Summary of selected literature reports on the effects of frequent milking (FM) on milk yield of dairy cowsa.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"},{slug:"intechopen-s-chapter-awarded-the-guenther-von-pannewitz-preis-2020-20200715",title:"IntechOpen's Chapter Awarded the Günther-von-Pannewitz-Preis 2020"},{slug:"suf-and-intechopen-announce-collaboration-20200331",title:"SUF and IntechOpen Announce Collaboration"}]},book:{item:{type:"book",id:"1807",leadTitle:null,fullTitle:"New Advances in the Basic and Clinical Gastroenterology",title:"New Advances in the Basic and Clinical Gastroenterology",subtitle:null,reviewType:"peer-reviewed",abstract:"The purpose of this book was to present the integrative, basic and clinical approaches based on recent developments in the field of gastroenterology. The most important advances in the pathophysiology and treatment of gastrointestinal disorders are discussed including; gastroesophageal reflux disease (GERD), peptic ulcer disease, irritable bowel disease (IBD), NSAIDs-induced gastroenteropathy and pancreatitis. Special focus was addressed to microbial aspects in the gut including recent achievements in the understanding of function of probiotic bacteria, their interaction with gastrointestinal epithelium and usefulness in the treatment of human disorders. We hope that this book will provide relevant new information useful to clinicians and basic scientists as well as to medical students, all looking for new advancements in the field of gastroenterology.",isbn:null,printIsbn:"978-953-51-0521-3",pdfIsbn:"978-953-51-6966-6",doi:"10.5772/2238",price:159,priceEur:175,priceUsd:205,slug:"new-advances-in-the-basic-and-clinical-gastroenterology",numberOfPages:568,isOpenForSubmission:!1,isInWos:1,hash:"a7ec52cb83e9fc2064e573afcfc87a71",bookSignature:"Thomas Brzozowski",publishedDate:"April 18th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/1807.jpg",numberOfDownloads:98476,numberOfWosCitations:57,numberOfCrossrefCitations:29,numberOfDimensionsCitations:82,hasAltmetrics:1,numberOfTotalCitations:168,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 7th 2011",dateEndSecondStepPublish:"May 5th 2011",dateEndThirdStepPublish:"September 9th 2011",dateEndFourthStepPublish:"October 9th 2011",dateEndFifthStepPublish:"February 8th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr Thomas BRZOZOWSKI works as a professor of human physiology and holds the position of Chairman of the Department of Physiology and is v-Dean of Medical Faculty at Jagiellonian University Medical College, Cracow, Poland.His major area of interest is physiology and pathophysiology of gastrointestinal (GI) tract with the major focus addressed to the mechanism of GI mucosal defense, protection and ulcer healing. He was a postdoctoral NIH fellow at University of California and Gastroenterology VA Medical Center, Irvine and Long Beach, CA, USA and at Gastroenterology Clinics at Erlangen-Nuremberg and Munster in Germany. 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\r\n\tOrganic synthesis has always been one of the central topics of research for the scientific community in the academic laboratories and industrial world. Many striking journal articles and remarkable reviews and books have been published in the past year describing the practicability and applications of the subject demonstrating the importance of organic synthesis. In the present book, we will be putting together the topics in organic synthesis which may include but not limited to, (1) the basic terms and concepts, (2) various organic reactions including reduction, oxidation, addition, elimination, rearrangements, and cycloadditions, (3) Total Synthesis of Natural products, (4) transition metal catalysts, organocatalysts, enzymes and biotransformations, (5) applications in medicinal chemistry and drug design and development, (6) purification methods and characterization techniques, etc. To set a limit and to increase the scope of the book, author(s) are encouraged to send the chapters that include selected examples with practical applications and good yielding reactions reported within the past decade. Older topics with significant findings or their essence to prepare the foundation may be included in the chapter are welcomed as well.
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Deore was born in India. He received a Master’s degree in organic chemistry from Pune University in 2007. In the same year, he qualified with the SET and CSIR-NET (JRF) and joined in the group of Prof. Narshinha P. Argade for the doctoral studies in National Chemical Laboratory, India. In 2014, he awarded with a Ph. D. in Chemistry and was a recipient of the 2nd prize in “2014 Eli Lilly and Company Asia Outstanding Thesis Awards”. In July 2014 he moved to Canada and joined as a postdoctoral researcher in the group of Prof. Richard Manderville at the University of Guelph, Canada. Presently, Dr. Deore is working on the collaborative project between the University of Guelph and Aterica health Inc., and providing consulting to the company. 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One of the key findings that has enabled manipulation of lactation performance is that the milk yield of dairy cows is responsive to demands of offspring or milk removal; hence milk production can be increased by frequent milking or suckling. Early studies illustrated the galactopoietic effect of frequent milking during the entire lactation, with three times daily milking increasing milk yield by up to 20% relative to twice daily milking. Research using nurse cows revealed a long-term increase in milk production when cows and heifers were allowed to suckle a calf during the first 8 to 10 wk of lactation (Everitt & Phillips, 1971; Edmunds, 1977; Fulkerson, 1981). The results of these experiments laid the groundwork for current research, which has identified a time during early lactation wherein the mammary gland of dairy cows is especially receptive to the stimulus of frequent milking. More recently, it has been established that frequent milk removal (three or more times daily) for a short duration within the first three weeks of lactation can increase milk production through the remainder of lactation (Hale et al., 2003; Dahl et al., 2004b; Wall & McFadden, 2007b). Since the establishment of the galactopoietic effect on milk production, several experiments have been conducted to identify the factors that regulate the milk yield response. These reports have documented consistent responses to increased milking frequency; however, questions remain about the mechanisms involved in regulation of milk production efficiency.
As previously indicated, frequent milking of dairy cows has emerged as an effective management tool for dairy farmers to increase milk production efficiency. Although it is a relatively novel management practice, the original interest and research in this area dates back to the late 1800’s (Hills, 1890; 1898). Despite considerable variation in the magnitude of the milk yield response, it was recognized long ago that thrice-daily milking (3X) increased milk production relative to twice-daily milking (2X), and that frequent milking could be a profitable management tool if costs associated with the extra milkings are outweighed by the value of additional milk obtained (Riford, 1922; Dahlberg, 1924). Cows milked 3X generally produced about 20% more milk than those milked 2X, and milk production could be increased another 7% by milking four times daily (4X) instead of 3X (Woodward, 1931). Modern-day adjustment factors used to compare milk production of cows milked 2X to those milked 3X range from 12-14%, depending on the parity of the cow (VanRaden et al., 1999).
Much of the work on frequent milking for the entire lactation was conducted during the 1980s and 1990s, when there was great interest in switching milking regimes from 2X to 3X in order to increase milk production efficiency (Table 1). A typical response to 3X milking is illustrated in Figure 1, which shows the lactation curves of cows milked 2X or 3X for the entire lactation (re-drawn from Amos et al., 1985). Three-times daily milking increased milk production both at peak and through the entire lactation. Persistency of the lactation curve was also slightly increased, but this effect disappeared after approximately 180 DIM. In summaries of DHIA records, the increase in milk production with 3X was 13, 12, and 16% compared to 2X (Allen et al., 1986; Gisi et al., 1986; Smith et al., 2002). These reports were obtained from mostly Holstein herds, or combined Holstein and Jersey herds. Culotta and Schmidt (1988) suggested that smaller dairy breeds do not respond as well to frequent milking as larger breeds. Consistent with that hypothesis were observations of Campos et al. (1994), that relative to 2X, 3X increased milk production by 17.3 and 6.3% in Holsteins and Jerseys, respectively. In contrast, Copeland (1934) observed an impressive 21 and 19% increase in milk and fat production, respectively, from Jerseys milked 3X compared to those milked 2X. In addition, they reported a correlation (+.64) between the amount of milk cows produced prior to frequent milking and the magnitude of the response to frequent milking (Copeland, 1934). This led to speculation that higher producing cows better responded to increased milking frequency than did lower producing cows. The existence of such a relationship, however, has not been established. To the contrary, Erdman and Varner (1995) and Stockdale (2006) reviewed the literature on frequent milking, and reported no correlation between previous milk production and the response to changes in milking frequency. Instead, those researchers concluded that there was an incremental milk yield response. Relative to 2X, this fixed milk yield response was -6.2, +3.5 and +4.9 kg/d for once daily milking (1X), 3X, or 4X, respectively (Erdman & Varner, 1995). In agreement with this, Peel et al. (1979) estimated that the post-suckling increase in milk production of cows suckled for as little as one week during early lactation was 4.3 kg/d. They went so far as to provide the readers with the following equation to allow prediction of the milk yield response to various suckling regimes:
The effect of frequent milking on milk production of dairy cows. Lactation curves of multiparous cows milked twice (2X) or thrice (3X) daily for the entire lactation (re-drawn from Amos et al., 1985).
