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Sample records for bowel transplant model

  1. Small Bowel Transplant

    PubMed Central

    2003-01-01

    EXECUTIVE SUMMARY Objective The Medical Advisory Secretariat undertook a review of the evidence on the effectiveness and cost-effectiveness of small bowel transplant in the treatment of intestinal failure. Small Bowel Transplantation Intestinal failure is the loss of absorptive capacity of the small intestine that results in an inability to meet the nutrient and fluid requirements of the body via the enteral route. Patients with intestinal failure usually receive nutrients intravenously, a procedure known as parenteral nutrition. However, long-term parenteral nutrition is associated with complications including liver failure and loss of venous access due to recurrent infections. Small bowel transplant is the transplantation of a cadaveric intestinal allograft for the purpose of restoring intestinal function in patients with irreversible intestinal failure. The transplant may involve the small intestine alone (isolated small bowel ISB), the small intestine and the liver (SB-L) when there is irreversible liver failure, or multiple organs including the small bowel (multivisceral MV or cluster). Although living related donor transplant is being investigated at a limited number of centres, cadaveric donors have been used in most small bowel transplants. The actual transplant procedure takes approximately 12-18 hours. After intestinal transplant, the patient is generally placed on prophylactic antibiotic medication and immunosuppressive regimen that, in the majority of cases, would include tacrolimus, corticosteroids and an induction agent. Close monitoring for infection and rejection are essential for early treatment. Medical Advisory Secretariat Review The Medical Advisory Secretariat undertook a review of 35 reports from 9 case series and 1 international registry. Sample size of the individual studies ranged from 9 to 155. As of May 2001, 651 patients had received small bowel transplant procedures worldwide. According to information from the Canadian Organ Replacement

  2. The "Pavia model" of experimental small bowel transplantation in pigs: technical variations for ischemia reperfusion injury studies.

    PubMed

    Alessiani, M; Cobianchi, L; Viganò, J; Dominioni, T; Bottazzi, A; Zonta, S; Dionigi, P

    2014-01-01

    Ischemia reperfusion injury (IRI) is a major field of study in small bowel transplantation because of its implications regarding intestinal immunity. In this study, we have introduced some variations to the described models of IRI in pigs to make possible a complete isolation of the small bowel for IRI studies. In swine, two anatomical barriers make impossible a complete isolation of the small bowel at the origin of superior mesenteric artery (SMA) and vein (SMV): the main colic vessels, which originate distally to form SMA and SMV, and the blood supply of the distal portion of the duodenum and the cephalic part of the pancreas. In a group of Large White pigs (n = 5), we have performed a complete isolation of the small bowel, including sub-total colectomy and pancreaticoduodenectomy. Both SMA and SMV were isolated at the origin from the aorta and at the junction of the splenic vein, respectively. Intestinal continuity was restored with duodenojejunal anastomosis and with ileotransverse colon anastomosis. One pig died on postoperative day 5 from intestinal occlusion due to adhesions. The remaining four pigs were killed on postoperative day 7 after an uneventful postoperative course. No complications were found at autopsy. In swine, resection of part of the pancreas and duodenum and removal of the large bowel does not affect short-term survival, allowing a full isolation of the entire small bowel mimicking the transplantation procedure. Thus, this model appears to be attractive for IRI studies in the field of intestinal transplantation.

  3. Small Bowel and Liver/Small Bowel Transplantation in Children

    PubMed Central

    Reyes, Jorge; Tzakis, Andreas G.; Todo, Satoru; Nour, Bakr; Starzl, Thomas E.

    2010-01-01

    A clinical trial of intestinal transplantation was initiated at the University of Pittsburgh in May 1990. Eleven children received either a combined liver/small bowel graft (n = 8) or an isolated small bowel graft (n = 3). Induction as well as maintenance immunosuppression was with FK-506 and steroids. Four patients were male, and seven were female; the age range was 6 months to 10.2 years. There were 3 deaths (all in recipients of the combined liver/small bowel graft), which were attributed to graft-versus-host disease (n = 1), posttransplant lymphoproliferative disease (n = 1), and biliary leak (n = 1). Transplantation of the intestine has evolved into a feasible operation, with an overall patient and graft survival rate of 73%. These survivors are free of total parenteral nutrition, and the majority are home. These encouraging results justify further clinical trials. PMID:8062049

  4. Fecal Microbiota Transplantation in Inflammatory Bowel Disease.

    PubMed

    Reinisch, Walter

    2017-01-01

    The etiology of inflammatory bowel disease (IBD) is unknown, but it is thought to arise from an aberrant immune response to a change in colonic environment in a genetically susceptible individual. The intestinal microbiota are located at the complex interface of the epithelial barrier and are sensitive to changes in environmental factors, such as diets, drugs or smoking and signals derived from the intestinal immune system and the gut-brain axis. In patients with IBD, an imbalance in the structural and/or functional configuration of the intestinal microbiota leading to the disruption of the host-microorganism homeostasis (dysbiosis) has been reproducibly reported. As animal models of IBD require gut bacteria to induce inflammation, it is hypothesized that the dysbiosis observed in patients is not only a surrogate of changes at the intestinal barrier but also a potential cause or at least enhancer of the mucosal inflammatory process. That burgeoning notion has stimulated thoughts to modify the intestinal microbiota and rekindled interest in previous work on the efficacy of antibiotics in patients with IBD. The feasibility and tremendous success of fecal microbiota transplantation (FMT) to treat antibiotic resistant Clostridium difficile has finally paved the way to embark into the unchartered territory of IBD using FMT. Different routes and number of administrations, choices of donors, disease status and permitted therapies might have contributed to mixed results, particularly from the so far published randomized controlled trials. However, microbiome analysis suggests that a durable transplantation of donor bacteria to the host appears feasible and might be associated with a higher likelihood of response. On the other hand, this raises the concern of transplanting not only anti-inflammatory active bacteria and their products, but also not-yet-known dispositions for other diseases including cancer. Attempts are being made to better characterize those components of

  5. [Short bowel: from resection to transplantation].

    PubMed

    Rodríguez-Montes, José Antonio

    2014-09-17

    Short bowel syndrome (SBS) is characterized by a significant reduction in the effective intestinal surface by an anatomical or functional loss of the small intestine. It mainly occurs after extensive bowel resection, intestinal intrinsic disease or surgical bypass. The main complications are malabsorption, maldigestion, malnutrition, dehydratation and, potentially, lethal metabolic lesions. The treatment is based on appropiate, individualized nutritional support; however, the most recent outcomes on bowel transplantation (BT) and a great rate of survivors achieving complete digestive autonomy and able to carry out activities according to their age allow for considering BT as the first choice therapy in patients with irreversible intestinal failure in whom poor prognosis with parenteral nutrition is foreseen. In this paper the most outstanding aspects of SBS are revised.

  6. Where are we at with short bowel syndrome and small bowel transplant

    PubMed Central

    Yildiz, Baris Dogu

    2012-01-01

    Intestinal failure can be defined as the critical reduction of functional gut mass below the minimal amount necessary for adequate digestion and absorption to satisfy body nutrient and fluid requirements in adults or children. Short bowel syndrome (SBS) is characterized by a state of malabsorption following extensive resection of the small bowel. SBS may occur after resection of more than 50% and is certain after resection of more than 70% of the small intestine, or if less than 100 cm of small bowel is left. Several treatment modalities other than total parenteral nutrition, including hormones (recombinant human growth hormone, glucagon-like peptide-2) and tailoring surgeries (Bianchi procedure, serial transverse enteroplasty), had been proposed, however these were either experimental or inefficient. Small bowel transplant is a rather new approach for SBS. The once feared field of solid organ transplantation is nowadays becoming more and more popular, even in developing countries. This is partially secondary to the developments in immunosuppressive strategy. In this regard, alemtuzumab deserves special attention. There are more complex surgeries, such as multivisceral transplantation, for multi-organ involvement including small bowel. This latter technique is relatively new when compared to small bowel transplant, and is performed in certain centers worldwide. In this review, an attempt is made to give an insight into small bowel syndrome, small bowel transplantation, and related issues. PMID:24175201

  7. Fecal Microbiota Transplantation for Inflammatory Bowel Disease

    PubMed Central

    Lopez, Joanna

    2016-01-01

    The gut bacterial microbiome, particularly its role in disease and inflammation, has gained international attention with the successful use of fecal microbiota transplantation (FMT) in the treatment of Clostridium difficile infection. This success has led to studies exploring the role of FMT in other conditions, including inflammatory bowel disease (IBD). Both Crohn’s disease and ulcerative colitis are chronic inflammatory conditions of the gastrointestinal system that have multifactorial etiologies. A shift in gut microbial composition in genetically susceptible individuals, an altered immune system, and environmental factors are all hypothesized to have a role in the pathogenesis of IBD. While numerous case reports and cohort studies have described the use of FMT in patients with IBD over the last 2 decades, the development of new sequencing techniques and results from 2 recent randomized, controlled trials have allowed for a better understanding of the relationship between the microbiome and the human host. However, despite these efforts, knowledge remains limited and the role of FMT in the management of IBD remains uncertain. Further investigation is necessary before FMT joins the current armamentarium of treatment options in clinical practice. PMID:27493597

  8. Allograft biopsy findings in patients with small bowel transplantation.

    PubMed

    Koo, Jamie; Dawson, David W; Dry, Sarah; French, Samuel W; Naini, Bita V; Wang, Hanlin L

    2016-11-01

    In this study, we sought to determine the incidence of post-transplant complications including acute cellular rejection (ACR), infection, and post-transplant lymphoproliferative disease (PTLD) in mucosal allograft biopsies in patients with small bowel transplant at our institution. We retrospectively reviewed pathology reports from 5675 small bowel allograft biopsies from 99 patients and analyzed the following: indications for biopsy, frequency and grade of ACR, the presence of infectious agents, results of workup for potential PTLD, results of C4d immunohistochemistry (IHC), features of chronic mucosal injury, and findings in concurrent native bowel biopsies. Findings from 42 allograft resection specimens were also correlated with prior biopsy findings. Indeterminate, mild, moderate, and severe ACR were seen in 276 (4.9%), 409 (7.2%), 100 (1.8%), and 207 (3.6%) of biopsies, respectively. Although ACR may show histologic overlap with mycophenolate mofetil toxicity, we found the analysis of concurrent native bowel biopsies to be helpful in this distinction. Adenovirus was the most common infectious agent seen (11%), and we routinely performed adenovirus IHC on biopsies. Eighteen patients (18%) developed PTLD, 83% of which were EBV associated, but only 28% of PTLD cases were diagnosed on mucosal allograft biopsies. C4d IHC did not correlate with the presence of donor-specific antibodies in limited cases. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. [Indications and results of small bowel transplantation in adults].

    PubMed

    Joly, Francisca; Panis, Yves

    2012-02-01

    immunosuppression to control rejection. By 1990, the development of tacrolimus-based immunosuppression, as well as improved surgical techniques, the increased array of potent immunosuppressive medications, infection prophylaxis, and better patient selection helped to improve actuarial graft and patient survival rates for all types of intestine transplantation. In adult intestinal transplantation, three kinds of graft can be proposed: isolated small bowel, combined liver and small bowel, and multivisceral transplantation. In isolated small bowel transplantation, the length of the graft ranges between 1.5 and 2 meters, but depends on the size of the recipient (and the abdominal cavity volume, which is reduced). The graft is anastomosed with the recipient's duodenum or remnant proximal jejunum. the distal part of the small bowel graft is on a temporary stoma, in order to allow biopsies for early detection of rejection. Vascular anastomoses are usually performed directly on the aorta for the superior mesenteric artery and either the recipient's portal vein or vena cava for the donor superior mesenteric vein. In combined liver and intestinal transplantation, one venous anastomosis is avoided because the graft is in one piece. Finally, one specificity of this transplantation is the fact that it usually concerns patients with numerous previous abdominal operations and with total or subtotal enterectomy. Thus, the residual abdominal cavity is usually very small, and this can be a major problem for graft insertion. For this reason, abdominal closure is performed with a temporary prosthesis, because even cutaneous closure remains impossible if a compartment syndrome is to be avoided.

  10. In vitro allograft irradiation prevents graft-versus-host disease in small-bowel transplantation

    SciTech Connect

    Lee, K.K.; Schraut, W.H.

    1985-04-01

    In small-bowel transplantation, the transfer of large numbers of donor lymphocytes with the intestinal allograft may provoke a lethal graft-versus-host reaction. The effectiveness of allograft irradiation in vitro as a method of preventing graft-versus-host disease (GVHD) was studied in a rat model of small-bowel transplantation, with the Lewis----Lewis X Brown Norway F1 hybrid strain combination. Cold harvested small-bowel allografts were irradiated immediately prior to heterotopic or orthotopic transplantation. Animals that had received heterotopic allografts irradiated with 0, 250, or 500 rad all died of GVHD after 14.4 +/- 3.0, 15.0 +/- 1.3, and 14.2 +/- 1.9 days, respectively. None of the animals that had received allografts treated with 1000 rad developed clinical or pathologic evidence of GVHD, however, and all survived for more than 6 months (P less than 0.001). Allograft function was studied in animals that underwent orthotopic transplantation. Recipients of nonirradiated orthotopic allografts all died of GVHD after 14.0 +/- 0.7 days, whereas recipients of allografts irradiated with 1000 rad all survived for more than 5 months (P less than 0.001). After 120 days, weight gain (51.8 +/- 11.7%), serum albumin (3.9 +/- 0.7 g/dl), serum triglycerides (67.0 +/- 24.3 mg/dl), CBC, and differential in these animals were not statistically different from those in either age-matched isograft recipients or normal animals, and when the rats were sacrificed, irradiated allografts showed no changes suggestive of radiation injury. These results indicate that irradiation of small-bowel allografts in vitro prevents development of GVHD, and that this can be achieved at a dose which does not cause injury to or malfunction of the allograft.

  11. Bariatric surgery complications leading to small bowel transplant: a report of 4 cases.

    PubMed

    Abdal Raheem, Sulieman; Deen, Omer J; Corrigan, Mandy L; Parekh, Neha; Quintini, Cristiano; Steiger, Ezra; Kirby, Donald F

    2014-05-01

    Obesity is a major chronic disease affecting the U.S. population. Bariatric surgery has consistently shown greater weight loss and improved outcomes compared with conservative therapy. However, complications after bariatric surgery can be catastrophic, resulting in short bowel syndrome with a potential risk of intestinal failure, ultimately resulting in the need for a small bowel transplant. A total of 6 patients became dependent on home parenteral nutrition (HPN) after undergoing bariatric surgery at an outside facility. Four of the 6 patients required evaluation for small bowel transplant; 2 of the 6 patients were successfully managed with parenteral nutrition and did not require further small bowel transplant evaluation. Catheter-related bloodstream infection, a serious complication of HPN, occurred in 3 patients despite extensive patient education on catheter care and use of ethanol lock. Two patients underwent successful small bowel transplantation, 1 died before transplant could be performed, and 1 was listed for a multivisceral transplantation. Surgical procedures to treat morbid obesity are common and growing in popularity but are not without risk of serious complications, including intestinal failure and HPN dependency. Despite methods to prevent complications, failure of HPN may lead to the need for transplant evaluation. In selected cases, the best therapeutic treatment may be a small bowel transplant to resolve irreversible, post-bariatric surgery intestinal failure.

  12. [Fecal microbiota transplantation in treatment of inflammatory bowel diseases].

    PubMed

    Privalov, M A; Sizenko, A K

    2014-11-01

    Inflammatory bowel diseases (IBD) are chronic, recurrent disease associated with significant morbidity and disability rates and marked reduction of quality of life. The exact aetiology of these conditions is unknown, however, there is increasing data supporting the influence of gut microbiota in the pathogenesis of IBD. Despite of large number of actively exploring approaches to IBD treatment, some patients remain refractory to standard management or have significant adverse side effects. Given the probably role of the gastrointestinal microbiotain development of IBD, treatments that manipulate the microbiota have been investigated with varying degree of efficacy. Faecal microbiota transplantation (FMT) can be considered as alternative regimen for IBD management, but there is currently a lack of evidence supporting this approach in similar conditions. The comprehensive data are necessary to provide understandable and clear conclusion to guide current practice and future research.

  13. Small bowel transplantation induces adrenergic hypersensitivity in ileal longitudinal smooth muscle in rats.

    PubMed

    Ohtani, N; Balsiger, B M; Anding, W J; Duenes, J A; Sarr, M G

    2000-01-01

    Our aim was to determine the effects of small bowel transplantation on contractility of longitudinal muscle in the rat ileum. Full-thickness longitudinal muscle strips from four groups of rats (naive controls, sham-operated controls, and 1 week and 8 weeks after syngeneic orthotopic small bowel transplantation) were studied in vitro. Neither baseline contractility nor response to neural blockade (tetrodotoxin) or adrenergic/cholinergic blockade differed among the groups. Although the dose response to the cholinergic agonist bethanechol and to nitric oxide did not differ among groups, the ED50 (negative log of concentration giving half-maximal effect) for the adrenergic agonist norepinephrine was increased l week and 8 weeks after transplantation, indicating a hypersensitivity response not blocked by tetrodotoxin. Nonadrenergic, noncholinergic inhibitory responses to electrical field stimulation were of greater amplitude and occurred at lesser frequencies (>/=5 Hz) 1 week after small bowel transplantation, but returned to control values 8 weeks postoperatively. These inhibitory responses were blocked by the nitric oxide synthase inhibitor L-NMMA but not by methylene blue, a nonspecific inhibitor of guanylate cyclase. Small bowel transplantation induces a persistent adrenergic denervation hypersensitivity at the muscle and appears to upregulate, at least transiently, other inhibitory mechanisms mediated by neural release of nitric oxide. Small bowel transplantation does not alter muscle response to cholinergic pathways. These alterations in smooth muscle contractility may affect gut function early after clinical small bowel transplantation.

  14. Reduction of Acute Rejection by Bone Marrow Mesenchymal Stem Cells during Rat Small Bowel Transplantation

    PubMed Central

    Zhang, Wen; Wu, Ben-Juan; Fu, Nan-Nan; Zheng, Wei-Ping; Don, Chong; Shen, Zhong-Yang

    2014-01-01

    Background Bone marrow mesenchymal stem cells (BMMSCs) have shown immunosuppressive activity in transplantation. This study was designed to determine whether BMMSCs could improve outcomes of small bowel transplantation in rats. Methods Heterotopic small bowel transplantation was performed from Brown Norway to Lewis rats, followed by infusion of BMMSCs through the superficial dorsal veins of the penis. Controls included rats infused with normal saline (allogeneic control), isogeneically transplanted rats (BN-BN) and nontransplanted animals. The animals were sacrificed after 1, 5, 7 or 10 days. Small bowel histology and apoptosis, cytokine concentrations in serum and intestinal grafts, and numbers of T regulatory (Treg) cells were assessed at each time point. Results Acute cellular rejection occurred soon after transplantation and became aggravated over time in the allogeneic control rats, with increase in apoptosis, inflammatory response, and T helper (Th)1/Th2 and Th17/Treg-related cytokines. BMMSCs significantly attenuated acute cellular rejection, reduced apoptosis and suppressed the concentrations of interleukin (IL)-2, IL-6, IL-17, IL-23, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ while upregulating IL-10 and transforming growth factor (TGF)-β expression and increasing Treg levels. Conclusion BMMSCs improve the outcomes of allogeneic small bowel transplantation by attenuating the inflammatory response and acute cellular rejection. Treatment with BMMSCs may overcome acute cellular rejection in small bowel transplantation. PMID:25500836

  15. Strangulated Small Bowel Obstruction After Renal Transplant With No History of Laparotomy: Case Report.

    PubMed

    Miura, Yuichi; Sato, Kazushige; Kawagishi, Naoki; Ohuchi, Noriaki

    2015-06-01

    Strangulated small bowel obstruction is a complication after abdominal surgery, which is rare in renal transplant patients. A 61-year-old man with a strangulated small bowel obstruction underwent renal transplant surgery 7 years before the current admission. He was admitted to our hospital for abdominal pain, nausea, and abdominal distention. An abdominal computed tomography and an ultrasound examination showed intestinal expansion and fluid collection without ascites. His disease was diagnosed as a small bowel obstruction and conservative treatment was begun. However, because of increasing abdominal pain and the collection of ascites, he underwent an emergency laparotomy and was diagnosed as having a strangulated small bowel obstruction. A fibrous cord had formed between the peritoneum (beside the transplanted kidney) and the root of the sigmoid mesocolon, strangulating the looped ileum and causing bleeding necrosis and hemorrhagic ascites collection. The cord and the necrotic ileum were resected, followed by an end-to-end anastomosis. He was discharged 17 days after the surgery in good condition. This is the first reported case of a person having a strangulated small bowel obstruction by a fibrous cord, who did not have a history of laparotomy after renal transplant. A strangulated small bowel obstruction after a renal transplant in a patient with no history of a laparotomy is a rare, but possible postoperative complications should be considered when making a differential diagnosis.

  16. Fecal microbiota transplantation in inflammatory bowel disease: beyond the excitement.

    PubMed

    Ianiro, Gianluca; Bibbò, Stefano; Scaldaferri, Franco; Gasbarrini, Antonio; Cammarota, Giovanni

    2014-10-01

    The purpose of this article is to perform a systematic review of the literature on the use of fecal microbiota transplantation (FMT) in inflammatory bowel disease (IBD).There is an increasing interest of both physicians and patients in assessing the possible role of the FMT in the treatment of IBD.Electronic and manual bibliographic searches were performed to identify original reports in which subjects with IBD were treated with FMT. Because of the scarcity of studies with adequate sample size, case series and case reports were also considered. A critical appraisal of the clinical research evidence on the effectiveness, safety, and other parameters related to FMT was made. Data extraction was independently performed by 2 reviewers.We found a total of 31 publications on the use of FMT in IBD. The majority were case reports or case series, whereas 8 publications reported data from open-label trials including a very less number of patients. A total of 133 patients with IBD were managed with FMT. Of these, 57 subjects (43%) had a Clostridium difficile infection. A resolution or reduction of symptoms was reported in 80 of 113 (71%) patients with evaluable IBD. Moreover, FMT does not seem to provide the same safety profile showed for non-IBD individuals with C difficile infection.The available evidence is limited and weak. FMT has the potential to be somehow of help in managing patients with IBD, but considerable further efforts are necessary to make this procedure a valid option for these subjects.

  17. Fecal Microbiota Transplantation in Inflammatory Bowel Disease: Beyond the Excitement

    PubMed Central

    Ianiro, Gianluca; Bibbò, Stefano; Scaldaferri, Franco; Gasbarrini, Antonio; Cammarota, Giovanni

    2014-01-01

    Abstract The purpose of this article is to perform a systematic review of the literature on the use of fecal microbiota transplantation (FMT) in inflammatory bowel disease (IBD). There is an increasing interest of both physicians and patients in assessing the possible role of the FMT in the treatment of IBD. Electronic and manual bibliographic searches were performed to identify original reports in which subjects with IBD were treated with FMT. Because of the scarcity of studies with adequate sample size, case series and case reports were also considered. A critical appraisal of the clinical research evidence on the effectiveness, safety, and other parameters related to FMT was made. Data extraction was independently performed by 2 reviewers. We found a total of 31 publications on the use of FMT in IBD. The majority were case reports or case series, whereas 8 publications reported data from open-label trials including a very less number of patients. A total of 133 patients with IBD were managed with FMT. Of these, 57 subjects (43%) had a Clostridium difficile infection. A resolution or reduction of symptoms was reported in 80 of 113 (71%) patients with evaluable IBD. Moreover, FMT does not seem to provide the same safety profile showed for non-IBD individuals with C difficile infection. The available evidence is limited and weak. FMT has the potential to be somehow of help in managing patients with IBD, but considerable further efforts are necessary to make this procedure a valid option for these subjects. PMID:25340496

  18. Nitric oxide pathways in circular muscle of the rat jejunum before and after small bowel transplantation.

    PubMed

    Balsiger, B M; Duenes, J A; Ohtani, N; Shibata, C; Farrugia, G; Anding, W J; Sarr, M G

    2000-01-01

    Previous studies suggest that nitric oxide synthase is upregulated after small bowel transplantation which may have implications in enteric dysfunction after small bowel transplantation. The aim of this study was to determine the role of nitric oxide in nonadrenergic, noncholinergic inhibitory function after small bowel transplantation in rat jejunal circular muscle. The following four groups of rats (n = >/=8 rats per group) were studied: Neurally intact control animals; 1 week after anesthesia and sham celiotomy, and either 1 week or 8 weeks after isogeneic, orthotopic small bowel transplantation. Full-thickness jejunal circular muscle strips were evaluated under isometric conditions for spontaneous contractile activity, response to electrical field stimulation, and effects of exogenous nitric oxide and nitric oxide antagonists. Spontaneous activity did not differ among groups. Electrical field stimulation inhibited activity similarly in all groups. Exogenous nitric oxide, NG-monomethyl L-arginine monoacetate salt (a nitric oxide synthase inhibitor), and methylene blue (cGMP antagonist) had no effect on spontaneous activity. Neither nitric oxide antagonist altered the inhibitory response to neural excitation by electrical field stimulation in any group. Nitric oxide, a known inhibitory neurotransmitter in other gut smooth muscle, has no apparent role in rat jejunal circular muscle before or after small bowel transplantation.

  19. Combined kidney and intestinal transplantation in patients with enteric hyperoxaluria secondary to short bowel syndrome.

    PubMed

    Ceulemans, L J; Nijs, Y; Nuytens, F; De Hertogh, G; Claes, K; Bammens, B; Naesens, M; Evenepoel, P; Kuypers, D; Vanrenterghem, Y; Monbaliu, D; Pirenne, J

    2013-07-01

    Kidney transplantation is the treatment of choice for end-stage renal disease whereas indications for intestinal transplantation are currently restricted to patients with irreversible small bowel failure and severe complications of total parenteral nutrition (mostly shortage and infection of venous accesses, major electrolyte disturbances and liver failure). Enteric hyperoxaluria is secondary to certain intestinal diseases like intestinal resections, chronic inflammatory bowel disease and other malabsorption syndromes and can lead to end-stage renal disease requiring kidney transplantation. We report two patients suffering from renal failure due to enteric hyperoxaluria (secondary to extensive intestinal resection) in whom we elected to replace not only the kidney but also the intestine to prevent recurrence of hyperoxaluria in the transplanted kidney.

  20. The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation?

    PubMed

    Damman, Christopher J; Miller, Samuel I; Surawicz, Christina M; Zisman, Timothy L

    2012-10-01

    One hypothesis for the etiology of inflammatory bowel disease is that an altered or pathogenic microbiota causes inflammation in a genetically susceptible individual. Understanding the microbiota's role in the pathogenesis of the disease could lead to new IBD treatments aimed at shifting the bacteria in the gut back to eubiosis. Probiotics have some efficacy in the treatment of ulcerative colitis (UC), but our current repertoire is limited in potency. Fecal microbiota therapy (FMT) is an emerging treatment for several gastrointestinal and metabolic disorders. It has demonstrated efficacy in treating refractory Clostridium difficile infection, and there are case reports of FMT successfully treating UC. Further clinical studies are justified, and could be complemented by mouse models of fecal transplantation, in which variables can be controlled and manipulated.

  1. Mesenchymal stem cell therapy in patients with small bowel transplantation: single center experience.

    PubMed

    Doğan, Sait Murat; Kılınç, Selçuk; Kebapçı, Eyüp; Tuğmen, Cem; Gürkan, Alp; Baran, Maşallah; Kurtulmuş, Yusuf; Olmez, Mustafa; Karaca, Cezmi

    2014-07-07

    To study the effects of mesenchymal stem cell (MSC) therapy on the prevention of acute rejection and graft vs host disease following small bowel transplantation. In our transplantation center, 6 isolated intestinal transplants have been performed with MSC therapy since 2009. The primary reasons for transplants were short gut syndrome caused by surgical intestine resection for superior mesenteric artery thrombosis (n = 4), Crohn's disease (n = 1) and intestinal aganglionosis (n = 1). Two of the patients were children. At the time of reperfusion, the first dose of MSCs cultured from the patient's bone marrow was passed into the transplanted intestinal artery at a dose of 1000000 cells/kg. The second and third doses of MSCs were given directly into the mesenteric artery through the arterial anastomosis using an angiography catheter on day 15 and 30 post-transplant. The median follow-up for these patients was 10.6 mo (min: 2 mo-max: 30 mo). Three of the patients developed severe acute rejection. One of these patients did not respond to bolus steroid therapy. Although the other two patients did respond to anti-rejection treatment, they developed severe fungal and bacterial infections. All of these patients died in the 2(nd) and 3(rd) months post-transplant due to sepsis. The remaining patients who did not have acute rejection had good quality of life with no complications observed during the follow-up period. In addition, their intestinal grafts were functioning properly in the 13(th), 25(th) and 30(th) month post-transplant. The patients who survived did not encounter any problems related to MSC transplantation. Although this is a small case series and not a randomized study, it is our opinion that small bowel transplantation is an effective treatment for intestinal failure, and MSC therapy may help to prevent acute rejection and graft vs host disease following intestinal transplantation.

  2. Intestinal microbiota pathogenesis and fecal microbiota transplantation for inflammatory bowel disease

    PubMed Central

    Wang, Zi-Kai; Yang, Yun-Sheng; Chen, Ye; Yuan, Jing; Sun, Gang; Peng, Li-Hua

    2014-01-01

    The intestinal microbiota plays an important role in inflammatory bowel disease (IBD). The pathogenesis of IBD involves inappropriate ongoing activation of the mucosal immune system driven by abnormal intestinal microbiota in genetically predisposed individuals. However, there are still no definitive microbial pathogens linked to the onset of IBD. The composition and function of the intestinal microbiota and their metabolites are indeed disturbed in IBD patients. The special alterations of gut microbiota associated with IBD remain to be evaluated. The microbial interactions and host-microbe immune interactions are still not clarified. Limitations of present probiotic products in IBD are mainly due to modest clinical efficacy, few available strains and no standardized administration. Fecal microbiota transplantation (FMT) may restore intestinal microbial homeostasis, and preliminary data have shown the clinical efficacy of FMT on refractory IBD or IBD combined with Clostridium difficile infection. Additionally, synthetic microbiota transplantation with the defined composition of fecal microbiota is also a promising therapeutic approach for IBD. However, FMT-related barriers, including the mechanism of restoring gut microbiota, standardized donor screening, fecal material preparation and administration, and long-term safety should be resolved. The role of intestinal microbiota and FMT in IBD should be further investigated by metagenomic and metatranscriptomic analyses combined with germ-free/human flora-associated animals and chemostat gut models. PMID:25356041

  3. Intestinal microbiota pathogenesis and fecal microbiota transplantation for inflammatory bowel disease.

    PubMed

    Wang, Zi-Kai; Yang, Yun-Sheng; Chen, Ye; Yuan, Jing; Sun, Gang; Peng, Li-Hua

    2014-10-28

    The intestinal microbiota plays an important role in inflammatory bowel disease (IBD). The pathogenesis of IBD involves inappropriate ongoing activation of the mucosal immune system driven by abnormal intestinal microbiota in genetically predisposed individuals. However, there are still no definitive microbial pathogens linked to the onset of IBD. The composition and function of the intestinal microbiota and their metabolites are indeed disturbed in IBD patients. The special alterations of gut microbiota associated with IBD remain to be evaluated. The microbial interactions and host-microbe immune interactions are still not clarified. Limitations of present probiotic products in IBD are mainly due to modest clinical efficacy, few available strains and no standardized administration. Fecal microbiota transplantation (FMT) may restore intestinal microbial homeostasis, and preliminary data have shown the clinical efficacy of FMT on refractory IBD or IBD combined with Clostridium difficile infection. Additionally, synthetic microbiota transplantation with the defined composition of fecal microbiota is also a promising therapeutic approach for IBD. However, FMT-related barriers, including the mechanism of restoring gut microbiota, standardized donor screening, fecal material preparation and administration, and long-term safety should be resolved. The role of intestinal microbiota and FMT in IBD should be further investigated by metagenomic and metatranscriptomic analyses combined with germ-free/human flora-associated animals and chemostat gut models.

  4. Intestinal Transplant Inflammation: the Third Inflammatory Bowel Disease.

    PubMed

    Kroemer, Alexander; Cosentino, Christopher; Kaiser, Jason; Matsumoto, Cal S; Fishbein, Thomas M

    2016-11-01

    Intestinal transplantation is the most immunologically complex of all abdominal organ transplants. Understanding the role both humoral and innate and adaptive cellular immunity play in intestinal transplantation is critical to improving outcomes and increasing indications for patients suffering from intestinal failure. Recent findings highlighting the impact of donor-specific antibodies on intestinal allografts, the role of NOD2 as a key regulator of intestinal immunity, the protective effects of innate lymphoid cells, and the role of Th17 in acute cellular rejection are reviewed here.

  5. Adenovirus disease in six small bowel, kidney and heart transplant recipients; pathology and clinical outcome.

    PubMed

    Mehta, Vikas; Chou, Pauline C; Picken, Maria M

    2015-11-01

    Adenoviruses are emerging as important viral pathogens in hematopoietic stem cell and solid organ transplant recipients, impacting morbidity, graft survival, and even mortality. The risk seems to be highest in allogeneic hematopoietic stem cell transplant recipients as well as heart, lung, and small bowel transplant recipients. Most of the adenovirus diseases develop in the first 6 months after transplantation, particularly in pediatric patients. Among abdominal organ recipients, small bowel grafts are most frequently affected, presumably due to the presence of a virus reservoir in the mucosa-associated lymphoid tissue. Management of these infections may be difficult and includes the reduction of immunosuppression, whenever possible, combined with antiviral therapy, if necessary. Therefore, an awareness of the pathology associated with such infections is important in order to allow early detection and specific treatment. We reviewed six transplant recipients (small bowel, kidney, and heart) with adenovirus graft involvement from two institutions. We sought to compare the diagnostic morphology and the clinical and laboratory findings. The histopathologic features of an adenovirus infection of the renal graft and one native kidney in a heart transplant recipient included a vaguely granulomatous mixed inflammatory infiltrate associated with rare cells showing a cytopathic effect (smudgy nuclei). A lymphocytic infiltrate, simulating T cell rejection, with admixture of eosinophils was also seen. In the small bowel grafts, there was a focal mixed inflammatory infiltrate with associated necrosis in addition to cytopathic effects. In the heart, allograft adenovirus infection was silent with no evidence of inflammatory changes. Immunohistochemical stain for adenovirus was positive in all grafts and in one native kidney. All patients were subsequently cleared of adenovirus infection, as evidenced by follow-up biopsies, with no loss of the grafts. Adenovirus infection can

  6. Safety and Efficacy of Small Bowel Examination by Capsule Endoscopy for Patients before Liver Transplantation

    PubMed Central

    Tetsuya, Yasunaka; Yoshiyasu, Kono; Kou, Miura; Toshihiro, Inokuchi; Yoshiro, Kawahara; Yuzo, Umeda; Takahito, Yagi; Hiroyuki, Okada

    2017-01-01

    Background and Aims. Gastrointestinal surveillance is a requirement prior to liver transplantation (LT), but small intestine examination is not generally undertaken. The aim of the present study was to evaluate the safety and efficacy of capsule endoscopy (CE) for patients with end-stage liver disease. Methods. 31 patients who needed LT were enrolled, and 139 patients who underwent CE over the same period of time acted as controls. Results. Frequency of successful achievement of evaluation of the full length of the small bowel, the mean gastric transit time, and the mean small bowel transit time were not significantly different between the two groups. Abnormalities in the small bowel were found in 26 patients. Comparative analysis revealed that history of EV rupture, history of EV treatment, red color sign of EV, and presence of PHG or HCC were significantly associated with patients with >2 two such findings (high score group). Conclusions. Small bowel examination by CE in patients before liver transplantation could be performed safely and is justified by the high rate of abnormal lesions detected particularly in patients with history of EV therapy or bleeding, red color sign, and presence of PHG or HCC. This study was registered in the UMIN Clinical Trial Registry (UMIN 000008672). PMID:28168199

  7. Dietary omega-3 polyunsaturated fatty acids can inhibit expression of granzyme B, perforin, and cation-independent mannose 6-phosphate/insulin-like growth factor receptor in rat model of small bowel transplant chronic rejection.

    PubMed

    Kun, Zhao; Haiyun, Zhang; Meng, Wang; Li Ning; Li Yousheng; Li Jieshou

    2008-01-01

    The aim of our work was to investigate the effects of omega-3 polyunsaturated fatty acids on apoptosis and granzyme B, perforin, and cation-independent mannose 6-phosphate/insulin-like growth factor receptor (CI-MPR) expression of intestinal epithelial cells of chronic rejection after small intestinal transplantation. Small bowel transplantation was performed in a rat combination of 3 groups: group 1, Lewis-to-Lewis; group 2, F344-to-Lewis, dietary corn oil; group 3, F344-to-Lewis, dietary fish oil. All recipients were killed at 16 weeks posttransplantation. The apoptosis rate of mucosal cells was evaluated by flow cytometry. The expression of granzyme B, perforin, and CI-MPR was analyzed by reverse transcriptase PCR. A high apoptotic rate was observed when the allografts demonstrated 1 or more histologic features of chronic rejection. omega-3 Polyunsaturated fatty acids decreased in rate of the apoptosis, and it can inhibit the expression of granzyme B, perforin, and CI-MPR. omega-3 Polyunsaturated fatty acids can suppress the rejection to mucosal cells of allograft at the time of chronic rejection in small intestinal transplantation, which may be significant in increasing the surviving rate of allograft, delaying the chronic dysfunction, and prolonging the lifetime of both allograft and acceptor.

  8. Dietary ω-3 Polyunsaturated Fatty Acids Can Inhibit Expression of Granzyme B, Perforin, and Cation-Independent Mannose 6-Phosphate/Insulin-Like Growth Factor Receptor in Rat Model of Small Bowel Transplant Chronic Rejection.

    PubMed

    Kun, Zhao; Haiyun, Zhang; Meng, Wang; Li Ning; Li Yousheng; Li Jieshou

    2008-01-01

    The aim of our work was to investigate the effects ofω -3 polyunsaturated fatty acids on apoptosis and granzyme B, perforin, and cation-independent mannose 6-phosphate/insulin-like growth factor receptor (CI-MPR) expression of intestinal epithelial cells of chronic rejection after small intestinal transplantation. Small bowel transplantation was performed in a rat combination of 3 groups: group 1, Lewis-to-Lewis; group 2, F344-to-Lewis, dietary corn oil; group 3, F344-to-Lewis, dietary fish oil. All recipients were killed at 16 weeks posttransplantation. The apoptosis rate of mucosal cells was evaluated by flow cytometry. The expression of granzyme B, perforin, and CI-MPR was analyzed by reverse transcriptase PCR. A high apoptotic rate was observed when the allografts demonstrated 1 or more histologic features of chronic rejection. ω-3 Polyunsaturated fatty acids decreased in rate of the apoptosis, and it can inhibit the expression of granzyme B, perforin, and CI-MPR. ω-3 Polyunsaturated fatty acids can suppress the rejection to mucosal cells of allograft at the time of chronic rejection in small intestinal transplantation, which may be significant in increasing the surviving rate of allograft, delaying the chronic dysfunction, and prolonging the lifetime of both allograft and acceptor.

  9. Fecal microbial transplant for the treatment of pediatric inflammatory bowel disease

    PubMed Central

    Wang, Alice Yuxin; Popov, Jelena; Pai, Nikhil

    2016-01-01

    The role of fecal microbial transplant (FMT) in the treatment of pediatric gastrointestinal disease has become increasingly popular among pediatric practitioners, patients, and parents. The success of FMT for the treatment of recurrent Clostridium difficile infection (RCDI) has bolstered interest in its potential application to other disease states, such as inflammatory bowel disease (IBD). FMT has particular interest in pediatrics, given the concerns of patients and parents about rates of adverse events with existing therapeutic options, and the greater cumulative medication burden associated with childhood-onset disease. Published literature on the use of FMT in pediatrics is sparse. Only 45 pediatric patients treated for RCDI have been reported, and only 27 pediatric patients with pediatric IBD. The pediatric microbiome may uniquely respond to microbial-based therapies. This review will provide a comprehensive overview of fecal microbial transplant and its potential role in the treatment of pediatric inflammatory bowel disease. We will discuss the microbiome in pediatric inflammatory bowel disease, existing adult and pediatric literature on the use of FMT in IBD treatment, and pediatric FMT trials that are currently recruiting patients. This review will also discuss features of the microbiome that may be associated with host response in fecal transplant, and potential challenges and opportunities for the future of FMT in pediatric IBD treatment. PMID:28058011

  10. Graft-versus-host disease after liver and small bowel transplantation in a child

    PubMed Central

    Reyes, Jorge; Todo, Satoru; Green, Michael; Yunis, Eduardo; Schoner, David; Kocoshis, Samuel; Furukawa, Hiro; Abu-Elmagd, Kareem; Tzakis, Andreas; Bueno, Javier; Starzl, Thomas E.

    2010-01-01

    An 8-month-old child with an immunodeficiency disorder characterized by abnormal lymphocyte function and by low IgG and IgA levels had combined liver and small bowel transplantation under tacrolimus and steroid immunosuppression for the treatment of short gut syndrome and hepatic cirrhosis. The patient developed an early postoperative episode of Pnemocystis carinii pneumonia, and a subsequent surgical complication, prompting discontinuance of tacrolimus. A skin rash eventually shown to be graft-versus-host disease (GVHD) developed in the flank on the 12th post-transplant day and gradually became generalized. Peritonitis, sepsis, multisystem organ failure including the liver allograft led to death on the 23rd post-operative day. The mechanisms leading to post-transplant GVHD under the specific circumstances in this case are discussed. PMID:9361921

  11. Faecal Microbiota Transplantation for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

    PubMed

    Paramsothy, Sudarshan; Paramsothy, Ramesh; Rubin, David T; Kamm, Michael A; Kaakoush, Nadeem O; Mitchell, Hazel M; Castaño-Rodríguez, Natalia

    2017-10-01

    Faecal microbiota transplantation [FMT] has been investigated as a potential treatment for inflammatory bowel disease [IBD]. We thus performed a systematic review and meta-analysis assessing the effectiveness and safety of FMT in IBD. A systematic review was conducted until January 2017. Studies were excluded if patients had co-infection or data were pooled across disease subtypes (ulcerative colitis [UC], Crohn's disease [CD], pouchitis). Clinical remission was established as the primary outcome. Pooled effect sizes and 95% confidence intervals were obtained using the random effects model. In all, 53 studies were included [41 in UC, 11 in CD, 4 in pouchitis]. Overall, 36% [201/555] of UC, 50.5% [42/83] of CD, and 21.5% [5/23] of pouchitis patients achieved clinical remission. Among cohort studies, the pooled proportion achieving clinical remission was 33% (95% confidence interval [CI] = 23%-43%] for UC and 52% [95% CI = 31%-72%] for CD, both with moderate risk of heterogeneity. For four RCTs in UC, significant benefit in clinical remission (pooled odds ratios [[P-OR] = 2.89, 95% CI = 1.36-6.13, p = 0.006) with moderate heterogeneity [Cochran's Q, p = 0.188; I2 = 37%] was noted. Sub-analyses suggest remission in UC improved with increased number of FMT infusions and lower gastrointestinal tract administration. Most adverse events were transient gastrointestinal complaints. Microbiota analysis was performed in 24 studies, with many identifying increased diversity and a shift in recipient microbiota profile towards the donor post-FMT. FMT appears effective in UC remission induction, but long-term durability and safety remain unclear. Additional well-designed controlled studies of FMT in IBD are needed, especially in CD and pouchitis.

  12. Hematopoietic stem cell transplantation in a CD3 gamma-deficient infant with inflammatory bowel disease.

    PubMed

    Ozgür, Tuba Turul; Asal, Gülten Türkkani; Cetinkaya, D; Orhan, D; Kiliç, S S; Usta, Y; Ozen, H; Tezcan, Ilhan

    2008-12-01

    Partial or total CD3 chain expression defects including CD3 gamma, epsilon, delta, and zeta chain are among the autosomally inherited SCID presenting with T-B+NK+ phenotype with lymphopenia. The clinical findings are generally severe in all except for CD3 gamma deficiency. Here we present a 10-month-old CD3 gamma deficient boy with IBD. The patient had suffered from intractable diarrhea, recurrent pulmonary infections and oral moniliasis since two months of age. Following the first allogeneic HSCT from his HLA-identical (6/6) sister after a reduced intensity regimen, a second transplantation was performed five months later. On day +19 after second transplantation, the CD3 TCR alpha/beta chain expression increased to 66% with development of full donor chimerism (98.6%). A significant improvement in diarrhea, perianal lesions, and rectal fistula was observed suggesting an improvement in inflammatory bowel disease. The patient died at home on day +50 with a sudden respiratory failure secondary to an undetermined infection. The case was interesting being the first reported case with SCID and inflammatory bowel disease who responded very well to HSCT by full recovery of intractable diarrhea, failure to thrive, laboratory findings, and improvement of fistula formation.

  13. Effect of CXCR3/HO-1 genes modified bone marrow mesenchymal stem cells on small bowel transplant rejection.

    PubMed

    Yin, Ming-Li; Song, Hong-Li; Yang, Yang; Zheng, Wei-Ping; Liu, Tao; Shen, Zhong-Yang

    2017-06-14

    To investigate whether bone marrow mesenchymal stem cells (BMMSCs) modified with the HO-1 and CXCR3 genes can augment the inhibitory effect of BMMSCs on small bowel transplant rejection. Lewis rat BMMSCs were cultured in vitro. Third-passage BMMSCs were transduced with the CXCR3/HO-1 genes or the HO-1 gene alone. The rats were divided into six groups and rats in the experimental group were pretreated with BMMSCs 7 d prior to small bowel transplant. Six time points (instant, 1 d, 3 d, 7 d, 10 d, and 14 d) (n = 6) were chosen for each group. Hematoxylin-eosin staining was used to observe pathologic rejection, while immunohistochemistry and Western blot were used to detect protein expression. Flow cytometry was used to detect T lymphocytes and enzyme linked immunosorbent assay was used to detect cytokines. The median survival time of BMMSCs from the CXCR3/HO-1 modified group (53 d) was significantly longer than that of the HO-1 modified BMMSCs group (39 d), the BMMSCs group (26 d), and the NS group (control group) (16 d) (P < 0.05). Compared with BMMSCs from the HO-1 modified BMMSCs, BMMSCs, and NS groups, rejection of the small bowel in the CXCR3/HO-1 modified group was significantly reduced, while the weight of transplant recipients was also significantly decreased (P < 0.05). Furthermore, IL-2, IL-6, IL-17, IFN-γ, and TNF-α levels were significantly decreased and the levels of IL-10 and TGF-β were significantly increased (P < 0.05). BMMSCs modified with the CXCR3 and HO-1 genes can abrogate the rejection of transplanted small bowel more effectively and significantly increase the survival time of rats that receive a small bowel transplant.

  14. Computational Model for Corneal Transplantation

    NASA Astrophysics Data System (ADS)

    Cabrera, Delia

    2003-10-01

    We evaluated the refractive consequences of corneal transplants using a biomechanical model with homogeneous and inhomogeneous Young's modulus distributions within the cornea, taking into account ablation of some stromal tissue. A FEM model was used to simulate corneal transplants in diseased cornea. The diseased cornea was modeled as an axisymmetric structure taking into account a nonlinearly elastic, isotropic formulation. The model simulating the penetrating keratoplasty procedure gives more change in the postoperative corneal curvature when compared to the models simulating the anterior and posterior lamellar graft procedures. When a lenticle shaped tissue was ablated in the graft during the anterior and posterior keratoplasty, the models provided an additional correction of about -3.85 and -4.45 diopters, respectively. Despite the controversy around the corneal thinning disorders treatment with volume removal procedures, results indicate that significant changes in corneal refractive power could be introduced by a corneal transplantation combined with myopic laser ablation.

  15. Primate Models in Organ Transplantation

    PubMed Central

    Anderson, Douglas J.; Kirk, Allan D.

    2013-01-01

    Large animal models have long served as the proving grounds for advances in transplantation, bridging the gap between inbred mouse experimentation and human clinical trials. Although a variety of species have been and continue to be used, the emergence of highly targeted biologic- and antibody-based therapies has required models to have a high degree of homology with humans. Thus, the nonhuman primate has become the model of choice in many settings. This article will provide an overview of nonhuman primate models of transplantation. Issues of primate genetics and care will be introduced, and a brief overview of technical aspects for various transplant models will be discussed. Finally, several prominent immunosuppressive and tolerance strategies used in primates will be reviewed. PMID:24003248

  16. Role of the intestinal microbiota and fecal transplantation in inflammatory bowel diseases.

    PubMed

    Liang, Jie; Sha, Su Mei; Wu, Kai Chun

    2014-12-01

    Ulcerative colitis and Crohn's disease are the two major types of inflammatory bowel disease (IBD). Despite intensive study, it is still challenging because the precise etiology and pathogenesis remains unclear. Studies have shown that IBD is associated with changes in the composition of intestinal microbiota, as either a cause or a consequence of abnormal host immune response in genetic susceptible population. Two specific microorganisms (Mycobacterium avium subsp. paratuberculosis and Escherichia coli) get more widely studied, but till now no single microorganism has been identified as the only pathogen. Genetic susceptibility data also suggest impaired handling of bacteria as well as an improper immune response to potential pathogens. The microbiota provides new therapeutic methods, and fecal microbiota transplantation may restore the balance of intestinal flora to supplement or optimize the current therapies. © 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  17. THE EFFECT OF SMALL BOWEL TRANSPLANTATION ON THE MORPHOLOGY AND PHYSIOLOGY OF INTESTINAL MUSCLE

    PubMed Central

    Sugitani, Atsushi; Bauer, Anthony J.; Reynolds, James C.; Halfter, Willi M.; Nomoto, Minoru; Starzl, Thomas E.; Todo, Satoru

    2011-01-01

    The effects of acute (AR) and chronic rejection (CR) on intestinal smooth muscle that are responsible for the dysmotility following small bowel transplantation (SBTX) are incompletely understood. Jejunal and ileal specimens from normal control dogs (n=7), and auto-transplanted dogs were examined at 7 days (n=6) and 1 (n=7), 3 (n=6), 6 (n=6), and 12 months (n=6). Allo-transplanted dogs that developed AR (n=8) and CR (n=5) were examined for gross and microscopic morphology (muscle thickness, the number and size of myocytes, and inflammatory infiltrate), and for contractile and intracellular electrical function in vitro. Auto-SBTX did not alter morphology at any period, but contractile function was impaired at 7 days (73.6%) compared with normal intestine. Acute rejection did not influence myocyte number or size, but was associated with a prominent infiltrate of neutrophils and lymphocytes, and severely impaired contractile function (20.6%) compared with auto-SBTX controls. Acute rejection also significantly inhibited the amplitude of slow waves and of inhibitory junction potentials. Chronic rejection caused thickening of muscularis propria by both hyperplasia (175.5%) and hypertrophy (202.6%) accompanied by moderate inflammatory cell infiltrate compared with auto-SBTX controls. We conclude that the marked inflammatory infiltrate into the muscularis propria indicates that the graft muscle is injured by both acute and chronic rejection; impaired function of intestinal smooth muscle following SBTX results from both rejection and the injury associated with transplantation, and chronic rejection following SBTX is associated with both hyperplasia and hypertrophy of the muscularis propria. PMID:9020316

  18. Infection among adult small bowel and multivisceral transplant recipients in the 30-day postoperative period.

    PubMed

    Primeggia, J; Matsumoto, C S; Fishbein, T M; Karacki, P S; Fredette, T M; Timpone, J G

    2013-10-01

    Intestinal transplantation is a potential option for patients with short gut syndrome (SGS), and infection is common in the postoperative period. The aim of our study was to identify the incidence and characteristics of bacterial and fungal infections of adult small bowel or multivisceral (SB/MV) transplantation recipients in the 30-day postoperative period. This retrospective chart review assessed the incidence and characteristics of bacterial and fungal infections in patients who underwent SB/MV transplant at our center between April 2004 and November 2008. Patient data were retrieved from computerized databases, flow-charts, and medical records. A total of 40 adult patients with a mean age of 38.7 ± 13.4 years received transplants during this period: 27 patients received isolated SB, 12 received MV, and 1 received SB and kidney. Our immunosuppressive regimen included basiliximab for induction, and tacrolimus, sirolimus, and methylprednisolone for maintenance therapy. The most common indications for transplant were SGS, intestinal ischemia, Crohn's disease, trauma, motility disorders, and Gardner's syndrome. We report a 30-day postoperative infection rate of 57.5% and mean time to first infection of 10.78 ± 8.99 days. A total of 36 infections were documented in 23 patients. Of patients who developed infections, 56.5% developed 1 infection, 30.4% developed 2 infections, and 13% developed 3 infections. The most common site of infection was the abdomen, followed by blood, urine, lung, and wound infection. The isolates were gram-negative bacteria in 49.3%, gram-positive bacteria in 39.4%, and 11.3% were fungi. The most common organisms were Pseudomonas (19%), Enterococcus (15%), and Escherichia coli (13%). Overall, 47% of infections were due to drug-resistant pathogens; 31% of E. coli and Klebsiella species were extended-spectrum beta-lactamase-producing organisms, 36% of Pseudomonas was multidrug resistant (MDR), 75% of Enterococcus was vancomycin resistant

  19. Epidemiological investigation of Candida species causing bloodstream infection in paediatric small bowel transplant recipients.

    PubMed

    Suhr, Mallory J; Gomes-Neto, João Carlos; Banjara, Nabaraj; Florescu, Diana F; Mercer, David F; Iwen, Peter C; Hallen-Adams, Heather E

    2017-06-01

    Small bowel transplantation (SBT) can be a life-saving medical procedure. However, these recipients experience high risk of bloodstream infections caused by Candida. This research aims to characterise the SBT recipient gut microbiota over time following transplantation and investigate the epidemiology of candidaemia in seven paediatric patients. Candida species from the recipients' ileum and bloodstream were identified by internal transcribed spacer sequence and distinguished to strain by multilocus sequence typing and randomly amplified polymorphic DNA. Antifungal susceptibility of bloodstream isolates was determined against nine antifungals. Twenty-two ileostomy samples harboured at least one Candida species. Fungaemia were caused by Candida parapsilosis, Candida albicans, Candida glabrata, Candida orthopsilosis and Candida pelliculosa. All but three bloodstream isolates showed susceptibility to all the antifungals tested. One C. glabrata isolate showed multidrug resistance to itraconazole, amphotericin B and posaconazole and intermediate resistance to caspofungin. Results are congruent with both endogenous (C. albicans, C. glabrata) and exogenous (C. parapsilosis) infections; results also suggest two patients were infected by the same strain of C. parapsilosis. Continuing to work towards a better understanding of sources of infection-particularly the exogenous sources-would lead to targeted prevention strategies. © 2017 Blackwell Verlag GmbH.

  20. Optimizing a canine survival model of orthotopic lung transplantation.

    PubMed

    Farivar, A S; Yunusov, M Y; Chen, P; Leone, R J; Madtes, D K; Kuhr, C S; Spector, M R; Abrams, K; Hwang, B; Nash, R A; Mulligan, M S

    2006-06-01

    While acute models of orthotopic lung transplantation have been described in dogs, the technical considerations of developing a survival model in this species have not been elaborated. Herein, we describe optimization of a canine survival model of orthotopic lung transplantation. Protocols of orthotopic left lung transplantation and single lung ventilation were established in acute experiments (n=9). Four dogs, serving as controls, received autologous, orthotopic lung transplants. Allogeneic transplants were performed in 16 DLA-identical and 16 DLA-mismatched unrelated recipient dogs. Selective right lung ventilation was utilized in all animals. A Malecot tube was left in the pleural space connected to a Heimlich valve for up to 24 hours. To date, animals have been followed up to 24 months by chest radiography, pulmonary function tests, bronchoscopy with lavage, and open biopsies. Long-term survival was achieved in 34/36 animals. Two recipients died intraoperatively secondary to cardiac arrest. All animals were extubated on the operating table, and in all cases the chest tube was removed within 24 hours. Major complications included thrombosis of the pulmonary artery and subcritical stenosis of bronchial anastamosis. One recipient underwent successful treatment of a small bowel intussusception. We report our experience in developing a survival canine model of orthotopic single lung transplantation. While short-term survival following canine lung transplantation is achievable, we report particular considerations that facilitate animal comfort, early extubation, and lung reexpansion in the immediate postoperative period, further optimizing use of this species for experimental modeling of long-term complications after lung transplantation.

  1. Head Transplantation in Mouse Model.

    PubMed

    Ren, Xiao-Ping; Ye, Yi-Jie; Li, Peng-Wei; Shen, Zi-Long; Han, Ke-Cheng; Song, Yang

    2015-08-01

    The mouse model of allo-head and body reconstruction (AHBR) has recently been established to further the clinical development of this strategy for patients who are suffering from mortal bodily trauma or disease, yet whose mind remains healthy. Animal model studies are indispensable for developing such novel surgical practices. The goal of this work was to establish head transplant mouse model, then the next step through the feasible biological model to investigate immune rejection and brain function in next step, thereby promoting the goal of translation of AHBR to the clinic in the future. Our approach involves retaining adequate blood perfusion in the transplanted head throughout the surgical procedure by establishing donor-to-recipient cross-circulation by cannulating and anastomosing the carotid artery on one side of the body and the jugular vein on the other side. Neurological function was preserved by this strategy as indicated by electroencephalogram and intact cranial nerve reflexes. The results of this study support the feasibility of this method for avoiding brain ischemia during transplantation, thereby allowing for the possibility of long-term studies of head transplantation. © 2015 John Wiley & Sons Ltd.

  2. Acquired Epidermodysplasia Verruciformis Associated with Human Papilloma Virus Type 14 in a Small Bowel Transplanted Child--A Case Report.

    PubMed

    Hirschman, Derek; Tacastacas, Joselin; Rady, Peter L; Tyring, Stephen K; Cooper, Kevin; Honda, Kord

    2016-01-01

    A 3-year-old African American girl taking sirolimus and tacrolimus for a small bowel transplantation presented with hypopigmented macules and papules throughout her trunk. A biopsy diagnosed epidermodysplasia verruciformis (EV) that was found to be associated with human papillomavirus (HPV) type 14 according to polymerase chain reaction analysis. There are few cases of acquired EV in the setting of organ transplantation. Although there is no standardized treatment for acquired EV, prevention and surveillance for transformation to squamous cell carcinoma are primary concerns.

  3. Elevated ST2 Distinguishes Incidences of Pediatric Heart and Small Bowel Transplant Rejection

    PubMed Central

    Mathews, L.R.; Lott, J. M.; Isse, K.; Lesniak, A.; Landsittel, D.; Demetris, A. J.; Sun, Y.; Mercer, D. F.; Webber, S. A.; Zeevi, A.; Fischer, R. T.; Feingold, B.; Turnquist, H. R.

    2016-01-01

    Elevated serum soluble (s) Suppressor of Tumorigenicity 2 (ST2) is observed during cardiovascular and inflammatory bowel diseases. To ascertain whether modulated ST2 levels signify heart (HTx) or small bowel transplant (SBTx) rejection, we quantified sST2 in serially obtained pediatric HTx (n=41) and SBTx recipient (n=18) sera. At times of biopsy-diagnosed HTx rejection (cellular and/or antibody-mediated), serum sST2 was elevated compared to rejection-free time points (1714±329 vs. 546.5±141.6 pg/ml; P=0.0002). SBTx recipients also displayed increased serum sST2 during incidences of rejection (7536±1561 vs. 2662±543.8 pg/ml; P=0.0347). Receiver operator characteristic (ROC) analysis showed that serum sST2>600 pg/ml could discriminate time points of HTx rejection and non-rejection (Area under the curve (AUC)=0.724±0.053; P=0.0003). ROC analysis of SBTx measures revealed a similar discriminative capacity (AUC=0.6921±0.0820; P=0.0349). Quantitative evaluation of both HTx and SBTx biopsies revealed rejection significantly increased allograft ST2 expression. Pathway and Network Analysis of biopsy data pinpointed ST2 in the dominant pathway modulated by rejection and predicted TNF-α and IL-1β as upstream activators. In total, our data indicate that alloimmune-associated pro-inflammatory cytokines increase ST2 during rejection. They also demonstrate that routine serum sST2 quantification, potentially combined with other biomarkers, should be investigated further to aid in the non-invasive diagnosis of rejection. PMID:26663613

  4. Adrenergic denervation hypersensitivity in ileal circular smooth muscle after small bowel transplantation in rats.

    PubMed

    Shibata, C; Balsiger, B M; Anding, W J; Sarr, M G

    1997-11-01

    Effects of small bowel transplantation (SBT) on ileal motility are unknown. The aim of the present study was to investigate changes in spontaneous contractile activity and sensitivity to cholinergic and adrenergic agents in the ileal circular muscle after SBT in rats. Orthotopic SBT was performed in syngeneic rats to avoid immune phenomena. Distal ileal circular muscle strips from rats one week (N = 10) and eight weeks (N = 10) after SBT were stretched to optimal length (Lo), and basal spontaneous activity at Lo was measured. Dose-response experiments to the cholinergic agonist bethanechol (Be, 10(-8)-10(-4) M) were performed in the presence of tetrodotoxin (TTX, 10(-6) M) and to the adrenergic agonist norepinephrine (NE, 10(-8)-10(-4) M) with or without TTX. ED50 (negative log of drug-concentration that induced 50% effect) was calculated. We also studied rats with selective jejunoileal ischemia/ reperfusion, intestinal transection/reanastomosis, naive controls, and sham operated controls (N > or = 8/group). Spontaneous basal activity did not differ among groups. Sensitivity to Be was not different in rats after SBT or in other groups compared to control tissue. After SBT, hypersensitivity to NE was shown by a significant increase of ED50 at one and eight weeks after SBT (5.1 +/- 0.3 vs 6.2 +/- 0.4 and 6.2 +/- 0.2, respectively; P < 0.05) regardless of the presence of TTX. No hypersensitivity was observed after ischemia-reperfusion intestinal transection-reanastomosis, or sham operation. It is concluded that ileal hypersensitivity to NE was related to the extrinsic denervation obligated by the transplantation procedure, possibly mediated through an increase in number of receptors on smooth muscle, not on the enteric nerves.

  5. Modulating the microbiota in inflammatory bowel diseases: prebiotics, probiotics or faecal transplantation?

    PubMed

    Verbeke, Kristin A; Boesmans, Leen; Boets, Eef

    2014-11-01

    Crohn's disease (CD) and ulcerative colitis (UC) are the two major phenotypes of inflammatory bowel diseases (IBD) which constitute a spectrum of chronic, debilitating diseases characterised by a relapsing inflammation of the intestinal mucosal lining. Evidence from a variety of disciplines implicates the intestinal microbiota in the pathogenesis of idiopathic IBD and their complications, including pouchitis. Many studies have reported a dysbiosis in IBD, characterised by a decrease in diversity, a decreased abundance of some dominant commensal members (such as Clostridium IV and XIVa) and an increase in detrimental bacteria (such as sulphate reducing bacteria and Escherichia coli). Therapies such as prebiotics and probiotics aim to selectively manipulate the intestinal microbiota and have been evaluated as an attractive therapeutic option with few side effects. The multispecies product VSL#3 was found effective in preventing and maintaining remission in pouchitis, whereas both VSL#3 and E. coli Nissle were effective in maintaining remission in UC. A more drastic approach to restore the composition of the microbiota and correct the underlying imbalance is a faecal microbiota transplantation (FMT). FMT has been successfully applied to treat patients with even recalcitrant Clostridium difficile infection. Particularly in UC, the majority of studies suggest that FMT may be an effective treatment option although the evidence is still limited. It is anticipated that our increasing knowledge on the composition and function of the intestinal microbiota components will allow in the future for a better selection of highly performing bacteria with specific functions required for specific benefits.

  6. Alemtuzumab Plus Cyclosporine Treatment of the Autoimmune Hemolytic Anemia in an Adult Bowel Transplant

    PubMed Central

    Lauro, A.; Stanzani, M.; Finelli, C.; Zanfi, C.; Morelli, M. C.; Pasqualini, E.; Dazzi, A.; Ravaioli, M.; Di Simone, M.; Giudice, V.; Pironi, L.; Pinna, A. D.

    2014-01-01

    An adult male underwent a bowel transplant for tufting enteropathy, receiving alemtuzumab, tacrolimus, and steroids as immunosuppressants. Five years later, he developed an autoimmune hemolytic anemia (AIHA), anti-IgG positive, with reduced reticulocyte count, leukopenia, and thrombocytopenia with antiplatelet antibodies. After an unsuccessful initial treatment with high dose steroids, reduction in tacrolimus dose, and intravenous immunoglobulin (IVIG), a bone marrow biopsy revealed absence of erythroid maturation with precursor hyperplasia. The patient was switched to sirolimus and received four doses of rituximab plus two courses of plasmapheresis, which decreased his transfusion requirements. After a febrile episode one month later, the AIHA relapsed with corresponding decreases in platelet and leukocyte count: cyclosporine A (CsA) was started with a second course of rituximab and IVIG without response, even though repeat bone marrow biopsy did not reveal morphology correlated to an acquired pure red cell aplasia (APRCA). Considering the similarity in his clinical and laboratory findings to APRCA, alemtuzumab was added (three doses over a week) with CsA followed by steroids. The patient was eventually discharged transfusion-independent, with increasing hemoglobin (Hb) levels and normal platelet and leukocyte count. One year later he is still disease-free with functioning graft. PMID:25177510

  7. Inflammatory Bowel Disease Affects the Outcome of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection.

    PubMed

    Khoruts, Alexander; Rank, Kevin M; Newman, Krista M; Viskocil, Kimberly; Vaughn, Byron P; Hamilton, Matthew J; Sadowsky, Michael J

    2016-10-01

    A significant fraction of patients with recurrent Clostridium difficile infections (CDI) have inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) can break the cycle of CDI recurrence and can be performed without evaluation of the colon. We evaluated the efficacy of colonoscopic FMT in patients with and without IBD, and whether we could identify IBD in patients during this procedure. We collected clinical meta-data and colonoscopy results from 272 consecutive patients that underwent FMT for recurrent CDI at the University of Minnesota from 2008 through 2015. Patients had at least 2 spontaneous relapses of CDI following their initial episode and did not clear the infection after 1 extended antibiotic regimen. We collected random mucosal biopsies from patients' right colons to identify lymphocytic or collagenous colitis during the FMT procedure. Failure or success in clearing CDI was determined within or at 2 months after the FMT. Of patients undergoing FMT, 15% had established IBD and 2.6% were found to have IBD during the FMT procedure. A single colonoscopic FMT cleared CDI from 74.4% of patients with IBD and 92.1% of patients without IBD (P = .0018). Patients had similar responses to FMT regardless of immunosuppressive therapy. More than one-quarter of patients with IBD (25.6%) had a clinically significant flare of IBD after FMT. Lymphocytic colitis was documented in 7.4% of patients with endoscopically normal colon mucosa; only 3 of these patients (20%) required additional treatment for colitis after clearance of CDI. Based on an analysis of 272 patients, FMT is somewhat less effective in clearing recurrent CDI from patients with IBD, compared with patients without IBD, regardless of immunosuppressive therapy. More than 25% of patients with IBD have a disease flare following FMT. Lymphocytic colitis did not affect the outcome of FMT, but a small fraction of these patients required pharmacologic treatment after the procedure. Copyright

  8. Any Future for Fecal Microbiota Transplantation as Treatment Strategy for Inflammatory Bowel Diseases?

    PubMed

    Kump, Patrizia; Högenauer, Christoph

    Fecal microbiota transplantation (FMT) is a novel therapeutic procedure aiming at restoring a normal intestinal microbiota by application of fecal microorganisms from a healthy subject into the gastrointestinal tract of a patient. FMT is the most effective treatment for recurrent Clostridium difficile infections (CDI). These infections also occur in patients with inflammatory bowel diseases (IBDs), where case series demonstrated a successful treatment of CDI by FMT in 83-92% of patients. The effect of FMT on the activity of IBD has mainly been investigated in ulcerative colitis (UC) patients, including 3 randomized controlled trials. So far, 2 randomized controlled trials showed a superiority of FMT compared to placebo in inducing remission in UC, while 1 study found no significant difference to placebo. The variation in response to FMT between these studies as well as in the uncontrolled trials might be explained by many differences in the way of FMT application, patient pretreatment and patient and donor selection. The data for the use of FMT in Crohn's disease and pouchitis are sparse; currently, no conclusion can be drawn regarding the effectiveness of FMT in these indications. It needs to be noted that cases of IBD activation after FMT have been reported. So far, FMT can only be recommended to be used for the treatment of concomitant CDI in IBD in clinical practice. For treating IBD irrespective of CDI, FMT should be only used in clinical trials. Current forms of FMT, especially protocols using repeated application, are very time and personnel consuming. Future trends are the use of defined stable microbiota preparations, in particular oral preparations, which will enable better and larger controlled trails for investigating FMT in IBD. © 2016 S. Karger AG, Basel.

