*3.4. Characteristics of Patients with Adverse Events*

Adverse events were observed in 4 patients, and 4 patients died (Table 4 and Figure 1). Although cardiac death, LV assist device implantation, HT, and ICD shock were classified as MACEs in this study, none of the patients underwent HT or LV assist device implantation or experienced ICD shock. Aside from 1 patient, 3 died at early infancy and never underwent surgery.

The condition of 8 patients worsened postoperatively (Table 5 and Figure 1), all patients had VSDs, 3 had variants in *MYH7*, 6 underwent BVR, and long-term medical therapy were required in all patients for myocardial dysfunction after their latest surgeries.

The analysis of the multivariable proportional hazards model revealed that CHF during follow-up, LVEF of < 24%, LVDD z-score of > 8.56, and N/C ratio of the LV apex of > 8.33 at the last visit were risk factors for survival without MACE occurrence (Table 6). Patients with LVNC and CHD had a worse prognosis than those with VSDs (Figure 3).

**Figure 3.** Event-free survival to the endpoint of major adverse cardiac events in LVNC with CHD and VSD groups. LVNC; left ventricular noncompaction, VSD; ventricular septal defect.

**Table 4.** Summary of death cases.

septal disease, TVD; tricuspid valve dysplasia. BVR; biventricular repair, CHF; congestive heart failure.

CHD; congenital heart disease, FH; family history, CM; cardiomyopathy, DORV; double outlet of right ventricle, VSD; ventricular septal defect, IAA; interruption of aortic arch, Ebstein; Ebstein's anomaly, CoA; coarctation of aorta, TGA; transposition of the great arteries, ASD; atrial septal disease, PDA; patent ductus arteiosus, BVR; biventricular repair, PAB; pulmonary arterybanding,bilPAB;bilateralpulmonaryarterybanding.

**Table 6.** Univariate analysis of risk factors for death in the patients with LVNC.

CI, confidence interval, UCG; cardiac ultrasound, LVEF; left ventricular ejection fraction, LVDD; left ventricular diastolic dimension, N/C; ratio of noncompacted/compacted layer.

#### **4. Discussion**

LVNC is associated with CHD, ranging from PDA or atrial septal defects/VSDs to more severe diseases such as Ebstein's anomaly [4]. Our study demonstrated three features: (1) pathogenic variants were identified in more than half of the patients; (2) patients with LVNC had lower EFs than those with VSDs throughout the study period; and (3) postoperative deterioration was observed in several patients.

A variety of genetic disorders are associated with LVNC, including Z-disk and sarcomere gene variants, mitochondrial disorders, and ion channel gene variants [18–22]. Thus, structural congenital malformations and impaired LV myocardial differentiation may be caused by genetic abnormalities. Additionally, for the development of LVNC in a patient with genetic variants, remarkable change of hemodynamic circulation in the fetus may be a cofactor [23]. In our results, variants in *MYH7* were most commonly identified and the variants significantly increase the risk of LVNC by rare variant collapsing analysis. The mechanisms by which variants in the *MYH7* gene induce LVNC remain unclear. Analyzing the positions of these variants against their amino acid location showed several hotspots wherein variants are more popular, which seemed to tend to be in key functional locations. We observed that all variants in *MYH7* associated with LVNC were found in the segment 1 domain. Moreover, enrichment of pathogenic variants was observed in the crucial functional domains of the ATP-binding domain [24–26]. It suggested that the majority of the identified variants affect the force output by affecting either regulation of the ATPase cycle, movement of the lever, or interaction between myosin and actin. Remarkably, the location of variants in *MYH7* in LVNC was different from that in hypertrophic cardiomyopathy (HCM) patients. Hotspots of HCM were mostly located in the surface spanning the converter domain and the myosin mesa; the flat surface of the myosin catalytic domain [27]. It is important to distinguish variant types and assess them in light of well-known disease mechanisms. Therefore, to understand the pathophysiology and development of LVNC, it is critically notable for the patients with LVNC and CHD to characterize genetic variants and phenotypic abnormalities.

Children with LVNC and CHD have a higher incidence of CHF than patients with VSDs. Additionally, our results showed that the condition of 8 of the 30 patients (26.7%) worsened postoperatively, whether palliative or radical. The underlying pathophysiologic mechanisms of CHF remain unclarified. Systolic dysfunction in LVNC is believed to be due to subendocardial hypoperfusion [1,28]. It is also believed that diastolic dysfunction occurs by a restrictive filling pattern and abnormal relaxation because of the presence of LV hypertrabeculation [29]. These speculations are based on the evidence that the noncompact layer has typically low perfusion, which has been

demonstrated on multiple modalities [30]. Functionally, LV torsion is more common in patients with LVNC [31]. LV twist is generated by the movement of two orthogonally oriented muscular bands of a helical myocardial structure concomitant with a clockwise rotation of the base and counterclockwise rotation of the apex in LV [32]. Van Dalen et al. used two-dimensional speckle tracking echocardiography and demonstrated that LV basal and apical rotation are in the same direction, resulting in a lack of LV twist in patients with LVNC [33]. Bellavia et al. reported that in adults, the value of LV rotation/torsion excessively decreased in patients with LVNC, whereas normal EF were retained when compared with those in controls [31]. Nawaytow et al. reported that almost half of the children with LVNC exhibit reverse apical rotation, resulting in decreased LV torsion and untwist rate, which are associated with the degree of LVNC [34]. These previous studies might support that the deterioration of LV function occurs during the perioperative period, although LV systolic function was preserved preoperatively because of its unique structure.

In our study, 13 patients were diagnosed with LVNC postoperatively. The existence of additional triggers such as dynamic hemodynamic changes during the perioperative period were suggested. Indeed, the etiology of LVNC remains unknown. One possibility is that primary abnormality in early myocardial morphogenesis may cause LVNC. Another possibility is that prenatal or postnatal additional triggers such as pressure overload on the LV may cause LVNC. LVNC in the setting of CHD may be one of the models where both hemodynamic and genetic factors interact with each other, resulting in abnormal LV differentiation Thus, additional stress to the myocardium may trigger the worsening of systolic function in patients with LVNC and CHD because LVNC is more frequently associated with systolic dysfunction than that of CHD without LVNC.

There were no predictors of postoperative CHF in this study. Preoperative preserved systolic function did not predict the outcome of patients with LVNC and CHD. In fact, not all patients with LVNC had systolic dysfunction during the preoperative evaluation. Most patients with LVNC and CHD had mildly depressed systolic function preoperatively. These facts may complicate the establishment of medical treatment during the operative period and optimal timing of surgery.

In our study, patients with LVNC and CHD were observed to have a higher frequency of arrhythmias (24.5%). Recently, it was demonstrated in pediatric patients that LVNC with associated CHD confers additional risk [35]. Although there were no data relationships between mortality and the prevalence of arrhythmias in patients with LVNC and CHD, our data suggest that more attention should be paid to the occurrence of arrhythmia and CHF because of the higher prevalence of these symptoms.


