Animal Models of Human Disease

Paige Snider , Simon J. Conway , in Progress in Molecular Biology and Translational Science, 2011

B Tetralogy of Fallot

TOF is the most common cyanotic CHD and the most common cause of the "blue baby syndrome." Approximately, 9–14% of babies with CHDs will have TOF (American Heart Association, 2010; www.heart.org). In TOF, an anterior placement of the conotruncal septum results in unequal division of the conus, which produces four cardiovascular alterations. 40 The four CHDs associated with TOF are VSD, right ventricular hypertrophy, pulmonary stenosis, and overriding aorta. 40,105,106 In TOF, the VSD is present because of an antero-cephalad malalignment of the developing ventricular septum and a failure of the OFT cushions to muscularize. 40,106 Right ventricular hypertrophy is a hemodynamic consequence of the deviated outlet septum. 106 Pulmonary stenosis results from abnormal morphology of the septoparietal trabeculations surrounding the subpulmonary outflow tract, causing a narrowing of the right ventricular outflow and obstructing blood flow. 40,106 Overriding aorta is a result of the displacement of the outlet septum into the right ventricle, which causes the aortic root to be positioned directly over the VSD. 106 Cyanosis is the major hallmark of TOF and can be present in neonates based on the degree of the blood flow obstruction to the lungs. 105,106 Surgical intervention can result in complete repair, although adults have chronic issues such as pulmonary regurgitation, recurrence of pulmonary stenosis, and ventricular arrhythmias. 106 TOF is thought to be a multifactorial CHD and genetic associations of TOF are chromosomal aberrations such as trisomies 21, 18, 13 as well as microdeletions in chromosome 22. 106 Specific genetic associations via both mouse mutant analysis and patient screening also include FOG2, JAG1, NKX2.5, and VEGF. Cooperative morphological data analysis from mice and humans shows that TOF may be caused because the lack of longitudinal growth of the OFT prohibits the normal counterclockwise rotation of the OFT region. 107

Several mouse mutants have been shown to exhibit TOF. The isoform-specific Vascular endothelial growth factor (Vegf)Vegf120/120 knockin mice only express the 120 isoform and are highly predisposed to develop TOF. 108,109 The proposed etiology is that a localized increase in VEGF signaling within the secondary heart field-derived myocardium results in alterations of Notch signaling, causing OFT cushion hypoplasia, and subpulmonary myocardial apoptosis. 109 Significantly, VEGF haplotype correlates with increase risk for TOF in patients. 109,110 Similarly, as knockouts of mouse Growth differentiation factor-1 (Gdf1) left–right patterning gene exhibited CHDs, a population study was performed to determine if a spectrum of CHDs can be attributed to human GDF1. 111,112 Indeed, a heterozygous loss-of-function in the human GDF1 gene contributed to a distinct class of CHD affecting the conotruncus. 112 Thus, these studies confirmed that cardiac development in humans can be affected by left–right patterning signals and mutations in the entire pathway of left–right determination may be considered as candidates for CHD manifestations in humans on the basis of identifying a similar mechanism. 112 Finally, as mutations in the FOG-2 (friend of GATA 2) transcriptional cofactor that can physically interact with GATA-4/5/6, were shown to occur in patients with TOF, 113,114 a mouse knockout was generated. Significantly, Fog2 null mice die midgestation and display several cardiac malformations, including thin ventricular myocardium and TOF. 115 These Fog2 knockout mice are currently being used to examine Fog2's ability to act in a dose-dependent manner and decrease Fog2-related pathways. 114 Similarly, transgenic expression of truncated Fog2 alleles is being used to examine its in utero function. 114 Thus, via combining transgenic mice models and clinical and genetic characterization of patients, it is possible to gain a better understanding of the signaling pathways affecting cardiac development and the underlying causes of CHDs.

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Evaluating Water Quality to Prevent Future Disasters

Jason Berberich , ... Endalkachew Sahle-Demessie , in Separation Science and Technology, 2019

1.2.3 Natural Pollution Sources: The Case of Arsenic Pollution of Drinking Water Sources

Some water contaminants produce harmful health effects only when their concentrations are above certain thresholds. Nitrates (NO3) produce methaemoglobinaemia that can cause "blue baby" syndrome (Knobeloch et al., 2000). A second group consists of elements that are essential to human health, such as fluoride and arsenic, but exposure to excess quantities can create health risks. Many metal ions such as selenium, copper, and zinc are essential to health in low concentrations. However, metals tend to accumulate in tissues, and exposure to them over a long time or at high levels can lead to illness. Exposure to elevated concentrations of trace metals can have negative consequences for both wildlife and humans. Contaminants in the third group have very low thresholds of hazards. These include genotoxic substances such as pesticides and arsenic. Heavy metals occur naturally. High concentration of heavy metals can enter food and water as the result of environmental discharge from mining and heavy industry.