  9. Fecal microbiota transplantation as therapy for inflammatory bowel disease: a systematic review and meta-analysis.

    PubMed

    Colman, Ruben J; Rubin, David T

    2014-12-01

    Fecal microbiota transplantation (FMT) has gained interest as a novel treatment option for inflammatory bowel diseases (IBD). While publications describing FMT as therapy for IBD have more than doubled since 2012, research that investigates FMT treatment efficacy has been scarce. We conducted a systematic review and meta-analysis to evaluate the efficacy of FMT as treatment for patients with IBD. A systematic literature search was performed through May 2014. Inclusion criteria required FMT as the primary therapeutic agent. Clinical remission (CR) and/or mucosal healing were defined as primary outcomes. Studies were excluded if they did not report clinical outcomes or included patients with infections. Eighteen studies (9 cohort studies, 8 case studies and 1 randomized controlled trial) were included. 122 patients were described (79 ulcerative colitis (UC); 39 Crohn's disease (CD); 4 IBD unclassified). Overall, 45% (54/119) of patients achieved CR during follow-up. Among the cohort studies, the pooled proportion of patients that achieved CR was 36.2% (95% CI 17.4%-60.4%), with a moderate risk of heterogeneity (Cochran's Q, P=0.011; I(2)=37%). Subgroup analyses demonstrated a pooled estimate of clinical remission of 22% (95% CI 10.4%-40.8%) for UC (P=0.37; I(2)=0%) and 60.5% (95% CI 28.4%-85.6%) for CD (P=0.05; I(2)=37%). Six studies performed microbiota analysis. This analysis suggests that FMT is a safe, but variably efficacious treatment for IBD. More randomized controlled trials are needed and should investigate frequency of FMT administration, donor selection and standardization of microbiome analysis. Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  10. Fecal Microbiota Transplantation as Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

    PubMed Central

    Colman, Ruben J.; Rubin, David T.

    2014-01-01

    Background and aims Fecal microbiota transplantation (FMT) has gained interest as a novel treatment option for inflammatory bowel diseases (IBD). While publications describing FMT as therapy for IBD have more than doubled since 2012, research that investigates FMT treatment efficacy has been scarce. We conducted a systematic review and meta-analysis to evaluate the efficacy of FMT as treatment for patients with IBD. Methods A systematic literature search was performed through May 2014. Inclusion criteria required FMT as primary therapeutic agent. Clinical remission (CR) and/or mucosal healing were defined as primary outcomes. Studies were excluded if they did not report clinical outcomes or included patients with infections. Results Eighteen studies (9 cohort studies, 8 case studies and 1 randomized controlled trial) were included in the analysis. 122 patients were described (79 ulcerative colitis (UC); 39 Crohn's disease (CD); 4 IBD unclassified). Overall, 45% (54/119) of patients achieved CR during follow up. Among cohort studies, the pooled proportion of patients that achieved CR was 36.2% (95% CI 17.4%-60.4%), with a moderate risk of heterogeneity (Cochran's Q, P=0.011; I2 = 37%). Subgroup analyses demonstrated a pooled estimate of clinical remission of 22% (95% CI 10.4%-40.8%) for UC (Cochran's Q, P=0.37; I2 =0%) and 60.5% (95% CI 28.4%-85.6%) for CD (Cochran's Q, P=0.05; I2 = 37%). Six studies performed microbiota analysis. Conclusions This analysis suggests that FMT is a safe, but variably efficacious treatment for IBD. More randomized controlled trials are needed and should investigate frequency of FMT administration, donor selection and standardization of microbiome analysis. PMID:25223604

  11. [An experimental model of hepatointestinal transplant in the pig with clinical applications].

    PubMed

    López Santamaría, M; Gámez, M; Murcia, J; Bueno, J; Paz, J A; Canser, E; Reinoso, F; Muñoz, J; Lobato, R; Martínez, L; de Miguel, E; Polanco, I; Jara, P; Tovar, J

    1996-10-01

    A model of experimental hepatointestinal transplant in pigs, with clinical applications is presented. Ten animals received a graft composed by the liver and the full length of the small bowel. Two pigs died during the transplant and in eight the surgical procedure was well tolerated with a good revascularization of the grafts. The coagulation parameters were normal after the transplant and only minor biochemical disturbances were found. The main difficulties of the surgical technique are related with the poor tolerance of the pig to the portal and caval clamping, and the close relationships of the duodenum, pancreas and distal colon, produced by the 360 degrees anti-clockwise bowel rotation around the mesenteric vessels. Clamping the supraceliac aorta during the implant of the graft keeps the animal hemodynamically stable and makes unnecessary the use of the more complicated veno venous shunt.

  12. Acellular dermal matrix provides a good option for abdominal wall closure following small bowel transplantation: a case report.

    PubMed

    Asham, E; Uknis, M E; Rastellini, C; Elias, G; Cicalese, L

    2006-01-01

    Following small bowel transplantation (SBTx), approximating the midline abdominal fascia can be problematic in patients with severely retracted abdominal cavities. We first report the use of acellular dermal matrix (ADM) for abdominal closure following living related SBTx. A 44-year-old woman with ultra-short gut syndrome secondary to multiple bowel resections received a 160-cm segmental intestinal graft from her daughter. The graft ileocolic vessels were anastomosed end to side to the inferior vena cava and distal aorta. A terminal ileostomy was fashioned because the patient had previous panproctocolectomy. The graft perfused well, and the laparotomy was primarily closed. On postoperative day 1, the patient required surgical exploration for evacuation of hematoma. Due to graft edema in a significantly retracted abdominal cavity, a 12x7 cm fascia defect was evident. Leaving the abdomen open or using a mesh was not entertained as options due to the high risk of infections. Primary closure under tension would also jeopardize the transplant, increasing the risk of thrombosis. The fascia defect was closed using a segment of ADM. The patient did well and went home on the postoperative day 11. At 2-year follow-up she is well and on oral diet without fascia defect or incisional hernia. This is the first report of the use of ADM for abdominal closure in patients receiving a SBTx. ADM is considered safe when used in contaminated sites and can allow primary closure of difficult wounds often seen in SBTx patients.

  13. Nutritional Issues in the Short Bowel Syndrome - Total Parenteral Nutrition, Enteral Nutrition and the Role of Transplantation.

    PubMed

    O'Keefe, Stephen J D

    2015-01-01

    In this review, I focus on the extreme of the short bowel syndrome where the loss of intestine is so great that patients cannot survive without intravenous feeding. This condition is termed short bowel intestinal failure. The review outlines the principles behind diagnosis, assessing prognosis and management. The advent of intravenous feeding (parenteral nutrition) in the 1970s enabled patients with massive (>90%) bowel resection to survive for the first time and to be rehabilitated back into normal life. To achieve this, central venous catheters were inserted preferably into the superior vena cava and intravenous infusions were given overnight so that the catheter could be sealed by day in order to maximize ambulation and social integration. However, quality of life has suffered by the association of serious complications related to permanent catheterization - mostly in the form of septicemias, thrombosis, metabolic intolerance and liver failure - from the unphysiological route of nutrient delivery. This has led to intense research into restoring gut function. In addition to dietary modifications and therapeutic suppression of motility, novel approaches have been aimed at enhancing the natural adaptation process, first with recombinant growth hormone and more recently with gut-specific glucagon-like peptide-2 analogues, e.g. teduglutide. These approaches have met with some success, reducing the intravenous caloric needs by approximately 500 kcal/day. In controlled clinical trials, teduglutide has been shown to permit >20% reductions in intravenous requirements in over 60% of patients after 6 months of treatment. Some patients have been weaned, but more have been able to drop infusion days. The only approach that predictably can get patients with massive intestinal loss completely off parenteral nutrition is small bowel transplantation, which, if successful (1-year survival for graft and host >90%) is accompanied by dramatic improvements in quality of life.

  14. [Plasma citrulline concentration as a biomarker of intestinal function in short bowel syndrome and in intestinal transplant].

    PubMed

    Vecino López, R; Andrés Moreno, A M; Ramos Boluda, E; Martinez-Ojinaga Nodal, E; Hernanz Macías, A; Prieto Bozano, G; Lopez Santamaria, M; Tovar Larrucea, J A

    2013-10-01

    Citrulline is a non-essential amino acid produced solely in the enterocyte. The aim of this study was to analyse the role of serum citrulline as a biomarker of enterocyte load in children with intestinal failure due to short bowel syndrome (SBS) and its relationship to enteral adaptation. Plasma citrulline concentration was determined by chromatography (normal value>15 μmol/L) in 57 patients (age 0.5-18 years) admitted to our Intestinal Rehabilitation Unit with intestinal failure. Those who were dehydrated, with renal insufficiency, or other conditions able to modify the results were excluded. Patients were divided into 4 groups: group i: SBS totally dependent on parenteral nutrition (PN); group ii: SBS under mixed enteral-parenteral nutrition; group iii: IF weaned from PN after a rehabilitation period; group iv: small bowel transplanted patients weaned from PN and taking a normal diet. The mean ± SD plasma citrulline values were: group i (n=15): 7.1 ± 4.1; group ii (n=11): 15.8 ± 8.9; group iii (n=13): 20.6 ± 7.5; group iv (n=25): 28.8 ± 10.1. Values were significantly lower in group i in comparison with groups ii-iii-iv (P<.001), and in group ii in comparison with groups iii-iv (P<.001). A low citrulline was associated with remnant small bowel length (P<.001, r=0.85). In group iv citrulline levels decreased >50% in 3 patients who developed moderate-severe rejection, and in one patient who developed viral enteritis. 1. Plasma citrulline could be a sensitive and specific biomarker of the residual functional enterocyte load. 2. It is related to enteral feeding tolerance. 3. Its prognostic value in the process of intestinal adaptation and as a rejection marker in small bowel transplanted patients needs to be confirmed. Copyright © 2012 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  15. Rabbit trochlear model of osteochondral allograft transplantation.

    PubMed

    To, Nhat; Curtiss, Shane; Neu, Corey P; Salgado, Christopher J; Jamali, Amir A

    2011-10-01

    Allografting and autografting of osteochondral tissues is a promising strategy to treat articular cartilage lesions in damaged joints. We developed a new model of fresh osteochondral allografting using the entire rabbit trochlea. The objective of the current study was to demonstrate that this model would achieve reproducible graft-host healing and maintain normal articular cartilage histologic, immunolocalization, and biochemical characteristics after transplantation under diverse storage and transplantation conditions. New Zealand white (n = 8) and Dutch belted (n = 8) rabbits underwent a 2-stage transplantation operation using osteochondral grafts that had been stored for 2 or 4 wk. Trochlear grafts harvested from the left knee were transplanted to the right knee as either autografts or allografts. Grafts were fixed with 22-gauge steel wire or 3-0 nylon suture. Rabbits were euthanized for evaluation at 1, 2, 4, 6, and 12 wk after transplantation. All grafts that remained in vivo for at least 4 wk demonstrated 100% interface healing by microCT. Trabecular bridging was present at the host-graft interface starting at 2 wk after transplantation, with no significant difference in cartilage histology between the various groups. The combined histology scores indicated minimal evidence of osteoarthritis. Immunostaining revealed that superficial zone protein was localized at the surface of all transplants. The rabbit trochlear model met our criteria for a successful model in regard to the ease of the procedure, low rate of surgical complications, relatively large articular cartilage surface area, and amount of host-graft bone interface available for analysis.

  16. Humanized Mice as Preclinical Models in Transplantation.

    PubMed

    Safinia, N; Becker, P D; Vaikunthanathan, T; Xiao, F; Lechler, R; Lombardi, G

    2016-01-01

    Animal models have been instrumental in our understanding of the mechanisms of rejection and the testing of novel treatment options in the context of transplantation. We have now entered an exciting era with research on humanized mice driving advances in translational studies and in our understanding of the function of human cells in response to pathogens and cancer as well as the recognition of human allogeneic tissues in vivo. In this chapter we provide a historical overview of humanized mouse models of transplantation to date, outlining the distinct strains and share our experiences in the study of human transplantation immunology.

  17. [Cadaveric kidney transplantation: a model with limitations].

    PubMed

    Vilardell Bergadà, Jordi

    2005-01-01

    The first successful kidney transplant in Spain was performed in 1965. It's been forty years already and currently Spain is the country with the highest cadaver donation rates worldwide. The so-called Spanish model of transplantation is well known for its organization and excellent results. These results are the consequence of a perfect network organization. Furthermore, the organ procurement organization--Organización Nacional de Trasplantes--, regional coordinators, national health system hospital network, hospital transplant coordinators, and all professionals involved in the process of donation and transplantation have perfectly well defined functions and work with the common objective of optimizing resources and making the most of the opportunities. Provided that one of the main characteristics of the Spanish model is the possibility of adaptation to the moments necessities, we proceed to review and evaluate it from its beginning to current days.

  18. Transplant arteriosclerosis in a rat aortic model.

    PubMed Central

    Isik, F. F.; McDonald, T. O.; Ferguson, M.; Yamanaka, E.; Gordon, D.

    1992-01-01

    Transplant arteriosclerosis (TA) has emerged as an obstacle to the long-term survival of transplanted organs, especially cardiac transplants. The animal models that have been used to study TA have not been fully characterized with regard to features such as the time course of cell proliferation and the sequence of cell types arriving in the developing intimal lesion. We present a model of TA based on a transplanted segment of abdominal aorta that helps address these questions. Two strains of rats (PVG x DA) underwent orthotopic aortic transplantation without immunosuppression and were killed at 14, 20, 40, and 60 days after transplantation. The within-strain control group displayed minimal evidence of cellular rejection with minimal to absent intimal lesions. In contrast, the allograft group showed a linearly increasing intimal lesion, up through 60 days after transplantation. The mechanism of intimal thickening was by an increase in cell number at the earlier time points with the later deposition of extracellular matrix. The early intimal lesion consisted mostly of mononuclear inflammatory cells (45%) with gradually increasing presence of smooth muscle cells (SMC) in the intima between 20 and 60 days. Conversely, the media showed gradual infiltration by macrophage-type cells with virtual loss of all SMC from the media by 40 days. The proliferative index showed a peak of 6% and 8% at 20 days in both the intima and media, respectively, and was preceded by the presence of macrophages. In fact, most of the proliferating cells at the earlier time points were either monocytes/macrophages, or were immediately adjacent to monocyte-/macrophage-rich regions. This straight artery segment model of transplant arteriosclerosis provides an easily quantifiable system in which the effects of different interventions (e.g., immunosuppressive regimens) can be tested. Images Figure 2 Figure 3 Figure 6 Figure 7 Figure 8 Figure 9 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure

  19. Spontaneous and transgenic rodent models of inflammatory bowel disease

    PubMed Central

    Jurjus, Abdo

    2015-01-01

    Inflammatory Bowel Disease (IBD) is a multifactorial disorder with many different putative influences mediating disease onset, severity, progression and diminution. Spontaneous natural IBD is classically expressed as Crohn's Disease (CD) and Ulcerative Colitis (UC) commonly found in primates; lymphoplasmocytic enteritis, eosinophilic gastritis and colitis, and ulcerative colitis with neuronal hyperplasia in dogs; and colitis in horses. Spontaneous inflammatory bowel disease has been noted in a number of rodent models which differ in genetic strain background, induced mutation, microbiota influences and immunopathogenic pathways. Histological lesions in Crohn's Disease feature noncaseating granulomatous inflammation while UC lesions typically exhibit ulceration, lamina propria inflammatory infiltrates and lack of granuloma development. Intestinal inflammation caused by CD and UC is also associated with increased incidence of intestinal neoplasia. Transgenic murine models have determined underlying etiological influences and appropriate therapeutic targets in IBD. This literature review will discuss current opinion and findings in spontaneous IBD, highlight selected transgenic rodent models of IBD and discuss their respective pathogenic mechanisms. It is very important to provide accommodation of induced putative deficits in activities of daily living and to assess discomfort and pain levels in the face of significant morbidity and/or mortality in these models. Epigenetic, environmental (microbiome, metabolome) and nutritional factors are important in IBD pathogenesis, and evaluating ways in which they influence disease expression represent potential investigative approaches with the greatest potential for new discoveries. PMID:26155200

  20. Genetically Engineered Mouse Models for Studying Inflammatory Bowel Disease

    PubMed Central

    Mizoguchi, Atsushi; Takeuchi, Takahito; Himuro, Hidetomo; Okada, Toshiyuki; Mizoguchi, Emiko

    2015-01-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation. PMID:26387641

  1. Non-invasive algorithm for bowel motility estimation using a back-propagation neural network model of bowel sounds

    PubMed Central

    2011-01-01

    Background Radiological scoring methods such as colon transit time (CTT) have been widely used for the assessment of bowel motility. However, these radiograph-based methods need cumbersome radiological instruments and their frequent exposure to radiation. Therefore, a non-invasive estimation algorithm of bowel motility, based on a back-propagation neural network (BPNN) model of bowel sounds (BS) obtained by an auscultation, was devised. Methods Twelve healthy males (age: 24.8 ± 2.7 years) and 6 patients with spinal cord injury (6 males, age: 55.3 ± 7.1 years) were examined. BS signals generated during the digestive process were recorded from 3 colonic segments (ascending, descending and sigmoid colon), and then, the acoustical features (jitter and shimmer) of the individual BS segment were obtained. Only 6 features (J1, 3, J3, 3, S1, 2, S2, 1, S2, 2, S3, 2), which are highly correlated to the CTTs measured by the conventional method, were used as the features of the input vector for the BPNN. Results As a results, both the jitters and shimmers of the normal subjects were relatively higher than those of the patients, whereas the CTTs of the normal subjects were relatively lower than those of the patients (p < 0.01). Also, through k-fold cross validation, the correlation coefficient and mean average error between the CTTs measured by a conventional radiograph and the values estimated by our algorithm were 0.89 and 10.6 hours, respectively. Conclusions The jitter and shimmer of the BS signals generated during the peristalsis could be clinically useful for the discriminative parameters of bowel motility. Also, the devised algorithm showed good potential for the continuous monitoring and estimation of bowel motility, instead of conventional radiography, and thus, it could be used as a complementary tool for the non-invasive measurement of bowel motility. PMID:21831291

  2. Non-invasive algorithm for bowel motility estimation using a back-propagation neural network model of bowel sounds.

    PubMed

    Kim, Keo-Sik; Seo, Jeong-Hwan; Song, Chul-Gyu

    2011-08-10

    Radiological scoring methods such as colon transit time (CTT) have been widely used for the assessment of bowel motility. However, these radiograph-based methods need cumbersome radiological instruments and their frequent exposure to radiation. Therefore, a non-invasive estimation algorithm of bowel motility, based on a back-propagation neural network (BPNN) model of bowel sounds (BS) obtained by an auscultation, was devised. Twelve healthy males (age: 24.8 ± 2.7 years) and 6 patients with spinal cord injury (6 males, age: 55.3 ± 7.1 years) were examined. BS signals generated during the digestive process were recorded from 3 colonic segments (ascending, descending and sigmoid colon), and then, the acoustical features (jitter and shimmer) of the individual BS segment were obtained. Only 6 features (J1, 3, J3, 3, S1, 2, S2, 1, S2, 2, S3, 2), which are highly correlated to the CTTs measured by the conventional method, were used as the features of the input vector for the BPNN. As a results, both the jitters and shimmers of the normal subjects were relatively higher than those of the patients, whereas the CTTs of the normal subjects were relatively lower than those of the patients (p < 0.01). Also, through k-fold cross validation, the correlation coefficient and mean average error between the CTTs measured by a conventional radiograph and the values estimated by our algorithm were 0.89 and 10.6 hours, respectively. The jitter and shimmer of the BS signals generated during the peristalsis could be clinically useful for the discriminative parameters of bowel motility. Also, the devised algorithm showed good potential for the continuous monitoring and estimation of bowel motility, instead of conventional radiography, and thus, it could be used as a complementary tool for the non-invasive measurement of bowel motility.

  3. Solid Organ Transplantation in Patients with Inflammatory Bowel Diseases (IBD): Analysis of Transplantation Outcome and IBD Activity in a Large Single Center Cohort

    PubMed Central

    Schnitzler, Fabian; Friedrich, Matthias; Stallhofer, Johannes; Schönermarck, Ulf; Fischereder, Michael; Habicht, Antje; Karbalai, Nazanin; Wolf, Christiane; Angelberger, Marianne; Olszak, Torsten; Beigel, Florian; Tillack, Cornelia; Göke, Burkhard; Zachoval, Reinhart; Denk, Gerald; Guba, Markus; Rust, Christian; Grüner, Norbert; Brand, Stephan

    2015-01-01

    Background Currently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort. Methods Clinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment. Results 4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn’s disease (CD) underwent SOT (p = 2.69 x 10−6, UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26–84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%). Conclusions SOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated. PMID:26288187

  4. Incidence of bloodstream infections in small bowel transplant recipients receiving selective decontamination of the digestive tract: A single-center experience

    PubMed Central

    Galloway, David; Danziger-Isakov, Lara; Goldschmidt, Monique; Hemmelgarn, Trina; Courter, Joshua; Nathan, Jaimie D.; Alonso, Maria; Tiao, Greg; Fei, Lin; Kocoshis, Samuel

    2016-01-01

    Pediatric patients undergoing small bowel transplantation are susceptible to postoperative CLABSI. SDD directed against enteric microbes is a strategy for reducing CLABSI. We hypothesized that SDD reduces the frequency of CLABSI, infections outside the bloodstream, and allograft rejection during the first 30 days following transplant. A retrospective chart review of 38 pediatric small bowel transplant recipients at CCHMC from 2003 to 2011 was conducted. SDD antimicrobials were oral colistin, tobramycin, and amphotericin B. The incidence of CLABSI, infections outside the bloodstream, and rejection episodes were compared between study periods. The incidence of CLABSI did not difier between study periods (6.9 CLABSI vs. 4.6 CLABSI per 1000 catheter days; p = 0.727), but gram positives and Candida predominated in the first 30 days. Incidence of bacterial infections outside the bloodstream did not differ (p = 0.227). Rejection occurred more frequently during the first month following transplant (p = 0.302). SDD does not alter the incidence of CLABSI, bacterial infections outside the bloodstream, or allograft rejection in the immediate 30 days post-transplantation. However, SDD does influence CLABSI organism types (favoring gram positives and Candida) and Candidal infections outside the bloodstream. PMID:26332092

  5. Chronic rejection after combined liver and small bowel transplantation in a child with chronic intestinal pseudo-obstruction: a case report.

    PubMed

    Giovanelli, M; Gupte, G L; Sharif, K; Mayer, D A; Mirza, D F

    2008-06-01

    An 11-year-old boy with irreversible intestinal failure secondary to chronic intestinal pseudo-obstruction (CIPO) and intestinal failure-associated liver disease (IFALD) underwent a combined en bloc reduced liver and small bowel transplantation. He was discharged home after 9 weeks on full oral intake without requiring intravenous nutritional or fluid supplementation. The first episode of mild acute rejection, which occurred 18 months after transplantation, was successfully treated with steroids. An episode of rotavirus gastroenteritis led to severe exfoliative rejection of the bowel graft, which was resistant to steroid and Infliximab treatment but responded to OKT3. There was associated Epstein-Barr virus viremia with no evidence of posttransplant lymphoproliferative disease. Another episode of moderate to severe acute liver rejection occurred 5 months later. At the same time, multiple biliary strictures were diagnosed and treated. Persistent clinical symptoms of abdominal pain and increased stomal output as well as atrophy of the ileal mucosa on several biopsies, suggested the possibility of chronic rejection (CR). A second combined whole liver and small bowel transplant was performed. The diagnosis of CR was confirmed on histology of the explanted graft. The postoperative course was severely complicated and 71 days after the retransplantation, the boy died because of respiratory failure and multiorgan failure. In summary, intestinal transplantation can be successfully performed in children with CIPO, giving them the opportunity to be free from total parenteral nutrition. As survival following intestinal transplantation continues to improve, the problem of CR has become increasingly important and the only treatment available is retransplantation, which is associated with poor outcomes.

  6. [Research of modified rat laryngeal transplantation model].

    PubMed

    Li, Hao; Peng, Han-wei; Zeng, Zong-yuan; Guo, Zhu-ming

    2006-07-01

    To study modified rat laryngeal transplantation model. Eighty isogeneic histocompatible F344 rats were randomized into control and experimental groups. Strome model of laryngeal transplantation was established in the the control group, and in the experimental group, the ascending pharyngeal artery was preserved and the base of the tongue, larynx and pharyngolarynx were harvested as a complex allograft followed by end-to-end anastomosis of the both allograft common carotid arteries with the recipient common carotid artery and the anterior jugular vein, respectively. The arterial and nenous patency rate and allograft viability rate were compared between the two groups. The artery and vein patency rates and graft survival rate were 30%, 15%, and 30% in the control group, and 75%, 65%, and 80% in the experimental group, respectively, showing significant difference between the two groups (P<0.05). In modified rat laryngeal transplantation model, the allograft viability rate and vessel patency rate are improved, which provides a good model for immunological study of larynx transplantation.

  7. Inflammatory bowel disease as a model for translating the microbiome

    PubMed Central

    Huttenhower, Curtis; Kostic, Aleksandar D.; Xavier, Ramnik J.

    2014-01-01

    The inflammatory bowel diseases (IBD) are among the most closely studied chronic inflammatory disorders that involve environmental, host genetic, and commensal microbial factors. This combination of features has made IBD both an appropriate and a high-priority platform for translatable research in host-microbiome interactions. Decades of epidemiology have identified environmental risk factors, although most mechanisms of action remain unexplained. The genetic architecture of IBD has been carefully dissected in multiple large populations, identifying several responsible host epithelial and immune pathways but without yet a complete systems-level explanation. Most recently, the commensal gut microbiota have been found to be both ecologically and functionally perturbed during the disease, but with as-yet-unexplained heterogeneity among IBD subtypes and individual patients. IBD thus represents perhaps the most comprehensive current model for understanding the human microbiome’s role in complex inflammatory disease. Here, we review the influences of the microbiota on IBD and its potential for translational medicine. PMID:24950204

  8. Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice.

    PubMed

    De Palma, Giada; Lynch, Michael D J; Lu, Jun; Dang, Vi T; Deng, Yikang; Jury, Jennifer; Umeh, Genevieve; Miranda, Pedro M; Pigrau Pastor, Marc; Sidani, Sacha; Pinto-Sanchez, Maria Ines; Philip, Vivek; McLean, Peter G; Hagelsieb, Moreno-Gabriel; Surette, Michael G; Bergonzelli, Gabriela E; Verdu, Elena F; Britz-McKibbin, Philip; Neufeld, Josh D; Collins, Stephen M; Bercik, Premysl

    2017-03-01

    Irritable bowel syndrome (IBS) is a common disorder characterized by altered gut function and often is accompanied by comorbid anxiety. Although changes in the gut microbiota have been documented, their relevance to the clinical expression of IBS is unknown. To evaluate a functional role for commensal gut bacteria in IBS, we colonized germ-free mice with the fecal microbiota from healthy control individuals or IBS patients with diarrhea (IBS-D), with or without anxiety, and monitored gut function and behavior in the transplanted mice. Microbiota profiles in recipient mice clustered according to the microbiota profiles of the human donors. Mice receiving the IBS-D fecal microbiota showed a taxonomically similar microbial composition to that of mice receiving the healthy control fecal microbiota. However, IBS-D mice showed different serum metabolomic profiles. Mice receiving the IBS-D fecal microbiota, but not the healthy control fecal microbiota, exhibited faster gastrointestinal transit, intestinal barrier dysfunction, innate immune activation, and anxiety-like behavior. These results indicate the potential of the gut microbiota to contribute to both intestinal and behavioral manifestations of IBS-D and suggest the potential value of microbiota-directed therapies in IBS patients.

  9. Serial transverse enteroplasty enhances intestinal function in a model of short bowel syndrome.

    PubMed

    Chang, Robert W; Javid, Patrick J; Oh, Jung-Tak; Andreoli, Steven; Kim, Heung Bae; Fauza, Dario; Jaksic, Tom

    2006-02-01

    OBJECTIVE/SUMMARY BACKGROUND DATA: Serial transverse enteroplasty (STEP) is a new intestinal lengthening procedure that has been shown to clinically increase bowel length. This study examined the impact of the STEP procedure upon intestinal function in a model of short bowel syndrome. Young pigs (n=10) had a reversed segment of bowel interposed to induce bowel dilatation. Five pigs underwent a 90% bowel resection with a STEP procedure on the remaining dilated bowel while 5 served as controls and had a 90% bowel resection without a STEP procedure. Determinations of nutritional status, absorptive capacity, and bacterial overgrowth were conducted 6 weeks after resection. Statistical comparisons were made by 2-sample t test (significance at P<0.05). The STEP procedure lengthened the bowel from 105.2+/-7.7 cm to 152.2+/-8.3 cm (P<0.01). The STEP animals showed improved weight retention compared with controls (mean, -0.5%+/-1.8% body weight versus -17.6%+/-1.5%, P<0.001). Intestinal carbohydrate absorption, as measured by d-Xylose absorption and fat absorptive capacity as measured by serum vitamin D and triglyceride levels, were increased in the STEP group versus controls. Serum citrulline, a marker of intestinal mucosal mass, was significantly elevated in the STEP pigs compared with controls. None of the STEP animals but 4 of 5 control animals were noted to have gram-negative bacterial overgrowth in the proximal bowel. STEP improves weight retention, nutritional status, intestinal absorptive capacity, and serum citrulline levels in a porcine short bowel model. A salutary effect upon bacterial overgrowth was also noted. These data support the use of this operation in short bowel syndrome.

  10. Serial Transverse Enteroplasty Enhances Intestinal Function in a Model of Short Bowel Syndrome

    PubMed Central

    Chang, Robert W.; Javid, Patrick J.; Oh, Jung-Tak; Andreoli, Steven; Kim, Heung Bae; Fauza, Dario; Jaksic, Tom

    2006-01-01

    Objective/Summary Background Data: Serial transverse enteroplasty (STEP) is a new intestinal lengthening procedure that has been shown to clinically increase bowel length. This study examined the impact of the STEP procedure upon intestinal function in a model of short bowel syndrome. Methods: Young pigs (n = 10) had a reversed segment of bowel interposed to induce bowel dilatation. Five pigs underwent a 90% bowel resection with a STEP procedure on the remaining dilated bowel while 5 served as controls and had a 90% bowel resection without a STEP procedure. Determinations of nutritional status, absorptive capacity, and bacterial overgrowth were conducted 6 weeks after resection. Statistical comparisons were made by 2-sample t test (significance at P < 0.05). Results: The STEP procedure lengthened the bowel from 105.2 ± 7.7 cm to 152.2 ± 8.3 cm (P < 0.01). The STEP animals showed improved weight retention compared with controls (mean, −0.5% ± 1.8% body weight versus −17.6% ± 1.5%, P < 0.001). Intestinal carbohydrate absorption, as measured by d-Xylose absorption and fat absorptive capacity as measured by serum vitamin D and triglyceride levels, were increased in the STEP group versus controls. Serum citrulline, a marker of intestinal mucosal mass, was significantly elevated in the STEP pigs compared with controls. None of the STEP animals but 4 of 5 control animals were noted to have gram-negative bacterial overgrowth in the proximal bowel. Conclusions: STEP improves weight retention, nutritional status, intestinal absorptive capacity, and serum citrulline levels in a porcine short bowel model. A salutary effect upon bacterial overgrowth was also noted. These data support the use of this operation in short bowel syndrome. PMID:16432355

  11. Emerging Piglet Models of Neonatal Short Bowel Syndrome.

    PubMed

    Lim, David W; Turner, Justine M; Wales, Paul W

    2015-08-01

    Short bowel syndrome (SBS) is a growing problem in the human neonatal population. In infants, SBS is the leading cause of intestinal failure, the state of being unable to absorb sufficient nutrients for growth and development. Neonates with SBS are dependent on long-term parenteral nutrition therapy, but many succumb to the complications of sepsis and liver disease. Research in neonatal SBS is challenged by the ethical limits of studying sick human neonates and the heterogeneous nature of the disease process. Outcomes in SBS vary depending on residual intestinal anatomy, intestinal length, patient age, and exposure to nutrition therapies. The neonatal piglet serves as an appropriate translational model of the human neonate because of similarities in gastrointestinal ontogeny, physiological maturity, and adaptive processes. Re-creating the disease process in a piglet model presents a unique opportunity for researchers to discover novel insights and therapies in SBS. Emerging piglet models of neonatal SBS now represent the entire spectrum of disease seen in human infants. This review aims to contextualize these emerging piglet models within the context of SBS as a heterogeneous disease. We first explore the factors that account for SBS heterogeneity and then explore the suitability of the neonatal piglet as an appropriate translational animal model. We then examine differences between the emerging piglet models of neonatal SBS and how these differences affect their translational potential to human neonates with SBS.

  12. Pattern of growth after pediatric living-donor small bowel transplantation.

    PubMed

    Porubsky, Marian; Testa, Giuliano; John, Eunice; Holterman, Mark; Tsou, Marc; Benedetti, Enrico

    2006-09-01

    The aim of our study was to analyze growth in children who underwent LDSB. The question was whether these children obtain linear growth and improvement of the Z-score for height and weight after the transplant. Three children with a mean age of 24 months underwent living-donor intestinal transplantation with 150 cm of terminal ileum. At a mean follow-up of 27 months height increased from 82.5 to 97.5 cm although Z-score for height did not improve, -2.679 to -2.675. Mean weight increased from 11.4 to 14.2 kg while Z-score for weight went from -1.916 to -2.409. Although these data are pertinent to only three children and the follow-up is slightly longer than two yr, it appears that while long-term survival and independency from TPN is achieved, only linear growth might be expected and catch-up growth does not occur.

  13. Mouse Models of Bone Marrow Transplantation

    PubMed Central

    Reddy, Pavan; Negrin, Robert; Hill, Geoffrey R.

    2010-01-01

    Over the last 50 years, mouse models of bone marrow transplantation have provided the critical links between graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) pathophysiology and clinical practice. The initial insight from mouse models that GVHD and GVL were T cell dependent has long been confirmed clinically. More recent translations from mouse models have included the important role of inflammatory cytokines in GVHD. Newly developed concepts relating to the ability of antigen presenting cell (APC) and T cell subsets to mediate GVHD now promise significant clinical advances. The ability to use knockout and transgenic approaches to dissect mechanisms of GVHD and GVL mean that mouse systems will continue as the predominant preclinical platform. The basic transplant approach in these models, coupled with modern “real-time” immunologic imaging of GVHD and GVL is discussed. PMID:18162233

  14. Intestinal permeability and bacterial translocation following small bowel transplantation in the rat

    SciTech Connect

    Grant, D.; Hurlbut, D.; Zhong, R.; Wang, P.Z.; Chen, H.F.; Garcia, B.; Behme, R.; Stiller, C.; Duff, J. )

    1991-08-01

    In addition to its role in absorbing nutrients, the intestinal mucosa provides an important barrier against toxins and bacteria in the bowel lumen. The present study evaluated gut barrier function following orthotopic (in continuity) intestinal grafting in rats. Graft histology, intestinal permeability, and bacterial translocation to the grafted mesenteric lymph nodes, the host's liver, and the host's spleen were assessed on the 3rd, 5th, and 7th postoperative days. The study group received no immunosuppression after allotransplantation. The two control groups included rats with isografts and rats with cyclosporine-treated allografts. On the 7th POD, the study animals had moderate transmural inflammation due to rejection, with normal histology in the isografts and CsA-treated allografts; increased intestinal permeability, measured by urinary excretion of oral 51Cr-EDTA (P less than 0.01); and increased number of bacteria in the MLN and spleen (P less than 0.05). The number of bacteria in the MLN and spleen of the study group positively correlated with the changes in intestinal permeability (P less than 0.05). Rejection of the orthotopic intestinal graft leads to increased intestinal permeability and bacterial translocation from the lumen of the graft to the host's reticuloendothelial system. Measures to improve gut barrier function and antibiotic therapy during rejection episodes may help reduce the incidence of septic complications after intestinal grafting.

  15. The Mongolian gerbil as a model for inflammatory bowel disease

    PubMed Central

    Bleich, Eva-Maria; Martin, Myriam; Bleich, André; Klos, Andreas

    2010-01-01

    Mongolian gerbils are used as biomedical research models for a variety of diseases and are in some cases suited better than other rodents for basic research and therapeutic studies. The aim of this study was to establish and characterize a dextran sulphate sodium (DSS)-induced model in gerbils for the human inflammatory bowel disease (IBD) and to utilize them for a therapeutic study in vivo. Four concentrations (0.5%, 1%, 2% and 4%) of DSS were administered via drinking water for 7 days; based on these results, a concentration of 3% DSS was given for 9 days in a second approach. Fluid uptake and general clinical condition were assessed daily using a clinical score. Caecum and colon were scored histologically. Fluid uptake was affected by addition of DSS to the drinking water. First clinical symptoms were observed at day 4 of DSS treatment with a considerable increase in clinical score parameters only in gerbils receiving 2% or 4% DSS. Histologically, ulceration and inflammation were observed predominantly in the caecum of gerbils treated with at least 1% DSS; reproducible inflammation in the colon required at least 2% DSS. Using 3% DSS for 9 days, considerably more inflammation was induced in the colon, comparable with lesions usually observed in the mouse model. Using an optimized protocol, DSS treatment induces reproducibly typhlocolitis in Mongolian gerbils, rendering them as a useful model for IBD. PMID:20113376

  16. Validation of Donor-Specific Tolerance of Intestinal Transplant by a Secondary Heart Transplantation Model.

    PubMed

    Pengcheng, Wang; Xiaosong, Li; Xiaofeng, Li; Zhongzhi, Li

    2017-02-01

    It is well accepted that survival after a second organ transplant without immunosuppressive agents indicates tolerance for the first transplant. To validate donor-specific tolerance, we established a rat model with a secondary heart transplant after intestinal transplant, which has so far not been described in the literature. We transplanted intestine from Fischer F344 rats to Lewis rats orthotopically. Lewis rats received tacrolimus pretreatment before transplant and a 14-day course of rapamycin 1 month after transplant. At 120 days after primary intestinal transplant, hearts from 6 F344 rats (group A) or 6 Brown Norway rats (group B) were transplanted to Lewis rats that had survived intestinal transplant and without additional immunosuppressive agents. We analyzed survival data, histologic changes, cells positive for the ED1 macrophage marker in transplanted hearts, and 3 lymphocyte levels in both groups. Thirty days after secondary heart transplant, group A hearts were continuously beating; however, group B hearts stopped beating at around 10 days after transplant (8.5 ± 1.5 d; P < .05). Our histologic study showed that both groups had muscle damage and cellular infiltration in hearts that were distinctly different from normal hearts, with ED1-positive cells counted in both groups (85 ± 16 in group A, 116 ± 28 in group B; P > .05). Fluorescence-activated cell sorting showed that CD4/CD25-positive regulatory T cell, CTLA4/CD4/CD25-positive regulatory T cell, and Natural killer T-cell levels were significantly higher level in group A versus B (P < .05). The donor-specific tolerance that we observed was possibly a state of "clinical tolerance" rather than "immunologic tolerance." Our rat model is a feasible and reliable model to study donor-specific tolerance. The higher levels of lymphocytic T cells shown in intestinal transplant recipients were associated with longer allograft survival, possibly contributing to donor-specific tolerance.

  17. The Iranian model of living renal transplantation.

    PubMed

    Mahdavi-Mazdeh, Mitra

    2012-09-01

    Organ shortage for transplantation remains a worldwide serious problem for kidney patients with end-stage renal failure, and several countries have tried different models to address this issue. Iran has 20 years of experience with one such model that involves the active role of the government and charity foundations. Patients with a desperate demand for a kidney have given rise to a black market of brokers and other forms of organ commercialism only accessible to those with sufficient financial resources. The current Iranian model has enabled most of the Iranian kidney transplant candidates, irrespective of socioeconomic class, to have access to kidney transplantation. The Iranian government has committed a large budget through funding hospital and staff at the Ministry of Health and Medical Education by supporting the brain death donation (BDD) program or redirecting part of the budget of living unrelated renal donation (LURD) to the BDD program. It has been shown that it did not prevent the development and progression of a BDD program. However, the LURD program is characterized by several controversial procedures (e.g., confrontation of donor and recipient at the end of the evaluation procedure along with some financial interactions) that should be ethically reviewed. Operational weaknesses such as the lack of a registration system and long-term follow-up of the donors are identified as the 'Achilles heel of the model'.

  18. A mouse model of in utero transplantation.

    PubMed

    Nijagal, Amar; Le, Tom; Wegorzewska, Marta; Mackenzie, Tippi C

    2011-01-27

    The transplantation of stem cells and viruses in utero has tremendous potential for treating congenital disorders in the human fetus. For example, in utero transplantation (IUT) of hematopoietic stem cells has been used to successfully treat patients with severe combined immunodeficiency. In several other conditions, however, IUT has been attempted without success. Given these mixed results, the availability of an efficient non-human model to study the biological sequelae of stem cell transplantation and gene therapy is critical to advance this field. We and others have used the mouse model of IUT to study factors affecting successful engraftment of in utero transplanted hematopoietic stem cells in both wild-type mice and those with genetic diseases. The fetal environment also offers considerable advantages for the success of in utero gene therapy. For example, the delivery of adenoviral, adeno-associated viral, retroviral, and lentiviral vectors into the fetus has resulted in the transduction of multiple organs distant from the site of injection with long-term gene expression. in utero gene therapy may therefore be considered as a possible treatment strategy for single gene disorders such as muscular dystrophy or cystic fibrosis. Another potential advantage of IUT is the ability to induce immune tolerance to a specific antigen. As seen in mice with hemophilia, the introduction of Factor IX early in development results in tolerance to this protein. In addition to its use in investigating potential human therapies, the mouse model of IUT can be a powerful tool to study basic questions in developmental and stem cell biology. For example, one can deliver various small molecules to induce or inhibit specific gene expression at defined gestational stages and manipulate developmental pathways. The impact of these alterations can be assessed at various timepoints after the initial transplantation. Furthermore, one can transplant pluripotent or lineage specific progenitor

  19. Transplant tourism and the Iranian model of renal transplantation program: ethical considerations.

    PubMed

    Ghods, Ahad J; Nasrollahzadeh, Dariush

    2005-12-01

    Currently, the buying and selling of kidneys through "transplant tourism" is occurring at an increasing rate, both in developed and developing countries. Since 1988, Iran has adopted a compensated and regulated living-unrelated donor renal transplant program, and by providing financial incentives to volunteer living donors, has eliminated the renal transplant waiting list. In the Iranian model of renal transplantation program, regulations have been put in place to prevent transplant tourism. Foreigners are not allowed to undergo renal transplantation from Iranian living-unrelated donors. They also are not permitted to volunteer as kidney donors for Iranian patients. A study at the transplant unit of Hashemi Nejad Kidney Hospital in Tehran, Iran, showed that of 1881 renal transplant recipients, 19 (1%) were Afghani or Iraqi refugees, 11 (0.6%) were other foreign nationals, and 18 (0.9%) were Iranian immigrants. Renal transplantations seemed ethically acceptable to all refugees and foreign nationals. However, transplantation of Iranian immigrants who had been residing abroad for years constituted true transplant tourism.

  20. The gut microbiota in mouse models of inflammatory bowel disease

    PubMed Central

    Gkouskou, Kalliopi K.; Deligianni, Chrysoula; Tsatsanis, Christos; Eliopoulos, Aristides G.

    2014-01-01

    The intestine and the intestinal immune system have evolved through a symbiotic homeostasis under which a highly diverse microbial flora is maintained in the gastrointestinal tract while pathogenic bacteria are recognized and eliminated. Disruption of the balance between the immune system and the gut microbiota results in the development of multiple pathologies in humans. Inflammatory bowel diseases (IBD) have been associated with alterations in the composition of intestinal flora but whether these changes are causal or result of inflammation is still under dispute. Various chemical and genetic models of IBD have been developed and utilized to elucidate the complex relationship between intestinal epithelium, immune system and the gut microbiota. In this review we describe some of the most commonly used mouse models of colitis and Crohn's disease (CD) and summarize the current knowledge of how changes in microbiota composition may affect intestinal disease pathogenesis. The pursuit of gut-microbiota interactions will no doubt continue to provide invaluable insight into the complex biology of IBD. PMID:24616886

  1. Functional changes in nonadrenergic, noncholinergic inhibitory neurons in ileal circular smooth muscle after small bowel transplantation in rats.

    PubMed

    Shibata, C; Balsiger, B M; Anding, W J; Duenes, J A; Miller, V M; Sarr, M G

    1998-11-01

    This experiment was designed to determine mechanisms of change in nonadrenergic, noncholinergic (NANC) inhibitory neurons in the ileum after small bowel transplantation (SBT) in the rat and whether nitric oxide (NO) serves as an important NANC inhibitory neurotransmitter in the rat ileum. Eight groups of rats (N > or =8 rats/group) were studied: neurally intact unoperated controls; rats one week after anesthesia and sham celiotomy; and separate groups one and eight weeks after either 40 min of cold ischemia of the jejunoileum, combined jejunal and ileal intestinal transection/reanastomosis, or orthotopic SBT of the entire jejunoileum. Contractile activity was evaluated in full-thickness ileal circular muscle strips under isometric conditions. Spontaneous activity did not differ among groups. In all groups, exogenous NO, NG-monomethyl-L-arginine (L-NMMA, an NO synthase inhibitor), and methylene blue (soluble guanylate cyclase inhibitor) had no effect on spontaneous activity, while 8-bromocyclic guanosine monophosphate (8Br-cGMP) inhibited contractile activity in all groups. Low frequency (2-10 Hz) electrical field stimulation (EFS) inhibited contractile activity only in control and SBT groups; L-NMMA and methylene blue did not alter the response to EFS in any group. These results suggest that each aspect of the SBT procedure, ischemia/reperfusion injury, disruption of enteric neural continuity by intestinal transection, and extrinsic denervation, alter function of enteric ileal inhibitory neurons separately early (one week) after operation. NO, a known inhibitory neurotransmitter in other gut regions, does not affect ileal circular muscle in neurally intact tissue nor mediate functional changes in inhibitory nerve function nor smooth muscle contractility after SBT.

  2. Changes in microbial ecology after fecal microbiota transplantation for recurrent C. difficile infection affected by underlying inflammatory bowel disease.

    PubMed

    Khanna, Sahil; Vazquez-Baeza, Yoshiki; González, Antonio; Weiss, Sophie; Schmidt, Bradley; Muñiz-Pedrogo, David A; Rainey, John F; Kammer, Patricia; Nelson, Heidi; Sadowsky, Michael; Khoruts, Alexander; Farrugia, Stefan L; Knight, Rob; Pardi, Darrell S; Kashyap, Purna C

    2017-05-15

    Gut microbiota play a key role in maintaining homeostasis in the human gut. Alterations in the gut microbial ecosystem predispose to Clostridium difficile infection (CDI) and gut inflammatory disorders such as inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) from a healthy donor can restore gut microbial diversity and pathogen colonization resistance; consequently, it is now being investigated for its ability to improve inflammatory gut conditions such as IBD. In this study, we investigated changes in gut microbiota following FMT in 38 patients with CDI with or without underlying IBD. There was a significant change in gut microbial composition towards the donor microbiota and an overall increase in microbial diversity consistent with previous studies after FMT. FMT was successful in treating CDI using a diverse set of donors, and varying degrees of donor stool engraftment suggesting that donor type and degree of engraftment are not drivers of a successful FMT treatment of CDI. However, patients with underlying IBD experienced an increased number of CDI relapses (during a 24-month follow-up) and a decreased growth of new taxa, as compared to the subjects without IBD. Moreover, the need for IBD therapy did not change following FMT. These results underscore the importance of the existing gut microbial landscape as a decisive factor to successfully treat CDI and potentially for improvement of the underlying pathophysiology in IBD. FMT leads to a significant change in microbial diversity in patients with recurrent CDI and complete resolution of symptoms. Stool donor type (related or unrelated) and degree of engraftment are not the key for successful treatment of CDI by FMT. However, CDI patients with IBD have higher proportion of the original community after FMT and lack of improvement of their IBD symptoms and increased episodes of CDI on long-term follow-up.

  3. Cost Effectiveness of Screening Colonoscopy Depends on Adequate Bowel Preparation Rates – A Modeling Study

    PubMed Central

    Kingsley, James; Karanth, Siddharth; Revere, Frances Lee

    2016-01-01

    Background Inadequate bowel preparation during screening colonoscopy necessitates repeating colonoscopy. Studies suggest inadequate bowel preparation rates of 20–60%. This increases the cost of colonoscopy for our society. Aim The aim of this study is to determine the impact of inadequate bowel preparation rate on the cost effectiveness of colonoscopy compared to other screening strategies for colorectal cancer (CRC). Methods A microsimulation model of CRC screening strategies for the general population at average risk for CRC. The strategies include fecal immunochemistry test (FIT) every year, colonoscopy every ten years, sigmoidoscopy every five years, or stool DNA test every 3 years. The screening could be performed at private practice offices, outpatient hospitals, and ambulatory surgical centers. Results At the current assumed inadequate bowel preparation rate of 25%, the cost of colonoscopy as a screening strategy is above society’s willingness to pay (<$50,000/QALY). Threshold analysis demonstrated that an inadequate bowel preparation rate of 13% or less is necessary before colonoscopy is considered more cost effective than FIT. At inadequate bowel preparation rates of 25%, colonoscopy is still more cost effective compared to sigmoidoscopy and stool DNA test. Sensitivity analysis of all inputs adjusted by ±10% showed incremental cost effectiveness ratio values were influenced most by the specificity, adherence, and sensitivity of FIT and colonoscopy. Conclusions Screening colonoscopy is not a cost effective strategy when compared with fecal immunochemical test, as long as the inadequate bowel preparation rate is greater than 13%. PMID:27936028

  4. Sildenafil normalizes bowel transit in preclinical models of constipation

    PubMed Central

    Sharman, Sarah K.; Islam, Bianca N.; Hou, Yali; Usry, Margaux; Bridges, Allison; Singh, Nagendra; Sridhar, Subbaramiah; Rao, Satish

    2017-01-01

    Guanylyl cyclase-C (GC-C) agonists increase cGMP levels in the intestinal epithelium to promote secretion. This process underlies the utility of exogenous GC-C agonists such as linaclotide for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Because GC-C agonists have limited use in pediatric patients, there is a need for alternative cGMP-elevating agents that are effective in the intestine. The present study aimed to determine whether the PDE-5 inhibitor sildenafil has similar effects as linaclotide on preclinical models of constipation. Oral administration of sildenafil caused increased cGMP levels in mouse intestinal epithelium demonstrating that blocking cGMP-breakdown is an alternative approach to increase cGMP in the gut. Both linaclotide and sildenafil reduced proliferation and increased differentiation in colon mucosa, indicating common target pathways. The homeostatic effects of cGMP required gut turnover since maximal effects were observed after 3 days of treatment. Neither linaclotide nor sildenafil treatment affected intestinal transit or water content of fecal pellets in healthy mice. To test the effectiveness of cGMP elevation in a functional motility disorder model, mice were treated with dextran sulfate sodium (DSS) to induce colitis and were allowed to recover for several weeks. The recovered animals exhibited slower transit, but increased fecal water content. An acute dose of sildenafil was able to normalize transit and fecal water content in the DSS-recovery animal model, and also in loperamide-induced constipation. The higher fecal water content in the recovered animals was due to a compromised epithelial barrier, which was normalized by sildenafil treatment. Taken together our results show that sildenafil can have similar effects as linaclotide on the intestine, and may have therapeutic benefit to patients with CIC, IBS-C, and post-infectious IBS. PMID:28448580

  5. The microbiota and inflammatory bowel disease: insights from animal models.

    PubMed

    Peloquin, Joanna M; Nguyen, Deanna D

    2013-12-01

    Inflammatory bowel disease (IBD) is thought to result from a dysregulated immune response to intestinal microbial flora in individuals with genetic predisposition(s). Genome-wide association studies (GWAS) in human IBD have identified more than 150 associated loci, some of which are key players in innate immunity and bacterial handling, reflecting the importance of the microbiota in disease pathogenesis. In fact, the presence of a microbial flora is not only crucial to the development of a normal murine immune system but also critical for the development of disease in the majority of animal models of IBD. Although animal models do not perfectly recapitulate human IBD, they have led to the discovery of important concepts in IBD pathogenesis, such as the central role of microbiota in disease development and perpetuation. Many genetically susceptible models do not develop colitis when raised in a germ-free or Helicobacter-free environment. In fact, disease in most models can be attenuated or completely abolished with antibiotic treatment. Moreover, an interplay between intestinal microbiota and mucosal immune activation is suggested by the presence of serum antibodies against the Cbir1 flagellin, an immunodominant antigen that activates TLR5, in certain models of spontaneous colitis as well as in human patients. Furthermore, T cells reactive to Cbir1 are able to induce disease in recipient mice upon adoptive cell transfer, demonstrating the pro-inflammatory properties of certain bacterial products. In fact, it has been shown that transfer of certain intestinal bacteria from a specific genetically altered mouse model with spontaneous colitis can induce disease in wild-type mice upon co-housing or direct feeding. These observations demonstrate the pathogenic potential of intestinal microbiota in IBD. However, intestinal bacteria are not always maladaptive in mucosal homeostasis. Both Bacteroides fragilis and Clostridium species promote the number and function of a

  6. Early onset, EBV(-) PTLD in pediatric liver-small bowel transplantation recipients: a spectrum of plasma cell neoplasms with favorable prognosis.

    PubMed

    Perry, Anamarija M; Aoun, Patricia; Coulter, Donald W; Sanger, Warren G; Grant, Wendy J; Coccia, Peter F

    2013-02-21

    EBV(-) posttransplantation lymphoproliferative disorders (PTLDs) are rare compared with EBV(+) PTLDs, occur later after transplantation, and have a poor response to treatment. Few studies have reported EBV(-) PTLD in pediatric solid-organ transplantation recipients. We describe 5 cases of EBV(-) PTLD in recipients of combined liver and small bowel allografts ranging in age from 16 months to 7 years. EBV(-) PTLD developed 9-22 months (median, 15) after transplantation. Morphologically, the lesions ranged from atypical plasma cell hyperplasia (a term not currently included in the World Health Organization classification) to plasmacytoma like. In all cases, in situ hybridization for EBV was negative, and molecular studies demonstrated clonal IgH gene rearrangements. Protein electrophoresis showed multiple clonal paraproteins in 4 of 5 cases. In 2 cases with a donor-recipient sex mismatch, FISH cytogenetics demonstrated that the plasma cells were of mixed donor/recipient origin. One patient died before therapy. Four patients were treated with high-dose dexamethasone, and 1 patient subsequently required thalidomide. All 4 remain in remission 75-128 months (median, 86) after diagnosis. In contrast to reports of EBV(-) PTLD in adults, these plasma cell lesions occurred early after transplantation and resolved completely after minimal treatment.

  7. Early Diagnosis and Hematopoietic Stem Cell Transplantation for IL10R Deficiency Leading to Very Early-Onset Inflammatory Bowel Disease Are Essential in Familial Cases

    PubMed Central

    Aksu, Guzide; Ulusoy, Ezgi; Gozmen, Salih; Genel, Ferah; Akarcan, Sanem; Gulez, Nesrin; Hirschmugl, Tatjana; Kansoy, Savas; Boztug, Kaan

    2016-01-01

    Alterations of immune homeostasis in the gut may result in development of inflammatory bowel disease. A five-month-old girl was referred for recurrent respiratory and genitourinary tract infections, sepsis in neonatal period, chronic diarrhea, perianal abscess, rectovaginal fistula, and hyperemic skin lesions. She was born to second-degree consanguineous, healthy parents. Her elder siblings were lost at 4 months of age due to sepsis and 1 year of age due to inflammatory bowel disease, respectively. Absolute neutrophil and lymphocyte counts, immunoglobulin levels, and lymphocyte subsets were normal ruling out severe congenital neutropenia and classic severe combined immunodeficiencies. Quantitative determination of oxidative burst was normal, excluding chronic granulomatous disease. Colonoscopy revealed granulation, ulceration, and pseudopolyps, compatible with colitis. Very early-onset colitis and perianal disease leading to fistula formation suggested probability of inherited deficiencies of IL-10 or IL-10 receptor. A mutation at position c.G477A in exon of the IL10RB gene, resulting in a stop codon at position p.W159X, was identified. The patient underwent myeloablative hematopoietic stem cell transplantation from full matched father at 11 months of age. Perianal lesions, chronic diarrhea, and recurrent infections resolved after transplantation. IL-10/IL-10R deficiencies must be considered in patients with early-onset enterocolitis. PMID:27699073

  8. Long-term follow-up in adult living donors for combined liver/bowel transplant in pediatric recipients: a single center experience.

    PubMed

    Ghafari, Jamie L; Bhati, Chandra; John, Eunice; Tzvetanov, Ivo G; Testa, Giuliano; Jeon, Hoonbae; Oberholzer, Jose; Benedetti, Enrico

    2011-06-01

    Pediatric candidates for combined liver/bowel transplant (LBTx) experience a very high mortality on the cadaver waiting list. Our transplant center has successfully used adult living donors to treat pediatric candidates for LBTx. We report the long-term follow-up of this unique cohort of organ donors. The charts of six adult donors for LBTx performed between 2004 and 2007 were reviewed. All the pertinent clinical data were carefully reviewed and integrated with phone interviews of all donors. A total of six children (average age 13.5 months) received living donor LBTx. Average follow-up for the donors was 42 months (range 29-51). The donors' median age was 25 yr (19-32); five women and one man. The average median hospital stay was nine days. There were no peri-operative complications. At present all donors remain in good health. Three of the five mothers became pregnant after donation. Five of the six children are currently alive and well whereas one died with functioning grafts six months post-transplant due to plasmoblastic lymphoma. Living donor LBTx is an effective therapy for combined hepatic and intestinal failure in children less than five yr. The donor operation can be performed with minimal morbidity.

  9. Treatment of Infantile Inflammatory Bowel Disease and Autoimmunity by Allogeneic Stem Cell Transplantation in LPS-Responsive Beige-Like Anchor Deficiency

    PubMed Central

    Bakhtiar, Shahrzad; Gámez-Díaz, Laura; Jarisch, Andrea; Soerensen, Jan; Grimbacher, Bodo; Belohradsky, Bernd; Keller, Klaus-Michael; Rietschel, Christoph; Klingebiel, Thomas; Koletzko, Sibylle; Albert, Michael H.; Bader, Peter

    2017-01-01

    Inflammatory bowel disease (IBD) in young children can be a clinical manifestation of various primary immunodeficiency syndromes. Poor clinical outcome is associated with poor quality of life and high morbidity from the complications of prolonged immunosuppressive treatment and malabsorption. In 2012, mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene were identified as the cause of an autoimmunity and immunodeficiency syndrome. Since then, several LRBA-deficient patients have been reported with a broad spectrum of clinical manifestations without reliable predictive prognostic markers. Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been performed in a few severely affected patients with complete or partial response. Herein, we present a detailed course of the disease and the transplantation procedure used in a LRBA-deficient patient suffering primarily from infantile IBD with immune enteropathy since the age of 6 weeks, and progressive autoimmunity with major complications following long-term immunosuppressive treatment. At 12 years of age, alloHSCT using bone marrow of a fully matched sibling donor—a healthy heterozygous LRBA mutant carrier—was performed after conditioning with a reduced-intensity regimen. During the 6-year follow-up, we observed a complete remission of enteropathy, autoimmunity, and skin vitiligo, with complete donor chimerism. The genetic diagnosis of LRBA deficiency was made post-alloHSCT by detection of two compound heterozygous mutations, using targeted sequencing of DNA samples extracted from peripheral blood before the transplantation. PMID:28197149

  10. An alternative model of vascularized bone marrow transplant: partial femur transplantation.

    PubMed

    Chen, Jian-Wu; Chen, Chen; Su, Ying-Jun; Yan, Lun; Wang, Shi-Ping; Guo, Shu-Zhong

    2014-12-01

    The vascularized whole femur transplantation model is one of the commonly used vascularized bone marrow transplant models. It involves technical complexity and morbidities. To optimize this model, we took 2/3 femur as the carrier of bone marrow cells, and developed a vascularized partial femur model. Four experimental groups were carried out, namely, the syngeneic partial femur transplantation, allogeneic partial femur transplantation with or without cyclosporine A, and allogeneic whole femur transplantation with cyclosporine A. The results showed that the partial femur model was technically simpler and shortened the operative and ischemia time compared to the whole femur model. Gross and histologic appearance confirmed the viability of femur, and its bone marrow inside the bone could also maintain normal morphologically at 60-day posttransplant. Besides, donor multilineage chimerism could be continuously detected in immunosuppressed allogeneic partial femur recipients at 1-, 2-, 3-, 4-, and 8-week posttransplant, and it showed no significant differences when compared with whole femur transplantation. Meanwhile, long-term engraftment of donor-origin cells was also confirmed in recipients' bone marrow, lymph nodes, and spleen, but not in thymus. Therefore, the vascularized partial femur can serve as a continuous resource of bone morrow cells and may provide a useful tool for the study of immune tolerance in vascularized composite allotransplantation.

  11. Donor chimera model for tolerance induction in transplantation.

    PubMed

    Rezaee, F; Peppelenbosch, M; Dashty, M

    2013-05-01

    Tolerance induction is the basis of a successful transplantation with the goal being the re-establishment of homeostasis after transplantation. Non-autograft transplantation disrupts this maintenance drastically which would be avoided by administration of a novel procedure. At present, the blood group antigens and the genotypes of the donor and recipient are cross-matched before transplantation combined with a drug regimen that confers general immunosuppression. But the 'specific' unresponsiveness of the recipient to the donor organ, implied by 'tolerance', is not achieved in this process. This article introduces the 'donor chimera model' via the concept of the 'closed transplantation loop' approach for tolerance induction which seeks to limit the use of immunosuppressive therapy after transplantation.

  12. Do iatrogenic serosal injuries result in small bowel perforation in a rabbit model?

    PubMed

    Tsai, M C; Candy, G; Costello, M A; Grieve, A D; Brand, M

    2017-06-01

    Surgical dogma dictates that serosal injuries should be repaired during laparotomy as these injuries may result in localised areas of bowel ischaemia and may perforate. No study has investigated whether there is a correlation between the extent of serosal injuries and the risk for perforation under normal physiological conditions. We hypothesized that small bowel serosal injuries do not result in early or late perforation at physiological intraluminal pressures regardless of their size. An in-vivo rabbit small bowel serosal injury model was developed and two experiments were conducted. The first - to determine whether and at which pressures various lengths and circumferences of serosal injuries in small bowel result in immediate bowel perforation - was performed infusing saline into isolated bowel segments with or without a variety of serosal injuries. In the second study - to determine whether or not serosal injuries result in delayed perforation - a range of injuries was created in rabbits and the effect assessed at re-laparotomy 5 days after the creation of the injury. No perforations were observed at the site of serosal injuries at physiological intraluminal pressures. Perforations occurred at 43.7+ 18.6 cmH₂O, 23.3+ 14.4 cmH₂O, and 24.4+ 23.9 cmH₂O for controls, 4 cm long and 100% circumference serosal injuries respectively (p-value = 0.18 for various lengths and 0.71 for various circumferences). No serosal injuries perforated within 72 or 120 hours after creation. Small bowel serosal injuries do not perforate or leak at physiological intraluminal pressures, either at the time of creation or up to 120 hours thereafter.

  13. A mouse model of orthotopic vascularized aerated lung transplantation.

    PubMed

    Okazaki, M; Krupnick, A S; Kornfeld, C G; Lai, J M; Ritter, J H; Richardson, S B; Huang, H J; Das, N A; Patterson, G A; Gelman, A E; Kreisel, D

    2007-06-01

    Outcomes after lung transplantation are markedly inferior to those after other solid organ transplants. A better understanding of cellular and molecular mechanisms contributing to lung graft injury will be critical to improve outcomes. Advances in this field have been hampered by the lack of a mouse model of lung transplantation. Here, we report a mouse model of vascularized aerated single lung transplantation utilizing cuff techniques. We show that syngeneic grafts have normal histological appearance with minimal infiltration of T lymphocytes. Allogeneic grafts show acute cellular rejection with infiltration of T lymphocytes and recipient-type antigen presenting cells. Our data show that we have developed a physiological model of lung transplantation in the mouse, which provides ample opportunity for the study of nonimmune and immune mechanisms that contribute to lung allograft injury.