**2. The lymphatic drainage of the ovaries**

An understanding of the lymphatic drainage of the ovary and fallopian tube is important in the management of women with ovarian cancer. There are three main lymphatic pathways. The principal pathway is along the ovarian vessels through the infundibulopelvic ligament to the para aortic and para caval nodes surrounding the aorta and inferior vena cava (IVC). The second pathway occurs through the broad ligaments into the pelvic nodal region. Of note, spread to contralateral pelvic nodes in women with a unilateral cancer is reported in up to 30% of women [3]. Therefore, a bilateral pelvic node dissection (PND) is recommended even with unilateral apparent stage 1 tumours.

the risk of nodal fracture leading to possible tumour dissemination and port site metastases. A PND may be performed either as an open procedure or as part of a laparoscopic procedure. Laparoscopic surgery lends itself to PND due to the increased magnification and illumination of the surgical field and dissected nodes can be removed through an 11/12 mm suprapubic

The Role of Lymphadenectomy in Ovarian Epithelial Cancer

http://dx.doi.org/10.5772/intechopen.72702

263

Para aortic assessment/dissection has in contrast to pelvic nodes not been well quantified. Pomel et al. [7] have published a proposed classification of para aortic node assessment which ranges from radiological assessment and palpation to a full systematic dissection of all nodal

Open para aortic dissection (type A1 to B1) requires a generous midline abdominal incision to the xiphisternum and a self-retaining retractor to allow access to the great vessels. The right side of the colon and small bowel are mobilised by incising the peritoneum at the level of the right common iliac artery extending medially and caudally to the fourth part of the duodenum and then incising the peritoneum along the right paracolic gutter to the hepatic flexure. This allows the surgeon to perform called 'Kocher manoeuvre' mobilising the bowel off both the right renal fascia and ureter and to be retracted out of the abdomen. Following this, the surgeon should identify the left ureter lying medially underneath the inferior mesenteric vein. The node dissection should not start until all the important anatomical structures

Laparoscopic PA node dissection is well described in the literature and can be performed either via the conventional transperitoneal route or via an extra peritoneal route. Both routes require a high degree of laparoscopic training and is considered unlikely to replicate a systematic node dissection (Pommel type A) but rather an extensive node sampling (Pommel type B1–2).

A1 Complete (includes infrarenal and suprarenal up to coeliac trunk to midpoint of common iliac vessels)

B1 Extensive (incudes para aortic areas, but does not allow full visualisation of structures—adventicia of vessels. Renal vessels, anterior common vertebral ligament, psoas muscle and sacrum B2 Minimal (includes limited para aortic areas, and does not allow visualisation of structures above)

A3 Infra inferior mesenteric artery (IMA) (as above but does not include dissection above IMA)

port or removed via the vagina if a hysterectomy is performed.

tissue including the dorsal surfaces of the vessel (**Table 1**).

have been identified including the inferior mesenteric artery (IMA).

A2 Infrarenal (as above, but does not include suprarenal dissection)

C1 Palpation (direct) following full exposure of PA area C2 Palpation (indirect), transperitoneal without any exposure

**Table 1.** Proposed classification of para aortic node assessment (Pomel et al. [7]).

C3 Radiological assessment by PET/CT or MRI

**A Systematic para aortic node dissection**

**B Para aortic sampling**

**C Non-excisional assessment**

**Type**

A third lesser route is through the uterine round ligament to the inguinal nodes. In addition, women with disease involving the rectum or sigmoid colon may have tumour spread to the mesocolic lymph nodes within the sigmoid mesentery.


**5.3 Photoacoustic imaging of prostate cancer**

This chapter starts with a brief history of photoacoustic effect and photoacoustic spectroscopy. A simple mathematical derivation for the generation of PA signal in gaseous and solid samples is followed by experimental methods. The design and construction of a variety of PA cells and detectors have been described along with their use in the investigation of gaseous, solid, and liquid samples. Some illustrative examples of trace detection of explosives and harmful chemicals have been discussed. A brief account of the principle and application of the emerging technique of PA imaging is discussed at the end of the chapter.

## **Acknowledgements**

I am grateful to all the authors and scientists whose results have been cited to make the presentation meaningful. I am thankful to Dr. Punam Rai for taking care of my health, Sudheer for the help with the computer, and to my grandchildren, Leo and Mia, for their innocent inquiries during the course of my writing.

### **Author details**

Surya Narayan Thakur Banaras Hindu University, Varanasi, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 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.

## **References**

[1] Bell AG. On the production and reproduction of sound by light. American Association for the Advancement of Science. 1880;**29**:115

[2] Kreuzer LB, Patel CKN. Nitric oxide air pollution: Detection by optoacoustic spectroscopy. Science. 1971;**173**:45

[3] Tyndall JG. Action of an intermittent beam of radiant heat upon gaseous matter. Royal Society of London. 1881; **31**:307

[4] Bell AG. Upon the production of sound by radiant energy. Philosophical Magazine. 1881;**11**:510

[5] Kasha M. Characterization of electronic transitions in complex molecules. Discussions of the Faraday Society. 1950;**9**:14

[6] Lewis GN, Kasha M. Phosphorescence and the triplet state. Journal of the American Chemical Society. 1944;**66**:2100

[7] Rosencwaig A, Gersho A. Theory of the photoacoustic effect with solids. Journal of Applied Physics. 1976;**47**:64

[8] Thakur SN. Photoacoustic spectroscopy of gases and powders. Bulletin of Laser and Spectroscopy Society of India. 1993;**7**:3

[9] Narayanan K, Thakur SN. Photoacoustic spectrum of iodine in the 490–680 nm (20402–14700 cm1 ) region. Applied Optics. 1992;**31**:4987

[10] Arnott WP, Moosmuller H, Rogers CF, Jin T, Bruch R. Photoacoustic spectrometer for measuring light absorption by aerosol: Instrument description. Atmospheric Environment. 1999;**33**:2845

[11] Lewis KA, Arnott WP, Moosmuller H, Wold CE. Strong spectral variation of biomass smoke light absorption and single scattering albedo observed with a novel dual-wavelength photoacoustic instrument. Journal of Geophysical Research. 2008;**113**:D16203

lasers. Journal of Quantum Electronics.

*DOI: http://dx.doi.org/10.5772/intechopen.88840*

*Photoacoustic Spectroscopy of Gaseous and Condensed Matter*

In: Meyers RA, editor. Encyclopedia of Analytical Chemistry. Chichester: John

[28] Prasad RL, Thakur SN, Bhar GC. CO2 laser photoacoustic spectra and vibrational modes of heroin, morphine and narcotine. Pramana. 2002;**59**:487

[29] Duck FA. Physical Properties of Tissue: A Comprehensive Reference Book. London: Academic Press; 1990

[30] Harrison T, Ranasinghesagara JC, Lu H, Mathewson K, Walsh A, Zemp R.

[31] Razansky D, Distel M, Vinegoni C, Ma R, Perrimon N, Koster RW, et al. Multispectral opto-acoustic tomography of deep-seated fluorescent proteins in vivo. Nature Photonics. 2009;**3**:412

[32] Dogra VS, Chinni BK, Valluru KS, Joseph JV, Ghazi A, Yao JL, et al. Multispectral photoacoustic imaging of prostate cancer: Preliminary ex-vivo results. Journal of Clinical Imaging

[33] Bungart BL, Lan L, Wang P, Li R, Koch MO, Cheng L, et al. Photoacoustic tomography of intact human prostates and vascular texture analysis identify prostate cancer biopsy targets. Photoacoustics. 2018;**11**:48

Combined photoacoustic and ultrasound biomicroscopy. Optics

Express. 2009;**17**(412)

Science. 2013;**3**:41

Wiley; 2000. pp. 2203-2226

[21] Altuzar V, Pacheco M, Tomás SA, Arriaga JL, Zelaya-Angel O, Sánchez-Sinencio F. Analysis of ethylene concentration in the Mexico City atmosphere by photoacoustic spectroscopy. Analytical Sciences (Special Issue) The Japan Society for Analytical Chemistry. 2001;**17**:s541

[22] Schmohl A, Miklos A, Hess P. Detection of ammonia by photoacoustic spectroscopy with semiconductor lasers.

