\r\n\tFurthermore, during the preparation of high-quality dairy products, several physical, chemical, enzymatic, and microbial transformations take place. We will consciously focus on this interaction of different constituents of milk under different processing conditions for the development of the products.
",isbn:"978-1-83768-093-1",printIsbn:"978-1-83768-092-4",pdfIsbn:"978-1-83768-094-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"420e687768b56ca7b3238d77f63f1302",bookSignature:"Dr. Neelam Upadhyay",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12173.jpg",keywords:"Protein, Fat, Lactose, Carbohydrates, Milk Processing, Milk Products, Milk Constituents, Acid Coagulated, Enzyme Treated, Heat Treated, Dairy Products, Protocols of Manufacturing",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 18th 2022",dateEndSecondStepPublish:"June 15th 2022",dateEndThirdStepPublish:"August 14th 2022",dateEndFourthStepPublish:"November 2nd 2022",dateEndFifthStepPublish:"January 1st 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"21 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Upadhyay has received many awards most notable being the Young Woman Scientist Award 2020 from the Agro-Environmental Development Society and the Best Poster Award 2021 from the National Conference on Moringa Food Conclave 2021. She is a dedicated researcher in food and dairy processing and has published many research articles and papers in both national and international journals and publications.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"269538",title:"Dr.",name:"Neelam",middleName:null,surname:"Upadhyay",slug:"neelam-upadhyay",fullName:"Neelam Upadhyay",profilePictureURL:"https://mts.intechopen.com/storage/users/269538/images/system/269538.jpg",biography:"BRIEF BIODATA\n1.\tName in full: Neelam Upadhyay \n2.\tDate & Place of Birth: 29th December, 1987 at Delhi\n3.\tField of specialization: Food Technology\n4.\tPresent Position/ Designation: Scientist- Senior Scale\n5.\tAddress:\t(a)\tOfficial:\tTel. No.:0184-2259258\n\t\t\t\tE-mail: \ticar.neelam@gmail.com; neelam.upadhyay@icar.gov.in \n\t\t\t\tAddress: \tLaboratory No. 146, Dairy Technology Division, ICAR- \n\t\t\t\t\t\tNational Dairy Research Institute, Karnal \n\t\t\t(b)\tResidential: Tel. No.: +91-9255772587\n\tAddress (Permanent): 41-D, MIG DDA Flats, Shivam Enclave, Delhi-110032\n6.\t(a) Academic career and (b) professional attainments\n(a) Examination\tClass/ Percentage\tYear of Passing\tSubjects Taken\tName of University / Board\nXth \t1st/83\n(415/500)\t2003\tMathematics, Social Science, Science, English, Hindi\tK.V., Mumbai (CBSE)\nXIIth\t1st/78.2 \n(391/500)\t2005\tPhysics, Mathematics, Chemistry, Biology, English\tK.V., Delhi (CBSE)\nB.A.Sc. (Hons.)\t1st/83.43 (2044/2450)\n(3rd position)\t2008\tFood Technology\tSRCASW, University of Delhi, Delhi\nM.Sc.\t1st/8.62\n(1st position)\t2010\tFood Science & Technology\tCCS Har. Agri. Uni., Hisar, Haryana\nTitle of Research:\tDevelopment of flavoured whey-soya milk beverage\nMajor Advisor:\tDr. R. S. Dabur (Professor and Head)\nPh.D.\t1st/8.0\n(1st position)\t2014\tDairy Chemistry\tNational Dairy Research Institute, Karnal, Haryana\nTitle of Research: \tDetection of vegetable oil and animal body fat adulteration in ghee using solvent fractionation technique\nMajor Advisor:\tDr. Darshan Lal (Principal Scientist and Ex-Head)\nDistinctions during Academics\nDegree\tDistinctions\nBachelor of Applied Science (Hons.)\ti.\tY.K. Kapoor Memorial Scholarship 2006 by All India Food Processor’s Association \nii.\t3rd position in university\niii.\tReceived highest attendance award\niv.\tReceived trophy for ‘Most Disciplined Student’ for the graduation period 2005-2008\nv.\tCertificate of Honor from Honb’le Mr. Justice K.G. Balakrishnan, Chief Justice of India\nMaster of Science\ti.\t1st position in discipline and 2nd position in college\nii.\tReceived recognition for academic excellence from Jawaharlal Nehru Memorial Fund; \niii.\tQualified GATE\niv.\t2nd in inter-college yoga competition\nv.\tParticipated in various events of All India Youth Festival organized at UAS, Bangalore.\nDoctor of Philosophy\ti.\tReceived Merit Certificate for Academic Excellence in PhD course work\nii.\tReceived Certificate of Appreciation for outstanding work in the field of Dairy Processing during PhD\niii.\tQualified ICAR’s National Eligibility Test in 2010; Qualified the ICAR’s All India Examination, ICAR-SRF (PGS_-2011-2012 for award of ICAR-SRF (PGS) with 2nd rank (both in first attempt) \niv.\tQualified Agricultural Research Service Examination-2013 conducted by Agricultural Scientist Recruitment Board against the single vacancy (for UR) in the discipline of Food Technology\nv.\tStage Management Secretary of student’s council 2010-11\nvi.\tLiterary secretary of Student’s Council 2011-12\nvii.\tCompleted certificate e-course on “Publishing a Journal Manuscript - the Groundwork” directed by Springer in 2013\nviii.\tHave successfully completed certificate e-course – “Peer Review Academy” directed by Springer in 2013\nix.\tReceived a certificate on accomplishment IRIS 4-2 Information Literacy Plagiarism Quiz (on-line) in 2013 developed by Distance Learning Council of Washington, USA \n (b) Position Held\tInstitution \tPeriod of Appointment\tNature of Appointment\nScientist (Food Technology)\tICAR- National Academy of Agricultural Research Management, Hyderabad\t3 months\n(1st January, 2015 till 31st March, 2015)\tPermanent\n(Received ‘A’ grade for FOCARS)\nScientist \n(Food Technology)\tICAR- National Dairy Research Institute, Karnal\t10th March, 2015 till 31st December, 2018\n(after availing 10 days of transfer period)\tPermanent\nScientist-Senior Scale\n(Food Technology)\tICAR- National Dairy Research Institute, Karnal\t1st January, 2019 till date\tPermanent\n\n7. Special attainments in Research\n(https://scholar.google.co.in/citations?hl=en&user=PRz0Tz4AAAAJ&view_op=list_works&sortby=pubdate)\nPublications\tNumbers\tRemarks \nResearch Articles\t35\n(24 Intl, 9 National, 2 others)\tTotal Impact: 72.302\n\nBook Chapters\t7\t5 APA/CRC Press; 1 InTech Open; \n1 National\nReview Articles\t2\tTotal Impact:8.327\nTechnical Articles\t7\tCompendium of trainings, seminars, etc\nInstitute publication\t1\t\nPopular Article\t12\t6 in English; 5 in hindi\nCitations \t1066\t(as per googlescholar)\nH-index/ i10-index\t15/ 17\t\n.\n.\nJournal\tNumber of publications\tImpact factor\nResearch Articles\t35\t72.302\nInternational\t24 (15 as either corresponding or first author)\t72.302\nNational\t9 (3 as first or corresponding author)\tNAAS score\nOthers\t2\t\nReview article (International)\t2\t8.327\nInternational\t2\t8.327\n.\n \n\n\n\nRESEARCH ARTICLES\nInternational Journals \n1.\tTiwari, S., Upadhyay, N.*, Singh, A. K. (2022). Stability assessment of emulsion of carotenoids extracted from carrot bio-waste in flaxseed oil and its application in food model system. Food Bioscience, 47, 101631. https://doi.org/10.1016/j.fbio.2022.101631.\n2.\tPatil, A. T., Meena, G. S., Upadhyay, N., Khetra, Y., Singh, A. K., & Borad, S. G. (2021). Buffalo milk protein concentrate 60: Effect of skim milk heat treatment on its reconstitutability and functionality. Food Science & Technology – Lebensmittel -Wissenschaft & Tech, 148, 111638. \n3.\tUttamrao, H. J., Meena, G. S., Khetra, Y., Upadhyay, N., Singh, A. K., Arora, S., & Borad, S. G. (2022). Homogenization and sodium hydrogen phosphate induced effect on physical and rheological properties of ultrafilterd concentrated milk. Journal of Food Science and Technology, 59(3), 956-967. \n4.\tTiwari, S., Upadhyay, N.*, Malhotra, R. (2021). Three way ANOVA for emulsion of carotenoids extracted in flaxseed oil from carrot bio-waste. Waste Management, 121, 67-76. \n5.\tRanvir, S., Sharma, R., Gandhi, K., Upadhyay, N., Mann, B. (2020). Assessment of proteolysis in ultra-high temperature milk using attenuated total reflectance–Fourier transform infrared spectroscopy. International Journal of Dairy Technology. 73(2): 366-375. doi: 10.1111/1471-0307.12683. \n6.\tPonbhagavathi, T.R., Singh, A.K., Raju, P.N., Upadhyay, N. (2020). High performance liquid chromatographic (HPLC) determination of available lysine in milk protein-maize composite extrudates and its stability during storage. Journal of the Indian Chemical Society, 97(11a), 2344-2350\n7.\tTiwari, S., Upadhyay, N.*, Singh, A. K., Meena, G. S., & Arora, S. (2019). Organic solvent-free extraction of carotenoids from carrot bio-waste and its physico-chemical properties. Journal of Food Science and Technology, 1-10. 10.1007/s13197-019-03920-5\n8.\tBaria, B., Upadhyay, N.*, Singh, A. K., & Malhotra, R. K. (2019). Optimization of ‘green’extraction of carotenoids from mango pulp using split plot design and its characterization. Food Science & Technology – Lebensmittel -Wissenschaft & Tech, 104, 186-194. \n9.\tPatil, A. T., Meena, G. S., Upadhyay, N., Khetra, Y., Borad, S. G., & Singh, A. K. (2019). Effect of change in pH, heat treatment and diafiltration on properties of medium protein buffalo milk protein concentrate. Journal of Food Science and Technology, 56(3), 1462-1472. \n10.\tUttamrao, H. J., Meena, G. S., Borad, S. G., Punjaram, S. A., Khetra, Y., Upadhyay, N., & Singh, A. K. (2019). Effect of disodium phosphate and homogenization on physico-chemical and rheological properties of buffalo skim milk based ultrafiltered retentate. Journal of food science and technology, 56(5), 2426-2435. \n11.\tMeena, G.S., Dewan, A., Upadhyay, N., Barapatre, R., Kumar, N., Singh, A.K., & Rana, J.S. (2019). Fuzzy Analysis of Sensory Attributes of Gluten Free Pasta Prepared From Brown Rice, Amaranth, Flaxseed Flours and Whey Protein Concentrates. Journal of Food Science and Nutrition Research, 2(1), 022-037. DOI: 10.26502/jfsnr.2642-1100006\n12.\tPatil, A. T., Meena, G. S., Upadhyay, N.*, Khetra, Y., Borad, S., & Singh, A. K. (2018). Production and characterization of milk protein concentrates 60 (MPC60) from buffalo milk. Food Science & Technology – Lebensmittel -Wissenschaft & Tech, 91, 368-374. https://doi.org/10.1016/j.lwt.2018.01.028 \n13.\tUpadhyay, N.*, Jaiswal, P., & Jha, S. N. (2018). Application of attenuated total reflectance Fourier Transform Infrared spectroscopy (ATR–FTIR) in MIR range coupled with chemometrics for detection of pig body fat in pure ghee (heat clarified milk fat). Journal of Molecular Structure, 1153, 275-281. \n14.\tUpadhyay, N.*, Kumar A., Goyal A. and Lal, D. (2017). Complete liquification time test coupled with solvent fractionation technique to detect adulteration of foreign fats in ghee (heat-clarified milk fat). International Journal of Dairy Technology. 70(1): 110-118. doi: 10.1111/1471-0307.12323. \n15.\tUpadhyay, N.*, Goyal A., Kumar A. and Lal, D. (2017). Detection of adulteration of caprine body fat and mixture of caprine body fat and groundnut oil in bovine and buffalo ghee using Differential Scanning Calorimetry. International Journal of Dairy Technology. 70(2): 297-303. May 2017.doi:10.1111/1471-0307.12336. \n16.\tKumar, A., Upadhyay, N.*, Ghai, D.L., Kumar, A. Gandhi, K. and Sharma, V. (2016). Effect of preparation and storage of khoa on physico-chemical properties of milk fat. International Journal of Dairy Technology. 69(2): 294-300. doi: 10.1111/1471-0307.12266. \n17.\tUpadhyay, N.*, Jaiswal, P. & Jha, S.N. (2016). Detection of goat body fat adulteration in pure ghee using ATR-FTIR spectroscopy coupled with chemometric strategy. Journal of Food Science and Technology. 53 (10): 3752-3760. doi:10.1007/s13197-016-2353-2 ISSN 0022-1155\n18.\tRathi, M., Upadhyay, N.*, Dabur, R.S. and Goyal A. (2015). Formulation and physic-chemical analysis of whey –soymilk dahi. Journal of Food Science and Technology. 52(2): 968-975. doi 10.1007/s13197-013-1074-z. ISSN: 0022-1155. \n19.\tKanthale, P., Kumar, A. Upadhyay, N.*, Lal, D., Rathod G. and Sharma, V. (2015). Qualitative test for the detection of extraneous Thiocyanate in Milk. Journal of Food Science and Technology. 52(3): 1698-1704. DOI: 10.1007/s13197-013-1174-9. ISSN: 0022-1155.\n20.\tGoyal, A., Sharma, V., Upadhyay, N., Singh, A.K., Arora, S. and Ghai, D.L. (2015). Development of stable flaxseed oil emulsions as a potential delivery system of ω-3 fatty acids. Journal of Food Science and Technology. 52(7):4256-4265. \n21.\tUpadhyay, N.*, Kumar, A., Rathod, G., Goyal, A. and Lal, D. (2015). Development of a method employing reversed-phase thin-layer chromatography for establishing milk fat purity with respect to adulteration with vegetable oils. International Journal of Dairy Technology. 68(2): 207-217. doi. 10.1111/1471-0307.12178. \n22.\tGoyal, A., Siddiqui, S. Upadhyay, N., Soni, J. (2014). Effects of ultraviolet irradiation, pulsed electric field, hot water and ethanol vapours treatment on functional properties of mung bean sprouts. Journal of Food Science and Technology. 51(4): 708-714. doi 10.1007/s13197-011-0538-2. Publisher Springer. ISSN (electronic version): 0975-8402. \n23.\tKundu, H., Grewal, R.B., Goyal, A., Upadhyay, N.*, and Prakash S. (2014). Effect of incorporation of pumpkin (Cucurbita moshchata) powder and guar gum on the rheological properties of wheat flour. Journal of Food Science and Technology. 51(10):2600-2607. DOI: 10.1007/s13197-012-0777-x. ISSN: 0022-1155. \n24.\tUpadhyay, N.*, Kumar, A., Goyal, A. and Lal, D. (2014). A planar chromatographic method to detect adulteration of vegetable oils in ghee. JPC-Journal of Planar Chromatography-Modern TLC. 27 (6): 431-437. DOI: 10.1556/JPC.27.2014.6.5 \nNational Journals\n1.\tPonbhagavathi, T. R., Singh, A. K., Raju, P. N., Upadhyay, N. (2021). Textural and Sensory Characteristics of Milk Protein-Maize Flour-based Extrudates. Journal of Agricultural Engineering, 58(2), 124-136. 10.52151/jae2021581.1740\n2.\tPonbhagavathi, T.R., Singh, A.K., Raju, P.N., Upadhyay, N. (2020). Effect of Rennet Casein and Whey Protein Concentrate on Extrusion Behavior of Maize Flour. Current Journal of Applied Science and Technology. 39(33), 16-27, Article no.CJAST.57830.\n3.\tUpadhyay, N.*, Kumar, A., Lal, D., Kant, R., & Goyal, A. (2018). Detection of groundnut oil and goat body fat adulteration in ghee using principal component analysis on fatty acid profile. Indian Journal of Dairy Science. 71(5):464-472. \n4.\tUpadhyay, N.*, Kumar, A., Gandhi, K., Goyal, A. and Lal, D. (2014). Standardization of solvent fractionation technique for detection of adulteration in ghee by enriching animal body fat and vegetable oil in different fractions. Indian Journal of Dairy Science. 