  14. A new composite facial and scalp transplantation model in rats.

    PubMed

    Ulusal, Betul G; Ulusal, Ali E; Ozmen, Selahattin; Zins, James E; Siemionow, Maria Z

    2003-10-01

    There are limited sources of autogenous tissue available for reconstruction of severe facial and scalp deformities caused by extensive tumor ablation, burns, or trauma. Allografts from cadaveric sources may serve as a reconstructive alternative. However, technical and immunological aspects of harvesting and transplanting face and scalp flaps limit the routine use of such procedures. For evaluation of the feasibility of composite-tissue reconstruction, an experimental model of composite face/scalp flap transplantation in rats was designed. Technical aspects of the model, survival rates, and the complications encountered during development of the model are presented. A total of 64 animals, in three experimental groups, were studied. In group I, the anatomical study group (n = 6), the anatomical features of the face and scalp region in rats were explored. Groups II and III were the transplantation groups. Isograft transplantations were performed between identical Lewis rats (RT11 to RT11), and allografts were transplanted, across major histocompatibility complex barriers, between Lewis-Brown Norway rats (RT1l/n) and Lewis rats (RT11). In group II (the control group, n = 8), transplantation of nonvascularized composite face/scalp isografts and allografts was performed. In group III (the transplantation group, n = 50), vascularized face/scalp isografts (n = 36) and allografts (n = 14) were transplanted. Complications included partial or total flap necrosis, death attributable to food aspiration, and poor general condition. To prevent acute and chronic allograft rejection, cyclosporine A (16 mg/kg per day) therapy was initiated 24 hours after transplantation; the dose was tapered to 2 mg/kg per day within 4 weeks and was maintained at that level thereafter. Long-term survival (>170 days) was achieved, without any signs of rejection, with low-dose (2 mg/kg per day) cyclosporine A therapy. This is the first report documenting successful composite face/scalp flap

  15. Laryngeal transplantation in the setting of cancer: a rat model.

    PubMed

    Shipchandler, Taha Z; Lorenz, Robert R; Lee, Walter T; Teker, Aysenur Meric; Dan, Olivia; Strome, Marshall

    2008-12-01

    Traditional immunosuppressive regimens make laryngeal transplantation in cancer patients prohibitive because of the increased risk of recurrence. Everolimus, a recently developed immunosuppressant, has demonstrated significant antitumor properties. The purpose of this study was to examine the effects of everolimus alone and in combination with other immunosuppressants on tumor growth in a combined laryngeal transplantation and tumor model. Animal, prospective, randomized, controlled, and blinded. One million squamous cell carcinoma cells (SCC-158) were injected intravenously into a total of 40 rats 1 day before laryngeal transplantation. Rats were divided into four groups differing by immunosuppressive regimens. Lung surface metastases were counted 21 days after inoculation, and numerical transplantation rejection scores were recorded. A separate experiment for comparison was performed with no transplant on 24 rats, but with the same immunosuppressive treatment groups. The median number of lung surface metastases were: a) control (i.e., no immunosuppression): 85; b) everolimus 1.0 mg/kg: 25; c) tacrolimus 1.2 mg/kg: 1650; d) everolimus 1.0 mg/kg + tacrolimus 0.05 mg/kg: 1300. Rats receiving everolimus alone showed a statistically significant decrease in pulmonary surface metastases compared with the other groups. Transplanted rats had no difference in their outcomes when compared with non-transplanted rats. Everolimus significantly decreases SCC-158 growth in our combined transplantation and tumor model compared with controls and other immunosuppressants.

  16. Short bowel syndrome.

    PubMed

    Wilmore, D W; Robinson, M K

    2000-12-01

    The short bowel syndrome is a symptom complex that occurs in adults who have less than 200 cm of jejunum-ileum remaining after intestinal resection. Similar symptoms are observed in infants and children following massive bowel resection or congenital anomalies and in individuals with longer segments of intestine with severe mucosal disease. Initial care should focus on a thorough excision of nonviable bowel, an exact measurement of the remaining viable bowel, placing all intestine in continuity at the initial or subsequent operation, and controlling initial food intake. With time, adaptation of the remnant intestine occurs, and absorptive function may be maximized by enhancing the enteral diet and minimizing parenteral nutrition. Growth factors and specialized nutrients may also enhance this process. Intestinal transplantation should be considered in selected individuals with the short bowel syndrome who fail intestinal rehabilitation protocols.

  17. Difficulties, guidelines and review of developing an acute rejection model after rat intestinal transplantation.

    PubMed

    Andres, Ane Miren; Santamaria, Monica; Hernandez-Oliveros, Francisco; Guerra, Laura; Lopez, Sergio; Stringa, Pablo; Vallejo, Maria Teresa; Largo, Carlota; Encinas, Jose Luis; Garcia de Las Heras, Maria Soledad; Lopez-Santamaria, Manuel; Tovar, Juan Antonio

    2016-05-01

    Experimental small bowel transplantation (SBT) in rats has been proven to be a useful tool for the study of ischemia-reperfusion and immunological aspects related to solid organ transplantation. However, the model is not completely refined, specialized literature is scarce and complex technical details are typically omitted or confusing. Most studies related to acute rejection (AR) use the orthotopic standard, with small sample sizes due to its high mortality, whereas those studying chronic rejection (CR) use the heterotopic standard, which allows longer term survival but does not exactly reflect the human clinical scenario. Various animal strains have been used, and the type of rejection and the timing of its analysis differ among authors. The double purpose of this study was to develop an improved unusual AR model of SBT using the heterotopic technique, and to elaborate a guide useful to implement experimental models for studying AR. We analyzed the model's technical details and expected difficulties in overcoming the learning curve for such a complex microsurgical model, identifying the potential problem areas and providing a step-by-step protocol and reference guide for future surgeons interested in the topic. We also discuss the historic and more recent options in the literature.

  18. Afghan refugees in Iran model renal transplantation program: ethical considerations.

    PubMed

    Ghods, A J; Nasrollahzadeh, D; Kazemeini, M

    2005-03-01

    During 23 years of civil war in Afghanistan, there has been a continuous flow of more than 5 million refugees out of the country. Iran has hosted about 40% of all refugees. The majority have resided outside of camps with opportunities to integrate locally, having access to the Iranian labor market and government services, such as dialysis and transplantation. Iran also has adopted a compensated living unrelated donor renal transplantation program in which foreigners can receive transplants from living related donors or volunteer living unrelated donors of the same nationality. In June 2004, among 241 refugees with end-stage kidney disease in Iran, 179 were on hemodialysis and 62 underwent renal transplantation. Nine patients received kidneys from living related donors, 1 from a spouse, 50 from Afghani living unrelated donors, and 1 from a cadaveric donor. No refugee had been used as a kidney donor to an Iranian patient. Transplantation of all Afghan refugees in need and the absence of their use as kidney donors to Iranian patients proffer strong evidence against commercialism and a reason to believe that the Iran Model transplantation is practiced with ethical standards. In the last 2 years since the civil war has ended, returning these patients to Afghanistan has raised important ethical concerns. Repatriation of dialysis patients and transplant recipients may be tantamount to their deaths. It is expected that The Transplantation Society and the World Health Organization will establish links with the United Nations High Commissioner for Refugee Offices to provide humanitarian assistance to these patients.

  19. Transplantation of Pulmonary Valve Using a Mouse Model of Heterotopic Heart Transplantation

    PubMed Central

    Lee, Yong-Ung; Yi, Tai; James, Iyore; Tara, Shuhei; Stuber, Alexander J.; Shah, Kejal V.; Lee, Avione Y.; Sugiura, Tadahisa; Hibino, Narutoshi; Shinoka, Toshiharu; Breuer, Christopher K.

    2014-01-01

    Tissue engineered heart valves, especially decellularized valves, are starting to gain momentum in clinical use of reconstructive surgery with mixed results. However, the cellular and molecular mechanisms of the neotissue development, valve thickening, and stenosis development are not researched extensively. To answer the above questions, we developed a murine heterotopic heart valve transplantation model. A heart valve was harvested from a valve donor mouse and transplanted to a heart donor mouse. The heart with a new valve was transplanted heterotopically to a recipient mouse. The transplanted heart showed its own heartbeat, independent of the recipient’s heartbeat. The blood flow was quantified using a high frequency ultrasound system with a pulsed wave Doppler. The flow through the implanted pulmonary valve showed forward flow with minimal regurgitation and the peak flow was close to 100 mm/sec. This murine model of heart valve transplantation is highly versatile, so it can be modified and adapted to provide different hemodynamic environments and/or can be used with various transgenic mice to study neotissue development in a tissue engineered heart valve. PMID:25079013

  20. Development of a Vascularized Heterotopic Neonatal Rat Heart Transplantation Model.

    PubMed

    Shimada, Shogo; Del Nido, Pedro J; Friehs, Ingeborg

    2016-01-01

    Rodent adult-to-adult heterotopic heart transplantation is a well-established animal model, and the detailed surgical technique with several modifications has been previously described. In immature donor organ transplantation, however, the surgical technique needs to be revised given the smaller size and fragility of the donor graft. Here, we report our surgical technique for heterotopic abdominal (AHTx) and femoral (FHTx) neonatal rat heart transplantation based on an experience of over 300 cases. Heterotopic heart transplantation was conducted in syngeneic Lewis rats. Neonatal rats (postnatal day 2-4) served as donors. AHTx was performed by utilizing the conventional adult-to-adult transplant method with specific modifications for optimal aortotomy and venous anastomosis. In the FHTx, the donor heart was vascularized by connecting the donor's aorta and pulmonary artery to the recipient's right femoral artery and vein, respectively, in an end-to-end manner. A specifically fashioned butterfly-shaped rubber sheet was used to align the target vessels properly. The transplanted graft was visually assessed for its viability and was accepted as a technical success when the viability met specific criteria. Successfully transplanted grafts were subject to further postoperative evaluation. Forty cases (AHTx and FHTx; n = 20 each) were compared regarding perioperative parameters and outcomes. Both models were technically feasible (success rate: AHTx 75% vs. FHTx 70%) by refining the conventional heterotopic transplant technique. Injury to the fragile donor aorta and congestion of the graft due to suboptimal venous connection were predominant causes of failure, leading to refractory bleeding and poor graft viability. Although the FHTx required significantly longer operation time and graft ischemic time, the in situ graft viabilities were comparable. The FHTx provided better postoperative monitoring as it enabled daily graft palpation and better echocardiographic

  1. Mouse Models in Bone Marrow Transplantation and Adoptive Cellular Therapy

    PubMed Central

    Arber, Caroline; Brenner, Malcolm K.; Reddy, Pavan

    2014-01-01

    Mouse models of transplantation have been indispensable to the development of bone marrow transplantation (BMT). Their role in the generation of basic science knowledge is invaluable and is subject to discussion below. However, this article focuses on the direct role and relevance of mouse models towards the clinical development and advances in BMT and adoptive T-cell therapy for human diseases. The authors aim to present a thoughtful perspective on the pros and cons of mouse models while noting that despite imperfections these models are obligatory for the development of science-based medicine. PMID:24216170

  2. A Pre-Clinical Canine Model for Composite Tissue Transplantation

    PubMed Central

    Mathes, David W.; Noland, Marie; Graves, Scott; Schlenker, Robert; Miwongtum, Tiffany; Storb, Rainer

    2010-01-01

    The feasibility of composite tissue allografts (CTA) has been demonstrated by the successful transplantation of the hand, abdomen and face. However, the survival of these transplants is dependent on immunosupression. Our laboratory is interested in achieving tolerance in order to decrease the risks associated with the use of chronic immunosuppression. The purpose of this experiment was to develop a large animal model for CTA. Four canine flaps were auto-transplanted to examine the use of a myocutaneous rectus flap based on the deep inferior epigastric vessels. Five CTA transplants were performed between Dog Leukocyte Antigen (DLA) identical littermates without any therapy. The allografts were followed clinically and underwent routine biopsies. The anatomic dissections and auto-transplants were all successful and revealed that the flap could be divided into two separate components. Skin is routinely perfused by the superficial epigastric artery. Rectus muscle is perfused by the deep inferior epigastrc system. This allows the allografts to be transplanted as muscle, skin or with both components based on the external iliac artery and veins. The DLA-identical littermates rejected the allografts in 15 to 30 days. This study demonstrates the versatility of the myocutaneous rectus flap for use in canines as composite tissue allograft models. PMID:20108180

  3. Testing the Efficacy of Contrast-Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation.

    PubMed

    Fischer, K; Ohori, S; Meral, F C; Uehara, M; Giannini, S; Ichimura, T; Smith, R N; Jolesz, F A; Guleria, I; Zhang, Y; White, P J; McDannold, N J; Hoffmeister, K; Givertz, M M; Abdi, R

    2016-12-23

    One of the key unmet needs to improve long-term outcomes of heart transplantation is to develop accurate, noninvasive, and practical diagnostic tools to detect transplant rejection. Early intragraft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in microvascular perfusion (MP) of cardiac transplants using contrast-enhanced ultrasonography (CEUS). The efficacy of CEUS in detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MP was demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, and 92% on days 4, 6, and 8 posttransplantation, respectively) and chronic rejection (33%, 33%, and 92% on days 5, 14, and 30 posttransplantation, respectively). Our perfusion studies showed restoration of MP following antirejection therapy, highlighting its potential to help monitor efficacy of antirejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MP decline observed in the allografts. High-resolution MP mapping may allow for noninvasive detection of heart transplant rejection. The data presented have the potential to help in the development of next-generation imaging approaches to diagnose transplant rejection.

  4. Compensating the transplant professional: time for a model change.

    PubMed

    Abouljoud, M; Whitehouse, S; Langnas, A; Brown, K

    2015-03-01

    Compensation models for physicians are currently based primarily on the work relative value unit (wRVU) that rewards productivity by work volume. The value-based payment structure soon to be ushered in by the Centers for Medicare and Medicaid Services rewards clinical quality and outcomes. This has prompted changes in wRVU value for certain services that will result in reduced payment for specialty procedures such as transplantation. To maintain a stable and competent workforce and achieve alignment between clinical activity, growth imperatives, and cost effectiveness, compensation of transplant physicians must evolve toward a matrix of measures beyond the procedure-based activity. This personal viewpoint proposes a redesign of transplant physician compensation plans to include the "virtual RVU" to recognize and reward meaningful clinical integration defined as hospital-physician commitment to specified and measurable metrics for current non-RVU-producing activities. Transplantation has been a leader in public outcomes reporting and is well suited to meet the challenges ahead that can only be overcome with a tight collaboration and alignment between surgeons, other physicians, support staff, and their respective institution and leadership. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  5. Introduction of modified cervical cardiac transplant model in mice.

    PubMed

    Gong, Weihua; Thornley, Thomas; Whitcher, Gregory H; Ge, Fangmin; Yuan, Shunzong; Liu, Derek J; Balasubramanian, Savithri

    2012-04-01

    The murine cervical heterotopic heart transplant model was initially designed to test the immune response to third-party allografts, modified by cuff techniques. While cuff techniques simplify the execution of this procedure, cutting of the carotid artery and the external jugular vein alters the blood supply to central nervous system and makes it difficult to achieve long-term graft survival. In the present study, we describe modified techniques that preserve the continuity and function of blood vessels and improve transplant integrity. The modified techniques in this study comprise the following aspects: (1) Preservation of the sternal head of the right sternocleidomastoid muscle, (2) use of the donor's intrathoracic inferior vena cava for anastomosis and (3) preservation of the function of the recipient's carotid artery and external jugular vein and thus, continuity of blood flow to the central nervous system. Stable, long-term, disease-free allograft survival has been achieved with syngeneic transplants (> 200 days), whereas allografts from fully major histocompatibility complex-mismatched donors were acutely rejected in a time similar to the traditional abdominal heterotopic heart transplant model (8.2 ± 1.3 vs 8.4 ± 1.4 days; P = .73 in the Mantel Cox test, and P = .61 in the Gehan-Breslow-Wilcoxon test). Similar alloresponses could be induced in these 2 models. It is possible and feasible to achieve long-term graft survival in the mouse cervical heart transplant model using the modified procedures described in the present study.

  6. Integrated models of care in managing inflammatory bowel disease: a discussion.

    PubMed

    Mikocka-Walus, Antonina A; Andrews, Jane M; Bernstein, Charles N; Graff, Lesley A; Walker, John R; Spinelli, Antonino; Danese, Silvio; van der Woude, C Janneke; Goodhand, James; Rampton, David; Moser, Gabriele

    2012-08-01

    The World Health Organization has recommended the integrated model of care as the current best practice of care, and, in recent years, it has been gaining popularity worldwide in various settings. However, there have been very few reports on applications of this model to the care of patients with gastrointestinal problems and no reports in the case of inflammatory bowel disease (IBD). However, several IBD centres worldwide have been using the model as part of their standard care. This discussion paper aims to bring together these units' shared experiences with a range of integrated models of care in order to identify common features and provide recommendations on aspirational care for IBD patients.

  7. Contractile activity of circular smooth muscle in rats one year after small bowel transplantation: differing adaptive response of the jejunum and ileum to denervation.

    PubMed

    Shibata, C; Murr, M M; Balsiger, B; Anding, W J; Sarr, M G

    1998-01-01

    The aim of the present study was to determine the long-term effects of isogeneic small bowel transplantation (SBT) on jejunal and ileal circular smooth muscle contractile activity in the rat. Transmural strips of circular muscle were prepared from proximal jejunum and distal ileum of 1-year-old control rats and rats 1 year after SBT (SBT-1Y) to measure isometric force. Spontaneous contractile activity and the dose-responses to bethanechol and norepinephrine were studied. Electrical field stimulation (EFS) at varying frequencies (1 to 20 Hz) was evaluated under adrenergic and cholinergic blockade to investigate inhibitory nerves. Spontaneous activity both in the jejunum and ileum in SBT-1Y rats was not different compared to control rats. Sensitivity to bethanechol did not differ between control and SBT-1Y rats in the jejunum or ileum. Sensitivity to norepinephrine, however, was significantly increased after SBT in the ileum but not in the jejunum. During EFS, inhibition was seen at low frequencies, and contractions were induced at high frequencies in all groups. The degree of inhibition did not differ between control and SBT-1Y rats in the jejunum; however, it tended to be increased in the ileum after SBT. The long-term adaptive response of smooth muscle to the extrinsic denervation accompanying SBT differs between the jejunum and the ileum.

  8. A predictive model identifies patients most likely to have inadequate bowel preparation for colonoscopy.

    PubMed

    Hassan, Cesare; Fuccio, Lorenzo; Bruno, Mario; Pagano, Nico; Spada, Cristiano; Carrara, Silvia; Giordanino, Chiara; Rondonotti, Emanuele; Curcio, Gabriele; Dulbecco, Pietro; Fabbri, Carlo; Della Casa, Domenico; Maiero, Stefania; Simone, Adriana; Iacopini, Federico; Feliciangeli, Giuseppe; Manes, Gianpiero; Rinaldi, Antonio; Zullo, Angelo; Rogai, Francesca; Repici, Alessandro

    2012-05-01

    An inadequate level of bowel preparation can affect the efficacy and safety of colonoscopy. Although some factors have been associated with outcome, there is no strategy to identify patients at high risk for inadequate preparation. We searched for factors associated with an inadequate level of preparation and tested the validity of a predictive clinical rule based on these factors. We performed a prospective study of 2811 consecutive patients who underwent colonoscopy examinations at 18 medical centers; clinical and demographic data were collected before the colonoscopy. Bowel preparation was classified as adequate or inadequate; 925 patients (33%) were found to have inadequate preparation. Multivariate analysis was used to identify factors associated with inadequate preparation, which were expressed as odds ratio (OR) and used to build a predictive model. Factors associated with inadequate bowel preparation included being overweight (OR, 1.5), male sex (OR, 1.2), a high body mass index (OR, 1.1), older age (OR, 1.01), previous colorectal surgery (OR, 1.6), cirrhosis (OR, 5), Parkinson disease (OR, 3.2), diabetes (OR, 1.8), and positive results in a fecal occult test (OR, 0.6). These factors predicted which patients would have inadequate cleansing with 60% sensitivity, 59% specificity, 41% positive predictive value, and 76% negative predictive value; they had an under the receiver operating characteristic curve value of 0.63. Assuming 100% efficacy of a hypothetical regimen to address patients predicted to be at risk of inadequate preparation, the rate would decrease from 33% to 13%. We identified factors associated with inadequate bowel preparation for colonoscopy and used these to build an accurate predictive model. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

  9. The importance of large animal models in transplantation.

    PubMed

    Dehoux, Jean-Paul; Gianello, Pierre

    2007-09-01

    Animal models have been extensively used in transplantation research. However, animal experimentation is contentious and subject to legal and ethical restrictions. Most experiments are carried out on rodents, but crucial prerequisites for the development of safe pre-clinical protocols in biomedical research are needed through suitable large animal models. In transplantation particularly, large animal models have developed dramatically. This article provides an overview of the large animal models commonly used to evaluate organ transplant experiments and analyzes the specificity of several models in various situations such as induction of allospecific tolerance and xenotransplantation. The key determination that remains be addressed is the most appropriate species and strains to model human immune and physiological systems. Because of their phylogenetic and physiologic similarities to man, non-human primates play an increasingly important role in pre-clinical testing. Nevertheless, a number of studies have shown the pig to be a reliable large animal model for transplantation research, and the availability of genetically defined or modified pigs establishes a stronger position for pigs as a large animal model.

  10. A murine model of orthotopic periorbital subunit transplantation.

    PubMed

    Gao, Bowen; Li, Bin; Li, Xinxin; Bae, Jinhong; Xiao, Kaiyan; Li, Qingfeng; Zhu, Hainan

    2017-03-01

    Conventional reconstructive methods fail to achieve satisfactory results in total eyelid defect cases. Vascularized composite tissue allotransplantation might provide both good appearance and function for these patients. We developed an orthotopic periorbital transplantation model in rats to facilitate further experimentation in this field. In anatomical studies, the vascular distribution to and innervation of the periorbital unit were identified and recorded. Then, according to the anatomical studies, eight orthotopic transplantations and two transplantations with pedicle ligation were performed. The posterior facial vein and the external carotid artery were selected as the graft pedicles, while the temporal and upper zygomatic facial nerves were used for graft innervation. All transplanted eyelids were assessed daily. Micro-CT scanning and hematoxylin and eosin staining of the grafts were performed 60 days after the operation. In total, 90% of recipients tolerated the operation well. All grafts without pedicle ligation survived, and new hair growth was observed. The position of the eyelid was maintained, and eyelid function was partially restored. In the recipients with graft pedicle ligation, the grafts became necrotic and mummified within four to five days. Micro-CT of the surviving grafts showed a good blood supply, and histological staining revealed normal morphology. A periorbital subunit orthotopic transplantation model was established, which might facilitate future eyelid allotransplantation-related experimentation. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

  11. Model predictions of myoelectrical activity of the small bowel.

    PubMed

    Miftakhov, R N; Abdusheva, G R; Wingate, D L

    1996-02-01

    A mathematical model for the periodic electrical activity of a functional unit of the small intestine is developed. Based on real morphological and electrophysiological data, the model assumes that: the functional unit is an electromyogenic syncytium; the kinetics of L, T-type Ca2+, mixed Ca(2+)-dependent K+, potential sensitive K+ and Cl- channels determines electrical activity of the functional unit; the basic neural circuit, represented by a single cholinergic neurone, provides an excitatory input to the functional unit via receptor-linked L-type Ca2+ channels. Numerical simulation of the model has shown that it is capable of displaying the slow waves and that slight modifications of some of the parameters result in different electrical responses. The effects of the variations of the main parameters have been analyzed for their ability to reproduce various electrical patterns. The results are in good qualitative and quantitative agreement with results of experiments conducted on the small intestine.

  12. [Stromal cell transplant in the 6-OHDA lesion model].

    PubMed

    Pavón-Fuentes, N; Blanco-Lezcano, L; Martínez-Martín, L; Castillo-Díaz, L; de la Cuétara-Bernal, K; García-Miniet, R; Lorigados-Pedre, L; Coro-Grave de Peralta, Y; García-Varona, A Y; Rosillo-Martí, J C; Macías-González, R

    A good deal of evidence currently exists to show that transplanting foetal mesencephalic tissue can produce symptomatic benefits both in patients and in disease models. Nevertheless, the technical and ethical difficulties involved in obtaining enough suitable foetal cerebral tissue have been a serious obstacle to its application. Stromal cells derived from bone marrow, due to their potential capacity to generate different types of cells, could be an ideal source of material for cell restoration in neurodegenerative diseases. Our aim was to evaluate the effect of transplanting stromal cells derived from bone marrow on the behaviour of 6-OHDA rats, when they are inserted into the striatum. In this study we used rats with a lesion in the substantia nigra induced by 6-hydroxydopamine, divided into several experimental groups. Rotary activity induced by D-amphetamine (5 mg/kg, intraperitoneally) was evaluated before and throughout the three months following the transplant in all the experimental groups, except in the group of healthy controls. Hemiparkinsonian rats received a total of 350 000 foetal ventral mesencephalic cells and 8 x 10(4) stromal cells/microL, which were implanted in the striatum. Animals with stromal cells transplanted in the body of the striatum significantly reduced the number of turns induced by amphetamine (p < 0.05); yet this reduction was not greater than that induced by foetal mesencephalic cell transplants. We were also unable to demonstrate any significant improvement in the motor skills of the forelimbs.

  13. Milnacipran is active in models of irritable bowel syndrome and abdominal visceral pain in rodents.

    PubMed

    Depoortère, Ronan; Meleine, Mathieu; Bardin, Laurent; Aliaga, Monique; Muller, Emilie; Ardid, Denis; Newman-Tancredi, Adrian

    2011-12-15

    The role of antidepressants in the treatment of visceral pain has not been extensively examined. Milnacipran, a serotonin/noradrenalin reuptake inhibitor, has recently been approved in the USA for fibromyalgia, a chronic pathology characterized by diffused/chronic musculoskeletal pain, and a high prevalence of irritable bowel syndrome. Here, we determined its antinociceptive efficacy in two visceral pain tests in rodents: the acetic acid-induced writhing model in mice and the butyrate/colonic distension assay in rats, a model of irritable bowel syndrome. Acute milnacipran (5-40 mg/kgi.p.) significantly and dose-dependently reduced writhing (72.2 ± 3.2 versus 17.0 ± 4.1 writhes at 40 mg/kg). Following repeated administration (40 m/kgi.p. for 5 days), milnacipran preserved its ability to significantly reduce writhing (76 ± 8.3 versus 21.1 ± 6.7 writhes). Similarly, in the butyrate model, acute milnacipran (17.5 and 35 mg/kg, i.p.) significantly and dose-dependently increased cramps induction thresholds (from 45.7 ± 5.7 to 66.3 ± 4.8 and 75.6 ± 2.9 mm Hg, for 17.5 and 35 mg/kg, respectively) and reduced the number of cramps (from 3.0 ± 0.8 to 1.2 ± 0.8 and 0.3 ± 0.3 following inflation of an intra-rectal balloon. To summarise, milnacipran was efficacious in the writhing test, after acute and semi-chronic administration. This effect was confirmed after acute administration in a more specific model of colonic hypersensitivity induced by butyrate. This suggests that milnacipran has potential clinical application in the treatment of visceral pain, such as in irritable bowel syndrome, highly co-morbid with fibromyalgia.

  14. Preservation of intestinal motility after the serial transverse enteroplasty procedure in a large animal model of short bowel syndrome.

    PubMed

    Modi, Biren P; Ching, Y Avery; Langer, Monica; Donovan, Kate; Fauza, Dario O; Kim, Heung Bae; Jaksic, Tom; Nurko, Samuel

    2009-01-01

    Serial transverse enteroplasty (STEP) has been shown to improve bowel function in short bowel syndrome. The effect of the STEP procedure on intestinal motility is not known, but some have hypothesized that it could disrupt bowel innervation and thus impair intestinal motility. Growing Yorkshire pigs (n = 7) underwent 3 operations at 6-week intervals: (1) reversal of 50 cm of jejunum, (2) 90% bowel resection +/- STEP to the proximal dilated bowel (4 STEP, 3 control), and (3) implantation of serosal strain gauges. At each operation, baseline and post-octreotide small intestinal motility was studied with continuously perfused manometry catheters using non-anticholinergic anesthesia. In addition, awake monitoring was performed using strain gauge analysis 1 week after the third operation. Characteristics of phase III of the migrating motor complex (MMC) were compared between and within groups using t test, chi(2), and analysis of variance, with significance set at P < .05. Manometry data from the third surgery revealed no differences between groups or compared with baseline within groups for the presence and characteristics of phase III of the MMC. Specifically, the mean amplitude and frequency of phase III after octreotide, and both the mean baseline and mean octreotide-stimulated motility indices were equivalent. The duration of phase III after octreotide stimulation was significantly increased in the STEP animals, suggesting a potential benefit of the STEP procedure. Strain gauge analysis, performed in awake animals, confirmed no differences between the groups for basal and octreotide-stimulated characteristics of phase III of the MMC. These preliminary data suggest that the STEP procedure in a porcine model of short bowel syndrome does not interfere with baseline or hormonally stimulated motility within the small bowel. These findings further support the STEP procedure as a safe option for the surgical management of short bowel syndrome.

  15. Effectiveness of trimebutine maleate on modulating intestinal hypercontractility in a mouse model of postinfectious irritable bowel syndrome.

    PubMed

    Long, Yanqin; Liu, Ying; Tong, Jingjing; Qian, Wei; Hou, Xiaohua

    2010-06-25

    Trimebutine maleate, which modulates the calcium and potassium channels, relieves abdominal pain in patients with irritable bowel syndrome. However, its effect on postinfectious irritable bowel syndrome is not clarified. The aim of this study was to investigate the effectiveness of trimebutine maleate on modulating colonic hypercontractility in a mouse model of postinfectious irritable bowel syndrome. Mice infected up to 8 weeks with T. spiralis underwent abdominal withdrawal reflex to colorectal distention to evaluate the visceral sensitivity at different time points. Tissues were examined for histopathology scores. Colonic longitudinal muscle strips were prepared in the organ bath under basal condition or to be stimulated by acetylcholine and potassium chloride, and consecutive concentrations of trimebutine maleate were added to the bath to record the strip responses. Significant inflammation was observed in the intestines of the mice infected 2 weeks, and it resolved in 8 weeks after infection. Visceral hyperalgesia and colonic muscle hypercontractility emerged after infection, and trimebutine maleate could effectively reduce the colonic hyperreactivity. Hypercontractility of the colonic muscle stimulated by acetylcholine and high K(+) could be inhibited by trimebutine maleate in solution with Ca(2+), but not in Ca(2+) free solution. Compared with 8-week postinfectious irritable bowel syndrome group, 2-week acute infected strips were much more sensitive to the stimulators and the drug trimebutine maleate. Trimebutine maleate was effective in reducing the colonic muscle hypercontractility of postinfectious irritable bowel syndrome mice. The findings may provide evidence for trimebutine maleate to treat postinfectious irritable bowel syndrome patients effectively.

  16. Microbiome changes associated with sustained eradication of Clostridium difficile after single faecal microbiota transplantation in children with and without inflammatory bowel disease.

    PubMed

    Hourigan, S K; Chen, L A; Grigoryan, Z; Laroche, G; Weidner, M; Sears, C L; Oliva-Hemker, M

    2015-09-01

    Little data are available regarding the effectiveness and associated microbiome changes of faecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI) in children, especially in those with inflammatory bowel disease (IBD) with presumed underlying dysbiosis. To investigate C. difficile eradication and microbiome changes with FMT in children with and without IBD. Children with a history of recurrent CDI (≥3 recurrences) underwent FMT via colonoscopy. Stool samples were collected pre-FMT and post-FMT at 2-10 weeks, 10-20 weeks and 6 months. The v4 hypervariable region of the 16S rRNA gene was sequenced. C. difficile toxin B gene polymerase chain reaction was performed. Eight children underwent FMT for CDI; five had IBD. All had resolution of CDI symptoms. All tested had eradication of C. difficile at 10-20 weeks and 6 months post-FMT. Pre-FMT patient samples had significantly decreased bacterial richness compared with donors (P = 0.01), in those with IBD (P = 0.02) and without IBD (P = 0.01). Post-FMT, bacterial diversity in patients increased. Six months post-FMT, there was no significant difference between bacterial diversity of donors and patients without IBD; however, bacterial diversity in those with IBD returned to pre-FMT baseline. Microbiome composition at 6 months in IBD-negative patients more closely approximated donor composition compared to IBD-positive patients. FMT gives sustained C. difficile eradication in children with and without IBD. FMT-restored diversity is sustained in children without IBD. In those with IBD, bacterial diversity returns to pre-FMT baseline by 6 months, suggesting IBD host-related mechanisms modify faecal microbiome diversity. © 2015 John Wiley & Sons Ltd.

  17. Multicentre, randomised, placebo-controlled trial of extract of Japanese herbal medicine Daikenchuto to prevent bowel dysfunction after adult liver transplantation (DKB 14 Study)

    PubMed Central

    Kaido, Toshimi; Shimamura, Tsuyoshi; Sugawara, Yasuhiko; Sadamori, Hiroshi; Shirabe, Ken; Yamamoto, Michio; Uemoto, Shinji

    2015-01-01

    Introduction This multicentre randomised controlled clinical trial will aim to determine the ability of an extract (TJ-100) of Daikenchuto (traditional Japanese herbal medicine; Kampo) to prevent bowel dysfunction in at least 110 patients after liver transplantation (LT). Methods and analysis The following co-primary end points will be evaluated on postoperative day 7: total oral and enteral caloric intake, abdominal distension and abdominal pain. The secondary end points will comprise sequential changes of total oral and enteral caloric intake after LT, sequential changes in numeric rating scales for abdominal distension and pain, elapsed time to the first postoperative passage of stool, quality of life assessment using the Gastrointestinal Symptom Rating Scale score (Japanese version), postoperative liver function, liver regeneration rate, incidence of bacteraemia and bacterial strain, trough level of immunosuppressants, occurrence of acute cellular rejection, discharge or not within 2 months after LT, sequential changes of portal venous flow to the graft and ascites discharge. The two arms of the study will comprise 55 patients per arm. Ethics and dissemination The study has been conducted according to the CONSORT statement. All participants signed a written consent form, and the study has been approved by the institutional review board of each participating institute and conducted in accordance with the Declaration of Helsinki of 1996. The findings will be disseminated through scientific and professional conferences, and in peer-reviewed journals. Trial registration number The DKB 14 Study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000014326) during 2014. PMID:26419681

  18. Composite hemiface/calvaria transplantation model in rats.

    PubMed

    Yazici, Ilker; Unal, Sakir; Siemionow, Maria

    2006-11-01

    Extensive craniomaxillofacial deformities including bone and soft-tissue defects are always challenging for reconstructive surgeons. The purpose of this study was to extend application of the face/scalp transplantation model in the rat by incorporation of the vascularized calvarial bone, based on the same vascular pedicle, as a new treatment option for extensive craniomaxillofacial deformities with large bone defects. Seven composite hemiface/calvaria transplantations were performed across major histocompatibility complex barrier between Lewis-Brown Norway and Lewis rats. Seven donor and seven recipient rats were used in this study. Hemicalvarial bone and face grafts were dissected on the same pedicle of the common carotid artery and jugular vein and were transplanted to the deepithelialized donor faces. All rats received tapered and continuous doses of cyclosporine A monotherapy. Evaluation methods included flap angiography, daily inspection, computed tomographic scan, and bone histology. Flap angiography demonstrated the vascular supply of the bone. The average survival time was 154 days. There were no signs of rejection and there was no flap loss noted at 220 days posttransplantation. Bone histology at days 7, 30, 63, and 100 after transplantation revealed viable bone at all time points, and computed tomographic scans taken at days 14, 30, and 100 revealed normal bones without resorption. For extensive face deformities involving large bone and soft-tissue defects, this new osteomusculocutaneous hemiface/calvaria flap model may serve to create new reconstructive options for covering during one surgical procedure.

  19. Age and equity in liver transplantation: An organ allocation model.

    PubMed

    Cucchetti, Alessandro; Ross, Lainie Friedman; Thistlethwaite, J Richard; Vitale, Alessandro; Ravaioli, Matteo; Cescon, Matteo; Ercolani, Giorgio; Burra, Patrizia; Cillo, Umberto; Pinna, Antonio Daniele

    2015-10-01

    A moral liver allocation policy must be fair. We considered a 2-step, 2-principle allocation system called "age mapping." Its first principle, equal opportunity, ensures that candidates of all ages have an equal chance of getting an organ. Its second principle, prudential lifespan equity, allocates younger donor grafts to younger candidates and older donors to older candidates in order to increase the likelihood that all recipients achieve a "full lifespan." Data from 2476 candidates and 1371 consecutive adult liver transplantations (from 1999 to 2012) were used to determine whether age mapping can reduce the gap in years of life lost (YLL) between younger and older recipients. A parametric Weibull prognostic model was developed to estimate total life expectancy after transplantation using survival of the general population matched by sex and age as a reference. Life expectancy from birth was calculated by adding age at transplant and total life expectancy after transplantation. In multivariate analysis, recipient age, hepatitis C virus status, Model for End-Stage Liver Disease score at transplant of >30, and donor age were significantly related to prognosis after surgery (P < 0.05). The mean (and standard deviation) number of years of life from birth, calculated from the current allocation model, for various age groups were: recipients 18-47 years (n = 340) = 65.2 (3.3); 48-55 years (n = 387) = 72.7 (2.1); 56-61 years (n = 372) = 74.7 (1.7) and for recipients >61 years (n = 272) = 77.4 (1.4). The total number of YLL equaled 523 years. Redistributing liver grafts, using an age mapping algorithm, reduces the lifespan gap between younger and older candidates by 33% (from 12.3% to 8.3%) and achieves a 14% overall reduction of YLL (73 years) compared to baseline liver distribution. In conclusion, deliberately incorporating age into an allocation algorithm promotes fairness and increases efficiency.

  20. Bowel incontinence

    MedlinePlus

    ... control of their bowels. Exercises to make the anal and pelvic muscles stronger can help the bowels ... Gynecological, prostate, or rectal surgery. Injury to the anal muscles due to childbirth (in women). Nerve or ...

  1. Bowel Movement

    MedlinePlus

    A bowel movement is the last stop in the movement of food through your digestive tract. Your stool passes out of ... what you eat and drink. Sometimes a bowel movement isn't normal. Diarrhea happens when stool passes ...

  2. Experimental colitis models: Insights into the pathogenesis of inflammatory bowel disease and translational issues.

    PubMed

    Valatas, Vassilis; Bamias, Giorgos; Kolios, George

    2015-07-15

    Inflammatory bowel diseases, ulcerative colitis and Crohn׳s disease are characterized by chronic relapsing inflammation of the gastrointestinal tract of unknown etiology that seems to be the consequence of a genetically driven dysregulated immune response against various local and environmental triggers through a defective epithelial barrier. During the last decades, a large number of animal experimental models of intestinal inflammation have been generated and provided valuable insights into the mechanisms that either maintain mucosal homeostasis or drive intestinal inflammation. Their study enabled the identification of various treatment targets and the development a large pipeline of new drugs, mostly biologics. Safety and therapeutic efficacy of these agents have been evaluated in a large number of clinical trials but only a minority has reached the clinic so far. Translational successes but mostly translational failures have prompted to re-evaluate results of efficacy and safety generated by pre-clinical testing and to re-examine the way to interpret experimental in vivo data. This review examines the contribution of the most popular experimental colitis models to our understanding of the pathogenesis of human inflammatory bowel diseases and their translational input in drug development and discusses ways to improve translational outcome.

  3. Oral insulin stimulates intestinal epithelial cell turnover following massive small bowel resection in a rat and a cell culture model.

    PubMed

    Ben Lulu, Shani; Coran, Arnold G; Shehadeh, Naim; Shamir, Raanan; Mogilner, Jorge G; Sukhotnik, Igor

    2012-02-01

    We have recently reported that oral insulin (OI) stimulates intestinal adaptation after bowel resection and that OI enhances enterocyte turnover in correlation with insulin receptor expression along the villus-crypt axis. The purpose of the present study was to evaluate the effect of OI on intestinal epithelial cell proliferation and apoptosis in a rat model of short bowel syndrome (SBS) and in a cell culture model. Caco-2 cells were incubated with increasing concentrations of insulin. Cell proliferation and apoptosis were determined by FACS cytometry. Cell viability was investigated using the Alamar Blue technique. Male rats were divided into three groups: Sham rats underwent bowel transection, SBS rats underwent a 75% bowel resection, and SBS-OI rats underwent bowel resection and were treated with OI given in drinking water (1 U/ml) from the third postoperative day. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined on day 15. Real time PCR was used to determine the level of bax and bcl-2 mRNA and western blotting was used to determine bax, bcl-2, p-ERK and AKT protein levels. Statistical analysis was performed using the one-way ANOVA test, with P < 0.05 considered statistically significant. Treatment of Caco-2 cells with insulin resulted in a significant increase in cell proliferation (twofold increase after 24 h and 37% increase after 48 h) and cell viability (in a dose-dependent manner), but did not change cell apoptosis. In a rat model of SBS, treatment with OI resulted in a significant increase in all parameters of intestinal adaptation. Elevated cell proliferation rate in insulin treated rats was accompanied by elevated AKT and p-ERK protein levels. Decreased cell apoptosis in SBS-INS rats corresponded with a decreased bax/bcl-2 ratio. Oral insulin stimulates intestinal epithelial cell turnover after massive small bowel resection in a rat model of SBS and a cell culture model.

  4. Validity of cardiovascular risk prediction models in kidney transplant recipients.

    PubMed

    Mansell, Holly; Stewart, Samuel Alan; Shoker, Ahmed

    2014-01-01

    Predicting cardiovascular risk is of great interest in renal transplant recipients since cardiovascular disease is the leading cause of mortality. To conduct a systematic review to assess the validity of cardiovascular risk prediction models in this population. Five databases were searched (MEDLINE, EMBASE, SCOPUS, CINAHL, and Web of Science) and cohort studies with at least one year of follow-up were included. Variables that described population characteristics, study design, and prognostic performance were extracted. The Quality in Prognostic Studies (QUIPS) tool was used to evaluate bias. Seven studies met the criteria for inclusion, of which, five investigated the Framingham risk score and three used a transplant-specific model. Sample sizes ranged from 344 to 23,575, and three studies lacked sufficient event rates to confidently reach conclusion. Four studies reported discrimination (as measured by c-statistic), which ranged from 0.701 to 0.75, while only one risk model was both internally and externally validated. The Framingham has underestimated cardiovascular events in renal transplant recipients, but these studies have not been robust. A risk prediction model has been externally validated at least on one occasion, but comprehensive validation in multiple cohorts and impact analysis are recommended before widespread clinical application is advocated.

  5. A new rat model links two contemporary theories in irritable bowel syndrome.

    PubMed

    Pimentel, Mark; Chatterjee, Soumya; Chang, Christopher; Low, Kimberly; Song, Yuli; Liu, Chengxu; Morales, Walter; Ali, Lemeesa; Lezcano, Sheila; Conklin, Jeffery; Finegold, Sydney

    2008-04-01

    Two proposed hypotheses for irritable bowel syndrome (IBS) are acute gastroenteritis and bacterial overgrowth. We studied whether acute infection with Campylobacter could precipitate bacterial overgrowth in a rat model in order to link the two hypotheses. Sprague-Dawley outbred rats were randomly administered a vehicle or Campylobacter jejuni strain 81-176 by oral gavage. Three months after clearance of the infectious agent, rats had a stool consistency evaluation. After euthanasia, lumenal bacteria counts were measured via quantitative real-time PCR from self-contained segments of the duodenum, jejunum, ileum, cecum and left colon. Adjacent sections of bowel were fixed in formalin for evaluation of intraepithelial lymphocyte counts. Three months after clearance of Campylobacter infection, 57% of Campylobacter infected rats had some alteration in stool consistency compared to 7.4% in mock-infected controls (P < 0.001). Among the rats that received Campylobacter, 27% had evidence of bacterial overgrowth by PCR. These rats also had the highest prevalence of altered stool form and had lower body weight. Consistent with post-infectious IBS in humans, bacterial overgrowth rats demonstrated a significant increase in rectal and left colon intraepithelial lymphocytes. Acute infection with C. jejuni 81-176 precipitates alterations in stool consistency, bacterial overgrowth and rectal lymphocytosis consistent with findings in IBS patients.

  6. The biopsychosocial model of treatment the patients with inflammatory chronic bowel disease.

    PubMed

    Rakovec-Felser, Zlatka

    2011-06-01

    We present the organised psychological group interventions for persons with inflammatory bowel disease (ulcerose colitis, Morbus Crohn). The actual bio-psychosocial model of health and illness is used to explain the situation of chronically ill patient as stressful life position and their ways of coping with such, health-related problems. Considering that numerous psychological factors can lead to insufficient illness adaptation and (non) adherence to treatment--and all those--to much more complications and higher use of therapies, we try to develop for group of those patients effective model of treatment. The group of 15 gastroenterological patients from treatment in UKC Maribor was included in the psycho-diagnostic procedure (semi-structural interview, The Freiburg's Personal Inventory, The Coping Inventory for Stressful Situations, Health-related Questionnaire of Quality of Life). The data that we had been gathered were significant to the C-type of coping, found in some other group of chronically ill patients, too. For such persons is typically their low emotions expressiveness, especially negative emotions (sadness, anger). In interpersonal contacts they usually show extreme social agreement and low level of assertiveness. So we formed our therapeutic model and its therapeutic aims to the course of being able to express the emotions, to reach higher personal autonomy, better assertively and self image--which at the end have all greater influence on the human's quality of life. After therapeutic model and aims of treatment has been formed, patients with inflammatory bowel disease were treated in cognitive-behavioural group, where also C. Roger's conditions for successful psychotherapy were taken in account and were the part of hole, integrative form of treatment.

  7. Murine Cervical Heart Transplantation Model Using a Modified Cuff Technique

    PubMed Central

    Kofler, Markus; Ritschl, Paul; Oellinger, Robert; Aigner, Felix; Sucher, Robert; Schneeberger, Stefan; Pratschke, Johann; Brandacher, Gerald; Maglione, Manuel

    2014-01-01

    Mouse models are of special interest in research since a wide variety of monoclonal antibodies and commercially defined inbred and knockout strains are available to perform mechanistic in vivo studies. While heart transplantation models using a suture technique were first successfully developed in rats, the translation into an equally widespread used murine equivalent was never achieved due the technical complexity of the microsurgical procedure. In contrast, non-suture cuff techniques, also developed initially in rats, were successfully adapted for use in mice1-3. This technique for revascularization involves two major steps I) everting the recipient vessel over a polyethylene cuff; II) pulling the donor vessel over the formerly everted recipient vessel and holding it in place with a circumferential tie. This ensures a continuity of the endothelial layer, short operating time and very high patency rates4. Using this technique for vascular anastomosis we performed more than 1,000 cervical heart transplants with an overall success rate of 95%. For arterial inflow the common carotid artery and the proximal aortic arch were anastomosed resulting in a retrograde perfusion of the transplanted heart. For venous drainage the pulmonary artery of the graft was anastomosed with the external jugular vein of the recipient5. Herein, we provide additional details of this technique to supplement the video. PMID:25350682

  8. Vascularized bone marrow transplantation model in rats as an alternative to conventional cellular bone marrow transplantation: preliminary results.

    PubMed

    Zamfirescu, D; Popovicu, C; Stefanescu, A; Bularda, A; Popescu, M; Zegrea, I; Lanzetta, M; Lascar, I

    2011-11-01

    The aim of the study was to follow the development of microchimerism after allogeneic vascularized bone marrow transplantation (VBMT) versus conventional bone marrow transplantation (BMT). In one group, a VBMT model consisted of donor Brown Norway rat hind limb heterotopic transplanted on recipient Lewis rats. An intravenous infusion of donor bone marrow cells in suspension equivalent to that grafted in the vascularized femur limb was administered intravenously to recipient rats in the second group. Cellular microchimerism was investigated in recipients of VBMT versus BMT. Donor-derived cells could be detected in VBMT recipients at 30 and 60 days but not in recipients of intravenous suspension of BMC. VBMT provides a theoretical alternative to conventional cellular bone marrow transplantation by addressing crucial clinical problems such as failure of engraftment or graft-versus-host disease. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. [Surgical techniques of organ transplants].

    PubMed

    Froněk, Jiří

    2015-01-01

    The list of surgical procedures of solid organ transplantations appears very interesting and colorful, even with overlap among techniques. Liver transplantation is a life-saving procedure in a majority of cases, the liver can be transplanted as a full or partial graft. The liver graft can be split for two recipients; it can also be reduced for a small recipient if splitting is not indicated. Kidney transplantation is the most common solid organ transplant procedure, the majority of kidney grafts come from brain-dead donors whereas the number of live donor transplants is increasing, also thanks to paired donation and blood group incompatible transplantation methods. The small bowel and multivisceral transplantation are rare procedures; they serve selected patients with short bowel syndrome, some patients with retroperitoneal tumors or with extensive visceral thrombosis. Solid organ transplants are well established treatment methods with good and proven outcomes. A majority of patients can return to a normal life after their transplants.

  10. Formation of independently revascularized bowel segments using the rectus abdominis muscle flap: a rat model for jejunal prefabrication.

    PubMed

    Tan, Bien-Keem; Chen, Hung-Chi; Wei, Fu-Chan; Ma, Shwu-Fan; Lan, Chyn-Tair; See, Lai-Chu; Wan, Yung-Liang

    2002-02-01

    Reconstruction of the pharyngoesophagus with free jejunal transfer is a major challenge when recipient neck vessels are absent because of previous surgery or irradiation. In such instances, jejunal transfer using a muscle flap as a "vascular carrier" may be a problem-solving alternative. Pretransfer vascularization of the jejunum is achieved by wrapping the muscle flap around the small bowel segment. After a short staging period, the mesenteric pedicle is divided and the bowel segment is transferred up to the neck based on its new blood supply. The objectives of this study were to develop an animal model for prefabricating independently revascularized jejunal segments using the rectus abdominis muscle flap and to determine the minimal time required for independent bowel survival. Twenty-four mature (500-g to 700-g) rats were divided into six experimental groups of four animals each. In each animal, a 1.5-cm segment of proximal jejunum was isolated on two jejunal arteries and wrapped with a superior pedicled rectus abdominis muscle flap. To determine the time of neovascular takeover, the mesenteric pedicles were ligated on postoperative day 2 (group I), day 3 (group II), day 4 (group III), day 5 (group IV), day 6 (group V), and day 7 (group VI). At the time of pedicle ligation, the composite flap was transposed to a new subcutaneous position. Viability of bowel was assessed according to gross appearance and histologic examination 48 hours after transfer. Complete survival of revascularized jejunum in 11 of 12 animals was obtained after pedicle ligation on postoperative day 5 and beyond (p < 0.0001, Fisher's exact test). These bowel segments demonstrated luminal patency, intact pink mucosa, mucus production, and visible peristalsis. Histologic examination showed healthy intestinal epithelium and tissue integration along the serosa-muscle interphase. In contrast, pedicle ligation on day 4 and earlier resulted in varying degrees of bowel necrosis characterized by

  11. A Review on Chemical-Induced Inflammatory Bowel Disease Models in Rodents

    PubMed Central

    Randhawa, Puneet Kaur; Singh, Kavinder; Singh, Nirmal

    2014-01-01

    Ulcerative colitis and Crohn's disease are a set of chronic, idiopathic, immunological and relapsing inflammatory disorders of the gastrointestinal tract referred to as inflammatory bowel disorder (IBD). Although the etiological factors involved in the perpetuation of IBD remain uncertain, development of various animal models provides new insights to unveil the onset and the progression of IBD. Various chemical-induced colitis models are widely used on laboratory scale. Furthermore, these models closely mimic morphological, histopathological and symptomatical features of human IBD. Among the chemical-induced colitis models, trinitrobenzene sulfonic acid (TNBS)-induced colitis, oxazolone induced-colitis and dextran sulphate sodium (DSS)-induced colitis models are most widely used. TNBS elicits Th-1 driven immune response, whereas oxazolone predominantly exhibits immune response of Th-2 phenotype. DSS-induced colitis model also induces changes in Th-1/Th-2 cytokine profile. The present review discusses the methodology and rationale of using various chemical-induced colitis models for evaluating the pathogenesis of IBD. PMID:25177159

  12. Composite vascularized skin/bone transplantation models for bone marrow-based tolerance studies.

    PubMed

    Ozmen, Selahattin; Ulusal, Betul G; Ulusal, Ali E; Izycki, Dariusz; Siemionow, Maria

    2006-03-01

    There is an ongoing need to understand the mechanisms of bone marrow-based allograft tolerance. This is important in clarifying the diverse variables influencing the ultimate outcome of the solid organ and composite tissue transplants. To establish bone marrow transplantation as a routine clinical application, further experimental studies should be conducted to overcome the obstacles related to the bone marrow transplantation. These obstacles include graft versus host disease, immunocompetence, and toxicity of the conditioning regimens. For these purposes, novel experimental models are needed. In an attempt to provide a reliable research tool for bone marrow-based tolerance induction studies, we introduced different experimental models of modified vascularized skin/bone marrow (VSBM) transplantation technique for tolerance induction, monitoring, and maintenance studies. In this skin/bone transplantation model, the technical feasibility of concurrent or consecutive transplantation of the combination of bilateral vascularized skin, vascularized bone marrow, or vascularized skin/bone marrow transplants was investigated. Isograft transplantations were performed between genetically identical Lewis (LEW, RT1) rats. Five different experimental designs in 5 groups of 5 animals each were studied. Group I: Bilateral vascularized skin (VS) transplantation; group II: bilateral vascularized skin/bone transplantation; group III: vascularized skin transplantation on one side and vascularized skin/bone transplantation on the contralateral side; group IV: vascularized bone transplantation on one side and vascularized skin/bone transplantation on the contralateral side; group V: vascularized bone transplantation on one side and vascularized skin transplantation on the contralateral side. Successful transplantations were performed in all groups. The survival of the isograft transplants was evaluated clinically and histologically. All skin flaps remained pink and pliable and grew new

  13. Arterial hypertension due to fructose ingestion: model based on intermittent osmotic fluid trapping in the small bowel

    PubMed Central

    2010-01-01

    Based on recently reported data that fructose ingestion is linked to arterial hypertension, a model of regulatory loops involving the colon role in maintenance of fluid and sodium homeostasis is proposed. In normal digestion of hyperosmolar fluids, also in cases of postprandial hypotension and in patients having the "dumping" syndrome after gastric surgery, any hyperosmolar intestinal content is diluted by water taken from circulation and being trapped in the bowel until reabsorption. High fructose corn sirup (HFCS) soft drinks are among common hyperosmolar drinks. Fructose is slowly absorbed through passive carrier-mediated facilitated diffusion, along the entire small bowel, thus preventing absorption of the trapped water for several hours. Here presented interpretation is that ingestion of hyperosmolar HFCS drinks due to a transient fluid shift into the small bowel increases renin secretion and sympathetic activity, leading to rise in ADH and aldosterone secretions. Their actions spare water and sodium in the large bowel and kidneys. Alteration of colon absorption due to hormone exposure depends on cell renewal and takes days to develop, so the momentary capacity of sodium absorption in the colon depends on the average aldosterone and ADH exposure during few previous days. This inertia in modulation of the colon function can make an individual that often takes HFCS drinks prone to sodium retention, until a new balance is reached with an expanded ECF pool and arterial hypertension. In individuals with impaired fructose absorption, even a higher risk of arterial hypertension can be expected. PMID:20579372

  14. Transplantation of human stem cell-derived hepatocytes in an animal model of acute liver failure.

    PubMed

    Ramanathan, Rajesh; Pettinato, Giuseppe; Beeston, John T; Lee, David D; Wen, Xuejun; Mangino, Martin J; Fisher, Robert A

    2015-08-01

    Hepatocyte cell transplantation can be life-saving in patients with acute liver failure (ALF); however, primary human hepatocyte transplantation is limited by the scarcity of donor hepatocytes. We investigated the effect of stem cell-derived, hepatocyte-like cells in an animal xenotransplant model of ALF. Intraperitoneal d-galactosamine was used to develop a lethal model of ALF in the rat. Human induced pluripotent stem cells (iPSC), human mesenchymal stem cells, and human iPSC combined with human endothelial cells (iPSC + EC) were differentiated into hepatocyte-like cells and transplanted into the spleens of athymic nude rats with ALF. A reproducible lethal model of ALF was achieved with nearly 90% death within 3 days. Compared with negative controls, rats transplanted with stem cell-derived, hepatocyte-like cells were associated with increased survival. Human albumin was detected in the rat serum 3 days after transplantation in more than one-half the animals transplanted with hepatocyte-like cells. Only animals transplanted with iPSC + EC-derived hepatocytes had serum human albumin at 14 days posttransplant. Transplanted hepatocyte-like cells homed to the injured rat liver, whereas the ECs were only detected in the spleen. Transplantation of stem cell-derived, hepatocyte-like cells improved survival with evidence of in vivo human albumin production. Combining ECs may prolong cell function after transplantation. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities.

    PubMed

    Moloney, Rachel D; O'Mahony, Siobhain M; Dinan, Timothy G; Cryan, John F

    2015-01-01

    Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities. The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent.

  16. Stress-Induced Visceral Pain: Toward Animal Models of Irritable-Bowel Syndrome and Associated Comorbidities

    PubMed Central

    Moloney, Rachel D.; O’Mahony, Siobhain M.; Dinan, Timothy G.; Cryan, John F.

    2015-01-01

    Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities. The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent. PMID:25762939

  17. Challenges in animal modelling of mesenchymal stromal cell therapy for inflammatory bowel disease.

    PubMed

    Chinnadurai, Raghavan; Ng, Spencer; Velu, Vijayakumar; Galipeau, Jacques

    2015-04-28

    Utilization of mesenchymal stromal cells (MSCs) for the treatment of Crohn's disease and ulcerative colitis is of translational interest. Safety of MSC therapy has been well demonstrated in early phase clinical trials but efficacy in randomized clinical trials needs to be demonstrated. Understanding MSC mechanisms of action to reduce gut injury and inflammation is necessary to improve current ongoing and future clinical trials. However, two major hurdles impede the direct translation of data derived from animal experiments to the clinical situation: (1) limitations of the currently available animal models of colitis that reflect human inflammatory bowel diseases (IBD). The etiology and progression of human IBD are multifactorial and hence a challenge to mimic in animal models; and (2) Species specific differences in the functionality of MSCs derived from mice versus humans. MSCs derived from mice and humans are not identical in their mechanisms of action in suppressing inflammation. Thus, preclinical animal studies with murine derived MSCs cannot be considered as an exact replica of human MSC based clinical trials. In the present review, we discuss the therapeutic properties of MSCs in preclinical and clinical studies of IBD. We also discuss the challenges and approaches of using appropriate animal models of colitis, not only to study putative MSC therapeutic efficacy and their mechanisms of action, but also the suitability of translating findings derived from such studies to the clinic.

  18. A cross-circulated bicephalic model of head transplantation.

    PubMed

    Li, Peng-Wei; Zhao, Xin; Zhao, Yun-Long; Wang, Bing-Jian; Song, Yang; Shen, Zi-Long; Jiang, Hong-Jun; Jin, Hai; Canavero, Sergio; Ren, Xiao-Ping

    2017-06-01

    A successful cephalosomatic anastomosis ("head transplant") requires, among others, the ability to control long-term immune rejection and avoidance of ischemic events during the head transference phase. We developed a bicephalic model of head transplantation to study these aspects. The thoracic aorta and superior vena cava of a donor rat were anastomosed with the carotid artery and extracorporeal veins of a recipient rat by vascular grafts. Before thoracotomy in the donor rat, the axillary artery and vein of the donor were connected to the carotid and the extracranial vein of the third rat through a silicone tube. The silicone tube was passed through a peristaltic pump to ensure donor brain tissue blood supply. There is no ischemia reperfusion injury in donor brain tissue analyzed by electroencephalogram. Postoperative donor has pain reflex and corneal reflex. Peristaltic pump application can guarantee the blood supply of donor brain tissue per unit time, while the application of temperature change device to the silicone tube can protect the brain tissue hypothermia, postoperative experimental data show that there is no brain tissue ischemia during the whole operation. The application of vascular grafting can also provide the possibility of long-term survival of the model. © 2017 John Wiley & Sons Ltd.

  19. Modeling the Chagas’ disease after stem cell transplantation

    NASA Astrophysics Data System (ADS)

    Galvão, Viviane; Miranda, José Garcia Vivas

    2009-04-01

    A recent model for Chagas’ disease after stem cell transplantation is extended for a three-dimensional multi-agent-based model. The computational model includes six different types of autonomous agents: inflammatory cell, fibrosis, cardiomyocyte, proinflammatory cytokine tumor necrosis factor- α, Trypanosoma cruzi, and bone marrow stem cell. Only fibrosis is fixed and the other types of agents can move randomly through the empty spaces using the three-dimensional Moore neighborhood. Bone marrow stem cells can promote apoptosis in inflammatory cells, fibrosis regression and can differentiate in cardiomyocyte. T. cruzi can increase the number of inflammatory cells. Inflammatory cells and tumor necrosis factor- α can increase the quantity of fibrosis. Our results were compared with experimental data giving a fairly fit and they suggest that the inflammatory cells are important for the development of fibrosis.

  20. Collaborative use of the peer assist model in large transplant programs in the United States.

    PubMed

    Peele, Amy S; Goldberg, Stefanie; Trompeta, Joyce A

    2011-06-01

    The basic assumption of the peer assist model is that nearly every transplant center is already doing something that other centers could adopt in order to streamline or enhance their own operations. To describe how the Transplant Growth and Management Collaborative used the peer assist model with 2 large transplant centers in the United States and to identify best practices and outcomes. The University of California, San Francisco, Medical Center. Transplant health care providers (surgeons, nurse transplant coordinators) and administrative staff (program directors, financial advisers, quality representatives). The peer assist model is a mechanism by which a transplant center receives feedback about a specific topic from another transplant center that encountered similar issues and developed effective action plans for overcoming barriers to success; it is a reciprocal model in which knowledge is shared. The peer assist model benefited the preparation for accelerated growth in 2 of the largest transplant centers in the United States. The collaboration during peer assist visits is an opportune time for transplant centers to learn from one another.

  1. Travel for transplantation in iran: pros and cons regarding Iranian model.

    PubMed

    Ossareh, Shahrzad; Broumand, Behrooz

    2015-04-01

    Transplant tourism is one of the main unacceptable aspects of medical tourism, implicating travel to another country to receive an allograft. Organ shortages in wealthier countries have persuaded patients to preclude organ waiting lists and travel to other countries for getting organs especially kidneys. On the other hand, in many countries, there is no transplant program, and hemodialysis is expensive. Hence, patients with end-stage kidney disease may have to travel to get a kidney allograft for the sake of their lives. In Iran, a legal compensated and regulated living unrelated donor kidney transplant program has been adopted since 1988, in which recipients are matched with liveunrelated donors through the Iran Kidney Foundation and the recipients are compensated dually by the government and the recipient. In this model regulations were adopted to prevent transplant tourism: foreigners were not allowed to receive a kidney from Iranian donors or donate a kidney to Iranian patients; however, they could be transplanted from donors of their own nationality, after full medical workup, with the authorization of the Ministry of Health. This was first considered as a humanitarian assistance to patients of the countries with no transplant program and limited and low quality dialysis. However, the policy of "foreign nationality transplant" gradually established a spot where residents of many countries, where living-unrelated donor transplant was illegal, could bring their donors and be transplanted mainly in private hospitals, with high incentives for the transplant teams. By June 2014, six hundred eight foreign nationality kidney transplants were authorized by Ministry of Health for citizens for 17 countries. In this review, we examine the negative aspects of transplant for foreign citizens in Iran and the reasons that changed "travel for transplant" to "transplant tourism " in our country and finally led us to stop the program after more than 10 years.

  2. The small intestine and irritable bowel syndrome (IBS): a batch process model.

    PubMed

    Dobson, Brian C

    2008-11-01

    Faults in a batch process model of the small intestine create the symptoms of all types of irritable bowel syndrome. The model has three sequential processing sections corresponding to the natural divisions of the intestine. It is governed by a brain controller that is divided into four sub-controllers, each with a unique neurotransmitter. Each section has a sub-controller to manage transport. Sensors in the walls of the intestine provide input and output goes to the muscles lining the walls of the intestine. The output controls the speed of the food soup, moves it in both directions, mixes it, controls absorption, and transfers it to the next section at the correct speed (slow). The fourth sub-controller manages the addition of chemicals. It obtains input from the first section of the process via the signalling hormone Cholecystokinin and sends output to the muscles that empty the gall bladder and pancreas. The correct amounts of bile salts and enzymes are then added to the first section. The sub-controllers produce output only when input is received. When output is missing the enteric nervous system applies a default condition. This default condition normally happens when no food is in the intestine. If food is in the intestine and a transport sub-controller fails to provide output then the default condition moves the food soup to the end of that section. The movement is in one direction only (forward), at a speed dependent on the amount and type of fibre present. Cereal, bean and vegetable fibre causes high speeds. This default high speed transport causes irritable bowel syndrome. A barrier is created when a section moving fast at the default speed, precedes a section controlled by a transport sub-controller. Then the sub-controller constricts the intestine to stop the fast flow. The barrier causes constipation, cramping, and bloating. Diarrhoea results when the section terminating the process moves at the fast default speed. Two problems can occur to prevent

  3. Murine animal models for preclinical islet transplantation: No model fits all (research purposes).

    PubMed

    Cantarelli, Elisa; Citro, Antonio; Marzorati, Simona; Melzi, Raffaella; Scavini, Marina; Piemonti, Lorenzo

    2013-01-01

    Advances in islet transplantation research have led to remarkable improvements in the outcome in humans with type 1 diabetes. However, pitfalls, mainly linked both to early liver-specific inflammatory events and to pre-existing and transplant-induced auto- and allo-specific adaptive immune responses, still remain. In this scenario research into pancreatic islet transplantation, essential to investigate new strategies to overcome open issues, needs very well-designed preclinical studies to obtain consistent and reliable results and select only promising strategies that may be translated into the clinical practice. This review discusses the main shortcomings of the mouse models currently used in islet transplantation research, outlining the main factors and variables to take into account for the design of new preclinical studies. Since several parameters concerning both the graft (i.e., islets) and the recipient (i.e., diabetic mice) may influence transplant outcome, we recommend considering several critical points in designing future bench-to-bedside islet transplantation research.

  4. Stress-Related Alterations of Visceral Sensation: Animal Models for Irritable Bowel Syndrome Study

    PubMed Central

    Mulak, Agata; Taché, Yvette

    2011-01-01

    Stressors of different psychological, physical or immune origin play a critical role in the pathophysiology of irritable bowel syndrome participating in symptoms onset, clinical presentation as well as treatment outcome. Experimental stress models applying a variety of acute and chronic exteroceptive or interoceptive stressors have been developed to target different periods throughout the lifespan of animals to assess the vulnerability, the trigger and perpetuating factors determining stress influence on visceral sensitivity and interactions within the brain-gut axis. Recent evidence points towards adequate construct and face validity of experimental models developed with respect to animals' age, sex, strain differences and specific methodological aspects such as non-invasive monitoring of visceromotor response to colorectal distension as being essential in successful identification and evaluation of novel therapeutic targets aimed at reducing stress-related alterations in visceral sensitivity. Underlying mechanisms of stress-induced modulation of visceral pain involve a combination of peripheral, spinal and supraspinal sensitization based on the nature of the stressors and dysregulation of descending pathways that modulate nociceptive transmission or stress-related analgesic response. PMID:21860814

  5. Stem cell derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model

    PubMed Central

    Donegan, Jennifer J.; Tyson, Jennifer A.; Branch, Sarah Y.; Beckstead, Michael J.; Anderson, Stewart A.; Lodge, Daniel J.