[23] Gustafsson LE, Leone AM, Persson

Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs

Biophysical Research Communications.

[24] Lanz MJ, Leung DYM, McCormick DR, Harbeck R, Szefler SJ, White CW. Comparison of exhaled nitric oxide, serum eosinophilic cationic protein, and

Applied Optics. 2002;**41**:1815

MG, Wikuld NP, Moncada S.

and humans. Biochemical and

soluble interleukin-2 receptor in exacerbations of pediatric asthma. Pediatric Pulmonology. 1997;**24**:305

[25] Elia A, Lugara PM, Giancaspro C. Photoacoustic detection of nitric oxide by use of a quantum-cascade laser. Optics Letters. 2005;**30**:988

[26] Spagnolo V, Kosterev AA, Dong L, Lewicki R, Tittle FK. NO trace gas sensor based on quartz-enhanced photoacoustic spectroscopy and external cavity quantum cascade laser. Applied

[27] Harren FJM, Gotti G, Oomens J,

spectroscopy in trace gas monitoring.

Physics. 2010;**B100**:125

**31**

Hekkert St L. Photoacoustic

1991;**181**:852

[20] Van Neste CW, Senesac LR, Thundat T. Standoff photoacoustic spectroscopy. Applied Physics Letters.

2002;**38**:582

2008;**92**:234102

[12] Prasad RL, Prasad R, Bhar GC, Thakur SN. Photoacoustic spectra and modes of vibration of TNT and RDX at CO2 laser wavelengths. Spectrochimica Acta. 2002;**A58**:3093

[13] Klenze R, Stumpe R, Kim JI. Laserinduced photoacoustic spectroscopy for the speciation of actinides in submicromol concentrations. In: Hess P, Pelzl J, editors. Photoacoustic and Photothermal Phenomena. Heidelberg: Springer-Verlag; 1988. p. 139

[14] Russo RE, Rojas D, Robouch PB, Silva RJ. Remote photoacoustic measurements in aqueous solutions using an optical fiber. The Review of Scientific Instruments. 1990;**61**:3729

[15] Kim JI. Actinide colloid generation in groundwater. Radiochimica Acta. 1991;**52/53**:71

[16] Kosterev AA, Bakhirikin YA, Curl RF, Tittle FK. Quartz-enhanced photoacoustic spectroscopy. Optics Letters. 2002;**27**:1902

[17] Weidmann D, Kosterev AA, Tittle FK, Ryan N, McDonald D. Application of widely electrically tunable diode laser to chemical gas sensing with quartzenhanced photoacoustic spectroscopy. Optics Letters. 2004;**29**: 1837

[18] Kosterev AA, Tittle FK. Ammonia detection using quartz-enhanced photoacoustic spectroscopy with a near-IR telecommunication diode laser. Applied Optics. 2004;**43**:6213

[19] Kosterev AA, Tittle FK. Chemical sensors based on quantum cascade

*Photoacoustic Spectroscopy of Gaseous and Condensed Matter DOI: http://dx.doi.org/10.5772/intechopen.88840*

lasers. Journal of Quantum Electronics. 2002;**38**:582

**References**

**31**:307

[1] Bell AG. On the production and reproduction of sound by light. American Association for the

*Photoacoustic Imaging - Principles, Advances and Applications*

biomass smoke light absorption and single scattering albedo observed with a novel dual-wavelength photoacoustic instrument. Journal of Geophysical

[12] Prasad RL, Prasad R, Bhar GC, Thakur SN. Photoacoustic spectra and modes of vibration of TNT and RDX at CO2 laser wavelengths. Spectrochimica

[13] Klenze R, Stumpe R, Kim JI. Laserinduced photoacoustic spectroscopy for

submicromol concentrations. In: Hess P, Pelzl J, editors. Photoacoustic and Photothermal Phenomena. Heidelberg:

[14] Russo RE, Rojas D, Robouch PB, Silva RJ. Remote photoacoustic measurements in aqueous solutions using an optical fiber. The Review of Scientific Instruments. 1990;**61**:3729

[15] Kim JI. Actinide colloid generation in groundwater. Radiochimica Acta.

[16] Kosterev AA, Bakhirikin YA, Curl RF, Tittle FK. Quartz-enhanced photoacoustic spectroscopy. Optics

[17] Weidmann D, Kosterev AA, Tittle FK, Ryan N, McDonald D. Application of widely electrically tunable diode laser

spectroscopy. Optics Letters. 2004;**29**:

[18] Kosterev AA, Tittle FK. Ammonia detection using quartz-enhanced photoacoustic spectroscopy with a near-IR telecommunication diode laser. Applied Optics. 2004;**43**:6213

[19] Kosterev AA, Tittle FK. Chemical sensors based on quantum cascade

Research. 2008;**113**:D16203

Acta. 2002;**A58**:3093

the speciation of actinides in

Springer-Verlag; 1988. p. 139

1991;**52/53**:71

1837

Letters. 2002;**27**:1902

to chemical gas sensing with quartzenhanced photoacoustic

Advancement of Science. 1880;**29**:115

[2] Kreuzer LB, Patel CKN. Nitric oxide air pollution: Detection by optoacoustic spectroscopy. Science. 1971;**173**:45

[3] Tyndall JG. Action of an intermittent beam of radiant heat upon gaseous matter. Royal Society of London. 1881;

[4] Bell AG. Upon the production of sound by radiant energy. Philosophical

[5] Kasha M. Characterization of electronic transitions in complex molecules. Discussions of the Faraday

Phosphorescence and the triplet state. Journal of the American Chemical

[7] Rosencwaig A, Gersho A. Theory of the photoacoustic effect with solids. Journal of Applied Physics. 1976;**47**:64

Magazine. 1881;**11**:510

Society. 1950;**9**:14

[6] Lewis GN, Kasha M.

Society. 1944;**66**:2100

[8] Thakur SN. Photoacoustic spectroscopy of gases and powders. Bulletin of Laser and Spectroscopy

[9] Narayanan K, Thakur SN.

Photoacoustic spectrum of iodine in the 490–680 nm (20402–14700 cm1

region. Applied Optics. 1992;**31**:4987

[10] Arnott WP, Moosmuller H, Rogers CF, Jin T, Bruch R. Photoacoustic spectrometer for measuring light absorption by aerosol: Instrument description. Atmospheric Environment.

