardi syndrome are female infants, and males with the XXY genotype (Hopkins et al., 1979). Mutations in the CDKL5 gene on chromosome Xp22 have been found in these patients (Nemos et al., 2009).

#### *2.1.4. Differential diagnosis*

174 Toxoplasmosis – Recent Advances

basis has been proposed.

**2. Clinical entities**

*2.1.1. Overview*

*2.1.2. History*

*2.1.3. Genetics*

**2.1. Aicardi syndrome**

al., 1965; Dennis & Bower, 1972).

and established the Aicardi Syndrome.

 Misdiagnosis would result in

Aicardi syndrome (MIM: 304050) is a congenital disorder characterized by a triad of signs, including corpus callosum agenesis, severe epilepsy, and chorioretinal lacunae (Aicardi et

In 1965, Aicardi et al. reported eight female infants with spasms in flexion, callosal agenesis and various ocular abnormalities. In 1972, Dennis & Bower also reported a female patient

The Aicardi syndrome is believed to an X-linked dominant disorder lethal to males and the cases of Aicardi syndrome are female infants, and males with the XXY genotype (Hopkins et

erroneous counseling as to risk of recurrence (Aicardi et al., 2012).

Although the Aicardi syndrome normally has a poor prognosis, there is a heterogeneity of clinical severity. A mild case of a chorioretinal defect and a hypoplastic disc has been reported (King et al., 1998). The case was misdiagnosed as having cerebral and retinal toxoplasmosis.

The presence of corpus dysgenesis supports the diagnosis of Aicardi syndrome. In addition, the Aicardi syndrome does not cause intracranial calcifications which are likely to be present in cases of congenital toxoplasmosis (Table 1). Ocular abnormality is various, however, chorioretinal lacunae are thought to be pathognomonic.

**Table 1.** Clinical findings of the patients affected by congnetial toxoplasmosis and the pseudo toxoplasmosis

#### **2.2. Aicardi-Goutières Syndrome (AGS)**

#### *2.2.1. Overview*

The AGS is a rare neurodevelopmental genetic disorder associated with intracranial calcification, leukocytosis in the cerebrospinal fluid (CSF), and microcephaly. (Aicardi & Goutières, 1984; Aicardi et al., 2012)

Pseudo Toxoplasmosis 177

*2.3.2. History*

*2.3.3. Genetics*

(Table 1)

*2.4.1. Overview*

*2.4.2. History*

*2.3.4. Differential diagnosis*

spectrum of genetic disorders.

In 1970, Hoyeraal et al. reported two brothers with hypoplastic thrombocytopenia, microcephaly and cerebral malformations. In 1988, Hreidarsson et al. also reported an affected boy. In 1995, Aalfs et al. reported another male patient and proposed to use the eponym HHS. The first symptoms of pancytopenia did not occur before the age of five months and continued to deteriorate for years, despite extensive therapeutic measures.

Mutations in the DKC1 gene on chromosome Xq28 have been found in the patients including the family reported by Aalfs et al. in 1995. (Knight et al., 1999) The gene is also responsible for X-linked dyskeratosis congenita (DKC, MIM: 305000), an inherited bonemarrow-failure syndrome characterized by skin pigmentation, nail dystrophy and leucoplakia which usually develop towards the end of the first decade of life. The HHS is

The HHS is marked by severe aplastic anemia. While retinopathy can be induced by anemia, ocular abnormality or intracranial calcification is not usually observed in cases of HSS.

**2.4. Microcephaly, lymphedema, chorioretinal dysplasia syndrome (MLCRD)**

As its name implies, the MLCRD (MIM: 152950) is characterized by a triad of signs including microcephaly, lymphedema, and chorioretinal dysplasia.  Mental retardation is also usually present. Different combinations of these signs inherited in an autosomal dominant pattern have been reported (Leung, 1985; Hordijk et al., 1996; Simonell et al., 2002). Cases with these signs have been assumed to belong to the same

An autosomal recessive form of microcephaly with chorioretinopathy (McKusick et al., 1966) has been reported and categorized as microcephaly and chorioretinopathy with or

In 1981, Tenconi et al. reported patients with microcephaly and chorioretinopathy in an autosomal dominant pattern, and Jarmas et al. reported two brothers with microcephaly and retinal folds. In 1985, Leung investigated the combination of microcephaly and lymphedema

without mental retardation, autosomal recessive (MIM: 251270) (2.5).

revealed to be a severe variant of DKC. (Knight et al., 1999; Pearson et al., 2008)

#### *2.2.2. History*

In 1984, Aicardi & Goutières reported eight infants with spasticity, acquired microcephaly, bilateral symmetrical calcifications in the basal ganglia and chronic CSF lymphocytosis in five consanguineous families.