Arsenic is distributed in the earth's crust at an average concentration of 2   mg   kg−   1. It occurs in trace quantities in all rock, soil, water, and air. The natural processes such as volcanic action and low-temperature volatilization are the most important natural source of arsenic, which also produces one-third of the atmospheric flux of arsenic. Schwarzenbach et al. studied the pollution of drinking water from natural arsenic and found that it affects as many as 140 million people in 70 countries. Fig. 3 shows estimates of the global levels of arsenic in drinking water supplies (Schwarzenbach et al., 2010) and Fig. 4 shows arsenic concentration in at least 25% of the groundwater samples in the United States. Although arsenic is present in more than 200 mineral species, the most common one is arsenopyrite, which is an iron arsenic sulfide (FeAsS). As deposits of arsenopyrite become exposed to the atmosphere, usually through mining, the mineral slowly oxidizes, converting the arsenic into oxides that are more soluble in water, leading to acid mine drainage (AMD) (Akai et al., 2004; Appelo and Postma, 2004). Other anthropogenic industrial activities such as smelting of nonferrous metals and the burning of fossil fuels are the major processes that contribute to anthropogenic arsenic contamination of air, water, and soil (Bhattacharya et al., 1997, 2002; Cullen and Reimer, 1989). The use of arsenic-containing pesticides has left vast tracts of agricultural land contaminated and leads to arsenic accumulation in crops such as rice (Abedin et al., 2002).

Fig. 3

Fig. 3. Levels of arsenic in drinking water at significant levels.

 Source: From Schwarzenbach, R.P., et al., 2010. Global water pollution and human health. Annu. Rev. Environ. Resour. 35, 109–136; United Nations Environment Program (UNEP).

Fig. 4

Fig. 4. A map of the United States showing available data on arsenic concentrations (μg/L or ppb) as of 2001 from samples of groundwater. Note that orange or red dots denote concentrations higher than that allowed in drinking water by US EPA regulations.

 Source: US geological survey.

The use of the waterborne wood preservative ammoniacal copper zinc arsenate (ACZA) has also led to arsenic contamination of the environment. Chromated arsenicals-treated wood is used to produce commercial wood shakes, shingles, permanent foundation support beams, and other wood products permitted by approved labeling. Copper-chromated arsenicals (CCA), is a waterborne wood preservative that has been used for pressure treatment of lumber since the 1930s. Pressure treatment of lumber has been used to protect wood against termites, fungi, and other pests that can degrade the integrity of wood products. The unintended environmental release of heavy metals from CCA-treated timber can occur at many points along the life cycle of the product, from manufacture, to handling and use, and to disposal (Khan et al., 2006). Although elemental arsenic is not soluble in water, arsenic salts exhibit a wide range of solubility depending on pH and the ionic environment in water. Arsenite [As(III)] is the dominant form under reducing conditions; however, arsenate [As(V)] is generally the stable form in oxygenated environments such as surface waters.

There are several laboratory instrumental methods for the determination of arsenic. These include spectroscopic methods (atomic absorption spectroscopy—AAS, atomic fluorescence spectroscopy), inductively coupled plasma–mass spectrometry (ICP-MS), and voltammetry methods. These instruments can be integrated with other fractionating or chromatographic techniques, commonly known as "hyphenated" methods, such as LC-MS, LC-ICP-MS to determine species of metallic pollutants, such as arsenic. These hyphenated methods have increased sensitivity range for arsenic compounds. Although laboratory systems are highly sensitive, they are unsuitable for field measurements. A field test kit based on the color reaction of arsine with mercuric bromide had been used for blanket groundwater testing in Bangladesh, and the detection limit was 50–100   μg/L under field conditions (Rahman et al., 2002; van Geen et al., 2005).