67 (4):323-327.\n5.\tGandhi. K., Upadhyay, N., Aghav, A.D., Sharma, V., and Lal, D. (2014). Detection of adulteration of ghee (clarified milk fat) with palmolein and sheep body fat using Reichert-Meissl (RM) value coupled with solvent fractionation technique. Indian Journal of Dairy Science. 67(5): 387-393. Received Second Best Paper Award during 44th Dairy Industry Conference organized by ICAR-NDRI, Karnal and Indian Dairy Association from 18-20, February 2016.\n6.\tAghav, A.D., Gandhi, K., Upadhyay, N., Kumar, A. and Lal, D. (2014). A study on the physico-chemical changes occurring in the milk fat during preparation of Paneer. Indian Journal of Dairy Science. 67 (5): 398-404.\n7.\tKumar, A., Upadhyay, N., Gandhi, K., Lal, D. and Sharma, V. (2013). Detection of soybean oil and buffalo depot fat in ghee using Normal-Phase Thin Layer Chromatography. Indian Journal of Dairy Science. 66(4): 294-99. ISSN: 0019-5146.\n8.\tKumar, A., Upadhyay, N., Gandhi, K., Kumar, A., Lal, D. and Sharma, V. (2013). Reverse-Phase Thin Layer Chromatography of Unsaponifiable Matter of ghee for detecting adulteration with soybean oil and buffalo depot fat. Indian Journal of Dairy Science. 66(6): 496-501. ISSN: 0019-5146.\n9.\tUpadhyay, N.*, Dabur R.S. and Rathi, M. (2011). Development and Shelf life Study of Flavoured Whey-soya milk beverage. Indian Journal of Dairy Science. 64(2): 92-101. ISSN: 0019-5146.\nOther Journals\n1.\tDewan, A., Meena, G.S., Upadhyay, N., Barapatre, R. Singh, A.K., Rana, J.S. (2017). Formulation of non-Gluten Pasta from the Optimized levels of Dairy and Non-Dairy ingredients. Madridge Journal of Food Technology. 2(2): 92–98. \n2.\tGalmessa, U., Prasad, S., Kumaresan, A., Oberoi, P. S., Baithalu, R. K., Upadhyay, N., and Dang, A. K. (2015). Modulation of Milk Fatty acid profile milk yield and composition through supplementation of omega-3 fatty acid in transition cow’s diet. Journal of Science and Sustainable Development. 3(1): 25-38. ISSN: 2070-1748\nREVIEW ARTICLES\n1.\tUpadhyay, N.*, Goyal, A. Kumar, A., Lal, D. and Singh, D. (2014). Preservation of milk and milk products for analytical purposes: A review. Food Reviews International. 30(3):203-224. DOI 10.1080/87559129.2014.913292. ISSN: 1525-6103\n2.\tGoyal, A., Sharma, V., Upadhyay, N., Gill, S. and Sihag, M. (2014). Flax and flaxseed oil: an ancient medicine & modern functional food. Journal of Food Science and Technology. 51(9): 1633-1653. DOI 10.1007/s13197-013-1247-9. ISSN: 0975-8402. \nBOOK CHAPTERS\n1.\tKumari, L., Sharma, M., & Upadhyay, N. (2021). Three-Dimensional Printing of Food Products: Printing Techniques, Novel Applications, and Printable Food Materials. Handbook of Research on Food Processing and Preservation Technologies: Volume 3: Computer-Aided Food Processing and Quality Evaluation Techniques, 55. Boca Raton, CRC Press\n2.\tUpadhyay, N.*, Harshitha, C. G., Pathak, N. K., & Sharma, R. (2021). Fourier Transform Infrared (FTIR) Spectroscopy with Chemometrics: Evaluation of Food Quality and Safety. Handbook of Research on Food Processing and Preservation Technologies: Volume 5: Emerging Techniques for Food Processing, Quality, and Safety Assurance, 271.\n3.\tNagarajappa, V., Upadhyay, N., Chawla, R., Mishra, S.K., & Nath, S. (2019). Functional Properties of Milk Proteins. In: Engineering Practices for milk products- Dairyceuticals, Novel Technologies, and Quality (pp 3-26). Apple Academic Press.\n4.\tUpadhyay, N., Kumar, M. C. T., Sharma, H., Borad, S., & Singh, A. K. (2019). Pulse Electric Field Processing of Milk and Milk Products. In: Non-thermal Processing of Foods (pp.129-144). Boca Raton, CRC Press\n5.\tUpadhyay, N., Nagaraj, V., & Singh, A. K. (2019). Advances in Fractionation of Milk Lipids: Analysis and Applications of fractions In: Recent Technologies in Dairy Science (pp. 325-344). Today and Tomorrow’s Printers and Publishers.\n6.\tNagaraj, V., Upadhyay, N.*, Nath, B. S., & Singh, A. K. (2018). Advances in Fractionation and Analysis of Milk Carbohydrates. In Technological Approaches for Novel Applications in Dairy Processing (pp. 127-147). IntechOpen. http://dx.doi.org/10.5772/intechopen.76312\n7.\tUpadhyay, N.*, Veena, N., Borad, S., & Singh, A. K. (2017). Application of Natural Antioxidants in Dairy Foods. In Natural Antioxidants (pp. 281-318). London: Apple Academic Press.\nINSTITUTE PUBLICATION\n1.\tDr. T. K. Datta, Dr. Meena Malik and Dr. Neelam Upadhyay (2017). Foundation Programme for Freshers at ICAR-NDRI 2017.\nPOPULAR AND LEAD ARTICLES\n1.\tPatil, A. T., Meena, G. S., Upadhyay, N., & Singh, A.K. (2017). Milk protein concentrates- Their Applications. Indian Dairyman, 69(9), 44-48.\n2.\tUpadhyay, N.* and R.K. Malik (2015). Nutritive Value of Milk. In: In Touch, Heinz Nutrition Foundation of India. Volume 17, Number 2&3, 2-11. (Lead Article). \n3.\tGoyal, A., Sharma, V., Upadhyay, N., Sihag, M. and Kaushik, R. (2013). High Pressure Processing and its impact on milk proteins: A Review. Research and Reviews: Journal of Dairy Science and Technology. 2 (1): 1-9. ISSN: 2319-3409.\n4.\tKumar, A., Upadhyay, N., and Naagar, S. (2012). Allergenicity of Milk Proteins, and its Management. Indian Food Industry. 31 (5&6): 45-50. ISSN: 0972-2610.\n5.\tGoyal, A. and Upadhyay, N. (2012). Nuclear Magnetic Resonance Spectroscopy in Dairy Science. Indian Food Industry. 31(1): 39-45. ISSN: 0972-2610.\n6.\tUpadhyay, N.*, Goyal, A. and Rathod, G. (2011). Microwave Spectroscopy and its applications in online processing. Indian Food Industry. 30(5&6): 63-73. ISSN: 0972-2610.\n7.\tउपाध्याय, नी*. (२०१८) भारत में कुपोषण: स्थिति और इससे निपटने के लिए रणनीतियाँ. दुग्ध—गंगा (आठवाँ अंक). अप्रैल-सितम्बर. २४-२९. \n8.\tउपाध्याय, नी.*, सिंह, आ.कु., गांगुली, स., सबिखी, ल. (२०१८) खाध्य और डेयरी क्षेत्र मे महिला उद्यमिता: कारण, समस्याए एवम उपलब्ध मंच. दुग्ध—गंगा (आठवाँ अंक). अप्रैल-सितम्बर. ६४-६९.\n9.\tउपाध्याय, नी*. (२०१९) ek¡ dk nw/k % f'k'kqvksa ds ekufld] 'kkjhfjd ,oa lkekftd mRFkku gsrq ve`r. दुग्ध—गंगा (नवाँ अंक). अकटूबर –मार्च १०२-१०४.\n10.\tउपाध्याय, नी*, fç;k ;koys (२०१९) [kk| inkFkksaZ esa —f=e ds cnys çk—frd jax o.kZd ds mi;ksx dh vko';drk दुग्ध—गंगा (दसवाँ अंक). अकटूबर –मार्च १०२-१०५.\n11.\tuhye mikè;k;, fuys'k dqekj ikBd (२०१९) d`f\"k] [kk| ,oa Ms;jh m|ksx ds Hkfo\"; eas lkSj ÅtkZ dk egRo दुग्ध—गंगा (दसवाँ अंक). अकटूबर –मार्च १२६-१३०. \n12.\tवैज्ञानिक और तकनीकी विषय के मूल हिंदी लेख जोकि गेहूँ एवम् जौ स्वर्णिमा में प्रकाशित हुए: उपाध्याय, नी*, राकेश कुमार (2020) महिला उद्यमिता के माध्यम से महिला सशक्तिकरण. गेहूँ एवम् जौ स्वर्णिमा (बारहवााँ अंक), पृष्ठ सं. 55-58; भाकृअनुप- भारतीय गेहूँ एवम् जौ अनुसंधान संस्थान, करनाल- १३२००१ द्वारा प्रकाशित\n\n8. Concepts/Processes/Products/Technologies/Patents/Others\n(i)\tConcepts \nCurrently, I am working on the integrated approach of application of green technology for the development of functional foods by utilizing under-utilized/ indigenous fruits and vegetables and/ or bio-waste. In the research projects, I am also keenly working on food chemistry and instrumental food analysis and applications of technologies/ products in dairy and non-dairy products. \nBesides this, I am working on development of functional food for addressing menopausal symptoms in osteopenic mice model. \n(ii)\tProducts/ Technologies ready for commercialization- 5\n1. Production of Milk Protein Concentrate 60 (MPC60), a high protein low lactose powder from buffalo milk (Co-Inventor)\n2. Technology for omega-3 rich mixed fat table spread (Inventor)\n3. Lipid and water soluble yellow natural colouring ingredient from bio-waste (Inventor)\n4. Technology for preparation of encapsulated flaxseed oil for its applications in foods (Inventor)\n5. Production of buffalo milk based Milk Protein Concentrate 60 (MPC60) powder with improved solubility (Co-Inventor)\n(iii) Expertise on\n1.Gas Liquid Chromatography\t5.Thin Layer Chromatography\n2.Fourier Transform Infra-red Spectroscopy\t6. Spectrophotometry\n3.Differential Scanning Calorimetry\t7.Chemical analysis including titration, distillation, etc.\n4.High Pressure Liquid Chromatography\t\n\n\n9. List of completed, on-going and submitted projects\nTitle of Project\tDuration\tRole\tFunding\tStatus\tRemarks\nEffect of storage on Baudouin test, sesamin test and RP-TLC test to detect adulteration of vanaspati and vegetable oils in ghee\t2015-2017\tCo-PI\tICAR-NDRI\n\tCompleted\tTwo research articles on RP-TLC\nPreparation and Characterization of Micro/nano delivery systems for “green” carotenoids\t2016-2019\tPI\t-Do-\t\t3 research articles+ 3 products/ technologies\nTechnology Development for the Production of Milk Protein Concentrate (MPC60) From Buffalo Milk\t2016-2019\tCo-PI\t-Do-\t\t4 research articles+ 2 products/ technologies\nTechnology of Goat Milk based Functional Beverage\t2017-2020\tCo-PI\t-Do-\t\tOne oral presentation\nTechnology for Moringa oleifera enriched cheese spread\t2020-2023\tPI\t-Do-\tOn-going\tCharacterization and incorporation of M. oleifera- pods in cheese spread is complete; shelf life study and animal trial is in progress\nDevelopment of flaxseed-rich probiotic dairy foods to address menopause symptoms\t2020-2023\tCo-PI\tDST\t\tDeveloped method -estimation of phytoestrogen; validation -in progress\nNutritional and therapeutic validation of chhachh and ghee prepared from indigenous cows by traditional method\tThree years (proposed)\tPI\tSEED Division, DST\tSubmitted \n \t\nCharacterization of Moringa oleifera leaves for functional bioactives and its application in table spread as model food system\tThree years (proposed)\tPI\tSYST, DST\t\t\nOther research work: \nDetection of adulteration of goat body fat and pig body fat in ghee using ATR-FTIR coupled with chemometrics; carried out during Professional Attachment Training at ICAR-CIPHET, Ludhiana\n\n\n\n10. Awards & honours \nName of Award\tYear\tAwarding Agency\nBest Paper Award\t2022\tGSAT (Gender Advancement for Transforming Institutions Self-Assessment Team), NDRI\nBest Poster Award\t2021\tNational Conference on Moringa Food Conclave-2021\nYoung Woman Scientist Award\t2020\tAgro Environmental Development Society during International Web-conference \nSecond Best Poster Award\t2020\tIndian Dairy Association\nCommendation certificate for Institute’s Magazine in which I am co-Editor\t2020\tTown Official Language Implementation Committee, Karnal\nLetter of Appreciation to editorial board of Institute’s magazine for receiving ICAR’s Second Prize and Trophy under Ganesh Shankar Vidyarthi Hindi Patrika Puraskar (2018-19)\t2020\tICAR- National Dairy Research Institute, Karnal\nAssociate Fellowship\t2019\tNational Academy of Dairy Science India\nFirst Prize in E-poster \t2018\tIndian Dairy Association\nOne Best oral Presentation\t2018\tHome Science Association of India\nBest Oral Presentation to my Master’s student\t2018\tICMR- National Institute of Nutrition\nBest Poster Award\t2016\tIndian Dairy Association\nSecond Best Paper Award\t2016\tIndian Dairy Association\nICAR-SRF (PGS) with 2nd rank\t2011-12\tICAR\nGATE (Engg Sciences: Food Tech; Thermodynamics)\t2010\tMHRD, GoI\nInstitution level awards\nThird prize in poster presentation \t2021\tICAR- National Dairy Research Institute, Karnal\nInstitute’s Rajbhasha Gaurav Certificate\t2020\t\nFirst prize in Scientific and Technical writing\t2019\t\nConsolation prize in Scientific and Technical writing \t2020, 2019 \t\nFirst prize in Poster Presentation- 2020, 2018, 2017\t\t\nThird prize in poster presentation\t2019\t\nFirst Prize in hindi extempore\t2017\t\nThird, first and second prize in hindi essay writing in consecutive years – 2020, 2019, 2018\t\t\n\n\n11. Teaching Assignments \n(a) Teaching: Actively involved either as course in-charge or associate \nClass\tB.Tech (DT)\tMSc/ MTech\n(FT) (till 2021)\tM.Tech (DT)\tPhD (DT/ DC/ FSQA)\nNo. of courses\t1-2\t2-3\t0-1\t2-3\nDT- Dairy Technology, DC- Dairy Chemistry, FT- Food Technology, FSQA- Food Safety Quality Assurance\n(b) Student’s guided\nDegree\tMajor Advisor \tCo-Advisory\tStatus/ Remarks\nM. Tech (DT)\t8\t2\tCompleted\n\t1\t0\tOn going\nM. Tech/ M Sc (FT/ FSN)\t2\t1\tCompleted\nM. Tech (DC)\t0\t3\tCompleted\nM. Tech (DM)\t0\t1\tCompleted\nPhD (DT)\t2 \t0\tOngoing \n\t0\t2\tCompleted\nPhD (DC)\t0\t1 \tCompleted\n\t\t1\tOn going\ni.\tThree students under my guidance as major advisor and one student as co-advisory member nominated for Best thesis award; \nii.\tOne represented NDRI at zonal-level student research convention ANVESHAN-2018\n\n12. Lectures/ member/convener of committees: \ni.\tLectures: \na.\tEntrepreneurship Development Programme (EDP) (conducted by SINED-TBI/BPD unit, ICAR-NDRI) and Online Training of Master Trainers on Fat and Oilseed processing conducted by SINED-TBI/BPD unit (ICAR-CIPHET); \nb.\tStudent’s Counselling session at SRCASW, University of Delhi, \nc.\tWorkshop conducted at DAV college, Karnal, etc\nd.\tDelivered talks at various villages on the importance of mother’s milk, nutrition in first 1000 days of an infant’s life, nutri-thali, etc\nii.\tTraining Organized: \na.\tTwenty one days Training at Centre for Advanced Faculty Training (DT Division) on ‘R & D strategies and interventions for effective agribusiness and entrepreneurship development in dairy and food sector’; \nb.\tone/two months or shorter duration trainings for students and others under BPD unit and KVK, NDRI, Karnal\nc.\tFive days training on the aspects of dairy processing to the farmers of Karnal district. \niii.\tGeneral Secretary, Staff Club, NDRI, Karnal\niv.\tMember: Student Empowerment Unit, Conferences organized from 2015 till 2018, convocation, credit seminar evaluation committees; Mera Gaon Mera Gaurav program, Farmer’s First Door programme, Swatchh Bharat Abhiyan, coordinator and mentor of different groups for organizing Foundation Program-2017, 2018, Nodal officer of Poshan Maah-2020 etc\nv.\tConvener/ Rapporteur of sessions: Conference, Dr. K. K. Iya Memorial oration; International conference of Proteomics Society of India\nvi.\tOther responsibilities: Management Representative of QMS-IS/ISO 9001:2008 and HACCP- IS 15000:2013 of Experimental Dairy (essential part of institute) until Jan 2019; one of the editors of Institute hindi magazine Dudgh Ganga which also received coveted award from ICAR (until 2019).\nvii.\tResource Generation on account of consultancy provided in field of dairy processing and by conducting sponsored trainings \nMore than ₹ 2 50 000/- (Two lakhs fifty thousand only)\nviii.\tBesides research, teaching and extension activities, I am also involved in promotion of Hindi language and have won several prizes during competitions (like extempore, essay, e-mail writing) organized by Official Language Units.\nix.\tLifetime Member of three scientific bodies: Indian Dairy Association- RE/NZ/LM/10852/HR; Association of Food Scientists & Technologists (INDIA)- AFST/LM/9-2018/KRN/2444; Lifetime member of Home Science Association of India; Membership number: HSAI-2017-HR-127-LF\nx.\tReviewed research papers of Journal of Ayurveda and Integrative Medicine (Elsevier), LWT, International Journal of Food Properties, Indian Journal of Dairy Science, Indian Journal of Natural Products and Resources, United Scientific Group, etc. \n\n\n\n\n\n\n\n\nDated: 12-04-2022\t \nNeelam Upadhyay",institutionString:"National Dairy Research Institute",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Dairy Research Institute",institutionURL:null,country:{name:"India"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"5",title:"Agricultural and Biological Sciences",slug:"agricultural-and-biological-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444312",firstName:"Sara",lastName:"Tikel",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/444312/images/20015_n.jpg",email:"sara.t@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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1. Introduction