#### *2.2.3. Genetics*

Approximately 90% of individuals with characteristic findings of AGS have been found to have mutations in the TREX1 gene on chromosome 3p21.31 (AGS1, MIM: 225750), RNASEH2A gene on chromosome 19p13.2 (AGS4, MIM: 610333), RNASEH2B gene on chromosome 13q14.3 (AGS2, MIM: 610181), RNASEH2C gene on chromosome 11q13.1 (AGS3, MIM: 610329), and SAMHD1 gene on chromosome 20q11.23 (AGS5, MIM: 612952). (Aicardi et al., 2012)

Mutations in TREX1 have also been found in some patients with systemic lupus erythematodes (SLE). Siblings with SLE who present with congenital infection-like intracranial calcification (Dale et al., 2000), may be associated with AGS. (Aicardi et al., 2012) It has also been suggested that the narrowly-defined pseudo-TORCH syndrome (2.6) shows a phenotypic overlap and that most cases of pseudo-TORCH syndrome are in fact AGS. (Aicardi et al., 2012)

#### *2.2.4. Differential diagnosis*

In case of AGS, leukocytosis in the CSF and increased concentrations of interferon-alfa (IFNα) in the CSF are found (Aicardi et al., 2012) and microcephaly is absent at birth (Aicardi & Goutières, 1984). The onset occurs at 3-6 months of age in many patients.

Ocular structures are almost invariably normal on examination. (Aicardi et al., 2012) (Table 1)

#### **2.3. Hoyeraal-Hreidarsson syndrome (HHS)**

#### *2.3.1. Overview*

The HHS (MIM: 300240) is a severe multisystemic disorder with pre- and postnatal growth retardation, progressive pancytopenia, microcephaly, and cerebellar hypoplasia. (Aalfs et al., 1995; Knight et al., 1999; Pearson et al., 2008)

#### *2.3.2. History*

176 Toxoplasmosis – Recent Advances

*2.2.1. Overview*

*2.2.2. History*

*2.2.3. Genetics*

(Aicardi et al., 2012)

(Aicardi et al., 2012)

(Table 1)

*2.3.1. Overview*

*2.2.4. Differential diagnosis*

**2.2. Aicardi-Goutières Syndrome (AGS)**

Goutières, 1984; Aicardi et al., 2012)

five consanguineous families.

The AGS is a rare neurodevelopmental genetic disorder associated with intracranial calcification, leukocytosis in the cerebrospinal fluid (CSF), and microcephaly. (Aicardi &

In 1984, Aicardi & Goutières reported eight infants with spasticity, acquired microcephaly, bilateral symmetrical calcifications in the basal ganglia and chronic CSF lymphocytosis in

Approximately 90% of individuals with characteristic findings of AGS have been found to have mutations in the TREX1 gene on chromosome 3p21.31 (AGS1, MIM: 225750), RNASEH2A gene on chromosome 19p13.2 (AGS4, MIM: 610333), RNASEH2B gene on chromosome 13q14.3 (AGS2, MIM: 610181), RNASEH2C gene on chromosome 11q13.1 (AGS3, MIM: 610329), and SAMHD1 gene on chromosome 20q11.23 (AGS5, MIM: 612952).

Mutations in TREX1 have also been found in some patients with systemic lupus erythematodes (SLE). Siblings with SLE who present with congenital infection-like intracranial calcification (Dale et al., 2000), may be associated with AGS. (Aicardi et al., 2012) It has also been suggested that the narrowly-defined pseudo-TORCH syndrome (2.6) shows a phenotypic overlap and that most cases of pseudo-TORCH syndrome are in fact AGS.

In case of AGS, leukocytosis in the CSF and increased concentrations of interferon-alfa (IFNα) in the CSF are found (Aicardi et al., 2012) and microcephaly is absent at birth (Aicardi &

Ocular structures are almost invariably normal on examination. (Aicardi et al., 2012)

The HHS (MIM: 300240) is a severe multisystemic disorder with pre- and postnatal growth retardation, progressive pancytopenia, microcephaly, and cerebellar hypoplasia. (Aalfs et

Goutières, 1984). The onset occurs at 3-6 months of age in many patients.

