Commercially available nutritional supplements with iodine content exceeding the daily intake recommended by WHO (RDA—recommended daily allowances).
\r\n\t
\r\n\tThe aim of this book project is to compile the updated research work on medicinal applications of noble metal complexes mainly focusing the structure activity relationship of metal complexes with targeting biological components.
Thyroxine (T4) and 3,5,3′-triiodothyronine (T3) are the two thyroid hormones, each of them containing two iodine atoms on their inner (tyrosine) ring. The difference between them is that T3 has only one iodine atom on its outer (phenyl) ring, whereas T4 has two. Synthesis of reasonable quantities of thyroid hormones requires adequate iodine intake to allow sufficient thyroidal uptake. The World Health Organization (WHO) recommendation for daily intake of iodine is 90 μg for infants and children up to 5 years, 120 μg for children 6–12 years, 150 μg for children ≥12 years and adults, and 250 μg for pregnant and lactating women [1]. The worldwide variability of the dietary intake of iodine depends on the iodine content of the soil, water, and the dietary practice. After Iodine Global Network data [2], the iodine uptake in Romania in 2004 was considered adequate, the median urinary iodine content (MUIC, normal value ≥100 μg/L) being 102 μg/L in school-aged children, but in some geographic regions, such as mountainous villages of Mureș County, a mild iodine deficiency was detected [3]. The MUIC value (68 μg/L) in pregnant women confirmed that iodine intake in this population of Romania is insufficient [2]. Administration of supplemental iodine to subjects with iodine deficiency goiter can result in iodine-induced hyperthyroidism in nonpregnant persons [4], but iodine supplementation in mild and moderate iodine-deficient pregnant women lowers thyroid hormone level [5].
\nThyroid hormone secretion is regulated by two mechanisms: a central hypothalamic-pituitary and a local autoregulatory mechanism depending on the iodine content of the gland. The autoregulatory mechanism reduces the fluctuation of thyroid hormone secretion in the event of sudden changes in iodine supply. Iodine excess inhibits iodide accumulation, organogenesis, tyrosine binding, and thyroid hormone release. However, this inhibitory effect (Wolff-Chaikoff effect) lasts only 10–14 days, followed by the so-called escape phenomenon [6].
\nIodine is a micronutrient that is present in foods (e.g., seaweed, seafood, dairy- and grain products, eggs), added to processed foods as iodized salt, and available as a dietary supplement, but the iodine concentration of water and foods is highly variable. Studies of iodine balance, based on the assumption that a healthy subject on an adequate diet maintains equilibrium between iodine intake and losses, have provided highly variable results, thus, cannot be used for setting daily reference values [7]. When iodine losses exceed intake (negative balance), deposits are progressively depleted resulting in biological signs and in clinical symptoms of deficiency. The physiological response to iodine deficiency is the preferential synthesis of T3 instead of T4. Long-term follow-up suggests that chronic iodine deficiency may lead to insufficient thyroid function (hypothyroidism) associated with a compensatory thyroid hypertrophy/hyperplasia with goiter (enlarged thyroid gland). Myxedema, observed with severe iodine deficiency, also results from hormone deficiency and is associated with reduced metabolic rate, weight gain, swollen face, edemas, hypothermia, and mental slowness. In euthyroid subjects, the plasma concentration of iodine (inorganic and organic iodine) ranged from 40 to 80 μg/L. Concentrations between 80 and 250 μg/L are associated with hyperthyroidism, whereas concentrations above 250 μg/L usually result from iodine overload with iodinated drugs [8, 9]. The thyroid gland, being highly flexible, is able to concentrate iodine up to 80-fold, and in most healthy adults, no clinical signs will appear at an iodine intake of up to 2 g/day [10]. However, if the adaptation to high iodine intake fails, various diseases occur. Chronic excessive iodine supply can also lead to goiter [11] and may accelerate the development of subclinical thyroid disorders to overt hypothyroidism or hyperthyroidism, increase the incidence of autoimmune thyroiditis, and increase the risk of thyroid cancer [10, 12, 13]. Recently, high iodine intake (exceeding 160 μg daily) was suggested as a risk factor for type 2 diabetes [14].
\nIodine-induced hyperthyroidism (thyrotoxicosis) or Jod-Basedow effect is most frequently observed following iodine supplementation in individuals who had previously experienced severe iodine deficiency [15, 16]. A plausible explanation of this phenomenon can be the thyroid stimulating hormone (TSH) hyperstimulation of the thyroid gland, which may occur as an adaptive response to the iodine-deficient conditions and results in autonomous growth and function of thyrocyte clusters. When iodine intake increases, these nodules may synthesize an excessive amount of thyroid hormones [10]. The mechanism consists of escape phenomenon when high doses of iodine are used for thyroid hormone synthesis, which can lead to severe thyrotoxicosis. The high iodine containing amiodarone and its metabolite N-desethylamiodarone (DEA) affects T cell function by increasing the number of both helper and cytotoxic T lymphocytes and induces destructive thyroiditis, resulting in transient thyrotoxicosis, as suggested by clinical, histological, and in vitro studies [17, 18, 19].
\nHigh levels of organic iodide (thyroid hormones) also reduce the accumulation of iodide ions in the thyroid gland inhibiting the TSH secretion.
\nThe effects of iodine administration differ in patients with pre-existing thyroid pathology from those in healthy subjects and depend upon the underlying disease process.
\nThe assessment of iodine deficiency can be accomplished by assessing the prevalence and severity of goiter, by testing the excretion of iodine in urine, and by determining hormonal levels (e.g., TSH, FT4). When used alone, neither of these are sufficiently sensitive and specific to measure iodine deficiency of a population, but urinary iodine remains the index of choice in the monitoring of iodine supplementation programmes. The most successful method of intervention for iodine deficiency control is salt iodization, iodine being added to salt as potassium iodide (KI), potassium iodate (KIO3), or sodium iodide (NaI). Due to the high prevalence of hypertension and cardiovascular diseases, many countries proposed to promote the reduction of salt intake to 5 g/day (<2 g of sodium), so complementary measures are needed in order to tackle iodine deficiency [20]. But iodine also binds to fatty acids, so iodine oil can also be given orally or intravenously to severely iodine-deficient patients in the short term. Nascent iodine is like the precursor form of iodine, which converts into thyroid hormones. The human body can recognize and assimilate this form more easily than potassium salt. Lugol’s solution is a widely used commercial iodine source, which contains elemental iodine and potassium iodide also. If someone consumes high quantities of iodine-rich foods (e.g., marine food, kelp), the use of iodized salt or iodinated water may increase iodine levels above the safe upper level as recommended by WHO. Individuals, who consume large amounts of seaweed regularly, are also exposed to the risk of iodine-induced hyperthyroidism [21, 22]. Several reports are available describing diet-induced thyrotoxicosis in patients consuming seaweed-containing foods or beverages [23]. Risk factors for iodineinduced hyperthyroidism include nontoxic or diffuse nodular goiter, latent Graves’ disease, and long-standing iodine deficiency [24].
\nMost dietary supplements, as well as food and water, contains iodine as salts: sodium iodide, sodium iodate, potassium iodide, and potassium iodate. Different solid dosage forms of potassium iodide are available, but around 20% is assimilated from inorganic forms of iodine into the body [25]. Iodine is also present in most multivitamin/mineral supplements. Some case reports described that previously euthyroid patients taking nutritional supplements developed iodine-induced hyperthyroidism [26, 27, 28]. The iodine content of dietary supplements shows high variability; some supplements may contain up to 160-fold of the recommended daily intake (\nTable 1\n). Short-term increase of basal and poststimulation TSH was described even in euthyroid patients administering dietary supplements with kelp [29, 30].
\nNutritional supplement | \nIodine content per serving (μg) | \n% RDA iodine per serving (%) | \n
---|---|---|
Natural Living Iodine Plus-2®\n | \n12500 | \n8333 | \n
Terry Naturally® (Europharma) Tri-Iodine®\n | \n25000, 12500, 6250, 3000 | \n16667, 8333, 4167, 2000 | \n
Oradix StemDetox™ | \n5000 | \n3333 | \n
Survival shield X-2, Detoxadine® (nascent iodine) | \n1950 | \n1300 | \n
Dr. Mercola Iodine | \n1500, 500 | \n1000, 333 | \n
Life Extension® sea iodine | \n1000 | \n667 | \n
Commercially available nutritional supplements with iodine content exceeding the daily intake recommended by WHO (RDA—recommended daily allowances).
Iodinated contrast media (ICM) is given for computed tomography (CT), angiography, myelography, and arthrogram. The route of administration could be systemic as i.v, i.a., oral, rectal, and local. The pharmacokinetics of all currently available ICMs is similar. The half-life of ICM in normal renal function subjects is approximately 2 hours. Thus, approximately 20 hours are required for the total excretion of the administered ICM [31]. Referring to their iodine content and osmolarity, the contrast media are divided into ionic ICM with high osmolarity (1500–2000 mOsm/kg) or nonionic ICM with low and iso-osmolarity (600–1000 mOsm/kg). A list of iodinated contrast agents available in Romania and their molecular properties can be found in \nTable 2\n.
\nNonionic ICM | \nIodine content, mg/mL | \nOsmolarity | \n
---|---|---|
\n | \n||
Iobitridol | \n300, 350 | \nLow | \n
Iodixanol | \n270, 320 | \nLow | \n
Iohexol | \n240, 300, 350 | \nLow | \n
Iomeprol | \n300, 350, 400 | \nLow | \n
Iopamidol | \n300, 370 | \nLow | \n
Iopromide | \n300, 370 | \nLow | \n
Ioversol | \n240, 300, 320, 350 | \nLow | \n
\n | \n||
Ethiodized oil | \n480 | \n\n |
The iodine content of nonionic iodinated contrast media (ICM) and their molecular properties.
The safety profile of the systemic administered nonionic low- or iso-osmolar contrast currently in use is 5- to 10-fold better than the ionic high-osmolar agents [32, 33]. The ratio of iodine atoms to the number of contrast particles in low-osmolar solution is higher than compared with high osmolar ICM and hence have a greater concentration of iodine than the high osmolar [32]. In both low and high osmolar ICM, the iodine content is far greater than the recommended daily allowance. Patients generally are given 50 and 100 mL of contrast per CT scan; however, it is essential to know that not all CT scans require contrast media administration (see \nTable 3\n) [31, 33, 34, 35].