Arsenic is naturally present in rocks and sediments that form aquifers tapped for drinking water (see Fig. 5). However, the arsenic found in rock and sediment is immobile; thus, only trace levels of arsenic are found in groundwater. Certain natural geochemical conditions and processes can lead to the release of arsenic from the rocks and into the groundwater that is subsequently used for drinking. Monitoring metals in surface and groundwater supplies provides background information needed to determine the suitability of water resources for human consumption. Evidence suggests that levels of arsenic in groundwater aquifers in many parts of the world are below the World Health Organization (WHO) and the US Environmental Protection Agency (EPA) drinking water guideline (10   μg/L). However, arsenic remains a serious threat to health in some parts of the world such as Bangladesh and Cambodia, where shallow aquifer tube wells are abundant (Akai et al., 2004). Up to half of the estimated 10 million tube wells in Bangladesh might be contaminated with arsenic (Smith et al., 2000). As a result, up to 70 million people in Bangladesh were exposed to water with arsenic at greater than 10   μg/L (Berg et al., 2001). The effects of high levels of arsenic exposures, such as occurred in Bangladesh, have been well documented. Although well water reduced the high levels of cholera and other waterborne diseases, they have led to high rates of arsenic poisoning (Bhattacharjee, 2007; Bhattacharya et al., 2007).

Fig. 5

Fig. 5. Some arsenic is naturally present in all rocks and sediments that form aquifers tapped for drinking. Bars show average and lines show the range arsenic contents.

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The Genetics of Fetal and Neonatal Cardiovascular Disease

Wendy Chung MD, PhD , ... Punita Gupta MD , in Hemodynamics and Cardiology: Neonatology Questions and Controversies (Second Edition), 2012

Tetralogy of Fallot

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect, occurring in approximately 400 per million live births and the most common cause of blue baby syndrome. It occurs slightly more often in males than in females. Its cause is thought to be due to environmental or genetic factors or a combination. TOF can be caused by mutations in the human homolog of rat Jagged-1 (JAG1) or in the NKX2-5 gene encoding the cardiac-specific homeobox. 135,136 Mutations in the ZFPM2, GDF1, GATA4, and TBX1 genes have been identified in sporadic cases of TOF (Table 17c-1). 137 Lambrechts and colleagues (2005) found that a haplotype of single nucleotide polymorphisms in the VEGF gene increased the risk for TOF. 138 VEGF was said to be the first modifier gene identified for TOF. Greenway and colleagues (2009) performed a genomewide survey of 114 subjects with TOF and their unaffected parents and identified 11 de novo copy number variants that were absent or extremely rare (less than 0.1%) in 2265 controls. They identified copy number variants at chromosome 1q21.1 in 1% of nonsyndromic sporadic TOF cases as well as at 3p25.1, 7p21.3 (gain), and 22q11.2 (loss). They concluded that their findings predicted at least 10% of sporadic nonsyndromic TOF cases result from de novo copy number variants. 137

Tetralogy of Fallot is also a well-recognized feature of the 22q11 microdeletion syndrome and trisomy 21. Johnson and colleagues conducted a cytogenetic evaluation of 159 cases of tetralogy of Fallot. 139 A deletion (22q11) was identified in 14% who underwent FISH testing. Rauch and colleagues found that 22q11.2 deletion was the most common genetic anomaly among 230 patients with TOF, found in 7.4% of patients. 140 The second most common anomaly was trisomy 21, found in 5.2% of patients, which was often associated with atrioventricular septal defect. Other chromosomal aberrations or submicroscopic copy number changes were found in 3% of patients.

Digilio and colleagues (1997) calculated empiric risk figures for recurrence of isolated tetralogy of Fallot in families after exclusion of del(22q11). 141 Their results showed that the frequency of congenital heart defect was 3% in siblings, 0.5% in parents, 0.3% in grandparents, 0.2% in uncles or aunts, and 0.6% in first cousins and concluded that genes different from those located on 22q11 must be involved in causing familial aggregation of nonsyndromic tetralogy of Fallot in these cases. 134

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Tetralogy of Fallot

In Diagnostic Imaging: Pediatrics (Third Edition), 2017

Terminology

•

Most common cyanotic congenital heart lesion

•

Tetralogy: 4 heart defects from embryological anterocephalad deviation of conoventricular septum

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Infundibular or subpulmonary narrowing

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Anterior malalignment ventricular septal defect (VSD)

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Aorta overriding VSD

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Secondary right ventricular hypertrophy (RVH)

•

"Fallot" = French physician who first described 4 characteristic heart defects of "blue baby syndrome" in 1888

•

Spectrum of tetralogy of Fallot disease

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"Blue Tet": More subpulmonary obstruction → VSD shunts right-to-left → cyanotic appearance