**2.3. Hoyeraal-Hreidarsson syndrome (HHS)**

al., 1995; Knight et al., 1999; Pearson et al., 2008)

In 1970, Hoyeraal et al. reported two brothers with hypoplastic thrombocytopenia, microcephaly and cerebral malformations. In 1988, Hreidarsson et al. also reported an affected boy. In 1995, Aalfs et al. reported another male patient and proposed to use the eponym HHS. The first symptoms of pancytopenia did not occur before the age of five months and continued to deteriorate for years, despite extensive therapeutic measures.

#### *2.3.3. Genetics*

Mutations in the DKC1 gene on chromosome Xq28 have been found in the patients including the family reported by Aalfs et al. in 1995. (Knight et al., 1999) The gene is also responsible for X-linked dyskeratosis congenita (DKC, MIM: 305000), an inherited bonemarrow-failure syndrome characterized by skin pigmentation, nail dystrophy and leucoplakia which usually develop towards the end of the first decade of life. The HHS is revealed to be a severe variant of DKC. (Knight et al., 1999; Pearson et al., 2008)

#### *2.3.4. Differential diagnosis*

The HHS is marked by severe aplastic anemia. While retinopathy can be induced by anemia, ocular abnormality or intracranial calcification is not usually observed in cases of HSS. (Table 1)

#### **2.4. Microcephaly, lymphedema, chorioretinal dysplasia syndrome (MLCRD)**

#### *2.4.1. Overview*

As its name implies, the MLCRD (MIM: 152950) is characterized by a triad of signs including microcephaly, lymphedema, and chorioretinal dysplasia.  Mental retardation is also usually present. Different combinations of these signs inherited in an autosomal dominant pattern have been reported (Leung, 1985; Hordijk et al., 1996; Simonell et al., 2002). Cases with these signs have been assumed to belong to the same spectrum of genetic disorders.

An autosomal recessive form of microcephaly with chorioretinopathy (McKusick et al., 1966) has been reported and categorized as microcephaly and chorioretinopathy with or without mental retardation, autosomal recessive (MIM: 251270) (2.5).

#### *2.4.2. History*

In 1981, Tenconi et al. reported patients with microcephaly and chorioretinopathy in an autosomal dominant pattern, and Jarmas et al. reported two brothers with microcephaly and retinal folds. In 1985, Leung investigated the combination of microcephaly and lymphedema

in at least 4 generations of a Chinese family. In 1992, Feingold & Bartoshesky described two unrelated boys with microcephaly, lymphedema and chorioretinal dysplasia and proposed that the combination represents a single syndrome.

Pseudo Toxoplasmosis 179

(2.4). Intracranial calcifications are not observed as in MLCRD. (Table 1) Lymphedema is considered to be pathognomonic for the MLCRD, has not been reported in cases of Microcephaly and chorioretinopathy with or without mental retardation, autosomal

Narrowly-defined pseudo-TORCH syndrome (al-Dabbous et al., 1998; Baraitser et al., 1983; Briggs et al., 2008; Burn et al., 1986; Cohen et al., 2012; Ishitsu et al., 1985; Knoblauch et al., 2003; Kulkarni et al., 2010; Nakamura et al., 2011; Reardon et al., 1994; Vivarelli et al., 2001; Watts et al., 2008; Wieczorek et al. 1995), also called Baraitser-Reardon syndrome (Vivarelli et al., 2001), or band-like calcification with simplified gyration and polymicrogyria (BLCPMG; MIM: 251290) (Abdel-Salam & Zaki, 2009; Briggs et al., 2008; O'Driscoll et al., 2010), is associated with microcephaly and intracranial calcifications mimicking congenital

In 1983, Baraitser et al. reported two brothers with microcephaly and intracranial calcifications. The bilateral symmetrical calcification was in white matter and thalamus. In 1994, Reardon et al. reported nine patients from four families with microcephaly, intracranial calcifications and CNS disease and described them as "congenital intrauterine

In 2001, Vivarelli et al. reported five patients in three families and proposed to use the eponym, Baraitser-Reardon syndrome. In 2008, Briggs et al. also reported five patients in three families with a pattern of BLCPMG as a distinct "pseudo-TORCH"