    2016-01-01

    An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol (MAM) rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity, and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia. PMID:27480492

  6. Assessing overall patient satisfaction in inflammatory bowel disease using structural equation modeling.

    PubMed

    Soares, João-Bruno; Marinho, Ana S; Fernandes, Dália; Moreira Gonçalves, Bruno; Camila-Dias, Cláudia; Gonçalves, Raquel; Magro, Fernando

    2015-08-01

    Structural equation modeling (SEM) is a very popular data-analytic technique for the evaluation of customer satisfaction. We aimed to measure the overall satisfaction of inflammatory bowel disease (IBD) patients with healthcare in Portugal and to define its main determinants using SEM. The study included three steps: (i) specification of a patient satisfaction model that included the following dimensions: Image, Expectations, Facilities, Admission process, Assistant staff, Nursing staff, Medical staff, Treatment, Inpatient care, Outpatient care, Overall quality, Overall satisfaction, and Loyalty; (ii) sample survey from 2000 patients, members of the Portuguese Association of the IBD; and (iii) estimation of the satisfaction model using partial least squares (XLSTAT-PLSPM). We received 498 (25%) valid questionnaires from 324 (66%) patients with Crohn's disease and 162 (33%) patients with ulcerative colitis. Our model provided a substantial explanation for Overall satisfaction (R=0.82). The mean index of overall satisfaction was 74.4 (0-100 scale). The main determinants of Overall satisfaction were the Image (β=0.26), Outpatient care (β=0.23), and Overall quality (β=0.21), whose mean indices were 83, 75, and 81, respectively. Facilities and Inpatient care were the variables with a significant impact on Overall satisfaction and the worst mean indices. SEM is useful for the evaluation of IBD patient satisfaction. The Overall satisfaction of IBD patients with healthcare in Portugal is good, but to increase it, IBD services need to focus on the improvement of Outpatient care, Facilities, and Inpatient care. Our model could be a matrix for a global model of IBD patient satisfaction.

  7. Simulation Modeling of the Impact of Proposed New Simultaneous Liver and Kidney Transplantation Policies

    PubMed Central

    Chang, Yaojen; Gallon, Lorenzo; Shetty, Kirti; Chang, Yuchia; Jay, Colleen; Levitsky, Josh; Ho, Bing; Baker, Talia; Ladner, Daniela; Friedewald, John; Abecassis, Michael; Hazen, Gordon; Skaro, Anton I.

    2014-01-01

    Background Increasing use of kidney grafts for simultaneous liver and kidney (SLK) transplants is causing concern about the most effective utilization of scarce kidney graft resources. This study evaluated the impact of implementing the proposed United Network for Organ Sharing (UNOS) SLK transplant policy on outcomes for end-stage liver disease (ESLD) and end-stage renal disease (ESRD) patients awaiting transplant. Methods A Markov model was constructed to simulate a hypothetical cohort of ESLD patients over a 30-year time horizon starting from age 50. The model applies the different criteria being considered in the UNOS policy and tallies outcomes, including numbers of procedures and life years after liver transplant alone (LTA) or SLK transplant. Results When1-week pre-transplant dialysis duration is required, the numbers of SLK transplants and LTAs would be 648 and 9,065, respectively. If the pre-transplant dialysis duration is extended to 12 weeks, there would be 240 SLK transplants and 9,426 LTAs. These change results in a decrease of 6,483 life years among SLK transplant recipients and an increase of 4,971 life years among LTA recipients. However, by increasing the dialysis duration to 12 weeks from 1 week, 408 kidney grafts would be released to the kidney waitlist due to the decline in SLK transplants; this yields 796 additional life years gained among ESRD patients. Conclusion Implementation of the proposed SLK transplant policy could restore access to kidney transplants for patients with ESRD albeit at the detriment of patients with ESLD and renal impairment. PMID:25099700

  8. Surgical management of short bowel syndrome.

    PubMed

    Iyer, Kishore R

    2014-05-01

    For patients with short bowel syndrome (SBS), surgery can play an important role in preventing, mitigating, and, in some cases, reversing intestinal failure (IF). During intestinal resection, bowel length should be conserved to the fullest extent possible to avoid dependence on parenteral nutrition (PN). Bowel salvage may be improved by initially preserving tissue of questionable viability and later reevaluating during "second-look" procedures. Once the patient is stabilized, ostomy reversal and recruitment of distal unused bowel should be prioritized whenever feasible. Following progression to IF, surgical management of SBS depends on the symptoms and anatomical characteristics of the individual patient. For carefully selected patients with rapid intestinal transit and dilated bowel, longitudinal intestinal lengthening and tailoring (LILT) and serial transverse enteroplasty (STEP) procedures may provide benefit. Outcomes following STEP and LILT are generally similar, and the choice between these procedures may rest on surgeon preference. For patients with rapid intestinal transit in the absence of bowel dilation, segmental reversal of the small bowel may reduce PN requirements. Intestinal transplantation is the standard of care for patients in whom intestinal rehabilitation attempts have failed and who are at risk of life-threatening complications of PN. Because patients awaiting isolated intestine transplant show increased survival compared with patients awaiting combined intestine-liver transplant, early referral of appropriate patients, before the development of advanced liver disease, is critical to enhancing patient outcomes.

  9. Bowel Obstruction.

    PubMed

    Gore, Richard M; Silvers, Robert I; Thakrar, Kiran H; Wenzke, Daniel R; Mehta, Uday K; Newmark, Geraldine M; Berlin, Jonathan W

    2015-11-01

    Small bowel obstruction and large bowel obstruction account for approximately 20% of cases of acute abdominal surgical conditions. The role of the radiologist is to answer several key questions: Is obstruction present? What is the level of the obstruction? What is the cause of the obstruction? What is the severity of the obstruction? Is the obstruction simple or closed loop? Is strangulation, ischemia, or perforation present? In this presentation, the radiologic approach to and imaging findings of patients with known or suspected bowel obstruction are presented.

  10. Cardiomyocyte transplantation in a porcine myocardial infarction model.

    PubMed

    Watanabe, E; Smith, D M; Delcarpio, J B; Sun, J; Smart, F W; Van Meter, C H; Claycomb, W C

    1998-01-01

    Transplantation of cardiomyocytes into the heart is a potential treatment for replacing damaged cardiac muscle. To investigate the feasibility and efficiency of this technique, either a cardiac-derived cell line (HL-1 cells), or normal fetal or neonatal pig cardiomyocytes were grafted into a porcine model of myocardial infarction. The myocardial infarction was created by the placement of an embolization coil in the distal portion of the left anterior descending artery in Yorkshire pigs (n = 9). Four to 5 wk after creation of an infarct, the three preparations of cardiomyocytes were grafted, at 1 x 10(6) cells/20 microL into normal and into the middle of the infarcted myocardium. The hearts were harvested and processed for histologic examinations 4 to 5 wk after the cell grafts. Histologic evaluation of the graft sites demonstrated that HL-1 cells and fetal pig cardiomyocytes formed stable grafts within the normal myocardium without any detrimental effect including arrhythmia. In addition, a marked increase in angiogenesis was observed both within the grafts and adjacent host myocardium. Electron microscopy studies demonstrated that fetal pig cardiomyocytes and the host myocardial cells were coupled with adherens-type junctions and gap junctions. Histologic examination of graft sites from infarct tissue failed to show the presence of grafted HL-1 cells, fetal, or neonatal pig cardiomyocytes. Cardiomyocyte transplantation may provide the potential means for cell-mediated gene therapy for introduction of therapeutic molecules into the heart.

  11. Probabilistic (Bayesian) Modeling of Gene Expression in Transplant Glomerulopathy

    PubMed Central

    Elster, Eric A.; Hawksworth, Jason S.; Cheng, Orlena; Leeser, David B.; Ring, Michael; Tadaki, Douglas K.; Kleiner, David E.; Eberhardt, John S.; Brown, Trevor S.; Mannon, Roslyn B.

    2010-01-01

    Transplant glomerulopathy (TG) is associated with rapid decline in glomerular filtration rate and poor outcome. We used low-density arrays with a novel probabilistic analysis to characterize relationships between gene transcripts and the development of TG in allograft recipients. Retrospective review identified TG in 10.8% of 963 core biopsies from 166 patients; patients with stable function were studied for comparison. The biopsies were analyzed for expression of 87 genes related to immune function and fibrosis by using real-time PCR, and a Bayesian model was generated and validated to predict histopathology based on gene expression. A total of 57 individual genes were increased in TG compared with stable function biopsies (P < 0.05). The Bayesian analysis identified critical relationships between ICAM-1, IL-10, CCL3, CD86, VCAM-1, MMP-9, MMP-7, and LAMC2 and allograft pathology. Moreover, Bayesian models predicted TG when derived from either immune function (area under the curve [95% confidence interval] of 0.875 [0.675 to 0.999], P = 0.004) or fibrosis (area under the curve [95% confidence interval] of 0.859 [0.754 to 0.963], P < 0.001) gene networks. Critical pathways in the Bayesian models were also analyzed by using the Fisher exact test and had P values <0.005. This study demonstrates that evaluating quantitative gene expression profiles with Bayesian modeling can identify significant transcriptional associations that have the potential to support the diagnostic capability of allograft histology. This integrated approach has broad implications in the field of transplant diagnostics. PMID:20688906

  12. Comparison of Listing Strategies for Allosensitized Heart Transplant Candidates Requiring Transplant at High Urgency: A Decision Model Analysis

    PubMed Central

    Feingold, Brian; Webber, Steven A.; Bryce, Cindy L.; Park, Seo Young; Tomko, Heather E.; Comer, Diane M.; Mahle, William T.; Smith, Kenneth J.

    2016-01-01

    Allosensitized children who require a negative prospective crossmatch have a high risk of death awaiting heart transplantation. Accepting the first suitable organ offer, regardless of the possibility of a positive crossmatch, would improve waitlist outcomes but it is unclear whether it would result in improved survival at all times after listing, including post-transplant. We created a Markov decision model to compare survival after listing with a requirement for a negative prospective donor cell crossmatch (WAIT) versus acceptance of the first suitable offer (TAKE). Model parameters were derived from registry data on status 1A (highest urgency) pediatric heart transplant listings. We assumed no possibility of a positive crossmatch in the WAIT strategy and a base-case probability of a positive crossmatch in the TAKE strategy of 47%, as estimated from cohort data. Under base-case assumptions TAKE showed an incremental survival benefit of 1.4 years over WAIT. In multiple sensitivity analyses, including variation of the probability of a positive crossmatch from 10-100%, TAKE was consistently favored. While model input data were less well suited to comparing survival when awaiting transplantation across a negative virtual crossmatch, our analysis suggest that taking the first suitable organ offer under these circumstances may also be favored. PMID:25612495

  13. Intestinal proteomics in pig models of necrotising enterocolitis, short bowel syndrome and intrauterine growth restriction.

    PubMed

    Jiang, Pingping; Sangild, Per Torp

    2014-10-01

    Necrotising enterocolitis (NEC), short bowel syndrome (SBS) and intrauterine growth restriction (IUGR) are three conditions associated with intestinal dysfunction in newborn infants, particularly those born preterm. Piglet (Sus scrofa) models have recently been developed for NEC, SBS and IUGR, and tissue proteomic analyses have identified unknown pathways and new prognostic disease markers. Intestinal HSPs, iron metabolism proteins and proteins related to amino acid (e.g. arginine) and glucose metabolism are consistently affected by NEC progression and some of these proteins are also affected by SBS and IUGR. Parallel changes in some plasma and urinary proteins (e.g. haptoglobin, globulins, complement proteins, fatty acid binding proteins) may mirror the intestinal responses and pave the way to biomarker discovery. Explorative non-targeted proteomics provides ideas about the cellular pathways involved in intestinal adaptation during the critical neonatal period. Proteomics, combined with other -omic techniques, helps to get a more holistic picture of intestinal adaptation during NEC, SBS and IUGR. Explorative -omic research methods also have limitations and cannot replace, but only supplement, classical hypothesis-driven research that investigate disease mechanisms using a single or few endpoints.

  14. Streptococcus thermophilus NCIMB 41856 ameliorates signs of colitis in an animal model of inflammatory bowel disease.

    PubMed

    Bailey, J R; Vince, V; Williams, N A; Cogan, T A

    2017-08-24

    Treatment of inflammatory bowel disease (IBD) is mainly based on suppression of symptoms, often with numerous side effects. Trials of probiotics in IBD have frequently produced disappointing results. The majority of probiotics are unusual, since they do not require iron for growth, unlike many bacteria resident in the intestine. The IBD intestine is iron-rich due to bleeding and use of oral iron supplements; conventional probiotics would be rapidly outcompeted. We have evaluated an iron-responsive Streptococcus thermophilus strain for its potential to reduce signs of colitis. Efficacy of S. thermophilus was evaluated in the dextran sodium sulphate mouse model of colitis. Treated animals were given 1×10(8) cfu S. thermophilus per day and clinical observations were taken daily. At termination, gross and histopathological signs of disease, cellular infiltration, location of bacteria, and cytokine expression in the intestine were determined. S. thermophilus delayed onset of colitis and reduced clinical signs of disease, including bodyweight loss and gastrointestinal bleeding. It reduced bacterial translocation into the colonic tissue. Increased numbers of CD8(+) intraepithelial lymphocytes were seen in control animals treated with S. thermophilus. S. thermophilus had no effect on gross pathology, histopathology or cytokine production in either colitic or control animals. We propose that S. thermophilus promotes maintenance of mucosal barrier function which reduces bacterial translocation, thereby reducing immune stimulation and associated inflammation. This allows mucosal healing, reducing gastrointestinal bleeding and weight loss. This could be studied as a locally-acting adjunct or alternative to current IBD treatments.

  15. Oligomannan Prebiotic Attenuates Immunological, Clinical and Behavioral Symptoms in Mouse Model of Inflammatory Bowel Disease

    PubMed Central

    Ferenczi, Szilamér; Szegi, Krisztián; Winkler, Zsuzsanna; Barna, Teréz; Kovács, Krisztina J.

    2016-01-01

    Inflammatory bowel disease shows increasing prevalence, however its pathomechanism and treatment is not fully resolved. Prebiotics are non-digestible carbohydrates which might provide an alternative to treat inflammatory conditions in the gut due to their positive effects either on the microbiome or through their direct effect on macrophages and mucosa. To test the protective effects of an oligomannan prebiotic, yeast cell wall mannooligosaccharide (MOS) was administered in dextran-sulphate-sodium (DSS)-induced mouse model of acute colitis. MOS reduced DSS-induced clinical- (weight loss, diarrhea) and histological scores (mucosal damage) as well as sickness-related anxiety. DSS treatment resulted in changes in colon microbiome with selective increase of Coliform bacteria. MOS administration attenuated colitis-related increase of Coliforms, normalized colonic muc2 expression and attenuated local expression of proinflammatory cytokines IL-1a, IL1b, IL6, KC, G-CSF and MCP1 as well as toll-like receptor TLR4 and NLRP3 inflammasome. Some of the protective effects of MOS were likely be mediated directly through local macrophages because MOS dose-dependently inhibited IL-1b and G-CSF induction following in vitro DSS challenge and IL1a, IL1b, G-SCF-, and IL6 increases after LPS treatment in mouse macrophage cell line RAW264.7. These results highlight oligomannan prebiotics as therapeutic functional food for testing in clinical trials. PMID:27658624

  16. Heligmosomoides polygyrus abrogates antigen-specific gut injury in a murine model of inflammatory bowel disease.

    PubMed

    Leung, John; Hang, Long; Blum, Arthur; Setiawan, Tommy; Stoyanoff, Korynn; Weinstock, Joel

    2012-08-01

    Developing countries have a low incidence of inflammatory bowel disease (IBD), perhaps prevented by the high prevalence of helminth infections and other alterations in intestinal flora and fauna. Helminth infections prevent colitis in various murine models of IBD. IBD may be driven by an aberrant immune response to luminal antigen(s). We developed a murine model of IBD in which gut injury was induced by a specific antigen to better simulate the IBD disease process and to determine if helminth infections could abolish gut injury induced by an orally administered antigen. The model features pan-enterocolitis triggered by feeding ovalbumin (OVA). The intestinal inflammation is antigen-specific and generates interleukin (IL)-17 and interferon-gamma (IFN-γ), but not IL-4. Full expression of the disease required T cells with defective capacity to make IL-10 and treatment with a noninjurious, low dose of a nonsteroidal antiinflammatory drug. Exposure to Heligmosomoides polygyrus abrogated this antigen-induced gut injury. H. polygyrus colonization induced Foxp3(+) T regulatory cells (Tregs) and mucosal production of IL-10 from non-T cells. Lamina propria mononuclear cells from H. polygyrus-infected mice released less IL-17 and IFN-γ constitutively and when stimulated with OVA or anti-CD3/CD28 monoclonal antibodies. We developed a murine IBD model featuring antigen-specific enterocolitis and demonstrate for the first time that gut inflammation induced by an antigen could be abrogated by H. polygyrus infection. Protection was associated with suppressed IL-17 and IFN-γ production, induction of Foxp3(+) Tregs, and elevated secretion of non-T-cell-derived IL-10, all of which could be part of the protective processes. Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.

  17. Use of Nonvascularized Abdominal Rectus Fascia After Liver, Small Bowel, and Multiorgan Transplantation: Long-Term Follow-up of a Single-Center Series.

    PubMed

    Farinelli, P A; Rubio, J S; Padín, J M; Rumbo, C; Solar, H; Ramisch, D; Gondolesi, G E

    2017-10-01

    The abdominal wall may be severely compromised in the vast majority of intestinal and multiorgan transplant candidates, and sometimes as a consequence of complex liver transplantation. Multiple options have been described to overcome this problem, varying from component separation to the extreme need of performing an abdominal wall transplantation. The aim of the present paper is to report the largest and longest-term results of patients that received an abdominal rectus fascia (ARF) after liver, intestinal, or multiorgan transplantation at a single transplant center. This is a retrospective report of a prospectively collected dataset of all the patients that received ARF during liver, isolated intestine, combined, or multiorgan transplantation at Fundación Favaloro from May 2006 to June 2016. A total of 19 out of 528 patients (3.5%) that underwent abdominal organ transplant received an ARF graft: 17 patients after receiving an intestine-containing graft, and 2 after liver retransplantations. Three patients required changing the ARF, 2 with a synthetic mesh and 1 with another ARF. Five patients required late reoperations: A relaparotomy was performed by transecting the ARF without encountering adhesions on the inner ARF surface. None of the 2 patients who received liver retransplantations and ARF developed acute or chronic ventral defects. The use of ARF is a simple and reliable surgical option to close abdominal wall defects during transplantation, the fascia adequately incorporates to the abdominal wall, allowing it to be transected and resutured in the long term and preserving the integrity of the peritoneal layer. Copyright © 2017. Published by Elsevier Inc.

  18. National Survey of Hematopoietic Cell Transplantation Center Personnel, Infrastructure, and Models of Care Delivery.

    PubMed

    Majhail, Navneet S; Mau, Lih-Wen; Chitphakdithai, Pintip; Payton, Tammy; Eckrich, Michael; Joffe, Steven; Lee, Stephanie J; LeMaistre, Charles F; LeRademacher, Jennifer; Loberiza, Fausto; Logan, Brent; Parsons, Susan K; Repaczki-Jones, Ramona; Robinett, Pam; Rizzo, J Douglas; Murphy, Elizabeth; Denzen, Ellen M

    2015-07-01

    Hematopoietic cell transplantation (HCT) is a complex procedure that requires availability of adequate infrastructure, personnel, and resources at transplantation centers. We conducted a national survey of transplantation centers in the United States to obtain data on their personnel, infrastructure, and care delivery models. A 42-item web-based survey was administered to medical directors of transplantation centers in the United States that reported any allogeneic HCT to the Center for International Blood and Marrow Transplant Research in 2011. The response rate for the survey was 79% for adult programs (85 of 108 centers) and 82% for pediatric programs (54 of 66 centers). For describing results, we categorized centers into groups with similar volumes based on 2010 total HCT activity (adult centers, 9 categories; pediatric centers, 6 categories). We observed considerable variation in available resources, infrastructure, personnel, and care delivery models among adult and pediatric transplantation centers. Characteristics varied substantially among centers with comparable transplantation volumes. Transplantation centers may find these data helpful in assessing their present capacity and use them to evaluate potential resource needs for personnel, infrastructure, and care delivery and in planning for growth. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  19. [Organizational models in the Italian nephrology, dialysis and transplantation network].

    PubMed

    Manno, Carlo; Zuccalà, Alessandro

    2013-01-01

    In this article, the Italian Society of Nephrology discusses the recent statement of the Italian National Government regarding the 'The definition of the structure and technological standards of hospital health care' and suggests a new model of organization of the Italian Nephrology, Dialysis and Transplantation Network. In particular, the Italian Society of Nephrology proposes the presence of a nephrologist as part of the Emergency Hospital Network, to oversee all extracorporeal replacement treatments taking place in Intensive Care Units. Finally, this article recommends the cooperation of the nephrologist with primary health care teams and general practitioners as a move to prevent the complications of chronic kidney disease, thus improving short-term and long-term survival outcomes and reducing the costs to the National Health System.

  20. Calea zacatechichi dichloromethane extract exhibits antidiarrheal and antinociceptive effects in mouse models mimicking irritable bowel syndrome.

    PubMed

    Sałaga, M; Kowalczuk, A; Zielinska, M; Błażewicz, A; Fichna, J

    2015-10-01

    Calea zacatechichi Schltdl. (Asteraceae alt. Compositae) is a Mexican plant commonly used in folk medicine to treat respiratory and gastrointestinal (GI) disorders. The objective of this study is to characterize the effect of C. zacatechichi extracts in mouse models mimicking the symptoms of irritable bowel syndrome (IBS). Powdered C. zacatechichi herb (leaves, stems, and flowers) was extracted with methanol. Methanolic extract was filtered and evaporated giving methanolic fraction. The residue was extracted with dichloromethane (DCM). Methanolic and DCM (200 mg/kg, per os) extracts were screened for their effect on GI motility in several in vitro tests, and the antidiarrheal and antinociceptive effects were assessed using mouse models. The influence of the DCM extract on motoric parameters and exploratory behaviors was also assessed. Finally, the composition of C. zacatechichi DCM extract was qualitatively analyzed using liquid chromatography-mass spectrometry (LC-MS) method. C. zacatechichi DCM extract significantly inhibited the contractility of mouse colon in vitro (IC50 = 17 ± 2 μg/ml). Administration of the DCM extract in vivo (200 mg/kg, per os) significantly prolonged the time of whole GI transit (46 ± 1 vs. 117 ± 27 min for control and DCM-treated animals, respectively; P = 0.0023), inhibited hypermotility, and reduced pain in mouse models mimicking functional GI disorders. Our findings suggest that constituents of the C. zacatechichi DCM extract exhibit antidiarrheal and analgesic activity. The extract may thus become an attractive material for isolation of compounds that may be used as a supplementary treatment for pain and diarrhea associated with IBS in the future.

  1. Irritable Bowel Syndrome

    MedlinePlus

    ... Want to Know About Puberty Train Your Temper Irritable Bowel Syndrome KidsHealth > For Kids > Irritable Bowel Syndrome Print A ... to minimize or prevent these symptoms. What Is Irritable Bowel Syndrome? Irritable bowel syndrome (IBS) is a fairly common ...

  2. Effect of nitrergic system on colonic motility in a rat model of irritable bowel syndrome.

    PubMed

    Temiz, Tijen Kaya; Demir, Omer; Simsek, Fatma; Kaplan, Yusuf Cem; Bahceci, Selen; Karadas, Barıs; Celik, Aslı; Koyluoglu, Gokhan

    2016-01-01

    The aim of this study is to investigate whether nitric oxide (NO)-mediated colonic motility was altered in rat irritable bowel syndrome (IBS) model, using different isoforms of NO-synthase (NOS) inhibitors. The animal model of IBS-like visceral hypersensitivity was induced by intra-colonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8 to 21. Control animals received saline instead of AA. Experiments were performed at the end of 8 weeks. Distal colon tissues were resected and direct effects of different NOS inhibitors; N-omega-nitro-L-arginine methyl ester hydrochloride, (L-NAME), ARL-17477 dihydrochloride hydrate (ARL 17477), N-[3-(Aminomethyl) phenyl] methyl]-ethanimidamidedihydrochloride (1400 W), and N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO) were evaluated concentration-dependently in vitro tissue bath. Besides, morphology of both groups was assessed with hematoxylin and eosin (H and E) staining and the impact of NO antibodies was determined using the immunohistochemical method. The mean pressure values of spontaneous contractions and KCL (80 mmol/L) responses of distal colonic segments were similar in normal and IBS rats. L-NAME and ARL-17477 significantly increased the mean pressure of spontaneous colonic contractions in normal rats versus own base values (P < 0.05), but this increase did not significantly different when compared to IBS rats. In H and E staining, there was no difference with regard to morphology between two groups. Neuronal NOS (nNOS) immunoreactivity was found to be significantly decreased in IBS when compared to control groups (P < 0.05). L-NAME and ARL-17477 mediated mean pressure values were found to be slightly decreased in IBS rats. These findings may be related to a decrease in nNOS level in IBS.

  3. Effect of nitrergic system on colonic motility in a rat model of irritable bowel syndrome

    PubMed Central

    Temiz, Tijen Kaya; Demir, Omer; Simsek, Fatma; Kaplan, Yusuf Cem; Bahceci, Selen; Karadas, Barıs; Celik, Aslı; Koyluoglu, Gokhan

    2016-01-01

    Aim: The aim of this study is to investigate whether nitric oxide (NO)-mediated colonic motility was altered in rat irritable bowel syndrome (IBS) model, using different isoforms of NO-synthase (NOS) inhibitors. Materials and Methods: The animal model of IBS-like visceral hypersensitivity was induced by intra-colonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8 to 21. Control animals received saline instead of AA. Experiments were performed at the end of 8 weeks. Distal colon tissues were resected and direct effects of different NOS inhibitors; N-omega-nitro-L-arginine methyl ester hydrochloride, (L-NAME), ARL-17477 dihydrochloride hydrate (ARL 17477), N-[3-(Aminomethyl) phenyl] methyl]-ethanimidamidedihydrochloride (1400 W), and N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO) were evaluated concentration-dependently in vitro tissue bath. Besides, morphology of both groups was assessed with hematoxylin and eosin (H and E) staining and the impact of NO antibodies was determined using the immunohistochemical method. Results: The mean pressure values of spontaneous contractions and KCL (80 mmol/L) responses of distal colonic segments were similar in normal and IBS rats. L-NAME and ARL-17477 significantly increased the mean pressure of spontaneous colonic contractions in normal rats versus own base values (P < 0.05), but this increase did not significantly different when compared to IBS rats. In H and E staining, there was no difference with regard to morphology between two groups. Neuronal NOS (nNOS) immunoreactivity was found to be significantly decreased in IBS when compared to control groups (P < 0.05). Conclusion: L-NAME and ARL-17477 mediated mean pressure values were found to be slightly decreased in IBS rats. These findings may be related to a decrease in nNOS level in IBS. PMID:27756955

  4. Investigation of pulmonary involvement in inflammatory bowel disease in an experimental model of colitis.

    PubMed

    Aydin, Bunyamin; Songur, Yıldıran; Songur, Necla; Aksu, Oğuzhan; Senol, Altug; Ciris, I Metin; Sutcu, Recep

    2016-09-01

    Inflammatory bowel disease (IBD) may also involve various extra-intestinal organs. Clinical studies have found asymptomatic/symptomatic pulmonary involvement in 1% to 6% of patients with IBD. The present study histopathologically investigated pulmonary involvement in an experimental model of colitis in order to demonstrate pulmonary tissue involvement in IBD and to expose potential etiological factors. It also explored the relation between inflammation and tissue concentrations of vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF-α). The study comprised 24 male Wistar albino rats. The rats were divided into four groups of six rats each. Acute colitis was induced in two separate groups using either the dextran sulphate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) method, while the other two groups were used as controls for each model of colitis. Wallace scoring was used for macroscopic assessment of colitis, and the lungs were histopathologically examined. Concentrations of VEGF and TNF-α in pulmonary tissue were measured by the enzyme-linked immunosorbent assay method. The number of animals that had alveolar hemorrhage was significantly higher in the TNBS-induced colitis and DSS-induced colitis groups compared to their own control groups (p = 0.015 and p = 0.015, respectively). VEGF and TNF-α concentrations in pulmonary tissues were significantly increased in both the TNBS colitis and DSS colitis groups compared to their own control groups (p = 0.002 and p = 0.004, respectively; and p = 0.002 and p = 0.002, respectively). The present study demonstrated that significant and serious histopathological changes directly associated with colitis occur in the lungs in IBD.

  5. Bowel Retraining: Strategies for Establishing Bowel Control

    MedlinePlus

    ... Jump to Topic Biofeedback Bowel Retraining Dietary Fiber Fruit Juice Laxatives Tips on Finding a Doctor Bowel training ... Treatment Treatment Overview Biofeedback Bowel Retraining Dietary Fiber Fruit Juice Hirschsprung's Disease Laxatives Stool Form Guide Tips on ...

  6. Short bowel syndrome.

    PubMed

    Donohoe, Claire L; Reynolds, John V

    2010-10-01

    The short bowel syndrome (SBS) is a state of malabsorption following intestinal resection where there is less than 200 cm of intestinal length. The management of short bowel syndrome can be challenging and is best managed by a specialised multidisciplinary team. A good understanding of the pathophysiological consequences of resection of different portions of the small intestine is necessary to anticipate and prevent, where possible, consequences of SBS. Nutrient absorption and fluid and electrolyte management in the initial stages are critical to stabilisation of the patient and to facilitate the process of adaptation. Pharmacological adjuncts to promote adaptation are in the early stages of development. Primary restoration of bowel continuity, if possible, is the principle mode of surgical treatment. Surgical procedures to increase the surface area of the small intestine or improve its function may be of benefit in experienced hands, particularly in the paediatric population. Intestinal transplant is indicated at present for patients who have failed to tolerate long-term parenteral nutrition but with increasing experience, there may be a potentially expanded role for its use in the future.

  7. A new data-driven model for post-transplant antibody dynamics in high risk kidney transplantation.

    PubMed

    Zhang, Yan; Briggs, David; Lowe, David; Mitchell, Daniel; Daga, Sunil; Krishnan, Nithya; Higgins, Robert; Khovanova, Natasha

    2017-02-01

    The dynamics of donor specific human leukocyte antigen antibodies during early stage after kidney transplantation are of great clinical interest as these antibodies are considered to be associated with short and long term clinical outcomes. The limited number of antibody time series and their diverse patterns have made the task of modelling difficult. Focusing on one typical post-transplant dynamic pattern with rapid falls and stable settling levels, a novel data-driven model has been developed for the first time. A variational Bayesian inference method has been applied to select the best model and learn its parameters for 39 time series from two groups of graft recipients, i.e. patients with and without acute antibody-mediated rejection (AMR) episodes. Linear and nonlinear dynamic models of different order were attempted to fit the time series, and the third order linear model provided the best description of the common features in both groups. Both deterministic and stochastic parameters are found to be significantly different in the AMR and no-AMR groups showing that the time series in the AMR group have significantly higher frequency of oscillations and faster dissipation rates. This research may potentially lead to better understanding of the immunological mechanisms involved in kidney transplantation.

  8. Is resectable hepatocellular carcinoma a contraindication to liver transplantation? A novel decision model based on "number of patients needed to transplant" as measure of transplant benefit.

    PubMed

    Vitale, A; Cucchetti, A; Qiao, G L; Cescon, M; Li, J; Ramirez Morales, R; Frigo, A C; Xia, Y; Tuci, F; Shen, F; Cillo, U; Pinna, A D

    2014-06-01

    Number-needed-to-treat is used in assessing the effectiveness of a health-care intervention, and reports the number of patients who need to be treated to prevent one additional bad outcome. Although largely used in medical literature, there are no studies measuring the benefit of liver transplantation (LT) over hepatic resection (HR) for hepatocellular carcinoma (HCC) in terms of "Number of patients needed to transplant (NTT)." Child-Turcotte-Pugh (CTP) Classes B-C, very large (>10 cm) and multi-nodular (>2 nodules) tumours, macroscopic vascular invasion and extra-hepatic metastases. 1028 HCC cirrhotic patients from one Eastern (n=441) and two Western (n=587) surgical units. Patient survival observed after HR by proportional hazard regression model was compared to that predicted after LT by the Metroticket calculator. The benefit obtainable from LT compared to resection was analysed in relationship with number of nodules (modelled as ordinal variable: single vs. oligonodular), size of largest nodule (modelled as a continuous variable), presence of microscopic vascular invasion (MVI), and time horizon from surgery (5-year vs. 10-year). 330 patients were beyond the Milan criteria (32%) and 597 (58%) had MVI. The prevalence of MVI was 52% in patients within Milan criteria and 71% in those beyond (p<0.0001). In the 5-year transplant benefit analysis, nodule size and HCC number were positive predictors of transplant benefit, while MVI had a strong negative impact on NTT. Transplantation performed as an effective therapy (NTT <5) only in oligonodular HCC with largest diameter >3cm (beyond conventional LT criteria) when MVI was absent. The 10-year scenario increased drastically the transplant benefit in all subgroups of resectable patients, and LT became an effective therapy (NTT <5) for all patients without MVI whenever tumor extension and for oligonodular HCC with MVI within conventional LT criteria. Based on NTT analysis, the adopted time horizon (5-year vs. 10-year

  9. Meaning of free intraperitoneal fluid in small-bowel obstruction: preliminary results using high-frequency microsonography in a rat model.

    PubMed

    Iacobellis, Francesca; Berritto, Daniela; Belfiore, Maria Paola; Di Lanno, Imma; Maiorino, Manuela; Saba, Luca; Grassi, Roberto

    2014-05-01

    The aim of this study was to detect the onset, evolution, and meaning of extraluminal free fluid in a rat model of small-bowel obstruction using high-frequency microsonography. Small-bowel obstruction was surgically created in 8 rats divided into 2 groups of 4 rats each. All rats were examined by high-frequency microsonography to monitor the evolution of small-bowel obstruction and the abdominal sonographic findings. In group 2 rats, the obstruction was resolved 2 hours after surgery. In all rats, free peritoneal fluid was detected just near the obstructed loop after 1 hour and in the hepatorenal recess after 2 hours. These features progressively increased in the following hours in group 1 rats. In group 2, the amount of free fluid decreased shortly after removing the obstruction. Free fluid is an early finding in small-bowel obstruction, and the increase or decrease of its amount is correlated with the worsening or resolution of the obstruction.

  10. Development of an Information Model for Kidney Transplant Wait List.

    PubMed

    Bircan, Hüseyin Yüce; Özçelik, Ümit; Uysal, Nida; Demirağ, Alp; Haberal, Mehmet

    2015-11-01

    Deceased-donor kidney transplant is unique among surgical procedures that are an urgent procedure performed in an elective population. It has not been possible to accurately determine when a given patient will be called for transplant. Patients on the active transplant list can be called for a transplant at any time. As a result, every effort must be made to optimize their health according to best practices and published clinical practice guidelines. Once the patient is placed on the transplant wait list after undergoing an initial extensive evaluation, continued surveillance is required. Therefore, we developed a kidney transplant wait list surveillance software program that alerts organ transplant coordinator on time regarding which patients need a work-up. The new designed software has a database of our waiting patients with their completed and pending controls. The software also has built-in functions to warn the responsible staff with an E-mail. If one of the controls of a recipient delayed, the software sends an automated E-mail to the staff regarding the patients delayed controls. The software is a Web application that works on any platform with a Web browser and Internet connection and allows access by multiple users. The software has been developed with NET platform. The database is SQL server. The software has the following functions: patient communication info, search, alert list, alert E-mail, control entry, and system management. As of January 2014, a total of 21 000 patients were registered on the National Kidney Transplant wait list in Turkey and the kidney transplant wait list had been expanding by 2000 to 3000 patients each year. Therefore computerized wait list programs are crucial to help to transplant centers to keep their patients up-to-date on time.

  11. Simulation modeling of the impact of proposed new simultaneous liver and kidney transplantation policies.

    PubMed

    Chang, Yaojen; Gallon, Lorenzo; Shetty, Kirti; Chang, Yuchia; Jay, Colleen; Levitsky, Josh; Ho, Bing; Baker, Talia; Ladner, Daniela; Friedewald, John; Abecassis, Michael; Hazen, Gordon; Skaro, Anton I

    2015-02-01

    Increasing use of kidney grafts for simultaneous liver and kidney (SLK) transplants is causing concern about the most effective utilization of scarce kidney graft resources. This study evaluated the impact of implementing the proposed United Network for Organ Sharing SLK transplant policy on outcomes for end-stage liver disease (ESLD) and end-stage renal disease (ESRD) patients awaiting transplant. A Markov model was constructed to simulate a hypothetical cohort of ESLD patients over a 30-year time horizon starting from age 50. The model applies the different criteria being considered in the United Network for Organ Sharing policy and tallies outcomes, including numbers of procedures and life years after liver transplant alone (LTA) or SLK transplant. When 1-week pretransplant dialysis duration is required, the numbers of SLK transplants and LTAs would be 648 and 9,065, respectively. If the pretransplant dialysis duration is extended to 12 weeks, there would be 240 SLK transplants and 9,426 LTAs. This change results in a decrease of 6,483 life years among SLK transplant recipients and an increase of 4,971 life years among LTA recipients. However, by increasing the dialysis duration to 12 weeks from 1 week, 408 kidney grafts would be released to the kidney waitlist because of the decline in SLK transplants; this yields 796 additional life years gained among ESRD patients. Implementation of the proposed SLK transplant policy could restore access to kidney transplants for patients with ESRD albeit at the detriment of patients with ESLD and renal impairment.

  12. Increased VGLUT3 involved in visceral hyperalgesia in a rat model of irritable bowel syndrome.

    PubMed

    Yang, Chang-Qing; Duan, Li-Ping; Qiao, Pei-Tang; Zhao, Li; Guo, Li-Li

    2015-03-14

    To investigate the activity of vesicular glutamate transporter-3 (VGLUT3) in a visceral hyperalgesia rat model of irritable bowel syndrome, and the role of mast cells (MCs). Transient intestinal infection was induced by oral administration of Trichinella spiralis larvae in rats. On the 100(th) day post-infection (PI), the rats were divided into an acute cold restraint stress (ACRS) group and a non-stressed group. Age-matched untreated rats served as controls. The abdominal withdrawal reflex was used to measure the visceromotor response to colorectal distension (CRD). The expression levels of VGLUT3 in peripheral and central neurons were analyzed by immunofluorescence and western blotting. VGLUT3 expression in the L6S1 dorsal root ganglion cells was significantly higher in the PI group than in the control group (0.32 ± 0.009 vs 0.22 ± 0.008, P < 0.01), and there was no significant difference in the expression of VGLUT3 between MC-deficient rats and their normal wild-type littermates. Immunofluorescence showed that the expression levels of VGLUT3 in PI + ACRS rats were enhanced in the prefrontal cortex of the brain compared with the control group. VGLUT3 is involved in the pathogenesis of visceral hyperalgesia. Coexpression of c-fos, 5-hydroxytryptamine and VGLUT3 after CRD was observed in associated neuronal pathways. Increased VGLUT3 induced by transient intestinal infection was found in peripheral nerves, and was independent of MCs. Moreover, the expression of VGLUT3 was enhanced in the prefrontal cortex in rats with induced infection and stress.

  13. Development of a predictive model of Crohn's disease proximal small bowel involvement in capsule endoscopy evaluation.

    PubMed

    Rodrigues-Pinto, Eduardo; Cardoso, Helder; Rosa, Bruno; Santos-Antunes, João; Rodrigues, Susana; Marques, Margarida; Lopes, Susana; Albuquerque, Andreia; Carvalho, Pedro; Moreira, Maria; Cotter, José; Macedo, Guilherme

    2016-06-01

    One of the indications for capsule endoscopy (CE) is the detection of proximal small bowel (SB) involvement in Crohn's disease (CD) patients. Our aim was to assess clinical, laboratory and endoscopic predictors associated with proximal SB involvement in CD patients submitted to CE. Retrospective multicenter study in which Lewis score (LS) was systematically determined in 190 CE of patients diagnosed with CD between 2003 and 2014. Significant inflammatory activity (LS > 135) was present in 23 % of the patients in the first tertile and in 31 % of the patients in the second tertile. Albumin, haemoglobin, and total proteins were significantly lower in patients with a LS > 790 compared to patients with a LS < 135, while white blood cell counts and C-reactive protein were significantly higher. In the univariable analysis, a higher risk for proximal SB involvement at CE was associated with ileal involvement at ileocolonoscopy (OR 2.858, P = 0.006), higher platelets levels (OR 1.005, P = 0.004) and significant weight loss (OR 2.450, P = 0.006). In logistic regression, ileal involvement at ileocolonoscopy (OR 6.817, P = 0.003), stricturing behavior (OR 8.653, P = 0.011) and significant weight loss (OR 3.629, P = 0.028) were independently associated with proximal SB involvement at CE. Considering the ROC curve of this model, a cut-off > 0.249 predicts proximal SB involvement with 90 % sensitivity and 40 % specificity (AUROC 0.732). One-third of patients had proximal SB involvement. Predictive factors were significant weight loss, stricturing behaviour, and ileal involvement at ileocolonoscopy. These data help to select CD patients that benefit the most from performing a CE.

  14. Post-Infectious Irritable Bowel Syndrome, an Inflammation-Immunological Model with Relevance for Other IBS and Functional Dyspepsia

    PubMed Central

    2010-01-01

    This review presents studies that support an inflammation-immunological model for the pathogenesis of post-infectious irritable bowel syndrome (IBS), and highlights recent studies that support a similar disease model in non-post-infectious IBS, in particular, diarrhoea-predominant IBS, as well as in post-infectious functional dyspepsia. These recent studies are highlighted to demonstrate that one line of research in functional gastrointestinal disorders has moved away from the old psychosomatic concepts. It is hoped that this will encourage future students of this field to explore the role of immunological events. PMID:20535323

  15. Reproduction and Growth in a Murine Model of Early Life-Onset Inflammatory Bowel Disease

    PubMed Central

    Nagy, Eniko; Rodriguiz, Ramona M.; Wetsel, William C.; MacIver, Nancie J.; Hale, Laura P.

    2016-01-01

    Studies in transgenic murine models have provided insight into the complexity underlying inflammatory bowel disease (IBD), a disease hypothesized to result from an injurious immune response against intestinal microbiota. We recently developed a mouse model of IBD that phenotypically and histologically resembles human childhood-onset ulcerative colitis (UC), using mice that are genetically modified to be deficient in the cytokines TNF and IL-10 (“T/I” mice). Here we report the effects of early life onset of colon inflammation on growth and reproductive performance of T/I mice. T/I dams with colitis often failed to get pregnant or had small litters with pups that failed to thrive. Production was optimized by breeding double homozygous mutant T/I males to females homozygous mutant for TNF deficiency and heterozygous for deficiency of IL-10 (“T/I-het” dams) that were not susceptible to spontaneous colon inflammation. When born to healthy (T/I-het) dams, T/I pups initially gained weight similarly to wild type (WT) pups and to their non-colitis-susceptible T/I-het littermates. However, their growth curves diverged between 8 and 13 weeks, when most T/I mice had developed moderate to severe colitis. The observed growth failure in T/I mice occurred despite a significant increase in their food consumption and in the absence of protein loss in the stool. This was not due to TNF-induced anorexia or altered food consumption due to elevated leptin levels. Metabolic studies demonstrated increased consumption of oxygen and water and increased production of heat and CO2 in T/I mice compared to their T/I-het littermates, without differences in motor activity. Based on the clinical similarities of this early life onset model of IBD in T/I mice to human IBD, these results suggest that mechanisms previously hypothesized to explain growth failure in children with IBD require re-evaluation. The T/I mouse model may be useful for further investigation of such mechanisms and for

  16. Reproduction and Growth in a Murine Model of Early Life-Onset Inflammatory Bowel Disease.

    PubMed

    Nagy, Eniko; Rodriguiz, Ramona M; Wetsel, William C; MacIver, Nancie J; Hale, Laura P

    2016-01-01

    Studies in transgenic murine models have provided insight into the complexity underlying inflammatory bowel disease (IBD), a disease hypothesized to result from an injurious immune response against intestinal microbiota. We recently developed a mouse model of IBD that phenotypically and histologically resembles human childhood-onset ulcerative colitis (UC), using mice that are genetically modified to be deficient in the cytokines TNF and IL-10 ("T/I" mice). Here we report the effects of early life onset of colon inflammation on growth and reproductive performance of T/I mice. T/I dams with colitis often failed to get pregnant or had small litters with pups that failed to thrive. Production was optimized by breeding double homozygous mutant T/I males to females homozygous mutant for TNF deficiency and heterozygous for deficiency of IL-10 ("T/I-het" dams) that were not susceptible to spontaneous colon inflammation. When born to healthy (T/I-het) dams, T/I pups initially gained weight similarly to wild type (WT) pups and to their non-colitis-susceptible T/I-het littermates. However, their growth curves diverged between 8 and 13 weeks, when most T/I mice had developed moderate to severe colitis. The observed growth failure in T/I mice occurred despite a significant increase in their food consumption and in the absence of protein loss in the stool. This was not due to TNF-induced anorexia or altered food consumption due to elevated leptin levels. Metabolic studies demonstrated increased consumption of oxygen and water and increased production of heat and CO2 in T/I mice compared to their T/I-het littermates, without differences in motor activity. Based on the clinical similarities of this early life onset model of IBD in T/I mice to human IBD, these results suggest that mechanisms previously hypothesized to explain growth failure in children with IBD require re-evaluation. The T/I mouse model may be useful for further investigation of such mechanisms and for development

  17. A model for assessment and referral of clients with bowel symptoms in community pharmacies.

    PubMed

    Sriram, Deepa; McManus, Alexandra; Emmerton, Lynne M; Parsons, Richard W; Jiwa, Moyez

    2016-01-01

    To expedite diagnosis of serious bowel disease, efforts are required to signpost patients with high-risk symptoms to appropriate care. Community pharmacies are a recognized source of health advice regarding bowel symptoms. This study aimed to examine the effectiveness of a validated self-administered questionnaire, Jodi Lee Test (JLT), for detection, triage, and referral of bowel symptoms suggestive of carcinoma, in pharmacies. 'Usual Practice' was monitored for 12 weeks in 21 pharmacies in Western Australia, documenting outcomes for 84 clients presenting with bowel symptoms. Outcome measures were: acceptance of verbal advice from the pharmacist; general practitioner consultation; and diagnosis. Trial of the JLT involved staff training in the research protocol and monitoring of outcomes for 80 recruited clients over 20 weeks. Utility of the JLT was assessed by post-trial survey of pharmacy staff. Significantly more referrals were made by staff using the JLT than during Usual Practice: 30 (38%) vs 17 (20%). Clients' acceptance of referrals was also higher for the intervention group (40% vs 6%). Two-thirds of pharmacy staff agreed that the JLT could be incorporated into pharmacy practice, and 70% indicated they would use the JLT in the future. A pre-post design was considered more appropriate than a randomized control trial due to an inability to match pharmacies. Limitations of this study were: lack of control over adherence to the study protocol by pharmacy staff; no direct measure of client feedback on the JLT; and loss to follow-up. The JLT was effective in prompting decision-making by pharmacy staff and inter-professional care between pharmacies and general practice, in triage of clients at risk of bowel cancer.

  18. Faecal microbiota transplantation-A clinical view.

    PubMed

    Mattner, J; Schmidt, F; Siegmund, B

    2016-08-01

    Faecal microbiota transplantation has gained increasing attention over the last decade as various phenotypes could be transferred from a donor to a recipient in different animal models. Clinically, however, the sole indication with evidence from a randomized placebo controlled trial is refractory Clostridium difficile infection. Despite revealing successful clinical outcomes, questions concerning regulatory affairs, the identification of the best donor, the optimal mixture of the transplant as well as the preferred route of administration remain to be clarified even for this indication. Initiated by the idea that alterations in the composition of the intestinal microbiota are associated with intestinal inflammation in inflammatory bowel disease, several studies investigated whether faecal microbiota transplantation would be an equally suitable approach for these devastating disorders. Indeed, the available data indicate changes in the microbiota composition following faecal microbial transplantation depending on the degree of intestinal inflammation. Furthermore, first data even provide evidence that the transplantation of an "optimized" microbiota induces clinical remission in ulcerative colitis. However, despite these intriguing results it needs to be considered that not only "a cure of inflammation", but also risk factors and phenotypes including obesity can be transferred via faecal microbiota transplantation. Thus, a deeper understanding of the impact of a distinct microbiota composition is required before "designing" the optimal faecal microbiota transplant.

  19. A transient parabiosis skin transplantation model in mice

    PubMed Central

    Duyverman, Annique MMJ; Kohno, Mitsutomo; Duda, Dan G; Jain, Rakesh K; Fukumura, Dai

    2012-01-01

    Parabiosis—conjoined surgery to provide a shared circulation between two mice—has been previously developed to study the hematopoietic system. This protocol describes the use of parabiosis for efficient transplantation of skin from a transgenic to a wild-type mouse. It can be used to study the role of stromal cells in a spontaneous model of distant cancer dissemination (metastasis). We have recently shown that primary tumor-derived stromal cells may facilitate metastasis by providing a provisional stroma at the secondary site. Studying the role of primary tumor–derived stroma cells requires methods for distinguishing and targeting stromal cells originating from the primary tumor versus their counterparts in the metastatic site. Parabiosis may also be used, taking advantage of the shared circulation between the parabiosed mice, to study tumor metastasis from one parabiont to another, or to investigate the role of circulating inflammatory cells or stem cells. Studying the role of stromal cells in metastasis using this model typically takes up to 11 weeks. PMID:22441295

  20. [Analysis of contractual incentives for kidney transplants in Brazil using the principal-agent model].

    PubMed

    Costa, Cassia Kely Favoretto; Balbinotto, Giácomo; Sampaio, Luciano Menezes Bezerra

    2016-09-12

    The aim of this article was to analyze contractual incentives for kidney transplants in Brazil based on the principal-agent model. The approach assumes that the Brazilian Ministry of Health is the principal and the public hospitals accredited by the National Transplant System are the agent. The Ministry of Health's welfare depends on measures taken by hospitals in kidney uptake. Hospitals allocate administrative, financial, and management efforts to conduct measures in kidney donation, removal, uptake, and transplantation. Hospitals may choose the levels of effort that are consistent with the payments and incentives received in relation to transplantation costs. The solution to this type of problem lies in structuring an optimal incentives contract, which requires aligning the interests of both parties involved in the transplantation system.

  1. Myoblast transplantation in the porcine model: a potential technique for myocardial repair.

    PubMed

    Van Meter, C H; Claycomb, W C; Delcarpio, J B; Smith, D M; deGruiter, H; Smart, F; Ochsner, J L

    1995-11-01

    The use of transgenic cells transplanted in syngeneic rodents has shown modest success, but allogeneic and xenogeneic transplants have not been uniformly successful. To assess the feasibility of xenogeneic and allogeneic myoblast transplantation, we subjected seven adult swine to transplantation of murine atrial tumor cells (xenogeneic), neonatal porcine myocytes (allogeneic), and human fetal cardiomyocytes into the left ventricular wall. After general anesthesia, isolated cells were injected along the anterior and posterior walls of the porcine left ventricle. All the animals were immuno-suppressed and observed for 1 month after injection, at which time they were killed and analyzed. This report will present results primarily concerned with the success of human cell transfers. In all injected sites examined, the transplanted cells thrived within the host myocardium with no significant rejection. Transplant cells formed close associations with host myocytes that resembled nascent intercalated disks on electron microscopy. These cells also contained myofibrils and other cell architecture resembling the transplanted cell lines. Additionally, these cells appeared to produce an angiogenic influence resulting in the proliferation of the surrounding microvasculature. We believe that these findings indicate successful xenogeneic and allogeneic myoblast cell transplantation in a large animal model. These experiments set the stage for future studies to assess the ability of these cells to form a syncytium, contract, and potentially repair failed myocardium.

  2. Sparse Modeling Reveals miRNA Signatures for Diagnostics of Inflammatory Bowel Disease.

    PubMed

    Hübenthal, Matthias; Hemmrich-Stanisak, Georg; Degenhardt, Frauke; Szymczak, Silke; Du, Zhipei; Elsharawy, Abdou; Keller, Andreas; Schreiber, Stefan; Franke, Andre

    2015-01-01

    The diagnosis of inflammatory bowel disease (IBD) still remains a clinical challenge and the most accurate diagnostic procedure is a combination of clinical tests including invasive endoscopy. In this study we evaluated whether systematic miRNA expression profiling, in conjunction with machine learning techniques, is suitable as a non-invasive test for the major IBD phenotypes (Crohn's disease (CD) and ulcerative colitis (UC)). Based on microarray technology, expression levels of 863 miRNAs were determined for whole blood samples from 40 CD and 36 UC patients and compared to data from 38 healthy controls (HC). To further discriminate between disease-specific and general inflammation we included miRNA expression data from other inflammatory diseases (inflammation controls (IC): 24 chronic obstructive pulmonary disease (COPD), 23 multiple sclerosis, 38 pancreatitis and 45 sarcoidosis cases) as well as 70 healthy controls from previous studies. Classification problems considering 2, 3 or 4 groups were solved using different types of penalized support vector machines (SVMs). The resulting models were assessed regarding sparsity and performance and a subset was selected for further investigation. Measured by the area under the ROC curve (AUC) the corresponding median holdout-validated accuracy was estimated as ranging from 0.75 to 1.00 (including IC) and 0.89 to 0.98 (excluding IC), respectively. In combination, the corresponding models provide tools for the distinction of CD and UC as well as CD, UC and HC with expected classification error rates of 3.1 and 3.3%, respectively. These results were obtained by incorporating not more than 16 distinct miRNAs. Validated target genes of these miRNAs have been previously described as being related to IBD. For others we observed significant enrichment for IBD susceptibility loci identified in earlier GWAS. These results suggest that the proposed miRNA signature is of relevance for the etiology of IBD. Its diagnostic value

  3. Bowel Incontinence

    MedlinePlus

    ... adults. It is not a normal part of aging. Causes include Constipation Damage to muscles or nerves of the anus and rectum Diarrhea Pelvic support problems Treatments include changes in diet, medicines, bowel training, or surgery. NIH: National Institute of Diabetes and Digestive and Kidney Diseases

  4. Total Face, Eyelids, Ears, Scalp, and Skeletal Subunit Transplant Research Procurement: A Translational Simulation Model.

    PubMed

    Sosin, Michael; Ceradini, Daniel J; Hazen, Alexes; Sweeney, Nicole G; Brecht, Lawrence E; Levine, Jamie P; Staffenberg, David A; Saadeh, Pierre B; Bernstein, G Leslie; Rodriguez, Eduardo D

    2016-05-01

    Cadaveric face transplant models are routinely used for technical allograft design, perfusion assessment, and transplant simulation but are associated with substantial limitations. The purpose of this study was to describe the experience of implementing a translational donor research facial procurement and solid organ allograft recovery model. Institutional review board approval was obtained, and a 49-year-old, brain-dead donor was identified for facial vascularized composite allograft research procurement. The family generously consented to donation of solid organs and the total face, eyelids, ears, scalp, and skeletal subunit allograft. The successful sequence of computed tomographic scanning, fabrication and postprocessing of patient-specific cutting guides, tracheostomy placement, preoperative fluorescent angiography, silicone mask facial impression, donor facial allograft recovery, postprocurement fluorescent angiography, and successful recovery of kidneys and liver occurred without any donor instability. Preservation of the bilateral external carotid arteries, facial arteries, occipital arteries, and bilateral thyrolinguofacial and internal jugular veins provided reliable and robust perfusion to the entirety of the allograft. Total time of facial procurement was 10 hours 57 minutes. Essential to clinical face transplant outcomes is the preparedness of the institution, multidisciplinary face transplant team, organ procurement organization, and solid organ transplant colleagues. A translational facial research procurement and solid organ recovery model serves as an educational experience to modify processes and address procedural, anatomical, and logistical concerns for institutions developing a clinical face transplantation program. This methodical approach best simulates the stressors and challenges that can be expected during clinical face transplantation. Therapeutic, V.

  5. Developing Statistical Models to Assess Transplant Outcomes Using National Registries: The Process in the United States.

    PubMed

    Snyder, Jon J; Salkowski, Nicholas; Kim, S Joseph; Zaun, David; Xiong, Hui; Israni, Ajay K; Kasiske, Bertram L

    2016-02-01

    Created by the US National Organ Transplant Act in 1984, the Scientific Registry of Transplant Recipients (SRTR) is obligated to publicly report data on transplant program and organ procurement organization performance in the United States. These reports include risk-adjusted assessments of graft and patient survival, and programs performing worse or better than expected are identified. The SRTR currently maintains 43 risk adjustment models for assessing posttransplant patient and graft survival and, in collaboration with the SRTR Technical Advisory Committee, has developed and implemented a new systematic process for model evaluation and revision. Patient cohorts for the risk adjustment models are identified, and single-organ and multiorgan transplants are defined, then each risk adjustment model is developed following a prespecified set of steps. Model performance is assessed, the model is refit to a more recent cohort before each evaluation cycle, and then it is applied to the evaluation cohort. The field of solid organ transplantation is unique in the breadth of the standardized data that are collected. These data allow for quality assessment across all transplant providers in the United States. A standardized process of risk model development using data from national registries may enhance the field.

  6. Inflammatory Bowel Disease in a Rodent Model Alters Osteocyte Protein Levels Controlling Bone Turnover.

    PubMed

    Metzger, Corinne E; Narayanan, Anand; Zawieja, David C; Bloomfield, Susan A

    2017-04-01

    Bone loss is a common comorbidity of inflammatory bowel disease (IBD), leading to elevated fracture risk in these patients. Inflammatory factors associated with IBD cause increased bone resorption and decreased bone formation with multiple factors implicated as instigators of these alterations. In this project, we examined the influence of IBD on osteocyte proteins in male rats (2 months old) divided into two groups: induced gut inflammation via 2,4,6-trinitrobenzenesulfonic acid (TNBS) enema, and vehicle control. We examined the prevalence of two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), an anti-inflammatory cytokine, interleukin-10 (IL-10), the anabolic factor insulin-like growth factor-I (IGF-I), osteoclastogenesis regulators RANKL and OPG, and the bone formation inhibitor sclerostin in osteocytes in three bone compartments 4 weeks after initiation of gut inflammation. Histomorphometry of the proximal tibia and fourth lumbar vertebra revealed lower bone volume, lower bone formation rate (BFR), lower osteoid surface (OS), and higher osteoclast surface (Oc.S) with TNBS. Tibial mid-shaft periosteal BFR was also lower with TNBS. Immunohistochemical staining of the distal femur demonstrated that %TNF-α(+) , %IL-6(+) , %RANKL(+) , and %OPG(+) osteocytes were elevated in cancellous bone in TNBS animals compared to vehicle. These changes were coincident with increased bone resorption. With regression analysis, %RANKL(+) osteocytes statistically predicted the increase in cancellous Oc.S (R(2)  = 0.565). Increased %sclerostin(+) osteocytes observed in the TNBS treatment predicted declines in cancellous OS (R(2)  = 0.581) as well as BFR in cancellous and cortical bone (R(2)  = 0.674, R(2)  = 0.908, respectively). Contrary to our hypothesis, %IGF-I(+) osteocytes increased in TNBS animals. In conclusion, the IBD model produced a systemic inflammation that altered the regulatory protein profile in osteocytes that

  7. Transamniotic stem cell therapy (TRASCET) mitigates bowel damage in a model of gastroschisis.

    PubMed

    Feng, Christina; Graham, Christopher D; Connors, John Patrick; Brazzo, Joseph; Pan, Amy H S; Hamilton, James R; Zurakowski, David; Fauza, Dario O

    2016-01-01

    We sought to determine whether intraamniotic delivery of concentrated amniotic-derived mesenchymal stem cells (afMSCs) could reduce damage to exposed bowel in experimental gastroschisis. Rat fetuses (n=117) with surgically created gastroschisis were divided into three groups: untreated animals (n=62) and two groups receiving volume-matched intraamniotic injections of either saline (n=25) or 2 × 10(6) cells/mL of syngeneic, labeled afMSCs (n=30). Animals were killed before term, along with normal controls (NL). Blinded observers performed computerized measurements of total and segmental (serosa, muscularis, and mucosa) intestinal wall thicknesses. Statistical comparisons were by ANOVA (P<0.05). Among survivors with gastroschisis, there were statistically significant decreases in total bowel wall, serosal, muscular, and mucosal thicknesses in the afMSC group vs. the untreated group (P=0.001/0.035/0.001/0.005, respectively) and vs. the saline group (P=0.003/0.05/<0.001/0.026, respectively). There were no such significant differences between the untreated and saline groups. There were no differences between the afMSC group and NL, except for a significantly thicker muscular layer in the afMSC group (P=0.014). Labeled afMSCs were scarcely identified, suggesting a paracrine effect. Amniotic mesenchymal stem cells mitigate bowel damage in experimental gastroschisis after concentrated intraamniotic injection. Transamniotic stem cell therapy (TRASCET) may become a practical component of the treatment of gastroschisis. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Impaired Endothelial Nitric Oxide Synthase Homodimer Formation Triggers Development of Transplant Vasculopathy - Insights from a Murine Aortic Transplantation Model

    PubMed Central

    Oberhuber, Rupert; Riede, Gregor; Cardini, Benno; Bernhard, David; Messner, Barbara; Watschinger, Katrin; Steger, Christina; Brandacher, Gerald; Pratschke, Johann; Golderer, Georg; Werner, Ernst R.; Maglione, Manuel

    2016-01-01

    Transplant vasculopathy (TV) represents a major obstacle to long-term graft survival and correlates with severity of ischemia reperfusion injury (IRI). Donor administration of the nitric oxide synthases (NOS) co-factor tetrahydrobiopterin has been shown to prevent IRI. Herein, we analysed whether tetrahydrobiopterin is also involved in TV development. Using a fully allogeneic mismatched (BALB/c to C57BL/6) murine aortic transplantation model grafts subjected to long cold ischemia time developed severe TV with intimal hyperplasia (α-smooth muscle actin positive cells in the neointima) and endothelial activation (increased P-selectin expression). Donor pretreatment with tetrahydrobiopterin significantly minimised these changes resulting in only marginal TV development. Severe TV observed in the non-treated group was associated with increased protein oxidation and increased occurrence of endothelial NOS monomers in the aortic grafts already during graft procurement. Tetrahydrobiopterin supplementation of the donor prevented all these early oxidative changes in the graft. Non-treated allogeneic grafts without cold ischemia time and syngeneic grafts did not develop any TV. We identified early protein oxidation and impaired endothelial NOS homodimer formation as plausible mechanistic explanation for the crucial role of IRI in triggering TV in transplanted aortic grafts. Therefore, targeting endothelial NOS in the donor represents a promising strategy to minimise TV. PMID:27883078

  9. Composite osseomusculocutaneous sternum, ribs, thymus, pectoralis muscles, and skin allotransplantation model of bone marrow transplantation.

    PubMed

    Bozkurt, Mehmet; Klimczak, Aleksandra; Nasir, Serdar; Zor, Fatih; Krokowicz, Lukasz; Siemionow, Maria

    2013-01-01

    Cellular and vascularized bone marrow cells have been used to induce donor-specific chimerism in various models of composite tissue allotransplantation. Although thymus transplantation has been reported in the literature, the effect of thymus transplantation on chimerism levels in vascularized bone containing composite tissue allotransplantation has not been reported. In this study, a new method for composite vascularized sternal bone marrow transplant model is descried that can be applied to augment chimerism after transplantation. A total of seven composite osseomusculocutaneous sternum, ribs, thymus, pectoralis muscles, and skin transplantations were performed in two groups. The first group (n = 5) was designed as an allotransplantation group and the second group (n = 2) was designed as an isotransplantation group. Composite osseomusculocutaneous sternum, ribs, thymus, and pectoralis muscles allografts were harvested on the common carotid artery and external jugular vein and a heterotopic transplantation was performed to the inguinal region of the recipient rat. Cyclosporine A monotherapy was administered in order to prevent acute and chronic allograft rejection. Animals sacrificed when any sign of rejection occurred. The longest survival was 156 day post-transplant. Assessment of bone marrow cells within sternum bone component and flow cytometry analysis of donor-specific chimerism in the peripheral blood of recipients were evaluated. Our results showed that this composite allograft carried 7.5 × 10(6) of viable hematopoietic cells within the sternum component. At day 7 post-transplant chimerism was developed in T-cell population and mean level was assessed at 2.65% for RT1(n) /CD4 and at 1.0% for RT1(n) /CD8. In this study, a new osseomusculocutaneous sternum, ribs, thymus, pectoralis muscle, and skin allotransplantation model is reported which can be used to augment hematopoietic activity for chimerism induction after transplantation.

  10. Pathological and MR-DWI study of the acute hepatic injury model after stem cell transplantation

    PubMed Central

    Shang, Quan-Liang; Xiao, En-Hua; Zhou, Qi-Chang; Luo, Jian-Guang; Wu, Hai-Jun

    2011-01-01

    AIM: To investigate apparent diffusion coefficient (ADC) values as an indication of reconditioning of acute hepatic injury (AHI) after allogeneic mononuclear bone marrow cell (MBMC) transplantation. METHODS: Three groups were used in our study: a cell transplantation group (n = 21), transplantation control group (n = 21) and normal control group (n = 10). AHI model rabbits in the cell transplantation group were injected with 5 mL of MBMC suspension at multiple sites in the liver and the transplantation controls were injected with 5 mL D-Hanks solution. At the end of the 1st, 2nd and 4th wk, 7 rabbits were randomly selected from the cell transplantation group and transplantation control group for magnetic resonance diffusion-weighted imaging (MR-DWI) and measurement of the mean ADC values of injured livers. After MR-DWI examination, the rabbits were sacrificed and the livers subjected to pathological examination. Ten healthy rabbits from the normal control group were used for MR-DWI examination and measurement of the mean ADC value of normal liver. RESULTS: At all time points, the liver pathological scores from the cell transplantation group were significantly lower than those in the transplantation control group (27.14 ± 1.46 vs 69.29 ± 6.16, 22.29 ± 2.29 vs 57.00 ± 1.53, 19.00 ± 2.31 vs 51.86 ± 6.04, P = 0.000). The mean ADC values of the cell transplantation group were significantly higher than the transplantation control group ((1.07 ± 0.07) × 10-3 mm2/s vs (0.69 ± 0.05) × 10-3 mm2/s, (1.41 ± 0.04) × 10-3 mm2/s vs (0.84 ± 0.06) × 10-3 mm2/s, (1.68 ± 0.04) × 10-3 mm2/s vs (0.86 ± 0.04) × 10-3 mm2/s, P = 0.000). The pathological scores of the cell transplantation group and transplantation control group gradually decreased. However, their mean ADC values gradually increased to near that of the normal control. At the end of the 1st wk, the mean ADC values of the cell transplantation group and transplantation control group were significantly lower

  11. Bowel Obstruction: Sonographic Evaluation.

    PubMed

    Hollerweger, A; Wüstner, M; Dirks, K

    2015-06-01

    Learning objectives: Sonographic examination concept in the case of suspicion of bowel obstruction. Recognition of the sonographic criteria of a bowel obstruction. Ability to detect the level of a bowel obstruction. Sonographic detection of typical causes of bowel obstruction. Detection of sonographic signs of complicated bowel obstruction. Ability to sonographically define important differential diagnoses. Further diagnostic procedures in unclear situations.