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"Pink Tet": Less subpulmonary obstruction → VSD shunts left-to-right (normal) → acyanotic appearance

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Tetralogy with pulmonary atresia & major aortopulmonary collaterals: Severe congenital heart disease

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Tetralogy with absent pulmonary valve: "To-fro" flow in pulmonary artery (PA) leading to massively dilated branch PAs, tracheobronchial compression

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Nitrate

A.M. Fan , in Encyclopedia of Toxicology (Third Edition), 2014

Background

Nitrate is commonly found in drinking water sources especially in agricultural areas where nitrogen fertilizer is used, and where unregulated shallow private wells are more at the risk of contamination. The World Health Organization (WHO) guideline of 50 ppm and the US maximum contaminant level (MCL) of 45 ppm for nitrate in drinking water have been established for protecting infants from methemoglobinemia, commonly known as blue baby syndrome. The health protective value continues to be a subject of public health interest for many years, with varying opinion on whether it is too high or too low. Evaluation of nitrate will need to include consideration of nitrite because both are closely related in the nitrogen cycle in the environment and the body, and nitrite plays a major role in inducing toxicity after its formation from nitrate. More recently, reports of nitrate in drinking water, especially at levels higher than 50 ppm, have been associated with other health effects other than methemoglobinemia. This toxicological review provides an update on the health effects of nitrate with a focus on methemoglobinemia, reproductive and developmental effects, potential carcinogenicity, and especially endocrine/thyroid effects.

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Use of the Woodcock–Johnson IV Tests of Cognitive Abilities in the Diagnosis of Intellectual Disability

Randy G. Floyd , ... Haley K. Hawkins , in WJ IV Clinical Use and Interpretation, 2016

Background Information

Demographic information and family history. Ronald Thompson is a 56-year-old man who is not currently employed and lives alone. Background information was obtained about Ronald's family, medical, developmental, educational, and psychological history through an interview with Ronald's older sister, Laura Thompson, who has power of attorney.

Ronald was previously married, but in 2008, his wife passed away. Prior to her death, Ronald's wife helped Ronald function and complete tasks. Ronald's older sister, Laura, lives in Mississippi and his other sister, Sophia, lives in Arkansas. Laura and Sophia support Ronald financially. Ronald maintains contact with his sisters about once per week via the telephone and visits them several times per year.

Developmental and medical history . Laura reported that her mother's pregnancy with Ronald was difficult due to an Rh blood incompatibility. This incompatibility occurs when the Rh antibodies cross the placenta and attack the fetus's red blood cells. It can lead to hemolytic anemia in the fetus, which is a condition in which red blood cells are destroyed faster than the body can replace them. Ronald was also born with "blue baby syndrome," which is also called methemoglobinemia. Blue baby syndrome occurs when newborn babies have cyanotic heart defects. Laura was unsure of the medical interventions that were used to treat these conditions. No other history of chronic illness, hospitalizations, or abuse was reported.

According to Laura, Ronald has had learning difficulties since birth. Most of Ronald's developmental milestones were met on time, but Ronald's speaking was delayed. Ronald had an electroencephalography (EEG) scan when he was about 4 years old. She stated that the scan showed "low brain activity." Subsequently, he was enrolled in speech therapy and attended twice per week. However, he did not speak well until he was 6 years old and stutters to this day. Laura stated that Ronald wears reading glasses and his last vision screening occurred in the summer of 2014. She did not recall Ronald's last hearing screening.

Educational and psychological history. Laura reported that Ronald was placed in a special education program at 123 Elementary School. Laura recalled that he was evaluated and diagnosed with mild mental retardation, but she could not remember when this evaluation occurred. Ronald remained in the special education program until he graduated from Star Academy in 1974.

Ronald is not currently employed and has not had a job since 2012. He previously held a job working on a box packing line for 20 years, but Laura noted that Ronald was injured on the job and was "let go" due to a lack of focus and ability. Laura reported that Ronald then worked at a mail distribution facility. He worked there for approximately 7 years until he was fired due to an "emotional breakdown." It was after this breakdown that Ronald began receiving psychiatric treatment from Dr. Matthew Wagner at Medical Psychiatric Association.

Ronald is currently seeing Dr. Wagner for anxiety and depression. According to Laura, prior to treatment, Ronald attempted suicide four times. Ronald is currently taking 50   mg of Zoloft and 25   mg of Doxepin daily. He sees Dr. Wagner every 3 months to monitor his medications.