Mutations in the OCLN gene on chromosome 5q13.2 have been found in a part of affected individuals, categorized as BLCPMG. (O'Driscoll et al., 2010) A part of the cases of the pseudo-TORCH syndrome without the OCLN mutation may in fact be cases of Aicardi-

As some cases of pseudo-TORCH syndrome are thought to be in fact AGS (Aicardi et al., 2012), there is a phenotype overlap between pseudo-TORCH syndrome and AGS

Ocular changes are not reported with pseudo-TORCH syndrome / AGS. (Table 1)

recessive. (Table 1)

**(narrowly-defined)**

*2.6.1. Overview*

*2.6.2. History*

phenotype.

(2.2).

*2.6.3. Genetics*

infection-like syndrome".

*2.6.4. Differential diagnosis*

**2.6 Pseudo-TORCH syndrome**

toxoplasmosis in the absence of infection.

Goutières Syndrome (2.2). (Aicardi et al., 2012)

#### *2.4.3. Genetics*

Mutations in the KIF11 gene on chromosome 10q23 have been identified in some patients with the MLCRD. (Ostergaard et al., 2012)

#### *2.4.4. Differential diagnosis*

Congenital lymphedema is confined to the dorsa of the feet (Angle et al., 1994; Casteels et al., 2001; Eventov-Friedman et al., 2009; Feingold & Bartoshesky 1992; Fryns et al., 1995; Leung, 1985; Limwongse et al., 1999; Strauss et al., 2005; Vasudevan et al., 2005) and this is hardly observed in cases of congenital toxoplasmosis. (Table 1)

Intracranial calcifications, which are likely to be present in cases of congenital toxoplasmosis are not observed in cases of MLCRD. (Table 1)

#### **2.5. Microcephaly and chorioretinopathy with or without mental retardation, autosomal recessive**

#### *2.5.1. Overview*

While the combination of microcephaly and chorioretinopathy with or without mental retardation can be caused by heterozygous mutation in the KIF11 gene known as MLCRD (MIM: 152950) (2.4), autosomal recessive inheritance has also been suggested in familial cases (McKusick et al., 1966). A discovery of causative homozygous mutation (Puffenberger et al., 2012) has proved the independent entity, microcephaly and chorioretinopathy with or without mental retardation, autosomal recessive (MIM: 251270).

#### *2.5.2. History*

The role of consanguinity in congenital microcephaly was repeatedly reported (Kloepfer et al., 1964; Komai et al., 1955; van den Bosch, 1959). In 1966, McKusick et al. described eight individuals of microcephaly in two sibships of an imbred group. All of them had pigmentary abnormality of the fundus with mental retardation.

#### *2.5.3. Genetics*

A homozygous mutation in the TUBGCP6 gene on chromosome 22q13.33 was found in four cases reported by McKusick et al. in 1966. (Puffenberger et al., 2012)

#### *2.5.4. Differential diagnosis*

Microcephaly and chorioretinopathy with or without mental retardation, autosomal recessive produces the symptoms similar to those of the MLCRD (MIM: 152950) spectrum (2.4). Intracranial calcifications are not observed as in MLCRD. (Table 1) Lymphedema is considered to be pathognomonic for the MLCRD, has not been reported in cases of Microcephaly and chorioretinopathy with or without mental retardation, autosomal recessive. (Table 1)

### **2.6 Pseudo-TORCH syndrome (narrowly-defined)**

#### *2.6.1. Overview*

178 Toxoplasmosis – Recent Advances

*2.4.3. Genetics*

that the combination represents a single syndrome.

hardly observed in cases of congenital toxoplasmosis. (Table 1)

without mental retardation, autosomal recessive (MIM: 251270).

pigmentary abnormality of the fundus with mental retardation.

cases reported by McKusick et al. in 1966. (Puffenberger et al., 2012)

with the MLCRD. (Ostergaard et al., 2012)

are not observed in cases of MLCRD. (Table 1)

*2.4.4. Differential diagnosis*

**autosomal recessive**

*2.5.1. Overview*

*2.5.2. History*

*2.5.3. Genetics*

*2.5.4. Differential diagnosis*

in at least 4 generations of a Chinese family. In 1992, Feingold & Bartoshesky described two unrelated boys with microcephaly, lymphedema and chorioretinal dysplasia and proposed