\nCT type | \nContrast indicated | \nContrast not indicated | \n
---|---|---|
Head | \nNeoplasm, meningitis, encephalitis, focal neurologic deficits, skull base disorders, orbital and vision disorders, pituitary imaging, complicated sinonasal disease, seizures, cerebral angiography | \nHead trauma, acute stroke, intracranial hemorrhage | \n
Cervical | \nCervical mass or lymphadenopathy, suspected tumor or infection, abnormalities of cranial nerves X, XI, and XII, brachial plexopathy | \nTrauma unless arterial injury is a possibility or the mechanism of injury is penetrating | \n
Cardiothoracic | \nHeart and thoracic vessels, trauma, staging primary thoracic neoplasms | \nCoronary calcium scoring, pulmonary parenchymal evaluation lymph node evaluation | \n
Abdominopelvic | \nVirtually all other gastrointestinal, hepatopancreaticobiliary, genitourinary, gynecologic indications | \nColonography, renal stone evaluation, extraparenchymal lymphoma | \n
Musculoskeletal | \nEvaluation of soft tissue masses and suspected septic arthritis or infected prostheses | \nExtremities and spine | \n
CT angiography | \nEvaluating the lumen of an artery, vein, or a pseudoaneurysm and to assess for end-organ ischemia outside the brain or lung to detect active bleeding | \nMonitoring a known aneurysm for growth or for detection of a hematoma | \n
Indications of contrast enhancement in CT imaging.
Higher doses of ICM may be required for invasive procedures such as cardiac catheterization. Typical doses for CT scans provide 2500–5000 μg of bioavailable free iodine and 15–37 g of total iodine [36]. Nonbioavailable iodine may be liberated to free iodide, particularly with increased half-times in the body (i.e., impaired kidney function) [35, 36]. After ICM administration, iodine deposits remain elevated for up to 4–8 weeks in patients with healthy thyroid. The urinary iodine excretion increased by 300–400% from baseline to peak levels after 1.1 week and normalized by 5.2 weeks following ICM administration [37].
\nAfter exposure to the iodine-containing contrast agent, the most rapid (hours to days) effect of pharmacologic doses of iodine is the Wolff-Chaikoff effect. The mechanism for this acute effect is partially explained by the generation of iodolactones, iodoaldehydes, and/or iodolipids, which inhibit thyroid peroxidase activity, necessary for thyroid hormone synthesis [37]. The decrease of thyroglobulin proteolysis resulting in reduced thyroid hormone secretion also may be contributing to the ICM-induced Wolff-Chaikoff effect. The diminished serum T4 and T3 concentrations temporarily increased the serum concentrations of TSH, in some cases above the normal range. The phenomenon is transient in euthyroid adult patients and does not typically determine permanent hypothyroidism [38].
\nICM use could lead to thyroid dysfunction, namely to hypo- and hyperthyroidism. Iodine excess-induced hypothyroidism appears when the thyroid fails to escape from the acute Wolff-Chaikoff effect. It occurs in patients with a wide variety of underlying thyroid abnormalities, including Hashimoto’s thyroiditis, previously treated Graves’ disease, history of thyroid lobectomy, postpartum lymphocytic thyroiditis, interferon therapy, or type 2 amiodarone-induced thyrotoxicosis [12, 39, 40]. Not only the previous thyroid disorder but also the age of the patients is a contributing factor in hypothyroidism development. A systematic review evidenced that hospitalized neonates, especially premature infants exposed to iodinated contrast media, are at increased risk for development of hypothyroidism [41]. It could be hypothesized that hypothyroidism in this case to be partially secondary to an immature thyroid gland and an exaggerated Wolff-Chaikoff effect. Older age patients are also at high risk of developing hypothyroidism after ICM exposure, as reported in a study including the Asian population [42].
\nPatients with one exposure to ICM showed the highest risk of thyroid dysfunction compared with non-ICM exposure and a correlation was still found between the frequency of ICM exposure and the risk of hypothyroidism [42]. Conflicting data appear regarding to the time of onset of hypothyroidism after ICM administration: Rhee et al. [43] showed that the median time interval until the occurrence of hypothyroidism was 1 year, but Kornelius et al. [42] reported that hypothyroidism may develop 2.1 years after ICM exposure.
\nICM-induced hyperthyroidism rarely occurs in individuals without prior thyroid dysfunction. Previously existent thyroid diseases, such as nodular goiter, Graves’ disease, and long-standing iodine deficiency followed by thyroid autonomy, were reported to be associated with a higher risk of hyperthyroidism after ICM exposure [4, 13, 24, 36, 42]. The mechanism of ICM-induced hyperthyroidism involves impairment of the acute Wolff-Chaikoff effect due to rapid iodine excess and influx into the thyroid gland. Excess iodine intake will result in transient or permanent hyperthyroidism [13, 24, 42]. Kornelius et al. [42] found in their study a 22% increased risk of hyperthyroidism after ICM administration. Older patients (between 20 and 60 years) presented a more than twofold increased risk of hyperthyroidism compared with younger patients (less than 20 years old). The number of ICM exposures did not increase the risk of hyperthyroidism. It could be hypothesized that the “stunning effect” plays a certain role in hyperthyroidism, involving a diminished absorption of excess iodine in patients with repeated iodine exposure.
\nAmiodarone is a class III antiarrhythmic agent, having short- and long-term actions on multiple molecular levels [44]. Its molecular structure resembles T3. However, amiodarone can alter thyroid function (inducing both hypo- and hyperthyroidism), which is due to amiodarone’s high iodine content and its direct toxic effect on the thyroid follicle cells. Amiodarone is a benzofuran derivative with great lipophilicity, which is extensively distributed in adipose tissue, cardiac and skeletal muscle, liver, lung, and the thyroid. During its liver metabolization, approximately 6 mg of inorganic iodine per 200 mg of amiodarone ingested is released into the systemic circulation [45]. The average iodine content in Romanian diet is approximately 50–75 μg/day [3, 46, 47]. Thus, 6 mg of iodine markedly increases the daily iodine load. Amiodarone elimination from the body occurs with a half-life of approximately 55–100 days. The long half-life of both amiodarone and his active metabolite, DEA, contributes to his toxicity. For a therapeutic effect, a plasma concentration between 0.5 and 2.5 μg/mL is required; however, serum levels do not correlate well with efficacy or with adverse effects [45, 48, 49, 50].
\nThe effects of amiodarone on thyroid function can be divided into those effects that are due to iodine and those effects that are intrinsic properties of the drug.
\nAfter chronic amiodarone administration, the thyroid dysfunctions may occur in 5–22% of the patients. Risk factors for the development of thyroid disease include not only treatment duration and cumulative amiodarone dose but also age, gender, pre-existing thyroid pathology, and associated nonthyroid conditions [51, 52, 53]. The normal autoregulation process of thyroid prevents normal individuals from becoming hyperthyroid after exposure to the high iodine content substances. When intrathyroidal iodine concentrations reach a critically high level, iodine transport and thyroid hormone synthesis are transiently inhibited until intrathyroidal iodine stores return to physiological levels (see the Wolff-Chaikoff effect). Patients with underlying thyroid pathology, however, have defects in autoregulation of iodine: for example, in autoimmune thyroid disease exists a “fail to escape” from the Wolff-Chaikoff effect. The result is the development of goiter and hypothyroidism in Hashimoto’s disease. Patients with areas of autonomous function within a nodular goiter do not autoregulate iodine and the addition of more substrate may result in excessive thyroid hormone synthesis and thyrotoxicosis (see Iod-Basedow) [13, 54, 55].
\nAmiodarone inhibits peripheral deiodinase (outer ring 5′-monodeiodination of T4), thus decreasing T3 production and increasing T4 level; reverse T3 (rT3) accumulates since it is not metabolized to T2 [4, 56, 57]; amiodarone and, particularly, the metabolite DEA block T3-receptor binding to nuclear receptors [58] and decrease the expression of some thyroid hormone-related genes [59]; amiodarone may have a direct cytotoxic effect on thyroid follicular structures, which results in a destructive thyroiditis [60]. Martino et al. described marked distortion of thyroid follicle architecture, necrosis, apoptosis, inclusion bodies, lipofuscinogenesis, markedly dilated endoplasmic reticulum, and macrophage infiltration after amiodarone [19]. The role of the pre-existing autoimmune process is widely debated, due to the conflicting results of the retrospective study data [17, 18, 55]. Even if amiodarone does not induce de novo autoimmune thyroid disease, by the direct cytotoxic effect, it may cause the release of pre-existing autoantibodies and thus worsen destructive thyroiditis. In a study [61], it was described that in women the prolonged amiodarone treatment (for over 2 years) increased the antithyroid peroxidase titer.
\nPredisposing factors for amiodarone-induced thyrotoxicosis include environmental factors such as dietary iodine (deficiency), as well as intrinsic factors such as pre-existing thyroid pathology. Depending on these factors, a great variability exists regarding the incidence of amiodarone-induced thyroid dysfunction ranges (5–22%) [51, 52, 62, 63].
\nDietary iodine intake affects an individual’s risk of amiodarone-induced thyroid dysfunction: in iodine-deficient areas, amiodarone-induced thyrotoxicosis (AIT) appears to be more common than hypothyroidism [64], whereas in iodine-sufficient areas, amiodarone-induced hypothyroidism is more common than hyperthyroidism [19]. The incidence of reported AIT in different studies varies but remains within the range of 5–10% in most studies [51, 52, 63]. As was reported in a previous study from the UK, AIT appears more frequently in men than in women [65], but the time of onset of AIT is unpredictable. It can occur at almost any time throughout the course of amiodarone treatment and last for as long as 6–9 months after treatment withdrawal, almost certainly because of the drug’s long half-life and associated iodine load [66]. One study illustrates the importance of the underlying thyroid status near the dietary iodine intake in relation to the risk of developing amiodarone-induced thyroid dysfunction. In Worcester, Massachusetts, an area with iodine sufficiency and a high prevalence of autoimmune thyroid disease, amiodarone was associated with a 2% rate of hyperthyroidism. In contrast, in Pisa, Italy, an area of borderline iodine intake and a high prevalence of nodular goiter, amiodarone was associated with 9.6% rate of hyperthyroidism [67].
\nThe clinical effects of amiodarone on thyroid function in any individual are dependent upon the underlying status of that individual’s thyroid gland. In euthyroid individuals receiving amiodarone, acute changes in thyroid function tests include [68, 69]:
Serum total T4 and free T4 concentrations rise by 20–40% during the first month of therapy.
Serum T3 concentrations decrease by up to 30% within the first few weeks of therapy.
Serum rT3 concentrations increase by 20% soon after the initiation of therapy.
Serum TSH concentration usually rises slightly after the initiation of treatment and may exceed the upper limit of normal.
After 3–6 months of therapy, a steady state is reached in most patients who were euthyroid at baseline:
Serum TSH concentration normalizes.
Serum total T4, free T4, and rT3 concentrations remain slightly elevated or in the upper normal range.
Serum T3 concentrations remain in the low normal range.
Amiodarone may also cause destructive thyroiditis with transient thyrotoxicosis followed by hypothyroidism in patients without underlying thyroid disease [60].
\nAbnormal thyroid process: in patients with underlying multinodular goiter or latent Graves’ disease, hyperthyroidism (increased synthesis of T4 and T3) may occur. The excess iodine from the amiodarone provides increased substrate, resulting in enhanced thyroid hormone production.
\nThree types of AIT can be distinguished. In type 1 AIT, thyroid hormone synthesis is increased, whereas in type 2 there is an excess release of T4 and T3 from the preformed thyroid hormones, due to destructive thyroiditis. Type 3 AIT is a mixed form, existing an overlapping condition between type 1 and type 2 AIT. These types differ in their pathogenesis, clinical or paraclinical signs, and management [63].