[11] Lewis KA, Arnott WP, Moosmuller H, Wold CE. Strong spectral variation of

)

Society of India. 1993;**7**:3

1999;**33**:2845

**30**

[20] Van Neste CW, Senesac LR, Thundat T. Standoff photoacoustic spectroscopy. Applied Physics Letters. 2008;**92**:234102

[21] Altuzar V, Pacheco M, Tomás SA, Arriaga JL, Zelaya-Angel O, Sánchez-Sinencio F. Analysis of ethylene concentration in the Mexico City atmosphere by photoacoustic spectroscopy. Analytical Sciences (Special Issue) The Japan Society for Analytical Chemistry. 2001;**17**:s541

[22] Schmohl A, Miklos A, Hess P. Detection of ammonia by photoacoustic spectroscopy with semiconductor lasers. Applied Optics. 2002;**41**:1815

[23] Gustafsson LE, Leone AM, Persson MG, Wikuld NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochemical and Biophysical Research Communications. 1991;**181**:852

[24] Lanz MJ, Leung DYM, McCormick DR, Harbeck R, Szefler SJ, White CW. Comparison of exhaled nitric oxide, serum eosinophilic cationic protein, and soluble interleukin-2 receptor in exacerbations of pediatric asthma. Pediatric Pulmonology. 1997;**24**:305

[25] Elia A, Lugara PM, Giancaspro C. Photoacoustic detection of nitric oxide by use of a quantum-cascade laser. Optics Letters. 2005;**30**:988

[26] Spagnolo V, Kosterev AA, Dong L, Lewicki R, Tittle FK. NO trace gas sensor based on quartz-enhanced photoacoustic spectroscopy and external cavity quantum cascade laser. Applied Physics. 2010;**B100**:125

[27] Harren FJM, Gotti G, Oomens J, Hekkert St L. Photoacoustic spectroscopy in trace gas monitoring. In: Meyers RA, editor. Encyclopedia of Analytical Chemistry. Chichester: John Wiley; 2000. pp. 2203-2226

[28] Prasad RL, Thakur SN, Bhar GC. CO2 laser photoacoustic spectra and vibrational modes of heroin, morphine and narcotine. Pramana. 2002;**59**:487

[29] Duck FA. Physical Properties of Tissue: A Comprehensive Reference Book. London: Academic Press; 1990

[30] Harrison T, Ranasinghesagara JC, Lu H, Mathewson K, Walsh A, Zemp R. Combined photoacoustic and ultrasound biomicroscopy. Optics Express. 2009;**17**(412)

[31] Razansky D, Distel M, Vinegoni C, Ma R, Perrimon N, Koster RW, et al. Multispectral opto-acoustic tomography of deep-seated fluorescent proteins in vivo. Nature Photonics. 2009;**3**:412

[32] Dogra VS, Chinni BK, Valluru KS, Joseph JV, Ghazi A, Yao JL, et al. Multispectral photoacoustic imaging of prostate cancer: Preliminary ex-vivo results. Journal of Clinical Imaging Science. 2013;**3**:41

[33] Bungart BL, Lan L, Wang P, Li R, Koch MO, Cheng L, et al. Photoacoustic tomography of intact human prostates and vascular texture analysis identify prostate cancer biopsy targets. Photoacoustics. 2018;**11**:48

**Chapter 3**

*Chin Hsia*

**Abstract**

systems.

**33**

**1. Introduction**

A Balanced Slew-Rate

High-Voltage Integrated Bipolar

Ultrasonic Imaging Applications

This chapter describes the use of silicon-on-insulator (SOI) technology to develop balanced slew-rate pulse generators for medical ultrasound scanners, especially for multi-channel portable systems. Since ultrasonic transducers are usually composed of piezoelectric materials, most of which are capacitive, and the resonant frequency is usually in the order of tens of MHz, it is preferred to convert the high-frequency excited signals into high-voltage pulses to efficiently drive the transducers. In addition, the second harmonic leakage of the high-voltage pulse signal output by the pulse generator needs to be controlled such that the pulse generator can be applied to tissue harmonic imaging. Based on these considerations, the pulse generator architecture with balanced rising and falling edges proposed in this chapter is designed by synthesizing low-power, high-speed level shifters and a high-voltage H-bridge output stage to output high-voltage pulse signals with low harmonic distortion. The entire circuit integrates an 8-channel pulse generator, producing pulse signals >100 Vpp. The rise and fall times of the pulses are within 18.6 and 18.5 ns, respectively. The overall quiescent current is <60 uA (including the on-chip power supply). The output current drive capability is >2 A and the second harmonic distortion is as low as 40 dBc, indicating that the integrated pulse generator can be used in advanced, portable ultrasonic harmonic imaging

**Keywords:** high-voltage pulse generator, ultrasound transmitter, medical imaging,

Compared with computed tomography (CT), X-ray and magnetic resonance imaging (MRI), medical ultrasound imaging is relatively fast, inexpensive, portable and radiation-free, and has become one of the most popular modalities in clinical examination. Currently, besides conventional B-mode and Doppler ultrasonic modality, advanced imaging formation method, such as photo-acoustic (PA) imaging, elasto-graphic imaging, as well as harmonic imaging is gradually becoming an important medical assessment tool for these echo-graphic systems. PA imaging offers unique capabilities in studying biological tissue based on optical absorption

harmonic distortion, low-power on-chip supply

Pulse Generator for Medical

## **Chapter 3**


*7.1. Target of Voltage, Frequency Variation and Stabilization Time*

With regard to synchronization of MCFC, ESS and diesel generation, the voltage, frequency variation, and frequency variation and stabilization time in the transient state of disconnection from the grid were tested with reference to the Korean Register of Shipping, "Class 6 Electrical Equipment and Control Systems" in Table 9 [36].

**Table 9.** Rules for the classification of electrical installation and control systems of the Korean Register of Shipping.


[8] UNICEF. Salud. 2015. Retrieved from El Paludismo: http://www.unicef.org/ spanish/health/index\_malaria.html

[9] Murillo OL. Desafios de la prestación de servicios de salud en zonas rurales de Colombia. "Experiencia del proyecto malaria fondo mundial". Universidad Nacional de Colombia. Bogotá: Universidad Nacional de Colombia; 2012. 0vector/05599416.2012.pdf

[10] Vargas Herrera J. Prevención y control de la malaria y otras

enfermedades transmitidas por vectores en el Perú. Revista Peruana de Epidemiología. 2003;**11**(1):1-19

[11] Instituto Nacional de Salud. Protocolo para la vigilancia en salud pública de la malaria. Bogotá: INS; 2014

[12] Fernández J. Los dominios culturales de la malaria: una aproximación a los saberes no institucionales. 2014. DOI: 10.7705/biomedica.v34i2.1629

[13] World Health Organization. World Malaria Report 2014. Geneva, Switzerland: WHO; 2014

[14] Instituto Nacional de Salud. Informe de evento malaria, Colombia, 2020. Bogotá: INS; 2020a

[15] Organización Panamericana de la Salud. Informe de la situación del paludismo en las Américas, 2008. Washington. 2010. Retrieved from: http:// www2.paho.org/hq/dmdocuments/2011/ PAHO\_SPA\_Malaria\_LR.pdf

[16] Instituto Nacional de Salud - Organización Panamericana de la Salud. Protocolo para la vigilancia en salud pública de malaria. 24. Colombia. 2015

[17] Instituto Nacional de Salud. Informe final de evento malaria, 2016, Colombia. Bogotá: INS; 2016

[18] Instituto Nacional de Salud. Informe final de evento malaria, 2017, Colombia. Bogotá: INS; 2017

[19] Instituto Nacional de Salud. Informe final de evento malaria, 2018, Colombia. Bogotá: INS; 2018

[20] Instituto Nacional de Salud. Informe final de evento malaria, 2019, Colombia. Bogotá: INS; 2019

[21] Helman C. Culture, Health and Illness. Londres: Oxford University press; 2007

[22] Stresman GH, Mwesigwa J, Achan J, Giorgi E, Worwui A, Jawara M, et al. Do hotspots fuel malaria transmission: a village-scale spatio-temporal analysis of a 2-year cohort study in The Gambia. BMC Medicine. 2018;**16**(1):160

[23] Word Health Organization. Malaria Surveillance, Monitoring & Evaluation: A Reference Manual. Geneva, Switzerland: Word Health Organization; 2018

[24] Yukich J, Bennett A, Yukich R, Stuck L, Hamainza B, Silumbe K, et al. Estimation of malaria parasite reservoir coverage using reactive case detection and active community fever screening from census data with rapid diagnostic tests in southern Zambia: a re-sampling approach. Malaria Journal. 2017;**16**:1