Overall, Laura reported that Ronald has significant difficulty comprehending information, specifically reading and writing. Additionally, Laura stated that Ronald has "never mastered mathematics at any level." Notably, she reported that Ronald has no concept of money. Laura added that if Ronald is in a highly stressful situation, his performance will significantly deteriorate. Laura noted that Ronald must be in a structured environment and needs constant supervision. He can perform well, but he needs very clear instructions, and they must be reinforced. Laura stated that their family has always organized living situations, paid bills, directed medical activities, and helped find jobs for Ronald. He has never lived independently, and Laura stated, "He could never survive on his own."

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ION EXCHANGE | Ion Chromatography Applications

B. Paull , in Encyclopedia of Analytical Science (Second Edition), 2005

Food and Beverages

As with most chromatographic methods applied to solid samples, sample digestion and analyte extraction methods are all important. IC is finding application in the analysis of foodstuffs following sample preparation using such techniques as microwave digestion, supercritical fluid extraction, accelerated solvent extraction, and pyrohydrolysis.

Inorganic anions

The predominant anionic species determined in foodstuffs are once again the nitrogen-, sulfur-, and phosphorus-containing species, as well as the halide ions. Table 2 lists some inorganic anions and some of the foodstuffs that have been analyzed for these anions using IC.

Table 2. Examples of foodstuffs to which IC has been applied for anion determinations following appropriate extraction methods

Anions Sample matrix
Nitrate, nitrite, sulfate, phosphate, chloride Milk products, fruits and fruit juices, beverages and alcoholic products, meat products, bakery products, vegetables, cereals
Fluoride As above plus citrus fruits and leaves and spinach
Iodide Seafood, food colorings, and iodized table salt
Sulfite Beer, lemon juice, potatoes, seafood, fruits (grapes)
Bromide Milk, food colorings, rice products, bakery products
Chlorite and chlorate Vegetables
Bromate Bakery products
Iodate Iodized table salt
Chromate Orange juice, potato products
Selenite and selenate Vegetables, cereals, orange juice
Arsenite and arsenate Food supplements, cereals, vegetables
Cyanide Fruits and fruit juices

Some of the more important applications in food analysis include nitrates and nitrites in baby food products, excess of which can lead to induce methemoglobinemia (blue baby syndrome), and the monitoring of sulfite, which is added to many foodstuffs as a preservative and to bleach food starches, and is only recently being linked to serious health effects. Also, residual bromate can be monitored in bakery products from the continuing use of bromate salts as dough conditioners.

Organic acids

In beverages such as wines, beers, and fruit juices, IC has also been widely applied in the determination of various organic acids, although in many cases ion exclusion chromatography is often used in preference to anion exchange.

Sugars

In the brewing industry, IC is used for the determination and monitoring of fermentable sugars, such as glucose, fructose, isomaltose, sucrose, maltose, maltotriose, and numerous others. For sensitive detection, pulsed amperometric detection is often preferred.

Inorganic and organic cations

In the analysis of foodstuff extracts and digests, IC has been predominantly applied to the determination of alkali and alkaline earth metal ions and, to a lesser extent, selected organic amines. Alkali and alkaline earth metal ions are naturally present in most foodstuffs, although accurate monitoring is still necessary to evaluate nutritional values, e.g., the sodium or calcium content of foodstuffs. As mentioned previously, ammonium content can also be determined using IC simultaneously with alkali metal ions, and is often used as an indicator of food quality.

Transition and heavy metal ions have also been determined in foodstuffs using IC, particularly seafood, where heavy metal contamination with metals such as cadmium and lead is often a problem. After separation using cation exchange or ion interaction chromatography, sensitive detection is generally achieved using postcolumn reaction detection with a suitable color-forming ligand, such as 4-(2-pyridylazo) resorcinol (PAR). Other metals such as zinc, copper, iron, cobalt, nickel, chromium, and manganese can also be detected in this way.

In an interesting recent application, the determination of acrylamide in foodstuffs has been shown using accelerated solvent extraction followed by IC with either UV or MS detection. Extracted samples can be analyzed directly using IC, with limits of determination of 50   ng   per   g acrylamide in foodstuffs possible using MS detection with single ion monitoring (SIM) at m/z 72.