The cerebellum plays an important role in coordinated movement, motor learning and vestibular function. Cerebellar damage results in impaired body balance and disturbance in gait and posture. The cerebellum is impaired by various genetic diseases, such as spinocerebellar ataxia and mucopolysaccharidosis, and these diseases could be good candidates for gene therapy. There are at least two challenges that should be overcome before the clinical application of gene therapy is used to treat cerebellar disorders. The first challenge results from its large size, as the cerebellum is the second largest component of the central nervous system. The cerebellum can be subdivided into three main parts: the cerebrocerebellum, the vestibulocerebellum and the spinocerebellum (see Section 2 for details). Each subdivision in the cerebellum plays a distinct role and, to attain a satisfactory rescue of the cerebellar function by gene therapy, a therapeutic gene should be delivered efficiently and extensively into the large cerebellum.
The second challenge is to deliver a gene into specific target cell populations in the cerebellum. In Parkinson\'s disease, which is caused by degeneration of nigra-striatal dopaminergic neurons, cell type-specific delivery of a therapeutic gene is a secondary matter, as the supply of sufficient amounts of dopamine, irrespective of neurons or glia, in the striatum is most critical for the functional recovery of the basal ganglia. By contrast, specific cell populations within the cerebellum, such as cerebellar Purkinje cells, Bergman glia or neurons in the deep cerebellar nuclei, are selectively impaired in most cerebellar diseases, such as spinocerebellar ataxia. Thus, affected cell types differ depending on the disease type, and the selective delivery of a therapeutic gene to a subset of affected cell types could be a key advance for rescuing cells that are degenerating from progressive damage, restoring cerebellar function and, ultimately, helping patients to recover from cerebellar ataxia.
To this end, we have developed methods that allow for Purkinje cell-specific and Bergmann glia-specific gene expression in mice by modifying the culture conditions of lentiviral vector-producing human embryonic kidney (HEK) 293FT cells in combination with cell-type-specific promoters in lentiviral vectors. Moreover, a new injection technique for efficient and widespread gene delivery into the cerebellar cortex has been devised, which takes advantage of the anatomical location of the cerebellum. Using the newly developed gene transfer method for the cerebellum, we aimed to restore the abnormal phenotypes of two types of ataxic mice, both of which are affected in Purkinje cells by different pathologies. The results showed that the efficient and widespread delivery of therapeutic genes into Purkinje cells significantly restored ataxia and morphological and functional abnormalities of these cells in mutant mice. In this chapter, we describe our method that efficiently permits the selective gene delivery to cerebellar Purkinje cells or Bergmann glia and the rescue of two examples of ataxic mice. We also describe existing problems that should be resolved for the future clinical application of lentiviral vectors to cerebellar disorders.
2. Cerebellar organization and neural circuits in the cerebellum
The cerebellum can be subdivided into three main parts based on differences in their sources of input. The largest subdivision in humans is the cerebrocerebellum, which occupies most of the lateral hemisphere and is involved in the regulation of highly skilled movements, including speech. The vestibulocerebellum is the phylogenetically oldest part of the cerebellum; it comprises the caudal lobes of the cerebellum, including the flocculus and the nodulus, and is primarily engaged in the regulation of movements underlying posture and equilibrium. The last of the major subdivisions is the spinocerebellum, which occupies the median and paramedian zone of the cerebellar hemispheres. The spinocerebellum is the only part that receives input directly from the spinal cord. The lateral part and central part (vermis) of the spinocerebellum are involved in the movements of distal and proximal muscles, respectively. The vermis also regulates eye movements in response to vestibular inputs.
The cerebellar cortex contains 5 neurons, the granule cell, the Purkinje cell and three inhibitory interneurons (stellate cell, basket cell and Golgi cell) and is divided into three morphologically distinct parts: the granule cell layer, the Purkinje cell layer, and the molecular layer (Fig. 1a and b). The granule cell layer contains numerous granule cells, in which Golgi cells are scattered. The Purkinje cell layer is a monolayer that consists of the soma of Purkinje cells and Bergmann glia; the Purkinje cells extend their well-differentiated dendrites into the molecular layer (Fig. 1c), where stellate cells and basket cells are located. The Bergmann glia also extend their processes into the molecular layer (Fig. 1b).
A major input to the cerebellar cortex are the mossy fibers, axon bundles projecting from neurons in the thalamus, the brain stem and the spinal cord (Fig. 1b). The excitation of granule cells triggered by mossy fibers is transferred through the axons called parallel fiber to Purkinje cells. One Purkinje cell has more than one hundred thousand dendritic spines (Fig. 1d, arrows), on which parallel fiber terminals make excitatory synapses. Parallel fiber - Purkinje cell synapses are tightly wrapped by processes of Bergmann glia, so as to quickly take up the glutamate released from parallel fiber terminals. In this context, the Bergmann glia prevent the prolonged excitation of Purkinje cells and the spillover of glutamate that would activate the adjacent synapses.
Another excitatory input to the cerebellar cortex is the climbing fiber that originates from neurons in the inferior olivary nucleus of the medulla oblongata. The climbing fiber makes excitatory synapses directly on proximal dendrites of Purkinje cells and neurons in the deep cerebellar nuclei. Excitatory activity of granule cells and Purkinje cells is modulated by 3 types of inhibitory interneurons: Golgi cells, stellate cells, and basket cells. The Purkinje cells eventually integrate the information entered into the cerebellar cortex and send an inhibitory signal as the sole source of output from the cerebellar cortex to neurons in the deep cerebellar nuclei.
Figure 1.
Projections to and neural circuits in the cerebellar cortex. (a) A sagittal section of the vermis of a mouse cerebellum. (b) A schematic diagram of the cerebellar cortex that enlarges the square region in (a). ML, molecular layer; PCL, Purkinje cell layer; GCL, granule cell layer. A Purkinje cell (PC) receives excitatory inputs via parallel fibers (PF) and climbing fibers (CF) and sends inhibitory signals to neurons of the deep cerebellar nuclei (DCN). GC, granule cell, MF, Mossy fiber. (c) Well-differentiated dendrites of Purkinje cells are visualized by GFP expression. (d) Dendritic spines of Purkinje cells (arrows).
3. Disorders of the cerebellum
As cerebellar defects can be easily detected from overt ataxia, such as widespread gait and motor coordination deficits, numerous types of mutant mice with cerebellar degeneration have been isolated over the past 50 years. These mutant mice have contributed significantly to the elucidation of cerebellar physiology. At present, in parallel with advances in the development of viral vectors, we may be able to restore cerebellar defects of ataxic mice by a potential therapeutic gene delivery. Such rescue experiments have significant implications in terms of the future clinical application of gene therapy for patients suffering from cerebellar diseases. The following subsections summarize the cerebellar abnormalities and genetic defects identified in ataxic mice and humans.
3.1. Spontaneously occurring ataxic mice
Table 1 summarizes well-known murine mutants that cause cerebellar impairment. Recently, the genes responsible for those mutants have been identified and include missense mutations, nonsense mutations or frameshift mutations in the causative genes. The hotfoot mice are spontaneously occurring recessive mutants (Guastavino et al., 1990) that carry mutations in Grid2, which encodes the 2 glutamate receptor (GluR2) (Wang et al., 2003). To date, more than 10 mutant alleles have been identified; among these, hotfoot5J mice have been shown to carry a point mutation in exon 12 of Grid2, which creates a stop codon in the region encoding transmembrane 3 of GluR2 protein (Wang et al., 2003). The aberrant GluR2 protein is easily degraded and is not detected in Purkinje cells of hotfoot5J mice; therefore, hotfoot5J mice are mutants lacking GluR2 function.
Table 1.
Genetic abnormalities and affected cell types in spontaneously occurring ataxic mice.
Other loss-of-function mutants are Staggerer and Purkinje cell degeneration (pcd) mice. The staggerer mutation causes a functional impairment in a transcription factor, retinoid-related orphan receptor ( (ROR(), which belongs to the nuclear receptor superfamily (Boukhtouche et al., 2006; Gold et al., 2007). Staggerer mice have a 122-base pair deletion within the ligand binding domain (LBD) of the ROR( gene (Hamilton et al., 1996). For PCD mice, 8 independent alleles have been identified, which carry genetic mutations in the Nna1 gene, encoding a putative nuclear protein (Fernandez-Gonzalez et al., 2002; Wang & Morgan, 2007). Most of the pcd alleles represent complete loss-of-function mutations. Because it is reasonable to postulate that aberrant phenotypes in loss-of-function mutants may be restored by introducing the intact gene, and, as Purkinje cells are the main cell type impaired in the loss-of-function mutants discussed here (hotfoot, staggerer and pcd), the efficient delivery of the intact gene into the specific subset of cells (Purkinje) may be a promising therapy for the recovery of those mutant mice from cerebellar degeneration and, ultimately, ataxia.
There are two important points that should be addressed. First, gene delivery should be performed before Purkinje cells are substantially lost or irreversibly damaged. Purkinje cells of pcd mice die gradually from approximately 18 days of age and are virtually lost by 4 months of age. Similarly, the Purkinje cell number in staggerer mice begins to decrease in the first week after birth, and at least 75-90% of Purkinje cells are lost in adult mutants (Vogel et al., 2000). The degeneration of Purkinje cells causes secondary defects of granule cells and neurons in the inferior olivary nucleus. Therefore, later gene delivery results in less or no functional recovery in staggerer and pcd mutants.
Another important point is that gene delivery should be carried out before the Purkinje cell loses its plasticity. The compensation of a missing gene during an inappropriate time may result in the insufficient restoration of Purkinje cell abnormalities. By the second to third postnatal week, Purkinje cells extend dendrites and make a hundred thousand synapses with different counterparts. A series of developmental processes requires the strictly regulated expression of numerous genes, suggesting that the exogenous delivery of an intact gene after termination of this period may have little therapeutic impact. This period, in which the brain displays a heightened sensitivity to exogenous stimuli (and still maintains capacity to respond to gene therapy), is referred to as the “critical period”. The critical period differs depending on the defects of the mutant animals; thus, a careful examination using animal models can provide clues to deduce the critical period for the human cerebellum.
The Lurcher (Lc) mouse is an autosomal semidominant mutant that displays the degeneration of virtually all of the cerebellar Purkinje cells (Vogel et al., 2007). In heterozygous mice (Lc/+), cerebellar Purkinje cells specifically start to degenerate in a cell-autonomous manner by postnatal day 8 (P8), and most die during the second postnatal week.; other cell types are eventually affected by secondary mechanisms (Wetts & Herrup, 1982). Lc/+ mice exhibit severe ataxia during the third postnatal week, when approximately 90% of the Purkinje cells have disappeared. Lc is caused by an alanine to threonine mutation in the highly conserved third hydrophobic segment of GluR2 (Zuo et al., 1997). As this region works as the gate of a cation channel (Kohda et al., 2000), the mutation converts the receptor into a constitutively leaky cation channel. Thus, lurcher is a gain-of-function mutation, suggesting that a simple delivery of the wild-type GluR(2 would not have a significant therapeutic impact on Lc Purkinje cells. A suppression of the mutant protein expression via, for example, RNA interference would be a promising gene therapy against disorders caused by a toxic-gain-of-function mutation.