  12. Stimulation of intestinal growth and function with DPP4 inhibition in a mouse short bowel syndrome model.

    PubMed

    Sueyoshi, Ryo; Woods Ignatoski, Kathleen M; Okawada, Manabu; Hartmann, Bolette; Holst, Jens; Teitelbaum, Daniel H

    2014-08-15

    Glucagon-like peptide-2 (GLP-2) has been shown to be effective in patients with short bowel syndrome (SBS), but it is rapidly inactivated by dipeptidyl peptidase IV (DPP4). We used an orally active DPP4 inhibitor (DPP4-I), MK-0626, to determine the efficacy of this approach to promote adaptation after SBS, determined optimal dosing, and identified further functional actions in a mouse model of SBS. Ten-week-old mice underwent a 50% proximal small bowel resection. Dose optimization was determined over a 3-day post-small bowel resection period. The established optimal dose was given for 7, 30, and 90 days and for 7 days followed by a 23-day washout period. Adaptive response was assessed by morphology, intestinal epithelial cell (IEC) proliferation (proliferating cell nuclear antigen), epithelial barrier function (transepithelial resistance), RT-PCR for intestinal transport proteins and GLP-2 receptor, IGF type 1 receptor, and GLP-2 plasma levels. Glucose-stimulated sodium transport was assessed for intestinal absorptive function. Seven days of DPP4-I treatment facilitated an increase in GLP-2 receptor levels, intestinal growth, and IEC proliferation. Treatment led to differential effects over time, with greater absorptive function at early time points and enhanced proliferation at later time points. Interestingly, adaptation continued in the group treated for 7 days followed by a 23-day washout. DPP4-I enhanced IEC proliferative action up to 90 days postresection, but this action seemed to peak by 30 days, as did GLP-2 plasma levels. Thus DPP4-I treatment may prove to be a viable option for accelerating intestinal adaptation with SBS.

  13. Composite vascularized skin/bone graft model: a viable source for vascularized bone marrow transplantation.

    PubMed

    Siemionow, Maria; Ulusal, Betul G; Ozmen, Selahattin; Ulusal, Ali E; Ozer, Kagan

    2004-01-01

    In this study, we introduce a new model for vascularized skin and bone marrow transplantation. Twenty-five Lewis (RT1(1)) rats were studied. Anatomic dissection studies were performed in 5 animals. In the experimental group, 10 isograft transplantations were performed between Lewis rats. Combined groin skin and femoral bone flaps were transplanted based on the femoral artery and vein. Transplants were evaluated on a daily basis. All flaps survived without problems over 100 days posttransplant. The skin component remained pink and pliable, and grew new hair. Histological examination of the femoral bone (except the femoral head) revealed active hematopoiesis with a viable compact and cancellous bone components on day 100 posttransplant. This model can be applied to tolerance induction studies across the major Histocompatibility (MHC) barrier, where bone will serve as donor of stem and progenitor cells, and the skin flap will serve as a monitor of graft rejection.

  14. Hippocampal interneuron transplants reverse aberrant dopamine system function and behavior in a rodent model of schizophrenia.

    PubMed

    Perez, S M; Lodge, D J

    2013-11-01

    Schizophrenia patients exhibit increased hippocampal activity that is correlated with positive symptoms. Although the cause of this hippocampal hyperactivity has not been demonstrated, it likely involves a decrease in GABAergic signaling. Thus, we posit that restoring GABAergic function may provide a novel therapeutic approach for the treatment of schizophrenia. It has been demonstrated that transplanted GABAergic precursor cells from the medial ganglionic eminence (MGE) can migrate and differentiate into mature interneurons. Here, we demonstrate that ventral hippocampal MGE transplants can restore hippocampal function and normalize downstream dopamine neuron activity in a rodent model of schizophrenia. Furthermore, MGE transplants also reverse the hyper-responsive locomotor response to amphetamine. Taken together, these data demonstrate that restoring interneuron function reverses neurophysiological and behavioral deficits in a rodent model of schizophrenia and moreover, demonstrate the feasibility of a neuronal transplant procedure as a potential novel therapeutic approach for the treatment of schizophrenia.

  15. The burden of inflammatory bowel disease: a patient-reported qualitative analysis and development of a conceptual model.

    PubMed

    Devlen, Jennifer; Beusterien, Kathleen; Yen, Linnette; Ahmed, Awais; Cheifetz, Adam S; Moss, Alan C

    2014-03-01

    The aim of this study was to describe the impacts of inflammatory bowel disease (IBD) from the patients' perspective and to inform the development of a conceptual model. Focus groups and one-on-one interviews were undertaken in adult patients with IBD. Transcripts from the focus groups and interviews were analyzed to identify themes and links between themes, assisted by qualitative data software MaxQDA. Themes from the qualitative research were supplemented with those reported in the literature and concepts included in IBD-specific patient-reported outcome measures. Twenty-seven patients participated. Key physical symptoms included pain, bowel-related symptoms such as frequency, urgency, incontinence, diarrhea, passing blood, and systemic symptoms such as weight loss and fatigue. Participants described continuing and variable symptom experiences. IBD symptoms caused immediate disruption of activities but also had ongoing impacts on daily activities, including dietary restrictions, lifestyle changes, and maintaining close proximity to a toilet. More distal impacts included interference with work, school, parenting, social and leisure activities, relationships, and psychological well-being. The inconvenience of rectal medications, refrigerated biologics, and medication refills emerged as novel burdens not identified in existing patient-reported outcome measures. IBD symptoms cause immediate disruption in activities, but patients may continue to experience some symptoms on a chronic basis. The conceptual model presented here may be useful for identifying target concepts for measurement in future studies in IBD.

  16. Systems Biology in Kidney Transplantation: The Application of Multi-Omics to a Complex Model.

    PubMed

    Bontha, S V; Maluf, D G; Mueller, T F; Mas, V R

    2017-01-01

    In spite of reduction of rejection rates and improvement in short-term survival post-kidney transplantation, modest progress has occurred in long-term graft attrition over the years. Timely identification of molecular events that precede clinical and histopathological changes might help in early intervention and thereby increase the graft half-life. Evolution of "omics" tools has enabled systemic investigation of the influence of the whole genome, epigenome, transcriptome, proteome and microbiome on transplant function and survival. In this omics era, systemic approaches, in-depth clinical phenotyping and use of strict validation methods are the key for further understanding the complex mechanisms associated with graft function. Systems biology is an interdisciplinary holistic approach that focuses on complex and dynamic interactions within biological systems. The complexity of the human kidney transplant is unlikely to be captured by a reductionist approach. It appears essential to integrate multi-omics data that can elucidate the multidimensional and multilayered regulation of the underlying heterogeneous and complex kidney transplant model. Herein, we discuss studies that focus on genetic biomarkers, emerging technologies and systems biology approaches, which should increase the ability to discover biomarkers, understand mechanisms and stratify patients and responses post-kidney transplantation. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  17. The cost effectiveness of tacrolimus versus microemulsified cyclosporin: a 10-year model of renal transplantation outcomes.

    PubMed

    Orme, Michelle E; Jurewicz, Wieslaw A; Kumar, Nagappan; McKechnie, Tracy L

    2003-01-01

    In 1983, the launch of cyclosporin was a significant clinical advance for organ transplant recipients. Subsequent drug research led to further advances with the introduction of cyclosporin microemulsion (cyclosporin ME) and tacrolimus. This paper presents the results from a long-term model comparing the clinical and economic outcomes associated with cyclosporin ME and tacrolimus immunosuppression for the prevention of graft rejection following renal transplantation. A model was developed to project the costs and outcomes over a 10-year period following transplantation. The model was based on the results of a prospective, randomised study of 179 renal transplantation recipients receiving either cyclosporin ME or tacrolimus, which was conducted by the Welsh Transplantation Research Group (median follow-up: 2.7 years). The short-term costs and outcomes were the averages from the actual head-to-head trial data. From this, the long-term costs and outcomes were extrapolated based on the rate of change in patient and graft survival at 3, 5 and 10 years post transplant, as reported in the 1995 United Kingdom Transplant Support Service Authority Renal Transplant Audit. PERSPECTIVE AND YEAR OF COST DATA: The analysis was conducted from the perspective of a UK transplant unit. Costs were at 1999 prices (pounds sterling 1 = dollars US 1.42 = Euro 1.5) and costs and outcomes were discounted at 6% and 1.5%, respectively. The model estimated that 10 years after transplantation, the proportion of patients surviving was 56% of the cyclosporin ME cohort and 64% of the tacrolimus cohort. The cumulative cost of maintenance therapy at 10 years was pounds sterling 23204 per patient maintained on cyclosporin ME versus pounds sterling 23803 per patient on tacrolimus. The cost per survivor at 10 years was pounds sterling 37000 (tacrolimus) versus pounds sterling 41000 (cyclosporin ME) and the cost per patient with a functioning graft was pounds sterling 39000 versus pounds sterling 45000

  18. Extrahepatic islet transplantation with microporous polymer scaffolds in syngeneic mouse and allogeneic porcine models.

    PubMed

    Gibly, Romie F; Zhang, Xiaomin; Graham, Melanie L; Hering, Bernhard J; Kaufman, Dixon B; Lowe, William L; Shea, Lonnie D

    2011-12-01

    Intraportal transplantation of islets has successfully treated select patients with type 1 diabetes. However, intravascular infusion and the intrahepatic site contribute to significant early and late islet loss, yet a clinical alternative has remained elusive. We investigated non-encapsulating, porous, biodegradable polymer scaffolds as a vehicle for islet transplantation into extrahepatic sites, using syngeneic mouse and allogeneic porcine models. Scaffold architecture was modified to enhance cell infiltration leading to revascularization of the islets with minimal inflammatory response. In the diabetic mouse model, 125 islets seeded on scaffolds implanted into the epididymal fat pad restored normoglycemia within an average of 1.95 days and transplantation of only 75 islets required 12.1 days. Increasing the pore size to increase islet-islet interactions did not significantly impact islet function. The porcine model was used to investigate early islet engraftment. Increasing the islet seeding density led to a greater mass of engrafted islets, though the efficiency of islet survival decreased. Transplantation into the porcine omentum provided greater islet engraftment than the gastric submucosa. These results demonstrate scaffolds support murine islet transplantation with high efficiency, and feasibility studies in large animals support continued pre-clinical studies with scaffolds as a platform to control the transplant microenvironment.

  19. Inflammatory Bowel Disease

    MedlinePlus

    ... work? How does inflammatory bowel disease interfere with digestion? Who gets inflammatory bowel disease? How is inflammatory ... top How does inflammatory bowel disease interfere with digestion? When the small intestine becomes inflamed, as in ...

  20. Detecting inflammation and fibrosis in bowel wall with photoacoustic imaging in a Crohn's disease animal model

    NASA Astrophysics Data System (ADS)

    Xu, Guan; Johnson, Laura A.; Hu, Jack; Dillman, Jonathan R.; Higgins, Peter D. R.; Wang, Xueding

    2015-03-01

    Crohn's disease (CD) is an autoimmune disease affecting 700,000 people in the United States. This condition may cause obstructing intestinal narrowings (strictures) due to inflammation, fibrosis (deposition of collagen), or a combination of both. Utilizing the unique strong optical absorption of hemoglobin at 532 nm and collagen at 1370 nm, this study investigated the feasibility of non-invasively characterizing intestinal strictures using photoacoustic imaging (PAI). Three normal controls, ten pure inflammation and 9 inflammation plus fibrosis rat bowel wall samples were imaged. Statistical analysis of the PA measurements has shown the capability of discriminating the purely inflammatory from mixed inflammatory and fibrotic strictures.

  1. Modeling the effects of functional performance and post-transplant comorbidities on health-related quality of life after heart transplantation.

    PubMed

    Butler, Javed; McCoin, Nicole S; Feurer, Irene D; Speroff, Theodore; Davis, Stacy F; Chomsky, Don B; Wilson, John R; Merrill, Walter H; Drinkwater, Davis C; Pierson, Richard N; Pinson, C Wright

    2003-10-01

    Health-related quality of life and functional performance are important outcome measures following heart transplantation. This study investigates the impact of pre-transplant functional performance and post-transplant rejection episodes, obesity and osteopenia on post-transplant health-related quality of life and functional performance. Functional performance and health-related quality of life were measured in 70 adult heart transplant recipients. A composite health-related quality of life outcome measure was computed via principal component analysis. Iterative, multiple regression-based path analysis was used to develop an integrated model of variables that affect post-transplant functional performance and health-related quality of life. Functional performance, as measured by the Karnofsky scale, improved markedly during the first 6 months post-transplant and was then sustained for up to 3 years. Rejection Grade > or =2 was negatively associated with health-related quality of life, measured by Short Form-36 and reversed Psychosocial Adjustment to Illness Scale scores. Patients with osteopenia had lower Short Form-36 physical scores and obese patients had lower functional performance. Path analysis demonstrated a negative direct effect of obesity (beta = - 0.28, p < 0.05) on post-transplant functional performance. Post-transplant functional performance had a positive direct effect on the health-related quality of life composite score (beta = 0.48, p < 0.001), and prior rejection episodes grade > or =2 had a negative direct effect on this measure (beta = -0.29, p < 0.05). Either directly or through effects mediated by functional performance, moderate-to-severe rejection, obesity and osteopenia negatively impact health-related quality of life. These findings indicate that efforts should be made to devise immunosuppressive regimens that reduce the incidence of acute rejection, weight gain and osteopenia after heart transplantation.

  2. [Heart transplantation and long-term lvad support cost-effectiveness model].

    PubMed

    Szentmihályi, Ilona; Barabás, János Imre; Bali, Ágnes; Kapus, Gábor; Tamás, Csilla; Sax, Balázs; Németh, Endre; Pólos, Miklós; Daróczi, László; Kőszegi, Andrea; Cao, Chun; Benke, Kálmán; Kovács, Péter Barnabás; Fazekas, Levente; Szabolcs, Zoltán; Merkely, Béla; Hartyánszky, István

    2016-12-01

    Heart transplantation is a high priority project at Semmelweis University. In accordance with this, the funding of heart transplantation and mechanical circulatory support also constitutes an important issue. In this report, the authors discuss the creation of a framework with the purpose of comparing the cost-effectiveness of heart transplantation and artificial heart implantation. Our created framework includes the calculation of cost, using the direct allocation method, calculating the incremental cost-effectiveness ratio and creating a cost-effectiveness plane. Using our model, it is possible to compare the initial, perioperative and postoperative expenses of both the transplanted and the artificial heart groups. Our framework can possibly be used for the purposes of long term follow-up and with the inclusion of a sufficient number of patients, the creation of cost-effectiveness analyses and supporting strategic decision-making.

  3. Assessment and Planning for a Pediatric Bilateral Hand Transplant Using 3-Dimensional Modeling: Case Report.

    PubMed

    Gálvez, Jorge A; Gralewski, Kevin; McAndrew, Christine; Rehman, Mohamed A; Chang, Benjamin; Levin, L Scott

    2016-03-01

    Children are not typically considered for hand transplantation for various reasons, including the difficulty of finding an appropriate donor. Matching donor-recipient hands and forearms based on size is critically important. If the donor's hands are too large, the recipient may not be able to move the fingers effectively. Conversely, if the donor's hands are too small, the appearance may not be appropriate. We present an 8-year-old child evaluated for a bilateral hand transplant following bilateral amputation. The recipient forearms and model hands were modeled from computed tomography imaging studies and replicated as anatomic models with a 3-dimensional printer. We modified the scale of the printed hand to produce 3 proportions, 80%, 100% and 120%. The transplant team used the anatomical models during evaluation of a donor for appropriate match based on size. The donor's hand size matched the 100%-scale anatomical model hand and the transplant team was activated. In addition to assisting in appropriate donor selection by the transplant team, the 100%-scale anatomical model hand was used to create molds for prosthetic hands for the donor.

  4. Predictive model for delayed graft function based on easily available pre-renal transplant variables.

    PubMed

    Zaza, Gianluigi; Ferraro, Pietro Manuel; Tessari, Gianpaolo; Sandrini, Silvio; Scolari, Maria Piera; Capelli, Irene; Minetti, Enrico; Gesualdo, Loreto; Girolomoni, Giampiero; Gambaro, Giovanni; Lupo, Antonio; Boschiero, Luigino

    2015-03-01

    Identification of pre-transplant factors influencing delayed graft function (DGF) could have an important clinical impact. This could allow clinicians to early identify dialyzed chronic kidney disease (CKD) patients eligible for special transplant programs, preventive therapeutic strategies and specific post-transplant immunosuppressive treatments. To achieve these objectives, we retrospectively analyzed main demographic and clinical features, follow-up events and outcomes registered in a large dedicated dataset including 2,755 patients compiled collaboratively by four Italian renal/transplant units. The years of transplant ranged from 1984 to 2012. Statistical analysis clearly demonstrated that some recipients' characteristics at the time of transplantation (age and body weight) and dialysis-related variables (modality and duration) were significantly associated with DGF development (p ≤ 0.001). The area under the receiver-operating characteristic (ROC) curve of the final model based on the four identified variables predicting DGF was 0.63 (95 % CI 0.61, 0.65). Additionally, deciles of the score were significantly associated with the incidence of DGF (p value for trend <0.001). Therefore, in conclusion, in our study we identified a pre-operative predictive model for DGF, based on inexpensive and easily available variables, potentially useful in routine clinical practice in most of the Italian and European dialysis units.

  5. Comparison of intracerebral transplantation effects of different stem cells on rodent stroke models.

    PubMed

    Wu, Yun; Wu, Jianyu; Ju, Rongkai; Chen, Zhiguo; Xu, Qunyuan

    2015-06-01

    In the present study, induced pluripotent stem cells (iPSCs), induced neural stem cells (iNSCs), mesenchymal stem cells (MSCs) and an immortalized cell line (RMNE6), representing different characteristics of stem cells, were transplanted into normal and/or injured brain areas of rodent stroke models, and their effects were compared to select suitable stem cells for cell replacement stroke therapy. The rat and mice ischaemic models were constructed using the middle cerebral artery occlusion technique. Both electrocoagulation of the artery and the intraluminal filament technique were used. The behaviour changes and fates of grafted stem cells were determined mainly by behaviour testing and immunocytochemistry. Following iPSC transplantation into the corpora striata of normal mice, a tumour developed in the brain. The iNSCs survived well and migrated towards the injured area without differentiation. Although there was no tumourigenesis in the brain of normal or ischaemic mice after the iNSCs were transplanted in the cortices, the behaviour in ischaemic mice was not improved. Upon transplanting MSC and RMNE6 cells into ischaemic rat brains, results similar to iNSCs in mice were seen. However, transplantation of RMNE6 caused a brain tumour. Thus, tumourigenesis and indeterminate improvement of behaviour are challenging problems encountered in stem cell therapy for stroke, and the intrinsic characteristics of stem cells should be remodelled before transplantation. © 2015 The Authors Cell Biochemistry and Function Published by John Wiley & Sons Ltd.

  6. Engendering Allograft Ignorance in a Mouse Model of Allogeneic Skin Transplantation to the Distal Hind Limb

    PubMed Central

    Agarwal, Shailesh; Loder, Shawn; Wood, Sherri; Cederna, Paul S.; Bishop, D. Keith; Wang, Stewart C.; Levi, Benjamin

    2015-01-01

    Objective The aim of this study was to demonstrate lymphatic isolation in a model of hind limb lymph node (LN) excision, consisting of ipsilateral popliteal and inguinal LN excision and to evaluate the immunologic response to allogeneic skin transplanted onto this region of lymphatic isolation. Methods To study lymphatic flow, C57BL/6 mice underwent lymphadenectomy (n = 5), sham lymphadenectomy (n = 5), or no intervention (n = 5), followed by methylene blue injection. Mice were dissected to determine whether methylene blue traveled to the iliac LN. To study host response to skin transplantation, C57BL/6 mice underwent allogeneic skin transplantation with LN excision (n = 6), allogeneic skin transplantation alone (n = 6), or syngeneic skin transplantation (n = 4). Skin grafts were placed distal to the popliteal fossa and mice were euthanized at day 10. Grafts were stained for endothelial cell and proliferation markers (CD31 and Ki67, respectively). Secondary lymphoid tissues (spleen, ipsilateral axillary LN, and contralateral inguinal LN) were removed and rechallenged with BALB/c alloantigen in vitro with subsequent assay of interferon-γ and interleukin 4 cell expression using ELISPOT technique. Results Mice that underwent LN excision had no evidence of methylene blue in the iliac nodes; mice without surgical intervention or with sham LN excision consistently had methylene blue visible in the ipsilateral iliac nodes. Mice treated with allogeneic skin transplantation and LN excision had lower expression of interferon-γ and interleukin 4 in the secondary lymphoid tissues. Conclusions Lymph node excision completely interrupts lymphatic flow of the hind limb. This model of lymphatic isolation impairs the ability of the transplant recipient to acutely mount a Th1 or Th2 response to allogeneic skin transplants. PMID:24509194

  7. Anti-inflammatory effects of orally administered glucosamine oligomer in an experimental model of inflammatory bowel disease.

    PubMed

    Azuma, Kazuo; Osaki, Tomohiro; Kurozumi, Seiji; Kiyose, Masatoshi; Tsuka, Takeshi; Murahata, Yusuke; Imagawa, Tomohiro; Itoh, Norihiko; Minami, Saburo; Sato, Kimihiko; Okamoto, Yoshiharu

    2015-01-22

    Anti-inflammatory effects of oral administration of the glucosamine oligomers (chito-oligosaccharides: COS) were evaluated in an experimental model of inflammatory bowel disease (IBD). Oral administration of COS improved shortening of colon length and tissue injury (as assessed by histology) in mice. Oral administration of COS inhibited inflammation in the colonic mucosa by suppression of myeloperoxidase activation in inflammatory cells, as well as activation of nuclear factor-kappa B, cyclooxygenase-2, and inducible nitric oxide synthase. Oral administration of COS also reduced serum levels of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6). Moreover, it prolonged survival time in mice. These data suggest that COS have anti-inflammatory effects in an experimental model of IBD, and could be new functional foods for IBD patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: translational relevance and challenges

    PubMed Central

    Ney, Denise M.; Sigalet, David L.; Vegge, Andreas; Burrin, Douglas

    2014-01-01

    Intestinal failure (IF), due to short bowel syndrome (SBS), results from surgical resection of a major portion of the intestine, leading to reduced nutrient absorption and need for parenteral nutrition (PN). The incidence is highest in infants and relates to preterm birth, necrotizing enterocolitis, atresia, gastroschisis, volvulus, and aganglionosis. Patient outcomes have improved, but there is a need to develop new therapies for SBS and to understand intestinal adaptation after different diseases, resection types, and nutritional and pharmacological interventions. Animal studies are needed to carefully evaluate the cellular mechanisms, safety, and translational relevance of new procedures. Distal intestinal resection, without a functioning colon, results in the most severe complications and adaptation may depend on the age at resection (preterm, term, young, adult). Clinically relevant therapies have recently been suggested from studies in preterm and term PN-dependent SBS piglets, with or without a functional colon. Studies in rats and mice have specifically addressed the fundamental physiological processes underlying adaptation at the cellular level, such as regulation of mucosal proliferation, apoptosis, transport, and digestive enzyme expression, and easily allow exogenous or genetic manipulation of growth factors and their receptors (e.g., glucagon-like peptide 2, growth hormone, insulin-like growth factor 1, epidermal growth factor, keratinocyte growth factor). The greater size of rats, and especially young pigs, is an advantage for testing surgical procedures and nutritional interventions (e.g., PN, milk diets, long-/short-chain lipids, pre- and probiotics). Conversely, newborn pigs (preterm or term) and weanling rats provide better insights into the developmental aspects of treatment for SBS in infants owing to their immature intestines. The review shows that a balance among practical, economical, experimental, and ethical constraints will determine the

  9. Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: Translational relevance and challenges

    USDA-ARS?s Scientific Manuscript database

    Intestinal failure (IF), due to short bowel syndrome (SBS), results from surgical resection of a major portion of the intestine, leading to reduced nutrient absorption and need for parenteral nutrition (PN). The incidence is highest in infants and relates to preterm birth, necrotizing enterocolitis,...

  10. Bowel Retraining: Strategies for Establishing Bowel Control

    MedlinePlus

    ... Survey Results Treatment Treatment Overview Biofeedback Bowel Retraining Dietary Fiber Fruit Juice Hirschsprung's Disease Laxatives Stool Form Guide ... Survey Results Treatment Treatment Overview Biofeedback Bowel Retraining Dietary Fiber Fruit Juice Hirschsprung's Disease Laxatives Stool Form Guide ...

  11. Practical whole-tooth restoration utilizing autologous bioengineered tooth germ transplantation in a postnatal canine model

    PubMed Central

    Ono, Mitsuaki; Oshima, Masamitsu; Ogawa, Miho; Sonoyama, Wataru; Hara, Emilio Satoshi; Oida, Yasutaka; Shinkawa, Shigehiko; Nakajima, Ryu; Mine, Atsushi; Hayano, Satoru; Fukumoto, Satoshi; Kasugai, Shohei; Yamaguchi, Akira; Tsuji, Takashi; Kuboki, Takuo

    2017-01-01

    Whole-organ regeneration has great potential for the replacement of dysfunctional organs through the reconstruction of a fully functional bioengineered organ using three-dimensional cell manipulation in vitro. Recently, many basic studies of whole-tooth replacement using three-dimensional cell manipulation have been conducted in a mouse model. Further evidence of the practical application to human medicine is required to demonstrate tooth restoration by reconstructing bioengineered tooth germ using a postnatal large-animal model. Herein, we demonstrate functional tooth restoration through the autologous transplantation of bioengineered tooth germ in a postnatal canine model. The bioengineered tooth, which was reconstructed using permanent tooth germ cells, erupted into the jawbone after autologous transplantation and achieved physiological function equivalent to that of a natural tooth. This study represents a substantial advancement in whole-organ replacement therapy through the transplantation of bioengineered organ germ as a practical model for future clinical regenerative medicine. PMID:28300208

  12. Nursing resources and responsibilities according to hospital organizational model for management of inflammatory bowel disease in Spain.

    PubMed

    Marín, Laura; Torrejón, Antonio; Oltra, Lorena; Seoane, Montserrat; Hernández-Sampelayo, Paloma; Vera, María Isabel; Casellas, Francesc; Alfaro, Noelia; Lázaro, Pablo; García-Sánchez, Valle

    2011-06-01

    Nurses play an important role in the multidisciplinary management of inflammatory bowel disease (IBD), but little is known about this role and the associated resources. To improve knowledge of resource availability for health care activities and the different organizational models in managing IBD in Spain. Cross-sectional study with data obtained by questionnaire directed at Spanish Gastroenterology Services (GS). Five GS models were identified according to whether they have: no specific service for IBD management (Model A); IBD outpatient office for physician consultations (Model B); general outpatient office for nurse consultations (Model C); both, Model B and Model C (Model D); and IBD Unit (Model E) when the hospital has a Comprehensive Care Unit for IBD with telephone helpline, computer, including a Model B. Available resources and activities performed were compared according to GS model (chi-square test and test for linear trend). Responses were received from 107 GS: 33 Model A (31%), 38 Model B (36%), 4 Model C (4%), 16 Model D (15%) and 16 Model E (15%). The model in which nurses have the most resources and responsibilities is the Model E. The more complete the organizational model, the more frequent the availability of nursing resources (educational material, databases, office, and specialized software) and responsibilities (management of walk-in appointments, provision of emotional support, health education, follow-up of drug treatment and treatment adherence) (p<0.05). Nurses have more resources and responsibilities the more complete is the organizational model for IBD management. Development of these areas may improve patient outcomes. Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  13. Liver transplantation for lethal genetic syndromes: a novel model of personalized genomic medicine.

    PubMed

    Petrowsky, Henrik; Brunicardi, F Charles; Leow, Voon Meng; Venick, Robert S; Agopian, Vatche; Kaldas, Fady M; Zarrinpar, Ali; Markovic, Daniela; McDiarmid, Sue V; Hong, Johnny C; Farmer, Douglas G; Hiatt, Jonathan R; Busuttil, Ronald W

    2013-04-01

    Our aim was to analyze our single-center experience with orthotopic liver transplantation for metabolic lethal genetic syndromes in children and adults. From 1984 to 2012, all pediatric (younger than 18 years) and adult (18 years and older) patients who underwent orthotopic liver transplantation for lethal genetic disorders were identified. Data on diagnostic pathways and specific outcomes were analyzed for both groups. Outcomes measures included recurrence rate as well as graft and patient survival. Metabolic lethal genetic syndrome was the primary indication for orthotopic liver transplantation in 152 of 4,564 patients (3.3%) at University of California, Los Angeles during the study period (74 pediatric patients and 78 adults). Genetic testing was performed in only 12% of the 152 patients and in 39% of patients after 2006. Two patients (1.3%) experienced a recurrence of the genetic disease. Overall 5- and 20-year survival rates were 89% and 77% for children and 73% and 50% for adults. Survival of pediatric patients was superior to adults (log-rank p < 0.009). Multivariate analysis identified age (hazard ratio = 2.18), preoperative life support (hazard ratio = 2.68), and earlier transplantation (hazard ratio = 3.41) as independent predictors of reduced survival. Orthotopic liver transplantation achieved excellent long-term survival in pediatric and adult patients with lethal genetic syndromes and represents a model of personalized genomic medicine by providing gene therapy through solid organ transplantation. Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

  14. [Effects of neural stem cells transplanted into an animal model of Alzheimer disease on Aβ plaques].

    PubMed

    Zhang, Wei; Wang, Pei-jun; Gu, Guo-jun; Li, Ming-hua; Gao, Xiao-long

    2013-12-03

    To explore the effects on Aβ plaques of neural stem cells transplanted into an Alzheimer disease mouse model. A total of twenty 12-months-old APP+PS1 double transgenic AD mice were randomly divided into two groups.One group received neural stem cells transplantation, that was NSC group, another mice received an equal quantity 0.01 mol/L PBS, as positive control group. After 5 weeks transplantation, the total number of Aβ plaques examined by immunohistochemistry, the ratio of compact of Aβ plaques by TS staining, and whether NSCs migrate into Aβ plaques by immunofluorescence monitoring. There was no difference in total number of Aβ plaques between NSC group (181 ± 12) and PBS (179 ± 14) group after transplantation (P > 0.05). There was no difference in the number of TS+ plaques between NSC group (54.9%) and PBS (55.7%) group after eight weeks NSCs transplantation (P > 0.05). (2) However, engrafted NSCs showed partial chemotaxis toward Aβ plaques. NSCs transplantation did not have a significant impact on Aβ plaques of AD mice, but the tropism of engrafted NSCs may be capable of replacing lost or damaged cells and reverse the course of AD mice in some extent.

  15. The effect of donor-specific transfusion upon rejection in a rat model of laryngeal transplantation.

    PubMed

    Akst, Lee M; Dan, Olivia; Strome, Marshall

    2006-01-01

    Lifelong immunosuppression carries significant morbidity, and techniques to reduce or eliminate such immunosuppression might expand laryngeal transplantation. This study investigates the ability of donor-specific transfusion to establish tolerance in a rat model of laryngeal transplantation. A total of 289 transplants were performed from Lewis-Brown-Norway donors to Lewis recipients. Donor-specific transfusion was provided as single intravenous injections of donor splenocytes 1 hour before transplantation. Different combinations of in vitro irradiation of donor larynges and postoperative cyclosporine doses provided additional immunomodulation. Allograft rejection was scored histologically at sacrifice 15 or 30 days posttransplant. Multivariate analysis was performed across all groups, and paired analyses compared groups with and without donor-specific transfusion. Donor-specific transfusion did not improve rejection score, although increased cyclosporine dose did (P < .001). Donor splenocyte injection on the day of transplantation does not establish tolerance to laryngeal allografts or permit reduction of other immunosuppression. Other immunomodulatory strategies to establish tolerance in rat laryngeal transplantation require further investigation.

  16. Small islets are essential for successful intraportal transplantation in a diabetes mouse model.

    PubMed

    Su, Z; Xia, J; Shao, W; Cui, Y; Tai, S; Ekberg, H; Corbascio, M; Chen, J; Qi, Z

    2010-12-01

    Optimization of islet transplantation protocols is necessary for improved success of treatment for type 1 diabetes. Here, we investigated whether the size of islets transplanted into the portal vein (PV) of the liver can affect engraftment in the early post-transplantation in an experimental mouse model. Small (average diameter < 250 μm, group A) or large (average diameter > 250 μm, group B) islets (400 islet equivalents/recipient) purified from normal BALB/c mice were transplanted into syngenic recipients with diabetes induced by STZ. The percentage of mice returning to a non-diabetic status was higher in group A (100%) than that of group B (62.5%). Focal areas of liver necrosis associated with the islets emboli were observed in both groups, but the pathology in group B was significantly worse. Multiple proinflammatory cytokines were significantly higher in group B than that of A at 3 h post-transplantation. Our study determined that the size of islets plays a critical role in the success of intraportal islet transplantation (IPIT) and should be taken into account in future IPIT protocols for the treatment of diabetes.

  17. Antinociceptive Effect of Ghrelin in a Rat Model of Irritable Bowel Syndrome Involves TRPV1/Opioid Systems.

    PubMed

    Mao, Yuqing; Li, Zhengyang; Chen, Kan; Yu, Huafang; Zhang, Shaoren; Jiang, Miao; Ma, Yuanhua; Liang, Chunli; Liu, Hongyan; Li, Huanqing; Hua, Qian; Zhou, Hao; Sun, Yonghong; Fan, Xiaoming

    2017-09-20

    Irritable bowel syndrome (IBS), defined as recurrent abdominal pain and changes in bowel habits, seriously affects quality of life and ability to work. Ghrelin is a brain-gut hormone, which has been reported to show antinociceptive effects in peripheral pain. We investigated the effect of ghrelin on visceral hypersensitivity and pain in a rat model of IBS. Maternal deprivation (MD) was used to provide a stress-induced model of IBS in Wistar rats. Colorectal distension (CRD) was used to detect visceral sensitivity, which was evaluated by abdominal withdrawal reflex (AWR) scores. Rats that were confirmed to have visceral hypersensitivity after MD were injected with ghrelin (10 µg/kg) subcutaneously twice a week from weeks 7 to 8. [D-Lys3]-GHRP-6 (100 nmol/L) and naloxone (100 nmol/L) were administered subcutaneously to block growth hormone secretagogue receptor 1α (GHS-R1α) and opioid receptors, respectively. Expression of transient receptor potential vanilloid type 1 (TRPV1) and µ and κ opioid receptors (MOR and KOR) in colon, dorsal root ganglion (DRG) and cerebral cortex tissues were detected by western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical analyses and immunofluorescence. Ghrelin treatment increased expression of opioid receptors and inhibited expression of TRPV1 in colon, dorsal root ganglion (DRG) and cerebral cortex. The antinociceptive effect of ghrelin in the rat model of IBS was partly blocked by both the ghrelin antagonist [D-Lys3]-GHRP-6 and the opioid receptor antagonist naloxone. The results indicate that ghrelin exerted an antinociceptive effect, which was mediated via TRPV1/opioid systems, in IBS-induced visceral hypersensitivity. Ghrelin might potentially be used as a new treatment for IBS. © 2017 The Author(s). Published by S. Karger AG, Basel.

  18. Probabilistic (Bayesian) Modeling of Gene Expression in Transplant Glomerulopathy

    DTIC Science & Technology

    2010-01-01

    Service, Walter Reed Army Medical Center 3 National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health 4...chronic allograft nephropathy . 8 Clinical presentation often occurs a year or more after transplantation, although in the context of protocol kidney...there are limited treatment options. This limits 13 the ability to judge the effectiveness of a biomarker panel in addressing a clinical disease

  19. Cell sheet transplantation of cultured mesenchymal stem cells enhances bone formation in a rat nonunion model.

    PubMed

    Nakamura, Akifumi; Akahane, Manabu; Shigematsu, Hideki; Tadokoro, Mika; Morita, Yusuke; Ohgushi, Hajime; Dohi, Yoshiko; Imamura, Tomoaki; Tanaka, Yasuhito

    2010-02-01

    Orthopedic surgeons have long been troubled by cases involving nonunion of fractured bones. This study aimed to enhance bone union by cell sheet transplantation of mesenchymal stem cells. A nonunion model was made in rat femur, and rat bone marrow cells were cultured in medium containing dexamethasone and ascorbic acid phosphate to create a cell sheet that could be scraped off as a single sheet. Cell sheets were transplanted onto fractured femurs without a scaffold in the model. X-ray and histological analysis were performed at 2, 4 and 8 weeks. Ultrasonography and biomechanical analysis were performed at 8 weeks. X-ray photographs and histological sections showed callus formation around the fracture site in the cell sheet-transplanted group (sheet group). Bone union was obtained in the sheet group at 8 weeks. By contrast, the control group (without sheet transplantation) showed nonunion of the femur. The results of pullout evaluation in the vertical direction of the femur in the sheet group were significantly better than that of the control group. Analysis of the origin of de novo formed bone using the Sry gene, which was used as a marker for donor cells, showed that transplanted cells without scaffolds could survive and differentiate into osteogenic lineage cells in vivo. These results showed that the femoral fracture in our model was completely cured by the transplantation of a cell sheet created by tissue engineering techniques. Thus, we think that cell sheet transplantation can contribute to hard tissue reconstruction in cases involving nonunion, bone defects and osteonecrosis. (c) 2009 Elsevier Inc. All rights reserved.

  20. Fate of bone marrow mesenchymal stromal cells following autologous transplantation in a rabbit model of osteonecrosis.

    PubMed

    Sugaya, Hisashi; Mishima, Hajime; Gao, Ran; Kaul, Sunil C; Wadhwa, Renu; Aoto, Katsuya; Li, Meihua; Yoshioka, Tomokazu; Ogawa, Takeshi; Ochiai, Naoyuki; Yamazaki, Masashi

    2016-02-01

    Internalizing quantum dots (i-QDs) are a useful tool for tracking cells in vivo in models of tissue regeneration. We previously synthesized i-QDs by conjugating QDs with a unique internalizing antibody against a heat shock protein 70 family stress chaperone. In the present study, i-QDs were used to label rabbit mesenchymal stromal cells (MSCs) that were then transplanted into rabbits to assess differentiation potential in an osteonecrosis model. The i-QDs were taken up by bone marrow-derived MSCs collected from the iliac of 12-week-old Japanese white rabbits that were positive for cluster of differentiation (CD)81 and negative for CD34 and human leukocyte antigen DR. The average rate of i-QD internalization was 93.3%. At 4, 8, 12, and 24 weeks after transplantation, tissue repair was evaluated histologically and by epifluorescence and electron microscopy. The i-QDs were detected at the margins of the drill holes and in the necrotized bone trabecular. There was significant colocalization of the i-QD signal in transplanted cells and markers of osteoblast and mineralization at 4, 8, and 12 weeks post-transplantation, while i-QDs were detected in areas of mineralization at 12 and 24 weeks post-transplantation. Moreover, i-QDs were observed in osteoblasts in regenerated tissue by electron microscopy, demonstrating that the tissue was derived from transplanted cells. These results indicate that transplanted MSCs can differentiate into osteoblasts and induce tissue repair in an osteonecrosis model and can be tracked over the long term by i-QD labeling. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  1. A kidney transplantation model in a low-resource country: an experience from Pakistan

    PubMed Central

    Rizvi, Syed Adibul Hasan; Naqvi, Syed Ali Anwar; Zafar, Mirza Naqi; Akhtar, Syed Fazal

    2013-01-01

    Pakistan is a low-resource country with a population of 185 million where expenditure on health is 1.3% of the gross national product. The estimated incidence of end-stage renal disease (ESRD) is 100 per million of the population. The paucity and high costs of renal replacement therapy render more than 90% of the ESRD population disenfranchised from replacement therapy. Our center, which is a government sector organization, established as an integrated dialysis and living related renal transplant program in the 1980s, where all services were provided free of cost to all patients with life-long follow-up care including medications. The model was based on a concept of community/government partnership where the contributions to funds vary between 40% and 60% for each partner. The model has been self sustaining for 25 years, with an annual budget of $28 million in 2010. Presently, over 600 patients are dialyzed each day and each week, 7–10 patients have received live related transplants. The overall 1- and 5-year graft survival rate of 3150 transplants is 92% and 85%, respectively. Free dialysis and transplantation established our institute as a focus of transplantation in the country. This model therefore allowed the institute to have a vital role in the campaign against transplant tourism and in the promulgation of the transplant law. It shows that in low-resource countries, specialized centers in the government sector can, with community support, provide high-quality ESRD care to the disenfranchised population. PMID:25018989

  2. Predicting patient survival after deceased donor kidney transplantation using flexible parametric modelling.

    PubMed

    Li, Bernadette; Cairns, John A; Robb, Matthew L; Johnson, Rachel J; Watson, Christopher J E; Forsythe, John L; Oniscu, Gabriel C; Ravanan, Rommel; Dudley, Christopher; Roderick, Paul; Metcalfe, Wendy; Tomson, Charles R; Bradley, J Andrew

    2016-05-25

    The influence of donor and recipient factors on outcomes following kidney transplantation is commonly analysed using Cox regression models, but this approach is not useful for predicting long-term survival beyond observed data. We demonstrate the application of a flexible parametric approach to fit a model that can be extrapolated for the purpose of predicting mean patient survival. The primary motivation for this analysis is to develop a predictive model to estimate post-transplant survival based on individual patient characteristics to inform the design of alternative approaches to allocating deceased donor kidneys to those on the transplant waiting list in the United Kingdom. We analysed data from over 12,000 recipients of deceased donor kidney or combined kidney and pancreas transplants between 2003 and 2012. We fitted a flexible parametric model incorporating restricted cubic splines to characterise the baseline hazard function and explored a range of covariates including recipient, donor and transplant-related factors. Multivariable analysis showed the risk of death increased with recipient and donor age, diabetic nephropathy as the recipient's primary renal diagnosis and donor hypertension. The risk of death was lower in female recipients, patients with polycystic kidney disease and recipients of pre-emptive transplants. The final model was used to extrapolate survival curves in order to calculate mean survival times for patients with specific characteristics. The use of flexible parametric modelling techniques allowed us to address some of the limitations of both the Cox regression approach and of standard parametric models when the goal is to predict long-term survival.

  3. Modelling seagrass growth and development to evaluate transplanting strategies for restoration.

    PubMed

    Renton, Michael; Airey, Michael; Cambridge, Marion L; Kendrick, Gary A

    2011-10-01

    Seagrasses are important marine plants that are under threat globally. Restoration by transplanting vegetative fragments or seedlings into areas where seagrasses have been lost is possible, but long-term trial data are limited. The goal of this study is to use available short-term data to predict long-term outcomes of transplanting seagrass. A functional-structural plant model of seagrass growth that integrates data collected from short-term trials and experiments is presented. The model was parameterized for the species Posidonia australis, a limited validation of the model against independent data and a sensitivity analysis were conducted and the model was used to conduct a preliminary evaluation of different transplanting strategies. The limited validation was successful, and reasonable long-term outcomes could be predicted, based only on short-term data. This approach for modelling seagrass growth and development enables long-term predictions of the outcomes to be made from different strategies for transplanting seagrass, even when empirical long-term data are difficult or impossible to collect. More validation is required to improve confidence in the model's predictions, and inclusion of more mechanism will extend the model's usefulness. Marine restoration represents a novel application of functional-structural plant modelling.

  4. Modelling seagrass growth and development to evaluate transplanting strategies for restoration

    PubMed Central

    Renton, Michael; Airey, Michael; Cambridge, Marion L.; Kendrick, Gary A.

    2011-01-01

    Background and Aims Seagrasses are important marine plants that are under threat globally. Restoration by transplanting vegetative fragments or seedlings into areas where seagrasses have been lost is possible, but long-term trial data are limited. The goal of this study is to use available short-term data to predict long-term outcomes of transplanting seagrass. Methods A functional–structural plant model of seagrass growth that integrates data collected from short-term trials and experiments is presented. The model was parameterized for the species Posidonia australis, a limited validation of the model against independent data and a sensitivity analysis were conducted and the model was used to conduct a preliminary evaluation of different transplanting strategies. Key Results The limited validation was successful, and reasonable long-term outcomes could be predicted, based only on short-term data. Conclusions This approach for modelling seagrass growth and development enables long-term predictions of the outcomes to be made from different strategies for transplanting seagrass, even when empirical long-term data are difficult or impossible to collect. More validation is required to improve confidence in the model's predictions, and inclusion of more mechanism will extend the model's usefulness. Marine restoration represents a novel application of functional–structural plant modelling. PMID:21821624

  5. Stem Cell-Derived Photoreceptor Transplants Differentially Integrate Into Mouse Models of Cone-Rod Dystrophy.

    PubMed

    Santos-Ferreira, Tiago; Völkner, Manuela; Borsch, Oliver; Haas, Jochen; Cimalla, Peter; Vasudevan, Praveen; Carmeliet, Peter; Corbeil, Denis; Michalakis, Stylianos; Koch, Edmund; Karl, Mike O; Ader, Marius

    2016-06-01

    Preclinical studies on photoreceptor transplantation provided evidence for restoration of visual function with pluripotent stem cells considered as a potential source for sufficient amounts of donor material. Adequate preclinical models representing retinal disease conditions of potential future patients are needed for translation research. Here we compared transplant integration in mouse models with mild (prominin1-deficient; Prom1-/-) or severe (cone photoreceptor function loss 1/rhodopsin-deficient double-mutant; Cpfl1/Rho-/-) cone-rod degeneration. For photoreceptor transplant production, we combined the mouse embryonic stem cell retinal organoid system with rhodopsin-driven GFP cell labeling by recombinant adeno-associated virus (AAV). Organoid-derived photoreceptors were enriched by CD73-based magnetic-activated cell sorting (MACS) and transplanted subretinally into wild-type, Prom1-/- and Cpfl1/Rho-/- hosts. The survival, maturation, and synapse formation of donor cells was analyzed by immunohistochemistry. Retinal organoids yielded high photoreceptor numbers that were further MACS-enriched to 85% purity. Grafted photoreceptors survived in the subretinal space of all mouse models. Some cells integrated into wild-type as well as Prom1-/- mouse retinas and acquired a mature morphology, expressing rod and synaptic markers in close proximity to second-order neurons. In contrast, in the novel Cpfl1/Rho-/- model with complete photoreceptor degeneration, transplants remained confined to the subretinal space, expressed rod-specific but only reduced synaptic markers, and did not acquire mature morphology. Comparison of photoreceptor grafts in preclinical models with incomplete or complete photoreceptor loss, showed differential transplant success with effective and impaired integration, respectively. Thus, Cpfl1/Rho-/- mice represent a potential benchmark model resembling patients with severe retinal degeneration to optimize photoreceptor replacement therapies.

  6. Cox Regression Model Analysis of Infection in Renal Transplants After Operation.

    PubMed

    Junchen, Z; Houjing, Z; Yun, F

    2016-10-01

    The objective of this study was to explore the factors that affect infections after renal transplant, establishing the Cox model to forecast infection for patients of renal transplant. Data were collected from patients who had renal transplantation in Nanking Jinlin Hospital from January 2011 to April 2015 (n = 305 transplants). There were 296 individual data that could be used after deleting the people who were lacking some data, changing the main immunosuppressants during the first year, losing follow-up, and data writing that was not fully 1 year after the operation; 296 individuals were divided by 3:7. The 206 data of patients (7/10 of the total individuals) were used to analyze and build a model, and the rest of the data were used to verify the model, analyzing the 206 data with Cox regression, discovering the factors that affect the infection after renal transplant independently, building the model, and verification. Cox regression showed that there are three independent factors that affect infections after renal transplant: X3, the donor type (relative risk [RR] = 1.929, P = .037); X9, dialysis time (RR = 1.017, P = .032); and X13, human leukocyte antigen (HLA) match (RR = 0.257, P = .013). The model is: PI = 0.657X3 + 0.017X9 - 1.359X13. All PI for the 206 individuals were calculated and then divided into three groups: the low-risk group, the median-risk group, and the high-risk group. The model was verified by calculating the PI for all 90 people. The log-rank test showed that the survival rates among these groups were significantly different (P < .001). Donor type, dialysis time, and HLA match are all factors that affect infection after renal transplant. Donor type and dialysis time were the dangerous factors for infection, but HLA match was the protecting factor. The model depends on these three factors and could forecast infection after renal transplant. Copyright © 2016. Published by Elsevier Inc.

  7. Adult zebrafish intestine resection: a novel model of short bowel syndrome, adaptation, and intestinal stem cell regeneration.

    PubMed

    Schall, K A; Holoyda, K A; Grant, C N; Levin, D E; Torres, E R; Maxwell, A; Pollack, H A; Moats, R A; Frey, M R; Darehzereshki, A; Al Alam, D; Lien, C; Grikscheit, T C

    2015-08-01

    Loss of significant intestinal length from congenital anomaly or disease may lead to short bowel syndrome (SBS); intestinal failure may be partially offset by a gain in epithelial surface area, termed adaptation. Current in vivo models of SBS are costly and technically challenging. Operative times and survival rates have slowed extension to transgenic models. We created a new reproducible in vivo model of SBS in zebrafish, a tractable vertebrate model, to facilitate investigation of the mechanisms of intestinal adaptation. Proximal intestinal diversion at segment 1 (S1, equivalent to jejunum) was performed in adult male zebrafish. SBS fish emptied distal intestinal contents via stoma as in the human disease. After 2 wk, S1 was dilated compared with controls and villus ridges had increased complexity, contributing to greater villus epithelial perimeter. The number of intervillus pockets, the intestinal stem cell zone of the zebrafish increased and contained a higher number of bromodeoxyuridine (BrdU)-labeled cells after 2 wk of SBS. Egf receptor and a subset of its ligands, also drivers of adaptation, were upregulated in SBS fish. Igf has been reported as a driver of intestinal adaptation in other animal models, and SBS fish exposed to a pharmacological inhibitor of the Igf receptor failed to demonstrate signs of intestinal adaptation, such as increased inner epithelial perimeter and BrdU incorporation. We describe a technically feasible model of human SBS in the zebrafish, a faster and less expensive tool to investigate intestinal stem cell plasticity as well as the mechanisms that drive intestinal adaptation.

  8. STAT3 accelerates uterine epithelial regeneration in a mouse model of decellularized uterine matrix transplantation

    PubMed Central

    Hiraoka, Takehiro; Saito-Fujita, Tomoko; Matsuo, Mitsunori; Egashira, Mahiro; Matsumoto, Leona; Haraguchi, Hirofumi; Dey, Sudhansu K.; Furukawa, Katsuko S.; Fujii, Tomoyuki; Osuga, Yutaka

    2016-01-01

    Although a close connection between uterine regeneration and successful pregnancy in both humans and mice has been consistently observed, its molecular basis remains unclear. We here established a mouse model of decellularized uterine matrix (DUM) transplantation. Resected mouse uteri were processed with SDS to make DUMs without any intact cells. DUMs were transplanted into the mouse uteri with artificially induced defects, and all the uterine layers were recovered at the DUM transplantation sites within a month. In the regenerated uteri, normal hormone responsiveness in early pregnancy was observed, suggesting the regeneration of functional uteri. Uterine epithelial cells rapidly migrated and formed a normal uterine epithelial layer within a week, indicating a robust epithelial-regenerating capacity. Stromal and myometrial regeneration occurred following epithelial regeneration. In ovariectomized mice, uterine regeneration of the DUM transplantation was similarly observed, suggesting that ovarian hormones are not essential for this regeneration process. Importantly, the regenerating epithelium around the DUM demonstrated heightened STAT3 phosphorylation and cell proliferation, which was suppressed in uteri of Stat3 conditional knockout mice. These data suggest a key role of STAT3 in the initial step of the uterine regeneration process. The DUM transplantation model is a powerful tool for uterine regeneration research. PMID:27358915

  9. A new composite hemiface/mandible/tongue transplantation model in rats.

    PubMed

    Kulahci, Yalcin; Siemionow, Maria

    2010-01-01

    Extensive head and neck deformities, including bone and soft tissue defects, are always challenging for reconstructive surgeons. The purpose of this study was to extend the application of the face/scalp transplantation model in rats by the incorporation of vascularized mandible, masseter and tongue (based on the same vascular pedicle), and to use this as a model to test new reconstructive options for extensive head and neck deformities with involving large soft and bone tissue defects.A total of 10 composite hemiface/mandible/tongue transplantations were performed in Lewis rats (RT1). Hemimandibular bone, masseter muscle, tongue and hemifacial skin flaps were dissected based on the same vascular pedicle of common carotid artery and external jugular vein. The flaps were then transplanted to the recipient inguinal region. Evaluation methods included flap angiography, plain x-ray, computed tomographic scan, and histology.All transplants survived indefinitely and no graft loss was noted. Flap angiography demonstrated intact vascular supply to the bone. Computed tomography scan and bone histology confirmed the viability of the bone components for the composite grafts. Hematoxylin and eosin staining determined the presence of viable bone marrow cells within the transplanted mandible. Viability of the tongue was confirmed by the presence of pink color and bleeding after puncture, as well as by histology.We have introduced a new composite hemiface/mandible/tongue transplant model. The main advantage of this model is the presence of vascularized bone marrow within the mandibular component, which may facilitate future studies on chimerism and tolerance induction. Although this mandible composite allograft is placed heterotopically to the recipient inguinal region, we believe that it may serve as a new reconstructive option for the coverage of combined bone and soft tissue defects within the head and neck region.

  10. [Therapeutic effect of GDNF gene-modified mesencephalic neural stem cell transplantation in a rat model of Parkinson disease].

    PubMed

    Duan, Kuijia; Wang, Xiangpeng; Yang, Zhiyong; Wang, Bo; Wang, Mingguo; Zhang, Hailong; Deng, Xingli

    2016-01-01

    To evaluate the therapeutic effect of transplantation of mesencephalic neural stem cells (mNSCs) genetically modified by glial cell line-derived neurotrophic factor (GDNF) gene in a rat model of Parkinson disease. mNSCs isolated from the lateral component of the midbrain of fetal rats at gestational age of 14 or 15 days were cultured for 5 days before genetic modification with GFP or GDNF gene. Rat models of Parkinson disease established by stereotactic injection of 6-hydroxy dopamine in the ventral area of the midbrain and the medial forebrain bundle were randomized into 3 groups to receive PBS injection, GFP gene-modified mNSCs transplantation, or GDNF gene-modified mNSCs transplantation into the right stratum. The behavioral changes of the rats were evaluated by observing rotations induced by intraperitoneal injection of apomorphine after the transplantation, and the survival, migration and differentiation of the transplanted cells were identified by immunohistochemistry. Transplantation with GDNF gene-modified mNSCs significantly improved the behavioral abnormalities of the rat models as compared with PBS injection and GFP gene-modified mNSCs transplantation. At 56 days after the transplantation, a greater number of the transplanted cells survived in the rat brain and more differentiated dopaminergic neurons were detected in GDNF gene-modified mNSCs transplantation group than in GFP gene-modified mNSCs transplantation group. GDNF gene-modified mNSCs transplantation can significantly improve dyskinesia in rat models of Parkinson disease, but the molecular mechanism needs further clarification.

  11. Effect of liver histopathology on islet cell engraftment in the model mimicking autologous islet cell transplantation.

    PubMed

    Desai, Chirag S; Khan, Khalid M; Ma, Xiaobo; Li, Henghong; Wang, Juan; Fan, Lijuan; Chen, Guoling; Smith, Jill P; Cui, Wanxing

    2017-09-13

    The inflammatory milieu in the liver as determined by histopathology is different in individual patients undergoing autologous islet cell transplantation. We hypothesized that inflammation related to fatty-liver adversely impacts islet survival. To test this hypothesis, we used a mouse model of fatty-liver to determine the outcome of syngeneic islet transplantation after chemical pancreatectomy. Mice (C57BL/6) were fed a high-fat-diet from 6 weeks of age until attaining a weight of ≥28 grams (6-8 weeks) to produce a fatty liver (histologically > 30% fat);steatosis was confirmed with lipidomic profile of liver tissue. Islets were infused via the intra-portal route in fatty-liver and control mice after streptozotocin induction of diabetes. Outcomes were assessed by the rate of euglycemia, liver histopathology, evaluation of liver inflammation by measuring tissue cytokines IL-1β and TNF-α by RT-PCR and CD31 expression by immunohistochemistry. The difference in the euglycemic fraction between the normal liver group (90%, 9/10) and the fatty-liver group (37.5%, 3/8) was statistically significant at the 18(th) day post- transplant and was maintained to the end of the study (day 28) (p = 0.019, X(2) = 5.51). Levels of TNF-α and IL-1β were elevated in fatty-liver mice (p = 0.042, p = 0.037). Compared to controls cytokine levels were elevated after islet cell transplantation and in transplanted fatty-liver mice as compared to either fatty- or islet transplant group alone (p = NS). A difference in the histochemical pattern of CD31 could not be determined. Fatty-liver creates an inflammatory state which adversely affects the outcome of autologous islet cell transplantation.

  12. Pregnancy in an intestinal transplant recipient.

    PubMed

    Gomez-Lobo, Veronica; Landy, Helain J; Matsumoto, Cal; Fishbein, Thomas M

    2012-08-01

    Intestinal transplantation is a relatively new form of therapy for short gut syndrome. Pregnancy after intestinal transplantation is rare. A 26-year-old small bowel transplant recipient presented for prenatal care. She previously had undergone bariatric surgery and later experienced small bowel necrosis and resection. The resulting short gut syndrome was treated with an isolated small bowel transplant. Medications during this pregnancy included prednisone, esomeprazole, diphenoxylate-atropine, ascorbic acid, tacrolimus, and magnesium supplementation. Throughout her pregnancy, her creatinine level was elevated. Labor was induced at 39 3/7 weeks and resulted in a spontaneous vaginal delivery of a healthy female neonate. Twelve weeks after delivery, the mother was admitted for a rejection reaction that was treated successfully. A successful pregnancy in an intestinal transplant recipient resulted in delivery of a healthy term newborn.

  13. Selective Enhancement of Donor Hematopoietic Cell Engraftment by the CXCR4 Antagonist AMD3100 in a Mouse Transplantation Model

    PubMed Central

    Kang, Yubin; Chen, Benny J.; DeOliveira, Divino; Mito, Jeffrey; Chao, Nelson J.

    2010-01-01

    The interaction between stromal cell-derived factor-1 (SDF-1) with CXCR4 chemokine receptors plays an important role in hematopoiesis following hematopoietic stem cell transplantation. We examined the efficacy of post transplant administration of a specific CXCR4 antagonist (AMD3100) in improving animal survival and in enhancing donor hematopoietic cell engraftment using a congeneic mouse transplantation model. AMD3100 was administered subcutaneously at 5 mg/kg body weight 3 times a week beginning at day +2 post-transplant. Post-transplant administration of AMD3100 significantly improves animal survival. AMD3100 reduces pro-inflammatory cytokine/chemokine production. Furthermore, post transplant administration of AMD3100 selectively enhances donor cell engraftment and promotes recovery of all donor cell lineages (myeloid cells, T and B lymphocytes, erythrocytes and platelets). This enhancement results from a combined effect of increased marrow niche availability and greater cell division induced by AMD3100. Our studies shed new lights into the biological roles of SDF-1/CXCR4 interaction in hematopoietic stem cell engraftment following transplantation and in transplant-related mortality. Our results indicate that AMD3100 provides a novel approach for enhancing hematological recovery following transplantation, and will likely benefit patients undergoing transplantation. PMID:20596257

  14. Derivation of a Predictive Model for Graft Loss Following Acute Kidney Injury in Kidney Transplant Recipients

    PubMed Central

    Molnar, Amber O.; van Walraven, Carl; Fergusson, Dean; Garg, Amit X.; Knoll, Greg

    2017-01-01

    Background: Acute kidney injury (AKI) is common in the kidney transplant population. Objective: To derive a multivariable survival model that predicts time to graft loss following AKI. Design: Retrospective cohort study using health care administrative and laboratory databases. Setting: Southwestern Ontario (1999-2013) and Ottawa, Ontario, Canada (1996-2013). Patients: We included first-time kidney only transplant recipients who had a hospitalization with AKI 6 months or greater following transplant. Measurements: AKI was defined using the Acute Kidney Injury Network criteria (stage 1 or greater). The first episode of AKI was included in the analysis. Graft loss was defined by return to dialysis or repeat kidney transplant. Methods: We performed a competing risk survival regression analysis using the Fine and Gray method and modified the model into a simple point system. Graft loss with death as a competing event was the primary outcome of interest. Results: A total of 315 kidney transplant recipients who had a hospitalization with AKI 6 months or greater following transplant were included. The median (interquartile range) follow-up time was 6.7 (3.3-10.3) years. Graft loss occurred in 27.6% of the cohort. The final model included 6 variables associated with an increased risk of graft loss: younger age, increased severity of AKI, failure to recover from AKI, lower baseline estimated glomerular filtration rate, increased time from kidney transplant to AKI admission, and receipt of a kidney from a deceased donor. The risk score had a concordance probability of 0.75 (95% confidence interval [CI], 0.69-0.82). The predicted 5-year risk of graft loss fell within the 95% CI of the observed risk more than 95% of the time. Limitations: The CIs of the estimates were wide, and model overfitting is possible due to the limited sample size; the risk score requires validation to determine its clinical utility. Conclusions: Our prognostic risk score uses commonly available

  15. Derivation of a Predictive Model for Graft Loss Following Acute Kidney Injury in Kidney Transplant Recipients.

    PubMed

    Molnar, Amber O; van Walraven, Carl; Fergusson, Dean; Garg, Amit X; Knoll, Greg

    2017-01-01

    Acute kidney injury (AKI) is common in the kidney transplant population. To derive a multivariable survival model that predicts time to graft loss following AKI. Retrospective cohort study using health care administrative and laboratory databases. Southwestern Ontario (1999-2013) and Ottawa, Ontario, Canada (1996-2013). We included first-time kidney only transplant recipients who had a hospitalization with AKI 6 months or greater following transplant. AKI was defined using the Acute Kidney Injury Network criteria (stage 1 or greater). The first episode of AKI was included in the analysis. Graft loss was defined by return to dialysis or repeat kidney transplant. We performed a competing risk survival regression analysis using the Fine and Gray method and modified the model into a simple point system. Graft loss with death as a competing event was the primary outcome of interest. A total of 315 kidney transplant recipients who had a hospitalization with AKI 6 months or greater following transplant were included. The median (interquartile range) follow-up time was 6.7 (3.3-10.3) years. Graft loss occurred in 27.6% of the cohort. The final model included 6 variables associated with an increased risk of graft loss: younger age, increased severity of AKI, failure to recover from AKI, lower baseline estimated glomerular filtration rate, increased time from kidney transplant to AKI admission, and receipt of a kidney from a deceased donor. The risk score had a concordance probability of 0.75 (95% confidence interval [CI], 0.69-0.82). The predicted 5-year risk of graft loss fell within the 95% CI of the observed risk more than 95% of the time. The CIs of the estimates were wide, and model overfitting is possible due to the limited sample size; the risk score requires validation to determine its clinical utility. Our prognostic risk score uses commonly available information to predict the risk of graft loss in kidney transplant patients hospitalized with AKI. If validated

  16. Intravenous transplantation of bone marrow-derived mononuclear cells prevents memory impairment in transgenic mouse models of Alzheimer's disease.

    PubMed

    Kanamaru, Takuya; Kamimura, Naomi; Yokota, Takashi; Nishimaki, Kiyomi; Iuchi, Katsuya; Lee, Hyunjin; Takami, Shinya; Akashiba, Hiroki; Shitaka, Yoshitsugu; Ueda, Masayuki; Katsura, Ken-Ichiro; Kimura, Kazumi; Ohta, Shigeo

    2015-04-24

    Stem cell transplantation therapy is currently in clinical trials for the treatment of ischemic stroke, and several beneficial aspects have been reported. Similarly, in Alzheimer's disease (AD), stem cell therapy is expected to provide an efficient therapeutic approach. Indeed, the intracerebral transplantation of stem cells reduced amyloid-β (Aβ) deposition and rescued memory deficits in AD model mice. Here, we show that intravenous transplantation of bone marrow-derived mononuclear cells (BMMCs) improves cognitive function in two different AD mouse models, DAL and APP mice, and prevents neurodegeneration. GFP-positive BMMCs were isolated from tibiae and femurs of 4-week-old mice and then transplanted intravenously into DAL and APP mice. Transplantation of BMMCs suppressed neuronal loss and restored memory impairment of DAL mice to almost the same level as in wild-type mice. Transplantation of BMMCs to APP mice reduced Aβ deposition in the brain. APP mice treated with BMMCs performed significantly better on behavioral tests than vehicle-injected mice. Moreover, the effects were observed even with transplantation after the onset of cognitive impairment in DAL mice. Together, our results indicate that intravenous transplantation of BMMCs has preventive effects against the cognitive decline in AD model mice and suggest a potential therapeutic effect of BMMC transplantation therapy.

  17. Benefits of Zataria multiflora Boiss in Experimental Model of Mouse Inflammatory Bowel Disease

    PubMed Central

    Nakhai, Leila Ashtaral; Mohammadirad, Azadeh; Yasa, Narges; Minaie, Bagher; Nikfar, Shekoufeh; Ghazanfari, Ghazal; Zamani, Mohammad Jafar; Dehghan, Gholamreza; Jamshidi, Hamidreza; Boushehri, Vahid Shetab; Khorasani, Reza

    2007-01-01

    Inflammatory bowel disease (IBD) is a chronic condition of the intestine with unknown etiology involving multiple immune, genetic and environmental factors. We were interested to examine the effect of total extract from Zataria multiflora Boiss, a folk medicinal plant on prevention and treatment of experimental IBD. Z. multiflora was administered (400, 600, 900 p.p.m.) through drinking water to IBD mice induced by intrarectal administration of acetic acid. Prednisolone was used as the standard drug for comparison. Biochemical, macroscopic and microscopic examinations of colon were performed. Biochemical evaluation of inflamed colon was done using assay of myeloperoxidase (MPO) activity and thiobarbituric acid reactive substances (TBARS) concentration as indicators of free radical activity and cell lipid peroxidation. The activity of MPO and lipid peroxidation products (TBARS) increased in acetic acid-treated groups while recovered by pretreatment of animals with Z. multiflora (400–900 p.p.m.) and prednisolone. Z. multiflora (600 and 900 p.p.m.) and prednisolone-treated groups showed significantly lower score values of macroscopic and microscopic characters when compared with the acetic acid-treated group. The beneficial effect of Z. multiflora (900 p.p.m.) was comparable with that of prednisolone. The antioxidant, antimicrobial and anti-inflammatory potentials of Z. multiflora might be the mechanisms by which this herbal extract protects animals against experimentally induced IBD. Proper clinical investigation should be carried out to confirm the activity in human. PMID:17342240

  18. Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Zinöcker, Severin; Dressel, Ralf; Wang, Xiao-Nong; Dickinson, Anne M.; Rolstad, Bent

    2012-01-01

    Allogeneic hematopoietic cell transplantation (alloHCT) extends the lives of thousands of patients who would otherwise succumb to hematopoietic malignancies such as leukemias and lymphomas, aplastic anemia, and disorders of the immune system. In alloHCT, different immune cell types mediate beneficial graft-versus-tumor (GvT) effects, regulate detrimental graft-versus-host disease (GvHD), and are required for protection against infections. Today, the “good” (GvT effector cells and memory cells conferring protection) cannot be easily separated from the “bad” (GvHD-causing cells), and alloHCT remains a hazardous medical modality. The transplantation of hematopoietic stem cells into an immunosuppressed patient creates a delicate environment for the reconstitution of donor blood and immune cells in co-existence with host cells. Immunological reconstitution determines to a large extent the immune status of the allo-transplanted host against infections and the recurrence of cancer, and is critical for long-term protection and survival after clinical alloHCT. Animal models continue to be extremely valuable experimental tools that widen our understanding of, for example, the dynamics of post-transplant hematopoiesis and the complexity of immune reconstitution with multiple ways of interaction between host and donor cells. In this review, we discuss the rat as an experimental model of HCT between allogeneic individuals. We summarize our findings on lymphocyte reconstitution in transplanted rats and illustrate the disease pathology of this particular model. We also introduce the rat skin explant assay, a feasible alternative to in vivo transplantation studies. The skin explant assay can be used to elucidate the biology of graft-versus-host reactions, which are known to have a major impact on immune reconstitution, and to perform genome-wide gene expression studies using controlled combinations of minor and major histocompatibility between the donor and the recipient

  19. Repeated transplantation of hepatocytes prevents fulminant hepatitis in a rat model of Wilson's disease.

    PubMed

    Sauer, Vanessa; Siaj, Ramsi; Stöppeler, Sandra; Bahde, Ralf; Spiegel, Hans-Ullrich; Köhler, Gabriele; Zibert, Andree; Schmidt, Hartmut H J

    2012-02-01

    The outcome of consecutive hepatocyte transplants was explored in a rat model of Wilson's disease before the onset of fulminant hepatitis without preconditioning regimens. Rats received a high-copper diet in order to induce a rapid induction of liver failure. Sham-operated rats (15/15) developed jaundice and fulminant hepatitis, and they died within 4 weeks of first transplantation. Despite the continuation of a high dietary copper challenge, long-term survival was observed for a notable proportion of the transplanted animals (7/18). All survivors displayed normalized levels of hepatitis-associated serum markers and ceruloplasmin oxidase activity by posttransplant days 50 and 98, respectively. The liver copper concentrations, the liver histology, and the expression of marker genes were significantly restored within 4 months of transplantation in comparison with the control group. The high expression of a copper transporter gene (ATPase Cu++ transporting beta polypeptide) in the livers of the survivors indicated a high rate of repopulation by donor hepatocytes. Our data suggest that repeated cell transplantation can overcome the limitations of a single therapy session in rats with severe hepatic disease by functionally restoring the host liver without preconditioning.

