\r\n\tThe applications are those related to intelligent monitoring activities such as the quality assessment of the environmental matrices through the use of innovative approaches, case studies, best practices with bottom-up approaches, machine learning techniques, systems development (for example algorithms, sensors, etc.) to predict alterations of environmental matrices. The goal is also to be able to protect natural resources by making their use increasingly sustainable.
\r\n
\r\n\tContributions related to the development of prototypes and software with an open-source component are very welcome.
\r\n
\r\n\tThis book is intended to provide the reader with a comprehensive overview of the current state of the art in the field of Ambient Intelligence. A format rich in figures, tables, diagrams, and graphical abstracts is strongly encouraged.
",isbn:"978-1-83969-069-3",printIsbn:"978-1-83969-068-6",pdfIsbn:"978-1-83969-070-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"3fbf8f0bcc5cdff72aaf0949d7cbc12e",bookSignature:"Dr. Carmine Massarelli",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10391.jpg",keywords:"Embedded Systems, Technologies, Sensors, Remote Sensing, Smart Homes, Smart Cities, Integrated Monitoring Techniques, Agroecosystem, Smart Public Spaces, Computer Vision, Image Processing, Open-Source",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 12th 2020",dateEndSecondStepPublish:"November 9th 2020",dateEndThirdStepPublish:"January 8th 2021",dateEndFourthStepPublish:"March 29th 2021",dateEndFifthStepPublish:"May 28th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Environmental technologist expert in the development of Smart Technologies for water management and environmental monitoring, characterization, and monitoring of contaminated and degraded sites, integration of spatial data such as standard methodologies, interoperability, spectral data infrastructures.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"315689",title:"Dr.",name:"Carmine",middleName:null,surname:"Massarelli",slug:"carmine-massarelli",fullName:"Carmine Massarelli",profilePictureURL:"https://mts.intechopen.com/storage/users/315689/images/system/315689.jpg",biography:"Main activities:\n-development of Smart Technologies for water management and environmental monitoring;\n-characterization and monitoring of contaminated and degraded sites;\n-implementation of early warning systems and impact assessment systems also from multitemporal monitoring;\n-integration of spatial data: methodologies, standards, interoperability, spatial data infrastructures;\n-use of open source IT systems for the processing, analysis, and integration of remote sensing data with airborne and satellite sensors for thematic purposes such as characterization, control, and analysis of the territory in support of environmental policies relating to contaminated sites;\n-evaluation of the contamination of environmental matrices with specific tests and chemical analyses;\n-installation of airborne sensors and definition of flight parameters for Earth observation, CASI-1500 hyperspectral and TABI-320 thermal sensors;\n-acquisition of spectral signatures of objects through Fieldspec portable spectroradiometer and creation of databases in SQL language;\n-use of tools such as Ground Penetrating Radar for the advanced investigation of the subsoil with law enforcement agencies.",institutionString:"National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.p@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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\n\t\t\t
1. Introduction
\n\t\t\t
Diabetes mellitus is a disease of insulin insufficiency, which causes hyperglycemia and has both acute and chronic complications. Acute complications consist of hyperglycemic ketoacidosis and hypoglycemic episodes. Chronic complications consist of micro- and macro-angiopathies. Micro-angiopathy leads to diabetic nephropathy, neuropathy and retinopathy; macro-angiopathy leads to brain infarction, brain hemorrhage and cardiac infarction. Both acute and chronic complications significantly deteriorate the quality of life of diabetic patients and are sometimes fetal.
\n\t\t\t
More than 23.7 million people suffer from diabetes in the USA today and that number will reach 44.1 million in 2034 (Huang et al., 2009). It has been demonstrated that the loss of beta-cell mass is approximately 95% in type 1 diabetic patients, 65% in type 2 diabetic patients, and even 50% in metabolic syndrome patients (Butler et al., 2003, 2007; Meier et al., 2005, 2008).
\n\t\t\t
From the treatment viewpoint, diabetes is categorized into non-insulin dependent diabetes mellitus (NIDDM) and insulin dependent diabetes mellitus (IDDM). The standard therapy for the IDDM is insulin injection (Table 1). However, in the advanced phase, those patients are not able to control blood glucose levels by insulin injection. Beta cell replacement therapies including whole pancreas transplantation and islet cell transplantation are currently applied clinically for such patients (Matsumoto, 2010a) (Table 1). Unfortunately, there are more than one million IDDM patients in the United States and the number of cadaveric organs available is approximately 7,000 in each year. There is a clear donor shortage and regenerative medicine and/or tissue engineering for creating insulin-producing cells are critical to overcome this issue.
\n\t\t\t
Diabetes is an excellent candidate for regenerative medicine and tissue engineering because only the beta cell with or without alpha cells is necessary to be generated for improving glycemic control. Since islet cell transplantation has already been proven to be an effective treatment for diabetic patients, generating insulin-producing cells is guaranteed for clinical effectiveness.
\n\t\t\t
Indeed, tissue engineering using pig islet cells has already been clinically attempted as a bio-artificial islet transplantation for the treatment of IDDM patients (Table 1). In addition, some approaches including direct signal delivery to pancreas and neural relay of signal from liver to pancreas have been established for beta cell regeneration experimentally (Table 1).
Current and future treatments for insulin dependent diabetes mellitus (IDDM). Allogeneic islet transplantation for the treatment of type 1 diabetes is considered as the standard therapy in some countries. Of note, bio-artificial islet transplantation using pig islets has been already initiated for the treatment of type 1 diabetic patients. ES cells: Embryonic stem cells, iPS cells: induced pluripotent stem cells, N.A.: not applicable
\n\t\t\t
Thus this field is one of the most advanced areas for regenerative medicine and tissue engineering.
\n\t\t\t
In this book chapter we describe the current status of regenerative medicine and tissue engineering for creating insulin-producing cells and clinical application or the path to the clinical application of those technologies.
\n\t\t
\n\t\t
\n\t\t\t
2. Regenerative medicine of beta cells
\n\t\t\t
Regenerative medicine of beta cells consists of two major categories. The one is a replacement/implantation of alternative cell sources instead of human islets from cadaver donors. Such cell sources include embryonic stem (ES) cells, induced pluripotent stem (iPS) cells, or other systemic stem cells. They are expanded and differentiated to insulin producing cells in vitro, and implanted into a diabetic patient. However, although several straightforward protocols were established, both the efficiency of in vitro programming and the function of derived-beta cells remain unsatisfactory. In addition, safety concerns due to inherent risks of neoplasm originating from residual stem cells remain a major hurdle (Borowiak & Melton, 2009; Ricordi & Edlund, 2008; McKnight et al., 2010). To avoid the risks of neoplasm of beta cell generation from stem cells, beta cell transdifferentiation from exocrine tissues has been performed (Minami et al., 2005). Impressively, simple culture of exocrine tissue with EGF and nicotinamide enabled the transdifferentiation of exocrine tissue to beta cells. Additionally, exocrine tissues from type 1 diabetic mice model were able to trans-differentiate into beta cells (Okuno et al., 2006). However, the efficacy was not effective yet to generate enough beta cells to reverse diabetes, and this approach requires human exocrine tissue.
\n\t\t\t
Another medical approach is bona fide regeneration of islet cells/beta cells in a patient. Because there is a slow rate of beta cell turnover in the human pancreas even after injury, regenerative medicine is focusing on stimulating either beta cell replication or neogenesis. Finding a molecular intervention that can be safely used in vivo seems challenging but not impossible. There are ways in which neogenesis might be stimulated to expand beta cell mass using agents such as exendin-4, gastrin and epidermal growth factor (Bonner-Weir & Weir, 2005). Another method is differentiation/transdifferentiation in which either existing stem cells or differentiated cells can be programmed/reprogrammed to change their identity. To achieve this goal, most studies have used a gene induction method with a viral vector. It was demonstrated that pancreatic acinar cells might be reprogrammed in mice with injections into the pancreas of adenoviruses expressing three transcription factors, pancreatic duodenal homeobox-1 (PDX-1), musculoaponeurotic fibrosarcoma oncogene homolog A and neurogenin-3 (Zhou et al., 2008). However, gene delivery with viral vectors has shown adverse effects, which have been related to enhancer-mediated mutagenesis of genomic DNA (Hacein-Bey-Abina S et al., 2003) or immunological responses to viral proteins (Manno et al., 2006). Before these permanent or long-term side effects are fully understood and resolved, the safety of using viral vectors must be established.
\n\t\t\t
In this chapter, for bona fide beta cell regeneration, we will introduce two unique methods. The first method is gene delivery using ultrasound targeted micro-bubble destruction (UTMD) technology. UTMD technology allows us to deliver genes specifically into the pancreas by using ultrasound without using viral vectors (Chen et al., 2006, 2010). The other method is activating neural relay mechanism to stimulate beta cell regeneration and insulin secretion in naïve pancreas (Imai et al., 2010). The initial signal is activated in the liver and the signal relay to pancreas via neural system. The unique signal in the liver can actually stimulate beta cell regeneration and insulin secretion in the naïve pancreas.
\n\t\t\t
\n\t\t\t\t
2.1. Ultrasound targeted micro-bubble destruction (UTMD) for gene delivery to regenerate beta cells
\n\t\t\t\t
\n\t\t\t\t\t
2.1.1. Development of UTMD for gene delivery
\n\t\t\t\t\t
In order to obtain high gene expression after gene delivery in vivo without viral vectors, we have established an ultrasound-mediated gene transfer method named Ultrasound Targeted Microbubble Destruction (UTMD) and achieved efficient gene transfer of plasmid DNA (pDNA) in vivo (Chen S et al., 2006, 2010; Korpanty G et al., 2005). Delivery of pDNA does not transport toxic or immunogenic viral protein or polymer particles. UTMD is known to be a novel and potential gene delivery method in vivo. The mechanism of gene delivery is as follows: the microbubbles consist of lipid shell and perfluorocarbon gas on the inside. The plasmid gene to be delivered resides in the shell. After infusing the microbubbles with pDNA intravenously, they are detected in the target organ by echography. Under ultrasound exposure, the microbubbles burst and the energy creates transient pores in membranes of surrounding cells, and pDNAs are inserted into the cells (Figure 1).
\n\t\t\t\t\t
UTMD has many of the desired characteristics of gene therapy including low toxicity, low immunogenicity, potential for repeated application, organ specificity and broad applicability to acoustically accessible organs.
\n\t\t\t\t\t
Figure 1.