\nThe risk of either type increases with higher cumulative doses or reintroduction of amiodarone [53, 70].
\nThe distribution of AIT by type (1 or 2) varies by geographical region. This is thought to be primarily due to differences in dietary iodine intake. In iodine-deficient regions, as some geographical zones were in Romania before universal salt iodization [3], AIT occurs in approximately 10–12% of patients with type 1 AIT usually predominating [64, 67]. However, the distribution of cases by type may be changing, as illustrated in a report of 215 consecutive patients with AIT seen at a single institution in Italy over 26 years [71]. In 1980 compared with 2006, 2 of 6 (40%) versus 12 of 14 (86%) of new AIT cases were type 2. Possible explanations for this observation include improved dietary iodine intake in the region and the avoidance of amiodarone use in case of previously diagnosed thyroid disease. Our unpublished data from a study conducted in a single institute (Endocrinology Clinic, Târgu Mureș, Romania) in two different periods, which included 5 years, similarly show a moderate increase of type 2 AIT after the introduction of universal salt iodization (governmental decision no. 586/5 June 2002; see \nTable 4\n).
\nStudy period | \nType 1 AIT/total patients | \nType 2 AIT/total patients | \nType 3 AIT/total patients | \n
---|---|---|---|
1994–1998 | \n4/7 (57%) | \n1/7 (14%) | \n2/7 (29%) | \n
2001–2005 | \n17/38 (45%) | \n9/38(24%) | \n12/38 (31%) | \n
Distribution of AIT types in patients of the Endocrinology Clinic, Târgu Mureș, Romania, in two study periods (1994–1998 and 2001–2005).
Clinical signs of AIT are classical thyrotoxicosis symptoms such as unexplained weight loss, proximal myopathy, restlessness, heat intolerance, low-grade fever, or exacerbation of tachyarrhythmia, heart failure, or angina pectoris; however, the adrenergic manifestations of amiodarone-induced hyperthyroidism are often masked because its distinct antiadrenergic properties and impairment of conversion of T4 to T3 [68, 72]. Patients with amiodarone-induced hyperthyroidism have a threefold higher rate of major adverse cardiovascular events (mostly ventricular arrhythmias) compared with euthyroid controls [73]. The presence of severe left ventricular dysfunction, especially in older patients with AIT, may be associated with increased mortality [74].
\nDifferentiating the two types of AIT is critical since therapy differs. However, the distinction may be difficult using clinical criteria, partly because some patients may have a mixture of both mechanisms, presenting the type 3 (type 1 + type 2) AIT. Thyroid function tests (TSH, T4 and T3 plasma levels) do not help to distinguish type 1 AIT (hyperthyroidism) from type 2 AIT (transient thyrotoxicosis).
\nType 1 AIT appears usually early after amiodarone introduction (3–20 months after exposure) [19, 66, 71]. It is characterized by hyperfunctional thyroid tissue with elevated blood flow on color Doppler [75, 76]. Furthermore, the enlarged or nodular thyroid tissue fixes either on 24-hour 123I-scan or on 99 mTc-SestaMIBI radio isotope scan despite the daily ingestion of 6 mg or more bioavailable iodine [77, 78].
\nType 2 AIT is a destructive thyroiditis which onset time is after 20–30 months of amiodarone introduction. It appears in patients with apparently normal thyroid morphology and is due to the massive release of thyroid hormones. The mechanism is similar to that of subacute thyroiditis, but the thyrotoxicosis is usually less severe and could spontaneously resolve in some cases [79]. The features of the two types of AIT are presented in \nTable 5\n.
\n\n | Type 1 AIT | \nType 2 AIT | \n
---|---|---|
Pre-existing thyroid disease | \nYes | \nNo | \n
Pathophysiology | \nIodine overload | \nDestruction/inflammation | \n
Ultrasound findings | \nGoiter/nodule(s) | \nNormal | \n
Color flow Doppler | \nIncreased or vascularity | \nReduced or absent vascularity | \n
Radio iodine uptake (I123-Scan)/SestaMIBI-Scan | \nNormal or increased | \nAbsent | \n
Characteristics of type 1 and type 2 amiodarone-induced thyrotoxicosis (AIT—amiodarone-induced thyrotoxicosis).
However, interpretations of color flow Doppler sonogram in amiodarone-associated hyperthyroidism require an experienced sonographer, and other markers for differential diagnosis were also sought. In two studies, serum interleukin-6 concentrations were higher in patients with type 2 AIT [80, 81]. In a third study, interleukin-6 concentrations were not useful for distinguishing type 1 from type 2 AIT [76].
\nPreventing therapy for iodine-induced hyperthyroidism is not generally recommended. However, older patients with known multinodular goiter and/or subclinical hyperthyroidism should be told of the risk for iodine-induced hyperthyroidism, and alternatives to contrast-enhanced CT scanning should be considered when appropriate (e.g., noncontrast CT, magnetic resonance imaging). Iodine-induced hyperthyroidism is particularly important in geriatric patients for several reasons: (1) the prevalence of thyroid nodular disease is higher in older patients than in younger patients, (2) the hyperthyroidism may be more difficult to detect clinically, (3) apathetic hyperthyroidism often being present, and (4) older adults more often have underlying heart disease [21]. In high-risk patients (older, history of multinodular goiter with autonomy), treatment with a thioamide or perchlorate prior to the administration of an iodine load may blunt or prevent the induction of hyperthyroidism [82, 83]. However, there are insufficient randomized trial data to support the use of thioamides or perchlorate. Routine measurement of thyroid function tests (TSH, and if low, free T4 and T3) in older patients after exposure to iodinated radiographic contrast agents is favored by some experts, particularly since the symptoms of hyperthyroidism in older adults may be atypical [84, 85, 86].
\nIodine-induced hyperthyroidism (iodine content supplements and dietary nutrients, ICM, type 1 AIT) is usually self-limited (lasting 1–18 months) if the source of iodine is discontinued. The American Thyroid Association (ATA) [87] and European Thyroid Association (ETA) recommendations [40] as initial therapy for patients with iodine-induced hyperthyroidism are discontinuation of iodine (except for amiodarone, which could be continued in type 2 AIT), avoidance of further exposure, and administration of a beta-adrenergic antagonist drug (assuming there are no contraindications to its use) to minimize the manifestations of the overactive thyroid. Thyroid tests (TSH, free T4, total T3) should be measured initially at 4- to 6-week interval and then less frequently (TSH and free T4 every 3 months) depending upon the results of prior testing. Beta blockers can be tapered and discontinued after thyroid tests return to normal.
\nDue to the lack of sufficient evidence, there is no consensus regarding the decision to continue or stop amiodarone in patients with type 1 AIT. The decision should be individualized taking into account the risks of patients and taken jointly by cardiologists and endocrinologist [40]. Amiodarone should be continued in critically ill patients with life-threatening cardiac disorders [88]. When deciding whether to discontinue amiodarone, the following should be considered: amiodarone may be necessary to control a life-threatening arrhythmia; since the half-life of elimination from the body is prolonged, there is no immediate benefit to stopping amiodarone; amiodarone appears to ameliorate hyperthyroidism by blocking T4 to T3 conversion, beta-adrenergic receptors, and possibly T3 receptors. Stopping amiodarone might actually exacerbate hyperthyroid symptoms and signs.
\nIn case of amiodarone withdrawal, after the restoration of euthyroidism and normalization of urinary iodine excretion (generally 6–12 months), radioactive iodine (RAI) therapy can be performed. Recombinant human TSH (rhTSH) administration increases the sensibility of the thyroid gland to RAI therapy. If RAI administration is contraindicated, total thyroidectomy should be considered for definitive treatment of the underlying thyroid disease [40]. In the absence of the thyroid gland, amiodarone reintroduction, when necessary, could be safe. In the case of the thyroid gland is conserved, the recurrence rate of type 1 AIT after amiodarone reintroduction is 9% [89]. As ETA suggested, emergency thyroidectomy in severe cardiac patients may be required not only in type 1 but also in all types of AIT. Prior to thyroid surgery, plasmapheresis is able to remove the excess of thyroid hormones [40]. It was reported in a study, including seven patients with AIT, that iopanoic acid short-course administration prior surgery permitted a safe and uneventful thyroidectomy [90].
\nThioamides (thiamazole, carbimazole, propylthiouracil) are effective in older patients with underlying heart disease having severe and prolonged (>1 month) hyperthyroid symptoms, except the emergency situations. All thioamides are blocking thyroid hormones synthesis, propylthiouracil having an additional inhibiting effect on T4–T3 transformation. ATA recommended, the starting dose of thiamazole, to be 10–20 mg once daily because of its long duration of action, allowing for once-daily dosing, more rapid efficacy, and lower incidence of side effects [87]. ETA recommended very high daily doses of the drug (40–60 mg/day of thiamazole) for a more extended time, considering that in type 1 AIT the iodine-enriched thyroid gland of patients is less responsive to thioamides [40]. Carbimazole, the prodrug of thiamazole, is an alternative choice of treatment, available in some European countries, but not in Romania. Due to the teratogenicity of thiamazole, propylthiouracil (not currently available in Romania) can be used in the first trimester of pregnancy [68]. To increase the sensitivity and response of the thyroid gland to thioamides, potassium or sodium perchlorate (not available in Romania) has been used. Perchlorate reduces thyroid iodine uptake by sodium/iodide symporter inhibiting action and discharge iodine from the thyroid, but toxic effects are limiting its use. To minimize the nephro- and medullotoxicity of the drug, doses not exceeding 4 × 250 mg/day and a shorter period than 4–6 weeks were used [40, 87, 91]. Thyroid function should be assessed after 4 weeks by measurement of serum TSH, free T4, and T3. The dose of thiamazole is then tapered with the goal of maintaining a euthyroid state. Thereafter, thyroid function tests (TSH, free T4) should be measured every 3 months. Many patients with underlying autonomous nodular thyroid disease are able to taper and discontinue thiamazole within 6–12 months. In case of thioamide allergy, lithium is used to control the hyperthyroidism temporarily [91, 92], but it has a narrow therapeutic range, produces nephrotoxicity, and its efficacy is not well documented. Therefore, it is not recommended by ETA for the type 1 AIT treatment [40]. However, it was reported that lithium-associated rhTSH administration increases RAI sensibility of the thyroid follicles in AIT [93].
\nAfter resolution of the acute episode of iodine-induced hyperthyroidism, treatment of the underlying thyroid disease should be addressed. For patients with underlying Graves’ disease, treatment options include continuing thiamazole, radioiodine ablation, or surgery. Patients with underlying autonomous adenoma or multinodular goiter who return to euthyroidism after discontinuation of iodine do not necessarily require definitive treatment. However, these patients are at risk for recurrent hyperthyroidism if given iodine again.