[25] Sturrock HJ, Hsiang MS, Cohen JM, Smith DL, Greenhouse B, Bousema T, et al. Targeting asymptomatic malaria infections: Active surveillance in control and elimination. PLoS Medicine. 2013;**10**(6):e1001467

[26] Stresman G, Whittaker C, Slater H, Bousema T, Cook J. Quantifying Plasmodium falciparum infections clustering within households to inform household-based intervention strategies for malaria control programs: An observational study and metaanalysis from 41 malaria-endemic countries. PLoS Medicine. 2020;**17**(10):e1003370

[27] Organización Panamericana de la Salud. La Organización Panamericana de la Salud y el estado colombiano 1902- 2002. Bogotá: OPS; 2002

[28] Franco Agudelo S. El paludismo en América Latina. Guadalajara: Editorial Universidad de Guadalajara; 1990

[29] Blair S. Retos para la eliminación de la malaria en Colombia: un problema

de saber o de poder. 2011. Available from redalyc: http://www.redalyc.org/ pdf/843/84323434013.pdf. [Accessed: 15 Feb 2015]

[30] Fondo Mundial Malaria. Uso de la inteligencia epidemiológica con participación social, para fortalecer la gestión del programa, mejorar el acceso al diagnóstico y tratamiento y ejecutar intervenciones eficaces para la prevención y control de la malaria, Colombia 2010-2015. Bogotá: Instituto Nacional de Salud, Universidad de Antioquia, FONADE, Ministerio de Protección Social; 2012

[31] Hurtado L, Cumbrera A, Rigg C, et al. Long-term transmission patterns and public health policies leading to malaria elimination in Panamá. Malaria Journal. 2020;**19**:265

[32] Rosero CY, Jaramillo GI, Montenegro FA, Garcia C, Coral A. Community perception of malaria in a vulnerable municipality in the Colombian Pacific. Malaria Journal. 2020;**19**(1):343

[33] Alvarado BE, Gomez E, Serra M, Carvajal R, Carrasquilla G. Evaluación de una estrategia educativa en malaria aplicada en localidades rurales del Pacífico colombiano. Biomédica. 2006;**26**:342-352

[34] Girón S, Mateus J, Castellar C. Análisis de costo efectividad de dos inervenciones para el control de la malaria en el area urbana de Buenaventura, Colombia. Biomédica. 2006;**26**:379-386

[35] Guzman V, Correa AM, Fonseca J, Blair S. Seguridad alimentaria y nutricional en un espacio de riesgo para la malaria. Archivos Latinoamericanos de Nutrición. 2003;**53**(3):1-12


**Acknowledgements**

Fettig et al. [14] reported mean deposition values from 0.04 ± 0.02 mg carbaryl/m2 at 38.1 m

fected the amount of deposition. Deposition was greatest 7.6 m from the tree bole and de‐ clined quickly thereafter. Approximately 97% of total spray deposition occurred within 15.2 m of the tree bole (Fig. 6). To evaluate the potential risk to aquatic environments, the authors converted mean deposition to mean concentration assuming a water depth of 0.3 m selected to represent the average size of lotic systems, primarily small mountain streams, adjacent to many recreational sites where bole sprays are often applied [14]. No adjustments were made for the degradation of carbaryl by hydrolysis, which is rapid in streams or for dilution by natural flow. Comparisons were made with published toxicology data available for select aquatic organisms. No-spray buffers of 7.6 m are sufficient to protect freshwater fish, am‐ phibians, crustaceans, bivalves and most aquatic insects. In laboratory studies, carbaryl was found to be highly toxic to stoneflies (Plecoptera) and mayflies (Ephemeroptera), which are widely distributed and important food sources for freshwater fishes, but negative impacts in field populations are often short-lived and undetectable several hours after contamination [55]. No-spray buffers >22.9 m appear sufficient to protect the most sensitive aquatic insects

An advantage of tree injections is that they can be used on environmentally-sensitive sites as these treatments represent an essentially closed system and therefore little or no contamina‐ tion occurs outside of the tree. However, following injection residues move within the tree and are frequently detected in the foliage [e.g., 44,56-57], which could pose a risk to decom‐ posers and other soil fauna when needles senesce. This has been shown for imidacloprid in maple [57], but injections of emamectin benzoate in pines appear of little risk. For example, [56] reported emamectin benzoate was not detected in the roots or the surrounding soil, but was present at 0.011–0.025 µg/g in freshly fallen pine needles. However, levels gradually de‐

The results of the many studies presented in this chapter indicate that preventative applica‐ tions of insecticides are a viable option for protecting individual trees from mortality due to bark beetle attack. Bole sprays of bifenthrin, carbaryl and permethrin are most commonly used. Several formulations are available and effective if properly applied. Residual activity varies with active ingredient, bark beetle species, tree species and associated climatic condi‐ tions, but generally one to three years of protection can be expected with a single applica‐ tion. Recent advances in methods and formulations for individual tree injection are promising, and further research and development is ongoing. We expect the use of tree in‐ jections to increase in the future. In general, preventative applications of insecticides pose little threat to adjacent environments, and few negative impacts have been observed. We hope that forest health professionals and other resource managers use this publication and other reports to make informed, judicious decisions concerning the appropriate use of pre‐ ventative treatments to protect trees from mortality due to bark beetle attack. Additional

clined to below detectable thresholds after 2 months [56].

at 7.6 m. Overall, distance from the tree bole significantly af‐

to 13.30 ± 2.54 mg carbaryl/m2

486 Insecticides - Development of Safer and More Effective Technologies

such as stoneflies.

**8. Conclusions**

We thank Stanislav Trdan (University of Ljubljana) and Romana Vukelic and Danijela Duric (InTech) for their invitation to contribute and guidance during the publishing process. Nu‐ merous colleagues from Arborjet Inc., BASF, Bayer ES, Bureau of Land Management (U.S.), FMC Corp., Fruit Grower's Supply Co., Mauget Inc., Nevada Division of Forestry, Sierra Pa‐ cific Industries, Southern Ute Reservation, Syngenta Crop Protection, Texas A&M Forest Service, Univar USA Inc., University of Arizona, University of California, University of Georgia, and USDA Forest Service have contributed to the success of much of the research discussed in this chapter. We are thankful for their support and helpful insights.

This publication concerns pesticides. It does not contain recommendations for their use, nor does it imply that the uses discussed here have been registered. All uses of pesticides in the United States must be registered by appropriate State and/or Federal agencies. CAUTION: Pesticides can be injurious to humans, domestic animals, desirable plants, and fish or other wildlife—if they are not handled or applied properly. Follow recommended practices for the disposal of surplus pesticides and their containers.


**Abstract**

Viruses exhibit a marked variation in their susceptibilities to chemical and physical inactivation. Identifying a trend within these variations, if possible, could be valuable in the establishment of an effective and efficient infection control or risk mitigation strategy. It has been observed that non-enveloped viruses are generally less susceptible than enveloped viruses and that smaller sized viruses seem less susceptible than larger viruses. A theory of a "hierarchy" of pathogen susceptibility has been proposed and widely referenced. This concept provides a useful general guide for predicting the susceptibility of a newly emerged pathogen. It also serves as a theoretical basis for implementing a limited scale viral inactivation study that is to be extrapolated onto many other viruses. The hierarchy concept should be interpreted with caution since the actual viral inactivation efficacy may, in some cases, be different from the general prediction. The actual efficacy is dependent on the type of chemistry and application conditions. The order of susceptibility is not always fixed; and viruses within the same family or even the same genus may exhibit drastic differences. This chapter reviews viral inactivation data for several commonly used chemistries against non-enveloped viruses, highlighting the cases wherein the order of susceptibility varied or even flipped. Possible underlying mechanisms are also discussed.