  20. Kidney transplantation process in Brazil represented in business process modeling notation.

    PubMed

    Peres Penteado, A; Molina Cohrs, F; Diniz Hummel, A; Erbs, J; Maciel, R F; Feijó Ortolani, C L; de Aguiar Roza, B; Torres Pisa, I

    2015-05-01

    Kidney transplantation is considered to be the best treatment for people with chronic kidney failure, because it improves the patients' quality of life and increases their length of survival compared with patients undergoing dialysis. The kidney transplantation process in Brazil is defined through laws, decrees, ordinances, and resolutions, but there is no visual representation of this process. The aim of this study was to analyze official documents to construct a representation of the kidney transplantation process in Brazil with the use of business process modeling notation (BPMN). The methodology for this study was based on an exploratory observational study, document analysis, and construction of process diagrams with the use of BPMN. Two rounds of validations by specialists were conducted. The result includes the kidney transplantation process in Brazil representation with the use of BPMN. We analyzed 2 digital documents that resulted in 2 processes with 45 total of activities and events, 6 organizations involved, and 6 different stages of the process. The constructed representation makes it easier to understand the rules for the business of kidney transplantation and can be used by the health care professionals involved in the various activities within this process. Construction of a representation with language appropriate for the Brazilian lay public is underway.

  1. Transplantation of magnetically labeled mesenchymal stem cells in a model of perinatal brain injury.

    PubMed

    Chen, Aiqing; Siow, Bernard; Blamire, Andrew M; Lako, Majlinda; Clowry, Gavin J

    2010-11-01

    Periventricular white matter injury (PVWMI) in preterm infants is a leading cause of cerebral palsy. Mesenchymal stem cell (MSC) transplantation in experimental models of adult demyelinating conditions is reported to reduce neurological deficits so we investigated their potential for treating developmental PVWMI. Neonatal rat MSCs, when cultured and labeled in vitro with fluorescent, micrometer-sized paramagnetic iron oxide particles (MPIO), retained their differentiation potential. Rats received bilateral intracerebral injections of ibotenic acid at postnatal day 5 causing PVWMI-like lesions with localized hypomyelination and sensorimotor deficits. MPIO-labeled MSCs were transplanted near the lesion in the right hemisphere 1 day postlesioning. Animals receiving cell transplants showed significantly increased antimyelin immunoreactivity in the corpus callosum, and improved reaching and retrieval skills, compared to animals receiving conditioned medium only. In separate experiments, in vivo MRI demonstrated that MPIO-labeled cells migrated away from the injection site toward lesioned areas in both hemispheres, confirmed by microscopy postmortem, but double-labeling studies found little evidence of differentiation into neural phenotypes. MSC transplantation led to significantly more forebrain cell proliferation, assayed by bromodeoxyuridine incorporation, than in controls. MSC transplants may have been neuroprotective and indirectly contributed to brain repair. Copyright © 2010 Elsevier B.V. All rights reserved.

  2. Bone and cartilage repair by transplantation of induced pluripotent stem cells in murine joint defect model.

    PubMed

    Uto, Sakura; Nishizawa, Satoru; Takasawa, Yutaka; Asawa, Yukiyo; Fujihara, Yuko; Takato, Tsuyoshi; Hoshi, Kazuto

    2013-01-01

    The establishment of cartilage regenerative medicine has been an important issue in the clinical field, because cartilage has the poor ability of self-repair. Currently, tissue engineering using autologous chondrocytes has risen, but we should investigate more appropriate cell sources that can be obtained without any quantitative limitation. In this study, we focused on induced pluripotent stem (iPS) cells, in which the ethical hurdle does not seem higher than that of embryonic stem cells. Mouse iPS cells were transplanted into the mouse joint defect model of the knee. Strains of the transplants and hosts were arranged to be either closest (homology 75% in genetic background) or identical (100%). For transplantation, we embedded the iPS cells within the collagen hydrogel in order to obtain the effective administration of the cells into defects, which induced the differentiation of the iPS cells. At 8 weeks of transplantation, although the iPS cells with a 75% homology to the host in the genetic background tended to form teratoma, those of 100% showed a joint regeneration. GFP immunohistochemistry proved that the transplanted iPS cells were responsible for the bone and cartilage repair. Taking these results together, the iPS cells are regarded as a promising cell source for the cartilage tissue engineering.

  3. A Peptide to Reduce Pulmonary Edema in a Rat Model of Lung Transplantation

    PubMed Central

    Finsterwalder, Richard; Friedl, Heinz P.; Rauscher, Sabine; Gröger, Marion; Kocher, Alfred; Wagner, Christine; Wagner, Stephan N.; Fischer, Gottfried; Schultz, Marcus J.; Wiedemann, Dominik; Petzelbauer, Peter

    2015-01-01

    Background Despite significant advances in organ preservation, surgical techniques and perioperative care, primary graft dysfunction is a serious medical problem in transplantation medicine in general and a specific problem in patients undergoing lung transplantation. As a result, patients develop lung edema, causing reduced tissue oxygenation capacity, reduced lung compliance and increased requirements for mechanical ventilatory support. Yet, there is no effective strategy available to protect the grafted organ from stress reactions induced by ischemia/reperfusion and by the surgical procedure itself. Methods We assessed the effect of a cingulin-derived peptide, XIB13 or a random peptide in an established rat model of allogeneic lung transplantation. Donor lungs and recipients received therapeutic peptide at the time of transplantation and outcome was analyzed 100min and 28 days post grafting. Results XIB13 improved blood oxygenation and reduced vascular leak 100min post grafting. Even after 28 days, lung edema was significantly reduced by XIB13 and lungs had reduced fibrotic or necrotic zones. Moreover, the induction of an allogeneic T cell response was delayed indicating a reduced antigen exchange between the donor and the host. Conclusions In summary, we provide a new tool to strengthen endothelial barrier function thereby improving outcomes in lung transplantation. PMID:26536466

  4. Osteochondral allograft transplantation in cartilage repair: Graft storage paradigm, translational models, and clinical applications.

    PubMed

    Bugbee, William D; Pallante-Kichura, Andrea L; Görtz, Simon; Amiel, David; Sah, Robert

    2016-01-01

    The treatment of articular cartilage injury and disease has become an increasingly relevant part of orthopaedic care. Articular cartilage transplantation, in the form of osteochondral allografting, is one of the most established techniques for restoration of articular cartilage. Our research efforts over the last two decades have supported the transformation of this procedure from experimental "niche" status to a cornerstone of orthopaedic practice. In this Kappa Delta paper, we describe our translational and clinical science contributions to this transformation: (1) to enhance the ability of tissue banks to process and deliver viable tissue to surgeons and patients, (2) to improve the biological understanding of in vivo cartilage and bone remodeling following osteochondral allograft (OCA) transplantation in an animal model system, (3) to define effective surgical techniques and pitfalls, and (4) to identify and clarify clinical indications and outcomes. The combination of coordinated basic and clinical studies is part of our continuing comprehensive academic OCA transplant program. Taken together, the results have led to the current standards for OCA processing and storage prior to implantation and also novel observations and mechanisms of the biological and clinical behavior of OCA transplants in vivo. Thus, OCA transplantation is now a successful and increasingly available treatment for patients with disabling osteoarticular cartilage pathology.

  5. Mesenchymal Stem Cells Enhance Nerve Regeneration in a Rat Sciatic Nerve Repair and Hindlimb Transplant Model

    PubMed Central

    Cooney, Damon S.; Wimmers, Eric G.; Ibrahim, Zuhaib; Grahammer, Johanna; Christensen, Joani M.; Brat, Gabriel A.; Wu, Lehao W.; Sarhane, Karim A.; Lopez, Joseph; Wallner, Christoph; Furtmüller, Georg J.; Yuan, Nance; Pang, John; Sarkar, Kakali; Lee, W. P. Andrew; Brandacher, Gerald

    2016-01-01

    This study investigates the efficacy of local and intravenous mesenchymal stem cell (MSC) administration to augment neuroregeneration in both a sciatic nerve cut-and-repair and rat hindlimb transplant model. Bone marrow-derived MSCs were harvested and purified from Brown-Norway (BN) rats. Sciatic nerve transections and repairs were performed in three groups of Lewis (LEW) rats: negative controls (n = 4), local MSCs (epineural) injection (n = 4), and systemic MSCs (intravenous) injection (n = 4). Syngeneic (LEW-LEW) (n = 4) and allogeneic (BN-LEW) (n = 4) hindlimb transplants were performed and assessed for neuroregeneration after local or systemic MSC treatment. Rats undergoing sciatic nerve cut-and-repair and treated with either local or systemic injection of MSCs had significant improvement in the speed of recovery of compound muscle action potential amplitudes and axon counts when compared with negative controls. Similarly, rats undergoing allogeneic hindlimb transplants treated with local injection of MSCs exhibited significantly increased axon counts. Similarly, systemic MSC treatment resulted in improved nerve regeneration following allogeneic hindlimb transplants. Systemic administration had a more pronounced effect on electromotor recovery while local injection was more effective at increasing fiber counts, suggesting different targets of action. Local and systemic MSC injections significantly improve the pace and degree of nerve regeneration after nerve injury and hindlimb transplantation. PMID:27510321

  6. The effects of interferon-alpha/beta in a model of rat heart transplantation

    NASA Technical Reports Server (NTRS)

    Slater, A. D.; Klein, J. B.; Sonnenfeld, G.; Ogden, L. L. 2nd; Gray, L. A. Jr

    1992-01-01

    Interferons have multiple immunologic effects. One such effect is the activation of expression of cell surface antigens. Interferon alpha/beta enhance expression of class I but not class II histocompatibility antigens. Contradictory information has been published regarding the effect of interferon-alpha/beta administration in patients with kidney transplantation. In a model of rat heart transplantation we demonstrated that administration of interferon-alpha/beta accelerated rejection in a dose-dependent fashion in the absence of maintenance cyclosporine. Animals treated with maintenance cyclosporine had evidence of increased rejection at 20 days that was resolved completely at 45 days with cyclosporine alone.

  7. Neural stem cell transplantation promotes behavioral recovery in a photothrombosis stroke model.

    PubMed

    Ma, Junning; Gao, Junwei; Hou, Boru; Liu, Jixing; Chen, Sihua; Yan, Guizhong; Ren, Haijun

    2015-01-01

    Stem cell-based therapy provides a promising approach for treat stroke. Neural stem cells isolated from mice hippocampus possessing the capacity of differentiate into neurons and astrocytes both in vitro and vivo. Here, we investigated the capability of neural stem cell transplantation in photothrombosis stroke model. Nissl staining revealed that the cortical infarct significantly decreased by 16.32% (Vehicle: 27.93le: an mm(3), n=6, NSC: 23.37le: ai mm(3), n=6, P<0.05) in the NSC group compared with the vehicle. More over transplantation of neural stem cells significantly (P<0.01) improved neurological performance compared with vehicle. These results indicate that transplantation of neural stem cell is an effective therapy in ischemic stroke.

  8. Neural stem cell transplantation promotes behavioral recovery in a photothrombosis stroke model

    PubMed Central

    Ma, Junning; Gao, Junwei; Hou, Boru; Liu, Jixing; Chen, Sihua; Yan, Guizhong; Ren, Haijun

    2015-01-01

    Stem cell-based therapy provides a promising approach for treat stroke. Neural stem cells isolated from mice hippocampus possessing the capacity of differentiate into neurons and astrocytes both in vitro and vivo. Here, we investigated the capability of neural stem cell transplantation in photothrombosis stroke model. Nissl staining revealed that the cortical infarct significantly decreased by 16.32% (Vehicle: 27.93le: an mm3, n=6, NSC: 23.37le: ai mm3, n=6, P<0.05) in the NSC group compared with the vehicle. More over transplantation of neural stem cells significantly (P<0.01) improved neurological performance compared with vehicle. These results indicate that transplantation of neural stem cell is an effective therapy in ischemic stroke. PMID:26339348

  9. Corticosteroids and immunosuppressive agents in rabbit heterolamellar corneal transplant model.

    PubMed

    Ohia, E; Kulkarni, P

    1991-09-01

    Bovine cornea (epithelium and stroma) was transplanted on to the rabbit cornea from which the epithelium and stroma had been removed. Conjuntival hyperemia and edema occurred from day 1-5 post-operation, followed by neovascularization and graft rejection within 7-10 days. Topical dexamethasone (0.1%) and prenisolone (1%) t.i.d. inhibited post-surgical hyperemia, edema, delayed hypersensitivity and neovascularization. These agents and the immunosuppressants (cyclosporin A and rapamycin) inhibited graft rejection observed up to 20 days. After cessation of treatment on the 20th day, grafts remained viable up to 35 days with dexamethasone, 10 days with prednisolone and rapamycin, and 5 days with cyclosporin A.

  10. MODEL OF COLONIC INFLAMMATION: IMMUNE MODULATORY MECHANISMS IN INFLAMMATORY BOWEL DISEASE

    PubMed Central

    Wendelsdorf, Katherine; Bassaganya-Riera, Josep; Hontecillas, Raquel; Eubank, Stephen

    2010-01-01

    Inflammatory Bowel Disease (IBD) is an immunoinflammatory illness of the gut initiated by an immune response to bacteria in the microflora. The resulting immunopathogenesis leads to lesions in epithelial lining of the colon through which bacteria may infiltrate the tissue causing recurring bouts of diarrhea, rectal bleeding, and mal-nutrition. In healthy individuals such immunopathogenesis is avoided by the presence of regulatory cells that inhibit the inflammatory pathway. Highly relevant to the search for treatment strategies is the identification of components of the inflammatory pathway that allow regulatory mechanisms to be overridden and immunopathogenesis to proceed. In vitro techniques have identified cellular interactions involved in inflammation-regulation crosstalk. However, tracing immunological mechanisms discovered at the cellular level confidently back to an in vivo context of multiple, simultaneous interactions has met limited success. To explore the impact of specific interactions, we have constructed a system of 29 ordinary differential equations representing different phenotypes of T-cells, macrophages, dendritic cells, and epithelial cells as they move and interact with bacteria in the lumen, lamina propria, and lymphoid tissue of the colon. Simulations revealed the positive inflammatory feedback loop formed by inflammatory M1 macrophage activation of T-cells as a driving force underlying the immunopathology of IBD. Furthermore, strategies that remove M1 from the site of infection, by either i) increasing its potential to switch to a regulatory M2 phenotype or ii) increasing the rate of reversion (for M1 and M2 alike) to a resting state, cease immunopathogenesis even as bacteria are eliminated by other inflammatory cells. Based on these results, we identify macrophages and their mechanisms of plasticity as key targets for mucosal inflammation intervention strategies. In addition, we propose that the primary mechanism behind the association of

  11. DNBS/TNBS colitis models: providing insights into inflammatory bowel disease and effects of dietary fat.

    PubMed

    Morampudi, Vijay; Bhinder, Ganive; Wu, Xiujuan; Dai, Chuanbin; Sham, Ho Pan; Vallance, Bruce A; Jacobson, Kevan

    2014-02-27

    Inflammatory Bowel Diseases (IBD), including Crohn's Disease and Ulcerative Colitis, have long been associated with a genetic basis, and more recently host immune responses to microbial and environmental agents. Dinitrobenzene sulfonic acid (DNBS)-induced colitis allows one to study the pathogenesis of IBD associated environmental triggers such as stress and diet, the effects of potential therapies, and the mechanisms underlying intestinal inflammation and mucosal injury. In this paper, we investigated the effects of dietary n-3 and n-6 fatty acids on the colonic mucosal inflammatory response to DNBS-induced colitis in rats. All rats were fed identical diets with the exception of different types of fatty acids [safflower oil (SO), canola oil (CO), or fish oil (FO)] for three weeks prior to exposure to intrarectal DNBS. Control rats given intrarectal ethanol continued gaining weight over the 5 day study, whereas, DNBS-treated rats fed lipid diets all lost weight with FO and CO fed rats demonstrating significant weight loss by 48 hr and rats fed SO by 72 hr. Weight gain resumed after 72 hr post DNBS, and by 5 days post DNBS, the FO group had a higher body weight than SO or CO groups. Colonic sections collected 5 days post DNBS-treatment showed focal ulceration, crypt destruction, goblet cell depletion, and mucosal infiltration of both acute and chronic inflammatory cells that differed in severity among diet groups. The SO fed group showed the most severe damage followed by the CO, and FO fed groups that showed the mildest degree of tissue injury. Similarly, colonic myeloperoxidase (MPO) activity, a marker of neutrophil activity was significantly higher in SO followed by CO fed rats, with FO fed rats having significantly lower MPO activity. These results demonstrate the use of DNBS-induced colitis, as outlined in this protocol, to determine the impact of diet in the pathogenesis of IBD.

  12. DNFB-DNS hapten-induced colitis in mice should not be considered a model of inflammatory bowel disease.

    PubMed

    Bailón, Elvira; Cueto-Sola, Margarita; Utrilla, Pilar; Nieto, Ana; Garrido-Mesa, Natividad; Celada, Antonio; Zarzuelo, Antonio; Xaus, Jordi; Gálvez, Julio; Comalada, Mònica

    2011-10-01

    The dinitrofluorobenzene/dinitrosulfonic acid (DNFB/DNS) model was originally described as an experimental model of intestinal inflammation resembling human ulcerative colitis (UC). Due to the absence of acceptable UC experimental models for pharmacological preclinical assays, here we examine the immune response induced in this model. Balb/c mice were sensitized by skin application of DNFB on day 1, followed by an intrarectal challenge with DNS on day 5. We further expanded this model by administering a second DNS challenge on day 15. The features of colonic inflammation and immune response were evaluated. The changes observed in colonic tissue corresponded, in comparison to the trinitrobenzene sulfonic acid (TNBS) colitis model, to a mild mucosal effect in the colon, which spontaneously resolved in less than 5 days. Furthermore, the second hapten challenge did not exacerbate the inflammatory response. In contrast to other studies, we did not observe any clear involvement of tumor necrosis factor alpha (TNF-α) or other Th1 cytokines during the initial inflammatory response; however, we found that a more Th2-humoral response appeared to mediate the first contact with the hapten. An increased humoral response was detected during the second challenge, although an increased Th1/Th17-cytokine expression profile was also simultaneously observed. On the basis of these results, although the DNFB/DNS model can display some features found in human UC, it should be considered as a model for the study of the intestinal hypersensitivity seen, for example, during food allergy or irritable bowel syndrome but not intestinal inflammation per se. Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

  13. Colonic GLP-2 is not Sufficient to Promote Jejunal Adaptation in a PN-Dependent Rat Model of Human Short Bowel Syndrome

    PubMed Central

    Koopmann, Matthew C.; Liu, Xiaowen; Boehler, Christopher J.; Murali, Sangita G.; Holst, Jens J.; Ney, Denise M.

    2013-01-01

    Background Bowel resection may lead to short bowel syndrome (SBS), which often requires parenteral nutrition (PN) due to inadequate intestinal adaptation. The objective of this study was to determine the time course of adaptation and proglucagon system responses after bowel resection in a PN-dependent rat model of SBS. Methods Rats underwent jugular catheter placement and a 60% jejunoileal resection + cecectomy with jejunoileal anastomosis or transection control surgery. Rats were maintained exclusively with PN and killed at 4 hours to 12 days. A nonsurgical group served as baseline. Bowel growth and digestive capacity were assessed by mucosal mass, protein, DNA, histology, and sucrase activity. Plasma insulin-like growth factor I (IGF-I) and bioactive glucagon-like peptide 2 (GLP-2) were measured by radioimmunoassay. Results Jejunum cellularity changed significantly over time with resection but not transection, peaking at days 3–4 and declining by day 12. Jejunum sucrase-specific activity decreased significantly with time after resection and transection. Colon crypt depth increased over time with resection but not transection, peaking at days 7–12. Plasma bioactive GLP-2 and colon proglucagon levels peaked from days 4–7 after resection and then approached baseline. Plasma IGF-I increased with resection through day 12. Jejunum and colon GLP-2 receptor RNAs peaked by day 1 and then declined below baseline. Conclusions After bowel resection resulting in SBS in the rat, peak proglucagon, plasma GLP-2, and GLP-2 receptor levels are insufficient to promote jejunal adaptation. The colon adapts with resection, expresses proglucagon, and should be preserved when possible in massive intestinal resection. PMID:19644131

  14. Anti-CD45 radioimmunotherapy using 211At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model

    SciTech Connect

    Orozco, Johnnie J.; Back, Tom; Kenoyer, Aimee L.; Balkin, Ethan R.; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Frayo, Shani; Hylarides, Mark; Green, Damian J.; Gopal, Ajay K.; Press, Oliver W.; Pagel, John M.

    2013-05-15

    Anti-CD45 Radioimmunotherapy using an Alpha-Emitting Radionuclide 211At Combined with Bone Marrow Transplantation Prolongs Survival in a Disseminated Murine Leukemia Model ABSTRACT Despite aggressive chemotherapy combined with hematopoietic cell transplant (HCT), many patients with acute myeloid leukemia (AML) relapse. Radioimmunotherapy (RIT) using antibodies (Ab) labeled primarily with beta-emitting radionuclides has been explored to reduce relapse.

  15. [Comparison of 2-octyl cyanoacrylate adhesive and suturing for wound closure in the canine small bowel model].

    PubMed

    Escalante-Piña, Oscar; García-Nieto, Gabriela; Hernández-Jasso, Alma Rocío; Reyes-Castellanos, Liliana; Flores-Aragón, Mariana; Rivera-Cruz, Jose María

    2009-01-01

    We undertook this study to evaluate 2-octyl cyanoacrylate (2OCA) glue and suture for wound closure in the small bowel. This was a comparative and experimental study. Male and female domestic dogs (n = 10) underwent a 2.0-cm small bowel closure of two wounds. All of these had closure with 2OCA in the first wound. The controls (second wound in the same dog) were closed with suture. Four weeks later the wounds were observed to evaluate the repair. Wound closure time and macrophage count were lower with the 2OCA glue than in the suture group. 2OCA glue has the strength to seal a small bowel wound. The inflammatory response to the glue is less than that of the suture at 4 weeks. These properties may make it a suitable material for replacing suture in a small bowel wound.

  16. Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model

    SciTech Connect

    Buck, Nicole E.; Pennell, Samuel D.; Wood, Leonie R.; Pitt, James J.; Allen, Katrina J.; Peters, Heidi L.

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer Fetal cells were transplanted into a methylmalonic acid mouse model. Black-Right-Pointing-Pointer Cell engraftment was detected in liver, spleen and bone marrow. Black-Right-Pointing-Pointer Biochemical disease correction was measured in blood samples. Black-Right-Pointing-Pointer A double dose of 5 million cells (1 week apart) proved more effective. Black-Right-Pointing-Pointer Higher levels of engraftment may be required for greater disease correction. -- Abstract: Methylmalonic aciduria is a rare disorder caused by an inborn error of organic acid metabolism. Current treatment options are limited and generally focus on disease management. We aimed to investigate the use of fetal progenitor cells to treat this disorder using a mouse model with an intermediate form of methylmalonic aciduria. Fetal liver cells were isolated from healthy fetuses at embryonic day 15-17 and intravenously transplanted into sub-lethally irradiated mice. Liver donor cell engraftment was determined by PCR. Disease correction was monitored by urine and blood methylmalonic acid concentration and weight change. Initial studies indicated that pre-transplantation sub-lethal irradiation followed by transplantation with 5 million cells were suitable. We found that a double dose of 5 million cells (1 week apart) provided a more effective treatment. Donor cell liver engraftment of up to 5% was measured. Disease correction, as defined by a decrease in blood methylmalonic acid concentration, was effected in methylmalonic acid mice transplanted with a double dose of cells and who showed donor cell liver engraftment. Mean plasma methylmalonic acid concentration decreased from 810 {+-} 156 (sham transplanted) to 338 {+-} 157 {mu}mol/L (double dose of 5 million cells) while mean blood C3 carnitine concentration decreased from 20.5 {+-} 4 (sham transplanted) to 5.3 {+-} 1.9 {mu}mol/L (double dose of 5 million cells). In conclusion, higher levels of engraftment may

  17. Tolerance induction in composite facial allograft transplantation in the rat model.

    PubMed

    Demir, Yavuz; Ozmen, Selahattin; Klimczak, Aleksandra; Mukherjee, Abir Lal; Siemionow, Maria

    2004-12-01

    Clinical application of composite tissue allograft transplants opened discussion on the restoration of facial deformities by allotransplantation. The authors introduce a hemifacial allograft transplant model to investigate the rationale for the development of functional tolerance across the major histocompatibility complex barrier. Eighteen rats in three groups were studied. The composite hemifacial allotransplantations including the ear and scalp were performed between Lewis-Brown Norway (RT1l+n) and Lewis (RT1l) rats and isotransplantations were performed between Lewis rats. Isograft controls (n = 6) and allograft controls (n = 6) did not receive treatment. Allografts in treatment group (n = 6) were treated with cyclosporine A 16 mg/kg/day during the first week; this dose was tapered to 2 mg/kg/day over 4 weeks and maintained at this level thereafter. Functional tolerance to face allografts was evaluated clinically and histologically. Donor-specific chimerism was assessed at days 21 and 63 by flow cytometry. In vitro evaluation of donor-specific tolerance was performed by mixed lymphocyte reaction at day 160 after transplantation. Isograft controls survived indefinitely. All nontreated allografts were rejected within 5 to 7 days after transplantation, as confirmed by histopathologic analysis. Five of six face allografts under the cyclosporine A protocol showed no signs of rejection for up to 240 days and remained alive and under evaluation, whereas one animal showed signs of rejection at day 140. This was reversed by adjustment of the cyclosporine A dose. At day 21 after transplantation, flow cytometric analysis of the donor-specific chimerism showed 1.11 percent of double-positive CD4FITC/RT1Ac-Cy7 and 1.43 percent of double-positive CD8PE/RT1Ac-Cy7 T-cell populations in the peripheral blood of hemiface allotransplant recipients. The chimerism level of double-positive CD4FITC/RT1Ac-Cy7 T cells increased to 3.39 percent, whereas it remained stable for the double

  18. Sheep Model for Uterine Transplantation: The Best Option Before Starting a Human Program

    PubMed Central

    Andraus, Wellington; Ejzenberg, Dani; dos Santos, Rafael Miyashiro Nunes; Mendes, Luana Regina Baratelli Carelli; Arantes, Rubens Macedo; Baracat, Edmund Chada; D’Albuquerque, Luiz Augusto Carneiro

    2017-01-01

    OBJECTIVE: This study reports the first four cases of a uterine transplant procedure conducted in sheep in Latin America. The aim of this study was to evaluate the success of uterine transplantation in sheep. METHOD: The study was conducted at Laboratory of Medical Investigation 37 (LIM 37) at the University of São Paulo School of Medicine. Four healthy mature ewes weighing 40-60 kg were used as both the donor and recipient for a transplant within the same animal (auto-transplant). Institutional guidelines for the care of experimental animals were followed. RESULTS: The first two cases of auto-transplant were performed to standardize the technique. After complete uterine mobilization and isolation of the blood supply, the unilateral vascular pedicle was sectioned and anastomosed on the external iliac vessels. After standardization, the protocol was implemented. Procurement surgery was performed without complications or bleeding. After isolation of uterine arteries and veins as well as full mobilization of the uterus, ligation of the distal portion of the internal iliac vessels was performed with subsequent division and end-to-side anastomosis of the external iliac vessels. After vaginal anastomosis, the final case presented with arterial thrombosis in the left uterine artery. The left uterine artery anastomosis was re-opened and flushed with saline solution to remove the clot from the artery lumen. Anastomosis was repeated with restoration of blood flow for a few minutes before another uterine artery thrombosis appeared on the same side. All four animals were alive after the surgical procedure and were euthanized after the experimental period. CONCLUSION: We describe the success of four uterine auto-transplants in sheep models. PMID:28355364

  19. Monitoring of Liver Cell Transplantation in a Preclinical Swine Model Using Magnetic Resonance Imaging

    PubMed Central

    Raschzok, Nathanael; Teichgräber, Ulf; Billecke, Nils; Zielinski, Anja; Steinz, Kirsten; Kammer, Nora N.; Morgul, Mehmet H.; Schmeisser, Sarah; Adonopoulou, Michaela K.; Morawietz, Lars; Hiebl, Bernhard; Schwartlander, Ruth; Rüdinger, Wolfgang; Hamm, Bernd; Neuhaus, Peter; Sauer, Igor M.

    2010-01-01

    Liver cell transplantation (LCT) is a promising treatment approach for certain liver diseases, but clinical implementation requires methods for noninvasive follow-up. Labeling with superparamagnetic iron oxide particles can enable the detection of cells with magnetic resonance imaging (MRI). We investigated the feasibility of monitoring transplanted liver cells by MRI in a preclinical swine model and used this approach to evaluate different routes for cell application. Liver cells were isolated from landrace piglets and labeled with micron-sized iron oxide particles (MPIO) in adhesion. Labeled cells (n = 10), native cells (n = 3), or pure particles (n = 4) were transplanted to minipigs via intraportal infusion into the liver, direct injection into the splenic parenchyma, or intra-arterial infusion to the spleen. Recipients were investigated by repeated 3.0 Tesla MRI and computed tomography angiography up to 8 weeks after transplantation. Labeling with MPIO, which are known to have a strong effect on the magnetic field, enabled noninvasive detection of cell aggregates by MRI. Following intraportal application, which is commonly applied for clinical LCT, MRI was able to visualize the microembolization of transplanted cells in the liver that were not detected by conventional imaging modalities. Cells directly injected into the spleen were retained, whereas cell infusions intra-arterially into the spleen led to translocation and engraftment of transplanted cells in the liver, with significantly fewer microembolisms compared to intraportal application. These findings demonstrate that MRI can be a valuable tool for noninvasive elucidation of cellular processes of LCT and—if clinically applicable MPIO are available—for monitoring of LCT under clinical conditions. Moreover, the results clarify mechanisms relevant for clinical practice of LCT, suggesting that the intra-arterial route to the spleen deserves further evaluation. PMID:27004132

  20. The Tuscany model of a regional transplantation service authority: Organizzazione Toscana Trapianti.

    PubMed

    Filipponi, F; De Simone, P; Rossi, E

    2007-12-01

    In 2003, the Tuscan Regional Government appointed a transplantation service authority to reorganize all regional donation and transplantation activities: the Organizzazione Toscana Trapianti (OTT). Herein we have presented a retrospective review of deceased donation and transplantation activities from 1993 until 2006 in Tuscany to illustrate the results of OTT activity and the methodology in reorganizing the regional network. After the advent of OTT, the mean rate of recovered deceased donors (DDs) rose from 16.9+/-7.7 per million population (pmp) to 32.7+/-4.3 pmp (Delta=+93.4%); multiorgan DDs increased by 48.6%, from a mean of 12.8+/-5.2 pmp to 21.1+/-2.9 pmp, despite a 55.2% increase in recovered DDs>or=60 years. Recovered DD solid organs rose by 78.4% after the advent of OTT (from a mean of 53+/-20.1 pmp to 89.5+/-13.6 pmp), and the number of DD organ transplants rose by 87.3% (ie, from a mean of 49.9+/-23.9 to 91.9+/-5.2 pmp). The experience of OTT showed that an efficient regional network requires a global approach to donation and transplantation, according to the principles of clinical governance. A region-based model, whereby health care professionals share clinical governance with regional authorities and regional networks integrated at a national level, may prove favorable not only to increase donor procurement rates but also to improve the quality of the whole transplantation care process.

  1. Adipose-derived stem cell sheet transplantation therapy in a porcine model of chronic heart failure.

    PubMed

    Ishida, Osamu; Hagino, Ikuo; Nagaya, Noritoshi; Shimizu, Tatsuya; Okano, Teruo; Sawa, Yoshiki; Mori, Hidezo; Yagihara, Toshikatsu

    2015-05-01

    Adipose-derived stem cells (ASCs) are a promising resource for cell transplantation therapy for damaged heart tissue. Cell death in the graft early after transplantation represents the main cause of unsatisfactory therapeutic efficacy, but tissue-engineered cell sheets grown in temperature-responsive cell culture dishes may enable improved engraftment of transplanted cells. We investigated the therapeutic potential of this method in chronic myocardial ischemia in swine. We created a porcine model of chronic heart failure by implanting an ameroid constrictor around the main trunk of the left anterior descending artery, just distal to the circumflex branch. Simultaneously, ASCs were obtained from a piece of subcutaneous adipose tissue and expanded to form ASC sheets using temperature-responsive dishes. Four weeks after ameroid constrictor placement, triple-layered ASC sheets were transplanted onto the area of the ischemic myocardium (sheet group, n = 7). Controls (n = 7) received no sheet. Just before and 4 weeks after transplantation, left ventriculography (LVG) and coronary angiography (CAG) were performed. LVG revealed a significant improvement in the left ventricular ejection fraction of the sheet group compared with controls (47.6 ± 2.9% vs 41.4 ± 2.8%, P < 0.05). Furthermore, development of collateral vessels was only detected in the sheet group with right CAG. Histologic analysis demonstrated that engrafted ASC sheets grew to form a thickened layer that included newly formed vessels. ASC sheet transplantation therapy is an intriguing therapeutic method for ischemic heart failure. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Acute renal graft-versus-host disease in a murine model of allogeneic bone marrow transplantation.

    PubMed

    Schmid, Peter M; Bouazzaoui, Abdellatif; Schmid, Karin; Birner, Christoph; Schach, Christian; Maier, Lars S; Holler, Ernst; Endemann, Dierk H

    2017-03-23

    Acute kidney injury (AKI) is a very common complication after allogeneic bone marrow transplantation (BMT) and associated with poor prognosis. Generally kidneys are assumed to be no direct target of Graft-versus-Host Disease (GvHD), and renal impairment is often attributed to several other factors occurring in the early phase after BMT. Our study aimed to prove the existence of renal GvHD in a fully MHC-mismatched model of BALB/c mice conditioned and transplanted according to two different intensity protocols. Syngeneically transplanted and untreated animals served as controls. 4 weeks after transplantation, allogeneic animals developed acute GvHD that was more pronounced in the high-intensity protocol (HIP) group than in the low-intensity protocol (LIP) group. Urea and creatinine as classic serum markers of renal function could not verify renal impairment 4 weeks after BMT. Creatinine levels were even reduced as a result of catabolic metabolism and loss of muscle mass due to acute GvHD. Proteinuria, albuminuria, and urinary N-acetyl-beta-Dglucosaminidase (NAG) levels were measured as additional renal markers before and after transplantation. Albuminuria and NAG were only significantly increased after allogeneic transplantation, correlating with disease severity between HIP and LIP animals. Histological investigations of the kidneys showed renal infiltration of T-cells and macrophages with endarteriitis, interstitial nephritis, tubulitis, and glomerulitis. T-cells consisted of CD4+, CD8+, and FoxP3+ cells. Renal expression analysis of allogeneic animals showed increases in indoleamine-2,3 dioxygenase (IDO), different cytokines (TNFα, IFN-γ, IL-1α, IL2, IL-6, and IL-10), and adhesion molecules (ICAM-1 and VCAM-1), resembling findings from other tissues in acute GvHD. In summary, our study supports the entity of renal GvHD with histological features suggestive of cell-mediated renal injury. Albuminuria and urinary NAG levels may serve as early markers of renal

  3. Porcine pulmonary auto-transplantation for ex vivo therapy as a model for new treatment strategies.

    PubMed

    Krüger, Marcus; Zinne, Norman; Biancosino, Christian; Höffler, Klaus; Rajab, Taufiek K; Waldmann, Karl-Heinz; Jonigk, Danny; Avsar, Murat; Haverich, Axel; Hoeltig, Doris

    2016-09-01

    Lung auto-transplantation is the surgical key step in experiments involving ex vivo therapy of severe or end-stage lung diseases. Ex vivo therapy has become a clinical reality because of systems such as the Organ Care System (OCS) Lung, which is the only commercially available portable lung perfusion system. However, survival experiments involving porcine lung auto-transplantation pose special surgical and anaesthesiological challenges. This current study was designed to describe the development of surgical techniques and aneasthesiological management strategies that facilitate lung auto-transplantation survival surgery including a follow-up period of 4 days. Left pneumonectomy was performed in 12 Mini-Lewe miniature pigs. After ex vivo treatment of the harvested lungs within the OCS Lung for 2 h, the lungs were retransplanted into the same animal (auto-transplantation). Four animals were used to develop the optimal techniques and establish an experimental protocol. According to the final protocol, eight additional animals were operated. The follow-up period was 4 days. There were four severe intraoperative surgical complications [anatomical variant of the superior vena cava (two times), a complication related to the bronchial anastomosis and a complication related to the pulmonary arterial anastomosis]. The major postoperative problems were hyperkalaemia, prolonged recovery from anaesthesia and pulmonary oedema after reperfusion. Establishment of the surgical technique showed that using a pericardial tube to facilitate the anastomosis of the thin left superior pulmonary vein should be considered to prevent thrombosis. However, routine use of the patch technique to construct venous and arterial anastomoses is not necessary. Furthermore, traction on the venous anastomoses can be avoided by performing the bronchial anastomosis first. Lung auto-transplantation is a feasible experimental model for ex vivo therapy of lung diseases and is applicable for experimental

  4. Local transplantation is an effective method for cell delivery in the osteogenesis imperfecta murine model.

    PubMed

    Pauley, Penelope; Matthews, Brya G; Wang, Liping; Dyment, Nathaniel A; Matic, Igor; Rowe, David W; Kalajzic, Ivo

    2014-09-01

    Osteogenesis imperfecta is a serious genetic disorder that results from improper type I collagen production. We aimed to evaluate whether bone marrow stromal cells (BMSC) delivered locally into femurs were able to engraft, differentiate into osteoblasts, and contribute to formation of normal bone matrix in the osteogenesis imperfect murine (oim) model. Donor BMSCs from bone-specific reporter mice (Col2.3GFP) were expanded in vitro and transplanted into the femoral intramedullary cavity of oim mice. Engraftment was evaluated after four weeks. We detected differentiation of donor BMSCs into Col2.3GFP+ osteoblasts and osteocytes in cortical and trabecular bone of transplanted oim femurs. New bone formation was detected by deposition of dynamic label in the proximity to the Col2.3GFP+ osteoblasts, and new bone showed more organized collagen structure and expression of type I α2 collagen. Col2.3GFP cells were not found in the contralateral femur indicating that transplanted osteogenic cells did not disseminate by circulation. No osteogenic engraftment was observed following intravenous transplantation of BMSCs. BMSC cultures derived from transplanted femurs showed numerous Col2.3GFP+ colonies, indicating the presence of donor progenitor cells. Secondary transplantation of cells recovered from recipient femurs and expanded in vitro also showed Col2.3GFP+ osteoblasts and osteocytes confirming the persistence of donor stem/progenitor cells. We show that BMSCs delivered locally in oim femurs are able to engraft, differentiate into osteoblasts and osteocytes and maintain their progenitor potential in vivo. This suggests that local delivery is a promising approach for introduction of autologous MSC in which mutations have been corrected.

  5. Intestinal adaptation in short bowel syndrome: A case report.

    PubMed

    Palla, Viktoria-Varvara; Karaolanis, Georgios; Pentazos, Panagiotis; Ladopoulos, Alexios; Papageorgiou, Evaggelos

    2015-06-01

    Short bowel syndrome is a clinical entity that includes loss of energy, fluid, electrolytes or micronutrient balance because of inadequate functional intestinal length. This case report demonstrates the case of a woman who compensated for short bowel syndrome through intestinal adaptation, which is a complex process worthy of further investigation for the avoidance of dependence on total parenteral nutrition and of intestinal transplantation in such patients.

  6. A model-driven methodology for exploring complex disease comorbidities applied to autism spectrum disorder and inflammatory bowel disease.

    PubMed

    Somekh, Judith; Peleg, Mor; Eran, Alal; Koren, Itay; Feiglin, Ariel; Demishtein, Alik; Shiloh, Ruth; Heiner, Monika; Kong, Sek Won; Elazar, Zvulun; Kohane, Isaac

    2016-10-01

    We propose a model-driven methodology aimed to shed light on complex disorders. Our approach enables exploring shared etiologies of comorbid diseases at the molecular pathway level. The method, Comparative Comorbidities Simulation (CCS), uses stochastic Petri net simulation for examining the phenotypic effects of perturbation of a network known to be involved in comorbidities to predict new roles for mutations in comorbid conditions. To demonstrate the utility of our novel methodology, we investigated the molecular convergence of autism spectrum disorder (ASD) and inflammatory bowel disease (IBD) on the autophagy pathway. In addition to validation by domain experts, we used formal analyses to demonstrate the model's self-consistency. We then used CCS to compare the effects of loss of function (LoF) mutations previously implicated in either ASD or IBD on the autophagy pathway. CCS identified similar dynamic consequences of these mutations in the autophagy pathway. Our method suggests that two LoF mutations previously implicated in IBD may contribute to ASD, and one ASD-implicated LoF mutation may play a role in IBD. Future targeted genomic or functional studies could be designed to directly test these predictions.

  7. Therapeutic effect of the immunomodulatory drug lenalidomide, but not pomalidomide, in experimental models of rheumatoid arthritis and inflammatory bowel disease

    PubMed Central

    Lopez-Millan, Belen; Diaz de la Guardia, Rafael; Roca-Ho, Heleia; García-Herrero, Carmen M; Lavoie, Jessie R; Rosu-Myles, Michael; Gonzalez-Rey, Elena; O'Valle, Francisco; Criado, Gabriel; Delgado, Mario; Menendez, Pablo

    2017-01-01

    Thalidomide is an immunomodulatory drug (IMiD) with proven therapeutic action in several autoimmune/inflammatory diseases; however, its inherent high toxicity has led to the development of more powerful and safer thalidomide analogs, including lenalidomide and pomalidomide. These are new generation IMiDs that exhibit direct antitumor activity as well as anti-inflammatory/immunomodulatory properties, and are FDA-approved for the treatment of several hematological malignances. Here we investigated the potential therapeutic effects of lenalidomide and pomalidomide in several experimental murine models of autoimmune/inflammatory diseases: 2,4,6-trinitrobenzene sulfonic acid- and dextran sulfate sodium-induced inflammatory bowel disease and type II collagen-induced arthritis. Lenalidomide displayed a strong therapeutic effect in all these models of autoimmune/inflammatory diseases, while the effect of pomalidomide was less pronounced. In vitro experiments confirmed the immunosuppressive effect of both IMiDs on the proliferative response of stimulated human lymphocytes and on the balance of secreted cytokines toward an anti-inflammatory profile. We conclude that lenalidomide may offer a therapeutic opportunity against autoimmune/inflammatory diseases. PMID:28154372

  8. Therapeutic effects of mouse bone marrow-derived clonal mesenchymal stem cells in a mouse model of inflammatory bowel disease

    PubMed Central

    Park, Jin Seok; Yi, Tac-Ghee; Park, Jong-Min; Han, Young Min; Kim, Jun-Hyung; Shin, Dong-Hee; Tak, Seon Ji; Lee, Kyuheon; Lee, Youn Sook; Jeon, Myung-Shin; Hahm, Ki-Baik; Song, Sun U; Park, Seok Hee

    2015-01-01

    Mouse bone marrow-derived clonal mesenchymal stem cells (mcMSCs), which were originated from a single cell by a subfractionation culturing method, are recognized as new paradigm for stem cell therapy featured with its homogenous cell population. Next to proven therapeutic effects against pancreatitis, in the current study we demonstrated that mcMSCs showed significant therapeutic effects in dextran sulfate sodium (DSS)-induced experimental colitis model supported with anti-inflammatory and restorative activities. mcMSCs significantly reduced the disease activity index (DAI) score, including weight loss, stool consistency, and intestinal bleeding and significantly increased survival rates. The pathological scores were also significantly improved with mcMSC. We have demonstrated that especial mucosal regeneration activity accompanied with significantly lowered level of apoptosis as beneficiary actions of mcMSCs in UC models. The levels of inflammatory cytokines including TNF-α, IFN-γ, IL-1β, IL-6, and IL-17 were all significantly concurrent with significantly repressed NF-κB activation compared to the control group and significantly decreased infiltrations of responsible macrophage and neutrophil. Conclusively, our findings provide the rationale that mcMSCs are applicable as a potential source of cell-based therapy in inflammatory bowel diseases, especially contributing either to prevent relapse or to accelerate healing as solution to unmet medical needs in IBD therapy. PMID:26566304

  9. Therapeutic effect of the immunomodulatory drug lenalidomide, but not pomalidomide, in experimental models of rheumatoid arthritis and inflammatory bowel disease.

    PubMed

    Lopez-Millan, Belen; Diaz de la Guardia, Rafael; Roca-Ho, Heleia; García-Herrero, Carmen M; Lavoie, Jessie R; Rosu-Myles, Michael; Gonzalez-Rey, Elena; O'Valle, Francisco; Criado, Gabriel; Delgado, Mario; Menendez, Pablo

    2017-02-03

    Thalidomide is an immunomodulatory drug (IMiD) with proven therapeutic action in several autoimmune/inflammatory diseases; however, its inherent high toxicity has led to the development of more powerful and safer thalidomide analogs, including lenalidomide and pomalidomide. These are new generation IMiDs that exhibit direct antitumor activity as well as anti-inflammatory/immunomodulatory properties, and are FDA-approved for the treatment of several hematological malignances. Here we investigated the potential therapeutic effects of lenalidomide and pomalidomide in several experimental murine models of autoimmune/inflammatory diseases: 2,4,6-trinitrobenzene sulfonic acid- and dextran sulfate sodium-induced inflammatory bowel disease and type II collagen-induced arthritis. Lenalidomide displayed a strong therapeutic effect in all these models of autoimmune/inflammatory diseases, while the effect of pomalidomide was less pronounced. In vitro experiments confirmed the immunosuppressive effect of both IMiDs on the proliferative response of stimulated human lymphocytes and on the balance of secreted cytokines toward an anti-inflammatory profile. We conclude that lenalidomide may offer a therapeutic opportunity against autoimmune/inflammatory diseases.

  10. Adult zebrafish intestine resection: a novel model of short bowel syndrome, adaptation, and intestinal stem cell regeneration

    PubMed Central

    Schall, K. A.; Holoyda, K. A.; Grant, C. N.; Levin, D. E.; Torres, E. R.; Maxwell, A.; Pollack, H. A.; Moats, R. A.; Frey, M. R.; Darehzereshki, A.; Al Alam, D.; Lien, C.

    2015-01-01

    Loss of significant intestinal length from congenital anomaly or disease may lead to short bowel syndrome (SBS); intestinal failure may be partially offset by a gain in epithelial surface area, termed adaptation. Current in vivo models of SBS are costly and technically challenging. Operative times and survival rates have slowed extension to transgenic models. We created a new reproducible in vivo model of SBS in zebrafish, a tractable vertebrate model, to facilitate investigation of the mechanisms of intestinal adaptation. Proximal intestinal diversion at segment 1 (S1, equivalent to jejunum) was performed in adult male zebrafish. SBS fish emptied distal intestinal contents via stoma as in the human disease. After 2 wk, S1 was dilated compared with controls and villus ridges had increased complexity, contributing to greater villus epithelial perimeter. The number of intervillus pockets, the intestinal stem cell zone of the zebrafish increased and contained a higher number of bromodeoxyuridine (BrdU)-labeled cells after 2 wk of SBS. Egf receptor and a subset of its ligands, also drivers of adaptation, were upregulated in SBS fish. Igf has been reported as a driver of intestinal adaptation in other animal models, and SBS fish exposed to a pharmacological inhibitor of the Igf receptor failed to demonstrate signs of intestinal adaptation, such as increased inner epithelial perimeter and BrdU incorporation. We describe a technically feasible model of human SBS in the zebrafish, a faster and less expensive tool to investigate intestinal stem cell plasticity as well as the mechanisms that drive intestinal adaptation. PMID:26089336

  11. Bone Marrow Transplantation Confers Modest Benefits in Mouse Models of Huntington’s Disease

    PubMed Central

    Kwan, Wanda; Magnusson, Anna; Chou, Austin; Adame, Anthony; Carson, Monica J.; Kohsaka, Shinichi; Masliah, Eliezer; Möller, Thomas; Ransohoff, Richard; Tabrizi, Sarah J.; Björkqvist, Maria; Muchowski, Paul J.

    2013-01-01

    Huntington’s disease (HD) is caused by an expanded polyglutamine tract in the protein huntingtin (htt). Although HD has historically been viewed as a brain-specific disease, htt is expressed ubiquitously, and recent studies indicate that mutant htt might cause changes to the immune system that could contribute to pathogenesis. Monocytes from HD patients and mouse models are hyperactive in response to stimulation, and increased levels of inflammatory cytokines and chemokines are found in pre-manifest patients that correlate with pathogenesis. In this study, wild-type (WT) bone marrow cells were transplanted into two lethally irradiated transgenic mouse models of HD that ubiquitously express full-length htt (YAC128 and BACHD mice). Bone marrow transplantation partially attenuated hypokinetic and motor deficits in HD mice. Increased levels of synapses in the cortex were found in HD mice that received bone marrow transplants. Importantly, serum levels of interleukin-6, interleukin-10, CXC chemokine ligand 1, and interferon-γ were significantly higher in HD than WT mice but were normalized in mice that received a bone marrow transplant. These results suggest that immune cell dysfunction might be an important modifier of pathogenesis in HD. PMID:22219276

  12. Neuro-immune interactions of neural stem cell transplants: from animal disease models to human trials.

    PubMed

    Giusto, Elena; Donegà, Matteo; Cossetti, Chiara; Pluchino, Stefano

    2014-10-01

    Stem cell technology is a promising branch of regenerative medicine that is aimed at developing new approaches for the treatment of severely debilitating human diseases, including those affecting the central nervous system (CNS). Despite the increasing understanding of the mechanisms governing their biology, the application of stem cell therapeutics remains challenging. The initial idea that stem cell transplants work in vivo via the replacement of endogenous cells lost or damaged owing to disease has been challenged by accumulating evidence of their therapeutic plasticity. This new concept covers the remarkable immune regulatory and tissue trophic effects that transplanted stem cells exert at the level of the neural microenvironment to promote tissue healing via combination of immune modulatory and tissue protective actions, while retaining predominantly undifferentiated features. Among a number of promising candidate stem cell sources, neural stem/precursor cells (NPCs) are under extensive investigation with regard to their therapeutic plasticity after transplantation. The significant impact in vivo of experimental NPC therapies in animal models of inflammatory CNS diseases has raised great expectations that these stem cells, or the manipulation of the mechanisms behind their therapeutic impact, could soon be translated to human studies. This review aims to provide an update on the most recent evidence of therapeutically-relevant neuro-immune interactions following NPC transplants in animal models of multiple sclerosis, cerebral stroke and traumas of the spinal cord, and consideration of the forthcoming challenges related to the early translation of some of these exciting experimental outcomes into clinical medicines.

  13. Improvements of surgical techniques in a rat model of an orthotopic single lung transplant

    PubMed Central

    2013-01-01

    Background Rats are widely used in modeling orthotopic lung transplantation. Recently the introduction of the cuff technique has greatly facilitated the anastomosing procedure used during the transplant. However, the procedure is still associated with several drawbacks including twisting of blood vessels, tissue injury and the extensive time required for the procedure. This study was performed to optimize the model of rat lung transplantation (LT) with the cuff technique. Methods A total of 42 adult Lewis rats received orthotopic LT with our newly modified procedures. The modified procedures were based on the traditional procedure and incorporated improvements involving orotracheal intubation; a cuff without a tail; conservative dissection in the hilum; preservation of the left lung during anastomosis; successive anatomizing of the bronchus, the pulmonary vein, and the pulmonary artery; and one operator. Results Transplants were performed in 42 rats with a successful rate of 95.23% (40/42). The mean duration for the complete procedure was 82.93 ± 14.56 minutes. All anastomoses were completed in one attempt without vessel laceration, twisting or angulation. In our study, two animals died within three days and one animal died ten days after the operation. All grafts were well inflated with robust blood perfusion and functioned normally as demonstrated by blood gas analysis. Conclusions We have developed a modified orthotopic LT technique that can be easily performed while overcoming major drawbacks. The modified technique has many advantages, such as easy graft implanting, shortened operation time, fewer complications and high reproducibility. PMID:23295132

  14. Neuro-immune interactions of neural stem cell transplants: From animal disease models to human trials

    PubMed Central

    Cossetti, Chiara; Pluchino, Stefano

    2014-01-01

    Stem cell technology is a promising branch of regenerative medicine that is aimed at developing new approaches for the treatment of severely debilitating human diseases, including those affecting the central nervous system (CNS). Despite the increasing understanding of the mechanisms governing their biology, the application of stem cell therapeutics remains challenging. The initial idea that stem cell transplants work in vivo via the replacement of endogenous cells lost or damaged owing to disease has been challenged by accumulating evidence of their therapeutic plasticity. This new concept covers the remarkable immune regulatory and tissue trophic effects that transplanted stem cells exert at the level of the neural microenvironment to promote tissue healing via combination of immune modulatory and tissue protective actions, while retaining predominantly undifferentiated features. Among a number of promising candidate stem cell sources, neural stem/precursor cells (NPCs) are under extensive investigation with regard to their therapeutic plasticity after transplantation. The significant impact in vivo of experimental NPC therapies in animal models of inflammatory CNS diseases has raised great expectations that these stem cells, or the manipulation of the mechanisms behind their therapeutic impact, could soon be translated to human studies. This review aims to provide an update on the most recent evidence of therapeutically-relevant neuroimmune interactions following NPC transplants in animal models of multiple sclerosis, cerebral stroke and traumas of the spinal cord, and consideration of the forthcoming challenges related to the early translation of some of these exciting experimental outcomes into clinical medicines. PMID:23507035

  15. Sutureless anastomoses using magnetic rings in canine liver transplantation model.

    PubMed

    Liu, Shi-Qi; Lei, Peng; Cui, Xiao-Hai; Lv, Yi; Li, Jian-Hui; Song, Yu-Long; Zhao, Ge

    2013-12-01

    In the first posttransplant month, the most frequent complications are due to technical problems related to complex vascular and bile duct reconstructions during the operation. Moreover, despite great improvements in suturing technique and materials, severe organ ischemia-reperfusion caused by time-consuming hand suturing is still an important factor in graft survival. During the operation, severe hypotension, hypoxic acidosis, hyperkalemia, and renal dysfunction may occur during the anhepatic phase due to the prolonged venous clamping time required for hand suturing. Therefore, hand suturing is a handicap in the development of further advancements in liver transplantation. In this study, we aimed to test a new "mechanical installation method" for rapid vascular reconstruction. The magnetic pinning-ring device was developed consisting of paired magnetic rings coated with titanium oxide and embedded in a polypropylene shell. The rings were equipped with alternately spaced holes and titanium pins. Forty adult mongrel dogs were randomly divided into groups: A (n = 16), all vascular and bile duct reconstruction by magnetic ring without venous bypass; B (n = 16), all vascular and bile duct reconstruction by hand suturing with venous bypass; C (n = 8), sham transplantation group, transection of all vessels and common bile duct followed by anastomosis with the magnetic rings without liver transplantation. From groups A and B, dogs were randomly selected as donors (n = 8) or recipients (n = 8) of liver transplantations. We recorded operation time, vascular and bile duct anastomosis time, anhepatic time, administration of supplemental fluids during operation, and survival; blood samples were collected for the detection of liver damage (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and tumor necrosis factor α level. Patency was confirmed using ultrasound scans at various time points as late as 24 wk after surgery. Angiography was used to evaluate the

  16. Irritable Bowel Syndrome

    MedlinePlus

    Irritable bowel syndrome (IBS) is a problem that affects the large intestine. It can cause abdominal cramping, bloating, and a change in bowel ... go back and forth between the two. Although IBS can cause a great deal of discomfort, it ...

  17. Are Your Bowels Moving?

    MedlinePlus

    ... have sensitive bowels — a common problem doctors call irritable bowel syndrome (IBS). IBS is also called spastic colon, mucous colitis, or ... Tummy pain is the most common problem of IBS. Also, people with IBS can have diarrhea, constipation, ...

  18. Prevalence of Bowel Incontinence

    MedlinePlus

    ... Treatment Lifestyle Changes Dietary Tips Medication Bowel Management Biofeedback Surgical Treatments Newer Treatment Options Tips on Finding ... Treatment Lifestyle Changes Dietary Tips Medication Bowel Management Biofeedback Surgical Treatments Newer Treatment Options Tips on Finding ...

  19. Validating prediction models of kidney transplant outcome using single center data.

    PubMed

    Tang, Hongying; Hurdle, John F; Poynton, Mollie; Hunter, Cheri; Tu, Ming; Baird, Bradley C; Krikov, Sergey; Goldfarb-Rumyantzev, Alexander S

    2011-01-01

    Prediction of kidney transplant outcome represents an important and clinically relevant problem. Although several prediction models have been proposed based on large, national collections of data, their utility at the local level (where local data distributions may differ from national data) remains unclear. We conducted a comparative analysis that modeled the outcome data of transplant recipients in the national US Renal Data System (USRDS) against a representative local transplant dataset at the University of Utah Health Sciences Center, a regional transplant center. The performance of an identical set of prediction models was evaluated on both national and local data to assess how well national models reflect local outcomes. Compared with the USRDS dataset, several key characteristics of the local dataset differed significantly (e.g., a much higher local graft survival rate; a much higher local percentage of white donors and recipients; and a much higher proportion of living donors). This was reflected in statistically significant differences in model performance. The area under the receiver operating characteristic curve values of the models predicting 1, 3, 5, 7, and 10-year graft survival on the USRDS data were 0.59, 0.63, 0.76, 0.91, and 0.97, respectively. In contrast, in the local dataset, these values were 0.54, 0.58, 0.58, 0.61, and 0.70, respectively. Prediction models trained on a national set of data from the USRDS performed better in the national dataset than in the local data. This might be due to the differences in the data characteristics between the two datasets, suggesting that the wholesale adoption of a prediction model developed on a large national dataset to guide local clinical practice should be done with caution.

  20. Irritable bowel syndrome and active inflammatory bowel disease diagnosed by faecal gas analysis.

    PubMed

    Aggio, R B M; White, P; Jayasena, H; de Lacy Costello, B; Ratcliffe, N M; Probert, C S J

    2017-01-01

    Inflammatory bowel disease and irritable bowel syndrome may present in a similar manner. Measuring faecal calprotectin concentration is often recommended to rule out inflammatory bowel disease, however, there are no tests to positively diagnose irritable bowel syndrome and invasive tests are still used to rule out other pathologies. To investigate a platform technology for diagnosing inflammatory bowel disease and irritable bowel syndrome based on faecal gas. The platform technology is composed of a gas chromatography column coupled to a metal oxide gas sensor (OdoReader) and a computer algorithm. The OdoReader separates the volatile compounds from faecal gas and the computer algorithm identifies resistance patterns associated with specific medical conditions and builds classification models. This platform was applied to faecal samples from 152 patients: 33 patients with active inflammatory bowel disease; 50 patients with inactive inflammatory bowel disease; 28 patients with irritable bowel syndrome and 41 healthy donors (Control). The platform classified samples with accuracies from 75% to 100% using rigorous validation schemes: namely leave-one-out cross-validation, 10-fold cross-validation, double cross-validation and their Monte Carlo variations. The most clinically important findings, after double cross-validation, were the accuracy of active Crohn's disease vs. irritable bowel syndrome (87%; CI 84-89%) and irritable bowel syndrome vs. controls (78%; CI 76-80%). These schemes provide an estimate of out-of-sample predictive accuracy for similar populations. This is the first description of an investigation for the positive diagnosis of irritable bowel syndrome, and for diagnosing inflammatory bowel disease. © 2016 John Wiley & Sons Ltd.

  1. Current management of the short bowel syndrome.

    PubMed

    Thompson, Jon S; Weseman, Rebecca; Rochling, Fedja A; Mercer, David F

    2011-06-01

    Short bowel syndrome is a challenging clinical problem that benefits from a multidisciplinary approach. Much progress has recently been made in all aspects of management. Medical intestinal rehabilitation should be the initial treatment focus, and several new potential pharmacologic agents are being investigated. Surgical rehabilitation using nontransplant procedures in selected patients may further improve intestinal function. Intestinal lengthening procedures are particularly promising. Intestinal transplantation has increasingly been used with improving success in patients with life-threatening complications of intestinal failure.

  2. [Improved treatment options for a short bowel syndrome patient].

    PubMed

    Pakarinen, Mikko

    2014-01-01

    Short bowel syndrome necessitates long-term parenteral nutrition, which exposes to decreased quality of life and increased morbidity. In recent years the understanding of short bowel pathophysiology and related complications has expanded, forming the basis for improved treatment options. In addition to evolving nutritional therapy, new pharmacological and surgical therapies have emerged, enhancing the patients' possibilities to achieve intestinal autonomy. Increasingly efficient prevention of intestinal failure-associated liver disease and central line-associated septic episodes improves patient survival. Bowel function can be restored by intestinal transplantation in those developing life-threatening complications.

  3. Unravelling the metabolic impact of SBS-associated microbial dysbiosis: Insights from the piglet short bowel syndrome model

    PubMed Central

    Pereira-Fantini, Prue M.; Byars, Sean G.; Pitt, James; Lapthorne, Susan; Fouhy, Fiona; Cotter, Paul D.; Bines, Julie E.

    2017-01-01

    Liver disease is a major source of morbidity and mortality in children with short bowel syndrome (SBS). SBS-associated microbial dysbiosis has recently been implicated in the development of SBS-associated liver disease (SBS-ALD), however the pathological implications of this association have not been explored. In this study high-throughput sequencing of colonic content from the well-validated piglet SBS-ALD model was examined to determine alterations in microbial communities, and concurrent metabolic alterations identified in urine samples via targeted mass spectrometry approaches (GC-MS, LC-MS, FIA-MS) further uncovered impacts of microbial disturbance on metabolic outcomes in SBS-ALD. Multi-variate analyses were performed to elucidate contributing SBS-ALD microbe and metabolite panels and to identify microbe-metabolite interactions. A unique SBS-ALD microbe panel was clearest at the genus level, with discriminating bacteria predominantly from the Firmicutes and Bacteroidetes phyla. The SBS-ALD metabolome included important alterations in the microbial metabolism of amino acids and the mitochondrial metabolism of branched chain amino acids. Correlation analysis defined microbe-metabolite clustering patterns unique to SBS-ALD and identified a metabolite panel that correlates with dysbiosis of the gut microbiome in SBS. PMID:28230078

  4. Protective effect of aqueous extract of Bombax malabaricum DC on experimental models of inflammatory bowel disease in rats and mice.

    PubMed

    Jagtap, A G; Niphadkar, P V; Phadke, A S

    2011-05-01

    There is little evidence regarding role of B. malabaricum in the treatment of inflammatory bowel disease (IBD); though it is clinically employed as a constituent of a polyherbal preparation for IBD. To establish its role as a monotherapy for IBD, preliminary phytochemical screening of aqueous extract of B. malabaricum (AEBM) was undertaken. Subsequently, its protective effect in indomethacin and iodoacetamide induced colitis in rats (45, 90, 180, 270 mg/kg) and acetic acid induced colitis in mice (65, 130, 250, 500 mg/kg) was assessed. AEBM (270 mg/kg) in indomethacin and iodoacetamide induced colitis significantly reduced the ulcer score and myeloperoxidase (MPO) activity. AEBM/500 mg/kg dose/significantly reduced the ulcer score and MPO activity in acetic acid induced colitis. The extract (270 mg/kg in rats and 500 mg/kg in mice) was found to be comparable with prednisolone (10 mg/kg) and 5-aminosalicylic acid (5-ASA) (100 mg/kg) used as standard treatments. AEBM provided reduction in edema of the intestinal tissues, ulcer protection and lowering of MPO activity in a dose dependent manner. AEBM (500 mg/kg) significantly reduced colonic and serum TNF-alpha level when compared with the positive control in acetic acid induced colitis model. The results suggest a protective role of AEBM in IBD.

  5. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease

    PubMed Central

    Bloom, Seth M.; Bijanki, Vinieth N.; Nava, Gerardo M.; Sun, Lulu; Malvin, Nicole P.; Donermeyer, David L.; Dunne, W. Michael; Allen, Paul M.; Stappenbeck, Thaddeus S.

    2011-01-01

    SUMMARY The intestinal microbiota is important for induction of inflammatory bowel disease (IBD). IBD is associated with complex shifts in microbiota composition, but it is unclear whether specific bacterial subsets induce IBD and, if so, whether their proportions in the microbiota are altered during disease. Here we fulfilled Koch’s postulates in host-genotype-specific fashion using a mouse model of IBD with human-relevant disease-susceptibility mutations. From screening experiments we isolated common commensal Bacteroides species, introduced them into antibiotic-pretreated mice, and quantitatively re-isolated them in culture. The bacteria colonized IBD-susceptible and non-susceptible mice equivalently, but induced disease exclusively in susceptible animals. Conversely, commensal Enterobacteriaceae were >100-fold enriched during spontaneous disease but an Enterobacteriaceae isolate failed to induce disease in antibiotic-pretreated mice despite robust colonization. We thus demonstrate that IBD-associated microbiota alterations do not necessarily reflect underlying disease etiology. These findings establish important experimental criteria and a conceptual framework for understanding microbial contributions to IBD. PMID:21575910

  6. Administration of Wasabia koreana Ameliorates Irritable Bowel Syndrome-Like Symptoms in a Zymosan-Induced Mouse Model.