\nType 2 AIT generally is self-limited and amiodarone is not necessary to discontinue. When the efficacy of non-thioamide type antithyroid drugs to restore euthyroid state was compared, the best results were obtained with 30 mg oral prednisone therapy. The rate of achievement of euthyroid state was 100% when glucocorticoids were used versus 71% obtained after perchlorate administration [94]. ETA recommendation, for this reason, is oral glucocorticoids as the first-line treatment for type 2 AIT. In patients in whom a mixed form of AIT is suspected, thioamides together with glucocorticoids should be given initially, or glucocorticoids should be added after a period of 4–6 weeks of inadequate response [40]. In addition, it must be noted that i.v. administration of glucocorticoids (hydrocortisone, dexamethasone) has crucial benefits (inhibiting T4 transformation to T3) in thyroid storm and preoperative management of any type of thyrotoxicosis [91]. It was reported that glucocorticoid therapy (oral prednisone) restored the normal thyroid function and shrink goiter, preventing surgery, in a patient diagnosed with iodine containing supplement-induced hyperthyroidism [95].
\nIodine, as an essential microelement of the human body, plays a very important role in thyroid physiology. Adequate intake is necessary to keep thyroid hormone synthesis at normal rate. Dietary intake and urinary excretion should be equivalent, but a remarkable adaptive capacity of the thyroid gland can compensate for excess intake on short term. However, existing thyroid disease (subclinical or overt) or specific risk factors may impair the patient’s response to high iodine exposure, which can result in hypothyroidism or hyperthyroidism. On the other hand, iodine excess may also be hardly recognizable because various sources (e.g. seafood, kelp, dairy products, iodized salt, iodized water, nutritional supplements, iodine containing contrast media, and drugs) can all contribute to iodine intake. Of these, iodine containing contrast media and drugs are administered only under controlled conditions but represent the most frequent cause of iodine-induced thyrotoxicosis. In general, preventive actions are not recommended, but screening for risk factors, such as elderly patients, persons with multinodular goiter, subclinical hyperthyroidism, or manifest hyperthyroidism should take place prior to iodine administration. Consequently, high-risk patients should benefit preventive treatment with thioamide or perchlorate. Amiodarone-induced thyrotoxicosis has remained a difficult task requiring a close collaboration between cardiology and endocrinology to overcome complications, but individualization of the therapy should be undertaken. Based on the specific features of thyrotoxicosis, thioamides, perchlorate, or high-dose glucocorticoids may be considered for an optimal therapeutic intervention. If contraindicated, radioiodine therapy may also be useful to treat amiodarone-induced thyrotoxicosis.
\nThe authors declare no conflict of interest.
AIT | amiodarone-induced thyrotoxicosis |
ATA | American Thyroid Association |
CT | computed tomography |
DEA | N-desethylamiodarone |
ETA | European Thyroid Association |
ICM | iodinated contrast media |
MUIC | median urinary iodine content |
RAI | radioactive iodine |
RDA | recommended daily allowances |
rhTSH | recombinant human thyroid stimulating hormone |
rT3 | reverse 3,3′,5′-triiodothyronine |
T3 | 3,5,3′-triiodothyronine |
T4 | thyroxine |
TSH | thyroid stimulating hormone |
WHO | World Health Organization |
Decontamination is a fundamental requirement for research facilities where pathogen elimination is critical, and laboratory facility managers routinely employ various methods of fumigation or fogging disinfection in the never-ending battle against contamination. Historically, technologies such as chlorine dioxide and formaldehyde gas systems have been applied in these areas for pathogen disinfection. Likewise, high concentration vaporized hydrogen peroxide has also been relied on to achieve similar outcomes. A large percentage of these methods follow a familiar pattern of solution injection, dwell (contact time), evacuation, and validation; however, not every system delivers the same functionality or efficacy. Differences in formula and design influence personnel hours, material compatibility, and risk management.
While effective, these high concentration solutions come with inherent risks to health and safety. A recent innovation significantly lowers the risk of exposure to high-concentration chemicals— an HHP™ system which combines a 7% hydrogen peroxide solution with a calibrated fogging device to deliver a mixture of gaseous and micro aerosolized particles. Studies performed with this technology demonstrate high level pathogen disinfection across a variety of tested viruses, bacteria, and substrates. This chapter will provide readers with a deeper understanding of essential components and considerations when implementing systems for viral decontamination. This chapter introduces the latest evolution in hydrogen peroxide disinfection of viral pathogens to address these challenges: an HHP system using patented Pulse™ technology.
A dichotomy of virology work is the need for both viral presence within the confines of research and the equally consistent need to establish pathogen-free research spaces. Throughout the world, contagious disease through viral contamination is an ever-present concern, and SARS-CoV-2 has brought the need to decontaminate to the forefront of virtually every industry. Scientific industries performing research, manufacturing pharmaceuticals, or providing healthcare services, all employ protocols for the disinfection of their environments in order for safe, successful, timely work to take place. These industries depend upon disinfection chemicals, and perhaps just as importantly the chemical delivery systems, that ensure the integrity of their work, personnel safety, and efficient transition from one research project or product type to the next.
Today, a number of distinct categories are used to classify and understand disinfection methods. Disinfection chemicals are tested with established protocols and classified according to their relative success at eliminating specific pathogens. The
Decontamination | The use of physical and/or chemical means to remove, inactivate, or destroy microbial pathogens (e.g., bloodborne or aerosolized) on a surface or item to the point where they are no longer capable of transmitting infectious particles and the item or surface is rendered safe to handle: however, this definition has been broadened by infection control specialists to include all pathogens and physical spaces (e.g., patient rooms, laboratories, buildings). |
Disinfectant | A substance, or mixture of substances, that destroys or irreversibly inactivates bacteria, fungi, and viruses, but not necessarily bacterial spores or prions, in the inanimate environment. |
Disinfection | A process that destroys pathogens and other microorganisms, except prions, by physical or chemical means. |
High-Level Disinfection | A lethaI process utilizing a sterilant under less than sterilizing conditions (e.g., 10–30 min contact time instead of 6–10 h needed for sterilization). The process kills all forms of microbiaI life except for large numbers of bacterial spores. |
lnactivation | A procedure to render a pathogen non-viable, viral nucleic acid sequences non-infectious, or a toxin non-toxic whiIe retaining characteristic(s) of interest for future use. Methods targeting tropism may be host-specific. |
Sterilization | A physical or chemical process that kills or inactivates all microbial life forms including highly resistant bacterial spores. |
Sterilant | A substance or mixture of substances that destroys or eliminates all forms of microbial life in the inanimate environment including all forms of vegetative bacteria, bacterial spores, fungi, fungal spores, and viruses. |
Validation | Establishment of the performance characteristics of a method and provision of objective evidence that the performance requirements for a specified intended use are fulfilled. |
Aerosol | Particulate matter, solid or liquid, larger than a molecule but small enough to remain suspended in the atmosphere [4]. |
Gas | A substance or matter in a state in which it will expand freely to fill the whole of a container, having no fixed shape (unlike a solid) and no fixed volume (unlike a liquid) [5]. |
Hybrid H2O2 | A mixture of gaseous and micro aerosolized substance which remain suspended in the air to fill the whole container [6] |
Vapor | A substance diffused or suspended in the air, especially one normally Iiquid or solid [7]. |
One growing understanding is that the application method of a disinfectant plays a critical role in the success of the disinfection results. While some of the most common spray and wipe surface disinfectants have been in use for decades, there are challenges to their application which can result in inconsistent or ineffective results. Adequate distribution and required contact time are difficult to achieve on a consistent basis by hand application methods, especially in large spaces with high ceilings and complex surface profiles. These accessibility issues and failures may result in inconsistent and incomplete elimination of surface contamination [13]. To address inherent inconsistencies in manual disinfection and to provide alternative methods of delivery, various technologies have been applied. Those technologies include fumigation with formaldehyde, chlorine dioxide gas, fogging of hydrogen peroxide as vapor, silver hydrogen peroxide systems, and hybrid hydrogen peroxide systems. Their gaseous and vaporous form allows access to, and contact with, surfaces that spray and wipe methods alone often cannot access. Automated systems have taken these chemicals with known disinfectant action and paired them with dispersion devices, aiming to deliver an appropriate contact time and maximize surface exposure. These systems automate much of the disinfection process, helping to remove human error and mitigate safety concerns from contact with potentially caustic chemicals. In particular, H2O2-based systems have become a front-runner among automated high-level disinfection technologies due to H2O2’s effectiveness, material compatibilities, lack of chemical residues, and increased safety over other technologies such as formaldehyde or chlorine dioxide gas [14, 15, 16, 17, 18]. When applied in multiple life science environments, H2O2 fogging is well documented to have efficacy against numerous viral pathogens and has seen a rise in use in environments where thorough efficacy and decontamination of a room and its contents are needed [19, 20, 21, 22].
Anyone who has skinned their knee and poured hydrogen peroxide on the wound to stave off infection is familiar with the use of H2O2 as an antiseptic and anti-bacterial agent. Indeed, hydrogen peroxide is produced naturally in the body, acting as a beacon triggering the accumulation of white blood cells of the immune response [23]. Hydrogen Peroxide was first discovered in 1818 by Louis Jacque Theénard, who described it as ‘eau oxygénéé or water oxygen for its composition containing one more oxygen atom than water [24]. This single oxygen–oxygen or peroxide bond is naturally unstable and prone to decomposition with or without the presence of a catalyst [25]. During decomposition, the active oxygen atom cleaves off, releasing energy and resulting in water and oxygen molecules [26]. The oxidizing activity, resulting from the presence of the extra oxygen atom, is what makes hydrogen peroxide an effective disinfectant. It is the reactive formulation of hydrogen peroxide which causes destruction of pathogens by breaking apart structures, interrupting key functions, causing damage to DNA, and eliminating infectious particles.
One of the biggest challenges to any disinfectant application is ensuring a thorough and consistent disinfectant exposure to contaminated surfaces for an effective contact time. To achieve success, fogging technologies must perform a complicated dance between the amount of chemical injected, temperature, humidity, dew point, and method, all of which can affect efficacy from one application to the next. To answer this need, CURIS System designed and patented the concept of replenishing any naturally decomposing solution and called it Pulse technology, simplifying the complicated balance of a successful disinfection. Combining a 7% hydrogen peroxide solution with a calibrated fogging device, this HHP system delivers hybrid hydrogen peroxide, a mixture of gaseous and micro aerosol particles. While effective in a liquid solution, fogging with hydrogen peroxide in this hybrid form increases the availability of each H2O2 molecule, maximizing oxidation opportunities and leading to the destruction of pathogens on surfaces. Beyond just inactivating pathogens, this oxidation causes a physical destructive action of pathogen components, which further delineates this substance as a decontaminant as defined by the BMBL.
A fundamental distinction of this system is its ability to disperse a lower concentration of 7% hydrogen peroxide at calibrated intervals, maximizing contact time while using less H2O2 to achieve microbicidal efficacy. The HHP device operates by delivering the HHP mixture in a two-part process. First, it fills an enclosure with disinfecting fog to an optimal level for killing pathogens. Second, it maintains the fog at the optimal level without oversaturation by periodically injecting more solution into the space being treated, and thereby prolonging the active contact time of the H2O2 (Figure 1). This not only helps to keep surfaces dry, it also reduces sensitivity to variations in temperature and other factors. One might consider this similar to cruise control in a vehicle—the initial phase continuously revs the engine to get the vehicle up to speed, while the second phase uses the engine just enough to keep it at the cruising speed without exceeding the limit. In the case of disinfection, it means keeping the fog concentration at the optimum “kill” level to achieve efficacy in a relatively short time, yet without exceeding this optimum level to the point where the fog condenses on surfaces in the treatment area.