The mechanism of Ultrasound Targeted Microbubble Destruction (UTMD) for gene delivery. In vessels, microbubbles can be destroyed with high mechanical index ultrasound in the target organ, and the released genes (pDNAs) pass through the vasculature, thus releasing the genes (pDNAs) into the surrounding tissue. The microbubble destruction can only happen under ultrasound
\n\t\t\t\t\t
Using this technology, plasmids containing rat insulin 1 promoter (RIP)-human insulin and RIP-hexokinase I were successfully delivered to the islets of adult rats (Chen S et al., 2006). Delivery of RIP-human insulin plasmid resulted in clear increases in circulating human C-peptide and decreased blood glucose levels. Delivery of RIP-hexokinase plasmid resulted in a clear increase in hexokinase I protein expression in islets. Furthermore, delivery of RIP-NeuroD1 by UTMD technology into streptozotocin induced diabetic rats resulted in promotion of islet regeneration in the naïve pancreas with the return of normal glucose, insulin and C-peptide levels (Chen S et al., 2010). Thus, an exciting new possibility has emerged with this technology. Much work is now underway to determine the potential clinical applications of this in vivo gene induction used alone or in combination with other regeneration techniques.
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\n\t\t\t\t\t
2.1.2. Path to clinical application of beta cell regeneration by UTMD
\n\t\t\t\t\t
Even though UTMD for gene delivery is promising for beta cell regeneration, there are several issues that remain to be solved before clinical application. First of all, the safety of this technology needs to be confirmed using a large animal model. Microbubbles have been clinically used as contrast agents for ultrasound; however, the material of microbubbles for UTMD is modified for gene delivery. Therefore, it is necessary to assure the microbubbles for UTMD is safe. Furthermore, since the ability of beta cell regeneration in rodent is much higher in human or large animal (Noguchi et al., 2009b, 2010), it is important to confirm the efficacy of beta cell regeneration in large animal. The next issue is the long-term effect of beta cell regeneration by gene delivery with UTMD. In the rodent model, normoglycemia were maintained for up to 3 months (Chen et al., 2010). Identifying the mechanisms of failure to maintain long-term insulin independence is important. On the other hand, the UTMD technology is relatively easy to be applied. Therefore repeating this technology is feasible. In such case, the effect and safety of repeated UTMD need to be assessed.
\n\t\t\t\t\t
When applying the UTMD method for type 1 diabetic patients, it is necessary to prevent autoimmune recurrence. Therefore, immunosuppressive drugs might be necessary to prevent the immunological rejection of regenerated beta cells.
\n\t\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
2.2. Neural relay for beta cell regeneration in naïve pancreas
\n\t\t\t\t
The concept of neural relay is very unique. Beta cell proliferative activity changes dynamically to meet systemic needs throughout life. One condition in which beta cell proliferation is enhanced is obesity-related insulin resistance. However, the mechanism underlying this compensatory beta cell response is not well understood.
\n\t\t\t\t
Recently, Katagiri et al. have identified a neuronal relay, originating in the liver, which enhances both insulin secretion and pancreatic beta cell proliferation for the possible mechanism of obesity-related insulin resistance (Katagiri et al., 2009). Blockade of this neural relay in murine obesity models inhibited pancreatic islet expansion during obesity development, showing this inter-organ communication system to be physiologically involved in compensatory beta cell proliferation. They demonstrated that proliferation of pre-existing beta cells contributes to a beta cell increment by neural relay mechanism. Therefore, this neural relay system is not only for explaining the mechanism of obesity-related insulin resistance but also might be applicable for beta cell regeneration in the naïve pancreas for the treatment of diabetes.
\n\t\t\t\t
\n\t\t\t\t\t
2.2.1. Discovery of neural relay
\n\t\t\t\t\t
Metabolism in different organs and tissues works in a coordinated manner. This coordinated metabolism requires inter-organ/tissues communication, therefore the communication among organs and tissues are critical for maintaining normal metabolism (Katagiri et al., 2009). It has been demonstrated that humoral factors including hormones and cytokines play major roles. However, a number of studies have shown that unexpected metabolic phenotypes also make a contribution suggesting the presence of currently unknown metabolic communication systems.
\n\t\t\t\t\t
Recently, it was demonstrated that neuronal signaling plays important roles in inter-organ metabolic communication (Yamada et al., 2006). Obesity induces insulin hypersecretion and pancreatic beta cell hyperplasia in response to insulin resistance. These compensatory responses of pancreatic beta cells prevent hyperglycemia; however, this causes hyperinsulinemia which is involved in the pathogenesis of the metabolic syndrome. To elucidate the mechanisms of these compensatory mechanisms, Katagiri et al. activated several proteins which are known to be activated in the livers of obese and lean mice. They discovered that extracellular signal-regulated kinase (ERK) plays an important role in compensatory pancreatic beta cell responses. To activate ERK in the liver, they used adenoviral gene transduction system and discovered that liver-selective ERK activation induced insulin hypersecretion and pancreatic beta cell proliferation (Fujishiro et al., 2003). These pancreatic effects of hepatic ERK activation were inhibited by either splanchnic afferent blockade with pancreatic vagus dissection or midbrain transection. This result indicated that a neuronal relay system from liver to the pancreas consists of the afferent splanchnic nerve, the central nervous system and efferent vagus (Figure 2).
\n\t\t\t\t\t
Furthermore, blockage of the neuronal relay at several levels in murine obesity model inhibited pancreatic islet expansion during obesity development indicating that the neural relay played an important role in the inter-organ mechanism in compensatory beta cell responses.
\n\t\t\t\t\t
Figure 2.
The concept of neural relay for beta cell regeneration. The signal of hepatic ERK activation reaches the brain via the splanchnic nerve. Then the signal reaches the pancreas via the vagal nerve. This signal stimulates insulin hypersecretion and beta cell proliferation in the pancreas
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2.2.2. Potential application of neural relay for beta cell regeneration
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Regeneration of beta cells in the original pancreas could be an ideal cure for type 1 diabetic patients. Since the neural relay system can stimulate beta cell proliferation and insulin secretion, this system might be used for beta cell regeneration.
\n\t\t\t\t\t
Indeed, it has been demonstrated that liver-selective activation of extracellular signal-regulated kinase (ERK) using an adenoviral gene transduction system resulted in an increase in beta cell mass and normalization of serum glucose levels in streptozotocin (STZ) induced diabetic mice and Akita diabetic mice (Imai et al., 2008). A bromodeoxyuridine (BrdU) staining study demonstrated that beta cell proliferation was the mechanism for increasing beta cell mass by neural relay (Imai et al., 2008). Therefore, stimulating the ERK pathway is a promising idea for beta cell regeneration in the naïve pancreas. However, it should be noted that they used only the STZ model and Akita diabetic mice model. STZ model is a model of insulin dependent diabetes mellitus, however, no autoimmune mechanism is involved. Therefore, although the neural relay works on the STZ model it is still unknown whether this method can be effective on the type 1 diabetic patients with autoimmune disease. In addition, the STZ model cannot completely eliminate beta cells therefore beta cell proliferation was possible. On the contrary, type 1 diabetic patients without insulin secretory ability have completely lost their beta cells. Therefore, it might be impossible to induce beta cell proliferation because no beta cells remain. In order to apply neural relay technology for type 1 diabetes, it is necessary to confirm the efficacy using NOD mice which is an autoimmune induced type 1 diabetes model. Additionally, it is necessary to examine the minimum number of remaining beta cells which will be proliferated to reverse diabetes. If a significant amount of beta cells are necessary, this method can only be applied for the patients who still have insulin secretory ability. Akita diabetic mouse is a model of type 2 diabetes. In general, patients with type 2 diabetes do not require insulin injection; therefore the indication of neural relay for type 2 diabetes should be limited. However, currently, insulin therapy is applied for type 2 diabetic patients in order to save functional beta cell mass. Therefore, neural relay therapy might be an excellent option for type 2 diabetic patients with insulin therapy.
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The advantage of this method is that no stem cells such as embryonic stem (ES) cells (Thomson et al., 1998) or induced pluripotent stem (iPS) cells (Takahashi et al., 2007) or pancreatic stem cells are necessary. Therefore, the notorious problem of carcinogenesis of those stem cell derived beta cells is no longer an issue. In addition, ex vivo manipulation to create beta cells from stem cells is not necessary.
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The possible disadvantage of this method is hepatic injury by activation of hepatic ERK. Also, the adenoviral system may not be appropriate for clinical trials because of the risk of viral infection. UTMD system for activation of hepatic ERK might be useful approach to avoid using viral transfection. Identifying the efficient activation of hepatic ERK should be the key for beta cell regeneration. When ERK stimulation for beta cell regeneration will be applied for type 1 diabetic patients, the prevention autoimmune recurrence and immunosuppressive drugs might be necessary. Furthermore, in advanced type 1 diabetes, all beta cells are destroyed as mentioned above. Therefore, it might be impossible to proliferate islets because no original islets exist. In this case, a combination of beta cell generation from pancreatic stem cells and neural relay might be useful.
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\n\t\t
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3. Bio-artificial islets using pig islets
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Islet transplantation using the bio-artificial islets created from alternative sources instead of human islets is very attractive to overcome the issue of severe donor shortage for the treatment of diabetes.
\n\t\t\t
Very importantly, two clinical trials using bio-artificial islets consisting of piglet islets have been already clinically performed with promising results. The first trial was performed in Mexico using neonatal pig islets combined with Sertoli cells for the treatment of pediatric type 1 diabetic patients (Valdes-Gonzales et al., 2005a, 2007). Islets and Sertoli cells were put into a chamber. The Sertoli cells protected islets from immunological attacks. The other series were performed by New Zealand group for the treatment of adult type 1 diabetic patients with severe hypoglycemic episodes (Elliott et al., 2000). The New Zealand group used microencapsulated pig islets and those bio-artificial islets were transplanted into the abdominal cavity.
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Impressively, both groups achieved insulin independence after transplantation in some cases without use of immunosuppressive drugs.
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3.1. Bio-artificial islets with Sertoli cells
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3.1.1. Preparation of bio-artificial islets with Sertoli cells and transplantation
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Valdes-Gonzalez et al. performed bio-artificial islet transplantation into twelve pediatric type 1 diabetic patients (Valdes-Gonzalez et al., 2005a). Their bio-artificial islet consists of collagen-generating devices, islets from neonatal pigs and Sertoli cells. The collagen-generating devices were not considered as immune-isolation devices. Islets were isolated from male 7-10 days old piglets. The animals were bred in New Zealand in a specific pathogen-free environment in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care. After pancreas retrieval, pancreases were digested using collagenase for islet isolation (Elliott et al., 2000; Valdes-Gonzalez et al., 2005b). Islets were placed in RPMI-1640, 2% human serum albumin, 0.12% nicotinamide and 1.5mg/l ciproxine at room temperature and centrifuged at 1000 rpm for 20 min. The average islet yield was 290,730 islet equivalents (IEQ: 1IEQ=1 of 150 μm islet). The purity of islets was assessed with dithizone staining and was greater than 85% in all cases. The viability of islets assessed by acridine orange/propidium iodide staining was more than 85% in all cases. Isolated Sertoli cell-enriched testicular cells were placed in DMEM media with 0.12% nicotinamide and 1.5mg/l ciproxine. All cell preparations underwent full microbiologic screening both in New Zealand and again at the time of transplantation. Cells from ten neonatal pigs were used for each transplant. Sertoli cells and islets were mixed together immediately prior to transplantation.