Reference | Parity | Breed | Duration of FM | Change in milk yieldb (2X vs. 3Xc) | Change in milk yield (2X vs. 4X) |
Riford, 1922 | ≥ 1 | Holstein; Guernsey | Unknown | + 4.6 kg/d | |
Woodward, 1931 | ≥ 1 | Holstein | Full lactation | + 20% | |
Copeland, 1934 | ≥ 1 | Jersey | Through late lactation | + 21% | |
Rao and Ludri, 1984 | ≥ 2 | Brown Swiss x Sahiwal | 50 to 130 DIMd | + 1.34 kg/d | + 1.73 kg/d |
DePeters et al., 1985 | ≥ 2 | Holstein | Full lactation | + 17% | |
1 | Holstein | Full lactation | + 6% (NS) | ||
Amos et al., 1985 | ≥ 2 | Holstein | Full lactation | + 18.5% | |
1 | Holstein | Full lactation | + 25.2% | ||
Allen et al., 1986 | ≥ 2 | Holstein | Full lactation | + 13.4% | |
1 | Holstein | Full lactation | + 19.4% | ||
Gisi et al., 1986 | ≥ 2 | Holstein | Full lactation | + 12% | |
1 | Holstein | Full lactation | + 14% | ||
Barnes et al., 1990 | 1 | Holstein | Full lactation | + 14% | |
Campos et al., 1994 | 1 | Holstein | Full lactation | + 17.3% | |
1 | Jersey | Full lactation | + 6.3% | ||
Klei et al., 1997 | ≥ 1 | Holstein | Full lactation | + 10.4% | |
Smith et al., 2002 | ≥ 1 | Holstein | Full lactation | + 16% |
Summary of selected literature reports on the effects of frequent milking (FM) on milk yield of dairy cowsa.
Importantly, the increase in milk yield in response to frequent milking or suckling is not specific to dairy cows; milk production was increased with frequent milking or suckling of other dairy ruminants, including goats (Wilde et al., 1986), sheep (Geenty & Davison, 1982; Negrao et al., 2001; Nudda et al., 2002), and buffalo (Dash et al., 1976), as well as various cross breeds (Little et al., 1991; Krohn, 2001; Sidibe-Anago et al., 2008; Alvarez-Rodriguez et al., 2010).
Reported effects of frequent milking on milk composition, somatic cell count (SCC) and herd health have been inconsistent. Many researchers have observed no effect of frequent milking on milk composition (Poole, 1982; Rao & Ludri, 1984; Amos et al., 1985; DePeters et al., 1985; Gisi et al., 1986), whereas some have observed a decrease in fat percentage (Allen et al., 1986; Smith et al., 2002). Due to the increase in milk production in response to frequent milking, however, there is often an increase in the total yield of fat and protein (Klei et al., 1997; Dahl et al., 2004b). With respect to SCC, some reports have indicated an association between frequent milking and decreased SCC, and these authors concluded that frequent milking may improve mammary health (Poole, 1982; Armstrong et al., 1985; Smith et al., 2002; Dahl et al., 2004b). Others have reported no effect of frequent milking on SCC (Waterman et al., 1983; DePeters et al., 1985; Gisi et al., 1986; Bar-Peled et al., 1995; Klei et al., 1997; Hale et al., 2003; Patton et al., 2006; Wall & McFadden, 2007a; Shields et al., 2011; Wright et al., 2011). The inconsistencies in the above reports may be the result of variations in timing and methods of sampling across experiments. Suckling of cows during early lactation has consistently been associated with a decrease in SCC and a decrease in the incidence of clinical mastitis, in some cases by up to 50% or more (Walsh, 1974; Edmunds, 1977; Little et al., 1991; Krohn, 2001). In fact, Walsh (1974) suggested that the increase in milk production elicited by suckling was probably due to the additional stimulus of the gland as well as the markedly improved mammary health of suckled animals.
Discrepancies also exist in the reported effects of frequent milking on reproductive performance and herd health. Some researchers have observed decreased reproductive performance in 3X cows compared to 2X cows (Ludwin, 1942; Armstrong et al., 1985; DePeters et al., 1985; Smith et al., 2002), whereas others have observed no effect (Poole, 1982; Amos et al., 1985; Gisi et al., 1986) or an improvement (Allen et al., 1986) in reproductive performance with 3X. Armstrong et al. (1985) suggested that any negative effects of frequent milking on herd health or reproductive performance may be associated with poor herd management. Well-controlled field studies using standardized sampling procedures will be necessary to verify the impact of milking frequency on milk composition, SCC and herd health, as well as identifying the interaction between frequent milking and herd management on these factors.
Similarly, suckling of a calf during early lactation of the cow is associated with increased weight loss and an increase in the days to first estrus (Margerison et al., 2002). In most cases, however, the delay in resumption of estrous cyclicity is offset by an increase in conception rate (Little et al., 1991; Krohn, 2001). Consequently, the effects of suckling on reproductive performance appear to be negligible, or in some cases positive (Table 2). In addition, Perez-Hernandez et al. (2002) reported that exposure of cows to a teaser bull decreased the effects of suckling on days to first estrus. Therefore, in agreement with the suggestion by Armstrong et al. (1985), simple changes in management - when feasible - can be used to overcome any potential negative impact of frequent milking or suckling regime on reproductive performance. Table 2 summarizes the findings of Little et al. (1991), who looked at lactation and reproductive performance of cows allowed to suckle calves for the first 90 days of lactation.
Suckled & machine milked | Machine milked | |
Total milk production (kg) | 1,894.10 | 1,644.60 |
Lactation length (d) | 341 | 305 |
Dry matter feed intake (kg/d) | 13.25 | 13.14 |
Days to estrus | 101 | 41 |
Services per conception | 1.3 | 1.9 |
Productivity characteristics of crossbred cows subjected to suckling compared to machine-milked herdmates. Cows were allowed to suckle their calves for the first 90d of lactation and were also machine milked twice daily for the entire lactation (Little et al., 1991).
In addition to the increase in milk yield, suckling during early lactation has also been associated with an increase in lactation length (Everitt & Phillips, 1971; Little et al., 1991; Krohn, 2001). This is particularly relevant since some producers are interested in incorporating an extended lactation management scheme into their herd. Extended lactation offers the benefit of decreased health risk to the cow because there is less exposure to risk of metabolic disease, which highest during the transition period. This, in turn, decreases costs to the producer associated with treating sick cows and veterinary expenses. The use of frequent milking or suckling offers a tool for increasing lactation persistency during extended lactations. Indeed, Sorensen et al. (2008) reported that the use of increased milking frequency makes an extended lactation cycle economically viable for the producer, in addition to an observed improvement in the health of the cow.
There are health benefits of keeping the calf with the cow and allowing the calf to suckle. Edmunds (1977) suggested that suckling calves generally perform better than those raised on milk replacer. Little et al. (1991) reported an increase in growth rate from birth to weaning of 0.2 kg/d for calves that were allowed to suckle vs. those that were raised on milk replacer. Similar observations were made by Alvarez-Rodríguez et al. (2010). In some cases, however, there is wide variation in the daily weight gain of suckling calves, especially if there are multiple calves on a single cow. Therefore, depending on the suckling scheme used, calves allowed to suckle don’t always have higher growth rates than calves raised on milk replacer (Krohn, 2001). In a review of the literature, Edmunds (1977) reported that suckling calves had superior daily weight gain, a decrease in scours, and minimal incidence of other diseases compared to bucket-reared herdmates. The author suggested that this was a result of decreased stress associated with separation from the cow, since suckling calves are allowed almost constant contact with their mothers.
An interesting study conducted by Bar-Peled et al. (1997) reported on the performance of first lactation heifers that were allowed to suckle as calves, and compared them to heifers that were reared on milk replacer. Their findings are summarized in table 3, and have major implications regarding the effects of suckling on performance as adults; suckling clearly improved production efficiency in several areas.