With a concentration of 7% H2O2, the solution, known as CURoxide™, is below the 8% hazard threshold [27, 28]. Being below the threshold means special shipping considerations are not required. Moreover, this enables safer handling for personnel than the 35–59% H2O2 solutions traditionally employed for fogging applications [18, 29, 30, 31]. Likewise, the 7% solution is safer for laboratory materials than the 28.1–52% concentration of corrosive industrial strength grade hydrogen peroxide [27, 32]. This material safety (compatibility) is perhaps most evident when considering how the hydrogen peroxide concentration of a solution will evolve when the solution transitions through states of matter. Hydrogen peroxide is more resistant to leaving the liquid state and more likely to return to it than the water in the solution. When transitioning from vapor back into liquid, this can result in surface condensation at more than double the initial liquid concentration (Figure 2). At 7% H2O2, the HHP solution remains below the 45% known level of material incompatibility [33].
The levels of particle concentration used in typical high-level disinfection are of particular concern to facility managers. These concerns may be lessened by employing lower particle-producing products. Technologies utilizing formaldehyde, chlorine dioxide, and high concentration H2O2 operate at concentrations as high as 1,400 parts per million (ppm) [34, 35, 36]. By contrast, the HHP 7% solution has a lower operating concentration of approximately 138 ppm [37]. Traditional vaporized approaches require a concentration that is up to 10× higher than the lower 7% H2O2 concentration enables, which accordingly may result in a greater risk to personnel from leakage with typical high concentration systems [38]. This is particularly important because, according to the National Library of Medicine, “Inhalation of vapors from concentrated (greater than 10%) solutions may result in severe pulmonary irritation” [39]. This may be why there is a substantial safety concern among facility managers when it comes to typical fogging approaches, as these approaches utilize caustic chemicals at very high concentrations which are known to penetrate through gaps as small as a keyhole [38, 40].
Roughly the size of a small suitcase, the 36-pound (16 kg) HHP system fogs enclosures from an adjustable stainless-steel nozzle at the top of the unit. It can be wheeled or carried throughout a facility to disinfect a wide variety of spaces, large or small, and its Rotomold design provides durability for long-term use and sturdiness during transport. A push-button design allows users to input area dimensions through the device’s manual digital interface, or users may operate the device remotely via a tablet for touchless disinfection from outside the treatment space. The system self-calculates the cubic footage of the space to be fogged to determine the amount of disinfectant needed, and an indicator light shows users when the appropriate amount of solution has been added to the reservoir. An electronically sequenced A/C electrical outlet provides optional connection for any desired additional equipment.
In a world where everything is documented to defend, reinforce, train, and track information, technologies with the ability to employ these methods are invaluable to present and future decontamination applications. The HHP system incorporates patented smart technology, allowing operation not only from a device interface but also remotely through its control app for phones and tablets (Figure 3). For larger spaces, multiple devices may simultaneously work together via wireless communication to combine their capacities to fill the larger volume without the added complications of cables. Whether used alone or in a network, the fogging device(s) self-calculates the dosage required for a space once dimensions are provided. For each disinfection cycle, a job report is wirelessly generated and saved into a secure data system, providing the facility with trackable records in support of risk management protocols. On-demand training, reference materials, and technical support are also available through this secure data storage system, which includes security codes, usernames, and password protection against unauthorized operation and modifications. These smart technology components give laboratory personnel the ability to remotely operate and monitor the system, lessening concerns affiliated with exposure to high concentrations of H2O2.
The HHP device offers the ability to decontaminate enclosed spaces as large as 14,000 ft3 (396 m3) by itself or wirelessly pair up to 25 devices together to treat spaces as large as 350,000 ft3 (9,911 m3) at once. Although the EPA approvals are for 3,682 ft3 (103 m3) due to the size limitation of the testing laboratory, efficacy of bacterial spores are documented in much larger spaces [41]. The small, compact design also reaches tall ceilings efficaciously, as noted in studies where 6-log10 reductions of
Since many life science facilities are made up of diversely sized spaces and needs, the next generation of Pulse technology device was developed. Retaining the core fogging unit’s design, the new attachment model offers the ability to fog, hand spray, or port in, all from the same unit. This fogging model can disinfect large open spaces with a hand sprayer (with proper personal protective equipment). The device can also port into enclosed spaces, such as labs or mobile equipment, with extension nozzles, or it can connect to various enclosures found within laboratories.
To enable decontamination of small enclosures, the HHP system pairs with a mobile cart designed to attach to biological safety cabinets, isolators, incubators, filters, and filter housings (Figure 4a) [42]. This modular pairing delivers low concentration H2O2 solution to the closed system environment, extracts vapor once decontamination has been achieved, and conditions the space to return it to its normal operating environment. No disassembly of lab equipment is required. The system achieves decontamination of the entire chamber, including filters, and contents. The rolling cart weighs approximately 50 pounds (22 kg) and includes a pullout tray to house the HHP fogging device. For scalable applications, the fogging device can fog a whole laboratory or be coupled to the mobile cart as needed for smaller enclosures.
The HHP system also enables integration with a laboratory or stand-alone chamber. This modular design allows for custom installation into facilities—including integrated nozzles and touchscreen operation—to provide decontamination to these essential spaces (Figure 4b). For facilities requiring unified operation of environmental or electronic controls, the HHP system works in tandem with smart integration technology to provide remote operation, automation, and mounted disinfection for one or more enclosed spaces at a time. Decontamination chamber or washer integration includes cycles of less than 120 minutes, including aeration. This chamber integration enables users to operate the entire chamber from one common point, the display screen. It is suitable for coupling with chambers from a variety of manufacturers.
During the 2020–2021 COVID-19 pandemic, the HHP system was approved by the EPA for use against SARS-CoV-2 through the Emerging Viral Pathogen designation due to its sporicidal efficacy [37]. As a result, the HHP system was used in many different environments as a tool for mitigating risk to personnel, research, and equipment. Healthcare facilities faced with shortages of personal protective equipment (PPE) employed the system to decontaminate and safely reuse PPE until the supply could be reestablished. Life science facilities incorporated the HHP system for decontaminating manufacturing spaces where vaccine work was taking place. The HHP system was also instrumental in multiple military applications, significantly aided by the portable design and accessible use. Some prior and ongoing uses include disinfection of manufacturing facilities with a need for sterilization, sterile processing facilities, drug manufacturing facilities, vivariums, laboratory contents, laboratories with interstitial spaces, laboratory filter housings, compounding pharmacies, surgical suites, healthcare patient rooms, ambulances, equipment for service providers, biological safety cabinets, isolator filters, and gnotobiotics.
Studies performed with Pulse technology demonstrate high-level pathogen disinfection across a variety of tested viruses, bacteria, and bacterial spores. The data presented here include a mixture of peer-reviewed studies, Good Laboratory Practice (GLP)-regulated testing, and real-world applications where disinfection can be further complicated by condition-dependent factors such as biofilms, soil loads, and surface type (porous/non-porous), all of which can protect and harbor infectious pathogens [13, 43]. Across the body of this work, the target of high-level disinfection is not only to reduce the present contamination, but to reduce it sufficiently to prevent an infectious dose or the potential for colony regrowth. The work presented here demonstrates the HHP system’s ability to decontaminate, destroying microbial pathogens. This complete decontamination is critical as any surviving pathogens have the potential to interfere with or invalidate research, contaminate sterile products, and cause health hazards.
When targeting pathogens invisible to the eye, there must be some way to measure the efficacy of disinfection. Employing validation tools gives the ability to verify a disinfection process using living organisms and giving results rooted in science. Though several types of chemical and pH indicators exist, indicators of
Recognizing a disinfectant’s ability to kill less susceptible pathogens as an indicator of broader effectiveness, the EPA offers a variety of specific designations a chemical or system can claim. In 2018, the HHP system was approved for sporicidal classification by the EPA for a 6-log10 reduction of
Norovirus, a single stranded non-enveloped virus of the Caliciviridae family, is a leading cause of acute gastroenteritis in humans. The most common genogroup GII is responsible for 95% of infections, which can have severe and even fatal outcomes in at-risk populations such as young children or the elderly. Norovirus, once present, can become a pervasive problem due to the environmental stability of the virus, low infectious dose, resistance to alcohol and chlorine-based disinfectants, and the potential for prolonged asymptomatic shedding of infected individuals. Norovirus is also used as a target organism for testing, as it is considered to be a non-enveloped virus with relatively low susceptibility to disinfectants [48].
In 2018, a 1,600-bed assisted living facility had a norovirus outbreak affecting 1/4 of the residents within a 2-week period with an average of 40 new cases a day, despite protective measures such as the quarantine of afflicted individuals. A bio-decontamination company employing HHP technology was brought into the facility for outbreak response and control. HHP fogging was implemented as part of a 5-point process including continued quarantine and enhanced staff education. After a four-day implementation period, no new cases were reported, effectively ending the outbreak [49].
The HHP system was also tested under GLP conditions for efficacy against the norovirus testing surrogate feline calicivirus [20]. In this testing, 21 inoculated glass agar carrier plates were placed throughout the test room, ranging from floor level to 12 feet (3.6 m) in height, and exposed to the HHP fogging protocols. There was no recovered virus from the challenged plates for an overall reduction of 7.6 log10 (Table 1). Interestingly, efficacious results were also noted in GLP compliant testing when a carrier plate lid was accidentally left on during the HHP fogging cycle. This protocol deviation allowed for the observation that, even under these challenging conditions, the HHP fog migrated underneath the lid and achieved inactivation of viral particles [20].
HHP Efficacy | ||||
---|---|---|---|---|
Pathogen [reference] | Characteristics | Strain/Source | Carrier Type | Results |
Gram-positive, rod-shaped, endospore formation | 19615 | Dacron suture loop Porcelain Penicylinders (50% Tyvek/Tyvek) | 75 of 77 carriers negative 5.2 log10 reduction (Penicylinder) 6.2 log10 reduction (suture) | |
Gram-positive, rod-shaped, endospore formation | 3584 | Dacron suture loop Porcelain Penicylinders (50% Tyvek/Tyvek) | 73 of 74 carriers negative 6.1 log10 reduction (Penicylinder) 6.3 log10 reduction (suture) | |
Gram-positive, rod-shaped, endospore formation | ATCC 7953 | Tyvek/Tyvek stainless steel coupon | 206 carriers negative 6.2 log10 reduction | |
Gram-positive, rod-shaped, endospore formation | ATCC 43598 | Stainless Steel Disk | 90 carriers negative 6.6 log10 reduction | |
Enveloped, icosahedral | phi 6 | Porous N95 Mask | 36 of 37 ≥ 6.0 log10 reduction* | |
Non-enveloped, icosahedral | Unknown | Wild type | 100% reduction of cases | |
Non-enveloped, icosahedral | Strain F-9, ATCC VF-782 | Glass Petri Dish | 40 of 40 plates ≥7.58 log10 reduction | |
Enveloped, icosahedral | Strain F | Porous N95 Mask | 64 of 65 ≥ 5 log10 reduction* | |
Non-enveloped (naked), icosahedral | Strain B3 | Porous N95 Mask | 6o of 63 ≥ 4.3 log10 reduction* | |
Enveloped, no icosahedral capsid | Isolate USA-WA1/2020 | Porous N95 Mask | 48 of 48 reduced below LOD |
The combination of these two studies demonstrates that the HHP system effectively disinfects complex spaces contaminated with norovirus or its surrogates in both laboratory and real-world conditions. Though the assisted living facility case study did not measure a numerical reduction of viral burden, the effective outbreak control of 100% reduction in new cases leads to the conclusion that norovirus was reduced to levels less than the infectious dose.