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"The Policy of Truth"—Anchoring Toxicology in Regulation

Aalt Bast , Jaap C. Hanekamp , in Toxicology: What Everyone Should Know, 2017

Some Toxic Limits Seem to Be Carved in Stone

Once limits of some sort have been established, it seems that these values sometimes firmly remain set and cannot be modified easily. New convincing knowledge will not always readily lead to change of threshold concentrations. An interesting example is nitrate.

Nitrate in drinking water has for decades been thought to be the cause of which is called the "blue baby syndrome," infantile methemoglobinemia. Nitrate changes the hemoglobin (the transporter of oxygen in the red blood cells) via the reduced form of nitrate, nitrite, into methemoglobin, a state of hemoglobin in which the iron is oxidized and is in the Fe 3+ form which is unable to deliver oxygen to tissues. Transport of oxygen becomes hampered and a shortage of oxygen, cyanosis, leads to the bluish color of the intoxicated young child.

This general belief was fueled by the notion that infants under 6 months of age have a higher vulnerability for methemoglobin compared to adults because of lower enzyme activity to reduce the methemoglobin thus restoring the oxygen transport in the first months of life. Because victims of methemoglobinemia showed to have drunk nitrate containing well water, nitrate was blamed for this effect. Moreover it was known that nitrite is more toxic for hemoglobin than nitrate and even children that did not drink nitrate contaminated water belonged to the victims.

That led to the suggestion that a bacterial infection in the gastrointestinal tract might be involved in the conversion of nitrate to nitrite, which was the ultimate cause of the toxicity. It led to a strict regulation for nitrate in drinking water. The World Health Organization (WHO) established a maximum level of 50   mg/L of nitrate in drinking water. This had huge consequences in rural areas where nitrate in soil water exists as a consequence of the use of nitrate containing fertilizers. A stream of reports followed indicating that even infants, without exposure to high-nitrate drinking water but with symptoms of diarrhea, could suffer from methemoglobinemia. Suggestions to reexamine the strict WHO maximum levels because diarrhea appeared a causative role in methemoglobinemia were largely neglected.

It was subsequently found that in response to colonic inflammation several tissues produced nitric oxide (NO) via an enzyme called nitric oxide synthase. The NO oxidizes to nitrite and nitrate. Endogenously formed NO may thus eventually result in the methemoglobinemia observed in young children as a result of drinking bacterial contaminated water. It was for a long time thought that it was the combination of bacterial contamination and nitrate which could lead to methemoglobinemia.

Despite persistent regulatory and scientific focus on the risks of exposure to nitrate, new scientific perspectives emerged once NO was discovered to be a major physiological chemical component. This discovery created a multifaceted image on the role of nitrate, but also nitrite, in human physiology. NO production has been shown to be vital to maintain normal blood circulation and defense against infection. NO, subsequently, is oxidized via nitrite to nitrate, which is conserved by the kidneys and concentrated in the saliva. The discovery of NO as a vital physiological chemical explains the common knowledge that mammals produce nitrate de novo. Mayerhofer already observed this as early as 1913. Infections yield the most noticeable instance of nitrate biosynthesis, explaining methemoglobinemia as a result of intestinal infections that reduce nitrate to the deleterious nitrite, and not exposure to exogenous nitrate as such.

It is now recognized that nitrate may even have beneficial effects because it can be reduced (e.g., by mouth and intestinal bacteria) into NO which may lead to decrease in blood pressure. Nitrate-rich vegetables may thus have a beneficial effect on blood pressure. It is amazing how a compound-like nitrate changes its face from extremely toxic to health promoting. The health limits, though, remain the same, indeed carved in stone it seems. Apparently it is very difficult to change existing views based on new facts about certain chemical compounds such as nitrate.

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Volume 1

Marguerite B. Vigliani , in Emerging Technologies for Heart Diseases, 2020

1.15 Advanced cardiac surgery

In 1938, Robert Gross (1905–88), Chief Surgical Resident at the Children's Hospital in Boston ligated a patent ductus in a 7-year-old girl in defiance of his Chief of Surgery, who had forbidden him from performing the operation. Gross had developed the procedure in the autopsy room and had done it successfully in dogs, but he was put on probation for defying authority. Despite his reprimand, Gross went on to become known as the "patent ductus" doctor, and he co-authored a textbook on surgery in children with the same Chief who had suspended him. Gross continued his career as a surgical pioneer by developing several techniques for other vascular surgeries, like surgical correction of coarctation of the aorta, but he never operated on the heart itself [74].