Suckled | Milk replacer | |
Body weight at conception (kg) | 358.6 | 327.2 |
Average daily gain (kg) | 0.82 | 0.68 |
Age at conception (d) | 394 | 426 |
Conception rate (%) | 83.4 | 74.2 |
Calving age (d) | 669 | 700 |
Milk production (kg/300d) | 9624 | 9171 |
Productivity characteristics of heifers that were allowed to suckle as calves compared to herdmates raised on milk replacer. Heifers were allowed to suckle as calves for the first six weeks of life. Herdmates were raised on milk replacer (Bar-Peled et al., 1997).
It has been reported that the milk production response to frequent milking was more pronounced in animals with smaller udder capacity, such as heifers (Woodward, 1931; Copeland, 1934; Lush & Shrode, 1953). Copeland (1934) speculated that this may be a function of increased udder pressure associated with less udder capacity. In agreement with this, Allen et al. (1986) observed that relative to 2X, 3X increased milk production by 13.4 and 19.4% in cows and heifers, respectively. In the previous year, however, another group reported that mature cows respond better to frequent milking than primiparous cows (DePeters et al., 1985). Of the studies that measured the milk yield response in heifers separately, most reported that heifers responded to frequent milking similarly to or better than multiparous cows. Therefore, no relationship has been established between parity and the magnitude of the milk yield response to frequent milking. To the contrary, we observed that that relative to multiparous cows, heifers respond similarly to increased milking frequency during early lactation (Wright et al., 2011). Similar observations have been made on the response of primi- vs. multi-parous cows to suckling during early lactation (Everitt & Phillips, 1971).
Several research groups have characterized the economic impact of frequent milking. Factors contributing to the profitability of frequent milking were labor, herd size, herd health, management, feed costs, and milk price (Armstrong et al., 1985; Culotta & Schmidt, 1988; Maltz et al., 2003). Rao and Ludri (1984) reported that 3X increased net income by 21% relative to 2X. More recently, we estimated a net increase of approximately $93/cow/yr when cows were milked 4X for the first 3 wk of lactation and milked 2X thereafter (Table 4; Wall & McFadden, 2007b). With respect to suckling, McKusick et al. (2001) estimated an increase in net income of $25 per ewe/suckling lamb pair in a mixed rearing system (in which ewes are suckled and machine milked until lambs are weaned) relative to ewes solely machine milked and lambs raised on milk replacer. The increase in profitability of suckling management systems comes from eliminating the expenses associated with purchase of milk replacer, and also the increase in milk production of the dams after the suckling period. This, combined with the observation of Bar-Peled et al. (1997) that suckling calves perform better as adults, indicates multiple areas of economic gain with a suckling regime. Therefore, when there are no negative effects on animal health or reproductive performance, frequent milking or suckling has the potential to be a very profitable management tool.
An exciting development for both dairy producers and dairy scientists was the finding that the timing of implementation can influence the milk yield response to frequent milking. During middle and late lactation, frequent milking increased milk production; however cessation of frequent milking resulted in an immediate decrease in milk yield to pre-treatment levels (Elliott, 1961; Morag, 1973a, b; Svennersten et al., 1990). During early lactation, however, frequent milking for a short duration can stimulate milk production and the effect persists through the remainder of lactation, even after less frequent milking is resumed. This effect was originally observed in experiments designed to determine the milk yield loss associated with the use of nurse cows. Using identical twin cows, Everitt and Phillips (1971) discovered that suckling by calves in addition to machine milking during the first 8 to 10 weeks of lactation was associated with increased milk production after weaning and throughout the remainder of lactation in both primi- and multiparous cows (Figure 2). Shortly after this report, similar observations were made in both cows (Edmunds, 1977; Moss & O\'Grady, 1978; Thomas et al., 1978; Fulkerson, 1981) and heifers (Fulkerson et al., 1978; Peel et al., 1979). Pearson et al. (1979) assigned cows to 3X for the first 143 d of lactation, followed by 2X thereafter. Although they did not report the full lactation curves, they measured milk yield for the entire lactation and reported that relative to 2X, cows that were milked 3X for the first 143 d of lactation produced more milk through 280 DIM (Pearson et al., 1979). Subsequently, it has been observed in numerous experiments that frequent milking during early lactation was associated with both acute and persistent increases in milk production (Table 5). These findings presented an opportunity for dairy producers; that an initial investment in labor could increase milk production efficiency for the remainder of lactation. Poole (1982) speculated that the practice might not be adopted, however, because producers would be discouraged by the partial decrease in milk production upon cessation of frequent milking, despite the significant carry-over effect.
The effect of suckling during early lactation on milk production of dairy cows. Ad libitum suckling for the first 8 weeks of lactation increases milk production through late lactation (re-drawn from Everitt and Phillips, 1971). Cows were either milked 2X during the entire lactation (solid line), or were suckled by calves until 8 weeks of lactation, followed by 2X milking thereafter (dashed line).
Milking routineb | Feed cost during FMc | Feed cost after FMd | Labore | Miscellaneous costf | Extra milk income/cow/yrg | Total net income/cow/yr | 100-cow herdh |
4X 1 to 21 | $19.28 | $98.00 | $84.00 | $0.50 | $294.75 | $92.94 | $9,293.60 |
4X 1 to 14 | $12.86 | $100.75 | $56.00 | $0.34 | $210.29 | $40.33 | $4,032.85 |
4X 7 to 21 | $12.86 | $98.00 | $56.00 | $0.34 | $239.33 | $72.12 | $7,212.35 |
Potential economic return of milking four-times daily during early lactation.a
Reference | Treatment durationd | Parity | Change in milk yield (kg/d; 2X vs. 3X) | Change in milk yield (kg/d; 2X vs. 4X) | Change in milk yield (kg/d; 3X vs. 6X) |
Pearson et al., 1979 | 1 to 150 | ≥ 2 | + 2.2 | ||
Poole, 1982 | 1 to 140 | ≥ 2 | + 4.4 (acute) | ||
+ 1.84 (pers.) | |||||
1 | + 2.17 (acute) | ||||
+ .65 (pers.) | |||||
Bar-Peled et al., 1995 | 1 to 42 | ≥ 2 | + 7.3 (acute) | ||
+ 5.1 (pers.) | |||||
Sanders, 2000 | 1 to 42 | ≥ 2 | + 6.0 (acute) | ||
+ 3.7 (pers.) | |||||
1 | + 1.7 (acute) | ||||
Hale et al., 2003 | 1 to 21 | ≥ 2 | + 8.6 (acute) | ||
+ 2.6 (pers.) | |||||
Dahl et al., 2004b | 1 to 21 | ≥ 2 | + 14 (acute) | ||
+ 3.7 (full lactation) |
Summary of select literature reports on the effects of frequent milking during early lactation on milk yield of dairy cowsa
In an attempt to minimize additional costs associated with frequent milking, and to investigate the response of dairy cows to frequent milking or suckling during a short interval of time in early lactation, Bar-Peled et al. (1995) compared 3X to 6X or 3X+suckling for the first 6 wk of lactation, followed by 3X of all cows. Relative to cows milked 3X during the entire lactation, 6X and 3X + suckling acutely increased milk production by 7.3 and 14.7 kg/d, respectively (Bar-Peled et al., 1995). Cessation of frequent milking or suckling was associated with a partial decline in milk production; however, a carry-over effect was observed in 6X cows (+5.1 kg/d relative to 3X; Bar-Peled et al., 1995). In a similar experiment, Sanders et al. (2000) observed an acute increase of 6 kg/d and a carry over response of 3.7 kg/d in 6X cows relative to 3X cows. In heifers, the acute response to 6X was lower in magnitude (+1.7 kg/d), and no carry over effect was observed (Sanders et al., 2000).
A summary of literature reports on the effect of suckling during early lactation on milk production is presented in Table 6. The results of subsequent experiments have further narrowed down the ‘window’ during early lactation wherein frequent milking can increase milk production for the remainder of lactation. Hale et al. (2003) assigned cows to 2X or to 4X for the first 3 wk of lactation, followed by 2X. Four times daily milking was associated with an acute increase of 8.8 kg/d and a carry over effect of 2.6 kg/d for the remainder of lactation. A treatment interval of 1 to 21 DIM was also used in a field study by Dahl et al. (2004b), who observed similar effects of frequent milking during early lactation. In contrast, VanBaale et al. (2005) assigned cows to 3X or 6X for the first 7, 14, or 21 d of lactation and reported that 6X did not increase milk production relative to 3X. Their observations were inconsistent with previous reports, and the authors speculated that facility logistics may have influenced their results because 6X cows were housed farther away from the milking parlor and spent a considerably longer time away from their pen than 3X cows (VanBaale et al., 2005). With the exception of one negative report (VanBaale et al., 2005), and one abstract (Fernandez et al., 2004), it is generally accepted that frequent milking increases milk yield, and that frequent milking or suckling during early lactation can increase milk production for the remainder of lactation (see Tables 5 and 6). The mechanistic basis for the milk yield response to frequent milking, however, is poorly understood. Even less understood are the mechanisms involved in the persistent effect on milk yield of frequent milking during early lactation.