    PubMed

    Park, Bo-Kyung; Chun, Eunho; Choi, Jeong June; Shin, Younmin; Kho, Young Tak; Oh, Seung Hyun; Kim, Sun Yeou; Lee, Taek Hwan; Kim, Tae-Wan; Shin, Eunju; Do, Seon-Gil; Jin, Mirim

    2017-05-01

    Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with complex pathophysiology involving the brain-gut axis. To assess the effects of Wasabia koreana (WK) on IBS, we employed a mouse model of colonic zymosan injection presenting with diarrhea-predominant IBS-like symptoms. Oral WK administration significantly diminished stool score, suppressed colon length and weight change, and minimized body weight loss without affecting food intake. In WK-treated mice, the submucosal thickening and epithelial lining of the colon were inhibited and were similar to those of naïve mice. Infiltration of mast cells into the colon and serum tumor necrosis factor-α levels were markedly suppressed. These effects were comparable to those of sulfasalazine, an anti-inflammatory drug. Furthermore, the number of visceral pain-related behaviors was significantly decreased, and locomotion activities measured in the elevated plus maze and open field tests were significantly increased by WK in a dose-dependent manner compared with amitriptyline, an antidepressant. These changes were accompanied by reduced FosB2 expression in the brain. Taken together, these data suggest that WK may have potential as a medicinal food for IBS by acting on inflammatory diarrhea and neural activity.

  7. Flotillin-2 Expression in the Human Gut: from a Cell Model to Human Tissue in Health and Inflammatory Bowel Diseases

    PubMed Central

    Gauss, Annika; Buchholz, Inga; Zahn, Alexandra; Schmitz, Gerd; Stremmel, Wolfgang; Fuellekrug, Joachim; Ehehalt, Robert

    2013-01-01

    Background and aims: The etiopathogenesis of inflammatory bowel diseases (IBD) remains largely unexplained. Flotillins (flotillin-1 and flotillin-2) are ubiquitous proteins which have been linked to inflammation and regeneration. We hypothesized that alterations in the expression of flotillin-2 in enterocytes may be related to the pathogenesis of IBD as a classical example of an inflammatory disorder of mostly unknown origin. Methods: Cell and tissue localization of flotillin-2 (and -1) were investigated by immunofluorescent staining in 1. polarized and unpolarized CaCo-2w cells as a model of human enterocytes (native and after TNFα stimulation) and 2. intestinal biopsies from controls, patients with ulcerative colitis (UC) and patients with Crohn's disease (CD). For quantification of flotillin-2, we analyzed its expression in ileal and colonic biopsies from controls, UC patients and CD patients using real-time RT-PCR, Western blot and indirect immunofluorescence. Results: In polarized CaCo-2w cells and human enterocytes in biopsies, flotillins were localized at the basolateral membrane and on subapical vesicles, but not in the apical membrane. Flotillin-2 expression did not differ between UC patients, CD patients and controls. However, it was significantly higher in colonic biopsies compared to ileal biopsies in all groups. Conclusions: By virtue of its abundant expression in enterocytes, flotillin-2 must have an essential function in intestinal physiology, especially in the colon. Yet our data could not link flotillin-2 to the pathogenesis of IBD. PMID:23983584

  8. A model-driven methodology for exploring complex disease comorbidities applied to autism spectrum disorder and inflammatory bowel disease

    PubMed Central

    Somekh, Judith; Peleg, Mor; Eran, Alal; Koren, Itay; Feiglin, Ariel; Demishtein, Alik; Shiloh, Ruth; Heiner, Monika; Kong, Sek Won; Elazar, Zvulun; Kohane, Isaac

    2016-01-01

    We propose a model-driven methodology aimed to shed light on complex disorders. Our approach enables exploring shared etiologies of comorbid diseases at the molecular pathway level. The method, Comparative Comorbidities Simulation (CCS), uses stochastic Petri net simulation for examining the phenotypic effects of perturbation of a network known to be involved in comorbidities to predict new roles for mutations in comorbid conditions. To demonstrate the utility of our novel methodology, we investigated the molecular convergence of autism spectrum disorder (ASD) and inflammatory bowel disease (IBD) on the autophagy pathway. In addition to validation by domain experts, we used formal analyses to demonstrate the model’s self-consistency. We then used CCS to compare the effects of loss of function (LoF) mutations previously implicated in either ASD or IBD on the autophagy pathway. CCS identified similar dynamic consequences of these mutations in the autophagy pathway. Our method suggests that two LoF mutations previously implicated in IBD may contribute to ASD, and one ASD-implicated LoF mutation may play a role in IBD. Future targeted genomic or functional studies could be designed to directly test these predictions. PMID:27522000

  9. The Implications of Oxidative Stress and Antioxidant Therapies in Inflammatory Bowel Disease: Clinical Aspects and Animal Models

    PubMed Central

    Balmus, Ioana Miruna; Ciobica, Alin; Trifan, Anca; Stanciu, Carol

    2016-01-01

    Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder characterized by alternating phases of clinical relapse and remission. The etiology of IBD remains largely unknown, although a combination of patient's immune response, genetics, microbiome, and environment plays an important role in disturbing intestinal homeostasis, leading to development and perpetuation of the inflammatory cascade in IBD. As chronic intestinal inflammation is associated with the formation of reactive oxygen and reactive nitrogen species (ROS and RNS), oxidative and nitrosative stress has been proposed as one of the major contributing factor in the IBD development. Substantial evidence suggests that IBD is associated with an imbalance between increased ROS and decreased antioxidant activity, which may explain, at least in part, many of the clinical pathophysiological features of both CD and UC patients. Hereby, we review the presently known oxidant and antioxidant mechanisms involved in IBD-specific events, the animal models used to determine these specific features, and also the antioxidant therapies proposed in IBD patients. PMID:26831601

  10. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease.

    PubMed

    Bloom, Seth M; Bijanki, Vinieth N; Nava, Gerardo M; Sun, Lulu; Malvin, Nicole P; Donermeyer, David L; Dunne, W Michael; Allen, Paul M; Stappenbeck, Thaddeus S

    2011-05-19

    The intestinal microbiota is important for induction of inflammatory bowel disease (IBD). IBD is associated with complex shifts in microbiota composition, but it is unclear whether specific bacterial subsets induce IBD and, if so, whether their proportions in the microbiota are altered during disease. Here, we fulfilled Koch's postulates in host-genotype-specific fashion using a mouse model of IBD with human-relevant disease-susceptibility mutations. From screening experiments we isolated common commensal Bacteroides species, introduced them into antibiotic-pretreated mice, and quantitatively reisolated them in culture. The bacteria colonized IBD-susceptible and -nonsusceptible mice equivalently, but induced disease exclusively in susceptible animals. Conversely, commensal Enterobacteriaceae were >100-fold enriched during spontaneous disease, but an Enterobacteriaceae isolate failed to induce disease in antibiotic-pretreated mice despite robust colonization. We thus demonstrate that IBD-associated microbiota alterations do not necessarily reflect underlying disease etiology. These findings establish important experimental criteria and a conceptual framework for understanding microbial contributions to IBD. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Bowel perforation detection using metabolic fluorescent chlorophylls

    NASA Astrophysics Data System (ADS)

    Han, Jung Hyun; Jo, Young Goun; Kim, Jung Chul; Choi, Sujeong; Kang, Hoonsoo; Kim, Yong-Chul; Hwang, In-Wook

    2016-03-01

    Thus far, there have been tries of detection of disease using fluorescent materials. We introduce the chlorophyll derivatives from food plants, which have longer-wavelength emissions (at >650 nm) than those of fluorescence of tissues and organs, for detection of bowel perforation. To figure out the possibility of fluorescence spectroscopy as a monitoring sensor of bowel perforation, fluorescence from organs of rodent models, intestinal and peritoneal fluids of rodent models and human were analyzed. In IVIS fluorescence image of rodent abdominal organ, visualization of perforated area only was possible when threshold of image is extremely finely controlled. Generally, both perforated area of bowel and normal bowel which filled with large amount of chlorophyll derivatives were visualized with fluorescence. The fluorescence from chlorophyll derivatives penetrated through the normal bowel wall makes difficult to distinguish perforation area from normal bowel with direct visualization of fluorescence. However, intestinal fluids containing chlorophyll derivatives from food contents can leak from perforation sites in situation of bowel perforation. It may show brighter and longer-wavelength regime emissions of chlorophyll derivatives than those of pure peritoneal fluid or bioorgans. Peritoneal fluid mixed with intestinal fluids show much brighter emissions in longer wavelength (at>650 nm) than those of pure peritoneal fluid. In addition, irrigation fluid, which is used for the cleansing of organ and peritoneal cavity, made of mixed intestinal and peritoneal fluid diluted with physiologic saline also can be monitored bowel perforation during surgery.

  12. Liver transplant

    MedlinePlus

    Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

  13. Treatment Efficacy of NGF Nanoparticles Combining Neural Stem Cell Transplantation on Alzheimer's Disease Model Rats.

    PubMed

    Chen, Yan; Pan, Cuihuan; Xuan, Aiguo; Xu, Liping; Bao, Guoqing; Liu, Feiei; Fang, Jie; Long, Dahong

    2015-11-21

    Alzheimer's disease (AD) is the most common type of dementia. It causes progressive brain disorder involving loss of normal memory and thinking skills. The transplantation of neural stem cells (NSCs) has been reported to improve learning and memory function of AD rats, and protects basal forebrain cholinergic neurons. Nerve growth factor - poly (ethylene glycol) - poly (lactic-co-glycolic acid)-nanoparticles (NGF-PEG-PLGA-NPs) can facilitate the differentiation of NSCs in vitro. This study thus investigated the treatment efficacy of NGF-PEG-PLGA-NPs combining NSC transplantation in AD model rats. AD rats were prepared by injection of 192IgG-saporin into their lateral ventricles. Embryonic rat NSCs were separated, induced by NGF-PEG-PLGA-NPs in vitro, and were transplanted. The Morris water-maze test was used to evaluate learning and memory function, followed by immunohistochemical staining for basal forebrain cholinergic neurons, hippocampal synaptophysin, and acetylcholine esterase (AchE) fibers. Rats in the combined treatment group had significantly improved spatial learning ability compared to AD model animals (p<0.05). The number of basal forebrain cholinergic neurons, hippocampal synaptophysin, and AchE-positive fibers were all significantly larger than in the NSC-transplantation group, with no difference from control animals. NGF-PEG-PLGA-NPs plus NSC transplantation can significantly improve learning and memory functions of AD rats, replenish basal forebrain cholinergic neurons, and help form hippocampal synapses and AchE-positive fibers. These findings may offer practical support for and insight into treatment of Alzheimer's disease.

  14. Evaluation of Immunosuppressive Activity of Demethylzeylasteral in a Beagle Dog Kidney Transplantation Model.

    PubMed

    An, Huimin; Zhu, Yu; Xu, Wenping; Liu, Yujun; Zhang, Jianping; Lin, Zongming

    2015-12-01

    Several monomers isolated from Tripterygium wilfordii Hook f. (Celastraceae) have attracted worldwide interest. In this study, we established a simple and reliable kidney transplantation model in beagle dog to evaluate the immunosuppressive activity of demethylzeylasteral (T-96), an immunosuppressive monomer isolated from the root xylem of T. wilfordii. Recipient and donor male beagle dogs were obtained from two different breeders to ensure MHC mismatching. All dogs were randomly divided into six groups following kidney transplantation, and different doses of T-96 or cyclosporine A (CsA) were administered to each group during 14 days of observation. The results showed that T-96 alone at a dosage of 10 or 20 mg/kg/day prolonged graft survival up to 10.83 ± 1.47 or 11.17 ± 1.47 days. A combination of T-96 and CsA significantly prolonged the survival time to 13.33 ± 1.75 days. The results demonstrated that T-96 can inhibit acute rejection in kidney transplantation, and the inhibitory effect of T-96 was enhanced when combined with CsA, which suggests the possible use in organ transplantation to prevent immune rejection.

  15. CCN1 enhances angiogenic potency of bone marrow transplantation in a rat model of hindlimb ischemia.

    PubMed

    Yin, Cunping; Liang, Yuan; Guo, Shuguang; Zhou, Xingli; Pan, Xinghua

    2014-09-01

    Implantation of autologous bone marrow mononuclear cells (BM-MNCs) has been performed in ischemic tissues, for stimulation of angiogenesis, but the limited number of BM-MNCs in patients with hindlimb ischemia disease may offset their overall therapeutic efficacy. CCN1 is a novel and essential regulator during angiogenesis. We evaluated whether CCN1 and BM-MNC are capable of promoting angiogenesis in hindlimb ischemia. In this study, we created the rat model of hindlimb ischemia, and then the rats were randomly divided into four groups: CCN1 infusion plus BM-MNC transplantation (CCN1 + BM-MNCs group), CCN1 infusion plus PBS injection (CCN1 group), vehicle infusion plus BM-MNC transplantation (BM-MNCs group) and vehicle infusion plus PBS injection (control group). The combination of CCN1 and BM-MNC therapy could increase blood perfusion, capillary/muscle fiber ratio and tissue oxygenation in ischemic hindlimb. Moreover, CCN1 could not only inhibit the apoptosis of BM-MNCs, but also enhance the adhesiveness of BM-MNCs to HUVEC. Taken together, CCN1 enhanced angiogenesis of BM-MNC transplantation, and combining CCN1 with BM-MNC transplantation is a useful alternative for ischemic limbs.

  16. Transplantation of human umbilical cord blood cells benefits an animal model of Sanfilippo syndrome type B.

    PubMed

    Garbuzova-Davis, Svitlana; Willing, Alison E; Desjarlais, Tammy; Davis Sanberg, Cyndy; Sanberg, Paul R

    2005-08-01

    Sanfilippo syndrome type B is caused by alpha-N-acetylglucosaminidase (Naglu) enzyme deficiency leading to an accumulation of undegraded heparan sulfate, a glycosaminoglycan (GAG). Cell therapy is a promising new treatment and human umbilical cord blood (hUCB) cell transplantation may be preferred for delivery of the missing enzyme. We investigated the ability of mononuclear hUCB cells administered into the lateral cerebral ventricle to ameliorate/prevent histopathological changes in mice modeling Sanfilippo syndrome type B. These are the first results supporting enzyme replacement by administered hUCB cells. In vivo, transplanted hUCB cells survived long-term (7 months), migrated into the parenchyma of the brain and peripheral organs, expressed neural antigens, and exhibited neuron and astrocyte-like morphology. Transplant benefits were also demonstrated by stable cytoarchitecture in the hippocampus and cerebellum, and by reduced GAGs in the livers of treated mutant mice. A hUCB cell transplant may be an effective therapeutic strategy for enzyme delivery in Sanfilippo syndrome type B.

  17. Reversal of Early Diabetic Nephropathy by Islet Transplantation under the Kidney Capsule in a Rat Model

    PubMed Central

    Xu, Ziqiang; Zhou, Mingshi; Wu, Minmin; Chen, Xuehai; Wang, Silu; Qiu, Kaiyan; Cai, Yong; Fu, Hongxing

    2016-01-01

    Objective. Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus, and insulin therapy has many side effects in the treatment of DN. Islet transplantation has emerged as a promising therapy for diabetic patients. This study was established to investigate its advantageous effects in a rat model of early DN. Methods. Streptozotocin was administered to the rats to induce diabetes. Twelve weeks later, the diabetic rats were divided into 3 groups: the islet-transplanted group (IT group), the insulin-treated group (IN group), and the untreated group (DN group). Renal injury and kidney structure were assessed by urinalysis and transmission electron microscopy (TEM) detection. Immunohistochemical staining and western blotting were performed to assess renal fibrosis levels. Results. The early DN features were reversed and the glomerular filtration barrier and basement membrane structures were improved at 4 weeks after islet transplantation. The urine microalbumin-to-creatinine ratio (ACR), protein-to-creatinine ratio, and mean thickness of the glomerular basement membrane (GBM) were significantly decreased in the IT group. The expression of renal fibrotic factors was also significantly decreased. Conclusions. These data suggest that early DN can be reversed after islet transplantation, and they may facilitate the development of a clinical therapeutic strategy for human diabetes mellitus. PMID:27725943

  18. Angiogenesis characteristics of infantile hemangioma and feasibility observation of transplantation model of human hemangioma on mice.

    PubMed

    Fu, Y; Yang, Z-G; Zhao, L-Y

    2017-03-01

    To study pathogenic features of pediatric hemangiomas, we successfully established a model in mice, by transplanting human hemangioma tissues. The hemangioma from the leg of a two-month-old infant was dissected and sliced into several pieces. During a careful surgical procedure, the hemangioma tissues were individually transplanted into skin incisions in anesthetized mice. The volume of the transplanted tumors was measured and the changes in shape recorded at 1 day, and at 1, 2, 3, 4, 5 and 6 months after the transplantation. HE dyeing, CD31 and Glut1 IHC were applied to tumors in the proliferation and involuting phases. Also, 10 survival tumors and 10 normal tissues from infants undergoing circumcisions (control tissues) were used to determine their Angiotensin 1 (Ang1), Angiotensin 2 (Ang2), Tie2, and endothelium growth factor (VEGF) expression levels by IHC method. We observed all the tumors going through the same stages, where after two months their volumes increased sharply and then after 4 months they all began to recede. During the proliferative phase, newly born capillaries could be seen and the tumor elasticity increased (bright red color). During the involuting phase, the color faded away and the tumors became harder and were almost gone by 6 months. During the first two months after transplantation, HE dyeing showed hypertrophied and proliferating endothelial cells accumulating inside the tumors with irregular cavities inside blood vessels being filled by them. During the involuting phase (at 4 months), the lumen in blood vessels was distinctly enlarged while fiber and adipose tissue had significantly deposited. The transplanted and original tumors tested positive for CD31 and Glut1 dyeing, without significant differences. Compared with control samples, the Ang1 expression of the transplanted tumor in both the hyperplasia and proliferative phases was stably low (p<0.05), while expressions of Ang2 and Tie2 were both stably high (p<0.05). The VEGF

  19. Establishment of a dual-color fluorescence tracing orthotopic transplantation model of hepatocellular carcinoma.

    PubMed

    Chen, Qian; Wang, Xiaoping; Wu, Hao; Wang, Hui; Zhu, Mingao; Wang, Roushu; Wu, Ying; Zhang, Luyao; Meng, Qiao; Song, Ranran; Zhuang, Zhixiang; Huang, Qiang

    2016-01-01

    Different experimental models of hepatocellular carcinoma (HCC) have been used to investigate the biological mechanisms of hepatocarcinogenesis and its progression. However, previous studies have highlighted the difficulty of distinguishing between the tumor cells and stroma in experimental models of HCC. Therefore the aim of the present study was to establish a red‑green dual‑color fluorescence tracing orthotopic transplantation model of HCC, and investigate its practical values. Stable high red fluorescent protein (RFP)‑expressing HepG2 human hepatoma cells and Hepa1‑6 mice hepatoma cells were injected into the right liver lobe of green fluorescent protein‑expressing nude mice. The growth and metastasis of the tumors were visualized using a whole‑body in vivo fluorescence imaging system in real time. HCC tissues were extracted from tumor‑bearing mice, and cut into 5‑µm serial frozen slices. The organizational structure of the transplanted tumors was observed under a microscope. A dual‑color fluorescence tracing orthotopic transplantation tumor model of HCC was successfully established with a success rate of 100%. The growth and metastasis of the tumors were visualized at each stage of development in the tumor‑bearing mice. Tumor cells with red fluorescence and host cells with green fluorescence were identified to merge in the reconstruction region of tumor tissue. The invasion, migration, and cell fusion between tumor and host cells was observed clearly. The dual‑color fluorescence tracing orthotopic transplantation model of HCC was determined to be a stable and reliable method for tracking tumor progression. Mutual interactions between hepatoma cells and host tissues may be observed directly using this model, further elucidating the development of the tumor microenvironment.

  20. Future Economics of Liver Transplantation: A 20-Year Cost Modeling Forecast and the Prospect of Bioengineering Autologous Liver Grafts.

    PubMed

    Habka, Dany; Mann, David; Landes, Ronald; Soto-Gutierrez, Alejandro

    2015-01-01

    During the past 20 years liver transplantation has become the definitive treatment for most severe types of liver failure and hepatocellular carcinoma, in both children and adults. In the U.S., roughly 16,000 individuals are on the liver transplant waiting list. Only 38% of them will receive a transplant due to the organ shortage. This paper explores another option: bioengineering an autologous liver graft. We developed a 20-year model projecting future demand for liver transplants, along with costs based on current technology. We compared these cost projections against projected costs to bioengineer autologous liver grafts. The model was divided into: 1) the epidemiology model forecasting the number of wait-listed patients, operated patients and postoperative patients; and 2) the treatment model forecasting costs (pre-transplant-related costs; transplant (admission)-related costs; and 10-year post-transplant-related costs) during the simulation period. The patient population was categorized using the Model for End-Stage Liver Disease score. The number of patients on the waiting list was projected to increase 23% over 20 years while the weighted average treatment costs in the pre-liver transplantation phase were forecast to increase 83% in Year 20. Projected demand for livers will increase 10% in 10 years and 23% in 20 years. Total costs of liver transplantation are forecast to increase 33% in 10 years and 81% in 20 years. By comparison, the projected cost to bioengineer autologous liver grafts is $9.7M based on current catalog prices for iPS-derived liver cells. The model projects a persistent increase in need and cost of donor livers over the next 20 years that's constrained by a limited supply of donor livers. The number of patients who die while on the waiting list will reflect this ever-growing disparity. Currently, bioengineering autologous liver grafts is cost prohibitive. However, costs will decline rapidly with the introduction of new manufacturing

  1. Differing Complex Microbiota Alter Disease Severity of the IL-10−/− Mouse Model of Inflammatory Bowel Disease

    PubMed Central

    Hart, Marcia L.; Ericsson, Aaron C.; Franklin, Craig L.

    2017-01-01

    It is estimated that 1.4 million people in the United States suffer from Inflammatory Bowel Disease (IBD), with an overall annual health care cost of more than $1.7 billion. Although the exact etiology of this disease remains unknown, research suggests that it is a multifactorial disease associated with aberrant gastrointestinal microbial populations (dysbiosis). The C57BL/6 and C3H/HeJBir mouse strains with targeted mutations in the IL-10 gene are commonly used models to study IBD. However, anecdotally, disease phenotype can vary in severity from lab to lab. Moreover, studies using germfree and monocolonized mice have suggested that gut microbiota (GM) are critical to disease induction in these models. With recent studies suggesting variation in naturally occurring GM composition and complexity among mouse producers, we hypothesized that differences in these naturally occurring complex GM profiles may modulate disease severity in the IL-10−/− mouse model. To test this hypothesis, we use a technique referred to as complex microbiota targeted rederivation (CMTR) to transfer genetically identical C57BL/6 IL-10−/− and C3H/HeJBir IL-10−/− embryos into surrogate CD-1 or C57BL/6 dams from different commercial producers with varying microbiota complexity and composition. We found that disease severity significantly and reproducibly differed among mice in both IL-10−/− strains, dependent on differing maternally inherited GM. Furthermore, disease severity was associated with alterations in relative abundance of several physiologically relevant bacterial species. These findings suggest that the composition of the resident GM is a primary determinant of disease severity in IBD and provide proof-of-concept that CMTR can be used to investigate the contribution of contemporary complex GM on disease phenotype and reproducibility. PMID:28553262

  2. Exogenous Neural Stem Cells Transplantation as a Potential Therapy for Photothrombotic Ischemia Stroke in Kunming Mice Model.

    PubMed

    Hou, Boru; Ma, Junning; Guo, Xiumei; Ju, Furong; Gao, Junwei; Wang, Dengfeng; Liu, Jixing; Li, Xiaohui; Zhang, Shengxiang; Ren, Haijun

    2017-03-01

    Stroke is considered as the second leading cause of death worldwide. The survivors of stroke experience different levels of impairment in brain function resulting in debilitating disabilities. Current therapies for stroke are primarily palliative and may be effective in only a small population of stroke patients. In this study, we explore the transplantation of exogenous neural stem cells (NSCs) as the potential therapy for the photothrombotic ischemia stroke in a Kunming mice model. After stroke, mice receiving NSC transplantation demonstrated a better recovery of brain function during the neurobehavioral tests. Histology analysis of the brain samples from NSC transplanted mice demonstrated a reduction of brain damage caused by stroke. Moreover, immunofluorescence assay for biomarkers in brain sections confirmed that transplanted NSCs indeed differentiated to neurons and astrocytes, consistent with the improved brain function after stroke. Taken together, our data suggested that exogenous NSC transplantation could be a promising therapy for stroke.

  3. The role of a murine transplantation model of atherosclerosis regression in drug discovery.

    PubMed

    Feig, Jonathan E; Quick, John S; Fisher, Edward A

    2009-03-01

    Atherosclerosis is the leading cause of death worldwide. To date, the use of statins to lower LDL levels has been the major intervention used to delay or halt disease progression. These drugs have an incomplete impact on plaque burden and risk, however, as evidenced by the substantial rates of myocardial infarctions that occur in large-scale clinical trials of statins. Thus, it is hoped that by understanding the factors that lead to plaque regression, better approaches to treating atherosclerosis may be developed. A transplantation-based mouse model of atherosclerosis regression has been developed by allowing plaques to form in a model of human atherosclerosis, the apoE-deficient mouse, and then placing these plaques into recipient mice with a normolipidemic plasma environment. Under these conditions, the depletion of foam cells occurs. Interestingly, the disappearance of foam cells was primarily due to migration in a CCR7-dependent manner to regional and systemic lymph nodes after 3 days in the normolipidemic (regression) environment. Further studies using this transplant model demonstrated that liver X receptor and HDL are other factors likely to be involved in plaque regression. In conclusion, through the use of this transplant model, the process of uncovering the pathways regulating atherosclerosis regression has begun, which will ultimately lead to the identification of new therapeutic targets.

  4. Evaluation of Three-Dimensional Versus Conventional Laparoscopy for Kidney Transplant Procedures in a Human Cadaveric Model.

    PubMed

    He, Bulang; Mou, Lingjun; De Roo, Ronald; Musk, Gabrielle C; Hamdorf, Jeffrey M

    2017-10-01

    There are increased reports that kidney transplant can be performed by laparoscopic surgery. The further development of this technique could revolutionize human kidney transplant surgery. However, laparoscopic kidney transplant demands a high level of skill for vascular anastomoses. The emerging technology of the three-dimensional, high-definition laparoscopic system may facilitate the application of this technique. Therefore, in this study, we evaluated this system in performing kidney transplant surgery versus the two-dimensional laparoscopic system. Four fresh-frozen human cadavers were used in this study, with 2 for the 3-dimensional and 2 for the 2-dimensional system. Kidneys were retrieved by using the retroperitoneoscopic technique for living donor nephrectomy from the same cadaver. The kidney graft was transplanted at the right iliac fossa using a laparoscopic technique by extraperitoneal approach. The procedure was recorded, and the vessel anastomotic time was analyzed. Kidney transplant procedures were conducted successfully in the 3-dimensional, high-definition and the 2-dimensional groups. We recorded no significant differences in terms of vessel anastomotic time between the 2 groups. The total surgery time was shorter in the 3-dimensional, high-definition group than in the 2-dimensional group (P = .02). This pilot study reinforces that kidney transplant with either the 3-dimensional, high-definition or 2-dimensional laparoscopy is feasible in a human cadaveric model. The operation was the same as open kidney transplant, but the procedure was performed by a laparoscopic approach with a smaller incision.

  5. Mouse model of alloimmune-induced vascular rejection and transplant arteriosclerosis.

    PubMed

    Enns, Winnie; von Rossum, Anna; Choy, Jonathan

    2015-05-17

    Vascular rejection that leads to transplant arteriosclerosis (TA) is the leading representation of chronic heart transplant failure. In TA, the immune system of the recipient causes damage of the arterial wall and dysfunction of endothelial cells and smooth muscle cells. This triggers a pathological repair response that is characterized by intimal thickening and luminal occlusion. Understanding the mechanisms by which the immune system causes vasculature rejection and TA may inform the development of novel ways to manage graft failure. Here, we describe a mouse aortic interposition model that can be used to study the pathogenic mechanisms of vascular rejection and TA. The model involves grafting of an aortic segment from a donor animal into an allogeneic recipient. Rejection of the artery segment involves alloimmune reactions and results in arterial changes that resemble vascular rejection. The basic technical approach we describe can be used with different mouse strains and targeted interventions to answer specific questions related to vascular rejection and TA.

  6. Graft-vs.-lymphoma effect in an allogeneic hematopoietic stem cell transplantation model.

    PubMed

    Ito, M; Shizuru, J A

    1999-01-01

    It is known that an important curative benefit of allogeneic bone marrow transplantation (BAMT) in the treatment of hematolymphoid malignancies is a graft-vs.-tumor (GVT) effect. GVT activity has been attributed to mature immune cells contained within the graft because T-cell depletion of bone marrow results in increased rates of disease relapse post-transplantation. We previously demonstrated successful engraftment of highly purified hematopoietic stem cells (HSCs) transplanted across major histocompatibility complex (MHC) barriers in mice. In the present study, we have developed a preclinical model of allogeneic HSC transplantation into lymphoma-inoculated mice, allowing us to directly test whether purified HSCs have measurable GVT activity. We then performed cotransfer studies of HSCs with purified immune cells to identify which population(s) confers tumor protection and the mechanism by which such cells suppress tumor growth. MHC-mismatched donor-recipient combinations were studied. All of the GVT activity was contained in the CD8+ cell fraction and, at the doses of CD8+ cells tested, tumor protection was separable from acute graft-vs.-host disease (aGVHD). Although there appears to be no functional difference between BM- and splenic-derived CDS8+ cells with regard to GVT activity without aGVHD, this was not the case for purified CD3+ cells. CD3+ cells derived from BM were tumor protective, whereas transplantation of equivalent doses of CD3+ cells purified from spleen resulted in lethal GVHD. The mechanism by which the GVT-conferring cells protect recipient mice from tumors was studied using immune defective mice as donors. We found that an intact pathway of perforin-dependent cytolysis, as well as an intact Fas-ligand pathway, is required in order to exert maximal anti-tumor activity.

  7. A multiphase non-linear mixed effects model: An application to spirometry after lung transplantation.

    PubMed

    Rajeswaran, Jeevanantham; Blackstone, Eugene H

    2017-02-01

    In medical sciences, we often encounter longitudinal temporal relationships that are non-linear in nature. The influence of risk factors may also change across longitudinal follow-up. A system of multiphase non-linear mixed effects model is presented to model temporal patterns of longitudinal continuous measurements, with temporal decomposition to identify the phases and risk factors within each phase. Application of this model is illustrated using spirometry data after lung transplantation using readily available statistical software. This application illustrates the usefulness of our flexible model when dealing with complex non-linear patterns and time-varying coefficients.

  8. A Multiphase Non-Linear Mixed Effects Model: An Application to Spirometry after Lung Transplantation

    PubMed Central

    Rajeswaran, Jeevanantham; Blackstone, Eugene H.

    2014-01-01

    In medical sciences, we often encounter longitudinal temporal relationships that are non-linear in nature. The influence of risk factors may also change across longitudinal follow-up. A system of multiphase non-linear mixed effects model is presented to model temporal patterns of longitudinal continuous measurements, with temporal decomposition to identify the phases and risk factors within each phase. Application of this model is illustrated using spirometry data after lung transplantation using readily available statistical software. This application illustrates the usefulness of our flexible model when dealing with complex non-linear patterns and time varying coefficients. PMID:24919830

  9. A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation.

    PubMed

    Andrews, Louise M; Hesselink, Dennis A; van Gelder, Teun; Koch, Birgit C P; Cornelissen, Elisabeth A M; Brüggemann, Roger J M; van Schaik, Ron H N; de Wildt, Saskia N; Cransberg, Karlien; de Winter, Brenda C M

    2017-07-05

    Multiple clinical, demographic, and genetic factors affect the pharmacokinetics of tacrolimus in children, yet in daily practice, a uniform body-weight based starting dose is used. It can take weeks to reach the target tacrolimus pre-dose concentration. The objectives of this study were to determine the pharmacokinetics of tacrolimus immediately after kidney transplantation and to find relevant parameters for dose individualization using a population pharmacokinetic analysis. A total of 722 blood samples were collected from 46 children treated with tacrolimus over the first 6 weeks after renal transplantation. Non-linear mixed-effects modeling (NONMEM(®)) was used to develop a population pharmacokinetic model and perform a covariate analysis. Simulations were performed to determine the optimal starting dose and to develop dosing guidelines. The data were accurately described by a two-compartment model with allometric scaling for bodyweight. Mean tacrolimus apparent clearance was 50.5 L/h, with an inter-patient variability of 25%. Higher bodyweight, lower estimated glomerular filtration rate, and higher hematocrit levels resulted in lower total tacrolimus clearance. Cytochrome P450 3A5 expressers and recipients who received a kidney from a deceased donor had a significantly higher tacrolimus clearance. The model was successfully externally validated. In total, these covariates explained 41% of the variability in clearance. From the significant covariates, the cytochrome P450 3A5 genotype, bodyweight, and donor type were useful to adjust the starting dose to reach the target pre-dose concentration. Dosing guidelines range from 0.27 to 1.33 mg/kg/day. During the first 6 weeks after transplantation, the tacrolimus weight-normalized starting dose should be higher in pediatric kidney transplant recipients with a lower bodyweight, those who express the cytochrome P450 3A5 genotype, and those who receive a kidney from a deceased donor.

  10. Transplantation and Perfusion of Microvascular Fragments in a Rodent Model of Volumetric Muscle Loss Injury

    DTIC Science & Technology

    2014-07-01

    Microvascular transplantation after acute myocardial infarction . Tissue Eng 13: 2871-2879. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ...when grafts were implanted after murine myocardial infarction (Shepherd, 2007, text reference). However, caution should be made when extrapolating...these findings to the current study due to the differences between the models ( myocardial infarction vs. VML) and the time allowed for microvessel

  11. [Preliminary establishment of transplanted human chronic myeloid leukemia model in nude mice].

    PubMed

    Li, Xian-Min; Ding, Xin; Zhang, Long-Zhen; Cen, Jian-Nong; Chen, Zi-Xing

    2011-12-01

    Chronic myeloid leukemia (CML) is a malignant clonal disease derived from hematopoietic stem cells. CML stem cells were thought to be the root which could lead disease development and ultimately rapid change. However, a stable animal model for studying the characteristics of CML stem cells is currently lacking. This study was aimed to establish a transplanted human CML nude-mice model to further explore the biological behavior of CML stem cells in vivo, and to enrich CML stem cells in nude mice by series transplantation. The 4 - 6 weeks old BALB/c nude mice pretreated by splenectomy (S), cytoxan intraperitoneal injection (C) and sublethal irradiation (I) were transplanted intravenously with (5 - 7) × 10(7) of bone marrow mononuclear cells from CML patients in chronic phase. Alternatively, 4 - 6 weeks old BALB/c nude mice pretreated by lethal irradiation were transplanted intravenously with 5 × 10(6) homologous bone marrow cells of BALB/c nude mice together with (5 - 7) × 10(7) of bone marrow mononuclear cells from CML patients in chronic phase simultaneously. The leukemic cells engrafted and infiltrated in organs and bone marrow of the mice were tracked by reverse transcription-polymerase chain reaction (RT-PCR), plastic-embedded biopsy and flow cytometry. The results of these two methods were compared. The results showed that human CML cells engrafted and infiltrating into the bone marrow of two nude mice pretreated with SCI could be detected. In spite of the low successful rate, results suggested the feasibility of this method by using BALB/c nude mice as a human CML animal model. In contrast, in nude mice pretreated by the lethal dose irradiation, CML cells in the bone marrow could not be found. It is concluded that human bone marrow CML cells can results in leukemia in nude mice pretreated by SCI. Thus this study provides a new strategy for establishment of CML animal models which deserves further elaboration.

  12. Transplantation of Tissue-Engineered Cartilage in an Animal Model (Xenograft and Autograft): Construct Validation.

    PubMed

    Nemoto, Hitoshi; Watson, Deborah; Masuda, Koichi

    2015-01-01

    Tissue engineering holds great promise for cartilage repair with minimal donor-site morbidity. The in vivo maturation of a tissue-engineered construct can be tested in the subcutaneous tissues of the same species for autografts or of immunocompromised animals for allografts or xenografts. This section describes detailed protocols for the surgical transplantation of a tissue-engineered construct into an animal model to assess construct validity.

  13. Characterization of a mouse model with complete RPE loss and its use for RPE cell transplantation.

    PubMed

    Carido, Madalena; Zhu, Yu; Postel, Kai; Benkner, Boris; Cimalla, Peter; Karl, Mike O; Kurth, Thomas; Paquet-Durand, François; Koch, Edmund; Münch, Thomas A; Tanaka, Elly M; Ader, Marius

    2014-08-07

    Age-related macular degeneration (AMD) is a major leading cause of visual impairment and blindness with no cure currently established. Cell replacement of RPE is discussed as a potential therapy for AMD. Previous studies were performed in animal models with severe limitations in recapitulating the disease progression. In detail, we describe the effect of systemic injection of sodium iodate in the mouse retina. We further evaluate the usefulness of this animal model to analyze cell-specific effects following transplantation of human embryonic stem cell (hESC)-derived RPE cells. Morphologic, functional, and behavioral changes following sodium iodate injection were monitored by histology, gene expression analysis, electroretinography, and optokinetic head tracking. Human embryonic stem cell-derived RPE cells were transplanted 1 week after sodium iodate injection and experimental retinae were analyzed 3 weeks later. Injection of sodium iodate caused complete RPE cell loss, photoreceptor degeneration, and altered gene and protein expression in outer and inner nuclear layers. Retinal function was severely affected by day 3 and abolished from day 14. Following transplantation, donor hESC-derived RPE cells formed extensive monolayers that displayed wild-type RPE cell morphology, organization, and function, including phagocytosis of host photoreceptor outer segments. Systemic injection of sodium iodate has considerable effects on RPE, photoreceptors, and inner nuclear layer neurons, and provides a model to assay reconstitution and maturation of RPE cell transplants. The availability of an RPE-free Bruch's membrane in this model likely allows the unprecedented formation of extensive polarized cell monolayers from donor hESC-derived RPE cell suspensions. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  14. Latitude, sunshine, and human lactase phenotype distributions may contribute to geographic patterns of modern disease: the inflammatory bowel disease model.

    PubMed

    Szilagyi, Andrew; Leighton, Henry; Burstein, Barry; Xue, Xiaoqing

    2014-01-01

    Countries with high lactase nonpersistence (LNP) or low lactase persistence (LP) populations have lower rates of some "western" diseases, mimicking the effects of sunshine and latitude. Inflammatory bowel disease (IBD), ie, Crohn's disease and ulcerative colitis, is putatively also influenced by sunshine. Recent availability of worldwide IBD rates and lactase distributions allows more extensive comparisons. The aim of this study was to evaluate the extent to which modern day lactase distributions interact with latitude, sunshine exposure, and IBD rates. National IBD rates, national distributions of LP/LNP, and population-weighted average national annual ultraviolet B exposure were obtained, estimated, or calculated from the literature. Negative binomial analysis was used to assess the relationship between the three parameters and IBD rates. Analyses for 55 countries were grouped in three geographic domains, ie, global, Europe, and non-Europe. In Europe, both latitude and ultraviolet B exposure correlate well with LP/LNP and IBD. In non-Europe, latitude and ultraviolet B exposure correlate weakly with LP/LNP, but the latter retains a more robust correlation with IBD. In univariate analysis, latitude, ultraviolet B exposure, and LP/LNP all had significant relationships with IBD. Multivariate analysis showed that lactase distributions provided the best model of fit for IBD. The model of IBD reveals the evolutionary effects of the human lactase divide, and suggests that latitude, ultraviolet B exposure, and LP/LNP mimic each other because LP/LNP follows latitudinal directions toward the equator. However, on a large scale, lactase patterns also follow lateral polarity. The effects of LP/LNP in disease are likely to involve complex interactions.

  15. Latitude, sunshine, and human lactase phenotype distributions may contribute to geographic patterns of modern disease: the inflammatory bowel disease model

    PubMed Central

    Szilagyi, Andrew; Leighton, Henry; Burstein, Barry; Xue, Xiaoqing

    2014-01-01

    Countries with high lactase nonpersistence (LNP) or low lactase persistence (LP) populations have lower rates of some “western” diseases, mimicking the effects of sunshine and latitude. Inflammatory bowel disease (IBD), ie, Crohn’s disease and ulcerative colitis, is putatively also influenced by sunshine. Recent availability of worldwide IBD rates and lactase distributions allows more extensive comparisons. The aim of this study was to evaluate the extent to which modern day lactase distributions interact with latitude, sunshine exposure, and IBD rates. National IBD rates, national distributions of LP/LNP, and population-weighted average national annual ultraviolet B exposure were obtained, estimated, or calculated from the literature. Negative binomial analysis was used to assess the relationship between the three parameters and IBD rates. Analyses for 55 countries were grouped in three geographic domains, ie, global, Europe, and non-Europe. In Europe, both latitude and ultraviolet B exposure correlate well with LP/LNP and IBD. In non-Europe, latitude and ultraviolet B exposure correlate weakly with LP/LNP, but the latter retains a more robust correlation with IBD. In univariate analysis, latitude, ultraviolet B exposure, and LP/LNP all had significant relationships with IBD. Multivariate analysis showed that lactase distributions provided the best model of fit for IBD. The model of IBD reveals the evolutionary effects of the human lactase divide, and suggests that latitude, ultraviolet B exposure, and LP/LNP mimic each other because LP/LNP follows latitudinal directions toward the equator. However, on a large scale, lactase patterns also follow lateral polarity. The effects of LP/LNP in disease are likely to involve complex interactions. PMID:24971037

  16. Colonic mucosal N-methyl-D-aspartate receptor mediated visceral hypersensitivity in a mouse model of irritable bowel syndrome.

    PubMed

    Qi, Qing Qing; Chen, Fei Xue; Zhao, Dong Yan; Li, Li Xiang; Wang, Peng; Li, Yan Qing; Zuo, Xiu Li

    2016-07-01

    The aim of this study was to investigate whether colonic mucosal N-methyl-D-aspartate receptor (NMDAR) participates in visceral hypersensitivity in irritable bowel syndrome (IBS). C57BL/6 mice were administered intrarectally with trinitrobenzenesulfonic acid (TNBS) for the establishment of an IBS-like visceral hypersensitivity model. Those received an equivalent volume of 50% ethanol were regarded as the controls. Abdominal withdrawal reflex (AWR) scores in response to colorectal distention (CRD) were used to assess visceral sensitivity. NMDAR levels in the colonic mucosa were detected by both immunohistochemistry and Western blot. The concentrations of glutamate and ammonia in the feces of the mice were measured. Changes in visceral sensitivity after the intracolonic administration of ammonia or NMDAR antagonist were recorded. The established IBS-like mouse model of visceral hypersensitivity showed no evident inflammation in the colon. NMDAR levels in the colonic mucosa of the IBS-like mice were significantly higher compared with the controls, and were positively associated with AWR scores. The glutamate level in the feces of the TNBS-treated mice was similar to that of the controls, although the ammonia level was significantly higher. Intracolonic administration of ammonia induced visceral hypersensitivity in mice, which was repressed by pretreatment with NMDAR antagonist MK801. Overexpressed NMDAR in the colonic mucosa may participate in the pathogenesis of visceral hypersensitivity in IBS. Our study identifies the effect of ammonia in the colonic lumen on NMDAR in the colonic mucosa as a potential novel targeted mechanism for IBS treatment. © 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

  17. Pathogenesis, Experimental Models and Contemporary Pharmacotherapy of Irritable Bowel Syndrome: Story About the Brain-Gut Axis

    PubMed Central

    Tsang, S.W.; Auyeung, K.K.W.; Bian, Z.X.; Ko, J.K.S.

    2016-01-01

    Background Although the precise pathophysiology of irritable bowel syndrome (IBS) remains unknown, it is generally considered to be a disorder of the brain-gut axis, representing the disruption of communication between the brain and the digestive system. The present review describes advances in understanding the pathophysiology and experimental approaches in studying IBS, as well as providing an update of the therapies targeting brain-gut axis in the treatment of the disease. Methods Causal factors of IBS are reviewed. Following this, the preclinical experimental models of IBS will be introduced. Besides, both current and future therapeutic approaches of IBS will be discussed. Results When signal of the brain-gut axis becomes misinterpreted, it may lead to dysregulation of both central and enteric nervous systems, altered intestinal motility, increased visceral sensitivity and consequently contributing to the development of IBS. Interference of the brain-gut axis can be modulated by various psychological and environmental factors. Although there is no existing animal experiment that can represent this complex multifactorial disease, these in vivo models are clinically relevant readouts of gastrointestinal functions being essential to the identification of effective treatments of IBS symptoms as well as their molecular targets. Understanding the brain-gut axis is essential in developing the effective therapy for IBS. Therapies include improvement of GI motor functions, relief of visceral hypersensitivity and pain, attenuation of autonomic dysfunctions and suppression of mucosal immune activation. Conclusion Target-oriented therapies that provide symptomatic, psychological and physiological benefits could surely help to improve the quality of life of IBS patients. PMID:27009115

  18. Changes in Enteric Neurons of Small Intestine in a Rat Model of Irritable Bowel Syndrome with Diarrhea.

    PubMed

    Li, Shan; Fei, Guijun; Fang, Xiucai; Yang, Xilin; Sun, Xiaohong; Qian, Jiaming; Wood, Jackie D; Ke, Meiyun

    2016-04-30

    Physical and/or emotional stresses are important factors in the exacerbation of symptoms in irritable bowel syndrome (IBS). Several lines of evidence support that a major impact of stress on the gastrointestinal tract occurs via the enteric nervous system. We aimed to evaluate histological changes in the submucosal plexus (SMP) and myenteric plexus (MP) of the distal ileum in concert with the intestinal motor function in a rat model of IBS with diarrhea. The rat model was induced by heterotypic chronic and acute stress (CAS). The intestinal transit was measured by administering powdered carbon by gastric gavage. Double immunohistochemical fluorescence staining with whole-mount preparations of SMP and MP of enteric nervous system was used to assess changes in expression of choline acetyltransferase, vasoactive intestinal peptide, or nitric oxide synthase in relation to the pan neuronal marker, anti-Hu. The intestinal transit ratio increased significantly from control values of 50.8% to 60.6% in the CAS group. The numbers of enteric ganglia and neurons in the SMP were increased in the CAS group. The proportions of choline acetyltransferase- and vasoactive intestinal peptide-immunoreactive neurons in the SMP were increased (82.1 ± 4.3% vs. 76.0 ± 5.0%, P = 0.021; 40.5 ± 5.9% vs 28.9 ± 3.7%, P = 0.001), while nitric oxide synthase-immunoreactive neurons in the MP were decreased compared with controls (23.3 ± 4.5% vs 32.4 ± 4.5%, P = 0.002). These morphological changes in enteric neurons to CAS might contribute to the dysfunction in motility and secretion in IBS with diarrhea.

  19. Changes in Enteric Neurons of Small Intestine in a Rat Model of Irritable Bowel Syndrome with Diarrhea

    PubMed Central

    Li, Shan; Fei, Guijun; Fang, Xiucai; Yang, Xilin; Sun, Xiaohong; Qian, Jiaming; Wood, Jackie D; Ke, Meiyun

    2016-01-01

    Background/Aims Physical and/or emotional stresses are important factors in the exacerbation of symptoms in irritable bowel syndrome (IBS). Several lines of evidence support that a major impact of stress on the gastrointestinal tract occurs via the enteric nervous system. We aimed to evaluate histological changes in the submucosal plexus (SMP) and myenteric plexus (MP) of the distal ileum in concert with the intestinal motor function in a rat model of IBS with diarrhea. Methods The rat model was induced by heterotypic chronic and acute stress (CAS). The intestinal transit was measured by administering powdered carbon by gastric gavage. Double immunohistochemical fluorescence staining with whole-mount preparations of SMP and MP of enteric nervous system was used to assess changes in expression of choline acetyltransferase, vasoactive intestinal peptide, or nitric oxide synthase in relation to the pan neuronal marker, anti-Hu. Results The intestinal transit ratio increased significantly from control values of 50.8% to 60.6% in the CAS group. The numbers of enteric ganglia and neurons in the SMP were increased in the CAS group. The proportions of choline acetyltransferase- and vasoactive intestinal peptide-immunoreactive neurons in the SMP were increased (82.1 ± 4.3% vs. 76.0 ± 5.0%, P = 0.021; 40.5 ± 5.9% vs 28.9 ± 3.7%, P = 0.001), while nitric oxide synthase-immunoreactive neurons in the MP were decreased compared with controls (23.3 ± 4.5% vs 32.4 ± 4.5%, P = 0.002). Conclusions These morphological changes in enteric neurons to CAS might contribute to the dysfunction in motility and secretion in IBS with diarrhea. PMID:26645247

  20. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration

    PubMed Central

    Shirai, Hiroshi; Mandai, Michiko; Matsushita, Keizo; Kuwahara, Atsushi; Yonemura, Shigenobu; Nakano, Tokushige; Assawachananont, Juthaporn; Kimura, Toru; Saito, Koichi; Terasaki, Hiroko; Eiraku, Mototsugu; Sasai, Yoshiki; Takahashi, Masayo

    2016-01-01

    Retinal transplantation therapy for retinitis pigmentosa is increasingly of interest due to accumulating evidence of transplantation efficacy from animal studies and development of techniques for the differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells into retinal tissues or cells. In this study, we aimed to assess the potential clinical utility of hESC-derived retinal tissues (hESC-retina) using newly developed primate models of retinal degeneration to obtain preparatory information regarding the potential clinical utility of these hESC-retinas in transplantation therapy. hESC-retinas were first transplanted subretinally into nude rats with or without retinal degeneration to confirm their competency as a graft to mature to form highly specified outer segment structure and to integrate after transplantation. Two focal selective photoreceptor degeneration models were then developed in monkeys by subretinal injection of cobalt chloride or 577-nm optically pumped semiconductor laser photocoagulation. The utility of the developed models and a practicality of visual acuity test developed for monkeys were evaluated. Finally, feasibility of hESC-retina transplantation was assessed in the developed monkey models under practical surgical procedure and postoperational examinations. Grafted hESC-retina was observed differentiating into a range of retinal cell types, including rod and cone photoreceptors that developed structured outer nuclear layers after transplantation. Further, immunohistochemical analyses suggested the formation of host–graft synaptic connections. The findings of this study demonstrate the clinical feasibility of hESC-retina transplantation and provide the practical tools for the optimization of transplantation strategies for future clinical applications. PMID:26699487

  1. Bioluminescence imaging of human embryonic stem cells transplanted in vivo in murine and chick models.

    PubMed

    Priddle, Helen; Grabowska, Anna; Morris, Teresa; Clarke, Philip A; McKenzie, Andrew J; Sottile, Virginie; Denning, Chris; Young, Lorraine; Watson, Sue

    2009-06-01

    Research into the behavior, efficacy, and biosafety of stem cells with a view to clinical transplantation requires the development of noninvasive methods for in vivo imaging of cells transplanted into animal models. This is particularly relevant for human embryonic stem cells (hESCs), because transplantation of undifferentiated hESCs leads to tumor formation. The present study aimed to monitor hESCs in real time when injected in vivo. hESCs were stably transfected to express luciferase, and luciferase expression was clearly detected in the undifferentiated and differentiated state. When transfected hESCs were injected into chick embryos, bioluminescence could be detected both ex and in ovo. In the SCID mouse model, undifferentiated hESCs were detectable after injection either into the muscle layer of the peritoneum or the kidney capsule. Tumors became detectable between days 10-30, with approximately a 3 log increase in the luminescence signal by day 75. The growth phase occurred earlier in the kidney capsule and then reached a plateau, whilst tumors in the peritoneal wall grew steadily throughout the period analysed. These results show the widespread utility of bioluminescent for in vivo imaging of hESCs in a variety of model systems for preclinical research into regenerative medicine and cancer biology.

  2. Statistical evaluation and experimental design of a psoriasis xenograft transplantation model treated with cyclosporin A.

    PubMed

    Stenderup, Karin; Rosada, Cecilia; Alifrangis, Lene; Andersen, Søren; Dam, Tomas Norman

    2011-05-01

    Psoriasis xenograft transplantation models where human skin is transplanted onto immune-deficient mice are generally accepted in psoriasis research. Over the last decade, they have been widely employed to screen for new therapeutics with a potential anti-psoriatic effect. However, experimental designs differ in several parameters. Especially, the number of donors and grafts per experimental design varies greatly; numbers that are directly related to the probability of detecting statistically significant drug effects. In this study, we performed a statistical evaluation of the effect of cyclosporine A, a recognized anti-psoriatic drug, to generate a statistical model employable to simulate different scenarios of experimental designs and to calculate the associated statistical study power, defined as the probability of detecting a statistically significant anti-psoriatic drug treatment effect. Results showed that to achieve a study power of 0.8, at least 20 grafts per treatment group and a minimum of five donors should be included in the chosen experimental setting. To our knowledge, this is the first time that study power calculations have been performed to evaluate treatment effects in a psoriasis xenograft transplantation model. This study was based on a defined experimental protocol, thus other parameters such as drug potency, treatment protocol, mouse strain and graft size should, also, be taken into account when designing an experiment. We propose that the results obtained in this study may lend a more quantitative support to the validity of results obtained when exploring new potential anti-psoriatic drug effects.

  3. Stem cell transplantation in neurological diseases: improving effectiveness in animal models

    PubMed Central

    Adami, Raffaella; Scesa, Giuseppe; Bottai, Daniele

    2014-01-01

    Neurological diseases afflict a growing proportion of the human population. There are two reasons for this: first, the average age of the population (especially in the industrialized world) is increasing, and second, the diagnostic tools to detect these pathologies are now more sophisticated and can be used on a higher percentage of the population. In many cases, neurological disease has a pharmacological treatment which, as in the case of Alzheimer's disease, Parkinson's disease, Epilepsy, and Multiple Sclerosis can reduce the symptoms and slow down the course of the disease but cannot reverse its effects or heal the patient. In the last two decades the transplantation approach, by means of stem cells of different origin, has been suggested for the treatment of neurological diseases. The choice of slightly different animal models and the differences in methods of stem cell preparation make it difficult to compare the results of transplantation experiments. Moreover, the translation of these results into clinical trials with human subjects is difficult and has so far met with little success. This review seeks to discuss the reasons for these difficulties by considering the differences between human and animal cells (including isolation, handling and transplantation) and between the human disease model and the animal disease model. PMID:25364724

  4. Operational tolerance in nonvascularized transplant models induced by AR-C117977, a monocarboxylate transporter inhibitor.

    PubMed

    Påhlman, Clara; Malm, Helene; Qi, Zhongquan; Veress, Béla; Ferguson, Douglas; Bundick, Robert; Murray, Clare; Donald, David; Ekberg, Henrik

    2008-10-27

    AR-C117977, a monocarboxylate transporter inhibitor, reduces immune responses both in vitro and in vivo, maintains long-term graft survival, and induces operational tolerance. To evaluate the immunosuppressive limitations of AR-C117977, this study was performed in nonvascularized transplant models noted for their refractive response to standard immunosuppressive agents. Rat skin was transplanted from DA(RT1avl) into PVG(RT1c) and the reverse. Mouse islet allotransplantation was performed with BALB/c H2d donors and C57Bl/6J H2b recipients. In the skin graft model, AR-C117977 monotherapy was associated with long-term skin graft survival in one rat strain combination. AR-C117977 and cyclosporine A (CsA) in combination resulted in significant prolongation of graft survival in both rat strains. CsA monotherapy did not prevent acute rejection in either strain. Islet allograft survival was moderately prolonged with CsA or AR-C117977. AR-C117977 is an efficient immunosuppressive drug in stringent rodent transplant models and further studies are warranted.

  5. Factors affecting eGFR 5-year post-deceased donor renal transplant: analysis and predictive model.

    PubMed

    Elbadri, Abdalla; Traynor, Carol; Veitch, John T; O'Kelly, Patrick; Magee, Colm; Denton, Mark; O'Sheaghdha, Conall; Conlon, Peter J

    2015-04-01

    Long-term survival of renal allografts has improved over the last 20 years. However, less is known about current expectations for long-term allograft function as determined by estimated glomerular filtration rate (eGFR). The aim of this study was to investigate factors which affect graft function at 5 years' post-renal transplantation. The statistically significant factors were then used to construct a predictive model for expected eGFR at five years' post-transplant. We retrospectively reviewed all adult patients who received a renal transplant in the Republic of Ireland between 1990 and 2004. Data collected included era of transplantation (1990-1994, 1995-1999, 2000-2004), donor and recipient age and gender, number of human leucocyte antigen mismatches, cold ischemia time (CIT), number of prior renal transplants, immunosuppressive regimen used and acute rejection episodes. Estimated GFR was calculated at 5 years after transplantation from patient data using the Modified Diet in Renal Disease (MDRD) equation. Consecutive sampling was used to divide the study population into two equal unbiased groups of 489 patients. The first group (derivation cohort) was used to construct a predictive model for eGFR five years' post-transplantation, the second (validation cohort) to test this model. Nine hundred and seventy eight patients were analyzed. The median age at transplantation was 43 years (range 18-78) and 620 (63.4%) were male. One hundred and seventy five patients (17.9%) had received a prior renal transplant. Improved eGFR at five years' post-transplantation was associated with tacrolimus-based combination immunosuppression, younger donor age, male recipient, absence of cytomegalovirus disease and absence of acute rejection episodes as independently significant factors (p < 0.05). The predictive model developed using these factors showed good correlation between predicted and actual median eGFR at five years. The model explained 20% of eGFR variability. The

  6. A review of the efficacy of dietary polyphenols in experimental models of inflammatory bowel diseases.

    PubMed

    Martin, Derek A; Bolling, Bradley W

    2015-06-01

    Crohn's disease and ulcerative colitis presently have no cure and are treated with anti-inflammatory drugs or monoclonal antibodies targeting pro-inflammatory cytokines. A variety of rodent models have been used to model chronic and acute colitis. Dietary polyphenols in foods and botanicals are of considerable interest for prevention and treatment of colitis. Many dietary polyphenols have been utilized for prevention of colitis in rodent models. Berries, green tea polyphenols, curcumin, and stilbenes have been the most extensively tested polyphenols in rodent models of colitis. The majority of polyphenols tested have inhibited colitis in rodents, but increasing doses of EGCG and green tea, isoflavones, flaxseed, and α-mangostin have exacerbated colitis. Few studies have examined combination of polyphenols or other bioactives for inhibition of colitis. Translating polyphenol doses used in rodent models of colitis to human equivalent doses reveals that supplemental doses are most likely required to inhibit colitis from a single polyphenol treatment. The ability to translate polyphenol treatments in rodent models is likely to be limited by species differences in xenobiotic metabolism and microbiota. Given these limitations, data from polyphenols in rodent models suggests merit for pursuing additional clinical studies for prevention of colitis.

  7. Bone marrow transplant

    MedlinePlus

    Transplant - bone marrow; Stem cell transplant; Hematopoietic stem cell transplant; Reduced intensity nonmyeloablative transplant; Mini transplant; Allogenic bone marrow transplant; Autologous bone marrow transplant; ...

  8. Uterus transplantation model in sheep with heterotopic whole graft and aorta and cava anastomoses.

    PubMed

    Gonzalez-Pinto, I M; Tryphonopoulos, P; Avison, D L; Nishida, S; Tekin, A; Santiago, S; Tzakis, A G

    2013-06-01

    Uterine transplantation in the sheep model has been described as a partial or whole orthotopic graft from a living donor with vascular anastomoses. As an alternative to surrogate pregnancy or adoption uterus transplantation might be indicated for cases of infertility of uterine origin. The main complications might be rejection and thrombosis. The objective of this work was to develop a model of whole uterus transplantation that was applicable to the human setting, using grafts obtained from brain-dead donors, and suitable for immunologic and viability follow-up with a reduced risk of thrombosis. Two donors and 1 recipient were operated. The first graft was used for an anatomic study; the second was used for transplantation. The donor operation consisted of an en bloc harvest of the uterus, adnexa, and proximal vagina with the distal aorta and cava. After harvest the donor sheep was humanely killed. In the recipient ewe, heterotopic implantation was performed in the lower abdomen. An End-to-side anastomoses of aorta and cava were performed below the recipient's renal vessels. A cutaneous vaginal stoma was performed in the right lower quadrant. The recipient ewe was humanely killed for an autopsy study. The anatomy of uterine veins of the ewe differs from the human. The uterine and ovarian veins join, forming the utero-ovarian vein, which drains at the confluence of the common iliac to the cava. En bloc harvesting allows for rapid graft preparation, with vascular cuffs easily anastomosed with a low risk of thrombosis. The vaginal stoma seems appropriate to facilitate follow-up and graft biopsy. This approach can be a suitable experimental model applicable to humans using grafts from brain-dead donors.

  9. Directly auto-transplanted mesenchymal stem cells induce bone formation in a ceramic bone substitute in an ectopic sheep model

    PubMed Central

    Boos, Anja M; Loew, Johanna S; Deschler, Gloria; Arkudas, Andreas; Bleiziffer, Oliver; Gulle, Heinz; Dragu, Adrian; Kneser, Ulrich; Horch, Raymund E; Beier, Justus P

    2011-01-01

    Abstract Bone tissue engineering approaches increasingly focus on the use of mesenchymal stem cells (MSC). In most animal transplantation models MSC are isolated and expanded before auto cell transplantation which might be critical for clinical application in the future. Hence this study compares the potential of directly auto-transplanted versus in vitro expanded MSC with or without bone morphogenetic protein-2 (BMP-2) to induce bone formation in a large volume ceramic bone substitute in the sheep model. MSC were isolated from bone marrow aspirates and directly auto-transplanted or expanded in vitro and characterized using fluorescence activated cell sorting (FACS) and RT-PCR analysis before subcutaneous implantation in combination with BMP-2 and β-tricalcium phosphate/hydroxyapatite (β-TCP/HA) granules. Constructs were explanted after 1 to 12 weeks followed by histological and RT-PCR evaluation. Sheep MSC were CD29+, CD44+ and CD166+ after selection by Ficoll gradient centrifugation, while directly auto-transplanted MSC-populations expressed CD29 and CD166 at lower levels. Both, directly auto-transplanted and expanded MSC, were constantly proliferating and had a decreasing apoptosis over time in vivo. Directly auto-transplanted MSC led to de novo bone formation in a heterotopic sheep model using a β-TCP/HA matrix comparable to the application of 60 μg/ml BMP-2 only or implantation of expanded MSC. Bone matrix proteins were up-regulated in constructs following direct auto-transplantation and in expanded MSC as well as in BMP-2 constructs. Up-regulation was detected using immunohistology methods and RT-PCR. Dense vascularization was demonstrated by CD31 immunohistology staining in all three groups. Ectopic bone could be generated using directly auto-transplanted or expanded MSC with β-TCP/HA granules alone. Hence BMP-2 stimulation might become dispensable in the future, thus providing an attractive, clinically feasible approach to bone tissue engineering. PMID

  10. Directly auto-transplanted mesenchymal stem cells induce bone formation in a ceramic bone substitute in an ectopic sheep model.

    PubMed

    Boos, Anja M; Loew, Johanna S; Deschler, Gloria; Arkudas, Andreas; Bleiziffer, Oliver; Gulle, Heinz; Dragu, Adrian; Kneser, Ulrich; Horch, Raymund E; Beier, Justus P

    2011-06-01

    Bone tissue engineering approaches increasingly focus on the use of mesenchymal stem cells (MSC). In most animal transplantation models MSC are isolated and expanded before auto cell transplantation which might be critical for clinical application in the future. Hence this study compares the potential of directly auto-transplanted versus in vitro expanded MSC with or without bone morphogenetic protein-2 (BMP-2) to induce bone formation in a large volume ceramic bone substitute in the sheep model. MSC were isolated from bone marrow aspirates and directly auto-transplanted or expanded in vitro and characterized using fluorescence activated cell sorting (FACS) and RT-PCR analysis before subcutaneous implantation in combination with BMP-2 and β-tricalcium phosphate/hydroxyapatite (β-TCP/HA) granules. Constructs were explanted after 1 to 12 weeks followed by histological and RT-PCR evaluation. Sheep MSC were CD29(+), CD44(+) and CD166(+) after selection by Ficoll gradient centrifugation, while directly auto-transplanted MSC-populations expressed CD29 and CD166 at lower levels. Both, directly auto-transplanted and expanded MSC, were constantly proliferating and had a decreasing apoptosis over time in vivo. Directly auto-transplanted MSC led to de novo bone formation in a heterotopic sheep model using a β-TCP/HA matrix comparable to the application of 60 μg/ml BMP-2 only or implantation of expanded MSC. Bone matrix proteins were up-regulated in constructs following direct auto-transplantation and in expanded MSC as well as in BMP-2 constructs. Up-regulation was detected using immunohistology methods and RT-PCR. Dense vascularization was demonstrated by CD31 immunohistology staining in all three groups. Ectopic bone could be generated using directly auto-transplanted or expanded MSC with β-TCP/HA granules alone. Hence BMP-2 stimulation might become dispensable in the future, thus providing an attractive, clinically feasible approach to bone tissue engineering.

  11. Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

    SciTech Connect

    Kim, Manbok; Rahman, Masmudur M.; Cogle, Christopher R.

    2015-07-10

    Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases.

  12. Effect of human mesenchymal stem cell transplantation on cerebral ischemic volume‐controlled photothrombotic mouse model

    PubMed Central

    Choi, Yun‐Kyong; Urnukhsaikhan, Enerelt; Yoon, Hee‐Hoon; Seo, Young‐Kwon

    2016-01-01

    Abstract Various animal models of stroke have been developed to simulate the human stroke with the development of the ischemic method facilitates preclinical stroke research. The photothrombotic ischemia model, based on the intravascular photochemical reaction, is widely used for in vivo studies. However, this study has limitations, which generated a relatively small‐sized infarction model on superficial cortex compared to that of the MCAO stroke model. In this study, the photothorombosis mouse model is adapted and the optimum conditions for generation of cell death and deficits with high reproducibility is determined. The extent of damage within the cortex was assessed by infarct volume and cellular/behavioral analyses. In this model, the neural cell death and inflammatory responses is detected; moreover, the degree of behavioral impairment is correlated with the brain infarct volume. Further, to enhance the understanding of neural repair, the effect of neural differentiation by transplantation of human bone marrow‐derived mesenchymal stem cells (BM‐MSCs) is analyzed. The authors demonstrated that transplantation of BM‐MSCs promoted the neural differentiation and behavioral performance in their photothrombosis model. Therefore, this research was meaningful to provide a stable animal model of stroke with low variability. Moreover, this model will facilitate development of novel MSC‐based therapeutics for stroke. PMID:27440447

  13. From transplantation to transgenics: mouse models of developmental hematopoiesis.

    PubMed

    Schmitt, Christopher E; Lizama, Carlos O; Zovein, Ann C

    2014-08-01

    The mouse is integral to our understanding of hematopoietic biology. Serving as a mammalian model system, the mouse has allowed for the discovery of self-renewing multipotent stem cells, provided functional assays to establish hematopoietic stem cell identity and function, and has become a tool for understanding the differentiation capacity of early hematopoietic progenitors. The advent of genetic technology has strengthened the use of mouse models for identifying critical pathways in hematopoiesis. Full genetic knockout models, tissue-specific gene deletion, and genetic overexpression models create a system for the dissection and identification of critical cellular and genetic processes underlying hematopoiesis. However, the murine model has also introduced perplexity in understanding developmental hematopoiesis. Requisite in utero development paired with circulation has historically made defining sites of origin and expansion in the murine hematopoietic system challenging. However, the genetic accessibility of the mouse as a mammalian system has identified key regulators of hematopoietic development. Technological advances continue to generate extremely powerful tools that when translated to the murine system provide refined in vivo spatial and temporal control of genetic deletion or overexpression. Future advancements may add the ability of reversible genetic manipulation. In this review, we describe the major contributions of the murine model to our understanding of hematopoiesis. Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  14. The Application of Functional Magnetic Resonance Imaging in an Infant Rat Model of Irritable Bowel Syndrome

    PubMed Central

    Zhu, Xueping; Zhu, Xiaoli; Chen, Weichang; Chen, Jianhua

    2014-01-01

    The aim of this study was to use functional magnetic resonance imaging (BOLD-fMRI) to investigate the activated region associated with visceral pain in the brains of infant rats in a model of IBS. Sixteen newborn rats were randomized into an IBS model group and a control group. Those in the IBS group were separated from their mothers and were mechanically immobilized and had rectal sensitization with mustard essential oil for 1 week. The control group had no treatment. After 2 weeks, balloon catheters were inflated with 5 or 10 mL of air in the rectums of both groups. BOLD-fMRI was performed and the data analyzed by imaging software. In the IBS model group, rectal stimulation with 5 mL air distension activated the anterior cingulate cortex, insula cortex (IC), prefrontal cortex (PFC), and thalamus, while 10 mL air significantly activated the ACC, IC, PFC, and thalamus in the model, but not controls. IBS model group was hypersensitive to visceral stimulation by rectal balloon inflation. The major brain areas participating in visceral sensation included the IC, PFC, and thalamus. PMID:25093020

  15. Escherichia coli strain Nissle 1917 ameliorates experimental colitis by modulating intestinal permeability, the inflammatory response and clinical signs in a faecal transplantation model.