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Two devices were implanted subcutaneously in the upper anterior wall of the patient’s abdomen under general anesthesia. The devices were left in place for two months to allow formation of vascularized collagen tissue that completely surrounded and penetrated the device.
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Both islets and Sertoli cells were isolated in New Zealand and sent at room temperature in culture media to Mexico. Islets and Sertoli cells were cultured for one day before transplantation. The transplant procedure was carried out by infusing 250,000 islets with 30-100 Sertoli cells per islet. The number of islets per body weight ranged from approximately 14,000 to 21,000IEQ/kg. From 6 to 9 months later, all patients except one, received a second islet and Sertoli cell transplant into previously implanted new devices. No immunosuppressive drug was administered at any point.
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3.1.2. Clinical outcomes
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Immediately upon entering the study, the patients followed a diet and exercise regimen standard for diabetic patients, with periodic weight and height measurements. The patients were instructed to record blood glucose determination seven times a day (pre- and postprandial, and 3 am). Eleven age and disease matched control group was subjected for 10 months to exactly the same exhaustive endocrine monitoring, and diet and exercise program without receiving a transplant.
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In the transplanted patients following the first and more markedly after the second transplant, cluster analysis revealed that two distinct insulin requirement patterns appeared. Half of the patients had a 50% or greater reduction in their insulin requirements, and the other six patients showed a slight increase. This increase in these patients seen corresponded with that that seen in the control group. Half of the patients significantly reduced amount of insulin compared to the control group from the first month post transplant onwards. Two patients achieved insulin independence. The first one was a 15 year old female who had exogenous insulin requirements of 61 U/day before transplant and HbA1c was 13.4%. After the first transplant, she reduced her insulin requirements by 73% and after the second transplant she began to have intermittent period of 3-5 days, alternating between periods of no insulin injections, followed by periods of 1-2 U/day. This pattern last for 3 months, and HbA1c reached 9.6%. The second patient was a 16-year-old female who had exogenous insulin requirement of 55 U/day and HbA1c was 12%. Six months after the first transplant, the patient showed a 6 week reduction to 1-3 U/day and HbA1c was 6.8%. After the second transplant she was totally free of insulin for two consecutive months and her HbA1c was 6.5-7.8%. Interestingly all patients improved glycemic control after transplantation irrespective of the amount of insulin reduction. Long-term follow-up of those patients revealed that all patients have positive porcine C-peptides in urine (Valdes-Gonzalez et al., 2010).
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In terms of safety, routine microbiological screening of all patients and close family have been consistently negative, although two patients exhibited transient chimerism as evidenced by porcine DNA thru polymerase chain reaction (PCR). No complication related to the surgery or to the presence of the cells has occurred at any time.
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3.2. Bio-artificial islets using micro-encapsulation technology
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3.2.1. Preparation of bio-artificial islets using micro-encapsulation technology and transplantation
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Elliott et al. performed bio-artificial islet transplantation into adult type 1 diabetic patients with severe hypoglycemic episodes (Elliot et al., 2000). Their bio-artificial islets were made of micro-encapsulated islets from neonatal pigs. This group used the same islet isolation procedures using the same herd with Valdes-Gonzalez. The islets were micro-encapsulated using alginate. The capsule allows entering nutrients and glucose inside the capsule and passing insulin outside the capsule (Figure 3). Meanwhile, the capsule blocks antibodies resulting in protecting the islet from immunological attack (Figure 3).
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The encapsulation process was a modification of the method described by Calafiore (Calafiore et al., 2006). Encapsulation material was started with raw pharmaceutical grade alginate powder. The alginate powder was dissolved in sterile pyrogen-free deionized water over 24 to 36 hours in the dark at room temperature and 3% NaCl was added. The solution underwent multiple sequential passages through methylcellulose and polyester filters to ensure sterility. The final 1.6% solution was stored in the dark room at 4oC to avoid alginate depolymerization. The islet tissue pellet, usually amounting to a few tenths of a milliliter, was thoroughly mixed with the 1.6% alginate solution. The alginate/islet proportion was adjusted so that one capsule would contain one islet, with fewer than 5% empty capsules. The suspension was extruded through a microdroplet generator, combining air shears with mechanical pressure: the alginate droplets were collected in 1.2% CaCl2 immediately turning into gel micro-beads. They were sequentially overcoated with poly-L-ornithine and an outer alginate layer.
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Figure 3.
The concept of microencapsulation of an islet. Nutrients, glucose and insulin can pass through the capsule, but antibodies cannot enter into the capsule
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Bio-artificial islets consisted of microencaplusted neonatal pig islets were transplanted into the peritoneal cavity via a laparoscope under general anesthesia. Four patients received 10,000 IEQ/kg body weight islets and the other four patients received 15,000IEQ/kg body weight islets.
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3.2.2. Clinical outcomes
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In order to perform clinical trials, they gained regulatory approval from the relevant authorities after prolonged national and international consultation (Elliott et al., 2000). A national consensus on the bioethical issues was conducted and a separate national consultation on the acceptability of the science was also conducted. Approval from Medsafe the relevant department of the Ministry of Health was obtained. Eight adult patients with longstanding proven type 1 diabetes who met all inclusion and exclusion criteria, were selected on the basis of severe recurrent hypoglycemia usually with hypoglycemic unawareness.
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To date, most patients have shown modest reduction in insulin dose commencing about four weeks after transplantation with reduction in HbA1c levels. Most outstanding has been the reduction in severe hypoglycemic episodes and reduction or abolition of unaware hypoglycemia. For example, the first patient had an average of 4 episodes of unaware hypoglycemia per week, which was completely diminished after 8 weeks of transplantation. Transitory insulin independence of several months duration has been seen.
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In terms of safety, evidence of xenosis in the xenotransplant recipients has been diligently sought but not found. This is reasonable given the credentials of the source herd used. No serious adverse events related to the surgery or to the presence of the cells have occurred at any time.
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3.3. Future direction of bio-artificial islets
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Since year 2000 after the publication of the Edmonton protocol, allogeneic islet transplantation has become popular as the treatment of type 1 diabetes (Shapiro et al., 2000). Using the Edmonton protocol, type 1 diabetic patients who had severe hypoglycemic episodes became insulin independent and free from hypoglycemic episodes after allogenic islet transplantation (Shapiro et al., 2000). The allogeneic islet transplantation has been expanded using non-heart beating donors (Markmann et al., 2003; Matsumoto et al., 2006b) and even living donor (Matsumoto et al., 2005, 2006a). However, the drawbacks of the Edmonton protocol include necessity of multiple donor organs, unstable islet isolation results, necessity of immunosuppressive drugs, difficulty of maintaining long-term insulin independence and severe shortage of donor organs (Ryan et al., 2005; Shapiro et al., 2006). Currently, we introduced new pancreas preservation (Matsumoto et al., 2002a, 2002b, 2010b) and islet isolation strategies (Noguchi et al., 2009a; Shimoda et al., 2010) and immunosuppressive therapy to improve the efficacy of islet isolation (Matsumoto et al., 2011). Now, we have a very stable islet isolation method, in addition, a single donor pancreas is enough to achieve insulin independence (Matsumoto et al., 2011). Our preliminary data demonstrated that super-high dose islet transplantation could lead to long-term insulin independence after allogeneic islet transplantation (Matsumoto et al., 2010c). However, the severe donor shortage can be never be solved by allogeneic islet transplantation alone. Bio-artificial islets using porcine islets can solve the issue of donor shortage. In addition, both bio-artificial islets with encapsulated islets and islets with Sertoli cells do not require immunosuppressive drugs. This is huge benefit of bio-artificial islet transplantation because one of the major issues of allogeneic islet transplantation is the side effects and cost of immunosuppression (Hatanaka et al., 2010).
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Currently, bio-artificial islets were transplanted into the abdominal cavity or under skin. These transplant sites have unique advantages. In the case of allogeneic islet transplantation, islets were transplanted into liver. Multiple infusions of isolated islets into liver cause portal hypertension. Therefore allogenic islet transplantation has the limitation of the numbers of transplantation. In the case of bio-artificial islet transplantation, there is no risk for portal hypertension. Therefore, there is no limitation of number of transplantation. These comparisons were summarized in table 2.
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Impressively, pigs in New Zealand have been maintained in a clean, non-pathogenic environment and seem suitable for clinical use. Both clinical trials of bio-artificial islets used these pigs. Expansion of the herd of pigs should be the key to enhancing the bio-artificial islet project. Islet isolation from neonatal piglets is relatively easy and stable; this is important advantage for commercialization.
Comparison among the standard allogeneic islet transplantation, the advanced allogeneic islet transplantation and bio-artificial islet transplantation. Of note, bio-artificial islet transplantation has several important advantages including using alternative source, no immunosuppressive drugs and no limitation of re-transplantation
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As shown Elliott et al., the bio-artificial islets can eliminate hypoglycemic unawareness, and this is the one of the major goals of allogeneic islet transplantation. Therefore, the patients with hypoglycemic unawareness will be suitable candidates for bio-artificial islet transplantation instead of allogeneic islet transplantation in future.
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More importantly, allogeneic islet transplantation can reduce or eliminate diabetic secondary complications such as diabetic nephropathy, retinopathy and neuropathy (Thompson et al., 2011). Especially, if the bio-artificial islet transplantation can also reduce or eliminate such diabetic secondary complications, this treatment will be very valuable because the real problems of diabetes are the secondary complications.
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Cost effectiveness is an issue of bio-artificial islets, because maintenance of clean pigs is expensive. The system to maintain cleanness of a huge herd of pigs needs to be developed to overcome the cost issue. The major concern of bio-artificial islet transplantation is zoonosis. Especially, creating a new viral disease by xeno-transplantation must be avoided. Infection of porcine endogenous retrovirus after xeno-transplantation into immune compromised mice demonstrated the risk of the combination of immunosuppression and xeno-transplantation (van der Laan LJ et al., 2000). Therefore current bio-artificial islet transplantations have been performed without immunosuppression.
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Acceptance of pig islets by patients is an emotional and highly debated issue for xeno-transplantation. Our survey of type 1 diabetic patients revealed that more than 60% of type 1 diabetic patients were willingly to accept pig islets if the treatment was effective (Hatanaka et al., 2010).