Reference | Treatment Duration (DIM) | Parity | 2X vs. 1X + suckle | 2X vs. 2X + suckle | 3X vs. 3X + suckle |
Everitt and Phillips, 1971 | 1 to 70 | 2+ | (+) 1.2 kg/d (pers.a) | ||
1 | (+) .87 kg/d (pers.) | ||||
Walsh, 1974 | 1 to 100 | 2+ | (+) 11.3% (acuteb) | ||
(+) 7.7% (pers.) | |||||
Moss and O\'Grady, 1978 | 1 to 56 | 2+ | (+) 3.3 kg/d | ||
(no pers.) | |||||
Thomas et al., 1978 | 1 to 56 | 2+ | (+) 1.68 kg/d (acute) | ||
(+) 1.77 kg/d (pers.) | |||||
Fulkerson et al., 1978 | 1 to 56 | 1 | (+) 16% (full lactation) | ||
Pearson et al., 1979 | 1 to 150 | 2+ | |||
Peel et al., 1979 | 1 to 28 | 1 | (+) 13% (pers.) | ||
Fulkerson et al., 1981 | 1 to 7 | 2+ | (+) 9% (pers.) | ||
Teeluck et al., 1981 | 1 to 90 | 2+ | (+) 2.2 kg/d | (+) 3.33 kg/d | |
Poole, 1982 | 1 to 140 | 2+ | |||
Little et al., 1991 | 1 to 94 | 5 | (+) 15% (full lactation) | ||
Bar-Peled et al., 1995 | 1 to 42 | 2+ | + 14.7 kg/d (acute) |
Summary of select literature reports on the effects of suckling during early lactation on milk yield of dairy cows
Shortly after the report in the 1930s that frequent milking increased milk production, several studies utilized unilateral frequent milking (UFM) to investigate the effect. Half-udder designs are extremely powerful because they eliminate variation between animals due to environment, nutrition, and genetics. In addition, both udder halves are theoretically exposed to the same systemic factors, hence responses to frequent milking are strictly at the level of the mammary gland. A summary of the milk yield response to frequent milking in selected half-udder experiments is presented in Table 7. The early reports provided strong evidence for local regulation of milk production, and increases in milk yield from 8.4 to 32% in the frequently-milked udder half were observed (Ludwick et al., 1941; Cash & Yapp, 1950; Agarwala & Sundaresan, 1955; Claesson et al., 1959). Morag (1973b) reported that the increase in milk production in response to UFM occurs within 24 h, and the magnitude of the response was independent of previous milk production. In addition, heifers respond to UFM; Hillerton et al. (1990) milked udder halves 2X or 4X for 4 wk during mid-lactation. In both cows and heifers, milk production of 4X udder halves increased by 10.4% relative to 2X udder halves (Hillerton et al., 1990).
Reference | Stage of Lactation | Duration of UFM | Parity | Change in milk yield (%; 2X vs. 3X) | Change in milk yield (2X vs. 4X) |
Cash & Yapp, 1950 | - | Full lactation | ≥ 2 | + 32 | |
Agarwala & Sundaresan, 1955 | Early | 25 d intervals | ≥ 2 | + 8.4 | |
Hillerton et al., 1990 | Mid-late | 28 d | ≥ 1 | (+) 10.4% | |
Knight et al., 1992 | Mid | 14 d | 1 | (+) 14% | |
Knight, 1992 | Early | 42 d | ≥ 1 | + 10.4 | |
Norgaard et al., 2005 | Mid | 7 d | ≥ 1 | (+) 18% | |
Wall & McFadden, 2007a | 1 DIMd | 21 d | ≥ 2 | (+) 3.5 kg/d (acutee) | |
(+) 1.8 kg/d (pers.f) | |||||
Wall & McFadden, 2007b | 1 DIM | 14 d | ≥ 2 | (+) 3.7 kg/d (acute) | |
(+) 1.2 kg/d (pers.) | |||||
7 DIM | 14 d | ≥ 2 | (+) 2.9 kg/d (acute) | ||
(+) 1.5 kg/d (pers.) | |||||
Wright et al., 2011 | 1 DIM | 21 d | 1 | (+) 2.8 kg/d (acutee) | |
(+) 0.9 kg/d (pers.) | |||||
Shields et al., 2011 | 1 DIM | 21 d | ≥ 2 | (+) 3.4 kg/d |
Summary of select literature reports on the effects of unilateral frequent milking (UFM) on milk yielda
As mentioned previously, an emerging theme in these experiments has been that the effects of frequent milking during early lactation on milk production persist even after a lower milking frequency is resumed (Bar-Peled et al., 1995; Hale et al., 2003; Dahl et al., 2004b). Although this persistent milk yield response has been consistently observed (Table 5), it was unknown whether the response was regulated by hormones, by local factors within the mammary gland, or by the combination of the two. To investigate this question, we used a half-udder model and assigned cows to UFM (4X of the right udder half, 2X of the left udder half) for d 1 to 21 of lactation, followed by 2X for the remainder of lactation (Wall & McFadden, 2007a). When the half-udder milk yields were adjusted to the equivalent of a whole udder basis, the acute and long-term milk yield responses to frequent milking that we observed were consistent with those reported by Hale et al. (2003). Therefore, our results indicated that both the acute and persistent effects of frequent milking during early lactation are regulated by local factors within the mammary gland. This is illustrated in Figure 3A and B.\n\t\t\t\tFigure 3A (re-drawn from Bar-Peled et al., 1995) shows the milk yield response of multiparous cows to 6X for the first 6 wk of lactation, followed by 3X. We observed a similar effect using a half-udder experiment (Figure 3B), and the milk yield response lasted through 270 DIM. This finding presents some intriguing questions and research opportunities. First, what are the local factors that regulate milk production capacity of the mammary gland? Once the factor(s) have been identified and pathways understood, how can we refine our approach to maximize milk production efficiency of dairy cows? Now that it is established that the factors are indeed local, the problem has become relatively simplified. Extremely powerful, within cow experiments that are less sensitive to the influence of environment, genetics and nutrition can now be designed to ask such mechanistic questions.
A. Six-times daily milking for days 1 to 42 of lactation increases milk production through late lactation (re-drawn from Bar-Peled et al., 1995). B. Unilateral four-times daily milking for days 1 to 21 of lactation increases milk production for the remainder of lactation (Wall and McFadden, 2007).
On the road to refinement, one theme that has transpired is the existence of a ‘window’ of time wherein the mammary gland is especially responsive to frequent milking. The duration of this window has been shortened from the first 10 wk of lactation (Moss & O\'Grady, 1978; Thomas et al., 1978) to the first 6 wk of lactation (Bar-Peled et al., 1995; Sanders et al., 2000), and shortened further still to the first 3 wk of lactation (Hale et al., 2003; Dahl et al., 2004b; Wall & McFadden, 2007a). It was unknown whether a shorter duration or altered timing of frequent milking during early lactation would still elicit a persistent effect on milk production; however, since any costs associated with extra labor are increased only during frequent milking, it was of great interest to shorten the duration of frequent milking if a persistent increase in milk yield could still be observed. To answer this question, we assigned cows to UFM (4X of the right udder half, 2X of the left udder half) for d 1 to 14 or d 7 to 21 of lactation (Wall & McFadden, 2007b). We observed an acute milk yield response in both treatments; and a significant carry-over effect in the d 7 to 21 group. There was a numerical carry-over for the d 1 to 14 group; however it was not significant. Our results indicate that within the first 21 DIM, an interval of frequent milking as short as 2 wk can elicit a persistent increase in milk production. As mentioned previously, similar observations have been made on the response of cows and heifers to suckling during early lactation (Fulkerson et al., 1978; Peel et al., 1979). Further narrowing of this “window” within the first 21 of lactation, as well as characterization of the cellular response could provide insight into the mechanisms underlying the receptiveness of the mammary gland to stimulus during this time.