Gross' fame resulted in a suggestion by Helen Taussig, a noted pediatric cardiologist, that he operate on children with Tetralogy of Fallot by creating an anastomosis between the aorta and the pulmonary artery to correct the "blue-baby syndrome" of cyanotic heart disease. Gross refused, and Taussig had to wait to present her idea to another cardiac surgeon who might accept the challenge. That surgeon turned out to be Alfred Blalock (1899–1964) who had been experimenting with vascular anastomoses between systemic arteries and the pulmonary circulation [75]. The operation itself, the creation of an artificial ductus to shunt blood from the subclavian artery to the pulmonary artery, however, had to wait until the end of the Second World War.

By that time an entire generation of military thoracic surgeons had experienced the opportunity to operate on the heart surgically under emergency conditions to remove bullets and other foreign bodies. Initially, the indications for thoracic surgery were very strict, but toward the end of the war Dwight Harkin (1910–93) a young Army Surgeon had developed an experimental technique for removing heart penetrative projectiles using finger dissection like Sir Henry Soutter. In 1946, he reported on the removal of 134 heart penetrating projectiles without a single death [76].

Harkin's work helped overcome barriers to performing surgery on the heart. "Transmyocardial palpatory surgery" began in the late 1940s, at first for dilating stenotic valves, then for repairing intraventricular septal defects and valvular regurgitations, as well as for resecting hypertrophies and myomas, and other intracardiac surgeries. A variety of specialized instruments were developed for use in conjunction with the palpating finger—valvulotomes, dilators, and special knives, even a cardioscope [77]. Despite careful patient selection, the mortality from blind closed valvuloplasties in rheumatic hearts was unacceptably high, but surgical correction of congenital anomalies in patients who had no myocardial damage were routinely and safely practiced.

The first open heart procedure in a human was done in 1952 by F. John Lewis (1916–93) and C. Walton Lillehei (1918–99) after years of experimental research in dogs with controlled hypothermia and temporary occlusion of blood flow to the heart [78]. Remarkably, they repaired a large atrial septal defect (ASD) under direct vision in less than 6 minutes in a bloodless field at 26°C. Simple repairs like ASD were able to be accomplished in less than 8 minutes of occlusion, but soon it was realized that more extensive surgeries would require extracorporeal perfusion.

There were isolated pioneer surgeon-inventors in the early 1950s who developed extracorporeal perfusion devices. Forest Dewey Dodrill (1902–97) used the Michigan Heart (Dodrill GMR Heart), built by engineers at General Motors (Fig 1.14) to repair a mitral valve [78].

Figure 1.14. The Dodrill-GMR Heart, also known as the Michigan Heart had the ability to bypass the right and left side of the patient's heart allowing surgeons a "dry" field on which to work.

This artificial heart pump was a collaborative project led by Dr. Forest Dewey Dodrill of Harper Hospital in Detroit, Michigan and General Motors Research Laboratory.

 Reproduced with permission from an online resource [114].

John Gibbon (1903–73) developed the Gibbon IBM II pump-oxygenator which he used in 1953 for successful repair of an ASD in an 18-year-old girl. After Gibbon's second and third patients died at surgery, he never again performed open-heart surgery.

Thinking that the high fatality rate was either due to the machines or to the debilitated condition of the patient's cardiac muscle, C. Walton Lillehei forged ahead with a radical new approach, which he called cross-circulation. Using a compatible parent instead of a machine as a "temporary placenta," Lillehei connected his pediatric patient to a parent via venous and arterial cannulations so that he was able to do his surgery without using complicated machinery (Fig 1.15).

Figure 1.15. Controlled cross circulation for direct-vision intracardiac surgery: correction of ventricular septal defects.

 Adapted from Lillehei CW, et al. [120].

Lillehei used this method in 45 patients between 1954 and 1955 to repair ventricular septal defects, complete atrioventricular canal, and correct Tetralogy of Fallot [78]. In 1956, Lillehei and Richard DeWall (1926–2016) developed a "bubble-oxygenator" to address ethical objections to cross-circulation, a technique which was characterized by Dr. Cecil Watson, the Chief of Medicine at University of Minnesota University Hospital, as the only operation with a "200% mortality rate." [79]. Subsequently, cardiopulmonary bypass pumps were developed, permitting progress in open-heart surgery.