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4. Conclusions
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We introduced two unique gene therapies UMTD and neural relay for beta cell regenerations. Both methods are not clinically applied yet; however due to their relatively safe feature, we believe those methods can be clinically used in near future. We also described the clinical applications of bio-artificial islets using neonatal porcine islets with promising results. Most importantly, so far there are no severe adverse events. Although the results of bio-artificial islet transplantation are not as effective as allogeneic islet transplantation there are many aspects including islet isolation methods (Shimoda et al., 2011a, 2011b), islet culture methods, transplantation sites and patients’ treatments, which can be improved.
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Currently, diabetes is considered a non-curable disease therefore current treatments are focusing on improving quality of life and preventing diabetic complications (Takita 2011, Hatanaka 2011). However, we believe that the bio-artificial islets and/or gene therapy for beta cell regeneration will cure a majority of both types of diabetes in the future.
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Acknowledgments
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This work is partially supported by Juvenile Diabetes Research Foundation (JDRF).
\n\t\t
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/18205.pdf",chapterXML:"https://mts.intechopen.com/source/xml/18205.xml",downloadPdfUrl:"/chapter/pdf-download/18205",previewPdfUrl:"/chapter/pdf-preview/18205",totalDownloads:2281,totalViews:378,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"November 22nd 2010",dateReviewed:"April 12th 2011",datePrePublished:null,datePublished:"August 17th 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/18205",risUrl:"/chapter/ris/18205",book:{slug:"tissue-engineering-for-tissue-and-organ-regeneration"},signatures:"Matsumoto S, SoRelle JA and Shimoda M",authors:[{id:"49281",title:"Prof.",name:"Shinichi",middleName:null,surname:"Matsumoto",fullName:"Shinichi Matsumoto",slug:"shinichi-matsumoto",email:"shinichm@baylorhealth.edu",position:"Director",institution:null},{id:"55857",title:"Dr.",name:"Masayuki",middleName:null,surname:"Shimoda",fullName:"Masayuki Shimoda",slug:"masayuki-shimoda",email:"masayukis@baylorhealth.edu",position:null,institution:null},{id:"89088",title:"Mr.",name:"Jeffery A.",middleName:null,surname:"SoRelle",fullName:"Jeffery A. SoRelle",slug:"jeffery-a.-sorelle",email:"jeff.sorelle@baylorhealth.edu",position:null,institution:{name:"Baylor University",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Regenerative medicine of beta cells",level:"1"},{id:"sec_2_2",title:"2.1. Ultrasound targeted micro-bubble destruction (UTMD) for gene delivery to regenerate beta cells",level:"2"},{id:"sec_2_3",title:"2.1.1. Development of UTMD for gene delivery",level:"3"},{id:"sec_3_3",title:"2.1.2. Path to clinical application of beta cell regeneration by UTMD",level:"3"},{id:"sec_5_2",title:"2.2. Neural relay for beta cell regeneration in naïve pancreas",level:"2"},{id:"sec_5_3",title:"2.2.1. Discovery of neural relay",level:"3"},{id:"sec_6_3",title:"2.2.2. Potential application of neural relay for beta cell regeneration",level:"3"},{id:"sec_9",title:"3. Bio-artificial islets using pig islets",level:"1"},{id:"sec_9_2",title:"3.1. Bio-artificial islets with Sertoli cells",level:"2"},{id:"sec_9_3",title:"3.1.1. Preparation of bio-artificial islets with Sertoli cells and transplantation",level:"3"},{id:"sec_10_3",title:"3.1.2. Clinical outcomes",level:"3"},{id:"sec_12_2",title:"3.2. Bio-artificial islets using micro-encapsulation technology",level:"2"},{id:"sec_12_3",title:"3.2.1. Preparation of bio-artificial islets using micro-encapsulation technology and transplantation",level:"3"},{id:"sec_13_3",title:"3.2.2. Clinical outcomes",level:"3"},{id:"sec_15_2",title:"3.3. Future direction of bio-artificial islets",level:"2"},{id:"sec_17",title:"4. Conclusions",level:"1"},{id:"sec_18",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBonner-Weir\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTaneja\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeir\n\t\t\t\t\t\t\tG. 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Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDing\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrayburn\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy. Gene Ther,\n\t\t\t\t\t17\n\t\t\t\t\t1411\n\t\t\t\t\t20\n\t\t\t\t\n\t\t\t'},{id:"B9",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tElliott\n\t\t\t\t\t\t\tR. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEscobar\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGarkavenko\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCroxoson\n\t\t\t\t\t\t\tM. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBA\n\t\t\t\t\t\t\tSchroeder Mc\n\t\t\t\t\t\t\tGregor. 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Mol Endocrinol.\n\t\t\t\t\t17\n\t\t\t\t\t487\n\t\t\t\t\t97\n\t\t\t\t\n\t\t\t'},{id:"B11",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHacein-Bey-Abina\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvon\n\t\t\t\t\t\t\tKalle. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchmidt\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLe Deist\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWulffraat\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Intyre\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRadford\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVilleval\n\t\t\t\t\t\t\tJ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFraser\n\t\t\t\t\t\t\tC. 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Diab Res Clin Pract 89: e5\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B13",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHatanaka\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakita\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamaguchi\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKami\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011Development of a novel scale to assess the quality of life in type 1 diabetic patients for beta cell replacement therapy. Diabetology International in press\n\t\t\t'},{id:"B14",body:'\n\t\t\t\tHuang ES., Basu A, O’Grady M, & Capretta JC. 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Islets\n\t\t\t\t\t1\n\t\t\t\t\t75\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B16",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tImai\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKatagiri\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamada\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshigaki\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSuzuki\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKudo\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUno\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\thasegawa\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaneko\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshihara\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNiijima\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakazato\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAsano\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMinokoshi\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOka\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008Regulation of pancreatic beta cell mass by neuronal signals from the liver. Science 322\n\t\t\t\t\t1250\n\t\t\t\t\t4\n\t\t\t\t\n\t\t\t'},{id:"B17",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKatagiri\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tImai\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOka\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009Neural relay from the liver induces proliferation of pancreatic beta cells. A path to regenerative medicine using the self-renewal capabilities. Communicative & Integrative Biology\n\t\t\t\t\t2\n\t\t\t\t\t425\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B18",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKorpanty\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShohet\n\t\t\t\t\t\t\tR. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDing\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrenkel\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrayburn\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005Targeting of VEGF-mediated angiogenesis to rat myocardium using ultrasonic destruction of microbubbles. Gene Ther. 12\n\t\t\t\t\t1305\n\t\t\t\t\t12\n\t\t\t\t\n\t\t\t'},{id:"B19",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tManno\n\t\t\t\t\t\t\tC. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPierce\n\t\t\t\t\t\t\tG. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tArruda\n\t\t\t\t\t\t\tV. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGlader\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRagni\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRasko\n\t\t\t\t\t\t\tJ. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOzelo\n\t\t\t\t\t\t\tM. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoots\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlatt\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKonkle\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDake\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaye\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRazavi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZajko\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZehnder\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRustagi\n\t\t\t\t\t\t\tP. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakai\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChew\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeonard\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWright\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLessard\n\t\t\t\t\t\t\tR. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSommer\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTigges\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSabatino\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLuk\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMingozzi\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCouto\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tErtl\n\t\t\t\t\t\t\tH. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHigh\n\t\t\t\t\t\t\tK. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMA\n\t\t\t\t\t\t\tKay\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 12\n\t\t\t\t\t342\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B20",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarkmann\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeng\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDesai\n\t\t\t\t\t\t\tN. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVelidedeoglu\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrank\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrayman\n\t\t\t\t\t\t\tK. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMM\n\t\t\t\t\t\t\tLian\n\t\t\t\t\t\t\tWolf. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBell\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVitamaniuk\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDoliba\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatschinsky\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarkmann\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarker\n\t\t\t\t\t\t\tC. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNaji\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003The use of non-heart-beating donors for isolated pancreatic islet transplantation. Transplantation.75\n\t\t\t\t\t1423\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B21",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRigley\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQualley\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKuroda\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReems\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStevens\n\t\t\t\t\t\t\tR. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002aEfficacy of the oxygen-charged static two-layer method for short-term pancreas preservation and islet isolation from nonhuman primate and human pancreata. Cell Transplant 11\n\t\t\t\t\t769\n\t\t\t\t\t77\n\t\t\t\t\n\t\t\t'},{id:"B22",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQualley\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoel\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHagman\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSweet\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoitout\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStrong\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobertson\n\t\t\t\t\t\t\tR. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReems\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002bEffect of the two-layer (University of Wisconsin solution-perfluorochemical plus O2) method of pancreas preservation on human islet isolation, as assessed by the Edmonton Isolation Protocol. Transplantation\n\t\t\t\t\t74\n\t\t\t\t\t1414\n\t\t\t\t\t19\n\t\t\t\t\n\t\t\t'},{id:"B23",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkitsu\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIwanaga\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNagata\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYonekawa\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamada\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFukuda\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsukiyama\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSuzuki\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKawasaki\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShimodaira\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsuoka\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShibata\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKasai\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaekawa\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShapiro\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTanaka\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005Insulin independence after living-donor distal pancreatectomy and islet allotransplantation. Lancet 365\n\t\t\t\t\t1642\n\t\t\t\t\t4\n\t\t\t\t\n\t\t\t'},{id:"B24",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkitsu\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIwanaga\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNagata\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYonekawa\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKamiya\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUeda\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHatanaka\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamada\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiyakawa\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeino\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShapiro\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTanaka\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006aFollow-up study of the first successful living donor islet transplantation. Transplantation. 82\n\t\t\t\t\t1629\n\t\t\t\t\t33\n\t\t\t\t\n\t\t\t'},{id:"B25",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkitsu\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIwanaga\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNagata\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYonekawa\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamada\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFukuda\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShibata\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKasai\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMaekawa\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWada\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakamura\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTanaka\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006bSuccessful islet transplantation from non-heart-beating donor pancreata using modified Ricordi islet isolation method. Transplantation 82\n\t\t\t\t\t460\n\t\t\t\t\t5\n\t\t\t\t\n\t\t\t'},{id:"B26",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010aIslet cell transplantation for type 1 diabetic patients. J Diabetes, 2\n\t\t\t\t\t16\n\t\t\t\t\t22\n\t\t\t\t\n\t\t\t'},{id:"B27",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShimoda\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkemoto\n\t\t\t\t\t\t\tNaziruddin. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJackson\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTamura\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOlsen\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFujita\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChujo\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakita\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOnaca\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLevy\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010bSeven consecutive successful clinical islet isolations with pancreatic ductal injection. Cell Transplant\n\t\t\t\t\t19\n\t\t\t\t\t291\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B28",body:'\n\t\t\t\tMatsumoto S, Noguchi H, Takita M, Shimoda M, Tamura Y, Olsen G, Chujo D, Sugimoto K, Itoh T, Naziruddin B, Onaca N, & Levy MF. (2010c) Super high dose islet transplantation is associated with high SUITO index and prolonged insulin independence: A case report. Transplant Proc 42\n\t\t\t\t\t2156\n\t\t\t\t\t58\n\t\t\t\t\n\t\t\t'},{id:"B29",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakita\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChaussabel\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShimoda\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSugimoto\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tItoh\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChujo\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSo\n\t\t\t\t\t\t\tRelle. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOnaca\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNaziruddin\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLevy\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011Improving efficacy of clinical islet transplantation with iodixanol based islet purification, thymoglobulin induction and blockage of IL-1 beta and TNF-alpha. Cell Transplant in press\n\t\t\t'},{id:"B30",body:'\n\t\t\t\tMeier JJ, Bhushan A, Butler AE, Rizza RA, & Butler PC. (2005) Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 48:2221-2228\n\t\t\t'},{id:"B31",body:'\n\t\t\t\t\n\t\t\t\t\tMeier JJ.\n\t\t\t\t\t2008Beta cell mass in diabetes: a realistic therapeutic target? Diabetologia\n\t\t\t\t\t51\n\t\t\t\t\t703\n\t\t\t\t\t713\n\t\t\t\t\n\t\t\t'},{id:"B32",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMinami\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkuno\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiyawaki\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkumachi\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshizaki\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOyama\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKawaguchi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshizuka\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIwanaga\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeino\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells. Proc Natl Acad Sci U S A.