It has long been thought that the hormones released at milking may be involved in regulating the galactopoietic effects of frequent milking on milk production. Indeed, multiple hormones are released during milking including glucocorticoids, oxytocin, and prolactin (Tucker et al., 1975; Carruthers & Hafs, 1980; Akers & Lefcourt, 1982). Oxytocin is responsible for milk ejection. Cows suckling calves are thought to have more efficient milk ejection due to increased secretion of oxytocin elicited by the presence of the calf. In fact, on dairies using cross breeds and cows not bred for high milk production, the calf is often used as a facilitator of milk letdown during milkings (Little et al., 1991; Krohn, 2001; Bruckmaier & Wellnitz, 2008). In addition, treatment with exogenous oxytocin was associated with increased milk production of both dairy cows (Nostrand et al., 1991; Ballou et al., 1993; Lollivier & Marnet, 2005) and sheep (Zamiri et al., 2001). Therefore, it is possible that oxytocin is involved in regulating the increase in milk production elicited by frequent milking or suckling, perhaps by allowing for more complete milk removal and a decrease in negative feedback on the gland.
Along with enhanced milk production, Bar-Peled et al. (1995) observed increased concentrations of growth hormone, insulin-like growth factor-1, oxytocin and prolactin in circulation of cows that were frequently milked or suckled. In addition, the magnitude of milking-induced PRL release declines concomitantly with the decrease in milk production as lactation progresses (Koprowski & Tucker, 1973). Consequently, PRL has been hypothesized as a candidate regulator of the effects of frequent milking on milk production (Dahl et al., 2004a). In an attempt to determine whether milking-induced PRL release indeed mediates the effects of frequent milking on milk production, we assigned cows to 2X, 4X, or 2X + twice daily injections of PRL (Crawford et al., 2004; Wall et al., 2006). Four times daily milking or PRL injections increased milk production relative to 2X (Crawford et al., 2004); however our results indicated that PRL injection or frequent milking exerted distinct effects on mammary cell growth and gene expression, thus probably increased milk production via separate mechanisms (Wall et al., 2006). The response to unilateral frequent milking during early lactation supports this concept; frequent milking may stimulate milk production via local factors, whereas PRL injections may increase milk yield through a more systemic pathway.
Several authors have speculated that frequent milking increases milk yield via an increase in mammary cell number and (or) activity (Bar-Peled et al., 1995; Stelwagen & Knight, 1997; Sanders et al., 2000; Hale et al., 2003), both of which are critical to improved lactation performance (Capuco et al., 2003). Hillerton et al. (1990) observed an increase in activity of mammary enzymes, protein and lactose synthesis (in heifers only), DNA synthesis, and alveolar area in response to increased milking frequency, and concluded that cellular differentiation and proliferation were optimized with frequent milking. Hale et al. (2003) reported an increase in mammary cell proliferation at 7 DIM in cows that were milked 4X for the first 3 wk of lactation compared to cows milked 2X; however, differences in proliferation were only observed in one of the two frequently milked cow groups. In contrast to those experiments, Norgaard et al. (2005) reported that despite an increase in milk yield (+18%), there was no effect of frequent milking on cell death, proliferation, or enzyme activities in the mammary gland. In agreement with that report, we have observed across multiple experiments that relative to 2X, 4X did not affect mammary cell proliferation or apoptosis (Wall et al., 2006; Wall & McFadden, 2010; Wall et al., 2011b), indicating that changes in milking frequency influence milk yield through an alternative mechanism.
Using a unilateral frequent milking model and a functional genomics approach, we determined that the increase in milk yield associated with frequent milking is regulated by changes in gene expression elicited by removal of milk from the gland (Wall et al., 2011a). We then used a sequential biopsy approach and obtained mammary tissue at various times during and after exposure to unilateral frequent milking and determined that the temporal expression of 64 genes was co-regulated by unilateral frequent milking (Wall et al., 2011b). Importantly, the pattern of differential expression of the 64 genes was negatively correlated with differential milk yield (Figure 4); therefore, we hypothesize that we have identified a pathway for the autocrine regulation of milk production. Furthermore, this transcriptional signature appears to be malleable and adaptable to the needs of the offspring (mimicked by changes in milking frequency), since expression of some of the genes was still different between udder halves nearly three weeks after cessation of treatment (Figure 4). Future experiments will clarify the role of these genes in the mammary gland and their involvement in the autocrine regulation of milk production.
What is unique to early lactation, when the stimulus of frequent milking for a short duration can elicit a persistent increase in milk production? This question remains unanswered, but work by Stelwagen and Knight (1997) has provided some clues. Using a half-udder model, they compared 1X to 2X of cows in early or late lactation and reported a more dramatic increase in milk secretion efficiency in response to 2X during early lactation compared to late lactation (Stelwagen & Knight, 1997). In agreement, Walsh (1974) observed different effects of suckling during early vs. late lactation on mammary health. During early lactation, suckling of a calf was associated with a 27% decrease in clinical mastitis, whereas suckling during late lactation had no effect (Walsh, 1974). Taken together, the observations of Walsh (1974) and Stelwagen and Knight (1997) indicate that there are distinct differences in the cell population during early vs. late lactation. It is possible that during early lactation, there are more secretory cells present in the mammary gland, and these cells may have more potential to respond to stimulus than cells present in late lactation. Frequent milking may prevent otherwise unused cells from undergoing apoptosis, or may provide the stimulus to push the cells to reach higher levels of differentiation and secretory capacity. These scenarios could result in an increase in the number of cells in the gland throughout lactation, an increase in the activity of cells throughout the lactation, or both. Shorten et al. (2002) proposed a hypothetical model by which frequent milking for the entire lactation increases the number of active alveoli by reducing the rates of quiescence and senescence in the mammary gland. If such an event occurs with frequent milking during early lactation, this could permanently increase the number of actively secreting alveoli and enhance milk production potential for the remainder of lactation. Many of the biopsy studies that have been previously conducted could have captured changes in mammary cell activity, but would not have captured changes in total cell number or in rates of quiescence and senescence within the gland.
Unilateral four-times daily milking for days 1 to 21 of lactation is associated with coordinated changes in mammary expression of 64 genes, and this is negatively correlated with differential milk yield. Solid vertical line represents cessation of unilateral frequent milking.
Research in the area of frequent milking of dairy cows has established a robust milk yield response to increased milking frequency or suckling, and has identified a window of time during early lactation wherein the mammary gland is especially responsive to the stimulus of frequent milk removal. In addition, there is now evidence that this response is regulated within the mammary gland. Consequently, the concept of ‘use it or lose it’ is becoming more clearly established, that is, the stimulus of frequent milking or suckling during early lactation permanently increases the milk production capacity of the mammary gland. Exciting research opportunities now present themselves, and ongoing experiments seek to identify the local factor(s) that are involved in the regulation of milk production efficiency of dairy cows. The opportunity now exists for dairy scientists to identify the mechanisms involved in local regulation of milk production potential, and for dairy producers to further refine milking management practices to maximize milk production efficiency of their operations.
Type I interferonopathies are congenital genetic disorder of the interferon (IFN) system, characterized by certain clinical symptoms resulting from the overproduction of IFNα [1, 2, 3]. In our opinion, the term interferonopathy means a general pathology of the interferon system, congenital or acquired, which includes the following types of disorders of the IFN system: deficiency; paralysis of the IFN system; inadequate response on viruses, bacteria, and mutated tumor cells; and overproduction of type I IFN. Interferons are the cornerstone of immune defense against viral infections and are also involved in the regulation of immune responses. Currently there are isolated type I, II, and III interferons in accordance with their ability to interact with the three types of receptors. Type I interferons include IFNα/IFNβ; type II interferons, IFNγ; and type III interferons, interferon-like cytokines (IL-29, IL-28A, IL-28B) [4].