**Keywords:** enveloped viruses, non-enveloped viruses, hierarchy of susceptibility, disinfection, viral inactivation, virucidal efficacy


**Munir Ahmad, Nadeem Akhtar, Gul Jabeen, Muhammad Irfan, Muhammad Khalid Anser, Haitao Wu and Cem I¸sık**

Intention-Based Critical Factors Affecting Willingness to Adopt Novel Coronavirus Prevention in Pakistan: Implications for Future Pandemics

Reprinted from: *Int. J. Environ. Res. Public Health* **2021**, *18*, 6167, doi:10.3390/ijerph18116167 . . . **317**


**3.4. Image-based phenotyping**

Quantitative characterization of ventricular function has become important for the assessment of murine cardiac performance in heart disease [Wiesmann 2000, Wiesmann\_Circ\_Res 2001, Dawson 2004]. As the manipulation of the mammalian genome becomes routine, it is now possible to generate animal models to study cardiovascular function and dysfunction [Wiesmann\_Card\_Magn\_Reson 2001, Epstein 2002, Epstein 2007, Bucholz 2008, Stuckey 2012]. Critical to successful phenotypic screening of mouse models of the cardiovascular system using MRI are highly efficient four-dimensional (4D) acquisition ex-vivo and [Zamyadi 2010] in-vivo protocols [Bucholz 2010]. Such protocols ought to span the scales of the embryo to the adult, fully-developed mouse, and ought to lead to the reduction of the computational image processing complexity for accurate quantification of motion, global and regional cardiac function, strain, elasticity, and others.

#### *3.4.1. Quantification of global mechanical function and hemodynamic indices*

Traditionally, quantification of global hemodynamic indices has been associated with calculation of hemodynamic indices of function. MRI and other diagnostic techniques, (including microCT and ultrasound) are not the only existing techniques to accomplish functional characterization. While ultrasonic techniques are associated with inherent limitations for such quantification [Dawson 2004], microCT has been gaining interest and popularity [Badea 2005]. Miniature catheterization techniques introduced in the late 1990s [Georgakopoulos 1998] have revolutionized cardiac-based phenotypic in transgenic mice. However, their major drawbacks include their invasive nature and other technical limitations [Porterfield 2009, Constantinides\_IEEE 2011, Constantinides 2012]. As newly emerging techniques and applications develop to investigate in-vivo sarcomeric force generation with contrast agents [Constantinides\_ABME 2011], the current scientific focus is still on image-based calculations of global indices of function.

362 Practical Applications in Biomedical Engineering

**3.4. Image-based phenotyping**

In summary, numerous practical benefits are associated with mouse cardiac MR imaging, including the non-invasive nature of the technique, the inherent capability to map cardiac morphology and function, for both LV and RV chambers, and their motional patterns. High spatial and temporal resolution imaging can thus be achieved, through execution of highthroughput protocols, yielding direct, accurate estimates of global and regional indices of cardiac function, avoiding any assumptions whatsoever or model-based derivation

Despite the extensive use of cartesian imaging with adequate SNR performance and spatial resolution (using FLASH, SSFP, or FISP), 3D acquisition studies maybe more efficiently completed using radial or spiral imaging sequences, especially for dynamic cardiac imaging (with pharmacologic interventions or contrast agent infusions). Nevertheless important and critical drawbacks are associated with such sequences, including the necessity to maintain data density as sampling extends to outer k-space regions, the convoluted and complex reconstructions (often associated with data re-gridding, kernel de-convolution, filtering, and inverse fourier transformation), and inherently lower SNR performance than rectilinear imaging. Thus, the choice between cartesian and radial imaging reduces to a tradeoff

between SNR, spatial resolution, and efficiency of data sampling for 3D coverage.

motion, global and regional cardiac function, strain, elasticity, and others.

*3.4.1. Quantification of global mechanical function and hemodynamic indices*

Traditionally, quantification of global hemodynamic indices has been associated with calculation of hemodynamic indices of function. MRI and other diagnostic techniques, (including microCT and ultrasound) are not the only existing techniques to accomplish functional characterization. While ultrasonic techniques are associated with inherent limitations for such quantification [Dawson 2004], microCT has been gaining interest and popularity [Badea 2005]. Miniature catheterization techniques introduced in the late 1990s [Georgakopoulos 1998] have revolutionized cardiac-based phenotypic in transgenic mice. However, their major drawbacks include their invasive nature and other technical limitations [Porterfield 2009, Constantinides\_IEEE 2011, Constantinides 2012]. As newly

Quantitative characterization of ventricular function has become important for the assessment of murine cardiac performance in heart disease [Wiesmann 2000, Wiesmann\_Circ\_Res 2001, Dawson 2004]. As the manipulation of the mammalian genome becomes routine, it is now possible to generate animal models to study cardiovascular function and dysfunction [Wiesmann\_Card\_Magn\_Reson 2001, Epstein 2002, Epstein 2007, Bucholz 2008, Stuckey 2012]. Critical to successful phenotypic screening of mouse models of the cardiovascular system using MRI are highly efficient four-dimensional (4D) acquisition ex-vivo and [Zamyadi 2010] in-vivo protocols [Bucholz 2010]. Such protocols ought to span the scales of the embryo to the adult, fully-developed mouse, and ought to lead to the reduction of the computational image processing complexity for accurate quantification of

approaches endorsed by other imaging techniques such as ultrasound.

**Figure 10.** (Top) Typical bright blood true-short axis cardiac imaging at an apical, middle, and basal levels of the C57BL/6 murine heart using a liposomal contrast agent; (Bot) Black-blood spin-echo images of the murine heart at basal, mid, and apical levels**.**

**Figure 11.** (A) ECG-gated four chamber view of a healthy mouse heart at 78 x 78 μm2 in-plane resolution, and (B) corresponding self-gated (retrospective) view of a separate mouse using a navigator echo at the same spatial resolution, at 11.7 T using FLASH-MRI [Images courtesy of Bruker Biospin MRI, Ettlingen, Germany].

Correspondingly, estimated cardiac volumes can easily be computed using standard image processing tools and converted to absolute volume units using the voxel dimension and the myocardial tissue density. Hemodynamic indices such as end-diastolic (EDV) and end-

systolic volumes (ESV), stroke volume (SV), cardiac output (CO), and ejection fractions (EF) can now be routinely calculated according to standard cardiac mechanical functional relations [Constantinides\_SBI 2009], based on CINE-MRI (Figure 11). CINE based local contractile function, including estimation of wall thickness, motion and fractional shortening, indicators of systolic function and long-term prognostic biomarkers in dysfunction remain the gold-standard for assessment of motional patterns and cardiac function in small animals due to the excellent soft tissue contrast of MRI and its high spatial and temporal resolution (Figure 12).