In the spring/summer of 2020, the COVID-19 pandemic triggered a scarcity, and subsequent shortage of personal protective equipment (PPE) used by hospitals and other healthcare facilities. In an attempt to find ways to mitigate this emergency, researchers at Pennsylvania State University (Penn State) employed HHP to disinfect expired N95 respirators to assess the applicability of the HHP system for this use. Respirators were tested both for any physical degradation effects of the treatment on the respirator material and for efficacy of disinfection of respirator components via inoculation with three viral pathogens and one bacteriophage. Viral work performed at the Eva J Pell Biosafety Level 3 laboratory at Penn State used viruses of different characteristics, as well as a bacteriophage, to represent the range of physical characteristics of pathogens to which healthcare workers may be exposed (Table 1) [19]. Three viruses: herpes simplex virus (HSV-1; enveloped virus; family Herpesviridae), coxsackievirus (CVB3; non-enveloped virus; family Picornaviridae), and SARS-CoV-2 (isolate USA-WA1/2020; enveloped virus; family Coronaviridae), as well as pseudomonas bacteriophage (phi6; enveloped), were chosen for testing (Figure 6). The inside, outside, and strap materials of the respirators were used as inoculation sites. While the majority of these surfaces are made up of porous materials, at least one type of respirator had an outer layer of hydrophobic material which caused the inoculation droplet to dry into a ‘coffee ring’ pattern on the respirator. This testing of porous materials is significant because it presents a more difficult challenge to disinfection than non-porous surfaces, since the materials which absorb the pathogen may also provide a degree of protection, at least temporarily [51]. Disinfectant efficacy testing is commonly done on non-porous surfaces, which does not reflect the difficulty and variables that porous surfaces present.
Testing performed at Penn State also included the use of biological indicators as validation of the protocol for a successful HHP cycle. For each HHP cycle, 6 to 12 biological indicators (
The EPA and the Centers for Disease Control and Prevention (CDC) recognize that certain microorganisms can be ranked with respect to their tolerance to chemical disinfectants [7]. As a result, efficacy against less susceptible bacterial spores can be extrapolated to indicate efficacy against more susceptible microorganisms, including enveloped and non-enveloped viruses [8, 9, 52].
To assess efficacy within various Biosafety Level 3 Agricultural (BSL-3Ag) environments, Kansas State University challenged the HHP system within their Biosecurity Research Institute, a BSL-3Ag facility. Testing was performed in three laboratories representing a range of sizes: 2,281 ft3 (65 m3), 4,668 ft3 (132 m3), and 44,212 ft3 (1,252 m3). Each of the two smaller laboratories were tested over a series of three disinfection cycles with biological indicators of
Within the largest space tested, the 44,212 ft3 (1,252 m3) necropsy laboratory, four HHP devices were used for the disinfection cycle. The smart technology of the HHP system automated the connection of multiple Pulse fogging devices for a synchronized, custom-calibrated, HHP cycle. A total of 206 biological indicators were tested over two HHP cycles in locations throughout the laboratory, including at the 21-ft (6.4 m) ceiling height, soft-sided anteroom, walk-in cooler, and change rooms. All 206 challenged indicators were negative for spore growth, demonstrating a greater than 6-log10 reduction of
The BMBL (6th edition) defines sterilization as; “a physical or chemical process that kills or inactivates all microbial life forms including highly resistant bacterial spores.” The importance of sterilization is well understood in life science, pharmaceutical, and healthcare industries. Through the process of sterilization, researchers and physicians alike establish the basis for reliable and safe protocols and procedures. Standards for fogging sterilization testing are developed by the Association of Official Analytical Chemists (AOAC International), a globally recognized, third party not-for-profit, that provides education and facilitates the development of test methods and standards.
The HHP system was challenged with the Fogging Devices Sterilant Test (OCSPP 810.2100) for efficacy against
Formaldehyde is a naturally occurring compound consisting of hydrogen, oxygen, and carbon which is used as a disinfectant in both its liquid and gaseous states [55]. Used as a laboratory fumigant since the late 19th century, formaldehyde has remained in use due to its efficacy and low cost [56, 57]. For use as a disinfectant, formalin, the aqueous form of formaldehyde, is heated into a vapor producing formaldehyde gas [58]. When encountering microbes, this gas causes a cross-linking of molecules leading to protein clumping and loss of structure [59]. While an effective sterilant, formaldehyde must be handled with extreme care as exposure can cause asthma-like respiratory problems, cancer, or even be fatal to humans [55]. In gaseous form, formaldehyde is used at 8,000–10,000 ppm concentration and leaves behind a residue which must be removed through manual cleaning [56, 60]. Due to the potential health hazards and the required labor-intensive clean-up of residue, formaldehyde use is declining in favor of less hazardous and faster solutions. Indeed, the European Union lists formaldehyde as a substance of very high concern and has issued regulation calling for the progressive substitution when suitable alternatives have been identified [61]. While generally compatible with laboratory materials, formaldehyde can be absorbed into porous materials such as HEPA filters, off-gassing slowly and extending the time needed for safe re-entry [56, 62]. Formaldehyde production equipment ranges from as small as an electric fry pan requiring timers or externally controlled circuits to larger automated devices roughly the size of a household refrigerator and weighing approximately 396 pounds (180 kg) [63].
Chlorine dioxide (ClO2) is a synthetic, green-colored gas that gives off a bleach-like odor. Despite the familiar scent, chlorine dioxide gas is toxic and must be carefully contained when employed as a fumigant [64]. Consisting of unstable chlorine (Cl2) and oxygen molecules (O2), ClO2 disassociates when heated into chloride (Cl-), chlorite (ClO-) and chlorate ions (ClO3-). Some formulations can leave residues of sodium chlorite or inert salts, such as sodium chloride, on surfaces [65]. The disinfection cycle for ClO2 commonly consists of five steps: pre-conditioning, conditioning, charge (gas injection), exposure (contact time), and aeration [66]. The cycle is humidity-dependent, requiring a dosage increase of approximately 500 ppm for each 10% change in humidity, leading to an operating concentration range of 600–1550 ppm [66]. Similar to formaldehyde, ClO2 can be absorbed into porous surfaces and thus take longer to aerate than non-porous materials [65]. One consideration for system use is material compatibility with laboratory equipment. Some device manufacturers recommend that the ClO2-generating equipment remain outside the space being disinfected to prevent repeated exposure [34]. Instable in solution, chlorine dioxide must be mixed on-site by laboratory personnel. The effectiveness of ClO2 in penetrating treated spaces may also cause concern for personnel safety, as it can migrate out of seemingly enclosed spaces [38, 40]. As a result, facilities employing ClO2 systems must carefully monitor the disinfection cycle to ensure safety [64]. Roughly the size of an office bookcase and weighing approximately 230 pounds (104 kg), one system can treat up to 70,000 ft3 (2,000 m3) which may maximize the treatment space per device compared to other systems. ClO2 can also be dispensed from smaller devices which fit into a biological safety cabinet to treat that equipment [67, 68].
High concentration H2O2 devices are roughly the size of a medium file cabinet, wheeled around facilities on four castors and can be very heavy, weighing up to 500 pounds (227 kg). They are operated via touchscreen displays and the range of treatment area is between 8,800 to 20,000 ft3 (249 to 566 m3), depending on the device. One system can connect up to 10 devices via ethernet cables linking one device to another and enabling the treatment of larger spaces. Validation of these vaporous systems is determined using chemical and biological indicators, often
High concentration vaporous H2O2 systems traditionally employ a 35–59% H2O2 liquid solution, heated to a vaporous state [29]. These chemicals must be handled with care, since human contact with the liquid or vapor can be harmful and has been known to result in second- and third-degree burns [29, 30, 31]. Once heated, these chemicals are delivered to the treatment space, where vapor concentrations can reach peak levels of up to 1,400 ppm H2O2 [36], often necessitating precise operating conditions and continuous monitoring of the treatment cycle by the operator(s). A myriad of sensors precisely measures peak concentrations and these aid in delivering a specific combination of conditions to result in efficacy. These systems can be highly complex, accompanied by user manuals nearing a hundred pages of instructions. The four-part fogging process—dehumidification, conditioning, decontamination, and aeration—may require a technician to be present during the entire cycle of several hours [34, 69]. One reason for this vigilant monitoring may be to respond quickly should the system over or under deliver the high concentrations of H2O2 required. Another reason for persistent oversight may be a valid fear of escaped H2O2 vapor, which could migrate out of the treated space at high concentrations and affect personnel [38, 40].
Chemical solutions, even within the range of H2O2 technologies, differ not only in concentration, but also in their formulation. Some available H2O2 solutions contain additional active ingredients, such as the heavy metal silver nitrate [70]. Although silver has a long history of use in wound care, it is also known to cause a permanent retention of silver once in the body [71]. Silver ions are one of the most toxic known forms of heavy metal [70]. Accidental ingestion of these invisible silver residues can cause problems for the microbiome of the human digestive system, since these metals lack the ability to differentiate beneficial bacteria from pathogenic bacteria [72]. Silver persists not only in the body, but also in the environment, where it remains toxic and can be lethal to organisms [70]. As a result of a growing understanding of these unintended negative consequences, the use of silver for disinfection is regulated by the European Union (BPR, Regulation (EU) 528/2012) which states that “It may unnecessarily expose humans, animals and the environment to biocidal active substance, generate health and/or environmental risks and impacts, and may also contribute to the development of resistance to biocides leading to other health and/or environmental issues” [73]. Likewise the EPA acknowledges the potential health hazards related to exposure to silver, and has issued cautionary documents to this effect [74]. Due to the high level of potential exposure during residue cleanup, and the resulting inhalation or dermal absorption of this heavy metal, proper protocols and control should be always employed [74]. Devices for aerosolizing H2O2 with silver vary in size from toolbox-sized fixed systems in mobile transportation to large, stand-alone portable systems. Some of these systems spray in a mist, while others use a more wet delivery method which may impede the generation of floating aerosols [75].