\nThe main role of type I interferons is to control viral infection. The synthesis and secretion of type I IFN is activated when our immune cells come in contact with viruses. Type I IFN is synthesized by epithelial cells, many cells of the immune system, including plasmacytoid dendritic cells (pDC) that recognize foreign or auto nucleic acids. Although both epithelial and pDC synthesize type I IFN simultaneously in different tissues, pDC-derived type I IFN actually exerts various immune responses through its cognate receptors on target cells. This results in modulation of diverse processes such as antigen presentation and activation of adaptive immunological process involving B and T cells [5]. For the synthesis of interferons in the body, cell activation is necessary. Toll-like receptors (TLRs); RIG-like receptors (RLRs), RIG-I; melanoma differentiation-associated protein 5 (MDA5); and cyclic GMP-AMP synthase (cGAS) participate in the recognition of foreign and host nucleic acid sites [6]. The main inducers of the synthesis of type I interferons are double-stranded and single-stranded RNA of viruses, as well as bacterial DNA [7]. RIG-like receptors recognize both single- and double-stranded viral RNAs, whereas cGAS (cyclic GMP-AMP synthase), in contrast, recognizes double-stranded DNA and RNA: DNA duplexes are formed during the replication of retroviruses and catalyze the synthesis of cGMP-AMP, which is the main agonist of the adapter protein—STING. After binding RNA, RIG-I and MDA5 bind the mitochondrial antiviral-signaling (MAVS) adapter protein. Both STING and MAVS stimulate downstream signaling cascades that include multiple kinases and finally lead to phosphorylation of IRF3 and induction of interferon synthesis [8]. Then type I IFN binds to the corresponding IFNAR receptors located on the cell membrane, which leads to the activation of Tyk2 and Jak1 kinases, which undergo phosphorylation and activate signal transduction and transcription activation proteins (STAT1 and STAT2). As a result, a heterotrimeric complex is formed, known as IFN-stimulating gene factor-3 (ISGF3), which includes IFN regulatory factor 9 (IRF9). Janus kinase (Jak) activation is negatively regulated by IFNα-inducible proteins SOCS1 and SOCS3. The binding of ISGF3 promotes interferon-stimulated genes (ISGs), which leads to their transcriptional activation and the collective actions of hundreds of ISGs, resulting in the production of a large number of induced IFN, which inhibits both viral replication and the spread of viruses. Rapid type I IFN secretion and then rapid synthesis induce activity of congenital and adaptive immunity cells by activation of pro-inflammatory cytokines that activate cellular and humoral antiviral immune response [9] (\nFigure 1\n).
\nMolecular mechanisms of the induction of type I and III interferon synthesis. PAMPs: dsRNA, double-stranded RNA; ssRNA, single-stranded RNA. Nucleic acid sensors: cGAS, cyclic GMP-AMP synthase; MDA5, melanoma differentiation-associated protein 5; RIG-I, RIG-I-like receptor dsRNA helicase enzyme. Adaptor proteins: TIRAP, toll-interleukin 1 receptor (TIR) domain-containing adaptor protein; MAVS, mitochondrial antiviral-signaling protein; STAT, signal transducer and activator of transcription. Nuclear factors: IRF, IFN regulatory factor; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; IFNAR, IFNα receptor; ISGs, interferon-stimulated genes; Tyk, tyrosine kinase; Jak, Janus kinase.
During acute viral infection, IFN level is significantly elevated, and more than 70% of cells acquire antiviral status, i.e., they are protected against virus penetration and are able to efficiently neutralize them. Type I IFN has several very important positive effects: direct and indirect antiviral effect, protective antiviral effect, antitumor effect, and immunomodulatory effect. At the same time, it was shown that increased production of IFN can lead to negative consequences similar to autoimmune reactions.
\nThe information presented by several authors about interferon system pathologies is vast and diverse but is not well-systematized. All known defects of IFN system, including type I and II IFN, whether congenital or acquired, including various disorders (deficiency; inadequate response to contact with viruses, bacteria, and mutated or tumor cells; IFN system paralysis; IFN overexpression), are pathologies of IFN system. All those defects of IFN system are collectively known as interferonopathies. There is an urgent need to create a classification of congenital and acquired disorders of the IFN system. We believe that the classification of IFN pathology would help in determining the correct approaches to the differentiated choice of adequate treatment tactics.
\nBased on our own and others’ experience, we have developed the interferonopathies classification as per the following table [1, 2, 3, 10, 11, 12, 13, 14, 15] (\nTable 1\n).
\nRecently several studies have presented genetic and molecular disorders accompanying rare Mendelian diseases that are associated with type I IFN overexpression resulting from defects in intracellular nucleic acid metabolism, DNAse deficiency, or defects in sensor nucleic acid recognition. Genetic disorders—Mendelian diseases (Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, proteasome-associated autoinflammatory syndrome, Singleton-Merten syndrome)—resulting in inadequately high type I IFN overexpression accompanied by a certain range of clinical disorders are called type I interferonopathies. Interferonopathies have rare pathology; their occurrence varies from 1:10,000 to 1:1,000,000 people. According to the literature, the most common syndrome is Aicardi-Goutières [16]. The frequency of some recently described genetic disorders (e.g., PRAAS2) cannot be counted [17]. Such disorders cause a great number of own nucleic acids in cell cytoplasm to appear. It results in active DNA recognition and pathological overexpression of type I IFN which launch autoimmunity hyperactivation, thus leading to autoimmune inflammation affecting the central and peripheral nervous system. It also results to skin and vessel damage (vasculitis), lung damage, etc. Therefore rapid and efficient immune reaction to alien nucleic acids is positive when it causes type I IFN activation during pathogen invasion and antimicrobial protection. It becomes deleterious when it responds to own DNA which is due to the defect of own nucleic acid metabolism. Some neurological, vascular, and skin symptoms which are typical for type I interferonopathies are reviewed in such multifactorial diseases as exanthematous lupus erythematosus, widespread vasculitis, and autoimmune multiple myositis [6, 7, 18] (\nTable 2\n).
\nI. Congenital interferonopathies | \nII. Acquired—secondary interferonopathies | \n
---|---|
\n1. IFN deficiency\n 1.1 Interferon α deficiency (IFNα) 1.2 Interferon β deficiency (IFNβ) 1.3 Interferon γ deficiency (IFNγ) \n2. Interferon overexpression\n 2.1 IFNα overexpression 2.1.1 Autoinflammatory syndromes and autoimmune diseases (systemic lupus erythematosus (SLE), systemic angiitis, dermatomyositis), Down syndrome 2.1.2 Type I interferonopathies: Aicardi-Goutières syndrome (AGS), familial chilblain lupus (FCL), spondyenchondromatosis, proteasome-associated autoinflammatory syndrome (PRAAS), Singleton-Merten syndrome (SMS) | \n1. IFN deficiency\n 1.1 IFNα deficiency 1.2 IFNβ deficiency 1.3 IFNγ deficiency \n2. Interferon system paralysis\n 2.1 Blockage IFNα adequate response 2.2 Blockage IFNβ adequate response 2.3 Blockage IFNγ adequate response \n3. IFN overexpression\n 3.1 Cytokine storm | \n
Classification of interferonopathies.
Syndrome | \nResponsible gene | \nPhenotypes | \n
---|---|---|
Aicardi-Goutières syndrome | \nTREX1, RNASEH2B, RNASEH2C, RNASEH2A, SANHD, ADAR, IFIH1 | \nEncephalopathy, muscular dystonia, microcephaly, calcification of the basal ganglia in the substance of the brain, cramps, fever, increased acute phase blood markers, cytopenia, increased levels of interferon in the cerebrospinal fluid | \n
Singleton-Merten syndrome | \nIFIH1 DDX58 RIG-I | \nCardiovascular diseases with aortic calcification, osteoporotic manifestations, dental and skeletal abnormalities, psoriatic skin lesions | \n
Proteasome-associated autoinflammatory syndromes Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) | \nPSMB4 PSMB3 PSMB8 PSMB9 POMP | \nErythematous skin lesions, panniculitis, lipodystrophy, arthritis with the development of joint contractures, myalgia, hepatomegaly, splenomegaly, calcification of the basal ganglia in the brain, fever, increased acute phase blood markers Recurrent fevers in the first months of life, along with characteristic skin lesions, lipodystrophy, violaceous swollen eyelids, arthralgias, extremity contractures, and delayed physical development as well as systemic inflammation markers have been identified as CANDLE-related clinical manifestations | \n
STING-associated vasculopathy with onset in infancy (SAVI) | \nTMEM173 | \nVasculopathy with the formation of distal gangrene; necrosis; erythematous rash on the face, tip of the nose, and auricles; interstitial lung disease, arthralgia, fever | \n
Spondyloenchondrodysplasia (SPENCD) | \nACP5 | \nSpondylometaphyseal dysplasia, stunting, calcification of the basal ganglia in the substance of the brain, arthropathy, thrombocytopenia, deficiency of cellular and humoral immunity | \n
ISG15 deficiency | \nISG15 | \nCalcification of the basal ganglia in the substance of the brain, convulsions, mycobacterial infections | \n
USP18 deficiency (pseudo-TORCH syndrome) | \nUSP18 | \nCerebral hemorrhage and calcification, hepatomegaly, thrombocytopenia | \n
Trichohepatoenteric syndrome 2 | \nSKIV2L | \nWatery diarrhea, brittle and tangled hair, liver damage, mental retardation | \n
Retinal vasculopathy with cerebral leukodystrophy (RVCL) | \nTREX1 | \nThe main characteristics of RVCL include the middle-age onset, the progressive visual loss due to retinal vasculopathy (telangiectasias, microaneurysms, and retinal capillary obliteration around the macula), and variable neurological manifestations such as dementia or migraine | \n
Familial chilblain lupus | \nTREX1 | \nRare monogenic form of cutaneous lupus erythematosus; partly ulcerating acral lesions or painful bluish-red papules located in the fingers, toes, nose, and ears; arthralgias, affecting mainly large joints, without evidence of true arthritis; photosensitivity; or mouth ulcers | \n
X-linked reticulate pigmentary disorder (XLPDR) | \nPOLA1 | \nGeneralized hyperpigmentation intermingled with small hypomelanotic macules during early childhood, a distinctive face characterized by an upswept frontal hairline and arched eyebrows, as well as severe photophobia, recurrent respiratory infections, and severe gastrointestinal disorders | \n
Genetic disorders associated with immune dysregulations and clinical characteristics of interferonopathies associated with type I IFN overexpression.