Mutations in the KIF11 gene on chromosome 10q23 have been identified in some patients

Congenital lymphedema is confined to the dorsa of the feet (Angle et al., 1994; Casteels et al., 2001; Eventov-Friedman et al., 2009; Feingold & Bartoshesky 1992; Fryns et al., 1995; Leung, 1985; Limwongse et al., 1999; Strauss et al., 2005; Vasudevan et al., 2005) and this is

Intracranial calcifications, which are likely to be present in cases of congenital toxoplasmosis

While the combination of microcephaly and chorioretinopathy with or without mental retardation can be caused by heterozygous mutation in the KIF11 gene known as MLCRD (MIM: 152950) (2.4), autosomal recessive inheritance has also been suggested in familial cases (McKusick et al., 1966). A discovery of causative homozygous mutation (Puffenberger et al., 2012) has proved the independent entity, microcephaly and chorioretinopathy with or

The role of consanguinity in congenital microcephaly was repeatedly reported (Kloepfer et al., 1964; Komai et al., 1955; van den Bosch, 1959). In 1966, McKusick et al. described eight individuals of microcephaly in two sibships of an imbred group. All of them had

A homozygous mutation in the TUBGCP6 gene on chromosome 22q13.33 was found in four

Microcephaly and chorioretinopathy with or without mental retardation, autosomal recessive produces the symptoms similar to those of the MLCRD (MIM: 152950) spectrum

**2.5.  History*

In 1983, Baraitser et al. reported two brothers with microcephaly and intracranial calcifications. The bilateral symmetrical calcification was in white matter and thalamus. In 1994, Reardon et al. reported nine patients from four families with microcephaly, intracranial calcifications and CNS disease and described them as "congenital intrauterine infection-like syndrome".

In 2001, Vivarelli et al. reported five patients in three families and proposed to use the eponym, Baraitser-Reardon syndrome. In 2008, Briggs et al. also reported five patients in three families with a pattern of BLCPMG as a distinct "pseudo-TORCH" phenotype.

#### *2.6.3. Genetics*

Mutations in the OCLN gene on chromosome 5q13.2 have been found in a part of affected individuals, categorized as BLCPMG. (O'Driscoll et al., 2010) A part of the cases of the pseudo-TORCH syndrome without the OCLN mutation may in fact be cases of Aicardi-Goutières Syndrome (2.2). (Aicardi et al., 2012)

#### *2.6.4. Differential diagnosis*

As some cases of pseudo-TORCH syndrome are thought to be in fact AGS (Aicardi et al., 2012), there is a phenotype overlap between pseudo-TORCH syndrome and AGS (2.2).

Ocular changes are not reported with pseudo-TORCH syndrome / AGS. (Table 1)

#### **2.7. Revesz syndrome**

#### *2.7.1. Overview*

Revesz syndrome (MIM: 268130), also known as cerebroretinal microangiopathy with calcications and cysts (CRMCC) is a rare and fatal disorder, characterized by intrauterine growth retardation, bilateral exudative retinopathy, intracranial calcication and cysts. (Asai et al., 2012; Revesz et al. 1992; Savage et al., 2008)

Pseudo Toxoplasmosis 181

**3.2. Case report**

**Figure 1.**

A male infant was delivered by Cesarean section at 37 weeks of gestation. (Ozeki et al., 2010) There was no family history for microcephaly, retinitis pigmentosa or consanguinity. The mother was type 1 diabetic and had once experienced an intrauterine fetal death. At 20 weeks pregnant, microcephaly had been detected by ultrasonography. Toxoplasmosis had been suspected, but the treatment was withheld because of only a slightly elevated maternal *Toxoplasma* specific immunoglobulin M (IgM) antibody, 1.4 index by enzyme linked immnosorbent assay (ELISA) and a borderline IgG avidity index, 50% at 28 weeks pregnant. The infant weighing 2,858 g with Apgar score 9/10, respectively, had microcephaly, marked lymphoedema of dorsum of both feet and chorioretinal dysplasia in the both eyes (Figure 1). The electroretinogram was nearly nonrecordable. A computed tomography (CT) scan was negative for brain calcifications or hydrocephalus. Hepatic calcifications, splenomegaly, and ascites were not noted. *Toxoplasma* IgM (ELISA) was negative (0.1 index) while IgG was positive (70 index).