\n\t\t\t\t\t102\n\t\t\t\t\t15116\n\t\t\t\t\t21\n\t\t\t\t\n\t\t\t'},{id:"B33",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkemoto\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNaziruddin\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJackson\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShimoda\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFujita\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChujo\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakita\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOnaca\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLevy\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009aIodixanol-controlled density gradient during islet purification improves recovery rate in human islet isolation. Transplantation. 87\n\t\t\t\t\t1629\n\t\t\t\t\t35\n\t\t\t\t\n\t\t\t'},{id:"B34",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOishi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUeda\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYukawa\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHayashi\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLevy\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009bEstablishment of mouse pancreatic stem cell line. Cell Transplant\n\t\t\t\t\t18\n\t\t\t\t\t563\n\t\t\t\t\t71\n\t\t\t\t\n\t\t\t'},{id:"B35",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNaziruddin\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJackson\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShimoda\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkemoto\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFujita\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChujo\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakita\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOnaca\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHayashi\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLevy\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Characterization of human pancreatic progenitor cells. Cell Transplant 19; 879\n\t\t\t\t\t86\n\t\t\t\t\n\t\t\t'},{id:"B36",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkuno\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMinami\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkumachi\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiyawaki\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYokoi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tToyokuni\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeino\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes. Am J Physiol Endocrinol Metab. 292: E158\n\t\t\t\t\t65\n\t\t\t\t\n\t\t\t'},{id:"B37",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRicordi\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEdlund\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008Toward a renewable source of pancreatic beta-cells, Nat Biotechnol 26\n\t\t\t\t\t397\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B38",body:'\n\t\t\t\tRyan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JR, & Shapiro AM. (2005) Five-year follow-up after clinical islet transplantation. Diabetes 54\n\t\t\t\t\t2060\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B39",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShapiro\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLakey\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRyan\n\t\t\t\t\t\t\tE. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKorbutt\n\t\t\t\t\t\t\tG. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tToth\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWarnock\n\t\t\t\t\t\t\tG. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKneteman\n\t\t\t\t\t\t\tN. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRajotte\n\t\t\t\t\t\t\tR. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med\n\t\t\t\t\t343\n\t\t\t\t\t230\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B40",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShapiro\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRicordi\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHering\n\t\t\t\t\t\t\tB. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAuchincloss\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLindblad\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRobertson\n\t\t\t\t\t\t\tR. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSecchi\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMD\n\t\t\t\t\t\t\tBrendel\n\t\t\t\t\t\t\tBerney. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrennan\n\t\t\t\t\t\t\tD. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCagliero\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlejandro\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRyan\n\t\t\t\t\t\t\tE. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDi Mercurio\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorel\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPolonsky\n\t\t\t\t\t\t\tK. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReems\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBretzel\n\t\t\t\t\t\t\tR. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBertuzzi\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFroud\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKandaswamy\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSutherland\n\t\t\t\t\t\t\tD. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEisenbarth\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSegal\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPreiksaitis\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKorbutt\n\t\t\t\t\t\t\tG. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarton\n\t\t\t\t\t\t\tF. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tViviano\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeyfert-Margolis\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBluestone\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLakey\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006International trial of the Edmonton protocol for islet transplantation. N Engl J Med\n\t\t\t\t\t355\n\t\t\t\t\t1313\n\t\t\t\t\t30\n\t\t\t\t\n\t\t\t'},{id:"B41",body:'\n\t\t\t\tShimoda M, Noguchi H, Naziruddin B, Fujita Y, Chujo D, Takita M, Peng H, Tamura Y, Olsen GS, Sugimoto K, Itoh T, Onaca N, Levy MF, Grayburn PA, & Matsumoto S. (2010) Improved method of human islet isolation for young donors. Transplant Proc 42\n\t\t\t\t\t2024\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B42",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShimoda\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFujita\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakita\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkemoto\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChujo\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNaziruddin\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLevy\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrayburn\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011Improvement of porcine islet isolation by Aralast inhibition of trypsin with pancreatic ductal preservation method. Cell Transplant in press\n\t\t\t'},{id:"B43",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShimoda\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFujita\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakita\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkemoto\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChujo\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNaziruddin\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLevy\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrayburn\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011Islet purification method using large bottle effectively achieves high islet yield from pig pancreas. Cell Transplant in press\n\t\t\t'},{id:"B44",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakahashi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTanae\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOhnuki\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNarita\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIchisaka\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTomoda\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamanaka\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131\n\t\t\t\t\t861\n\t\t\t\t\t72\n\t\t\t\t\n\t\t\t'},{id:"B45",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakita\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsumoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQin\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNoguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShimoda\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tItoh\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSugimoto\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNaziruddin\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOnaca\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLevy\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011Secretory Unit of Islet Transplant Objects (SUITO) Index can predict severity of hypoglycemic episodes in clinical islet cell transplantation. Cell Transplant in press\n\t\t\t'},{id:"B46",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThompson\n\t\t\t\t\t\t\tD. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeloche\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAo\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaty\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKeown\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShapiro\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHo\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWorsley\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFung\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeneilly\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBegg\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAl\n\t\t\t\t\t\t\tMehthel. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKondi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarris\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFensom\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKozak\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTong\n\t\t\t\t\t\t\tS. O.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTrinh\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWarnock\n\t\t\t\t\t\t\tG. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 91\n\t\t\t\t\t373\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B47",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThomson\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tItskovitz-Eldor\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShapiro\n\t\t\t\t\t\t\tS. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMA\n\t\t\t\t\t\t\tWaknitz\n\t\t\t\t\t\t\tSwiergiel. J. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVS\n\t\t\t\t\t\t\tMarshal\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJones\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998Embryonic stem cell lines derived from human blastocytes. Science 282\n\t\t\t\t\t1145\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B48",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tValdés-González\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDorantes\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGaribay-Nieto\n\t\t\t\t\t\t\tG. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBracho-Blanchet\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMendez\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDávila-Pérez\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tElliott\n\t\t\t\t\t\t\tR. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerán\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWhite\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005aXenotransplantation of porcine neonatal islets of Lanberhans and Sertoli cells: a 4-year study. Eur J Endocrinol.\n\t\t\t\t\t153\n\t\t\t\t\t419\n\t\t\t\t\t27\n\t\t\t\t\n\t\t\t'},{id:"B49",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tValdés-González\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilva-Torres\n\t\t\t\t\t\t\tM. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRamírez-González\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerán\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCE\n\t\t\t\t\t\t\tOrmsby\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAyala-Sumuano\n\t\t\t\t\t\t\tJ. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005bImproved method for isolation of porcine neonatal pancreatic cell clusters. Xenotransplantation\n\t\t\t\t\t12\n\t\t\t\t\t240\n\t\t\t\t\t4\n\t\t\t\t\n\t\t\t'},{id:"B50",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tValdés-González\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWhite\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDorantes\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerán\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGaribay-Nieto\n\t\t\t\t\t\t\tG. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBracho-Blanchet\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDávila-Pérez\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEvia-Viscarra\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCE\n\t\t\t\t\t\t\tOrmsby-Sumuano\n\t\t\t\t\t\t\tAyala.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilva-Torres\n\t\t\t\t\t\t\tJ. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tM. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRamírez-González\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007Three-yr follow-up of a type 1 diabetes mellitus patient with an islet xenotransplant. Clin Transplant,\n\t\t\t\t\t21\n\t\t\t\t\t352\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B51",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tValdes-Gonzalez\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRodriguez-Ventura\n\t\t\t\t\t\t\tA. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWhite\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBracho-Blanchet\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCastillo\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRamírez-González\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLópez-Santos\n\t\t\t\t\t\t\tM. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeón-Mancilla\n\t\t\t\t\t\t\tB. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDorantes\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010Long-term follow of patients with type 1 diabetes transplanted with neonatal pig islets. Clin Exp Immunol. 162\n\t\t\t\t\t537\n\t\t\t\t\t42\n\t\t\t\t\n\t\t\t'},{id:"B52",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvan der Laan\n\t\t\t\t\t\t\tL. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLockey\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGriffeth\n\t\t\t\t\t\t\tB. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrasier\n\t\t\t\t\t\t\tF. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCA\n\t\t\t\t\t\t\tWilson\n\t\t\t\t\t\t\tOnions. D. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHering\n\t\t\t\t\t\t\tB. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLong\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOtto\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTorbett\n\t\t\t\t\t\t\tB. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSalomon\n\t\t\t\t\t\t\tD. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice. Nature.\n\t\t\t\t\t407\n\t\t\t\t\t6800\n\t\t\t\t\t90\n\t\t\t\t\t4\n\t\t\t\t\n\t\t\t'},{id:"B53",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamada\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKatagiri\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshigaki\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOgihara\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tImai\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUno\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHasegawa\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tJ. .\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshihara\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNiijima\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMano\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAburatani\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAsano\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOka\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006Signals from intra-abdominal fat modulate insulin and leptin sensitivity through different mechanisms: neuronal involvement in food-intake regulation. Cell Metab\n\t\t\t\t\t3\n\t\t\t\t\t223\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B54",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhou\n\t\t\t\t\t\t\tQ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrown\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKanarek\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRajagopal\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMelton\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature\n\t\t\t\t\t455\n\t\t\t\t\t627\n\t\t\t\t\t32\n\t\t\t\t\n\t\t\t'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"S Matsumoto",address:null,affiliation:'
Baylor Research Institute / Baylor University / Baylor University Medical Center, USA
In England Anne Longfield, England’s Children’s Commissioner, has written to the biggest social media companies, urging them to commit to tackling issues of disturbing content. Her letter follows the suicide of 14-year-old Molly Russell, who tragically killed herself after viewing distressing self-harm images on Instagram. The letter urges social media companies to back the introduction of a statutory duty of care where they would have to prioritise the safety and wellbeing of children using their platforms. Ms. Longfield’s letter ends with the following message to the digital industry:
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\nWith great power comes great responsibility and it is your responsibility to support measures that give children the information and tools they need growing up in this digital world—or to admit that you cannot control what anyone sees on your platforms.\n
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According to literature use of the internet has risen rapidly in the last decade [1]. The way in which young people interact has changed significantly over the last decade. Social media enables them to develop online connections with people within their immediate friendship group but also to form connects with people who are more geographically dispersed. As a result of the digital revolution in recent years, young people are now able to communicate with others more efficiently and gain access to knowledge and advice more rapidly. For those living in rural communities, social media can facilitate social communications which otherwise would not be possible.