There are several key elements to consider when deciding on a decontamination system. An ideal anti-microbial disinfectant should have the following characteristics: (1) is destructive to the greatest variety of pathogens, including bacterial spores, bacteria, viruses, molds, and fungi; (2) minimizes risks to personnel; (3) is non-corrosive and compatible with materials under normal application conditions; (4) is easy to implement; (5) imparts no harmful residue to the laboratory space or equipment; and (6) provides affordable decontamination. When comparing various disinfection systems, consider the most pertinent aspects below:
First and foremost, it is important for the system to not only be efficacious against more susceptible organisms, but efficacious against less susceptible organisms to the degree necessary to confidently implement the system as a regular component of the research cycle. Commensurate with the definitions of disinfection and decontamination [1], disinfection inactivates pathogens, while decontamination goes to the further degree of inactivating and denaturing them. In industries where pathogen-free environments form the foundational block for successful research, only decontamination will suffice. A detail-conscious manager should not only look for a decontaminant but select one which can demonstrate proof of efficacy with both porous and non-porous surfaces, most accurately representing the array found within life science sectors. Further supporting efficacy, laboratories should be able to validate their chosen system using biological indicators in adherence to international standards [44]. In support of risk management, the system should enable validation of sterilization through a 6-log10 sporicidal reduction that can be tracked and recorded [2]. With only the most efficacious systems under consideration, facility managers should evaluate each system’s impact on personnel safety, ideal laboratory operation, equipment material compatibility, and integrity of research.
Even more important than the safety of materials is the safety of personnel, which should be a top priority when implementing a decontamination system. Safety should be considered from the perspective of normal operation as well as in the event of an accidental exposure. Under normal conditions, devices which can be operated remotely create a layer of isolation between the decontamination system and the human operator, allowing for implementation without direct contact for personnel. In the unlikely event of an accidental exposure, higher concentration solutions may come with risks for exposure to high-consequence chemicals either from contact or inhalation [39]. Choosing a product with lower operating concentrations may likewise decrease the potential for risks associated with accidental exposure caused by unintended fog leakage [38, 40]. As with most gaseous systems, the Occupational Safety and Health Administration (OSHA) has defined a minimum reoccupation level, Permissible Exposure Limit (PEL), which must be considered: ClO2 = 0.1 ppm; H2O2 = 1 ppm; and formaldehyde = 0.75 ppm. Technologies employing lower operational ppm may reach reoccupation levels more quickly due to a lower peak threshold [15, 16, 76].
Decontamination within facilities is a recurring need, so both the physical devices as well as the chemicals or solutions used in them should be reviewed for the consequences of regular use. Devices with instructions requiring the operating machinery to remain outside of the room being disinfected may call into question the safety of exposed laboratory equipment within this space [34]. Likewise, systems with operating concentrations that can condense at levels beyond known material compatibility, such as 45% hydrogen peroxide, may also damage laboratory equipment [33].
Decision makers should critically examine the number of parts necessary for implementing a system. Multiple components may appear to create value but instead may only introduce complication and risks. Hosing laying on the floor add contamination risk in two ways: (1) hoses may impede a complete disinfection of any surfaces they touch and (2) those same hoses may contribute to cross contamination as they are moved throughout the facility. Additionally, a system with many components also comes with many opportunities to misplace or damage a critical element, potentially disrupting scheduled disinfection cycles. Quality and durability of the equipment is paramount as well.
While not strictly required, the degree of support available also contributes to the ease of use of a system. Whether creating new protocols, training personnel, or troubleshooting unique challenges, ensuring there is a commitment from the vendor to provide support can mean the difference between a quick phone call or time spent deciphering a 100-page manual.
Besides providing ease of use, the optimal disinfectant will also be free of byproducts which can leave precipitates or residues behind on the treated surfaces, or damage those surfaces [56, 65, 73, 74]. Additives such as metals are often marketed as beneficial catalysts, yet any benefit imparted can be overshadowed by what is left behind. Any disinfection system should benefit the facility by controlling contaminants, rather than introducing them to sensitive laboratory environments. It is essential for the integrity of research that no residual components be left in a space perceived sterile which can interfere with, invalidate, or otherwise impact the scientific work taking place.
As cost-cutting measures within laboratory spaces continue to be important, one way to save money is to choose a system that can readily be operated in-house by personnel who feel safe doing so. Outsourcing can be associated with significantly higher costs. Systems that are safer, scalable, trackable, easy to use, and modular can be employed for more than one application, resulting in even more cost savings.
When striving to meet strict viral disinfection requirements yet achieve balance with ease of use, timeliness, and safety requirements, facility managers should assess the disinfection needs of individual laboratory environments and the facility as a whole. Ideal disinfection systems should include technologies that have the ability to achieve validated decontamination with the lowest risk to equipment and personnel. We believe that the Hybrid Hydrogen Peroxide system introduced and discussed in detail here merits consideration as a versatile tool for viral disinfection. Pulse technology provides an unexpected efficacy with a 7% H2O2 solution equaling the best commercially available high-concentration H2O2 systems. The simplicity of one portable device with optional accessories and integration capabilities offers intriguing possibilities for reaching and decontaminating viral pathogens that may be found in the myriad of spaces within laboratory environments. Although conceived with sterilization efficacy in mind, its simplicity of use and safer operation enabled widespread adoption into multiple markets such as education and the military, with applicators ranging from entry level technicians to experienced personnel. As research continues to venture into unknown territories, awareness of potential viral threats has increased as well. Current adoption into the life sciences field is robust and underscores the value which can be added through implementing a targeted yet versatile system for facility decontamination. This chapter provides encouragement that innovations in disinfection technology, such as the HHP system, continue to keep pace with these viral threats with fact-based, science-driven results.
The authors would like to thank Jodi Woodson and Alyssa DeLotte for their invaluable contributions to this chapter.
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Biology"},signatures:"Sebastián Reyes-Cerpa, Kevin Maisey, Felipe Reyes-López, Daniela Toro-Ascuy, Ana María Sandino and Mónica Imarai",authors:[{id:"92841",title:"Dr.",name:"Mónica",middleName:null,surname:"Imarai",slug:"monica-imarai",fullName:"Mónica Imarai"},{id:"153780",title:"Dr.",name:"Sebastian",middleName:null,surname:"Reyes-Cerpa",slug:"sebastian-reyes-cerpa",fullName:"Sebastian Reyes-Cerpa"},{id:"157025",title:"Dr.",name:"Kevin",middleName:null,surname:"Maisey",slug:"kevin-maisey",fullName:"Kevin Maisey"},{id:"157026",title:"Dr.",name:"Felipe",middleName:"Esteban",surname:"Reyes-López",slug:"felipe-reyes-lopez",fullName:"Felipe Reyes-López"},{id:"157027",title:"MSc.",name:"Daniela",middleName:null,surname:"Toro-Ascuy",slug:"daniela-toro-ascuy",fullName:"Daniela Toro-Ascuy"},{id:"157028",title:"Dr.",name:"Ana",middleName:null,surname:"Sandino",slug:"ana-sandino",fullName:"Ana Sandino"}]},{id:"41576",doi:"10.5772/54133",title:"Ontogenetic Dietary Shifts in a Predatory Freshwater Fish Species: The Brown Trout as an Example of a Dynamic Fish Species",slug:"ontogenetic-dietary-shifts-in-predatory-freshwater-fish-species-the-brown-trout-as-an-example-of-a-d",totalDownloads:2625,totalCrossrefCites:5,totalDimensionsCites:22,abstract:null,book:{id:"3193",slug:"new-advances-and-contributions-to-fish-biology",title:"New Advances and Contributions to Fish Biology",fullTitle:"New Advances and Contributions to Fish Biology"},signatures:"Javier Sánchez-Hernández, María J. Servia, Rufino Vieira-Lanero and Fernando Cobo",authors:[{id:"154559",title:"Dr.",name:"Javier",middleName:null,surname:"Sánchez-Hernández",slug:"javier-sanchez-hernandez",fullName:"Javier Sánchez-Hernández"},{id:"156457",title:"Dr.",name:"María J.",middleName:null,surname:"Servia",slug:"maria-j.-servia",fullName:"María J. Servia"},{id:"156459",title:"Dr.",name:"Rufino",middleName:null,surname:"Vieira-Lanero",slug:"rufino-vieira-lanero",fullName:"Rufino Vieira-Lanero"},{id:"156460",title:"Prof.",name:"Fernando",middleName:null,surname:"Cobo",slug:"fernando-cobo",fullName:"Fernando Cobo"}]},{id:"41566",doi:"10.5772/54825",title:"Freshwater Fish as Sentinel Organisms: From the Molecular to the Population Level, a Review",slug:"fish-as-sentinel-organisms-from-the-molecular-to-the-population-level-a-review",totalDownloads:2460,totalCrossrefCites:3,totalDimensionsCites:11,abstract:null,book:{id:"3193",slug:"new-advances-and-contributions-to-fish-biology",title:"New Advances and Contributions to Fish Biology",fullTitle:"New Advances and Contributions to Fish Biology"},signatures:"Jacinto Elías Sedeño-Díaz and Eugenia López-López",authors:[{id:"153660",title:"M.Sc.",name:"Jacinto Elías",middleName:null,surname:"Sedeño-Díaz",slug:"jacinto-elias-sedeno-diaz",fullName:"Jacinto Elías Sedeño-Díaz"},{id:"156158",title:"Dr.",name:"Eugenia",middleName:null,surname:"López López",slug:"eugenia-lopez-lopez",fullName:"Eugenia López López"}]},{id:"40952",doi:"10.5772/54549",title:"The Potential Impacts of Global Climatic Changes and Dams on Amazonian Fish and Their Fisheries",slug:"potential-impacts-of-global-climate-change-and-dams-on-amazonian-freshwater-fish-and-its-fisheries",totalDownloads:2289,totalCrossrefCites:1,totalDimensionsCites:9,abstract:null,book:{id:"3193",slug:"new-advances-and-contributions-to-fish-biology",title:"New Advances and Contributions to Fish Biology",fullTitle:"New Advances and Contributions to Fish Biology"},signatures:"Carlos Edwar de Carvalho Freitas, Alexandre A. F. Rivas, Caroline Pereira Campos, Igor Sant’Ana, James Randall Kahn, Maria Angélica de Almeida Correa and Michel Fabiano Catarino",authors:[{id:"154232",title:"Prof.",name:"Carlos",middleName:null,surname:"Freitas",slug:"carlos-freitas",fullName:"Carlos Freitas"},{id:"156594",title:"Prof.",name:"Alexandre",middleName:null,surname:"Rivas",slug:"alexandre-rivas",fullName:"Alexandre Rivas"},{id:"156596",title:"M.Sc.",name:"Caroline",middleName:null,surname:"Campos",slug:"caroline-campos",fullName:"Caroline Campos"},{id:"156597",title:"MSc.",name:"Igor",middleName:null,surname:"Rechetnicow",slug:"igor-rechetnicow",fullName:"Igor Rechetnicow"},{id:"156598",title:"Prof.",name:"James",middleName:null,surname:"Kahn",slug:"james-kahn",fullName:"James