*Toxoplasma gondii* DNA was detected in the serum by polymerase chain reaction (PCR)

(Figure 1(d)) to confirm the diagnosis of congenital toxoplasmosis.

#### *2.7.2. History*

In 1992, Revesz et al. reported a 6-month old boy presenting with bilateral leucocoria. The retinal appearance resembled Coat's disease. Widespread grey and white matter calcification in the brain and severe aplastic anemia were also noted. His platelet count eventually became impossible to control and the patient died at 19 months of age. In 1994, Kajtár & Méhes reported the second case, a 2-year old girl with thrombocytopenic purpura and bilateral progressive Coats'-like retinopathy.

#### *2.7.3. Genetics*

A heterozygous mutation in the gene encoding TRF1-interacting nuclear factor-2 (TINF2) on chromosome 14q12 has been found in a case of Revesz syndrome. (Savage et al., 2008) Another heterozygous truncating mutation in the TINF2 gene has been identified in a case. (Sasa et al., 2012) TINF2 is a component of the shelterin telomere protection complex, TINF2 mutations result in very short telomeres.

An inherited bone marrow failure syndrome, dyskeratosis congenital-3 (MIM: 613990) is also caused by the mutations in the TINF2 mutations.

#### *2.7.4. Differential diagnosis*

While Revesz syndrome marked by the severe aplastic anemia is related to HHS (2.3), Revesz syndrome causes Coats'-like retinopathy and intracranial calcification. A case reported as "congenital infection-like syndrome with intracranial calcification" (Mizuno et al., 2011) may be a case of Revesz syndrome. (Asai et al., 2012)

Coats'-like retinopathy is exudative, easily distinguishable from chorioretinal lacunae or dysplasia on ophthalmoscopy. (Table 1)

#### **3. Pseudo-pseudo toxoplasmosis**

#### **3.1. Background**

Even though clinical differential diagnosis summarized in Table 1 can be helpful, there are exceptions. A case of congenital toxoplasmosis can have the look of one of pseudo toxoplasmosis entities. A serological investigation for toxoplasmosis also has its indications and limitations. (Johnson et al., 1993).

#### **3.2. Case report**

180 Toxoplasmosis – Recent Advances

**2.7. Revesz syndrome**

et al., 2012; Revesz et al. 1992; Savage et al., 2008)

and bilateral progressive Coats'-like retinopathy.

mutations result in very short telomeres.

dysplasia on ophthalmoscopy. (Table 1)

**3. Pseudo-pseudo toxoplasmosis**

and limitations. (Johnson et al., 1993).

*2.7.4. Differential diagnosis*

**3.1. Background**

also caused by the mutations in the TINF2 mutations.

al., 2011) may be a case of Revesz syndrome. (Asai et al., 2012)

Revesz syndrome (MIM: 268130), also known as cerebroretinal microangiopathy with calcications and cysts (CRMCC) is a rare and fatal disorder, characterized by intrauterine growth retardation, bilateral exudative retinopathy, intracranial calcication and cysts. (Asai

In 1992, Revesz et al. reported a 6-month old boy presenting with bilateral leucocoria. The retinal appearance resembled Coat's disease. Widespread grey and white matter calcification in the brain and severe aplastic anemia were also noted. His platelet count eventually became impossible to control and the patient died at 19 months of age. In 1994, Kajtár & Méhes reported the second case, a 2-year old girl with thrombocytopenic purpura

A heterozygous mutation in the gene encoding TRF1-interacting nuclear factor-2 (TINF2) on chromosome 14q12 has been found in a case of Revesz syndrome. (Savage et al., 2008) Another heterozygous truncating mutation in the TINF2 gene has been identified in a case. (Sasa et al., 2012) TINF2 is a component of the shelterin telomere protection complex, TINF2

An inherited bone marrow failure syndrome, dyskeratosis congenital-3 (MIM: 613990) is

While Revesz syndrome marked by the severe aplastic anemia is related to HHS (2.3), Revesz syndrome causes Coats'-like retinopathy and intracranial calcification. A case reported as "congenital infection-like syndrome with intracranial calcification" (Mizuno et

Coats'-like retinopathy is exudative, easily distinguishable from chorioretinal lacunae or