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My own discussions with young people in schools indicates that social media is an extremely important part of their daily lives. It brings many benefits but is also exposes them to risks. Young people are often very aware of these risks and understand how to keep themselves safe. However, sadly this does not prevent all of them from harm, as is evident through recent cases of teenage suicides as a result of social media, which have been highlighted in the media in the United Kingdom (UK) and more widely.
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This chapter highlights some of the detrimental and positive effects of social media use on children and young people’s mental health. The implications for schools, parents, social media and advertising companies and the government are addressed. This chapter highlights that schools cannot solve all of the problems and that other stakeholders also have a responsibility to keep young people safe when they are online.
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2. How do young people use social media?
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Research suggests that social media use is far more prevalent among young people than older generations [1]. Young people aged 16–24 are the most active social media users with 91% using the internet for social media [1]. Young people use social media for a variety of purposes, including for entertainment, to share information and network with others and to gain support and health information [1].
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3. Social media and its links to mental health
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Evidence suggests that social media use can result in young people developing conditions including anxiety, stress and depression [1]. There are various reasons for this, and this section will explore the contributing factors. Research has found that four of the five most used social media platforms make young people’s feelings of anxiety worse [1]. Research suggests that young people who use social media heavily, i.e., those who spend more than 2 hours per day on social networking sites are more likely to report poor mental health, including psychological distress [2].
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Cyber-bullying is a significant problem which affects young people. Evidence suggests that seven in 10 young people experience cyberbullying [1]. Cyberbullying exists in a variety of forms. It can include the posting of hurtful comments online, threats and intimidation towards others in the online space and posting photographs or videos that are intended to cause distress. This is not an exhaustive list. Cyberbullying is fundamentally different to bullying which takes place in person. The victim of the bullying may find it difficult to escape from because it exists within the victim’s personal and private spaces such as their homes and bedrooms. Additionally, the number of people witnessing the bullying can be extremely large because of the potential of social media for online posts to be shared across hundreds, thousands and millions of people. For the victim this can be significantly humiliating and result in a loss of confidence and self-worth. Humiliating messages, photographs and videos can be stored permanently online, resulting in the victim repeatedly experiencing the bullying every time they go online. Victims of cyberbullying can experience depression, anxiety, loss of sleep, self-harm and feelings of loneliness [3].
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Social media has also been associated with body image concerns. Research indicates that when young girls and women in their teens and early twenties view Facebook for only a short period of time, body image concerns are higher compared to non-users [4]. Young people view images of “ideal” bodies and start to make comparisons with their own bodies. This can result in low body-esteem, particularly if young people feel that their own bodies do not compare favourably to the “perfect” bodies they see online. Young people are heavily influenced by celebrities and may desire to look like them. If they feel that this is unattainable it can result in depression, body-surveillance and low body-confidence. Young people can then start to develop conditions such as eating disorders. The issue of body image is not just a female issue. Young males are also vulnerable and influenced by the muscular, well-toned bodies that they see online. We now live in an age when males are taking increasing interest in their appearance and viewing images of muscular, toned bodies can result in them putting their bodies through extensive fitness regimes and males are also vulnerable to developing eating disorders.
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The opportunity for people to use digital editing software to edit their appearance on photographs can also result in young people developing a false sense of beauty. It is worrying that there is a rise in the number of young people seeking to obtain cosmetic surgery [1] and the popularity of “selfies” in recent years has resulted in an increase in images which portray beauty and perfection. These images can have a negative impact on body-esteem and body-confidence.
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Research demonstrates that increased social media use has a significant association with poor sleep quality in young people [5]. It seems that young people enjoy being constantly connected to the online world. They develop a “Fear of Missing Out” (FoMO) which is associated with lower mood and lower life satisfaction [6]. This can result in young people constantly checking their devices for messages, even during the night, resulting in broken sleep. Sleep is particularly important during adolescence and broken sleep can result in exhaustion and lack of opportunity for the brain to become refreshed. Lack of sleep quality can have a range of detrimental effects, but it can also impact on school performance and their behaviour. My own conversations with school leaders suggest that many adolescents demonstrate signs of tiredness during the school day. This can result in disengagement in lessons, thus having a detrimental effect on academic attainment.
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The link between social media use, self-harm and even suicide is particularly worrying [1]. The fact that young people can access distressing content online that promotes self-harm and suicide is a significant cause for concern. This content attempts to “normalise” self-harm and suicide and can result in young people replicating the actions that they are exposed to.
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4. The benefits of social media
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Research suggests that young people are increasingly using social media to gain emotional support to prevent and address mental health issues [7]. This is particularly pertinent for young people who represent minority groups, including those who identify as lesbian, gay, bisexual or transgender (LGBT), those with disabilities and those representing black and minority ethnic groups. The use of social media to form online digital communities with others who share similar characteristics can be extremely powerful. Young people from minority groups are able to become “global citizens,” thus reducing isolation. Participating in online networks presents them with an opportunity to meet with others who share their identities, to gain mutual support and advice and to gain solidarity. These networks can reduce feelings of loneliness and support the development of a positive, personal identity. They can also support young people to become more resilient to adverse situations which can help them to stay mentally healthy.
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While online communities can be beneficial, they also bring associated risks. For example, members of the LGBT networks can become easy targets for abuse, discrimination, harassment and prejudice. It is therefore critical that young people understand how to keep themselves safe online and develop appropriate digital resilience to enable them to address these challenges.
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Social media use can allow young people to express themselves positively, letting young people put forward a positive image of themselves [8]. The problem with this is that people tend to use social media to present the best version of themselves and of their lives. This can result in others making unhealthy comparisons between their own lives and the idealised lives that are depicted on the internet, resulting in low self-esteem.
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Social media platforms enable young people to share creative content and express their interests and passions with others [1]. This can help to strengthen the development of a positive identity among young people and provide them with numerous opportunities to experiment with a range of interests. This is particularly important for young people who live in rural communities who may find it more challenging to develop social connections in the offline world.
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Students living in boarding schools benefit from using social media platforms because it enables them to maintain contact with family members and friends at home. This is particularly important because students living away from home may experience isolation and homesickness and social media platforms facilitate these connections.
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Social media platforms offer young people a useful tool to make, maintain or build social connections with others [1]. Additionally, research suggests that strong adolescent friendships can be enhanced by social media interactions [9]. Thus, young people can use social media to cement the friendships that they have formed in the offline world and to develop new friendships that would not have been possible in the offline word due to geographical restrictions.
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5. The role of schools
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Schools play a critical role in keeping children safe online. A well-planned digital curriculum should cover themes such as digital resilience and digital citizenship so that young people know how to respond to distressing content and how to behave responsibly online. The curriculum should also provide digital literacy skills so that children and young people have the skills to keep their own accounts safe through privacy settings, blocking perpetrators of abuse, reporting abuse and setting passwords. Schools should also support children and young people to critically engage with content they see online. They should be taught to question and interrogate content for accuracy, exploitation, abuse and discrimination.
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Schools also play a critical role in developing young people’s mental health literacy. This should cover common mental health conditions, including stress, anxiety, depression, self-harm and cyberbullying. Educating young people about mental health is essential and reduces the stigma that has traditionally been associated with mental health conditions. Young people also need to have strategies for managing their own mental health. If their mental health is adversely affected by their experiences online, they need to be taught strategies to self-regulate their emotions and strategies to aid digital resilience. Some young people who have negative experiences online respond by closing down their social media accounts. This situates the control with the perpetrators of abuse and removes control from the victim because they are disadvantaged. Developing practical approaches to aid digital resilience in the face of adversity must be a key component of the digital curriculum that schools provide. Young people need to know how to respond to abuse, who to report it to and how to block the accounts of perpetrators. In addition, they need to be taught about the importance of maintaining secure social media accounts and how to keep themselves safe by not sharing personal information.
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Schools need to provide a social need to provide a social media curriculum which is progressive and age appropriate. Given the prevalence of fake content online and content which has been digitally edited, young people need to be taught to critically evaluate content that appears online so that they understand the harmful effects of some content. Themes including exploitation, body-esteem and gender stereotyping can be addressed through critically evaluating online content.
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Children and young people often have a good understanding of the issues associated with social media because they are the users of it. Therefore, they experience the issues, sometimes frequently. Working in partnership with young people through empowering them to lead on aspects of social media education is a powerful way of developing student partnership and empowers them to be leaders. Often, young people understand the online applications better than teachers and they are acutely aware of the issues that occur online. Student-led events such as student-led workshops and conferences, which highlight the issues that relate to social media and mental health, are powerful ways of providing ownership to students. Developing digital ambassadors who act as peer mentors to younger students is also a powerful strategy for developing students’ confidence and leadership skills. Young people who need someone to talk to about the issues that they are experiencing online can be paired with a digital ambassador who can provide them with confidential advice. Processes for recruiting digital ambassadors would need to be carefully considered by schools and the scheme would need to be properly led and managed by a member of staff to monitor its effectiveness. Student-led peer mentoring schemes are valuable because some students prefer to talk to peers about the issues that they are experiencing rather than teachers or parents.