3.2. Human cerebellar diseases potentially treatable with gene therapy
3.2.1. Spinocerebellar ataxia
The cerebellum is impaired by various diseases, including neurodegenerative and enzyme-deficient disorders. Spinocerebellar ataxia (SCA) is one of the representative diseases that affect the cerebellum. Approximately one third of the SCA in patients is hereditary. So far, at least 29 types of SCA result from chromosomal loci of the causal genes (Carlson et al., 2009), in which the major lesion of SCA type 1 (SCA1), SCA2, SCA6, SCA14, SCA17 and SCA31 affects Purkinje cells. Neurons in the deep cerebellar nuclei are impaired in SCA3, and cortical Bergmann glia are primarily degenerated in SCA7. The well-known cause of hereditary SCAs is the abnormal expansion of trinucleotide (CAG) repeats in the coding region of genes responsible for the diseases. This expansion produces mutant proteins having an abnormally expanded polyglutamine stretch, leading to the formation of nuclear aggregates with other proteins that are critical for cellular functions. This type of hereditary SCAs is called polyglutamine disease and includes SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17. As these diseases are caused by the production of toxic polyglutamine proteins (polyQ), a potential therapeutic approach would be to reduce the mutant polyQ by, for example, RNA interference (Xia et al., 2004) or the facilitation of their degradation. The latter may include the enhancement of the ubiquitin-proteasome pathway (Al-Ramahi et al., 2006; Matsumoto et al., 2004; Torashima et al., 2008; Wang & Monteiro, 2007) and autophagy (Menzies et al., 2010; Menzies & Rubinsztein, 2010; Williams et al., 2006).
Autosomal dominant SCA14, characterized by severe cerebellar atrophy and ataxia, is caused by a missense mutation of the PRKCG gene, which encodes the protein kinase C (PKC) γ gene. γPKC-deficient mice show only mild ataxia and no gross morphological abnormalities in the cerebellum (Chen et al., 1995; Kano et al., 1995), suggesting that the gain-of-toxic function, rather than loss-of-function, of γPKC underlies the pathology of SCA14. Therefore, a decrease in the amount of mutant γPKC protein is thought to be an effective therapy for SCA14. Indeed, recent studies have shown the allele-specific inhibition of mutant gene expression (Alves et al., 2008; Hu et al., 2009), and such mutant allele-targeted RNA interference may result in better therapeutic efficacy.
3.2.2. Mucopolysaccharidosis
Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of undigested macromolecules in the lysosomes due to a significant decrease or a complete absence in the activity of soluble lysosomal enzymes (Neufeld, 1991). As most lysosomal enzymes are ubiquitously expressed, a deficiency in a single enzyme affects peripheral organs, as well as various regions of the brain, including the cerebellum. There are approximately 50 forms of inherited LSDs in humans with incidences of 1 in 7,000 live births (Haskins, 2009). LSDs are usually grouped biochemically by the accumulated metabolite into 3 subgroups: mucopolysaccharidoses (MPS), sphingolipidoses, and mucolipidoses.
The potential treatments for LSDs include bone marrow or cord blood transplantation, enzyme replacement and gene therapy. Among the LSDs, those due to soluble lysosomal enzyme deficiencies are generally considered good candidates for gene therapy. These include MPS I, MPS IIIB and Niemann-Pick AB diseases (Sands & Davidson, 2006). To overcome the blood-brain barrier (BBB), viral vectors should be applied intrathecally (Watson et al., 2006) or directly into the brain parenchyma (Dodge et al., 2005), except in neonates having an incomplete BBB (Hartung et al., 2004; Kobayashi et al., 2005). Recent studies using knockout mouse models of MPS I and Niemann-Pick type A disease have shown a significant rescue of the phenotypic manifestations of the diseases upon intravenous and intrathecal application of adeno-associated virus (AAV) or lentiviral vectors expressing a deficient enzyme (Dodge et al., 2005; Hartung et al., 2004; Kobayashi et al., 2005; Watson et al., 2006). In addition, the injection of AAV vectors expressing the deficient gene, acid sphingomyelinase, into the deep cerebellar nuclei alleviated storage accumulation and corrected behavior deficits in the mouse model of Niemann-Pick type A disease (Dodge et al., 2005). These results suggest that viral vector-based gene transfer is promising for clinical gene therapy of patients with LSDs.
4. Viral vector-mediated gene delivery to the cerebellum
Vectors derived from retrovirus, Sindbis virus, adenovirus, lentivirus and AAV are widely used for gene transfer to mammalian cells; the properties of these vectors are summarized in Table 2. Retroviral vectors can express a foreign gene only in proliferating cells because they cannot pass through the nuclear membrane of host cells: the viral genome that enters into the cytoplasm of an infected cell can access the host chromosome only when the nuclear membrane disappears during mitosis. Exploiting this unique feature of retroviral vectors, they have been used to label neural stem cells (Kageyama et al., 2003; Levison et al., 2003; Namba et al., 2007).
Table 2.
Properties of different viral vectors.
Vectors based on Sindbis virus, a member of the Togaviridae family in the alphavirus subfamily, can infect non-dividing cells, including neurons, and replication occurs entirely in the cytoplasm of the infected cell as an RNA molecule (Griffin, 1998). Therefore, a high level of gene expression starts quickly after infection. One drawback of the Sindbis virus vector is high toxicity, as infected cells deteriorate within a couple of days.
Adenoviral vectors are widely used as gene transfer vectors. They can accommodate a large gene of ~30 kb and infect both neurons and glia, with a higher tropism for glia. Therefore, adenoviral vectors have been used to modify the function of Bergmann glia (Iino et al., 2001). Adenoviral vectors can exert toxicity to infected cells by triggering immune responses, and gene expression generally lasts only for ~2 months (Terashima et al., 1997). The features of adenoviral vectors, including their high infectivity in glial cells and immunogenicity, in combination with the introduction of an apoptosis-triggering gene are often applied to the gene therapy of malignant glioma (Horowitz, 1999; Jiang et al., 2009; Parker et al., 2009; Shinoura & Hamada, 2003).
Vectors derived from lentiviruses, a genus of slow viruses of the Retroviridae family, can replicate in non-dividing neurons with little toxicity to the infected cells (Escors & Breckpot). Moreover, stable gene expression lasts for more than several years. In the cerebellum, lentiviral vectors pseudotyped with vesicular stomatitis virus glycoprotein (VSVG) can infect various types of cortical cells that include Purkinje cells, stellate cells, basket cells, Golgi cells, Bergmann glia and astrocytes (Croci et al., 2006; Torashima et al., 2006a). The properties of lentiviral vectors are described in more detail in the next section (Subsection 4.1).
AAV is a non-pathogenic, small (20 nm), icosahedral and non-enveloped virus that belongs to the genus Dependovirus of the Parvoviridae family. Similar to lentiviral vectors, it infects both dividing and non-dividing cells with very little toxicity and a minimal immune response in the infected cells. To date, a number of AAV serotypes and over one hundred AAV variants have been isolated from adenovirus stocks or from human and non-human primate tissues (Gao et al., 2005; Wu et al., 2006). For gene transfer to cerebellar cells, AAV serotype 1, serotype 2 and serotype 5 (AAV1, AAV2 and AAV5) vectors have been used for the successful transduction of Purkinje cells (Alisky et al., 2000; Hirai, 2008; Kaemmerer et al., 2000; Xia et al., 2004). Thus, lentiviral vectors and AAV vectors, which have the potential to transduce Purkinje cells with almost no substantial toxicity, are promising as gene therapy vectors for cerebellar disorders that affect Purkinje cells. Because of the lack of pathogenicity, AAV vectors are increasingly becoming the vectors of choice for a wide range of gene therapy approaches. One major limitation of AAV vectors is the insert capacity, which is less than 4.7 kb, whereas lentiviral vectors have a higher capacity, up to 8 kb, for transgene accommodation (Table 2) (Hirai, 2008).
4.1. Factors that control the tropism of lentiviral vectors for cerebellar neurons and glia
As the VSVG binds to the phospholipids that constitute cellular membranes, VSVG-pseudotyped lentiviral vectors are thought to infect mammalian cells without cell-type preference. In the cerebellar cortex, lentiviral vectors have successfully transduced Purkinje cells, three types of interneurons, Bergmann glia and astrocytes, but not granule cells. The efficient transduction of Golgi cells and astrocytes present in the granule cell layer suggest that the injected viral solution is accessible to granule cells: however, no or few transduced granule cells, if any, were detected upon injection of lentiviral vectors to the adult cerebellum in vivo (Croci et al., 2006; Torashima et al., 2006a).
The observed lentiviral tropism for Purkinje cells is affected by the serum-lot quality and cultivation period of the HEK293FT cells used for lentiviral production (Torashima et al., 2006b). A three-day culture that causes the degeneration and death of HEK293FT cells results in the production of glia-tropic lentiviral vectors. Although the mechanism underlying this phenomenon has not been clarified, increases in the protease activity in the culture medium seems to be involved because the addition of a protease inhibitor in medium reversed the shift of lentiviral tropism from Purkinje cells to Bergmann glia (our unpublished observation). These results suggest that VSVG is modulated by a protease released from dead HEK293FT cells, leading to the alteration of lentiviral tropism.
The L7/PCP2 promoter is a Purkinje cell-specific promoter, and the Gfa2 promoter works as an astrocyte-specific promoter. Therefore, the combination of the cultivation period of HEK293 FT cells for lentiviral production and the accommodation of the L7 or Gfa2 promoter into lentiviral vectors permits us to specifically transduce Purkinje cells or Bergmann glia, respectively. However, these cell-type specific promoters generally have weak promoter strength. Therefore, the modification of these promoters, by the addition of an enhancer sequence and/or a significant increase in the viral titer by ultracentrifugation, is needed to attain sufficient levels of transgene expression.
4.2. A method that enables efficient and widespread gene delivery to the cerebellum
The cerebellum is a second largest organ in the mammalian CNS. Neurodegenerative diseases and congenital enzyme deficiency usually affect the entire cerebellar cortex, ranging from the vermis to the hemisphere, lobule 1 to lobule 10.
For effective gene therapy, a wide range of therapeutic gene delivery methods is indispensable. Figure 2a is a photo of our viral injection system for the rodent brain.
The injection of viral solutions to the brain parenchyma mechanically damages the tissue around an injection site, and ~1 l is usually the limit for mouse brain regions, such as the striatum and hippocampus. However, we found that when injected at a speed of 0.2 – 0.3 l/minute, it was possible to apply 10 l of viral solution to the subarachnoidal space over lobule 6 of the cerebellar cortex (Fig. 2b) without substantial damage to the cortical tissue. Injected viral particles spread through subarachnoidal spaces and infect Purkinje cells via their well-differentiated dendrites, leading to markedly efficient transduction of the Purkinje cells (Fig. 3). We have also verified that this injection method is applicable to neonatal pups and mature mice (Fig. 2c) (Sawada et al., 2010; Torashima et al., 2006a; Torashima et al., 2006b).
5. Lentiviral vector-based rescue of mice with cerebellar ataxia
5.1. Hotfoot5J mice
Hotfoot mice are spontaneously occurring recessive mutants (Guastavino et al., 1990), and mice homozygous for the mutation showed severe ataxia with jerky tapping of the hindlimbs, which can be noted by two weeks after birth. The Hotfoot5J allele possesses a point mutation in exon 12 of the GluRδ2 gene, which creates a stop codon in the region encoding transmembrane 3 (Wang et al., 2003). Aberrant GluRδ2 protein is easily degraded and not detected in the Purkinje cells of hotfoot5J mice. Therefore, hotfoot5J mice are thought to exhibit a similar phenotype to that of GluRδ2 knock-out mice (Kashiwabuchi et al., 1995). Accordingly, we determined whether the ataxia of hotfoot5J mice could be reliably rescued by lentiviral-vector-based expression of the recombinant wild-type GluRδ2 gene (Iizuka et al., 2009).
Figure 2.
Injection of viral vectors into the mouse cerebellum. (a) A viral vector injection setup. Viral vectors are injected very slowly with a speed of 0.2-0.3 l/minute using an ultramicropump. (b) A schematic of the sagittal view of a mouse cerebellum depicting a viral injection site. (c) A schematic showing the availability of this injection method from a neonatal pup to a mature mouse.
Figure 3.
Highly efficient transduction of Purkinje cells. Lentiviral vectors expressing GFP was injected as shown in Fig. 2. (a and b) Stereoscopic images of GFP fluorescence (a) and the superimposition with the whole brain (b) 7 days after the viral injection. (c) A GFP fluorescent image of Purkinje cells in the sagittal section.
Lentiviral vectors expressing GluRδ2 plus GFP or GFP alone were injected into lobule 6 of the hotfoot5J cerebella at P6, and the motor control ability was assessed at P30 by footprints and a rotarod test. The footprint pattern of mutant mice was markedly ameliorated by the expression of GluRδ2 plus GFP (Fig. 4).
Figure 4.
Footprints of wild-type and hotfoot5J mice at P30. Ink was placed on the hindpaws of a non-injected wild-type mouse, a non-injected hotfoot5J mouse and hotfoot5J mice treated with GluRδ2 plus GFP (+ GluRδ2 & GFP); their footprints are shown. N.I., non-injected.
Figure 5.
Rescue of rotarod performance of hotfoot5J mice treated with GluRδ2 plus GFP. (a and b) Mice were assessed by two different tasks, an accelerating rod that reached 40 rpm from 0 rpm in 3 min (a) and a stably rotating rod with a speed of 10 rpm (b). The results of non-injected wild-type mice, non-injected hotfoot5J mice and hotfoot5J mice injected with lentiviral vectors expressing GluRδ2 plus GFP or GFP alone are presented. Asterisks indicate statistically significant differences compared with non-injected hotfoot5J mice: *p < 0.05, ***p < 0.001 (One-way ANOVA).
In the rotarod analysis, mice treated with GluRδ2 plus GFP showed significantly better performance at both acceleration and fixed-rod-speed tasks than non-injected mutant mice (Fig. 5), whereas neither the footprint pattern (not presented) nor the rotarod performance (Fig. 5) of hotfoot5J mice was altered by the injection of lentiviral vectors expressing only GFP. However, the rescue of ataxia by GluRδ2 expression was obviously incomplete; GluRδ2-treated hotfoot5J mice showed far poorer rotarod performance, particularly in the accelerating rod task (Fig. 5a), than wild-type mice. This was due partly to the expression of recombinant GluRδ2 in restricted lobules of hotfoot5J cerebellum.
Following the immunohistochemical examination, the GluRδ2 immunoreactivity was absent in the Purkinje cells from the non-injected hotfoot5J mice, whereas efficient GluRδ2 expression was detected in the dendritic spines of Purkinje cells from hotfoot5J mice treated with lentiviral vectors expressing GluRδ2 plus GFP.
Figure 6.