Data available on genetic defects of intracellular nucleic acid metabolism greatly facilitate understanding of the mechanisms of insufficient immune activation, which can help in the development of new therapeutic approaches to the treatment of autoinflammatory and autoimmune diseases [1, 2, 3]. The progress in understanding immunopathogenesis mechanism makes it possible to set the exact targets for new therapeutic strategy development [1, 2]. The immune dysregulation syndrome is characterized by a high level of IFNα, a deficiency of regulatory T-lymphocytes, impaired functioning of B cells, and low content of low-density neutrophils. These neutrophils easily form neutrophilic extracellular traps (NET), and the resulting DNA complexes provoke an increase in IFNα synthesis, and then pDC recognizes autoDNA and produces IFNα [10, 11, 19]. These disorders are observed primarily in systemic lupus erythematosus. New approaches in treatment of SLE and other type I interferonopathies have been developed. Monoclonal antibody therapy in type I interferonopathies treatment with SLE is sifalimumab, rontalizumab against IFNα, and anifrolumab against IFNα receptor (IFNAR). Baricitinib (JAK1/JAK2 inhibitor) is currently at clinical studies (phases 2 and 3) in small cohort of patients with interferonopathies [20, 21, 22]. It is also known that treatment with baricitinib decreased disease signs and symptoms and allowed a significant reduction of corticosteroid treatment in patients with CANDLE and SAVI [23] (\nFigure 2\n).
\nTarget therapies by biologics in the treatment of type I IFN overproduction. IFNAR, IFNα receptor; ISGs, interferon-stimulated genes; Tyk, tyrosine kinase; Jak, Janus kinase; pDC, plasmacytoid dendritic cell; STAT, signal transducer and activator of transcription.
There are genetic defects in the synthesis of IFNα/IFNβ and IFNγ and defects in the receptors for IFNα and IFNγ (IFNAR and IFNGR) including genetic disorders associated with low IFN production according to recent studies. Those genetic defects of IFNs are accompanied by clinical signs of severe recurrent viral and/or mycobacterial infection.
\nCongenital defects of type I IFN are associated with mutation of genes participating in synthesis of IFNα/IFNβ resulting to deficiency of various molecules (STAT1, UNC93B1, MCM4, TLR3, TRAF3, TRIF, TBK1) and decline level of IFNα/IFNβ. Deficiency of IFNγ, its receptor IFNGR (IFNγR1), and IL-12 plays an important role in IFNγ regulation [12, 24, 25]. Congenital defects of type I IFN have been globally systematized in 2015 by Bousfiha et al. [24]. It has been proven that it causes severe viral and bacterial intracellular infections which are the cause of deaths. Such patients are needed in replacement therapy with recombinant IFNα2b in complex with antioxidants. Congenital defects of IFNγR1 receptor are associated with severe intracellular mycobacterial infections. Combined genetic defects leading to deficiency of IFNα and IFNγ are associated with an autosomal recessive mutation in the STAT1 gene, which causes severe viral and mycobacterial infections [12, 24, 25] (\nTable 3\n).
\nPredominant susceptibility to viral infection | \n||
---|---|---|
Syndrome | \nResponsible gene | \nPhenotypes | \n
Herpes simplex encephalitis (HSE) | \nAR (autosomal recessive inheritance): UNC 9381 TLR3 TRIF AD (autosomal dominant inheritance): TLR3 TRIF TRAF3 TBK1 | \nDominant clinical phenotype is HSE during primary infection with HSV1, usually between 3 months and 6 years of age Specific tests examining the TLR3 pathway marked decrease on the ability of patient’s fibroblasts to produce IFNβ/IFNλ in response to TLR3 agonists and HSV1 infection | \n
Warts, hypogammaglobulinemia, infection, myelokathexis (WHIM) syndrome | \nAD: CCXR4 | \nWarts/human papilloma virus infection Neutropenia, reduced B cell numbers | \n
Epidermodysplasia verruciformis | \nEVER1/TMC6, EVER2/TMC8 | \nHuman papilloma virus (group B1) infection and skin cancer | \n
STAT1 deficiency STAT2 deficiency | \n\n | Viral infections | \n
CD16 deficiency | \n\n | Severe viral infections | \n
IRF7 deficiency | \n\n | Severe influenza disease | \n
\nSusceptibility to mycobacteria\n | \n||
Syndrome | \nResponsible gene | \nPhenotypes | \n
IRF8 deficiency | \nAR: IRF8 | \nSusceptibility to mycobacteria, Candida, myeloproliferation | \n
RORc deficiency | \nRORc | \nSusceptibility to mycobacteria, Candida\n | \n
MSMD IL-12-IFNγ axis deficiency | \nAD: IFNGR1 Complete AR IFNGR1 and AR IFNGR2 Partial STAT1 LOF (AD), partial IFNGR1, partial IFNGR2, complete IL-12R1, complete IL-12B, complete ISG15, XL CYBB, IRF8, Tyk2, XL NEMO | \nMycobacterial osteomyelitis Serious disseminated BCG and environmental mycobacteria infections (soft tissue, bone marrow, lungs, skin, bones, and lymph nodes), Salmonella spp., Listeria monocytogenes, and viruses Usually less severe | \n
Genetic disorders and clinical characteristics of interferonopathies associated with type I IFN deficiency.
There are secondary acquired disorders in the IFN system, which cause a weakening of antiviral resistance in adults and children [12]. Different viruses can damage synthesis and production of IFN at various interferonogenesis stages. These secondary defects of the type I IFN lead to the occurrence of severe viral infections (herpesviral encephalitis), recurrent acute respiratory viral infections (recARVI), chronic recurrent HSV1 infection, atypical chronic EBV infections, and other atypical cases of virus infection. It was shown that viruses can avoid the effects of IFN and inhibit the action and synthesis of IFN using various molecular mechanisms. Numerous studies demonstrated that a lot of viruses (all herpesviruses, majority of respiratory viruses, hepatitis B and C viruses, etc.) produce proteins capable of inhibiting synthesis and production of IFNα/IFNβ and IFNγ. Viruses can damage each stage of the expression of ISGs [9] (\nFigure 3\n).
\nBlockage of signaling pathways for the induction of interferon by viruses (red hexagons indicate the points of application of all herpesviruses, majority of respiratory viruses, chronic hepatitis B and C viruses, etc.). dsRNA, double-stranded RNA; IRF, IFN regulatory factor; IFNAR, IFNα receptor; ISGs, interferon-stimulated genes; Tyk, tyrosine kinase; Jak, Janus kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; cGAS, cyclic GMP-AMP synthase; MAVS, mitochondrial antiviral-signaling protein; MDA5, melanoma differentiation-associated protein 5; STAT, signal transducer and activator of transcription; TRIF, TIR domain-containing adaptor inducing interferon-beta; Ku70, component of the nonhomologous end-joining pathway that repairs DNA double-stranded breaks.