Study of the Murine Cardiac Mechanical Function Using Magnetic Resonance Imaging:

elicited post-transgenic modifications and the genetic basis of pathology [Henkelman 2010]. Therefore mouse imaging, combined with probabilistic, statistical atlas constructions and morphometric methods [Zamayadi 2010], is envisaged to play an increasing role in imagebased phenotyping and gene expression mapping of genetically altered mice [Ng 2010] in the future. Construction of probabilistic and statistical atlases [Perperidis 2011] can potentially enable the study of murine, global cardiac structure and function with increased quantitative accuracy, identifying modal components of shape variability (from embryogenesis to adulthood), and disseminating components of global mechanical motion. Similar to existing cardiac atlases [Perperidis 1995, Hoogendoorn 2007], these can be population-based instead of single-subject. Prior efforts have focused on modeling cardiac anatomy in humans [Helm 2006] but only limited attempts have been made to construct accurate, high-spatial and hightemporal resolution computerized atlases for mice [Perperidis 2011]. Despite multiple prior efforts with construction of human brain atlases [Young 2009], Frangi et al. [Frangi 2002], Mitchell et al. [Mitchell 2002], and Lotjonen et al. [Lotjonen 2004] were the first to develop human ventricular statistical shape models. More recently Ordas et al. [Ordas 2007] developed a computational atlas of the entire heart using registration-based techniques. Perperidis et al. [Perperidis 1995, Perperidis 2005] and Hoogendoorn et al. [Hoogendoorn 2007] proposed 4D spatio-temporal human cardiac probability atlases from (MRI), while Beg et al. [Beg 2004] developed a large deformation diffeomorphic mapping (LDDM) for construction of cardiac statistical atlases. As an extension to Beg's work, Helm et al. [Helm 2006] employed LDMM to achieve inter-subject registration to a reference anatomical template to compare cardiac geometric variability using Principle Component Analysis (PCA) from diffusion tensor MRI in

normal and failing human hearts.

*Manual and semi-automated segmentation and registration approaches*

ranking of 14 different non-linear deformation algorithms [Klein 2009].

diagrammatically summarized in Figure 14 [Perperidis 2011].

Critical to successful constructions of atlases and to the transformation of constructed surface models to the finite element models (for subsequent computational work of mechanical function), are efficient and accurate segmentation and registration techniques (Figures 13, 14). Using recently developed techniques in our group [Perperidis 2011], a segmented (template) reference MRI sequence is selected from the mouse database consisting of imaged anatomic structures (left and right ventricular myocardium, left and right ventricular blood pools, and papillary muscles) as representative sets of typical anatomic objects of interest. This template is subsequently used to register population images via global and local non-rigid transformations. Although such high-dimensional transformation differs from established one-to-one (invertible) diffeomorphic transformations [Helm 2006], its performance is comparable in accuracy, precision, simplicity, and computational intensity, as recently reported by a multi-center quantitative

Figure 13 show examples of manual, user-based spline segmentation and subsequent correction for left and right ventricular feature extraction, as discussed previously [Perperidis 2011]. Implementation of a global and local registration scheme is also

The Current Status, Challenges, and Future Perspectives 365

**Figure 12.** Single-slice, multiphase CINE functional cardiac imaging of the C57BL/6 mouse heart over 12 cardiac phases.

#### *Interstrain morphological and 4D motional variability – Statistical altases*

The advances in high-field, high-resolution cardiac imaging techniques, have also allowed the development of atlas-based approaches for the description of anatomical structures and their function [Ali 2005, Sharief 2008] in normal [Ruff 1998, Bucholz 1998, Badea 2005, Zamyadi 2010] and transgenic mice [Chien 2000, Epstein 2007]. Completion of the sequencing of the mouse genome has led to increased requirements for identifying the specific phenotype elicited post-transgenic modifications and the genetic basis of pathology [Henkelman 2010]. Therefore mouse imaging, combined with probabilistic, statistical atlas constructions and morphometric methods [Zamayadi 2010], is envisaged to play an increasing role in imagebased phenotyping and gene expression mapping of genetically altered mice [Ng 2010] in the future. Construction of probabilistic and statistical atlases [Perperidis 2011] can potentially enable the study of murine, global cardiac structure and function with increased quantitative accuracy, identifying modal components of shape variability (from embryogenesis to adulthood), and disseminating components of global mechanical motion. Similar to existing cardiac atlases [Perperidis 1995, Hoogendoorn 2007], these can be population-based instead of single-subject. Prior efforts have focused on modeling cardiac anatomy in humans [Helm 2006] but only limited attempts have been made to construct accurate, high-spatial and hightemporal resolution computerized atlases for mice [Perperidis 2011]. Despite multiple prior efforts with construction of human brain atlases [Young 2009], Frangi et al. [Frangi 2002], Mitchell et al. [Mitchell 2002], and Lotjonen et al. [Lotjonen 2004] were the first to develop human ventricular statistical shape models. More recently Ordas et al. [Ordas 2007] developed a computational atlas of the entire heart using registration-based techniques. Perperidis et al. [Perperidis 1995, Perperidis 2005] and Hoogendoorn et al. [Hoogendoorn 2007] proposed 4D spatio-temporal human cardiac probability atlases from (MRI), while Beg et al. [Beg 2004] developed a large deformation diffeomorphic mapping (LDDM) for construction of cardiac statistical atlases. As an extension to Beg's work, Helm et al. [Helm 2006] employed LDMM to achieve inter-subject registration to a reference anatomical template to compare cardiac geometric variability using Principle Component Analysis (PCA) from diffusion tensor MRI in normal and failing human hearts.

#### *Manual and semi-automated segmentation and registration approaches*

364 Practical Applications in Biomedical Engineering

and temporal resolution (Figure 12).

12 cardiac phases.

systolic volumes (ESV), stroke volume (SV), cardiac output (CO), and ejection fractions (EF) can now be routinely calculated according to standard cardiac mechanical functional relations [Constantinides\_SBI 2009], based on CINE-MRI (Figure 11). CINE based local contractile function, including estimation of wall thickness, motion and fractional shortening, indicators of systolic function and long-term prognostic biomarkers in dysfunction remain the gold-standard for assessment of motional patterns and cardiac function in small animals due to the excellent soft tissue contrast of MRI and its high spatial

**Figure 12.** Single-slice, multiphase CINE functional cardiac imaging of the C57BL/6 mouse heart over

The advances in high-field, high-resolution cardiac imaging techniques, have also allowed the development of atlas-based approaches for the description of anatomical structures and their function [Ali 2005, Sharief 2008] in normal [Ruff 1998, Bucholz 1998, Badea 2005, Zamyadi 2010] and transgenic mice [Chien 2000, Epstein 2007]. Completion of the sequencing of the mouse genome has led to increased requirements for identifying the specific phenotype

*Interstrain morphological and 4D motional variability – Statistical altases*

Critical to successful constructions of atlases and to the transformation of constructed surface models to the finite element models (for subsequent computational work of mechanical function), are efficient and accurate segmentation and registration techniques (Figures 13, 14). Using recently developed techniques in our group [Perperidis 2011], a segmented (template) reference MRI sequence is selected from the mouse database consisting of imaged anatomic structures (left and right ventricular myocardium, left and right ventricular blood pools, and papillary muscles) as representative sets of typical anatomic objects of interest. This template is subsequently used to register population images via global and local non-rigid transformations. Although such high-dimensional transformation differs from established one-to-one (invertible) diffeomorphic transformations [Helm 2006], its performance is comparable in accuracy, precision, simplicity, and computational intensity, as recently reported by a multi-center quantitative ranking of 14 different non-linear deformation algorithms [Klein 2009].

Figure 13 show examples of manual, user-based spline segmentation and subsequent correction for left and right ventricular feature extraction, as discussed previously [Perperidis 2011]. Implementation of a global and local registration scheme is also diagrammatically summarized in Figure 14 [Perperidis 2011].