Rescue from the persistent multiple CF innervation of hotfoot5J Purkinje cells by GluRδ2 expression. (a) Representative CF-EPSCs recorded from Purkinje cells clamped at −10 mV in non-injected wild-type, non-injected hotfoot5J, GluRδ2/GFP-treated hotfoot5J, and GFP-expressing hotfoot5J mice are shown. Scale bar, 500 pA, 10 ms. (B) Frequency histograms of Purkinje cells in terms of the number of discrete CF-EPSC steps in Purkinje cells from non-injected wild-type (42 cells, 3 animals), non-injected hotfoot5J (48 cells, 4 animals), GluRδ2/GFP-treated hotfoot5J (35 cells, 3 animals), and GFP-expressing hotfoot5J (40 cells, 3 animals) mice. N.I., non-injected.
Previous electrophysiological studies indicated that the multiple climbing fiber innervation of Purkinje cells continued even after maturation in the GluRδ2 knockout mice. GluRδ2-/- Purkinje cells were innervated persistently by multiple climbing fibers (Hashimoto et al., 2001; Ichikawa et al., 2002; Kashiwabuchi et al., 1995), and we examined whether the multiple innervations of hotfoot5J Purkinje cells were restored by the expression of recombinant GluRδ2 using a patch-clamp technique. Only 18% of the Purkinje cells in P31-P35 wild-type mice, and more than 60% of the Purkinje cells from age-matched GluRδ2-null mice, were innervated by multiple climbing fibers (Fig. 6). The failure of the developmental removal of surplus climbing fibers was completely rescued by the lentiviral vector-mediated expression of GluRδ2 plus GFP. However, no significant rescue was observed in hotfoot5J cerebella expressing GFP alone. These results suggest a therapeutic potential of lentiviral vector-based gene therapy for cerebellar disorders that result from a loss-of-function gene mutation.
5.2. The SCA model mice
Polyglutamine diseases, including several autosomal dominant types of SCA, are inherited neurodegenerative diseases caused by expanded polyQ accumulation in neurons (Koshy & Zoghbi, 1997). Recent studies have identified proteins that facilitate the degradation of polyQ aggregates through a ubiquitin-proteasome pathway in cultured cells. Previously, Yanagi and colleagues have identified a novel guanosine triphosphatase (GTPase), CRAG, as one of those proteins. Furthermore, these authors have shown that CRAG triggers the nuclear translocation of a CRAG-polyQ complex, leading to the degradation of polyQ in HeLa cells (Qin et al., 2006). Because the expression of CRAG decreases in the adult brain, it is plausible that a reduced level of CRAG could underlie the onset of polyglutamine diseases. Therefore, we examined the potential of CRAG expression for treating polyglutamine disease and tested our hypothesis by lentivirally introducing CRAG into the cerebellar neurons of mice overexpressing polyQ in the cerebellum.
Figure 7.
Severe cerebellar atrophy in the PolyQ mouse at P21 and P80. (a) A schematic depicting the transgene that drives the mutant ataxin-3(Q69) under the control of the L7 promoter; an HA-tag was fused at the N-terminus of the truncated ataxin-3. Wild-type (b d, and f) and SCA3 model (c, e, and g) mice were fixed at P21 (b and c) or P80 (d-g). (b-e) A dorsal view of the whole brain; cerebella are indicated by arrows. Cb; cerebrum, IC; inferior colliculus, SC; superior colliculus, Sp; spinal cord. (f and g) Klüver–Barrera staining of sagittal sections of the cerebellum from a P80 SCA3 model mouse (g) and a wild-type littermate (f). Scale bars, 500 µm.
For this project, we generated transgenic mice (SCA model mice) expressing an expanded polyQ in cerebellar Purkinje cells using a truncated form of human ataxin-3, the gene responsible for Machado-Joseph disease (SCA3) with 69 CAG triplet repeats (ataxin-3[Q69]) (Kawaguchi et al., 1994; Yoshizawa et al., 2000) (Fig. 7a). The transgene expression was driven by a Purkinje cell-specific L7 promoter (Hirai et al., 2005). The SCA model mice started to show ataxic gait at approximately P10, which became more obvious as they developed further.
The cerebella of SCA model mice at P21 and P80 were substantially smaller than that of wild-type littermates (Fig. 7b-g). A low magnification of the sagittal sections of the SCA model mouse cerebellum showed that the overall structure of the cortex was not grossly affected (Fig. 7g). However, examination at a higher magnification revealed that the Purkinje cells were markedly disarranged, concomitant with a substantial impairment of dendritic differentiation (Fig. 8).
Figure 8.
Drastic morphological alteration in Purkinje cells of the SCA3 model mouse. Cerebellar sections from a P21 SCA3 model mouse (a) and a wild-type littermate (b) immunolabeled for calbindin. Note the markedly decreased thickness of the molecular layer and disarrangement of the Purkinje cell soma in the SCA3 model mouse cerebellum. Scale bar, 50 m.
Immunostaining of the cerebellar sections for the hemagglutinin (HA)-tag at the N-terminus of polyQ revealed a weak and diffuse accumulation of polyQ mainly in the nucleus of Purkinje cells at P21. The polyQ was markedly increased and formed numerous inclusion bodies in or around the Purkinje cell bodies by P80. In addition to the immunoreactivity in the Purkinje cell layer, small inclusion bodies with strong immunoreactivity for polyglutamine and ubiquitin were detected in the axon terminals of the Purkinje cells in the deep cerebellar nuclei.
Lentiviral vectors expressing CRAG GTPase were injected into the midline cerebellar lobules of P21-P25 mice. The effect of CRAG or GFP expression was assessed by a rotarod test, in which mice were challenged with an accelerating rod paradigm just before or 4 or 8 weeks after the viral injection (Fig. 9a). The rotarod performance of the non-injected SCA3 model mice and the model mice expressing GFP alone deteriorated slightly at 8 weeks. In contrast, the performance of mice treated with CRAG was significantly improved at both 4 and 8 weeks after the injection, as compared with the results of non-injected mice. To examine the effect of CRAG expression on motor learning, mice were evaluated again by a rotarod test with a different paradigm, in which the rod speed was fixed at 5 rpm, and the trial was repeated 6 times. Non-injected SCA3 model mice and those treated with GFP showed almost no improvement in the performance even at the 6th trial (Fig. 9b). In contrast, mice treated with CRAG learned quickly how to stay on the rod, indicating the rescue of motor learning ability.
Figure 9.
Rescue of the ataxic phenotype in polyQ mice upon the lentivector-mediated expression of CRAG. (a and b) Results of the rotarod test. The rod was accelerated from 0 rpm and reached the maximum speed (40 rpm) in 3 min, as depicted above the graph (a). Mice treated with wild-type CRAG, but not those treated with GFP, exhibited significant improvement (a) (n = number of individual mice in each cohort). In the stable rod speed paradigm (5 rpm) administered 8 weeks after the injection, mice treated with CRAG learned quickly how to walk on the rod and showed a drastically better performance, compared with the non-injected and GFP-expressing mice (b). *p<0.05, **p<0.01, ***p<0.001, compared with results of non-injected mice.
We next examined the cerebellar sections from untreated mice or mice treated with the lentiviral vectors by immunohistochemistry. Whereas strong labeling with numerous polyQ inclusions was observed in the cerebellar slices from non-injected polyQ mice and those injected with virus expressing GFP, the overall labeling with an anti-HA antibody for polyQ was faint and diffusely distributed in the cytoplasm and nuclei of the Purkinje cells in CRAG-expressing slices (Fig. 10a-d). Notably, the arrangement and dendritic differentiation of the Purkinje cells was altered upon the expression of CRAG. Double immunolabeling for calbindin and Flag-tag fused with CRAG showed that only the CRAG-expressing Purkinje cells extended dendrites. Consistently, the molecular layer was significantly wider in the cerebella of polyQ mice treated with CRAG than in those of non-injected animals (p<0.01, Fig. 10e). These in vivo data substantiated previous cell-culture-based results and further extended the usefulness of the targeted delivery of genes facilitating the ubiquitin-proteasome pathway as a gene therapy against polyglutamine diseases and other neurodegenerative disorders.
Figure 10.
Degradation of polyQ aggregates in Purkinje cells by lentiviral-vector-mediated expression of CRAG. (a-d) Cerebellar sections from mice receiving no injection (a and b) or treated with CRAG (c and d). Upper panels are fluorescent images of polyQ immunolabeled for HA (green), which were merged with those of Purkinje cells immunolabeled for calbindin (magenta, lower panels). ML; molecular layer, PL; Purkinje cell layer. (e) A graph of the thickness of the molecular layer. The thickness of the molecular layer in the cerebellum from SCA3 model mice (Tg) treated without (Non-injected) or with CRAG and their wild-type littermates (WT) was measured, and the data were plotted on the graph. The average ± SD is presented beside the each plot. Three animals in each experimental group and virus vectors obtained from at least two independent cultures were used for quantitative analysis. Asterisks indicate significant differences compared with results of non-injected mice, **p<0.01.
6. Underlying problems for the clinical application of lentiviral vectors to cerebellar diseases
6.1. The significantly larger size of human cerebellum compared with the mouse cerebellum
Figure 11 is a comparison of the mouse cerebellum with that of the cynomolgus monkey. Although our injection method allowed us to deliver a transgene very efficiently to mouse cerebellar cells, the human cerebellum is much larger than that of the cynomolgus monkey. Therefore, it is a tremendous challenge to attain the efficient transduction of Purkinje cells in the human cerebellum. To overcome this volume problem, we are exploring ways to increase the amount of the viral solution from 10 l to 1,000 l and the number of injection sites from one to, for example, three points.
Figure 11.
Comparison of the mouse cerebellum (right) with that of the cynomolgus monkey (left).
6.2. Side effects that might be caused by the use of lentiviral vectors
6.2.1. Toxicity of lentiviral vector infection on Purkinje cells
Infection with Borna disease virus, an RNA virus tropic for cerebellar neurons, has been shown to cause developmental, neuroanatomical and behavioral abnormalities (Rubin et al., 1999). HIV infection has also been shown to cause a decreased expression of mRNA and protein of AMPA-type glutamate receptors in cerebellar Purkinje cells (Everall et al., 1995). Compared with adenoviral vectors that have immunogenicity, lentiviral vectors cause almost no immune responses to infected cells and are thought to exert little toxicity on host cells. However, it has not been fully clarified whether the infection of high-titer lentiviral vectors lacks an adverse influence on neurons in vivo. To clarify the influence of high-titer lentiviral vector infection and the subsequent expression of the transgene, we injected lentiviral vectors having a titer of 1.0 x 1010 transduction units (TUs) into the neonatal rat cerebellum. Neonates were used for examining lentiviral toxicity because the brain is extremely vulnerable to developmental damage following perinatal insult.
Lentiviral vectors expressing GFP under the control of the murine stem cell virus (MSCV) promoter were injected into the cerebellar cortex of neonatal rat pups. Three weeks after treatment, the GFP-expressing Purkinje cells were compared with control Purkinje cells from phosphate-buffered, saline-injected mice. An analysis of the dendritic tree showed that the total dendrite length in the GFP-expressing Purkinje cells was almost 80% of that in the control Purkinje cells. Furthermore, an electrophysiological examination showed that the short-term synaptic plasticity at the parallel fiber–Purkinje cell synapses and climbing fiber–Purkinje cell synapses was significantly altered in the GFP-expressing Purkinje cells. In contrast, the morphological and functional maldevelopment of infected Purkinje cells was attenuated substantially when lentiviral vectors with much weaker promoter activity were used. These results suggest that the maldevelopment of the Purkinje cells was caused mainly by the subsequent expression of a high amount of GFP driven by the strong MSCV promoter and that the toxic influence of lentiviral vector infection itself was minimal.
6.2.2. Insertional mutagenesis
Upon infection of a retrovirus into a cell, the viral RNA is inserted into the cytoplasm, where the RNA is reverse-transcribed into DNA by reverse transcriptase, which is then inserted into the host genome by an integrase. The viral genome sequence integrated into the host chromosome is called a “provirus”. The provirus insertion may disrupt regions of the host genome that are critical for cellular functions, such as the control of the cell cycle or apoptosis; this process is called “insertional mutagenesis”. In fact, ex vivo gene therapy using a murine leukemia virus (MLV) vector caused leukemia in 3 of the 11 children that were being treated for X-linked SCID (Hacein-Bey-Abina et al., 2003). However, lentiviral vectors are considered to be less likely to disturb the regulation and expression of host genes because of a difference of integration sites between the MLV vectors and lentiviral vectors: MLV vectors integrate primarily in promoter regions and CpG islands, whereas lentiviral vectors integrate into transcriptionally active genes (Mitchell et al., 2004; Schroder et al., 2002). Although it is not clear whether insertional mutagenesis can lead to the transformation of postmitotic neurons, lentiviral vectors do infect and cause insertional mutagenesis in glial cells with proliferative properties. Therefore, the risk of insertional mutagenesis should be considered when lentiviral vectors are used clinically to treat neurological diseases (Jakobsson & Lundberg, 2006).
7. Conclusion
The cerebellum develops significantly after birth (Goldowitz & Hamre, 1998), and, therefore, the expression of various genes is strictly regulated. Cerebellar granule cell precursors that proliferate vigorously in the external granule cell layer migrate along the processes of Bergmann glia to form the internal granule cell layer during the first postnatal two weeks in rodents. The migrating granule cells supply trophic factors, such as brain-derived neurotrophic factor (BDNF), which stimulates the Purkinje cells to form differentiated dendrites (Schwartz et al., 1997). During the migration process, parallel fibers, granule cell axons, (Granule cell axons are called “parallel fibers”) make synapses with extending dendrites of Purkinje cells. Synaptic clefts between the parallel fibers and dendritic spines of a Purkinje cell are wrapped by processes of Bergmann glia that reuptake released glutamate, thereby modulate the synaptic transmission. Thus, 5 neurons and Bergmann glia in the cerebellar cortex concertedly elaborate the functional cerebellar neuronal circuit. One attractive therapy against diseases that impair Purkinje cells is the transplantation of Purkinje cells or their precursors engineered from stem cells into the damaged cerebellum. However, unless other cells surrounding Purkinje cells, such as the granule cells and interneurons, have sufficient plasticity, the transplanted Purkinje cells are not properly integrated to form a functional network, resulting in little therapeutic impact.
In contrast, gene therapy aims to salvage degenerating Purkinje cells by delivering a therapeutic gene. Accordingly, when Purkinje cells are not lost, this approach is theoretically more effective than stem cell-based cell replacement therapy for diseases that impair Purkinje cells; this is despite the fact that the surrounding cells have only limited plasticity. To attain sufficient therapeutic efficacy in gene therapy, the broad and efficient gene delivery to cerebellar neuronal or glial cells is indispensable, and this has been a significant challenge for decades. However, the problem is being solved by recent marked progress in both lentiviral and AAV vectors. The further accumulation of knowledge, including therapeutic genes and the critical period corresponding to distinct cerebellar defects, along with the development of animal models, would facilitate the clinical application of viral vector-based gene therapy for patients with various cerebellar disorders.
Acknowledgments
This work was supported by KAKENHI (19670003) and the Funding Program for Next Generation World-Leading Researchers (LS021).