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Nitrate, Nitrite, Nitrosatable Drugs, and Congenital Malformations

Jean D. Brender PhD, RN, FACE , in Handbook of Fertility, 2015

Maternal exposures to nitrate, nitrite, and n-nitroso compounds

Various dietary components contribute to exogenous exposure to nitrate, nitrite, and N-nitroso compounds, although drinking water sources may also be a major contributor of daily nitrate intake if levels are high in the water supplies [11,12]. Estimates of daily nitrate intake from the dietary sources range from 31 mg in Norway to 245 mg in Italy [13], with vegetables contributing the largest proportion of daily intake [14,15]. In a study using control mothers from the National Birth Defects Prevention Study (NBDPS), one of the largest population-based, case-control studies conducted on the etiology of birth defects, Griesenbeck et al. [16] observed a median intake of 40.5 mg/day of nitrate from dietary sources. In this study population, vegetables contributed an estimated 50 to 75% of daily intake of nitrate from the diet, depending on the mother's race/ethnicity. In an earlier report, the National Academy of Sciences (NAS) [17] concluded that 87% of dietary nitrate was from vegetables. Nitrate content varies considerably in vegetables with asparagus, broccoli, carrots, peppers, and tomatoes containing less than 50 mg/100 g, to celery, lettuce, radishes, and spinach containing more than 250 mg/100 g nitrate (fresh weight) [18,19].

Nitrate is the most widespread chemical contaminant in aquifers around the world [20]. Generally, water nitrate contributes only a small percentage of total daily nitrate intake unless levels approach or exceed the allowable maximum contaminant level (MCL) [17]. The U.S. Environmental Protection Agency (EPA) has set the MCL for nitrate in public water supplies at 10 mg/L nitrate-nitrogen (45 mg/L total nitrate) primarily to protect against methemoglobinemia in infants ("blue-baby syndrome") [21]. Agricultural populations, who often obtain their drinking water from private wells, are more likely to be exposed to elevated levels of nitrate in drinking water than urban populations with an estimated 22% of domestic wells in US agricultural areas exceeding 10 mg/L nitrate-nitrogen [22].

Cured meats and baked goods and cereals contribute most of the dietary nitrite intake with drinking water being a negligible source [17]. However, the endogenous conversion of nitrate to nitrite is also a significant source of exposure to nitrite; an estimated 5% of ingested nitrate in food and water are converted to nitrite in the saliva [23]. Once ingested and absorbed, approximately 25% of nitrate is secreted in saliva [24], where about 20% is converted to nitrite by bacteria in the mouth [25]. The National Academy of Sciences estimated that 47% of dietary nitrite was from meat, with cured meat providing most of this contribution (39%), 34% from baked goods and cereals, 16% from vegetables, and 3% from other sources [17]. In contrast, relative contributions of nitrite in the NBDPS participants' diets included 61% from meat, 12% from grain products, 11% from vegetables, and 16% from other foods [16].

Humans are exposed to N-nitroso compounds from exogenous sources and through endogenous formation. Exogenous sources include cured meats and smoked fish [12], beer [26], tobacco products and tobacco smoke [27,28], cosmetics [29,30], and occupational exposures in rubber or rocket fuel factories and leather tanneries [17]. Endogenous formation of nitrosamines contributes 40 to 75% of exposure to these compounds in humans [31], and the formation depends on precursors such as nitrate, nitrite, and secondary/tertiary amines and amides. After several decades of research on nitrosation and N-nitroso compounds, Lijinsky concluded that "any circumstance in which a nitrosating agent and a nitrosatable amino compound come in contact is a potential source of N-nitroso compounds" [32].

Extensive experimental evidence indicates that N-nitroso compounds can be formed in vivo via the reaction of nitrosatable amines or amides and nitrosating agents, such as nitrite, in an acidic environment as found in the stomach [33]. Endogenous formation of these compounds can also occur through cell-mediated nitrosation with stimulated macrophages [34] and with some bacterial strains of Alcaligenes, Bacillus, Escherichia, Klebsiella, Neisseria, Proteus, and Pseudomonas that are capable of catalyzing the nitrosation of secondary amines [31]. A variety of drugs contribute nitrosatable amines or amides in the endogenous formation of N-nitroso compounds. In experiments with simulated gastric conditions, the combination of drugs containing secondary or tertiary amines or amides with nitrite have yielded a range of N-nitroso compounds depending on the chemical structure of the drug [10,35,36]. These drugs will be discussed in more detail in the next section of this chapter. Other significant sources of nitrosatable amino compounds include certain foods and beverages (fish, pork, cereals, spices, coffee, tea, beer, wine), cosmetics, tobacco products, and agricultural chemicals [17].

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