Study of the Murine Cardiac Mechanical Function Using Magnetic Resonance Imaging:

**Figure 14.** Graphical representation of land-marking as an initial step to image registration. The landmarks are propagated from a reference landmarked template heart model to each remaining mouse heart of each cohort. (B) Typical mid-short and long-axis images from a mouse heart; (C) RView corrected binary masks; (D) Example of five-point landmarked mesh for global registration; (E) 3D epicardial/endocardial reference surface model rendition used for local registration, and (F) construction of the three-dimensional (3D) mesh volumetric dataset using the marching cubes algorithm. [This work originally appeared in Perperidis et al. (Perperidis et al. 2011), published in

Despite its potential usefulness, the major limitations of such a technique is associated with the significant image post-processing, the need for accurate registration methods (often a challenging task for cardiac datasets), the inherent assumptions associated with the normality of distribution of independent datasets, and confounding factors on attempts to

analyze motion and variability (often as a direct modulation of anesthesia effects).

Computerized Medical Graphics; Reproduced with the permission of Elsevier].

The Current Status, Challenges, and Future Perspectives 367

**Figure 13.** Flow diagrammatical representation of the empirical optimization process for generation of quantitatively accurate finite element models of the murine myocardium. [Reproduced from Constantinides et al. [Constantinides\_SBI\_2010] with permission from IEEE]. Insert (top right): (top row) Seed-point segmentation and binary mask construction in short axis MRI; (middle and bottom rows) RView 3D binary mask correction. [This work originally appeared in Constantinides et al. [Constantinides 2010] and Perperidis et al. [Perperidis et al. 2011], and was published in Computerized Medical Graphics and the IEEE Proceedings of the International Society of Biomedical Imaging; Reproduced with the permission of Elsevier and IEEE].

Manual, image-based techniques seem to provide the best avenue for segmentation (despite their inherent intra- and inter-observer variability inaccuracies).

Certainly, atlas-based approaches are envisaged to be of tremendous benefit and value for cardiac phenotyping characterization in the upcoming years, aiding spatial mapping of gene expression using novel cellular and sub-cellular probes and markers, understanding embryogenesis and development, accurately mapping strain-, age-, and sex-based morphological dependencies, quantifying patterns of motional variability, and efficiently screening cardiac functional changes based on semi-automatic template segmentation techniques for efficient estimation of hemodynamic indices of function, and high throughput phenotypic screening.

**Figure 13.** Flow diagrammatical representation of the empirical optimization process for generation of

Manual, image-based techniques seem to provide the best avenue for segmentation (despite

Certainly, atlas-based approaches are envisaged to be of tremendous benefit and value for cardiac phenotyping characterization in the upcoming years, aiding spatial mapping of gene expression using novel cellular and sub-cellular probes and markers, understanding embryogenesis and development, accurately mapping strain-, age-, and sex-based morphological dependencies, quantifying patterns of motional variability, and efficiently screening cardiac functional changes based on semi-automatic template segmentation techniques for efficient estimation of hemodynamic indices of function, and high

quantitatively accurate finite element models of the murine myocardium. [Reproduced from Constantinides et al. [Constantinides\_SBI\_2010] with permission from IEEE]. Insert (top right): (top row) Seed-point segmentation and binary mask construction in short axis MRI; (middle and bottom rows) RView 3D binary mask correction. [This work originally appeared in Constantinides et al. [Constantinides 2010] and Perperidis et al. [Perperidis et al. 2011], and was published in Computerized Medical Graphics and the IEEE Proceedings of the International Society of Biomedical Imaging;

Reproduced with the permission of Elsevier and IEEE].

throughput phenotypic screening.

their inherent intra- and inter-observer variability inaccuracies).

**Figure 14.** Graphical representation of land-marking as an initial step to image registration. The landmarks are propagated from a reference landmarked template heart model to each remaining mouse heart of each cohort. (B) Typical mid-short and long-axis images from a mouse heart; (C) RView corrected binary masks; (D) Example of five-point landmarked mesh for global registration; (E) 3D epicardial/endocardial reference surface model rendition used for local registration, and (F) construction of the three-dimensional (3D) mesh volumetric dataset using the marching cubes algorithm. [This work originally appeared in Perperidis et al. (Perperidis et al. 2011), published in Computerized Medical Graphics; Reproduced with the permission of Elsevier].

Despite its potential usefulness, the major limitations of such a technique is associated with the significant image post-processing, the need for accurate registration methods (often a challenging task for cardiac datasets), the inherent assumptions associated with the normality of distribution of independent datasets, and confounding factors on attempts to analyze motion and variability (often as a direct modulation of anesthesia effects).


**Conflict of interest**

The authors declare no conflict of interest.

*Epigenetics and DNA Repair in Cancer DOI: http://dx.doi.org/10.5772/intechopen.94030*

*DNA - Damages and Repair Mechanisms*

L-OHP (oxaliplatin) [127].

**7. Conclusions**

cancer response.

**Acknowledgements**

**Conflict of interest**

Thanks to IntechOpen.

The authors declare no conflict of interest.

by promoting HR repair, implying an oncogenic role for METTL3 and m6A. At the same time, FTO becomes a promising target to develop FTO inhibitors like Rhein,

Hepatocarcinogenesis is correlated with abnormal m6A modifications, high METTL3 and YTHDF1 expression in hepatocellular carcinoma (HCC) is associated with poor prognosis, with its combination as a malignant marker, according to Zhou et al. [123]. The participation of the machinery regulating m6A was clarified by the work of Chen et al. [124]. They found a significant increase in mRNA m6A levels, supporting the role of m6A in liver cancers. When METTL3 is downregulated, it is unable to act on tumor suppressor SOCS2, being silenced by METTL3 through m6A-YTHDF2. SOCS2 transcripts are a direct target of YTHDF2 with mediated mRNA decay, promoting tumor progression. Recently, Lin et al. [125] found that METTL3 depletion leads to a resistant phenotype in HCC with sorafenib treatment through regulation of FOXO3 expression. FOXO3 m6A methylation maintains stability, but its absence accelerates degradation. The modification is read by YTHDF1, which stabilizes m6A-labeled RNA and promotes protein synthesis. These results contrast with those obtained by Taketo and colleagues [126] when they established a METTL3-KD using a pancreatic adenocarcinoma cell line. The authors concluded that these cells had higher sensitivity to gemcitabine, 5-fluorouracil, cisplatin, and irradiation. It is clear that METTL3 plays a key role in resistance to therapy, but the way this gene behaves in different types of cancer is not yet understood. In a study on colorectal cancer (CRC), it was found that c-Myc activates the YTHDF1 gene expression. YTHDF1 is overexpressed in CRC and has been associated with lymph node metastasis and poor prognosis, as the evidence in vitro with YTHDF1 knockdown indicates that cancer cells are sensitized to the exposure of 5-Fluorouracil and

The SWI/SNF complex has been shown to be a central regulator in DNA repair, over other epigenetic complexes such as Polycomb repressive complex 1 (PRC1) and 2 (PRC2), which require the cooperation of their subunits and epigenetic markers to trigger the on–off signaling cascade, generated by acetylation, methylation, or ubiquitination of genes involved in response to DNA damage. We see that participation of epigenetics in the cellular responses goes far beyond DNA promoter methylation and histone modification. Methylation of RNA has a critical role in cell maintenance, changing our notion about RNA functions. We do not know whether deregulation of the m6A machinery could result in cancer development or progression by altering DNA damage response, but knowledge of molecular mechanisms of regulation of m6A cellular modification in tumor cells may develop a combined therapy for m6A regulator proteins as targets that facilitate a better

Meclofenamic acid (MA2), or its ethyl ester form, MA2 [122].

**178**