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/17777.pdf",chapterXML:"https://mts.intechopen.com/source/xml/17777.xml",downloadPdfUrl:"/chapter/pdf-download/17777",previewPdfUrl:"/chapter/pdf-preview/17777",totalDownloads:3186,totalViews:636,totalCrossrefCites:0,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:59,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"October 21st 2010",dateReviewed:"April 6th 2011",datePrePublished:null,datePublished:"August 23rd 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/17777",risUrl:"/chapter/ris/17777",book:{id:"502",slug:"gene-therapy-applications"},signatures:"Hirokazu Hirai and Akira Iizuka",authors:[{id:"28666",title:"Prof.",name:"Hirokazu",middleName:null,surname:"Hirai",fullName:"Hirokazu Hirai",slug:"hirokazu-hirai",email:"hirai@gunma-u.ac.jp",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"28694",title:"Dr.",name:"Akira",middleName:null,surname:"Iizuka",fullName:"Akira Iizuka",slug:"akira-iizuka",email:"iiduka@med.gunma-u.ac.jp",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Cerebellar organization and neural circuits in the cerebellum",level:"1"},{id:"sec_3",title:"3. Disorders of the cerebellum",level:"1"},{id:"sec_3_2",title:"3.1. Spontaneously occurring ataxic mice",level:"2"},{id:"sec_4_2",title:"3.2. Human cerebellar diseases potentially treatable with gene therapy",level:"2"},{id:"sec_4_3",title:"3.2.1. Spinocerebellar ataxia",level:"3"},{id:"sec_5_3",title:"3.2.2. Mucopolysaccharidosis",level:"3"},{id:"sec_8",title:"4. Viral vector-mediated gene delivery to the cerebellum",level:"1"},{id:"sec_8_2",title:"4.1. Factors that control the tropism of lentiviral vectors for cerebellar neurons and glia",level:"2"},{id:"sec_9_2",title:"4.2. A method that enables efficient and widespread gene delivery to the cerebellum",level:"2"},{id:"sec_11",title:"5. Lentiviral vector-based rescue of mice with cerebellar ataxia",level:"1"},{id:"sec_11_2",title:"5.1. Hotfoot5J mice",level:"2"},{id:"sec_12_2",title:"5.2. The SCA model mice",level:"2"},{id:"sec_14",title:"6. Underlying problems for the clinical application of lentiviral vectors to cerebellar diseases",level:"1"},{id:"sec_14_2",title:"6.1. The significantly larger size of human cerebellum compared with the mouse cerebellum",level:"2"},{id:"sec_15_2",title:"6.2. Side effects that might be caused by the use of lentiviral vectors",level:"2"},{id:"sec_15_3",title:"6.2.1. Toxicity of lentiviral vector infection on Purkinje cells",level:"3"},{id:"sec_16_3",title:"6.2.2. Insertional mutagenesis",level:"3"},{id:"sec_19",title:"7. Conclusion",level:"1"},{id:"sec_20",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Al-RamahiI.LamY. C.ChenH. K.de GouyonB.ZhangM.PerezA. M.et al.2006CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J Biol Chem,\n\t\t\t\t\t281362671426724'},{id:"B2",body:'AliskyJ. M.HughesS. M.SauterS. L.JollyD.DubenskyT. W.Jr StaberP. 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Gunma University Graduate School of Medicine, Japan
Gunma University Graduate School of Medicine, Japan
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1. Introduction
Puerperium is the time following delivery during which pregnancy-induced maternal anatomical and physiological changes return to the nonpregnant state. Its duration is understandably inexact, but is considered to range between 4 and 6 weeks. By popular use, however, the meaning usually includes the six subsequent weeks of delivery.
The word puerperium is derived from Latin—puer- child andparus bringing forth.
The postpartum period is associated with much tradition and superstition because the health of a new infant is very important to the survival of any family. Puerperium begins as soon as the placenta is expelled and lasts for approximately 6 weeks when the uterus regress almost to the non pregnant size.
Puerperium can be divided into:
immediate – within 24 hours.
early – up to 7 days.
remote – up to 6 weeks.
2. Physiology of the puerperium
2.1 Uterus
The uterus weighs approximately 1000 gm and has a volume of 5 L immediately after delivery, compared with its non pregnant weight of approximately 70 g m and 5–10 ml.
Just after delivery, the height of the uterine fundus is halfway between the pubic symphysis and the umbilicus. It happens because of the delivery of the fetus, placenta and amniotic fluid. Also there is loss of hormonal stimulation.
The height of the fundus just after delivery is 13.5 cm above the symphysis pubis. The level remains constantfor first 24 hours. After that, there is a steady decrease in height by 1.25 cm in 24 hours, resulting in uterus so that by the end of 2nd week the uterus becomes a pelvic organ. The rate of involution thereafter slows down getting back the uterus to normal size in 6 weeks. Just after delivery, due to the rapidly decreasing endometrial surface that is attached to the placenta, placenta gets sheared from the decidual layer. The average diameter of the placenta attached to the deciduas is 18 cm; which goes down to 9 cm in the immediate postpartum period.
For the first 3 days after delivery, the placental site is infiltrated with granulocytes and mononuclear cells. It is a reactionary change that extends into the endometrium and superficial myometrium as well.
By the 7th day, the regeneration of endometrial glands is evident, and they often appear atypical with irregular chromatin patterns, enlarged nuclei, pleomorphism and increased cytoplasm.
By the end ofthe first week, regeneration of the endometrial stroma is also evident, and mitotic figures are noted in gland epithelium. By postpartum day 16, the endometrium gets fully restored.
Just after birth, hemostasis is achieved by arterial smooth muscle contraction and compression of vessels by the involuting uterine muscle. In the first 8 days, vessels in the placental site are characterized by thrombosis, hyalinization. Endophlebitis in the veins and hyalinization and obliterativefibrinoid endarteritis in the arteries are notable findings.
The postpartum uterine discharge, or lochia, begins as a flow of blood that lasts several hours, then rapidly diminishes to a reddish brown discharge through the third or fourth day postpartum.
The post partum discharge is termed lochia and it contains erythrocytes, shredded decidua, epithelial cells and bacteria. For the first few days after delivery, it is known as lochia rubra. After 3 or 4 days, lochia becomes progressively pale in color and is known as lochia serosa. Then at around 10th day, because of an admixture of leukocytes and reduced fluid content, lochia assumes a white or yellow-white color known as lochia alba. The average duration of puerperial lochial discharge is from 24 to 36 days [1].
Breastfeeding or the use of oral contraceptive agents does not affect the duration of lochia. The cervical os contracts slowly, and for a few days just after labor, it readily admits two fingers. Gradually, this opening narrows and the cervix thickens with reformation of endocervical canal in a week. The external os never resumes its pre gravid appearance. It remains somewhat wider with the ectocervical depressions getting permanent at the site of lacerations.
2.2 Birth canal
The vagina and the introitus gradually reduce in size but hardly regain the nulliparous size and shape. Rugae start appearing by the third week but are less prominent. The hymen is represented by several small tissue tags of tissue that form the myrtiform caruncles.
After delivery, the vaginal epithelium reflects the hypoestrogenic state, and it stops proliferating until 4 to 6 weeks. Some damage to the pelvic floor may be inevitable, and parturition predisposes to urinary incontinence and pelvic organ prolapse.
2.3 Ovarian function
Ovulation starts as early as 27 days after childbirth. It can start after about 70 to 75 days in non lactating women. But for breastfeeding women, the mean time to ovulation can be about 6 months.
Menstruation usually resumes by 12 weeks postpartum in 70% of non lactating women. The mean time to the first menses after childbirth is 7 to 9 weeks.
In a woman exclusively breastfeeding, the likelihood of ovulation within the first 6 months postpartum is 1% to 5%.
The persistent elevation of serum prolactin in lactating women is the basis for ovulation suppression in lactating women. Prolactin levels get back to the normal range by 3 weeks after delivery in nonlactating women but remains elevated till the 6th week in lactating women.
2.4 Peritoneum and abdominal wall
The broad and round ligaments require considerable time to recover from stretching and loosening during pregnancy.
After cesarean delivery, a 6-week interval to allow fascia to heal and abdominal soreness to diminish is reasonable.
Silvery abdominal striae commonly develop as striaegravidarum.
Marked separation of the rectus abdominis muscles—diastasis recti—may result.
2.5 Blood and blood volume
Marked leukocytosis and thrombocytosis may occur during and after labor. The greatest level of coagulability is observed immediately after delivery and remains for the following 48 hours. Fibrinogen concentrations gradually diminish over the first 2 weeks postpartum. Increased fibrinolytic activity is seen in the initial 4 days following delivery. The fibrinolytic activity is back to normal in a week and is shown by plasminogen activation inhibitor 1levels. D-dimer levels are more than pregnancy levels, but are a poor marker of thrombus formation. Protein-S levels and activated protein-C resistance are less for around 6 weeks in puerperium. The changes in the coagulation system, together with vessel trauma and immobility, account for the increased risk for thromboembolism noted in the puerperium, especially when an operative delivery has occurred.
2.6 Cardiovascular system
Plasma volume is diminished by about 1000 mL just after delivery and that is due to blood loss during delivery.
Due to the shift of extracellular fluid into the vascular space. The plasma volume is replenished by the 3rd day of puerperium. Also, the total blood volume declines by 16% of the pre delivery value, and that manifests as transient anemia.
By 8 weeks of puerperium, the red cell mass rebounds and the hematocrit becomes normal in most women. Since, the blood volume becomes normal, venous tone also gets to baseline. Pulse rate increases throughout gestation, like stroke volume and cardiac output. Just after delivery, these remain elevated or may rise even higher for initial 30 to 60 minutes. Following delivery, a transient rise of about 5% occurs in both diastolic and systolic blood pressures and that continues for the first 4 days postpartum.
2.7 Thyroid function
Thyroid volume increases to about 30% during pregnancy and then gets back to normal in a 12-week period in puerperium. Both thyroxine and triiodothyronine increase throughout pregnancy and becomes normal within 4 weeks post delivery. For women on thyroid medications, it is advisable to check thyroid profile at 6 weeks postpartum to titrate the dosage. Sometimes, during the postpartum period, there is an increased risk for the development of a transient autoimmune thyroiditis that may later evolve into permanent hypothyroidism.
2.8 Immune system
The immune system gets compromised during pregnancy—particularly cellular-mediated immunity. The rebound of cellular mediated immunity after delivery leads to “flare-ups” of autoimmune diseases and subclinical infections with inflammatory reactions. Autoimmune thyroiditis, multiple sclerosis, and lupus erythematosus are examples of auto immune diseases that show flare ups in the first few months of puerperium.
2.9 Urinary tract
Normal pregnancy-induced glomerular hyperfiltration persists during the puerperium but returns to prepregnancy baseline by 2 weeks [2].
Dilated ureters and renal pelves return to their prepregnant state by 2 to 8 weeks postpartum.
Postpartum, the bladder has an increased capacity and a relative insensitivity to intravesical pressure. Thus, over distention, incomplete emptying, and excessive residual urine are frequent in puerperium [3, 4].
2.10 Lactation
Breasts begin to secrete colostrum after delivery. It is a dark yellow liquid and usually can be expressed from the nipples by the second postpartum day. In comparison to mature milk, colostrum is rich in both immunological components and minerals and amino acids [5]. It also has more protein, mostly globulin, but contains less sugar and fat.
Colostrum secretion continues for 5 days to 2 weeks post partum, with later conversion from “transitional” to mature milk in next 4 to 6 weeks.
3. Management of puerperium
3.1 Hospital stay
For most parturients, the immediate puerperium is spent in the hospital or birthing center.
In the 1950s, the lying-in period after delivery used to be around 8 to 14 days. Now, most women stay in the hospital only for 24 to 48 hours after a vaginal birth. For patients with an uncomplicated postoperative course after caesarean delivery, the post partum stay is only 2 to 4 days. During the hospital stay, the focus should be on preparation of the mother for newborn care, infant feeding including the special issues involved with breastfeeding, and also the required newborn laboratory testing.
There are no dietary restrictions for women who have been delivered vaginally. Two hours after uncomplicated vaginal delivery, a woman is allowed to eat.
3.2 Postpartum complications
Infection commonly occurs in approximately 5% of post partum patients and significant immediate postpartum hemorrhage in approximately 1% of patients. Just after the delivery of the placenta, the uterus is palpated bimanually to ascertain its tonicity. Uterine palpation is very important and is repeated frequently during the immediate postpartum period to prevent and identify uterine atony promptly. In only 1% of cases, bleeding persists or is excessive and is called delayed postpartum hemorrhage. If the bleeding is heavy or the uterus is believed to contain blood clots, uterus should be massaged until it contracts and the clots expressed. The physician may be notified, and on order an oxytocin preparation such as syntocinon 1 ml given intramuscularly orIV infusion with 5% glucose is administered. When the general condition of the mother is satisfactory, the mother and baby should be transferred to the ward. As soon as the post natal ward is notified that the newly delivered mother and her baby is to be transferred to the ward, the mid wife should arrange for a bed to be prepared in a single room or in a quite area of a ward so that the mother will be able to sleep following her efforts during delivery.
On arrival, we should note the following:
Consistency of the uterus
Blood loss
Pulse
BP
Temperature
General condition of the mother-tired –feeling weak
Parity and age
Blood group and Rh factor
Events of labour and delivery including the amount of blood loss
The baby’s condition at birth and his birth weight
Mother’s chosen method of infant feeding
What examinations and tests have already been carried out and plan for those which must be done during the next few days.
3.3 Daily examination
Every morning the mother should be seen and asked as to how she is feeling. The midwife should particularly note if the mother complains of feeling unduly tired. Any woman who is anaemic or who is developing an infection will not feel well. Temperature, pulse and Blood pressure should be measured. The temperature and pulse rate may be recorded at least twice a day for the few days and then once daily until the 10th days of the puerperium. If the temperature exceeds 37.3 degree Celsius or 99 degree Fahrenheit, the physician is to be notified. The pulse rate is normally 80 or below per minute. Any rise in the pulse rate above 90 beats per minute should be reported to the physician irrespective of whether it is accompanied by rise in temperature or not. Any rise in temperature may be indicative of excessive bleeding or of a developing puerperal infection. Tachycardia which is due to excessive bleeding will be accompanied by hypotension. When a nurse notices a rising pulse rate and fall in blood pressure she must check the state of the uterus and lochia in order to identify post partumhaemorrhage. The blood pressure is checked during the first 24 hours following a normal delivery and for a longer period of time, if there has been any history of bleeding, hypertension during pregnancy, or if the mother has had a Caesarean section or has required any other surgical intervention.
The breasts should be examined daily and noted whether the breasts are soft and are free from lumps, redness and soreness.
3.4 Breasts problems: sore and damaged nipples
Abnormal nipples: Inverted and flat nipples.
The complications of breast feeding are engorgement of breasts. In breasts feeding mothers breast engorgement occurs around the third and fourth post partum day. The breasts arehard, painful and sometimes flushed. The mother may develop pyrexia along with that. Engorgement results from an increased amount of blood and edema in the breasts and indicates that the baby is not ready to take the full quantity. Warm compresses to the breasts and removal of excess milk at the end of each feeding will relieve the condition. Even tight brassieres help.
3.5 The Bowels
The bowels tends to be sluggish during the puerperium for the following reasons.
The woman is losing fluid from her body in quantities of urine, in perspiration and breastmilk.