Even though clinical differential diagnosis summarized in Table 1 can be helpful, there are exceptions. A case of congenital toxoplasmosis can have the look of one of pseudo toxoplasmosis entities. A serological investigation for toxoplasmosis also has its indications

*2.7.1. Overview*

*2.7.2. History*

*2.7.3. Genetics*

A male infant was delivered by Cesarean section at 37 weeks of gestation. (Ozeki et al., 2010) There was no family history for microcephaly, retinitis pigmentosa or consanguinity. The mother was type 1 diabetic and had once experienced an intrauterine fetal death. At 20 weeks pregnant, microcephaly had been detected by ultrasonography. Toxoplasmosis had been suspected, but the treatment was withheld because of only a slightly elevated maternal *Toxoplasma* specific immunoglobulin M (IgM) antibody, 1.4 index by enzyme linked immnosorbent assay (ELISA) and a borderline IgG avidity index, 50% at 28 weeks pregnant.

The infant weighing 2,858 g with Apgar score 9/10, respectively, had microcephaly, marked lymphoedema of dorsum of both feet and chorioretinal dysplasia in the both eyes (Figure 1). The electroretinogram was nearly nonrecordable. A computed tomography (CT) scan was negative for brain calcifications or hydrocephalus. Hepatic calcifications, splenomegaly, and ascites were not noted. *Toxoplasma* IgM (ELISA) was negative (0.1 index) while IgG was positive (70 index).

*Toxoplasma gondii* DNA was detected in the serum by polymerase chain reaction (PCR) (Figure 1(d)) to confirm the diagnosis of congenital toxoplasmosis.

**Figure 1.**

#### **3.3. Comment**

The newborn presented with the complete triad of the MLCRD (2.4), i.e., microcephaly, lymphedema and chorioretinal dysplasia. (Table 1) He had apparent dorsal lymphedema that is hardly observed with toxoplasmosis. Brain calcifications, hydrocephalus, ascites or splenomegaly, that are more likely present in cases of congenital toxoplasmosis, could not be found. Moreover, *Toxoplasma* IgM was negative.

Pseudo Toxoplasmosis 183

microcephaly, intracranial calcification, and CNS disease: report of another Bedouin

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Angle, B., Holgado, S., Burton, B. K, Miller, M. T., Shapiro, M. J. & Opitz, J. M. (1994). Microcephaly, lymphedema, and chorioretinal dysplasia: report of two additional cases,

Asai, D., Imamura, T. & Hosoi, H. (2012). Comments on the article by Mizuno Y. et al. entitled "Congenital infection-like syndrome with intracranial calcification", Brain Dev 34(6):539. Atchaneeyasakul, L. O., Linck, L. & Weleber, R. G. (1998). Microcephaly with chorioretinal

Baraitser, M., Brett, E. M. & Piesowicz, A. T. (1983). Microcephaly and intracranial

Bogdan, A. (1951). Microcephaly with chorioretinopathy, cerebral calcification and internal

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Briggs, T. A., Wolf, N. I., D'Arrigo, S., Ebinger, F., Harting, I., Dobyns, W. B., Livingston, J. H., Rice, G. I., Crooks, D., Rowland-Hill, C. A., Squier, W., Stoodley, N., Pilz, D. T. & Crow, Y. J. (2008). Band-like intracranial calcification with simplified gyration and polymicrogyria: a

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The present case indicates that suspected cases of congenital toxoplasmosis or pseudo toxoplasmosis should be examined for *Toxoplasma* DNA by PCR. (Ozeki et al., 2010)

#### **Author details**

Yoshiaki Shimada *Fujita Health University Banbuntane Hotokukai Hospital, Japan*

#### **4. References**

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182 Toxoplasmosis – Recent Advances

be found. Moreover, *Toxoplasma* IgM was negative.