Kahn"},{id:"156600",title:"MSc.",name:"Maria",middleName:null,surname:"Correa",slug:"maria-correa",fullName:"Maria Correa"},{id:"156601",title:"MSc.",name:"Michel",middleName:null,surname:"Catarino",slug:"michel-catarino",fullName:"Michel Catarino"}]},{id:"41564",doi:"10.5772/53505",title:"Cytokine Regulation of Teleost Inflammatory Responses",slug:"cytokine-regulation-of-teleost-inflammatory-responses",totalDownloads:2413,totalCrossrefCites:3,totalDimensionsCites:9,abstract:null,book:{id:"3193",slug:"new-advances-and-contributions-to-fish-biology",title:"New Advances and Contributions to Fish Biology",fullTitle:"New Advances and Contributions to Fish Biology"},signatures:"Leon Grayfer and Miodrag Belosevic",authors:[{id:"154146",title:"Distinguished Prof.",name:"Miodrag",middleName:null,surname:"Belosevic",slug:"miodrag-belosevic",fullName:"Miodrag Belosevic"}]}],mostDownloadedChaptersLast30Days:[{id:"59807",title:"Zebrafish or Danio rerio: A New Model in Nanotoxicology Study",slug:"zebrafish-or-danio-rerio-a-new-model-in-nanotoxicology-study",totalDownloads:1336,totalCrossrefCites:2,totalDimensionsCites:6,abstract:"Nanotoxicology represents a new research area in toxicology that allows to evaluate the toxicological properties of nanoparticles in order to determine whether and to what extent they represent an environmental threat. Behavior, fate, transport, and toxicity of nanoparticles are influenced to their particular properties and of several environmental factors. The mechanisms underlying the toxicity of nanomaterials have recently been studied specially in aquatic organisms. In particular, in recent years, the use of Danio rerio or zebrafish as an animal model system for nanoparticle toxicity assay increased exponentially. In this review, we compare the recent researches employing zebrafish, adults or embryos, for different nanoparticles’ toxicity assessment.",book:{id:"6474",slug:"recent-advances-in-zebrafish-researches",title:"Recent Advances in Zebrafish Researches",fullTitle:"Recent Advances in Zebrafish Researches"},signatures:"Maria Violetta Brundo and Antonio Salvaggio",authors:[{id:"225306",title:"Prof.",name:"Maria Violetta",middleName:null,surname:"Brundo",slug:"maria-violetta-brundo",fullName:"Maria Violetta Brundo"},{id:"225508",title:"Prof.",name:"Antonio",middleName:null,surname:"Salvaggio",slug:"antonio-salvaggio",fullName:"Antonio Salvaggio"}]},{id:"61014",title:"Zebrafish Aging Models and Possible Interventions",slug:"zebrafish-aging-models-and-possible-interventions",totalDownloads:1293,totalCrossrefCites:0,totalDimensionsCites:3,abstract:"Across the world, the aging population is expanding due to an increasing average life expectancy. The percentage of elderly over the age of 65 is expected to be more than 15% of the total world population by 2025. As the lifespan increases, there will be a need for maintaining a healthy state for these individuals. Our current knowledge on types and durations of potential anti-aging therapies is quite limited. Recently the zebrafish has emerged as a promising model for understanding the cognitive and neurobiological changes during aging, as well as its use with potential anti-aging interventions. Like humans this model organism ages gradually, displays similar behavioral properties and social characteristics, and in addition, there is a wealth of molecular and genetic tools to uncover the cellular mechanism that contribute to age-related cognitive declines. Drug effect and toxicity can be easily tested in the zebrafish. Therefore, this animal model can provide information about potential therapies that could be translated directly into human populations or provide a more focused treatment direction for testing in other mammalian animal models. The zebrafish will be a powerful tool for uncovering the mysteries of the aging brain.",book:{id:"6474",slug:"recent-advances-in-zebrafish-researches",title:"Recent Advances in Zebrafish Researches",fullTitle:"Recent Advances in Zebrafish Researches"},signatures:"Dilan Celebi-Birand, Begun Erbaba, Ahmet Tugrul Ozdemir, Hulusi\nKafaligonul and Michelle Adams",authors:[{id:"223775",title:"Associate Prof.",name:"Michelle",middleName:null,surname:"Adams",slug:"michelle-adams",fullName:"Michelle Adams"},{id:"224816",title:"BSc.",name:"Ergul Dilan",middleName:null,surname:"Celebi-Birand",slug:"ergul-dilan-celebi-birand",fullName:"Ergul Dilan Celebi-Birand"},{id:"224817",title:"MSc.",name:"Begun",middleName:null,surname:"Erbaba",slug:"begun-erbaba",fullName:"Begun Erbaba"},{id:"224819",title:"Ph.D. Student",name:"Ahmet Tugrul",middleName:null,surname:"Ozdemir",slug:"ahmet-tugrul-ozdemir",fullName:"Ahmet Tugrul Ozdemir"},{id:"224823",title:"Dr.",name:"Hulusi",middleName:null,surname:"Kafaligonul",slug:"hulusi-kafaligonul",fullName:"Hulusi Kafaligonul"}]},{id:"59711",title:"The Role of PSR in Zebrafish (Danio rerio) at Early Embryonic Development",slug:"the-role-of-psr-in-zebrafish-danio-rerio-at-early-embryonic-development",totalDownloads:1160,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"During development, the role of the phosphatidylserine receptor (PSR) in the professional removal of apoptotic cells that have died is few understood. Programmed cell death (PCD) began during the shield stage (5.4 hpf), with dead cells being engulfed by a neighboring cell that showed a normal-looking nucleus and the nuclear condensation multi-micronuclei of an apoptotic cell. Recently, in the zebrafish model system, PS receptor played a new role on corpse cellular cleaning for further normal development during early embryonic development, which also correlated with tissues’ or organs’ complete development and organogenesis. In the present, we summary new story that a transcriptional factor, YY1a, in the upstream of PSR is how to regulate PS receptor expression that linked to function of PSR-phagocyte mediated apoptotic cell engulfment during development, especially the development of organs such as the brain and heart. YY1a/PSR-mediated engulfing system may involve in diseases and therapy. This engulfing system may provide new insight into phosphatidylserine receptor how to dynamitic interaction with apoptotic cell during priming programmed cell death.",book:{id:"6474",slug:"recent-advances-in-zebrafish-researches",title:"Recent Advances in Zebrafish Researches",fullTitle:"Recent Advances in Zebrafish Researches"},signatures:"Wan-Lun Taung, Jen-Leih Wu and Jiann-Ruey Hong",authors:[{id:"66487",title:"Prof.",name:"Jiann",middleName:"Ruey",surname:"Hong",slug:"jiann-hong",fullName:"Jiann Hong"}]},{id:"60880",title:"Transient-Receptor Potential (TRP) and Acid-Sensing Ion Channels (ASICs) in the Sensory Organs of Adult Zebrafish",slug:"transient-receptor-potential-trp-and-acid-sensing-ion-channels-asics-in-the-sensory-organs-of-adult-",totalDownloads:1216,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Sensory information from the aquatic environment is required for life and survival of zebrafish. Changes in the environment are detected by specialized sensory cells that convert different types of stimuli into electric energy, thus originating an organ-specific transduction. Ion channels are at the basis of each sensory modality and are responsible or are required for detecting thermal, chemical, or mechanical stimuli but also for more complex sensory processes as hearing, olfaction, taste, or vision. The capacity of the sensory cells to preferentially detect a specific stimulus is the result of a characteristic combination of different ion channels. This chapter summarizes the current knowledge about the occurrence and localization of ion channels in sensory organs of zebrafish belonging to the superfamilies of transient-receptor potential and acid-sensing ion channels that are involved in different qualities of sensibility superfamilies in the sensory organs of zebrafish. This animal model is currently used to study some human pathologies in which ion channels are involved. 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These advances have helped foster better support for animal health, more humane animal production, and a better understanding of the physiology of endangered species to improve the assisted reproductive technologies or the pathogenesis of certain diseases, where animals can be used as models for human diseases (like cancer, degenerative diseases or fertility), and even as a guarantee of public health. Bridging Human, Animal, and Environmental health, the holistic and integrative “One Health” concept intimately associates the developments within those fields, projecting its advancements into practice. This book series aims to tackle various animal-related medicine and sciences fields, providing thematic volumes consisting of high-quality significant research directed to researchers and postgraduates. It aims to give us a glimpse into the new accomplishments in the Veterinary Medicine and Science field. 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She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}}]}},subseries:{item:{id:"1",type:"subseries",title:"Oral Health",keywords:"Oral health, Dental care, Diagnosis, Diagnostic imaging, Early diagnosis, Oral cancer, Conservative treatment, Epidemiology, Comprehensive dental care, Complementary therapies, Holistic health",scope:"
\r\n This topic aims to provide a comprehensive overview of the latest trends in Oral Health based on recent scientific evidence. Subjects will include an overview of oral diseases and infections, systemic diseases affecting the oral cavity, prevention, diagnosis, treatment, epidemiology, as well as current clinical recommendations for the management of oral, dental, and periodontal diseases.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/1.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11397,editor:{id:"173955",title:"Prof.",name:"Sandra",middleName:null,surname:"Marinho",slug:"sandra-marinho",fullName:"Sandra Marinho",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGYMQA4/Profile_Picture_2022-06-01T13:22:41.png",biography:"Dr. Sandra A. Marinho is an Associate Professor and Brazilian researcher at the State University of Paraíba (Universidade Estadual da Paraíba- UEPB), Campus VIII, located in Araruna, state of Paraíba since 2011. She holds a degree in Dentistry from the Federal University of Alfenas (UNIFAL), while her specialization and professional improvement in Stomatology took place at Hospital Heliopolis (São Paulo, SP). Her qualifications are: a specialist in Dental Imaging and Radiology, Master in Dentistry (Periodontics) from the University of São Paulo (FORP-USP, Ribeirão Preto, SP), and Doctor (Ph.D.) in Dentistry (Stomatology Clinic) from Hospital São Lucas of the Pontifical Catholic University of Rio Grande do Sul (HSL-PUCRS, Porto Alegre, RS). She held a postdoctoral internship at the Federal University from Jequitinhonha and Mucuri Valleys (UFVJM, Diamantina, MG). She is currently a member of the Brazilian Society for Dental Research (SBPqO) and the Brazilian Society of Stomatology and Pathology (SOBEP). Dr. Marinho's experience in Dentistry mainly covers the following subjects: oral diagnosis, oral radiology; oral medicine; lesions and oral infections; oral pathology, laser therapy and epidemiological studies.",institutionString:null,institution:{name:"State University of Paraíba",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,series:{id:"3",title:"Dentistry",doi:"10.5772/intechopen.71199",issn:"2631-6218"},editorialBoard:[{id:"267724",title:"Dr.",name:"Febronia",middleName:null,surname:"Kahabuka",slug:"febronia-kahabuka",fullName:"Febronia Kahabuka",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZpJQAW/Profile_Picture_2022-06-27T12:00:42.JPG",institutionString:null,institution:null}]},onlineFirstChapters:{paginationCount:7,paginationItems:[{id:"82405",title:"Does Board Structure Matter in CSR Spending of Commercial Banks? 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