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Schools also play a critical role in educating parents about the relationship between social media and mental health. It is important that parents understand the online applications that their children are using, and schools can play a critical role in developing their understanding. Schools can also provide guidance to parents on the signs and symptoms of mental ill health so that they are better able to identify mental health problems in their child. Schools can provide guidance to parents on how to support their child’s mental health at home and guidelines about responsible use of social media in the home. It is critical that parents understand the association between poor sleep quality, mental health and academic attainment and schools can play an important role in this. Schools also play a crucial role in developing parents’ knowledge about how to be a good social media role model for their child.
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6. The role of other stakeholders
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Schools cannot solve the problems associated with social media in isolation. This section outlines the responsibilities of parents, social media companies and advertising companies. The responsibilities of the government are also outlined.
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Parents are in a unique position to influence their child’s social media use. They should establish clear expectations about the amount of time their child spends online. However, imposing rules on children can lead to conflict and the breakdown of relationships between parents and children. It is far more effective for parents and children to negotiate the rules jointly so that young people have ownership of determining the boundaries of acceptable and unacceptable behaviour. If rules are imposed rather than negotiated it is likely that young people will find ways to break the rules and therefore adopting a top-down approach may not be the most effective way of encouraging young people to develop healthy social media use.
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Some parents may try to restrict their child’s use of social media by installing filters or by disconnecting the internet supply at specific times of the day or week. However, young people will find ways to subvert this and policing their use of the internet in this way is unlikely to foster digital responsibility. It might be more effective for parents to talk to their child about what it means to be a digitally responsible citizen and to explain why it is important to restrict screen time, particularly during the night. Families might want to consider allocating specific time each day or week when no-one accesses technology.
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In addition, parents also need to be role models. They cannot expect their child to demonstrate the skills of digital citizenship and digital responsibility if they are not prepared to demonstrate these skills. It is therefore important for parents to model healthy online behaviours so that their children can then replicate these. It is also important for parents to develop their own digital literacy, so they are aware of the platforms and software that their child is interacting with. Parents also need to develop knowledge of the risks that their children are exposed to, given that these are constantly changing. If parents do not keep abreast of developments, they will not be able to support their child effectively.
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Parents should negotiate rules with their children about what constitutes appropriate use of the internet. Imposing rules on children is unlikely to be effective because young people will find ways to resist or subvert these. It is also important that parents provide their children with a degree of autonomy about their internet use. It is unlikely to be helpful if parents continually monitor what their children are doing online. However, it is reasonable for parents to set some rules for appropriate use to protect their child from harm. Examples include:
not using technology during the night;
restricting technology use during mealtimes or other social occasions;
limiting the amount of screen time which children are exposed to.
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It will be more effective if young people are involved in discussions with their parents about what might constitute appropriate use of the internet.
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Social media companies have a responsibility to protect young people from harm. They can do this in a variety of ways by:
establishing strict and robust policies on the age at which users can access platforms;
blocking accounts of perpetrators of abuse;
reporting abuse to the police;
removing inappropriate content immediately;
filtering specific content before it goes live;
producing information to service users about responsible and safe use of social media;
generating warning messages when users have exceeded reasonable levels of screen time;
responding rapidly to reports of abuse.
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This is not an exhaustive list. However, it illustrates the sorts of actions that can be adopted by social media companies to protect children and young people from harm. Companies have not responded quickly enough to reports of abuse or inappropriate content as cases of suicide in the UK suggest that social media companies have failed to protect young people from harm. The government also has a clear responsibility to hold companies to account which fail to protect children and young people from harm. Simply fining companies is not enough and will not necessarily address the problem. The government needs to take firmer action against social media companies which breach their safeguarding responsibilities.
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In addition, advertising companies have a responsibility to ensure that young people do not develop low body confidence. They can achieve this in a variety of ways. These include:
providing warning messages that images may have been digitally edited;
ensuring that images of bodies on products represent a range of body types, including a range of body sizes, disabled bodies and people of colour;
avoiding gender-stereotypes when advertising products;
producing warning messages about the dangers associated with product-use so that young people are aware of the risks;
portraying natural bodies without make-up on some products.
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7. Young people’s perspectives
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Our own research in Cambridge [10] with students in secondary schools demonstrates that they had a good understanding of the benefits and risks associated with social media. Focus groups demonstrated that the students had developed an excellent understanding of the benefits of social media and the relationship between social media use and mental ill health, including sleep deprivation, cyberbullying and low body-esteem. They had also developed a better understanding of how to keep themselves safe online. The quotes and Figure 1 below are taken from our research report [10].
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Figure 1.
Students’ perspectives on social media.
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\nSocial media helps you to communicate with your friends if they are far away. It makes you feel good when you get a like on your posts. (Student Y8)
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\nYou can talk to your friends and family on social media. The disadvantages are that you can get stalked. People can create fake accounts. You can get cyber-bullied. People can hack into other people’s accounts and you might not know who is communicating with you. People can become jealous of other people’s lives and this can make you sad and depressed. (Student Y9)
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\nSome of the pictures can be fake so people can make out that they are leading an exciting life but really, they are not, and this can make others feel worthless. (Student Y8)
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\nSocial media results in an expectation to show the good part of your life. It can impact on others because they think you are having a good time and they might not be having such a good time. (Student Y9)
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\nPeople make mean comments and it makes you feel bad. The bullying can be anonymous, and it reaches a larger audience. You can ignore the insults and carry on with your life. You can report the person or block them. (Student Y9)
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\nMen are expected to be muscular. You get upset because you think “why don’t I look like that?” (Student Y8)
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\nI realize that social media has an impact on my sleep. I find it addictive and I am always checking what friends are doing through social media and texting. (Student Y9)
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\nI think online bullying is different to bullying in school. It is easier to say horrible things to someone through social media because you are not saying it to their face. (Student Y8)
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\nWe can become stressed through social media because celebrities show images of being slim. This mainly affects women but now men are becoming bothered about how they look. This is stress that becomes a mental health problem. (Student Y9)
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\nYou feel you must look as good as celebrity people because people feel you need to be as good looking otherwise you don’t get a good reputation. (Student Y8)
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\nCyber bullying is when you post hateful messages online to directly hurt a person. (Student Y8)
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\nSeeing slim models online (body image) can make your self-esteem feel low. (Student Y8).
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The students summarised the advantages and disadvantages of social media below:
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8. Cyberbullying
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Cyberbullying is bullying which takes place in the online world, including bullying which takes place on social media. It takes multiple forms. These include:
posting hurtful comments;
posting videos which are targeted directly at a person to cause distress;
posting photographs which are designed to cause distress;
inciting others to make hurtful comments aimed at a person;
sending hurtful text messages using a mobile phone;
sending hurtful private messages to a person [11].
\nCyberbullying is fundamentally different to face-to-face bullying in several ways. Firstly, victims cannot escape from it when they are at home because it takes place on mobile phones, tablets and computers. Secondly the abuse is witnessed by a larger audience; messages are in the public domain and can be repeatedly forwarded. This can result in victims experiencing the abuse on multiple occasions, which results in further psychological distress. Thirdly, the evidence of the abuse is usually permanently stored online which means that the abuse is not erased. These messages serve as a permanent reminder of the abuse and this can result in abuse being continually experienced by the victim.
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Forms of cyberbullying are outlined below and taken from Glazzard and Mitchell [11]:
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Harassment: Harassment is the act of sending offensive, rude, and insulting messages and being abusive. It includes nasty or degrading comments on posts, photos and in chat rooms and making offensive comments on gaming sites. Posting false and malicious things about people on the internet can be classed as harassment [11].
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Denigration: This is when someone may send information about another person that is fake, damaging and untrue. It includes sharing photographs of someone for the purpose to ridicule and spreading fake rumours and gossip. This can be on any site online or on apps. It includes purposely altering photographs of others to ridicule and cause distress [11].
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Flaming: Flaming is when someone purposely uses extreme and offensive language and deliberately gets into online arguments and fights. They do this to deliberately cause distress in others [11].
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Impersonation: Impersonation is when someone hacks into someone’s email or social networking account and uses the person’s online identity to send or post vicious or embarrassing material to or about others. It also includes making up fake profiles of others [11].
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Outing and trickery: This is when someone shares personal information about someone else or tricks someone into revealing secrets and subsequently forwards it to others. They may also do this with private images and videos too [11].
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Cyberstalking: Cyberstalking is the act of repeatedly sending messages that include threats of harm, harassment, intimidating messages, or engaging in other online activities that make a person afraid for their safety. The actions may be illegal depending on what they are doing. Cyberstalking can take place on the internet or via mobile ‘phones. Examples include:
Exclusion: This is when others intentionally leave someone out of a group such as group messages, online apps, gaming sites and other online engagement. This is also a form of social bullying and is very common [11].
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Bullying by spreading rumours and gossip: Online abuse, rumours and gossip can go viral very quickly and be shared by many people within several minutes. It is not uncommon for former close friends or partners to share personal secrets about victims [11].
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Threatening behaviour: Threatening behaviour which is directed at a victim to cause alarm and distress is a criminal offence. Taking screenshots of the evidence and reporting it is one way of challenging this [11].
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Happy slapping: This is an incident where a person is assaulted while other people take photographs or videos on their mobile phones. The pictures or videos are then circulated by mobile phone or uploaded on the internet [11].
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Grooming: Grooming is when someone builds an emotional connection with a child to gain their trust for the purposes of abuse and exploitation. It is conducted by strangers (or new “friends”) and may include:
pressurising someone to do something they do not wish to do;
making someone take their clothes off;
pressurising someone to engage in sexual conversations;
pressurising someone to take naked photographs of themselves;
making someone engage in sexual activity via the internet [11].
\n\n
Groomers may spend a long time establishing a “relationship” with the victim by using the following strategies:
pretending to be someone they are not, for example, saying they are the same age online;
Inappropriate images: It is very easy to save any pictures of anyone on any site and upload them to the internet. Uploading pictures of someone to cause distress is a form of cyberbullying. This also includes digitally altering pictures to embarrass someone [11].
\n
Bystander effect: Witnessing cyberbullying and doing nothing about it is not acceptable. Some people are worried about getting involved but victims of bullying need brave witnesses to make a stand. Perpetrators of bullying thrive when they have an audience. Making a stand against what they are doing is an important way to reduce their power. Most sites now operate a reporting facility so that online abuse can be reported and addressed. Bystanders are not innocent. They have a responsibility to report abuse that they witness [11].