The anus maybe insensitive to stimulation having been forcibly dilated by the pressure of baby’s head.
It is good to give some mild laxative for the first 36 hrs after delivery such as liquid paraffin or milk of magnesia. When diet contains sufficient roughage and fluid, the bowel needs less artificial stimulation. If the bowels do not move 48 hrs after delivery, glycerine or dulcolex suppository is usually given.
3.6 Diet
The nursing mother needs a liberal nourishing diet to build up her strength and enable her to produce sufficient breast milk. Good whole food is essential containing sufficient proteins, minerals and vitamins. As so many women are anaemic at this time the nurse must ensure that food rich in iron are included in the diet. The haemoglobin is estimated on 8th or 9th day. Iron supplements are usually prescribed for one month. As the woman is losing calcium when she breastfeeds, she should take adequate dietary calcium. Fruit and vegetables should be served at every meal.
3.7 Rest and sleep
The woman needs adequate rest, quietness and sleep because of the hypersensitive state of her nervous system. If kept awake by some discomfort such as after pains, haemorrhoids, or engorged breasts, the nurse should treat the cause before giving analgesics. The ward should be closed morning and afternoon for 1 hour. The patient is requested to relax and keep silent if they cannot sleep. The persistent insomnia in absence of pain should be viewed as a warning sign of ensuing puerperal psychosis at times.
3.8 Asepsis and antisepsis
Asepsis must be maintained, especially during the first week of puerperium. The woman is particularly vulnerable to infection at this time for the following reasons:
The uterus provides an ideal environment for the growth and multiplication of the micro organisms.
The lacerated and bruised tissues of the vulva and vagina being devitalised are unable to resist the invasion of organism.
The vaginal orifice is gaping and micro organisms can readily enter.
The woman’s immunity is lowered because of depletion of energy, lack of sleep and food.
Blood loss may have been excessive.
The nurse must wear a mask when the vulva is exposed during the first week of puerperium.
The room and bed linen, the women skin and clothing should be clean. Adequate use of soap and water is the first requirement.
What to report to the physician.
Temperature and pulse.
Appetite and sleep
Bowel and bladder movements
Character of lochia
Condition of sutured perineum
Pain eg. In the breasts, abdomen, leg, head
Any peculiarity in behaviour.
3.9 Perineal care
In puerperium, the woman is advised to maintain hygiene and clean the vulva from anterior to posterior toward the anus. A cool pack may be applied to the perineum to bring down edema and pain during the first 24 hours, especially in perineal laceration or an episiotomy.
3.10 After pains
Uterine involution manifests as several clinical findings. In primiparas, the uterus usually remains tonically contracted after delivery. Whereas in multiparas, the uterus contracts vigorously at intervals and manifests as afterpains, which are almost like labor pains. These pains are more pronounced as parity increases and worsen when the newborn lactates, because of oxytocin release. By the 3rd day post partum, afterpains decrease in intensity and become mild. In women with postpartum uterine infections, there may be severe and persistent after pains. Aspirin can be given with food in those cases.
Severe perineal, vaginal or rectal pain always warrants careful inspection and palpation. Hemorrhoidal veins are often congested at term. Thrombosis is common and may be promoted by second-stage pushing. Treatment for the condition includes topically applied anesthetics, warm soaks, and stool-softening agents.
3.11 Bowel and bladder function
Stool softeners may be prescribed, especially if the patient has had a fourth degree perineal tear or a laceration involving the rectal mucosaduring delivery.
Hemorrhoids are varicosities of the hemorrhoidal veins and are commonly found in puerperium. Surgical treatment may be considered only after 6 months postpartum to allow for natural involution. Sitz baths, stool softeners, and local medicinal preparations are useful alongwith reassurance.
She goes to the toilet after 6 hours to pass urine Periurethral edema after vaginal delivery may cause transitory urinary retention.
3.12 Retention of urine
3.12.1 Causes
Recumbent- posture and lack of privacy.
Stitches in perineum.
Bruises of bladder neck- bladder neck spasms.
Bladder atony.
3.12.2 Treatment
Women go to toilet or sit on bedpan withscreen. Hot and cold water bottles are applied on hypogastrium. Plenty of oral fluid to be given. Catherization if she cannot pass urine. Patients’ urinary output should be monitored for the first 24 hours after delivery. If catheterization is required more than twice in the first 24 hours, placement of an indwelling catheter for 1 to 2 days is advisable. Prolonged catheterization needs to be avoided.
3.12.3 Pain, mood, and cognition
Mild analgesics containing codeine, aspirin, or acetaminophen, preferably in various combinations are given as frequently as every 4 hours during the first few days. It is fairly common for mother to exhibit some degree of depressed mood a few days after delivery termed postpartum blues. Post partum blues can be multi factorial. Mostly, anticipation, recognition, and reassurance works. This disorder is usually mild and self-limited to 2 to 3 days, but sometimes may last up to 10 days. Persistence or worsening of moods calls for evaluation for symptoms of major depression.
3.12.4 Ambulation
Postpartum patients should be encouraged to begin ambulation as soon as possible after delivery. Early ambulation helps avoid urinary retention and prevents puerperal venous thromboses and pulmonary embolism. Early ambulation is the key to faster recovery post delivery.
3.12.5 Breast care
Nipples are cleansed with sterile water and cotton swab before and after feeding. They are covered with sterile bra. In non lactating women, breast engorgement occurs in the initial days of puerperium and gradually reduces over this period. Painful breasts should be supported with a well-fitting brassiere. Ice packs and analgesics may also help relieve breast discomfort and pain. Women who do not wish to breastfeed should be encouraged to avoid nipple stimulation and advised to avoid continued manual expression of milk. Mastitis, or infection of the breast tissue, most often occurs in lactating women and manifests as sudden-onset fever, localized pain and swelling in the breast. Mastitis is associated with infection by micro organisms like Staphylococcus aureus, Group A or B streptococci, β Haemophilus species, and Escherichia coli.
Treatment includes continuation of breastfeeding or emptying the breast with a breast pump to avoid engorgement and also use of appropriate antibiotics.
3.12.6 Immunizations
Women who do not have antirubella antibody should be immunized during the immediate postpartum period [6]. Breastfeeding is not a contraindication for that.
If a patient has not received the tetanus-diphtheria acellular pertussis vaccine, or it has been at least 2 years since her last tetanus-diphtheria booster, she should be administered a dose before discharge from hospital.
If the woman is Rh-negative blood group, not isoimmunized and has given birth to a Rh-positive or weak-Rh-positive baby, 300 micrograms of anti-D immune globulin should be administered postpartum, ideally within 72 hours of delivery.
3.12.7 Post partum posture and exercise
In sitting posture she feeds her baby for sometime daily, she lies in her face for three weeks.
Deep breathing and simple movement of limbs are encouraged. Some simple exercises are practised when she feels it for after a few days to tone up abdominal and pelvic floor muscles as:-.
Deep breathing.
Abdominal wall is tightened on deep inspiration and breatheholding followed by its relaxation. This is done 10 times on floor with knees pulled up.
Pelvic floor muscles- Bent knees press on a pillow followed by relaxation for a number of times. Encourage erect walks.
Sexual intercourse is permitted with use of contraceptive following first post natalcheck up at sixth week.
3.13 Contraception
Postpartum care in the hospital should include discussion of contraception. Approximately 15% of non-nursing women are fertile at 6 weeks postpartum. Progestin preparations (oral norethindrone or depo-medroxyprogesterone acetate) have no effect or may slightly facilitate lactation. Women may consider initiating progesterone-only contraceptives at 6 weeks if breastfeeding exclusively or at 3 weeks if not exclusively.
Postpartum sterilization is performed at the time of cesarean delivery or after a vaginal delivery and should not extend the patient’s hospital stay.
3.14 Sexual activity
Coitus may be resumed when the woman is pain free and comfortable. However, the risks of hemorrhage and infection are minimal at approximately 2 weeks postpartum. Women should be counseled, especially if breastfeeding, that coitus may initially be uncomfortable because of a dry vagina as a result of low estrogen levels. In such conditions, use of exogenous, water soluble lubrication is helpful.
3.15 Follow-up care
By discharge, women who had an uncomplicated vaginal delivery can resume most activities, including bathing, driving, and household functions. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2017) recommend a postpartum visit between 4 and 6 weeks. This has proven quite satisfactory to identify abnormalities beyond the immediate puerperium and to initiate contraceptive practices.
Advice on discharge for home:
Exclusive breast feeding for 6 months
Care of the newborn
Total infant immunization for protection of infant from six killer diseases.
Oral rehydration for mild diarrhoea
The discharge carries the following:
Discharge slip- carrying details of the delivery and childbirth date.
Instruction to mother on food, iron folic acid laxative.
betadime cream is applied once daily on perineal wound at home for 7 days.
She is instructed to put on sterile pad forlochial discharge and to return on sixth week for post natalcheck up.
She is also referred to infant immunization center for full immunization of infantsupto 10 months.
Post natal care:
3.16 Post natal examinations
First check up on discharge and second on sixth post partum week.
Mother: general health, pulse, BP, temperature breasts, uterine fundus is palpated per lower abdomen for normal involution.
Perineum is inspected and that of lochia.
Bladder and bowel functions are enquired.
Infant: weight, skin condition (jaundiced), eyes, condition of umbilical cord, feeding, stool, urination, any other problem are checked by referring to pediatric opd or paediatrician.
Second post natal check up on sixth week.
Mother and infant: duration of lochia, duration of first menses, sleep, bladder, bowel, perineal wound, breasts or bottle feeding.
Infants: weight, heart, lungs, umbilicus, Inj BCG are checked.
Advice on discharge: Food advices to mother, giving her a food chart and use of boiled water.
Rest, sleep, exercise and posture by mother.
Advice on contraceptives.
Breast feeding.
After delivery, the breasts start to secrete colostrum, which is a deep lemon yellow liquid usually by the second postpartum day. Compared with mature milk, colostrum is rich in immunological components and contains more minerals and amino acids, protein, much of which is globulin, but less sugar and fat. The colostrum content of immunoglobulin A (IgA) offers the newborn protection against enteric pathogens. Mature milk is a complex and dynamic biological fluid that consists of fat, proteins, carbohydrates, bioactive factors, minerals, vitamins, hormones and many other cellular products. The concentrations and contents of human milk change even during a single feed, but are affected by maternal diet and newborn age, health and needs.
A nursing mother usually produces 600 mL of milk daily. However, maternal gestational weight gain has little impact on the quantity or quality of milk. Milk is isotonic with plasma, and lactose alone accounts for half of the osmotic pressure. Essential amino acids in milk are derived from blood, and nonessential amino acids come from blood or synthesized in the mammary gland. Alpha-lactalbumin, beta-lactoglobulin and casein are some of the milk proteins. Fatty acids are synthesized in the breast alveoli from glucose and are secreted by an apocrine-like process. Though vitamins are found in human milk, but these are present in variable amounts. Vitamin K is virtually absent, and thus, an intramuscular dose is required to be given to the newborn [7].
Even the milk serum whey contains large amounts of interleukin-6. Human milk has a whey-to-casein ratio of 60:40 and that is considered ideal for absorption. Prolactin is also actively secreted into breast milk. Epidermal growth factor (EGF) found in milk is not destroyed by gastric proteolytic enzymes and hence may be absorbed to promote growth and maturation of newborn intestinal mucosa [8]. Lactoferrin, melatonin, oligosaccharides, and essential fatty acids are the other constituents of milk. The precise humoral and neural mechanisms involved in lactation are complex.
Progesterone, estrogen, and placental lactogen, as well as prolactin, cortisol, and insulin act in concert to stimulate the growth and development of the milk-secreting apparatus in lactating breasts [9]. With delivery, the maternal serum levels of progesterone and estrogen decline abruptly and significantly. The falling progesterone and estrogen levels remove the inhibitory influence on alpha-lactalbumin production and thus stimulates lactose synthase in milk. Progesterone withdrawal also allows prolactin to act unopposed and stimulates production of alpha-lactalbumin in milk. The intensity and duration of subsequent lactation are controlled, in large part, by the repetitive stimulus of nursing and emptying of milk from the breast. Prolactin is essential for lactation and women with extensive pituitary necrosis— Sheehan syndrome—does not lactate. Although after delivery, plasma prolactin levels drop to levels lower than during pregnancy, each act of suckling causes a rise in levels [10]. Suckling curtails the release of dopamine, also known as prolactin-inhibiting factor, from the hypothalamus. That in turn, also transiently induces prolactin secretion. Oxytocin is known to be secreted by the pituitary in pulsatile fashion. This oxytocin stimulates contraction of myoepithelial cells in the alveoli and small milk ducts and hence helps in milk expression. Milk ejection or letting down, is a reflex initiated especially by suckling, which stimulates the posterior pituitary to liberate oxytocin. The reflex may even be provoked by an infant cry and can be inhibited by maternal fright or stress.
3.17 Nursing
Human milk is known ideal food for newborns for it provides age-specific nutrients, immunological factors, and antibacterial substances to the newborn. Milk also helps in promoting cellular growth and differentiation. For both mother and infant, the benefits of breastfeeding are long-term and unique. World Health Organization (2011) recommends exclusive breastfeeding for up to 6 months.
3.18 Advantages of breastfeeding
Nutritional
Immunological
Developmental
Psychological
Social
Economical
Environmental
Optimal growth and development
Decrease risks for acute and chronic diseases
The Baby Friendly Hospital Initiative is an international program to promote exclusive breastfeeding. It is based on the World Health Organization (1989) Ten Steps to Successful Breastfeeding. World wide, almost 20,000 hospitals are designated as “baby-friendly hospitals.
Ten Steps to Successful Breastfeeding (Baby Friendly Hospital Initiative):
Have a written breastfeeding policy that is regularly communicated to all Health-care staff.
Train all staff in skills necessary to implement this policy.
Inform all pregnant women about the benefits and management of breastfeeding.
Help mothers initiate breastfeeding within an hour of birth.
Show mothers how to breastfeed and how to sustain lactation, even if they should be separated from their infants.
Feed newborns nothing but breast milk, unless medically indicated, and under no circumstances provide breast milk substitutes, feeding bottles, or pacifiers free of charge or at low cost.
Practice rooming-in, which allows mothers and newborns to remain together 24 hours a day.
Encourage breastfeeding on demand.
Give no artificial pacifiers to breastfeeding newborns.
Help start breastfeeding support groups and refer mothers to them.
3.19 Contraindications to breastfeeding
Nursing is contraindicated in some women who have intake of street drugs or alcohol abuse; have an infant with galactosemia; human immunodeficiency virus (HIV) infection; active, untreated tuberculosis; undergoing breast cancer treatment [11]. Breastfeeding has been recognized for some time as a mode of HIV transmission and is proscribed in developed countries in which adequate nutrition is otherwise available. Other viral infections do not contraindicate breastfeeding. Women with active herpes simplex virus may suckle their infants if there are no breast lesions and ifparticular care is directed to hand washing before nursing.
3.20 Other issues with lactation
With inverted and depressed nipples, nursing is very difficult. Here, lactiferous ducts open directly into a depression at the center of the areola. If the depression is not deep, milk can sometimes be expressed with the help of a breast pump. During the last few months of pregnancy, daily attempts can be madeto draw or “tease” the nipple out with the fingers.