*Fujita Health University Banbuntane Hotokukai Hospital, Japan*

The newborn presented with the complete triad of the MLCRD (2.4), i.e., microcephaly, lymphedema and chorioretinal dysplasia. (Table 1) He had apparent dorsal lymphedema that is hardly observed with toxoplasmosis. Brain calcifications, hydrocephalus, ascites or splenomegaly, that are more likely present in cases of congenital toxoplasmosis, could not

The present case indicates that suspected cases of congenital toxoplasmosis or pseudo

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toxoplasmosis should be examined for *Toxoplasma* DNA by PCR. (Ozeki et al., 2010)

**3.3. Comment**

**Author details**

Yoshiaki Shimada

**4. References**

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**1. Introduction**

Aortic stenosis is the most prevalent valve disease in the developed countries. Its prevalence increases in the elderly; in this population, transcatheter aortic valve replacement (TAVR) is a viable option for subjects with intermediate or high risk of cardiac surgery. Despite the development of new generations of TAVR, cerebrovascular events are one of the most severe and scary complications because of the increase

in morbidity and mortality, the risk of stroke at 30 days ranges from 2.7 to 10% [1, 2]. Apart from clinical strokes, subclinical strokes, defined by the appearance of new ischemic cerebral lesions by MRI, appear in 90% of patients undergoing TAVR [3]; however, their clinical significance is still unknown.

TAVR implantation-related strokes are divided into acute or periprocedural and late. For prevention, various methods have been identified. In the first group (acute), the main factors to take into consideration include optimization of the TAVR technique with reduction of embolization of calcified fragments and atheroma, and adequate anticoagulation during the procedure. For late strokes, the main factor is the use of an optimal antithrombotic regimen after implantation.

The greatest risk of embolization to the brain occurs during the procedure, during the positioning or implantation phase of the valve, as a result of manipulation of highly calcified structures or atheromatous embolization of thrombi or material [4]. Up to 70% of patients experience a stroke in the first 24 hours [5–7] with a considerable deterioration in quality of life and a 3–5-fold increase in mortality [8]. Cerebral protection devices (CPDs) have the potential to reduce stroke and ischemic brain injury associated with percutaneous aortic valve replacement. The results of a recent study that analyzed a database with 36,220 patients (525 of them with CPD systems and 35,695 without them) found that the use of a CPD was associated with a lower incidence of ischemic stroke (1.0% vs. 3.8%, p < 0.002) and lower in-hospital mortality. Importantly, silent strokes account for a significant proportion of these complications and are associated with a threefold increased risk of having a stroke, a further decline in cognitive function, and a twofold increased risk of developing dementia after follow-up for 4 years [9].

Until March 2023, only two authorized devices were identified as DPC, the Sentinel device, which is designed to capture emboli or debris detached during TAVI. It consists of a dual filter into the left common carotid and brachycephalic artery; inside a 6Fr catheter that is accessed through the radial artery, the proximal filter is placed in the brachiocephalic artery and the distal filter in the common carotid artery (available in United States and Europe) [1] and the TriGUARD 3 (available in Europe) is the only device that covers all the arteries of the aortic arch. Being a deflector device, it rejects emboli during TAVR placement. This device is advanced *via* femoral contralateral access to TAVI placement and is deployed to protect the supra-aortic vessels [10].


**4. Transmission**

*Overview on Echinococcosis*

**2.** *E. granulosus* **eggs**

**Figure 1.**

E. granulosus *adult.*

The eggs are spherical in shape (**Figure 2**) and have a diameter of about 40–30 μm and are similar in appearance to the eggs of other tapeworms, containing a hexacanth or oncosphere embryo because the embryo has sixth-hooks lets. The eggs are surrounded by clear coatings [8] and the eggs contain a sticky layer that adheres to the fur of animals and other things, which helps them to spread, as well as insects such as flies, beetles, and birds that play the role of mechanical carrier of eggs, in case of optimal conditions, the eggs remain viable for weeks or months in pastures and gardens as well as they remain viable with the right humidity and moderate temperatures, and the eggs are found in water and wet sand for 3 weeks at 30°C and 225 days at 6°C and 32 days at 10–21°C, also the eggs remain for a short time when exposed to sunlight and dry conditions and kill eggs when exposed to 3.75% of sodium hypochlorite for 10 minutes as well as killed when frozen at −70°C

for 4 days or −80°C for 2 days or by heat larger from 60°C for 3 minutes [9].

**48**

**Figure 2.**

E. granulosus *egg in feces [7].*

Transmission to humans is caused by fecal-oral route while eating food and water contaminated with parasite eggs, and these eggs are thrown out with feces of the definitive hosts such as dogs or through contamination of hands with eggs found in contaminated soil or sand or in the hair of infected dogs. The definitive hosts become infected with the adult worm when they feed on the hydatid cysts, which are found in the organs of the intermediate host, such as infected sheep [9, 11].