\nResearch from Queensland University of Technology has identified that half of young people aged 18–24 are less productive and more tired because of their mobile phones. Scientists have adopted the term “technoference” to describe the way that mobile phones intrude on and interrupt everyday conversations and the way they interrupt other aspects of people’s daily lives.
\n\n\n
\nIt is worrying that family life is being interrupted by technology. While technology has significant benefits, continual use of technology can impact detrimentally on the quality of people’s interactions and conversations. We live in a society where people are constantly attached to their technology. People interact with technology on public transport, in meetings and during leisure time rather than engaging in productive, meaningful conversations. It seems that people would rather interact with a phone rather than having a conversation and while this is not necessarily a problem in some contexts, it can have a negative impact in other contexts. For example, young children require social interaction with adults. This allows them to develop secure attachments with significant others, it enables them to learn about the world and through conversation children are exposed to language. Exposure to language underpins reading and writing development. Children who have rich exposure to language become better readers, better writers and understand far better what they are reading. Lack of exposure to language can impact detrimentally on the structure of the brain. This can create reading difficulties and even lead to difficulties which are consistent with dyslexia, even though the difficulties may not have a genetic origin. The brain is malleable. It is responsive to environmental influences and lack of exposure to language can impact on phonological and phonemic awareness. Both of these skills play a critical role in reading development. Interacting with technology can restrict opportunities for communication between babies, children and their parents and can interrupt the flow of normal conversation.\n
\n\n\n
\nIt would appear that adolescents seem to be attached to their phones during the night. They are desperate to network and keep up-to-date with their online peers. This results in broken sleep and tiredness during the school day. Adolescents need approximately 8–10 hours sleep but our research demonstrates that some get as little as 2 hours sleep. These students attend school in a state of exhaustion. They are too tired to concentrate and it affects their learning and their behaviour. Disengagement in lessons results in them falling behind in their schoolwork and they then develop other problems such as low confidence and low self-worth.
\n\n\n
\nReal-time social connections are vital for positive wellbeing. Schools play a key role in teaching young people about how to stay healthy and in particular, the need for sleep. However, parents also play a critical role in supporting young people to develop positive habits through setting boundaries. Examples of boundaries might include restricting access to technology in bedrooms and at mealtimes. Also, parents need to be good role models by ensuring that they do not allow technology to interrupt conversations and other daily experiences.\n
\n\n
\n
\n
10. Statistics
\n
Statistics demonstrate the risks of internet use on young people’s lives. Key statistics are summarised below [13]:
year on year increases in the numbers and rates of police-recorded online child sexual offences in England and Wales and Northern Ireland
increases in police-recorded offences of obscene publications or indecent photos in all four UK nations over the last 5 years
increases in the number of URLs confirmed by the Internet Watch Foundation (IWF) as containing child sexual abuse imagery since 2015
less than half of children aged 12–15 say they know how to change their settings to control who can view their social media
the majority of parents, carers and members of the public agree that social networks should have a legal responsibility to keep children safe on their platforms.
\n\n
Additionally:
a total of 5161 crimes of sexual communication with a child have been recorded in 18 months [14];
in 2019 there has been almost a 50% increase in offence in offences recorded in latest 6 months compared to same period in previous year [14];
in 2010 there has been a 200% rise in recorded instances in the use of Instagram to target and abuse children over the same time period [14];
there have been over 5000 online grooming offences recorded in 18 months [14].
\n\n
\n
\n
11. Conclusions
\n
Social media use can have a detrimental impact on children and young people’s mental health. It can result in anxiety, depression, body image concerns, self-harm, substance abuse and even death. However, for young people social media is a tool for networking, keeping in touch with friends, exchanging information, a source of support and advice and a rich source of knowledge. Preventing children and young people from using social media is not an appropriate solution, given all the benefits that come with it. Schools, parents and the digital industry need to do all they can to keep children safe from harm through adopting a proactive approach rather than a reactive approach when crises occur.
\n
\n
Acknowledgments
\n
We wish to thank Leeds Beckett University and the Carnegie Centre of Excellence for Mental Health in Schools for facilitating this research.
\n
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"social media, mental health, technology, children, young people",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68639.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68639.xml",downloadPdfUrl:"/chapter/pdf-download/68639",previewPdfUrl:"/chapter/pdf-preview/68639",totalDownloads:874,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 4th 2019",dateReviewed:"July 12th 2019",datePrePublished:"August 23rd 2019",datePublished:"June 24th 2020",dateFinished:null,readingETA:"0",abstract:"Evidence suggests that social media can impact detrimentally on children and young people’s mental health. At the same time, social media use can be beneficial and have positive effects. This chapter outlines the detrimental and positive effects of social media use for young people. Schools play a critical role in educating young people about how to use social media safely and responsibly. However, schools cannot address all the issues and parents, social media and advertising companies also have a responsibility to protect children and young people from harm. This chapter outlines some of the potential solutions to the issues that are identified.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68639",risUrl:"/chapter/ris/68639",signatures:"Jonathan Glazzard and Samuel Stones",book:{id:"7927",title:"Selected Topics in Child and Adolescent Mental Health",subtitle:null,fullTitle:"Selected Topics in Child and Adolescent Mental Health",slug:"selected-topics-in-child-and-adolescent-mental-health",publishedDate:"June 24th 2020",bookSignature:"Samuel Stones, Jonathan Glazzard and Maria Rosaria Muzio",coverURL:"https://cdn.intechopen.com/books/images_new/7927.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"309587",title:"Mr.",name:"Samuel",middleName:"Oliver James",surname:"Stones",slug:"samuel-stones",fullName:"Samuel Stones"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"294281",title:"Prof.",name:"Jonathan",middleName:null,surname:"Glazzard",fullName:"Jonathan Glazzard",slug:"jonathan-glazzard",email:"j.glazzard@leedsbeckett.ac.uk",position:null,institution:{name:"Leeds Beckett University",institutionURL:null,country:{name:"United Kingdom"}}},{id:"309587",title:"Mr.",name:"Samuel",middleName:"Oliver James",surname:"Stones",fullName:"Samuel Stones",slug:"samuel-stones",email:"sst@nortoncollege.net",position:null,institution:{name:"Leeds Beckett University",institutionURL:null,country:{name:"United Kingdom"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. How do young people use social media?",level:"1"},{id:"sec_3",title:"3. Social media and its links to mental health",level:"1"},{id:"sec_4",title:"4. The benefits of social media",level:"1"},{id:"sec_5",title:"5. The role of schools",level:"1"},{id:"sec_6",title:"6. The role of other stakeholders",level:"1"},{id:"sec_7",title:"7. Young people’s perspectives",level:"1"},{id:"sec_8",title:"8. Cyberbullying",level:"1"},{id:"sec_9",title:"9. Technoference",level:"1"},{id:"sec_10",title:"10. Statistics",level:"1"},{id:"sec_11",title:"11. Conclusions",level:"1"},{id:"sec_12",title:"Acknowledgments",level:"1"},{id:"sec_15",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'\nRoyal Society for Public Health (RSPH). #Status of Mind Social media and young people’s mental health and wellbeing. RSPH; 2017\n'},{id:"B2",body:'\nSampasa-Kanyinga H, Lewis RF. Frequent use of social networking sites is associated with poor psychological functioning among children and adolescents. Cyberpsychology, Behavior and Social Networking. 2015;18(7):380-385. DOI: 10.1089/cyber.2015.0055\n'},{id:"B3",body:'\nStop Bullying.gov. Effects of Bullying. 2017. Available from: https://www.stopbullying.gov/at-risk/effects/ [Accessed: 17 April]\n'},{id:"B4",body:'\nTiggeman M, Slater A. The internet and body image concerns in preteenage girls. The Journal of Early Adolescents. 2013;34(5):606-620. DOI: 10.1177/0272431613501083\n'},{id:"B5",body:'\nScott H, Gardani M, Biello S, Woods H. Social Media Use, Fear of Missing Out and Sleep Outcomes in Adolescents. 2016. Available from: https://www.researchgate.net/publication/308903222_Social_media_use_fear_of_missing_out_and_sleep_outcomes_in_adolescence [Accessed: 17 April]\n'},{id:"B6",body:'\nPryzbylski A, Murayama K, DeHaan C, Gladwell V. Motivational, emotional and behavioural correlates of fear of missing out. Computers in Human Behaviour. 2013;29(4):1841-1848. DOI: 10.1016/j.chb.2013.02.014\n'},{id:"B7",body:'\nFarnan JM, Snyder SL, Worster BK, et al. Online medical professionalism: Patient and public relationships: Policy statement from the American College of Physicians and the Federation of State Medical Boards. Annals of Internal Medicine. 2013;158(8):620-662\n'},{id:"B8",body:'\nUniversity of Minnesota-Introduction to Psychology. 6.3 Adolescents: Developing Independence and Identity. Available from: http://open.lib.umn.edu/intropsyc/chapter/6-3-adolescence-developing-independence-and-identity/ [Accessed: 17 April]\n'},{id:"B9",body:'\nLenhart A. Chapter 4: Social Media and Friendships. 2015. Available from: http://www.pewinternet.org/2015/08/06/chapter-4-social-media-and-friendships/ [Accessed: 17 April]\n'},{id:"B10",body:'\nCambridge United Community Trust/Leeds Beckett University. Mind Your Head-Programme Evaluation. Available from: https://leedsbeckett.ac.uk/-/media/files/School-of-Education/mind_your_head_evaluation_report.pdf\n\n'},{id:"B11",body:'\nGlazzard J, Mitchell C. Social Media and Mental Health in Schools. St Albans: Critical Publishing; 2018\n'},{id:"B12",body:'\nGlazzard J, Stones S. Technoference. Leeds Beckett University; 2019. Available from: https://www.leedsbeckett.ac.uk/blogs/carnegie-education/2019/04/technoference/\n\n'},{id:"B13",body:'\nNational Society for the Protection of Cruelty to Children (NSPCC). Available from: https://learning.nspcc.org.uk/research-resources/how-safe-are-our-children/\n\n'},{id:"B14",body:'\nNational Society for the Protection of Cruelty to Children (NSPCC). Available from: https://www.nspcc.org.uk/what-we-do/news-opinion/over-5000-grooming-offences-recorded-18-months/\n\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Jonathan Glazzard",address:"j.glazzard@leedsbeckett.ac.uk",affiliation:'
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At IntechOpen, we’re laying the foundations for the future by publishing the best research by women in STEM – Open Access and available to all. Our Women in Science program already includes six books in progress by award-winning women scientists on topics ranging from physics to robotics, medicine to environmental science. Our editors come from all over the globe and include L’Oreal–UNESCO For Women in Science award-winners and National Science Foundation and European Commission grant recipients.
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