Extra breasts—polymastia, or extra nipples—polythelia, may develop along the milk line or the former embryonic mammary ridge In some women, rests of accessory breast tissue may also be found in the mons pubis or vulva. In the general population, the incidence of accessory breast tissue ranges from 0.22 to 6 percent [12]. These accessory breasts are very small and are mistaken to be pigmented moles, lymphadenopathy or lipoma. However, polymastia has no obstetrical significance. But, occasional enlargement of these accessory breasts during pregnancy or postpartum cause patient discomfort and anxiety.
Galactocele is another complication wherein a milk duct gets obstructed by inspissated milk secretions. The amount is ordinarily limited, but an excess may form a fluctuant mass—a galactocele. Galactocoele may cause pressure symptoms and also form an abscess. It might get resolved spontaneously or might require aspiration.
Among individuals, the volume of milk secreted varies markedly. This depends on breast glandular development rather than maternal health. Rarely, there is a condition with complete lack of mammary secretion—agalactia. Again, mammary secretion might be excessive—polygalactia.
\n',keywords:"puerperium, postpartum, breastfeeding, lactation, parity",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75604.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75604.xml",downloadPdfUrl:"/chapter/pdf-download/75604",previewPdfUrl:"/chapter/pdf-preview/75604",totalDownloads:410,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 2nd 2020",dateReviewed:"February 2nd 2021",datePrePublished:"March 8th 2021",datePublished:"November 3rd 2021",dateFinished:"March 8th 2021",readingETA:"0",abstract:"Puerperium is the time following delivery during which pregnancy-induced maternal anatomical and physiological changes return to the nonpregnant state. Puerperium period of 6 weeks can be divided into: (a) immediate – within 24 hours (b) early – up to 7 days (c) remote – up to 6 weeks. The puerperal effects are seen in all organs and particularly in reproductive organs. Infection and haemorrhage are the common postpartum complications. Post partum care is very important. Advice on exclusive breast feeding and contraception is also mandatory after every childbirth.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75604",risUrl:"/chapter/ris/75604",signatures:"Subrat Panda, Ananya Das, Arindam Mallik and Surajit Ray Baruah",book:{id:"8557",type:"book",title:"Empowering Midwives and Obstetric Nurses",subtitle:null,fullTitle:"Empowering Midwives and Obstetric Nurses",slug:"empowering-midwives-and-obstetric-nurses",publishedDate:"November 3rd 2021",bookSignature:"Amita Ray",coverURL:"https://cdn.intechopen.com/books/images_new/8557.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-066-2",printIsbn:"978-1-83969-065-5",pdfIsbn:"978-1-83969-067-9",isAvailableForWebshopOrdering:!0,editors:[{id:"251100",title:"Prof.",name:"Amita",middleName:null,surname:"Ray",slug:"amita-ray",fullName:"Amita Ray"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"33073",title:"Dr.",name:"Ananya",middleName:null,surname:"Das",fullName:"Ananya Das",slug:"ananya-das",email:"mailmedrananyadas@rediffmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"33508",title:"Dr.",name:"Subrat",middleName:null,surname:"Panda",fullName:"Subrat Panda",slug:"subrat-panda",email:"pandadrsubrat@rediffmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"345371",title:"Dr.",name:"Arindam",middleName:null,surname:"Mallik",fullName:"Arindam Mallik",slug:"arindam-mallik",email:"arin007788@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"345618",title:"Dr.",name:"Surajit",middleName:null,surname:"Ray Baruah",fullName:"Surajit Ray Baruah",slug:"surajit-ray-baruah",email:"surajitraybaruah@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Physiology of the puerperium",level:"1"},{id:"sec_2_2",title:"2.1 Uterus",level:"2"},{id:"sec_3_2",title:"2.2 Birth canal",level:"2"},{id:"sec_4_2",title:"2.3 Ovarian function",level:"2"},{id:"sec_5_2",title:"2.4 Peritoneum and abdominal wall",level:"2"},{id:"sec_6_2",title:"2.5 Blood and blood volume",level:"2"},{id:"sec_7_2",title:"2.6 Cardiovascular system",level:"2"},{id:"sec_8_2",title:"2.7 Thyroid function",level:"2"},{id:"sec_9_2",title:"2.8 Immune system",level:"2"},{id:"sec_10_2",title:"2.9 Urinary tract",level:"2"},{id:"sec_11_2",title:"2.10 Lactation",level:"2"},{id:"sec_13",title:"3. Management of puerperium",level:"1"},{id:"sec_13_2",title:"3.1 Hospital stay",level:"2"},{id:"sec_14_2",title:"3.2 Postpartum complications",level:"2"},{id:"sec_15_2",title:"3.3 Daily examination",level:"2"},{id:"sec_16_2",title:"3.4 Breasts problems: sore and damaged nipples",level:"2"},{id:"sec_17_2",title:"3.5 The Bowels",level:"2"},{id:"sec_18_2",title:"3.6 Diet",level:"2"},{id:"sec_19_2",title:"3.7 Rest and sleep",level:"2"},{id:"sec_20_2",title:"3.8 Asepsis and antisepsis",level:"2"},{id:"sec_21_2",title:"3.9 Perineal care",level:"2"},{id:"sec_22_2",title:"3.10 After pains",level:"2"},{id:"sec_23_2",title:"3.11 Bowel and bladder function",level:"2"},{id:"sec_24_2",title:"3.12 Retention of urine",level:"2"},{id:"sec_24_3",title:"3.12.1 Causes",level:"3"},{id:"sec_25_3",title:"3.12.2 Treatment",level:"3"},{id:"sec_26_3",title:"3.12.3 Pain, mood, and cognition",level:"3"},{id:"sec_27_3",title:"3.12.4 Ambulation",level:"3"},{id:"sec_28_3",title:"3.12.5 Breast care",level:"3"},{id:"sec_29_3",title:"3.12.6 Immunizations",level:"3"},{id:"sec_30_3",title:"3.12.7 Post partum posture and exercise",level:"3"},{id:"sec_32_2",title:"3.13 Contraception",level:"2"},{id:"sec_33_2",title:"3.14 Sexual activity",level:"2"},{id:"sec_34_2",title:"3.15 Follow-up care",level:"2"},{id:"sec_35_2",title:"3.16 Post natal examinations",level:"2"},{id:"sec_36_2",title:"3.17 Nursing",level:"2"},{id:"sec_37_2",title:"3.18 Advantages of breastfeeding",level:"2"},{id:"sec_38_2",title:"3.19 Contraindications to breastfeeding",level:"2"},{id:"sec_39_2",title:"3.20 Other issues with lactation",level:"2"}],chapterReferences:[{id:"B1",body:'Fletcher S, Grotegut CA, James AH: Lochia patterns among normal women: a systematic review. J Womens Health (Larchmt) 21(12):1290, 2012'},{id:"B2",body:'Hladunewich MA, Lafayette RA, Derby GC, et al: The dynamics of glomerular filtration in the puerperium. Am J Physiol Renal Physiol 286:F496, 2004'},{id:"B3",body:'Buchanan J, Beckmann M: Postpartum voiding dysfunction: identifying the risk factors. Aust N Z JObstetGynaecol 54(1):41, 2014'},{id:"B4",body:'Mulder FE, Hakvoort RA, Schoffelmeer MA, et al: Postpartum urinary retention: a systematic review of adverse effects and management. IntUrogynecol J 25(12):1605, 2014'},{id:"B5",body:'Ballard O, Morrow AL: Human milk composition: nutrients and bioactive factors. PediatrClinNorth Am 60(1):49, 2013'},{id:"B6",body:'Swamy G, Heine RP: Vaccinations for pregnant women. ObstetGynecol 125:212, 2015'},{id:"B7",body:'Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding: Prevention ofrickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 122(5):1142,2008'},{id:"B8",body:'McCleary MJ: Epidermal growth factor: an important constituent of human milk. J Hum Lact7:123, 1991'},{id:"B9",body:'Stuebe AM: Enabling women to achieve their breastfeeding goals. ObstetGynecol 123:643, 2014'},{id:"B10",body:'Pang WW, Hartmann PE Initiation of human lactation: secretory differentiation and secretoryactivation. J Mammary Gland Biol Neoplasia 12:211, 2007'},{id:"B11",body:'Faupel-Badger JM, Arcaro KF, Balkam JJ, et al: Postpartum remodeling, lactation, and breastcancer risk: summary of a National Cancer Institute-sponsored workshop. J Natl Cancer Inst 105(3):166, 201'},{id:"B12",body:'Loukas M, Clarke P, Tubbs RS: Accessory breasts: a historical and current perspective. Am Surg 73(5):525, 2007'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Subrat Panda",address:"pandadrsubrat@rediffmail.com",affiliation:'
Department of Obstetrics and Gynecology, NEIGRIHMS, Shillong, Meghalaya, India
Department of Obstetrics and Gynecology, NEIGRIHMS, Shillong, Meghalaya, India
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Department of Obstetrics and Gynecology, NEIGRIHMS, Shillong, Meghalaya, India
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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
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In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
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The IntechOpen timeline
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2004
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Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
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Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
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2005
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IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
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2006
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IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
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2008
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Downloads milestone: 200,000 downloads reached
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2009
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Publishing milestone: the first 100 Open Access STM books are published
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2010
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Downloads milestone: one million downloads reached
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IntechOpen expands its book publishing into a new field: medicine.
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2011
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Publishing milestone: More than five million downloads reached
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IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
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IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
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IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
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2012
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Publishing milestone: 10 million downloads reached
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IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
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2013
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IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
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2014
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IntechOpen turns 10, with more than 30 million downloads to date.
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IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
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2015
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Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
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Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
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40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
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Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
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2016
\\n\\n
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IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
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2017
\\n\\n
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Downloads milestone: IntechOpen reaches more than 100 million downloads
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Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
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\n\n
2005
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IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
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2006
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IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
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\n\n
2008
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Downloads milestone: 200,000 downloads reached
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\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
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\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
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IntechOpen expands its book publishing into a new field: medicine.
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\n\n
2011
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Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
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\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
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\n\n
2013
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\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón",slug:"juan-carlos-gardon",fullName:"Juan Carlos Gardón",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:"Catholic University of Valencia San Vicente Mártir, Spain",institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain. She is a Full Professor at the Department of Medicine and Animal Surgery at the same University. She developed her research activity in the field of Endocrinology, Hematology, Biochemistry and Immunology of horses. She is a scientific reviewer of several international journals : American Journal of Obstetrics and Gynecology, Comparative Clinical Pathology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology. Since 2014, she has been the Head of the Clinical Analysis Laboratory of the Hospital Clínico Veterinario from the Faculty of Veterinary, CEU-Cardenal Herrera University.",institutionString:"CEU-Cardenal Herrera University",institution:{name:"CEU Cardinal Herrera University",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. She is currently a teacher in the medium / technical level courses at IFMT-Alta Floresta, as well as in the Bachelor\\\'s degree in Animal Science and in the Bachelor\\\'s degree in Business.',institutionString:null,institution:null},{id:"442807",title:"Dr.",name:"Busani",middleName:null,surname:"Moyo",slug:"busani-moyo",fullName:"Busani Moyo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Gwanda State University",country:{name:"Zimbabwe"}}},{id:"423023",title:"Dr.",name:"Yosra",middleName:null,surname:"Soltan",slug:"yosra-soltan",fullName:"Yosra Soltan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"349788",title:"Dr.",name:"Florencia Nery",middleName:null,surname:"Sompie",slug:"florencia-nery-sompie",fullName:"Florencia Nery Sompie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sam Ratulangi University",country:{name:"Indonesia"}}},{id:"345713",title:"Dr.",name:"Csaba",middleName:null,surname:"Szabó",slug:"csaba-szabo",fullName:"Csaba Szabó",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"345719",title:"Mrs.",name:"Márta",middleName:null,surname:"Horváth",slug:"marta-horvath",fullName:"Márta Horváth",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"420151",title:"Prof.",name:"Novirman",middleName:null,surname:"Jamarun",slug:"novirman-jamarun",fullName:"Novirman Jamarun",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Andalas University",country:{name:"Indonesia"}}},{id:"420149",title:"Dr.",name:"Rusmana",middleName:"Wijaya Setia",surname:"Wijaya Setia Ningrat",slug:"rusmana-wijaya-setia-ningrat",fullName:"Rusmana Wijaya Setia Ningrat",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Andalas University",country:{name:"Indonesia"}}},{id:"339759",title:"Mr.",name:"Abu",middleName:null,surname:"Macavoray",slug:"abu-macavoray",fullName:"Abu Macavoray",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Njala University",country:{name:"Sierra Leone"}}},{id:"339758",title:"Prof.",name:"Benjamin",middleName:null,surname:"Emikpe",slug:"benjamin-emikpe",fullName:"Benjamin Emikpe",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ibadan",country:{name:"Nigeria"}}},{id:"339760",title:"Mr.",name:"Moinina Nelphson",middleName:null,surname:"Kallon",slug:"moinina-nelphson-kallon",fullName:"Moinina Nelphson Kallon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Njala University",country:{name:"Sierra Leone"}}}]}},subseries:{item:{id:"17",type:"subseries",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11413,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,series:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983"},editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",slug:"attilio-rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",slug:"yanfei-(jacob)-qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},onlineFirstChapters:{paginationCount:0,paginationItems:[]},publishedBooks:{paginationCount:1,paginationItems:[{type:"book",id:"10654",title:"Brain-Computer Interface",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/10654.jpg",slug:"brain-computer-interface",publishedDate:"May 18th 2022",editedByType:"Edited by",bookSignature:"Vahid Asadpour",hash:"a5308884068cc53ed31c6baba756857f",volumeInSeries:9,fullTitle:"Brain-Computer Interface",editors:[{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour",profilePictureURL:"https://mts.intechopen.com/storage/users/165328/images/system/165328.jpg",institutionString:"Kaiser Permanente Southern California",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},testimonialsList:[{id:"27",text:"The opportunity to work with a prestigious publisher allows for the possibility to collaborate with more research groups interested in animal nutrition, leading to the development of new feeding strategies and food valuation while being more sustainable with the environment, allowing more readers to learn about the subject.",author:{id:"175967",name:"Manuel",surname:"Gonzalez Ronquillo",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",slug:"manuel-gonzalez-ronquillo",institution:{id:"6221",name:"Universidad Autónoma del Estado de México",country:{id:null,name:"Mexico"}}}},{id:"8",text:"I work with IntechOpen for a number of reasons: their professionalism, their mission in support of Open Access publishing, and the quality of their peer-reviewed publications, but also because they believe in equality.",author:{id:"202192",name:"Catrin",surname:"Rutland",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",slug:"catrin-rutland",institution:{id:"134",name:"University of Nottingham",country:{id:null,name:"United Kingdom"}}}},{id:"18",text:"It was great publishing with IntechOpen, the process was straightforward and I had support all along.",author:{id:"71579",name:"Berend",surname:"Olivier",institutionString:"Utrecht University",profilePictureURL:"https://mts.intechopen.com/storage/users/71579/images/system/71579.png",slug:"berend-olivier",institution:{id:"253",name:"Utrecht University",country:{id:null,name:"Netherlands"}}}}]},submityourwork:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],subseriesList:[],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:null},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/221075",hash:"",query:{},params:{id:"221075"},fullPath:"/profiles/221075",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()