Patients with recurrent acute respiratory viral infections and various chronic herpesvirus infections including recurrent herpes viral infections have secondary defects of IFN system. Immunocompromised children of various ages and adults may suffer from recARVI with the frequency of 10 to 16–24 and more times annually; almost in 100% of cases, it is associated with the presence of mono and mixed herpes viral infection. The frequency of recurrent chronic HSV1/HSV2 infection of facial and/or genital location in those patients may reach 16–24 times per year. Epstein-Barr virus may cause atypical virus infection associated with chronic fatigue syndrome [12].
\nThe problem of developing new approaches to the treatment of congenital and acquired defects of the IFN system is very acute [12, 26, 27, 28]. Acquired defects in the IFN system (93–96%) and impaired functioning of neutrophilic granulocytes (NG) are most often detected in patients with recurrent chronic herpes virus infections.
\nWe conducted experiment in vitro to study the effect of recombinant IFNα2b (rIFNα2b) on NG in viral (cells from patients with HSV1/HSV2 infection) and bacterial (model infection by fMLP) infections. The study showed positive regulation of the negatively charged IFNαβR1+IFNγR+TLR4+NG phenotype in patients with various chronic herpesvirus infections under the influence of rIFNα2b in vitro. It was noted that the number of NGs carrying IFNαβR1 and IFNγR and expression density of IFNαβR1 is increasing, wherein expression density of IFNγR and TLR4 is decreased [29]. rIFNα2b modulating effects on CD16+CD66b+CD33+CD11b+NG phenotype transformed by fMLP in experimental model of bacterial process in vitro, to promote remodeling of the pro-inflammatory NG phenotype into anti-inflammatory, have been shown [30]. Thus rIFNα2b has a protective effect on the NG phenotype according to experimental data.
\nIn clinical practice, the use of parenteral IFN to correct disorders in the IFN system is very difficult due to the presence of numerous side effects. One should also bear in mind the inefficiency of short courses of IFN therapy for restoration of the normal IFN system functioning in recARVI, recurrent chronic herpes viral infection of facial or genital location, and papilloma virus infection of the skin and mucosa characterized by recurrent episodes when the frequency of recARVI and/or recurrent attacks of HSV1/HSV2 infection may reach 14–24 and more per year. For over 20 years, we have been developing interferon therapy programs using drugs in Russian production—rectal suppositories and gel of recombinant human IFNα2b (rIFNα2b+aox) in combination with antioxidants (vitamins E and C) (Viferon) [12, 13, 14, 15, 26, 27]. During that period, we managed to demonstrate safety, antiviral, and immunomodulatory efficiency of this kind of IFN therapy, total absence of any side effects that are typical for parenteral IFN therapy, and total absence of antibodies against IFNα2b. Replacement therapy with rIFNα2b + aox is prescribed to patients with primary, genetically preconditioned, congenital or acquired IFN system disorders. In case of primary IFN system disorders, patients need a basic recovery therapy making it possible to eliminate viral antigens as much as possible; and then it is required to select dosage for permanent replacement therapy with rIFNα2b+aox. In case of acquired interferon deficiency, patients are prescribed with differentiated therapy with high, medium, and low doses of rIFNα2b+aox (\nFigure 4\n).
\nDynamics of changes in the system of IFN in immunocompromised children against the background of therapy with rIFNα2b+aox (Viferon).
At the same time, in case when we had treated the group of patients with combined immunodeficiency (defects of induced production of IFNα and IFNγ and dysfunctions of phagocytic and microbicidal activities of neutrophilic granulocytes) that was associated with recurrent acute respiratory viral infection and different chronic herpes viral coinfections, combined interferon and immunomodulatory therapy was used. The aim was to restore the levels of induced production of IFNα and IFNγ and to reconstruct dysfunctions of phagocytic and microbicidal activities of neutrophilic granulocytes and other deficient chains in antiviral immunity. One group of children, group 1, received an interferon therapy program (rIFNα2b+aox), and patients in group 2 received a program of combined interferon therapy (rIFNα2b+aox) and immunotherapy (glucosaminylmuramyldipeptide). The use of replacement and immunomodulatory mono-rIFNα2b+aox or in combination with immunotherapy (glucosaminylmuramyldipeptide) has helped us to receive very good clinical efficacies and has reached restoration of interferon status and normal functioning of neutrophilic granulocytes (p < 0.05) (\nFigure 5\n). At the same time, it is required to take into account both uneven viral infection syndrome manifestation and the rate of IFNα deficiency as well as peculiarities of immune system disorders in case of secondary immune deficiency [12, 13, 14, 15, 27].
\nThe state of the interferon system in immunocompromised children with recurrent respiratory infections on the background of differentiated programs interferon and immunotherapy. Note: group 1 received an interferon therapy program (rIFNα2b+aox); group 2 received a program of combined interferon therapy (rIFNα2b+aox) and immunotherapy (glucosaminylmuramyldipeptide); (*p < 0.05, reliability in relation to control).
Here is an example illustrating the change in clinical, immune, and interferon status in immunocompromised children with recurrent acute respiratory viral infections under the influence of interferonotherapy.
\nClinical case. Patient X, 3 years old. The child suffers from repeated acute respiratory viral infections 1–2 times per month (14–16 episodes per year); the duration of the acute period of respiratory viral infection is 7–10 days. The clinical symptoms of the disease were acute rhinitis, acute pharyngitis, acute laryngitis, acute tracheitis, febrile and subfebrile body temperature for 2–4 days, and severe symptoms of intoxication. The duration of the frequent incidence of acute respiratory viral infections is 2 years. The defects of the immune system are a decrease of CD3+CD4+ lymphocytes and CD3+CD8+ lymphocytes; a decrease of immunoregulatory index; neutropenia; a decrease of bacteria absorption and digestion processes by neutrophils; and a decrease of microbicidal activity of neutrophils. We tested spontaneous and Newcastle disease virus-induced IFN production during the incubation of peripheral blood (24 h, t 37°C in 5% CО2). The level of induced IFNα in the patient was 4 IU/ml versus 58 IU/ml in control. The patient was prescribed rIFNα2b+aox therapy with a total duration of 2.5 months.
\nTreatment program:
Local intranasal use of rIFNα2b+aox (Viferon gel, 36,000 IU/g), two to three times a day, 6 weeks.
Systemic rectal application of rIFNα2b+aox suppositories according to a “step-by-step” scheme:
300,000 IU per day, 10 days.
300,000 IU per day three times a week, 2 weeks.
300,000 IU per day two times a week, 2 weeks.
150,000 IU per day two times a week, 2 weeks.
150,000 IU per day once a week, 2 weeks.
Conducted local and systemic interferon therapy led to a reduction in the frequency of acute respiratory viral infections to three episodes per year lasting 5–7 days, proceeding in a milder form. Rehabilitation of immunity parameters occurred after 2.5 months of interferonotherapy, and the level of induced IFNα was normalized to 64 IU/ml.
\nSumming up the above information, we may conclude that new biological drugs based on mAb are effective and safe, and they are able to neutralize IFNα overexpression in type I interferonopathies, both in Mendelian’s diseases and in autoimmune disorders. At the same time, local and system use of rIFNα2b+aox (Viferon) in congenital and acquired IFN system defects associated with viral infection syndrome, where a differential dosage is selected individually taking into account the rate of deficiency and an adequate, extended course of therapy is optimal because it is associated with positive clinical and immunological effects without any negative and side effects. Our more than 20-year experience has shown that using recIFNα2b+aox in patients with congenital or acquired IFN system defects had demonstrated positive clinical effect and is safe [31]. IFN (rIFNα2b+aox) therapy can be used with very good clinical efficacy in cases of primary or secondary defects of induced production of IFNα and IFNγ. From the other side, it is very important that in patients with a genetic predisposition to the manifestation of autoimmune diseases, primarily vasculitis and systemic lupus erythematosus, we do not recommend to use IFN therapy.
\nIntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
",metaTitle:"Retraction and Correction Policy",metaDescription:"Retraction and Correction Policy",metaKeywords:null,canonicalURL:"/page/retraction-and-correction-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
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\\n\\n1.2. REMOVALS AND CANCELLATIONS
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\\n\\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\\n\\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
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\\n\\nA Correction will be issued by the Academic Editor when:
\\n\\n3.1. ERRATUM
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\\n\\n3.2. CORRIGENDUM
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\\n\\n4. FINAL REMARKS
\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\\n\\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\\n\\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
\n\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
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\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\n\nPolicy last updated: 2017-09-11
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