    PubMed

    Souza, Éricka L; Elian, Samir D; Paula, Laís M; Garcia, Cristiana C; Vieira, Angélica T; Teixeira, Mauro M; Arantes, Rosa M; Nicoli, Jacques R; Martins, Flaviano S

    2016-03-01

    Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions of the gut that include ulcerative colitis and Crohn's disease. Probiotics are live micro-organisms that may be used as adjuvant therapy for patients with IBD. The aim of this study was to evaluate the effect of prophylactic ingestion of Escherichia coli strain Nissle 1917 (EcN) in a murine model of colitis. For induction of colitis, mice were given a 3.5% dextran sodium sulfate (DSS) solution for 7 days in drinking water. EcN administration to mice subjected to DSS-induced colitis resulted in significant reduction in clinical and histopathological signs of disease and preservation of intestinal permeability. We observed reduced inflammation, as assessed by reduced levels of neutrophils, eosinophils, chemokines and cytokines. We observed an increase in the number of regulatory T-cells in Peyer's patches. Germ-free mice received faecal content from control or EcN-treated mice and were then subjected to DSS-induced colitis. We observed protection from colitis in animals that were colonized with faecal content from EcN-treated mice. These results suggest that preventative oral administration of EcN or faecal microbiota transplantation with EcN-containing microbiota ameliorates DSS-induced colitis by modifying inflammatory responsiveness to DSS.

  16. Transplantation of autologous chondrocytes ex-vivo expanded using Thermoreversible Gelation Polymer in a rabbit model of articular cartilage defect.

    PubMed

    Arumugam, Sivaraman; Bhupesh Karthik, Balasubramanyan; Chinnuswami, Rajeswar; Mori, Yuichi; Yoshioka, Hiroshi; Senthilkumar, Rajappa; Mathaiyan, Rajmohan; Ramalingam, Karthick; Senthilkumar, Preethy; Abraham, Samuel J K

    2017-06-01

    Graft failure due to de-differentiation of the chondrocytes during in vitro culture and after transplantation is a major hurdle in Autologous Chondrocyte Implantation (ACI). We, herein, report the transplantation of autologous chondrocytes ex vivo expanded using a Thermo-reversible Gelation Polymer (TGP) in a rabbit model. A full thickness chondral defect was created in one of the knee joints in each of the six rabbits of the study and autologous chondrocytes in vitro expanded using TGP scaffold were transplanted after 10 weeks. H & E staining of the biopsy after 6 months revealed maintenance of articular cartilage phenotype.

  17. FEA modeling and fluid flow simulation of human rectum with inserted bowel catheters.

    PubMed

    Yong Zhang; VanRiper, Tina; Rague, Brian; Weidman, Drew

    2016-08-01

    In this project, fluid flow and fluid-structure interaction are studied for the human lower gastrointestinal (GI) region. The study consists of two steps. First, we apply meshing methods to discretize both the human lower GI model and the catheter model at sufficient resolution suitable for importing into a Finite Element Analysis (FEA) tool. For model discretization, 3D models of the colon reconstructed from human MRI slices are used to obtain the valid inlet and outlet boundary surfaces. To resolve the viscous boundary layer in flow studies, a special structure of the near-wall volumetric mesh is built by triangular prisms that construct quasi-structured, multiple near-boundary sub-layers. Second, we study the computational fluid dynamics. Transient numerical calculation of flow profiles are conducted for velocity profiles, flow rate division, pressure gradient variation, and flow cosmetics. The analysis of biofluid interactions with medical catheters is conducted to help understand how the biofluid behaves in various conditions to address design related concerns such as leakage problems.

  18. A student leadership model for promoting educational programs in organ donation and transplantation.

    PubMed

    Reville, P; Zhao, C; Perez, T; Nowacki, A S; Phillips, D; Bowen, G; Starling, N; Pflaum, B; Strickland, R; Fung, J; Askar, M

    2013-05-01

    The global organ shortage is the strongest factor for the increase in transplant wait time and deaths on waitlists. Here we describe a model for involving high school students in education research around organ donation and transplantation and capitalize on the strength of a pre-existing educational program offered by the local organ procurement organization (OPO). While training in education research at Cleveland Clinic, a high school student embarked on a collaborative project with the local OPO. The project involved evaluating three educational programs, selecting the most appropriate program for administration at her school, coordinating with the student's school administration and teachers, administering an assessment tool for the effectiveness of the program, and analyzing the results. The local OPO program that was selected for implementation consisted of a video presentation entitled "Share your life, share your decision" prepared by the United States Health Resources and Services Administration (HRSA), lectures by invited speakers and an educational assessment (pre- and post-education). The assessment survey included 3 multiple choice and 7 true/false questions. Compared to the over 2500 programs administered in the last 5 years by the local OPO, this program had a higher volume of participation (n = 353 compared to an average of 150 students/day). Students correctly classified transplantation status of more organ and tissues post-education (P < .0001 for both). For 5 out of the 7 true/false questions, students correctly answered questions more frequently post-education (P ≤ .002 for all). This experience included for the first time a formal assessment of the program which will be utilized to address targeted areas for specific improvements. This student collaborative model of involving students in organ donation and transplantation related education research has the potential to promote and maximize the effectiveness of educational programs targeting

  19. Intrahepatic Tissue Implantation Represents a Favorable Approach for Establishing Orthotopic Transplantation Hepatocellular Carcinoma Mouse Models

    PubMed Central

    Zuo, Bingfeng; Gao, Xianjun; Zhang, Ti; Du, Zhi; Wu, Chenxuan; Yin, HaiFang

    2016-01-01

    Mouse models are commonly used for studying hepatocellular carcinoma (HCC) biology and exploring new therapeutic interventions. Currently three main modalities of HCC mouse models have been extensively employed in pre-clinical studies including chemically induced, transgenic and transplantation models. Among them, transplantation models are preferred for evaluating in vivo drug efficacy in pre-clinical settings given the short latency, uniformity in size and close resemblance to tumors in patients. However methods used for establishing orthotopic HCC transplantation mouse models are diverse and fragmentized without a comprehensive comparison. Here, we systemically evaluate four different approaches commonly used to establish HCC mice in preclinical studies, including intravenous, intrasplenic, intrahepatic inoculation of tumor cells and intrahepatic tissue implantation. Four parameters—the latency period, take rates, pathological features and metastatic rates—were evaluated side-by-side. 100% take rates were achieved in liver with intrahepatic, intrasplenic inoculation of tumor cells and intrahepatic tissue implantation. In contrast, no tumor in liver was observed with intravenous injection of tumor cells. Intrahepatic tissue implantation resulted in the shortest latency with 0.5cm (longitudinal diameter) tumors found in liver two weeks after implantation, compared to 0.1cm for intrahepatic inoculation of tumor cells. Approximately 0.1cm tumors were only visible at 4 weeks after intrasplenic inoculation. Uniform, focal and solitary tumors were formed with intrahepatic tissue implantation whereas multinodular, dispersed and non-uniform tumors produced with intrahepatic and intrasplenic inoculation of tumor cells. Notably, metastasis became visible in liver, peritoneum and mesenterium at 3 weeks post-implantation, and lung metastasis was visible after 7 weeks. T cell infiltration was evident in tumors, resembling the situation in HCC patients. Our study

  20. A CD52 antibody impairs mouse-transplanted intestinal tight junctions.

    PubMed

    Shen, Bo; Yu, Hong; Yu, Tunan; Shen, Jiliang; Meng, Ning; Cai, Xiujun

    2015-06-15

    Induction immunosuppression strategies using a CD52 monoclonal antibody (mAb) have been introduced for small bowel transplantation, resulting in improved outcomes. However, little information is known about the effects of the antibody on the microstructure of the intestinal barrier, which functions to prevent bacterial translocation. In this study, we used a murine orthotopic small bowel transplantation model to investigate the impact of a CD52 mAb on tight junctions (TJs), which are considered a central part of the intestinal barrier, of the transplanted intestine. C57BL/6 mice were used as recipients. The grafts were harvested from BALB/c mice in allogeneic groups and C57BL/6 mice in syngeneic groups. The anti-mouse CD52 mAb was applied as a surrogate antibody. Transmission electron microscopy was used to evaluate the TJ ultrastructure. The expression of the TJ proteins occludin and ZO-1 was analyzed by Western blot. The distribution of TJ proteins was observed by immunofluorescence, and the permeability of the transplanted intestine was assessed in vivo using FITC-dextran. After CD52 mAb application, a compromised TJ ultrastructure was observed. In addition, TJ protein expression (occludin and ZO-1) decreased and the intestinal permeability increased. The anti-mouse CD52 mAb impaired the transplanted intestinal TJ and barrier. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. The transplant center and business unit as a model for specialized care delivery.

    PubMed

    Gaber, A Osama; Schwartz, Roberta L; Bernard, David P; Zylicz, Susan

    2013-12-01

    Transplant centers are valuable assets to a transplantation hospital and essential to organize the delivery of patient care. A transplant center defined around physicians and activities of caring for patients with organ failure creates a team better equipped to manage care across the continuum of the diseases treated by transplantation. Through monitoring of clinical and financial outcomes, the transplant center can better respond to the changing regulatory and financial landscape of health care. This article seeks to explain the major organizational challenges facing the transplant center and how a transplant center can best serve its patients and parent organization.

  2. Diluted Blood Reperfusion as a Model for Transplantation of Ischemic Rat Livers: ALT is a Direct Indicator of Viability

    PubMed Central

    Uygun, Korkut; Tolboom, Herman; Izamis, Maria-Louisa; Uygun, Basak; Sharma, Nripen; Yagi, Hiroshi; Soto-Gutierrez, Alejandro; Hertl, Martin; Berthiaume, François; Yarmush, Martin L.

    2010-01-01

    Donors after Cardiac Death present a significant pool of untapped organs for transplantation, and use of machine perfusion strategies has been an active focus area in experimental transplantation. However, despite two decades of research, a gold standard is yet to emerge for machine perfusion systems and protocols. Whole blood reperfusion has been used as a surrogate for organ transplantation, especially as a model for the short-term response post transplantation, for optimization of perfusion systems. While it is known that there is a strong correlation between liver function in whole-blood reperfusion and survival, the exact nature of these correlations, and to what extent they can be considered as an indicator of viability for transplantation/recipient survival, remain unclear. In this work, we demonstrate that diluted whole-blood reperfusion can be used as a direct model for transplantation of ischemic rat liver grafts. Moreover, it was shown that recipient survival can be predicted based simply on the value of ALT during perfusion, and quantitative criteria of viability was developed for use in this animal model. These results indicate that in the rat model graft survival is highly correlated to hepatocellular damage. PMID:20832525

  3. Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach.

    PubMed

    Daher Abdi, Z; Essig, M; Rizopoulos, D; Le Meur, Y; Prémaud, A; Woillard, J B; Rérolle, J P; Marquet, P; Rousseau, A

    2013-06-01

    This study aimed to investigate the association between longitudinal exposure to mycophenolic acid (MPA) and acute rejection (AR) risk in the first year after renal transplantation, and to propose MPA exposure targets conditionally to this association. A joint model, adjusted for monitoring strategy (fixed-dose versus concentration-controlled) and recipient age, was developed; it combined a mixed-effects model to describe the whole pattern of MPA exposure (i.e. area under the concentration-time curve (AUC)) and a survival model. MPA AUC thresholds were determined using time-dependent receiver-operating characteristics (ROC) curves. Data from 490 adult renal-transplant recipients, representative of the general population of adult renal-transplant patients (i.e. including patients considered at low immunological risk-enrolled in the OPERA trial as well as second renal transplant and patients co-treated by either cyclosporine or tacrolimus), were analyzed. A significant association was found between the longitudinal exposure to MPA (MPA AUCs=f(t)) and AR (p=0.0081), and validated by bootstrapping. A significant positive correlation was observed between time post-transplantation and ROC thresholds which increased in average from 35 mg h/L in the first days to 41 mg h/L beyond six months post-transplantation (p<0.001). Using a new modeling approach which recognizes the repeated measures in a same patient, this study supports the association between MPA exposure and AR.

  4. Transplantation of human skin microbiota in models of atopic dermatitis

    PubMed Central

    Myles, Ian A.; Williams, Kelli W.; Reckhow, Jensen D.; Jammeh, Momodou L.; Pincus, Nathan B.; Sastalla, Inka; Saleem, Danial; Stone, Kelly D.; Datta, Sandip K.

    2016-01-01

    Atopic dermatitis (AD) is characterized by reduced barrier function, reduced innate immune activation, and susceptibility to Staphylococcus aureus. Host susceptibility factors are suggested by monogenic disorders associated with AD-like phenotypes and can be medically modulated. S. aureus contributes to AD pathogenesis and can be mitigated by antibiotics and bleach baths. Recent work has revealed that the skin microbiome differs significantly between healthy controls and patients with AD, including decreased Gram-negative bacteria in AD. However, little is known about the potential therapeutic benefit of microbiome modulation. To evaluate whether parameters of AD pathogenesis are altered after exposure to different culturable Gram-negative bacteria (CGN) collected from human skin, CGN were collected from healthy controls and patients with AD. Then, effects on cellular and culture-based models of immune, epithelial, and bacterial function were evaluated. Representative strains were evaluated in the MC903 mouse model of AD. We found that CGN taken from healthy volunteers but not from patients with AD were associated with enhanced barrier function, innate immunity activation, and control of S. aureus. Treatment with CGN from healthy controls improved outcomes in a mouse model of AD. These findings suggest that a live-biotherapeutic approach may hold promise for treatment of patients with AD. PMID:27478874

  5. Establishing the Number of Procedures for Optimal Renal Transplantation Training With the Use of a Canine Model.

    PubMed

    Ayala-Garcia, M A; Soel-Encalada, J M; Rios Zambudio, A; Rodea-Montero, E R; Gonzalez-Yebra, B

    2016-11-01

    The training of surgeons that perform renal transplantations can be diverse. For example, the training profile can vary greatly, involving urologists to general surgeons. The efficacy of training programs directed at transplantation surgeons is influenced by numerous factors, including the specialist profile who is trained, the number of procedures available to trainees in a given teaching hospital, and the duration of training. Here we determine the number of procedures necessary to consolidate and contribute to proficiency in renal transplantation technique. We used a canine model, comparing 32 renal transplantations performed by a urologist and by a general surgeon who had completed their respective training in renal transplantation. Our results demonstrated that with 12 surgical procedures, surgeons were able to consolidate their skills in renal transplantation, regardless of their educational background. This is an initial effort in the establishment of a system for targeted training of transplantation surgeons directed specifically at correcting deficiencies and consolidating skills acquired during training programs. These efforts should contribute to the improvement of patient safety in public and private health systems. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Bone marrow mesenchymal stem cell transplantation improves radiation-induced heart injury through DNA damage repair in rat model.

    PubMed

    Gao, Song; Zhao, Zhiying; Wu, Rong; Zeng, Yuecan; Zhang, Zhenyong; Miao, Jianing; Yuan, Zhengwei

    2017-03-01

    Radiotherapy is an effective form of therapy for most thoracic malignant tumors. However, myocardial injury resulting from the high doses of radiation is a severe complication. Here we aimed to study the possibility of reducing radiation-induced myocardial injury with mesenchymal stem cell (MSC) transplantation. We used MSCs extracted from bone marrow (BMSCs) to transplant via the tail vein into a radiation-induced heart injury (RIHI) rat model. The rats were divided into six groups: a Sham group, an IRR (irradiation) group, and four IRR + BMSCs transplantation groups obtained at different time points. After irradiation, BMSC transplantation significantly enhanced the cardiac function in rats. By analyzing the expression of PPAR-α, PPAR-γ, TGF-β, IL-6, and IL-8, we found that BMSC transplantation alleviated radiation-induced myocardial fibrosis and decreased the inflammatory reaction. Furthermore, we found that expression of γ-H2AX, XRCC4, DNA ligase4, and TP53BP1, which are associated with DNA repair, was up-regulated, along with increased secretion of growth factors SDF-1, CXCR4, VEGF, and IGF in rat myocardium in the IRR + BMSCs transplantation groups compared with the IRR group. Thus, BMSC transplantation has the potential to improve RIHI via DNA repair and be a new therapeutic approach for patients with myocardial injury.

  7. Effect of Saccharomyces cerevisiae strain UFMG A-905 in experimental model of inflammatory bowel disease.

    PubMed

    Tiago, F C P; Porto, B A A; Ribeiro, N S; Moreira, L M C; Arantes, R M E; Vieira, A T; Teixeira, M M; Generoso, S V; Nascimento, V N; Martins, F S; Nicoli, J R

    2015-01-01

    In the present study, the protective potential of Saccharomyces cerevisiae strain UFMG A-905 was evaluated in a murine model of acute ulcerative colitis (UC). Six groups of Balb/c mice were used: not treated with yeast and not challenged with dextran sulphate sodium (DSS) (control); treated with S. cerevisiae UFMG A-905 (905); treated with the non-probiotic S. cerevisiae W303 (W303); challenged with DSS (DSS); treated with S. cerevisiae UFMG A-905 and challenged with DSS (905 + DSS); and treated with S. cerevisiae W303 and challenged with DSS (W303 + DSS). Seven days after induction of UC, mice were euthanised to remove colon for enzymatic, immunological, and histopathological analysis. In vivo intestinal permeability was also evaluated. An improvement of clinical manifestations of experimental UC was observed only in mice of the 905 + DSS group when compared to animals from DSS and W303 + DSS groups. This observation was confirmed by histological and morphometrical data and determination of myeloperoxidase and eosinophil peroxidase activities, intestinal permeability and some pro-inflammatory cytokines. S. cerevisiae UFMG A-905 showed to be a potential alternative treatment for UC when used in an experimental animal model of the disease.

  8. Knowledge-based immunosuppressive therapy for kidney transplant patients--from theoretical model to clinical integration.

    PubMed

    Seeling, Walter; Plischke, Max; de Bruin, Jeroen S; Schuh, Christian

    2015-01-01

    Immunosuppressive therapy is a risky necessity after a patient received a kidney transplant. To reduce risks, a knowledge-based system was developed that determines the right dosage of the immunosuppresive agent Tacrolimus. A theoretical model, to classify medication blood levels as well as medication adaptions, was created using data from almost 500 patients, and over 13.000 examinations. This model was then translated into an Arden Syntax knowledge base, and integrated directly into the hospital information system of the Vienna General Hospital. In this paper we give an overview of the construction and integration of such a system.

  9. Biologic effects of bacterial superantigens in a xenogeneic transplantation model for psoriasis.

    PubMed

    Boehncke, W H

    2001-12-01

    Both clinical as well as experimental data support the concept of psoriasis being a T-cell-mediated immune disease possibly triggered by bacterial superantigens. Further analysis of its pathogenesis was facilitated by the generation of a xenogeneic transplantation model in which skin from psoriatic patients is grafted onto SCID mice lacking functional B and T cells. Applying this model it was demonstrated that psoriasis can be triggered by bacterial superantigens; this process depends on the presence of immunocytes. Mutated variants of the respective superantigens exhibiting no measurable affinity to HLA class II molecules can function as competitive inhibitors in vivo.

  10. Model of End-Stage Liver Disease Score and Derived Variants Lack Prognostic Ability after Liver Transplantation.

    PubMed

    Kaltenborn, Alexander; Salinas, Ricardo; Jäger, Mark D; Lehner, Frank; Sakirow, Larissa; Klempnauer, Jürgen; Schrem, Harald

    2015-08-04

    BACKGROUND The model of end-stage liver disease (MELD) score is currently used for donor liver allocation in many regions. The objective of this retrospective study was to assess the MELD score and its diverse variants as prognostic models for mortality after liver transplantation. MATERIAL AND METHODS An analysis of 454 consecutive adult liver transplants since the introduction of MELD-based donor liver allocation was conducted. Eight different MELD score variants were investigated. Receiver operating characteristic (ROC) curve analysis was performed to calculate the sensitivity, specificity, and overall model correctness of the investigated scores as a predictive model. The Brier score was used for the prediction of model accuracy and calculated as described before. Study endpoints were 90-day mortality and long-term patient mortality. RESULTS A 90-day mortality of 15.4% (n=69) and long-term mortality of 25% (n=112) were observed. All investigated models fail to reach relevant areas under the ROC curve greater than 0.700 for the prediction of mortality after liver transplantation. All calculated Brier scores were greater than 0.25, indicating a significant lack of model discrimination and calibration of the investigated scores. CONCLUSIONS A prognostic model for the prediction of outcome after transplantation still needs to be identified and should allow weighing urgency against utility in liver transplantation.

  11. Successful treatment of the murine model of cystinosis using bone marrow cell transplantation.

    PubMed

    Syres, Kimberly; Harrison, Frank; Tadlock, Matthew; Jester, James V; Simpson, Jennifer; Roy, Subhojit; Salomon, Daniel R; Cherqui, Stephanie

    2009-09-17

    Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The defective gene is CTNS encoding the lysosomal cystine transporter, cystinosin. Cystine accumulates in every organ in the body and leads to organ damage and dysfunction, including renal defects. Using the murine model for cystinosis, Ctns(-/-) mice, we performed syngeneic bone marrow cell (BMC), hematopoietic stem cell (HSC), and mesenchymal stem cell transplantation. Organ-specific cystine content was reduced by 57% to 94% in all organs tested in the BMC-treated mice. Confocal microscopy and quantitative polymerase chain reaction revealed a large quantity of transplanted BMC in all organs tested, from 5% to 19% of the total cells. Most of these cells were not from the lymphoid lineage but part of the intrinsic structure of the organ. The natural progression of renal dysfunction was prevented, and deposition of corneal cystine crystals was significantly improved in the BMC-treated mice. HSC had the same therapeutic effect as whole BMC. In contrast, mesenchymal stem cell did not integrate efficiently in any organ. This work is a proof of concept for using HSC transplantation as a therapy for cystinosis and highlights the efficiency of this strategy for a chronic, progressive degenerative disease.

  12. Transplantation models to characterize the mechanisms of stem cell-induced islet regeneration.

    PubMed

    Bell, Gillian I; Seneviratne, Ayesh K; Nasri, Grace N; Hess, David A

    2013-09-20

    This unit describes our current knowledge regarding the isolation human bone marrow-derived progenitor cells for the paracrine stimulation of islet regeneration after transplantation into immunodeficient mouse models of diabetes. By using high aldehyde dehydrogenase (ALDH(hi) ) activity, a conserved function in multiple stem cell lineages, a mixed population of hematopoietic, endothelial, and mesenchymal progenitor cells can be efficiently purified using flow cytometry. We describe in vitro approaches to characterize and expand these distinct cell types. Importantly, these cell types can be transplanted into immunodeficient mice rendered beta-cell deficient by streptozotocin (STZ) treatment, in order monitor functional recovery from hyperglycemia and to characterize endogenous islet regeneration via paracrine mechanisms. Herein, we provide detailed protocols for: (1) isolation and characterization of ALDH(hi) cells for the establishment of hematopoietic and multipotent-stromal progenitor lineages; (2) intravenous and intrapancreatic transplantation of human stem cell subtypes for the quantification of glycemic recovery in STZ-treated immunodeficient mice; and (3) immunohistochemical characterization of islet recovery via the stimulation of islet neogenic, beta-cell proliferative, and islet revascularization programs. Collectively, these systems can be used to support the pre-clinical development of human progenitor cell-based therapies to treat diabetes via islet regeneration.

  13. Transplantation of embryonic stem cells improves the regeneration of periodontal furcation defects in a porcine model.

    PubMed

    Yang, Jenn-Rong; Hsu, Chia-Wen; Liao, Shih-Chung; Lin, Yu-Ting; Chen, Lih-Ren; Yuan, Kuo

    2013-04-01

    Stem cell-based therapy promises to regenerate lost tissue. Embryonic stem (ES) cells are pluripotent and may provide a virtually unlimited source for transplantation. We investigated whether ES cell transplantation improved the regeneration of furcation defects in a porcine model. Experimental periodontitis was induced in the buccal furcations of the bilateral mandibular 2nd premolars of six minipigs. After 4 weeks, the lesions were surgically debrided and implanted with collagen matrix alone (control site) or collagen matrix overlaid with porcine ES cells expressing green fluorescent protein (pES/GFP(+) ) (test site). After 3 months of healing, the clinical parameters were measured again. The treated teeth with adjacent tissue, and part of the major organs, were processed for GFP immunohistochemistry. We found no obvious teratoma or rejection. The test group had significantly better clinical parameters. Immunohistochemistry (IHC) showed that transplanted pES/GFP(+) cells had differentiated to new periodontal ligament and cementum in the test sites. Surprisingly, GFP(+) cells were also detectable in the repaired control cementum and remote organs. We conclude that using ES cells to improve the regeneration of periodontal furcation defects is feasible. More studies are required to assess this potential treatment's efficacy and safety. © 2013 John Wiley & Sons A/S.

  14. New metastatic model of human small-cell lung cancer by orthotopic transplantation in mice.

    PubMed

    Sakamoto, Shuichi; Inoue, Hiroyuki; Ohba, Shunichi; Kohda, Yasuko; Usami, Ihomi; Masuda, Tohru; Kawada, Manabu; Nomoto, Akio

    2015-04-01

    Small-cell lung cancer (SCLC) is an aggressive cancer with high metastatic ability and novel strategies against the metastasis are urgently needed to improve SCLC treatment. However, the mechanism of metastasis of SCLC remains largely to be elucidated. For further studies of SCLC metastasis, we developed a new orthotopic transplantation model in mice. We established a GFP-labeled subline from the human SCLC cell line DMS273 and transplanted them orthotopically into the lung of nude mice with Matrigel. The GFP-labeled cells showed significant metastatic activity and formed metastatic foci in distant tissues such as bone, kidney, and brain, as observed in SCLC patients. From a bone metastasis focus of the mouse, we isolated another subline, termed G3H, with enhanced metastatic potential and higher hepatocyte growth factor (HGF) expression than the parental line. Further studies indicated that the HGF/MET signaling pathway was involved in in vitro motility and invasion activities of the G3H cells and treatments with MET inhibitors decreased formation of distant metastases in our orthotopic model using G3H cells. These data indicated that our model mimics the clinical aspect of SCLC such as metastatic tropism and autocrine of HGF/MET signaling. Compared with other orthotopic SCLC models, our model has a superior ability to form distant metastases. Therefore, our model will provide a valuable tool for the study of SCLC metastasis. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  15. Irritable bowel syndrome: a microbiome-gut-brain axis disorder?

    PubMed

    Kennedy, Paul J; Cryan, John F; Dinan, Timothy G; Clarke, Gerard

    2014-10-21

    Irritable bowel syndrome (IBS) is an extremely prevalent but poorly understood gastrointestinal disorder. Consequently, there are no clear diagnostic markers to help diagnose the disorder and treatment options are limited to management of the symptoms. The concept of a dysregulated gut-brain axis has been adopted as a suitable model for the disorder. The gut microbiome may play an important role in the onset and exacerbation of symptoms in the disorder and has been extensively studied in this context. Although a causal role cannot yet be inferred from the clinical studies which have attempted to characterise the gut microbiota in IBS, they do confirm alterations in both community stability and diversity. Moreover, it has been reliably demonstrated that manipulation of the microbiota can influence the key symptoms, including abdominal pain and bowel habit, and other prominent features of IBS. A variety of strategies have been taken to study these interactions, including probiotics, antibiotics, faecal transplantations and the use of germ-free animals. There are clear mechanisms through which the microbiota can produce these effects, both humoral and neural. Taken together, these findings firmly establish the microbiota as a critical node in the gut-brain axis and one which is amenable to therapeutic interventions.

  16. Irritable bowel syndrome: A microbiome-gut-brain axis disorder?

    PubMed Central

    Kennedy, Paul J; Cryan, John F; Dinan, Timothy G; Clarke, Gerard

    2014-01-01

    Irritable bowel syndrome (IBS) is an extremely prevalent but poorly understood gastrointestinal disorder. Consequently, there are no clear diagnostic markers to help diagnose the disorder and treatment options are limited to management of the symptoms. The concept of a dysregulated gut-brain axis has been adopted as a suitable model for the disorder. The gut microbiome may play an important role in the onset and exacerbation of symptoms in the disorder and has been extensively studied in this context. Although a causal role cannot yet be inferred from the clinical studies which have attempted to characterise the gut microbiota in IBS, they do confirm alterations in both community stability and diversity. Moreover, it has been reliably demonstrated that manipulation of the microbiota can influence the key symptoms, including abdominal pain and bowel habit, and other prominent features of IBS. A variety of strategies have been taken to study these interactions, including probiotics, antibiotics, faecal transplantations and the use of germ-free animals. There are clear mechanisms through which the microbiota can produce these effects, both humoral and neural. Taken together, these findings firmly establish the microbiota as a critical node in the gut-brain axis and one which is amenable to therapeutic interventions. PMID:25339800

  17. Large bowel resection

    MedlinePlus

    ... colectomy; Right hemicolectomy; Left hemicolectomy; Hand assisted bowel surgery; Low anterior resection; Sigmoid colectomy; Subtotal colectomy; Proctocolectomy; Colon resection; Laparoscopic colectomy; Colectomy - partial; Abdominal perineal resection

  18. Histologic changes in transplanted expanded polytetrafluoroethylene in an animal model.

    PubMed

    Kim, Ji Heui; Park, Chan Hum; Lee, Ok Joo; Lee, Jun Ho; Hong, Seok Min

    2012-01-01

    Several materials have been used for nasal augmentation surgery. Expanded polytetrafluoroethylene (e-PTFE) (Gore-Tex; W. L. Gore & Associates, Flagstaff, AZ) has proven to be an ideal synthetic material for nasal augmentation. Gore-Tex contains numerous pores that stabilize an implant, but this advantage has been tempered by unpredictable outcomes. The purpose of this study was to evaluate morphologic and histologic changes in nonreinforced Gore-Tex in a rabbit model. In vivo study using a rabbit model. To analyze histologic changes, we used 20 New Zealand white rabbits. Gore-Tex was implanted into the nasal dorsum of the rabbits. Then, en bloc specimens containing the implant and surrounding soft tissues were sampled 1, 3, 6, and 12 months after implantation. We evaluated the three-dimensional size of the implants over time using light and electron microscopy to investigate histologic and morphologic changes. Following gross analysis, none of the implants were lost or extruded, and there was no evidence of wound infection. Diminution rates of thickness, width, and height in the implants were 22%, 2%, and 5%, respectively. Histologically, connective tissue growth was observed in all specimens, and the internodal space decreased owing to connective tissue ingrowth over time. Neovascularization was observed 3 months after implantation, and degenerative changes were also observed after 6 months. Gore-Tex should be carefully trimmed for use in augmentation because of its potential to decrease in size over time. Additional studies are necessary before these results can be applied in clinical practice. Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.

  19. Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury.

    PubMed

    Haus, Daniel L; López-Velázquez, Luci; Gold, Eric M; Cunningham, Kelly M; Perez, Harvey; Anderson, Aileen J; Cummings, Brian J

    2016-07-01

    Traumatic brain injury (TBI) in humans can result in permanent tissue damage and has been linked to cognitive impairment that lasts years beyond the initial insult. Clinically effective treatment strategies have yet to be developed. Transplantation of human neural stem cells (hNSCs) has the potential to restore cognition lost due to injury, however, the vast majority of rodent TBI/hNSC studies to date have evaluated cognition only at early time points, typically <1month post-injury and cell transplantation. Additionally, human cell engraftment and long-term survival in rodent models of TBI has been difficult to achieve due to host immunorejection of the transplanted human cells, which confounds conclusions pertaining to transplant-mediated behavioral improvement. To overcome these shortfalls, we have developed a novel TBI xenotransplantation model that utilizes immunodeficient athymic nude (ATN) rats as the host recipient for the post-TBI transplantation of human embryonic stem cell (hESC) derived NSCs and have evaluated cognition in these animals at long-term (≥2months) time points post-injury. We report that immunodeficient ATN rats demonstrate hippocampal-dependent spatial memory deficits (Novel Place, Morris Water Maze), but not non-spatial (Novel Object) or emotional/anxiety-related (Elevated Plus Maze, Conditioned Taste Aversion) deficits, at 2-3months post-TBI, confirming that ATN rats recapitulate some of the cognitive deficits found in immunosufficient animal strains. Approximately 9-25% of transplanted hNSCs survived for at least 5months post-transplantation and differentiated into mature neurons (NeuN, 18-38%), astrocytes (GFAP, 13-16%), and oligodendrocytes (Olig2, 11-13%). Furthermore, while this model of TBI (cortical impact) targets primarily cortex and the underlying hippocampus and generates a large lesion cavity, hNSC transplantation facilitated cognitive recovery without affecting either lesion volume or total spared cortical or hippocampal

  20. Adoptive Transfer of Dendritic Cells Expressing Fas Ligand Modulates Intestinal Inflammation in a Model of Inflammatory Bowel Disease

    PubMed Central

    de Jesus, Edelmarie Rivera; Isidro, Raymond A; Cruz, Myrella L; Marty, Harry; Appleyard, Caroline B

    2016-01-01

    Background Inflammatory bowel diseases (IBD) are chronic relapsing inflammatory conditions of unknown cause and likely result from the loss of immunological tolerance, which leads to over-activation of the gut immune system. Gut macrophages and dendritic cells (DCs) are essential for maintaining tolerance, but can also contribute to the inflammatory response in conditions such as IBD. Current therapies for IBD are limited by high costs and unwanted toxicities and side effects. The possibility of reducing intestinal inflammation with DCs genetically engineered to over-express the apoptosis-inducing FasL (FasL-DCs) has not yet been explored. Objective Investigate the immunomodulatory effect of administering FasL-DCs in the rat trinitrobenzene sulfonic acid (TNBS) model of acute colitis. Methods Expression of FasL on DCs isolated from the mesenteric lymph nodes (MLNs) of normal and TNBS-colitis rats was determined by flow cytometry. Primary rat bone marrow DCs were transfected with rat FasL plasmid (FasL-DCs) or empty vector (EV-DCs). The effect of these DCs on T cell IFNγ secretion and apoptosis was determined by ELISPOT and flow cytometry for Annexin V, respectively. Rats received FasL-DCs or EV-DCs intraperitoneally 96 and 48 hours prior to colitis induction with TNBS. Colonic T cell and neutrophil infiltration was determined by immunohistochemistry for CD3 and myeloperoxidase activity assay, respectively. Macrophage number and phenotype was measured by double immunofluorescence for CD68 and inducible Nitric Oxide Synthase. Results MLN dendritic cells from normal rats expressed more FasL than those from colitic rats. Compared to EV-DCs, FasL-DCs reduced T cell IFNγ secretion and increased T cell apoptosis in vitro. Adoptive transfer of FasL-DCs decreased macroscopic and microscopic damage scores and reduced colonic T cells, neutrophils, and proinflammatory macrophages when compared to EV-DC adoptive transfer. Conclusion FasL-DCs are effective at treating colonic

  1. Solid lipid nanoparticles delivering anti-inflammatory drugs to treat inflammatory bowel disease: Effects in an in vivo model

    PubMed Central

    Dianzani, Chiara; Foglietta, Federica; Ferrara, Benedetta; Rosa, Arianna Carolina; Muntoni, Elisabetta; Gasco, Paolo; Della Pepa, Carlo; Canaparo, Roberto; Serpe, Loredana

    2017-01-01

    AIM To improve anti-inflammatory activity while reducing drug doses, we developed a nanoformulation carrying dexamethasone and butyrate. METHODS Dexamethasone cholesteryl butyrate-solid lipid nanoparticles (DxCb-SLN) were obtained with the warm microemulsion method. The anti-inflammatory activity of this novel nanoformulation has been investigated in vitro (cell adhesion to human vascular endothelial cells and pro-inflammatory cytokine release by lipopolysaccharide-induced polymorphonuclear cells) and in vivo (disease activity index and cytokine plasma concentrations in a dextran sulfate sodium-induced mouse colitis) models. Each drug was also administered separately to compare its effects with those induced by their co-administration in SLN at the same concentrations. RESULTS DxCb-SLN at the lowest concentration tested (Dx 2.5 nmol/L and Cb 0.1 μmol/L) were able to exert a more than additive effect compared to the sum of the individual effects of each drug, inducing a significant in vitro inhibition of cell adhesion and a significant decrease of pro-inflammatory cytokine (IL-1β and TNF-α) in both in vitro and in vivo models. Notably, only the DxCb nanoformulation administration was able to achieve a significant cytokine decrease compared to the cytokine plasma concentration of the untreated mice with dextran sulfate sodium-induced colitis. Specifically, DxCb-SLN induced a IL-1β plasma concentration of 61.77% ± 3.19%, whereas Dx or Cb used separately induced a concentration of 90.0% ± 2.8% and 91.40% ± 7.5%, respectively; DxCb-SLN induced a TNF-α plasma concentration of 30.8% ± 8.9%, whereas Dx or Cb used separately induced ones of 99.5% ± 4.9% and 71.1% ± 10.9%, respectively. CONCLUSION Our results indicate that the co-administration of dexamethasone and butyrate by nanoparticles may be beneficial for inflammatory bowel disease treatment. PMID:28694660

  2. Inflammatory Bowel Disease Therapies and Gut Function in a Colitis Mouse Model

    PubMed Central

    Nahidi, Lily; Leach, Steven T.; Mitchell, Hazel M.; Kaakoush, Nadeem O.; Lemberg, Daniel A.; Munday, John S.; Huinao, Karina; Day, Andrew S.

    2013-01-01

    Background. Exclusive enteral nutrition (EEN) is a well-established approach to the management of Crohn's disease. Aim. To determine effects of EEN upon inflammation and gut barrier function in a colitis mouse model. Methods. Interleukin-10-deficient mice (IL-10−/−) were inoculated with Helicobacter trogontum and then treated with EEN, metronidazole, hydrocortisone, or EEN and metronidazole combination. Blood and tissue were collected at 2 and 4 weeks with histology, mucosal integrity, tight junction integrity, inflammation, and H. trogontum load evaluated. Results. H. trogontum induced colitis in IL-10−/− mice with histological changes in the cecum and colon. Elevated mucosal IL-8 mRNA in infected mice was associated with intestinal barrier dysfunction indicated by decreased transepithelial electrical resistance and mRNA of tight junction proteins and increased short-circuit current, myosin light chain kinase mRNA, paracellular permeability, and tumor necrosis factor-α and myeloperoxidase plasma levels (P < 0.01 for all comparisons). EEN and metronidazole, but not hydrocortisone, treatments restored barrier function, maintained gut barrier integrity, and reversed inflammatory changes along with reduction of H. trogontum load (versus infected controls P < 0.05). Conclusion. H. trogontum infection in IL-10−/− mice induced typhlocolitis with intestinal barrier dysfunction. EEN and metronidazole, but not hydrocortisone, modulate barrier dysfunction and reversal of inflammatory changes. PMID:24027765

  3. Contribution of Large Pig for Renal Ischemia-Reperfusion and Transplantation Studies: The Preclinical Model

    PubMed Central

    Giraud, S.; Favreau, F.; Chatauret, N.; Thuillier, R.; Maiga, S.; Hauet, T.

    2011-01-01

    Animal experimentation is necessary to characterize human diseases and design adequate therapeutic interventions. In renal transplantation research, the limited number of in vitro models involves a crucial role for in vivo models and particularly for the porcine model. Pig and human kidneys are anatomically similar (characterized by multilobular structure in contrast to rodent and dog kidneys unilobular). The human proximity of porcine physiology and immune systems provides a basic knowledge of graft recovery and inflammatory physiopathology through in vivo studies. In addition, pig large body size allows surgical procedures similar to humans, repeated collections of peripheral blood or renal biopsies making pigs ideal for medical training and for the assessment of preclinical technologies. However, its size is also its main drawback implying expensive housing. Nevertheless, pig models are relevant alternatives to primate models, offering promising perspectives with developments of transgenic modulation and marginal donor models facilitating data extrapolation to human conditions. PMID:21403881

  4. Helminths in organ transplantation.

    PubMed

    Cooper, Andrew J R; Dholakia, Shamik; Holland, Celia V; Friend, Peter J

    2017-06-01

    With transplantation becoming an increasingly routine form of treatment for diverse populations, and with international travel becoming ever more accessible and affordable, the danger of transplantation-mediated helminth infections, exacerbated by coincident immunosuppression, must be considered. In this Review, we attempt to catalogue all clinically-relevant helminthiases that have been reported to coincide with transplantation, whether by transplantation-mediated transmission, reactivation of latent infections in an immunosuppressed context, or possible de-novo infection during the immunosuppressed peritransplant period. Helminthiasis has been reported in cases of kidney, liver, bowel, pancreas, heart, lung, and stem-cell transplant, and blood transfusion. For each helminthiasis, known risk factors, symptoms, and suggested options for screening and treatment are given. We conclude that helminths are a small but important and potentially severe source of disease after transplantation, and, with options for diagnosis and treatment, these pathogens warrant greater consideration during organ implantation. The achievement of immunological tolerance using helminth-derived products is also an exciting future prospect. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Establishment of a surgically induced cryptorchidism canine recipient model for spermatogonial stem cell transplantation

    PubMed Central

    Lee, Won-Young; Lee, Ran; Song, Hyuk; Hur, Tai-Young; Lee, Seunghoon; Ahn, Jiyun

    2016-01-01

    Transplantation of spermatogonial stem cells (SSCs) in experimental animal models has been used to study germ line stem cell biology and to produce transgenic animals. The species-specific recipient model preparation is important for the characterization of SSCs and the production of offspring. Here, we investigated the effects of surgically induced cryptorchidism in dog as a new recipient model for spermatogonial stem cell transplantation. Artificially unilateral or bilateral cryptorchidism was induced in ten mature male dogs by surgically returning the testis and epididymis to the abdominal cavity. The testes and epididymides were collected every week after the induction of artificial cryptorchidism (surgery) for one month. To determine the effect of surgical cryptorchidism, the seminiferous tubule diameter was measured and immunohistochemistry using PGP9.5 and GATA4 antibodies was analyzed. The diameters of the seminiferous tubules of abdominal testes were significantly reduced compared to those of the scrotal testes. Immunohistochemistry results showed that PGP9.5 positive undifferentiated spermatogonia were significantly reduced after surgical cryptorchidism induction, but there were no significant changes in GATA-4 positive sertoli cells. To evaluate the testis function recovery rate, orchiopexy was performed on two dogs after 30 days of bilateral cryptorchidism. In the orchiopexy group, SCP3 positive spermatocytes were detected, and spermatogenesis was recovered 8 weeks after orchiopexy. In this study, we provided optimum experimental conditions and time for surgical preparation of a recipient canine model for SSC transplantation. Additionally, our data will contribute to recipient preparation by using surgically induced cryptorchidism in non-rodent species. PMID:28053620

  6. Neural and marrow-derived stromal cell sphere transplantation in a rat model of traumatic brain injury.

    PubMed

    Lu, Dunyue; Li, Ya; Mahmood, Asim; Wang, Lei; Rafiq, Tahir; Chopp, Michael

    2002-10-01

    This study was designed to investigate the effect of treatment with a novel composite material consisting of embryonic neurospheres and bone marrow-derived stromal cell spheres (NMSCSs) in a rat model of traumatic brain injury (TBI). The NMSCS composite was injected into the TBI contusion site 24 hours after injury, and all rats were killed on Day 14 after the transplantation. The Rotarod test and the neurological severity score were used to evaluate neurological function. The transplanted NMSCS was analyzed in recipient rat brains by using histological staining and laser scanning confocal microscopy. The lesion volumes in the brains were also calculated using computer image analysis. Rats that received NMSCS transplants had reduced lesion volume and showed improved motor and neurological function when compared with control groups 14 days after the treatment. These results suggest that transplantation of this novel biological material (NMSCS) may be useful in the treatment of TBI.

  7. Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model.

    PubMed

    Donegan, J J; Tyson, J A; Branch, S Y; Beckstead, M J; Anderson, S A; Lodge, D J

    2016-08-02

    An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that the stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia.Molecular Psychiatry advance online publication, 2 August 2016; doi:10.1038/mp.2016.121.

  8. Meniscus regeneration by syngeneic, minor mismatched, and major mismatched transplantation of synovial mesenchymal stem cells in a rat model.

    PubMed

    Okuno, Makiko; Muneta, Takeshi; Koga, Hideyuki; Ozeki, Nobutake; Nakagawa, Yusuke; Tsuji, Kunikazu; Yoshiya, Shinichi; Sekiya, Ichiro

    2014-07-01

    We compared the effect of syngeneic and allogeneic transplantation of synovial mesenchymal stem cells (MSCs) for meniscus regeneration in a rat model. Synovium was harvested from the knee joints of three strains of rats. The anterior half of the medial meniscus in both knees of F344 rats was removed and 5 million synovial MSCs derived from F344 (syngeneic transplantation), Lewis (minor mismatched transplantation), and ACI (major mismatched transplantation) were injected into the knee of the F344 rats. At 4 weeks, the area of the regenerated meniscus in the F344 group was significantly larger than that in the ACI group. Histological score was significantly better in the F344 and Lewis groups than in the ACI group at 8 weeks. DiI labeled cells could be observed in the knee joint in the F344 group, but were hardly detected in the ACI group at 1 week. The number of macrophages and CD8 T cells at synovium around the meniscus defect was significantly lower in the F344 group than in the ACI group at 1 week. Syngeneic and minor mismatched transplantation of synovial MSCs promoted meniscus regeneration better than major mismatched transplantation in a rat meniscectmized model.

  9. Comparison of peritoneal adhesion formation in bowel retraction by cotton towels versus the silicone lap pak device in a rabbit model.

    PubMed

    Liu, Brian G; Ruben, Dawn S; Renz, Wolfgang; Santillan, Antonio; Kubisen, Steven J; Harmon, John W

    2011-01-01

    Manipulation of cotton operating room towels within the abdominal cavity in open abdominal surgery has been associated with the formation of peritoneal adhesions. In a rabbit model, the use of standard cotton operating room towels is compared to the Lap Pak, a silicone bowel-packing device, to determine the potential for reducing the risk of adhesions. Thirty rabbits were randomly assigned to 3 groups. The rabbits underwent a sham surgery with incision only (n = 10), placement of operating room towels (n = 10), or placement of a Lap Pak (n = 10). After 14 days, the rabbits were sacrificed and the peritoneal cavity explored for adhesions. The number, tenacity, ease of dissection, and density of adhesions were recorded, and the adhesions quantitatively graded using a Modified Hopkins Adhesion scoring system. The operating room towel group had an average adhesion score of 2.5, and 8 (80%) rabbits developed adhesions. The sham group had an average adhesion score of 0.3 and one rabbit (10%) developed adhesions. The Lap Pak group had an average adhesion score of 0.2 and 1 rabbit (10%) developed adhesions. The frequency and severity of adhesions in the operating room towel group were significantly greater from that of the baseline sham group. There was no significant difference between the Lap Pak and sham groups. In this rabbit laparotomy model, the use of the Lap Pak to retract the bowels resulted in significantly fewer adhesions compared to cotton operating room towels. Lap Pak may be beneficial for bowel packing in general abdominal surgeries.

  10. Comparison of Peritoneal Adhesion Formation in Bowel Retraction by Cotton Towels Versus the Silicone Lap Pak Device in a Rabbit Model

    PubMed Central

    Liu, Brian G.; Ruben, Dawn S.; Renz, Wolfgang; Santillan, Antonio; Kubisen, Steven J.; Harmon, John W.

    2011-01-01

    Objective: Manipulation of cotton operating room towels within the abdominal cavity in open abdominal surgery has been associated with the formation of peritoneal adhesions. In a rabbit model, the use of standard cotton operating room towels is compared to the Lap Pak, a silicone bowel-packing device, to determine the potential for reducing the risk of adhesions. Methods: Thirty rabbits were randomly assigned to 3 groups. The rabbits underwent a sham surgery with incision only (n = 10), placement of operating room towels (n = 10), or placement of a Lap Pak (n = 10). After 14 days, the rabbits were sacrificed and the peritoneal cavity explored for adhesions. The number, tenacity, ease of dissection, and density of adhesions were recorded, and the adhesions quantitatively graded using a Modified Hopkins Adhesion scoring system. Results: The operating room towel group had an average adhesion score of 2.5, and 8 (80%) rabbits developed adhesions. The sham group had an average adhesion score of 0.3 and one rabbit (10%) developed adhesions. The Lap Pak group had an average adhesion score of 0.2 and 1 rabbit (10%) developed adhesions. The frequency and severity of adhesions in the operating room towel group were significantly greater from that of the baseline sham group. There was no significant difference between the Lap Pak and sham groups. Conclusions: In this rabbit laparotomy model, the use of the Lap Pak to retract the bowels resulted in significantly fewer adhesions compared to cotton operating room towels. Lap Pak may be beneficial for bowel packing in general abdominal surgeries. PMID:22096614

  11. Current status of intestinal and multivisceral transplantation

    PubMed Central

    Bharadwaj, Shishira; Tandon, Parul; Gohel, Tushar D.; Brown, Jill; Steiger, Ezra; Kirby, Donald F.; Khanna, Ajai

    2017-01-01

    Clinical-nutritional autonomy is the ultimate goal of patients with intestinal failure (IF). Traditionally, patients with IF have been relegated to lifelong parenteral nutrition (PN) once surgical and medical rehabilitation attempts at intestinal adaptation have failed. Over the past two decades, however, outcome improvements in intestinal transplantation have added another dimension to the therapeutic armamentarium in the field of gut rehabilitation. This has become possible through relentless efforts in the standardization of surgical techniques, advancements in immunosuppressive therapies and induction protocols and improvement in postoperative patient care. Four types of intestinal transplants include isolated small bowel transplant, liver-small bowel transplant, multivisceral transplant and modified multivisceral transplant. Current guidelines restrict intestinal transplantation to patients who have had significant complications from PN including liver failure and repeated infections. From an experimental stage to the currently established therapeutic modality for patients with advanced IF, outcome improvements have also been possible due to the introduction of tacrolimus in the early 1990s. Studies have shown that intestinal transplant is cost-effective within 1–3 years of graft survival compared with PN. Improved survival and quality of life as well as resumption of an oral diet should enable intestinal transplantation to be an important option for patients with IF in addition to continued rehabilitation. Future research should focus on detecting biomarkers of early rejection, enhanced immunosuppression protocols, improved postoperative care and early referral to transplant centers. PMID:28130374

  12. Angiogenesis and bone regeneration by allogeneic mesenchymal stem cell intravenous transplantation in rabbit model of avascular necrotic femoral head.

    PubMed

    Li, Zhanghua; Liao, Wen; Zhao, Qiang; Liu, Ming; Xia, Wei; Yang, Yi; Shao, Ningsheng

    2013-07-01

    To explore the feasibility of allogeneic mesenchymal stem cells (MSCs) transplanted intravenously for angiogenesis and bone repair in a rabbit model of avascular necrosis of femoral head (ANFH). Forty-five rabbits were randomized into three groups: a blank control group (without treatment), a necrotic control group (ANFH induced but without therapy), and an MSC transplantation group (ANFH induced and treated with MSC transplantation). The biopsies, blood sampling, and imaging examinations were performed on each animal at different time points (2, 4, and 6 wk). To monitor angiogenesis and bone repair progress, examinations included real-time polymerase chain reaction, Western blot analysis, x-ray, computed tomography, Masson trichrome staining, picrosirius red staining, and immunohistochemical staining. Necrosis and bone collapse were observed in bilateral femoral heads of necrotic rabbits of the necrotic control group, whereas the femoral head morphology was generally restored in the MSC transplantation group. The mRNA levels of Cbfa1, BMP, VEGF, and OPN in bone tissue were significantly higher in the MSC transplantation group than in the necrotic control group. In addition, the total protein amount of Cbfa1 in the MSC transplantation group was also significantly higher than that in the necrotic control group (P < 0.05). Intravenous transplantation of allogeneic MSCs can promote vascular and bone regeneration in the necrotic region of the femoral head in a rabbit model of ANFH. The results of our study suggest that the intravenous transplantation of MSCs could be a potential and minimally invasive treatment option for ANFH patients. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. HUMAN CORNEAL ENDOTHELIAL CELL TRANSPLANTATION IN A HUMAN EX VIVO MODEL

    PubMed Central

    Patel, Sanjay V.; Bachman, Lori A.; Hann, Cheryl R.; Bahler, Cindy K.; Fautsch, Michael P.

    2009-01-01

    Purpose To determine the effects of incorporating superparamagnetic microspheres (SPMs) into cultured human corneal endothelial cells (HCECs), and to describe preliminary experiments of HCEC transplantation, facilitated by SPMs and an external magnetic field, in a human anterior segment ex vivo model. Methods HCECs were cultured in monolayer and incorporated with magnetite oxide SPMs (900 nm, 300 nm, and 100 nm) at different concentrations. Cell viability, migration toward a magnetic field, and light transmittance were measured after incorporation of SPMs. HCEC transplantation to human recipients was investigated with anterior segments in organ culture subjected to an external magnetic field. Light and electron microscopy were used to assess HCEC attachment to corneal stroma. Results SPMs were incorporated into the cytoplasm of HCECs after overnight incubation. None of the SPMs affected the short-term viability of cultured HCECs (P>0.14, n=6) or their light transmittance (P>0.06, n=5), although there was a trend toward decreased transmittance with higher concentrations of the 900 nm SPM. Cell migration toward a magnetic field was higher for HCECs with incorporated SPMs than for HCECs without SPMs (P≤ 0.01, n=6), with dose-response relationships evident for the 300 nm and 100 nm SPMs. SPMs facilitated the attachment of HCECs to corneal stroma in the human anterior segment model with minimal change in intracameral (intraocular) pressure. Conclusions SPMs facilitate migration of HCECs toward a magnetic source and attachment of cells to corneal stroma without affecting cell viability or light transmittance. The human anterior segment model can be used to study HCEC transplantation. PMID:19136716

  14. A Modified Heterotopic Swine Hind Limb Transplant Model for Translational Vascularized Composite Allotransplantation (VCA) Research

    PubMed Central

    Ibrahim, Zuhaib; Cooney, Damon S.; Shores, Jaimie T.; Sacks, Justin M.; Wimmers, Eric G.; Bonawitz, Steven C.; Gordon, Chad; Ruben, Dawn; Schneeberger, Stefan; Lee, W. P. Andrew; Brandacher, Gerald

    2013-01-01

    Vascularized Composite Allotransplantation (VCA) such as hand and face transplants represent a viable treatment option for complex musculoskeletal trauma and devastating tissue loss. Despite favorable and highly encouraging early and intermediate functional outcomes, rejection of the highly immunogenic skin component of a VCA and potential adverse effects of chronic multi-drug immunosuppression continue to hamper widespread clinical application of VCA. Therefore, research in this novel field needs to focus on translational studies related to unique immunologic features of VCA and to develop novel immunomodulatory strategies for immunomodulation and tolerance induction following VCA without the need for long term immunosuppression. This article describes a reliable and reproducible translational large animal model of VCA that is comprised of an osteomyocutaneous flap in a MHC-defined swine heterotopic hind limb allotransplantation. Briefly, a well-vascularized skin paddle is identified in the anteromedial thigh region using near infrared laser angiography. The underlying muscles, knee joint, distal femur, and proximal tibia are harvested on a femoral vascular pedicle. This allograft can be considered both a VCA and a vascularized bone marrow transplant with its unique immune privileged features. The graft is transplanted to a subcutaneous abdominal pocket in the recipient animal with a skin component exteriorized to the dorsolateral region for immune monitoring. Three surgical teams work simultaneously in a well-coordinated manner to reduce anesthesia and ischemia times, thereby improving efficiency of this model and reducing potential confounders in experimental protocols. This model serves as the groundwork for future therapeutic strategies aimed at reducing and potentially eliminating the need for chronic multi-drug immunosuppression in VCA. PMID:24145603

  15. Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

    PubMed Central

    Fu, Xuebin; Segiser, Adrian; Carrel, Thierry P.; Tevaearai Stahel, Hendrik T.; Most, Henriette

    2016-01-01

    Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation (hHTX) in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery. We herein review the current knowledge on the effects of volume unloading the left ventricle via different methods of hHTX in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under “reloaded” conditions. While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced changes in the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further improve our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients. PMID:27807535

  16. Teaching intestinal transplantation in the rat for medical student.

    PubMed

    Galvão, Flávio Henrique Ferreira; Bacchella, Telesforo; Cerqueira Machado, Marcel

    2007-01-01

    Technical difficulties hamper the widespread use of intestinal transplantation in rats. We evaluated the feasibility in training this microsurgical model for medical students. Thirty eight students were assessed. After information about intestinal transplantation in rats, they spontaneously agreed to be trained for this procedure. The course consisted of 4-h weekly lessons during 4-month period. The teaching process includes assessment in four phases: I) conception of intestinal transplantation and rat anatomy; II) basic microsurgery training; III) donor operation; IV) donor/recipient operation. Wistar rats were used as donors and recipients in one-step small bowel transplantation. All students (100%) reached phase II, seven students (18.42%) reached phase III and two students (5.26%) reached phase IV. Decreased interest about the theme, lack of time and patience, frustration and/or inability were all reasons given by the student that may have contributed to the low rate of success. Medical students achieved a low rate of completion for training in rat intestinal transplantation microsurgical procedures.

  17. Irritable Bowel Syndrome

    MedlinePlus

    ... your belly area), constipation (when you can't poop), and diarrhea (when you poop too much). If you have irritable bowel syndrome, ... food particles are also known as stool, a bowel movement, or poop. Here's why an intestine gets "irritable." ...

  18. Human motor neuron progenitor transplantation leads to endogenous neuronal sparing in 3 models of motor neuron loss.

    PubMed

    Wyatt, Tanya J; Rossi, Sharyn L; Siegenthaler, Monica M; Frame, Jennifer; Robles, Rockelle; Nistor, Gabriel; Keirstead, Hans S

    2011-01-01

    Motor neuron loss is characteristic of many neurodegenerative disorders and results in rapid loss of muscle control, paralysis, and eventual death in severe cases. In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs) and examined their histopathological effect in three animal models of motor neuron loss. Specifically, we transplanted hMNPs into rodent models of SMA (Δ7SMN), ALS (SOD1 G93A), and spinal cord injury (SCI). The transplanted cells survived and differentiated in all models. In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models. The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.

  19. Bone marrow transplant - discharge

    MedlinePlus

    Transplant - bone marrow - discharge; Stem cell transplant - discharge; Hematopoietic stem cell transplant - discharge; Reduced intensity; Non-myeloablative transplant - discharge; Mini transplant - discharge; Allogenic bone marrow transplant - ...

  20. Pediatric inflammatory bowel disease

    PubMed Central

    Diefenbach, Karen A; Breuer, Christopher K

    2006-01-01

    Inflammatory bowel disease is an important cause of gastrointestinal pathology in children and adolescents. The incidence of pediatric inflammatory bowel disease is increasing; therefore, it is important for the clinician to be aware of the presentation of this disease in the pediatric population. Laboratory tests, radiology studies, and endoscopic procedures are helpful in diagnosing inflammatory bowel disease and differentiating between Crohn’s disease and ulcerative colitis. Once diagnosed, the goal of medical management is to induce remission of disease while minimizing the side effects of the medication. Specific attention needs to be paid to achieving normal growth in this susceptible population. Surgical management is usually indicated for failure of medical management, complication, or malignancy. Algorithms for diagnostic evaluation and treatment of pediatric inflammatory bowel disease are presented. The specific psychosocial issues facing these patients are also discussed in this review as are the future goals of research in the complex problem of pediatric inflammatory bowel disease. PMID:16718840

  1. Development of a transplantable mouse myeloid leukemia model system: a preliminary report

    SciTech Connect

    Au, W.W.; Luippold, H.E.; Otten, J.A.

    1982-01-01

    Research progess has been hindered in some areas of carcinogenesis because of a lack of consistant biological markers that distinguish cancer from normal cells. Cell lines derived from x-ray induced RFM mouse myeloid leukemia were studied for the purpose of first identifying the genetic differences (by chromosome analysis) between leukemic and normal cells and second, developing a transplantable leukemia model system. Among the cell lines analyzed, one of them (MLI) appeared to be useful in development of such a model. In addition to two chromosome abnormalities, cell line MLI also has a large abnormal chromosome which may be useful as a biological marker for these leukemic cells. This marker was identified by banding study to be an isochromosome 8 derived from centromeric translocation of two chromosome 8s. Upon injection of 4 x 10/sup 6/ leukemic cells into RFM mice symptoms of leukemia appeared from 18 days onwards and mice would begin to die of leukemia from 21 days onwards. The presence or absence of the metacentric marker chromosome was the criteria for inequivocal identification of leukemic from co-existing normal cells in these two tissues. The ratio of these cell populations was quantitated and the time-dependent increase of the ratios was indicative of progression of leukemia. Thus, this transplantable myeloid leukemia model system may be useful in studying the proliferation of leukemic cells and the response of the co-existing cells to therapeutic agents. (ERB)

  2. Development of a Minor Histocompatibility Antigen Vaccine Regimen in the Canine Model of Hematopoietic Cell Transplantation.

    PubMed

    Rosinski, Steven Lawrence; Stone, Brad; Graves, Scott S; Fuller, Deborah H; De Rosa, Stephen C; Spies, Gregory A; Mize, Gregory J; Fuller, James T; Storb, Rainer

    2015-10-01

    Minor histocompatibility antigen (miHA) vaccines have the potential to augment graft-versus-tumor effects without graft-versus-host disease (GVHD). We used mixed hematopoietic chimerism in the canine model of major histocompatibility complex-matched allogeneic hematopoietic cell transplantation as a platform to develop a miHA vaccination regimen. We engineered DNA plasmids and replication-deficient human adenovirus type 5 constructs encoding large sections of canine SMCY and the entire canine SRY gene. Priming with replication-deficient human adenovirus type 5 constructs and boosting with ex vivo plasmid-transfected dendritic cells and cutaneous delivery of plasmids with a particle-mediated epidermal delivery device (PMED) in 2 female dogs induced antigen-specific T-cell responses. Similar responses were observed after a prime-boost vaccine regimen in three female hematopoietic cell transplantation donors. Subsequent donor lymphocyte infusion resulted in a significant change of chimerism in 1 of 3 male recipients without any signs of graft-versus-host disease. The change in chimerism in the recipient occurred in association with the development of CD4+ and CD8+ T-cell responses to the same peptide pools detected in the donor. These studies describe the first in vivo response to miHA vaccination in a large, outbred animal model without using recipient cells to sensitize the donor. This model provides a platform for ongoing experiments designed to define optimal miHA targets and develop protocols to directly vaccinate the recipient.

  3. A new vascularized cervical lymph node transplantation model: an anatomic study in rats.

    PubMed

    Uygur, Safak; Ozturk, Can; Bozkurt, Mehmet; Kwiecien, Grzegorz; Madajka, Maria; Siemionow, Maria

    2013-12-01

    Vascularized lymph node transfer is of high interest for the treatment of lymphedema. Currently, there are few experimental small animal models of vascularized lymph node transplantation. In this article, our aim was to describe a new vascularized cervical lymph node transplantation model in rats. Ten male Sprague-Dawley rats weighing 200 to 250 g were used in this study. The anatomic features of the neck lymph nodes in rats were explored. Anatomic neck dissections were performed, and lymph node flaps were harvested. The common carotid artery and the jugular vein were used as the vascular pedicles of the lymph node flap. Methylene blue dye was injected into the arterial pedicle. Lymph nodes were identified, and their structure was confirmed by histological evaluation. Laser-assisted indocyanine green angiography was used to confirm perfusion of the lymph node flap. An adequate perfusion was observed in the lymph node flap. The dye disseminated evenly within the lymph nodes, indicating that the flap had a well-established vascular network and an adequate blood supply. Macroscopically, perfusion of 5 to 6 lymph nodes was observed. Histological examination of tissue samples confirmed well-defined lymph nodes. After indocyanine green administration, fluorescence was observed throughout the lymph node flap and within the venous pedicle of the flap. To the best of our knowledge, this is the first report describing vascularized lymph node flap in the head and neck region of a rat. Our lymph node flap preparation technique confirmed the presence of 5 to 6 lymph nodes within the flap. The presented vascularized lymph node flap can be applied to transplantation studies, lymphedema studies, and to studies on immunological mechanism of tolerance and rejection.

  4. Glutathione Ethyl Ester Supplementation during Pancreatic Islet Isolation Improves Viability and Transplant Outcomes in a Murine Marginal Islet Mass Model

    PubMed Central

    Raposo do Amaral, Alexandre S.; Pawlick, Rena L.; Rodrigues, Erika; Costal, Flavia; Pepper, Andrew; Ferreira Galvão, Flávio H.; Correa-Giannella, Maria Lucia; Shapiro, A. M.James

    2013-01-01

    Background The success of pancreatic islet transplantation still faces many challenges, mainly related to cell damage during islet isolation and early post-transplant. The increased generation of reactive oxygen species (ROS) during islet isolation and the consumption of antioxidant defenses appear to be an important pathway related to islet damage. Methodology/Principal Findings In the present study we evaluated whether supplementation of glutathione-ethyl-ester (GEE) during islet isolation could improve islet viability and transplant outcomes in a murine marginal islet mass model. We also cultured human islets for 24 hours in standard CMRL media with or without GEE supplementation. Supplementation of GEE decreased the content of ROS in isolated islets, leading to a decrease in apoptosis and maintenance of islet viability. A higher percentage of mice transplanted with a marginal mass of GEE treated islets became euglycemic after transplant. The supplementation of 20 mM GEE in cultured human islets significantly reduced the apoptosis rate in comparison to untreated islets. Conclusions/Significance GEE supplementation was able to decrease the apoptosis rate and intracellular content of ROS in isolated islets and might be considered a potential intervention to improve islet viability during the isolation process and maintenance in culture before islet transplantation. PMID:23424628

  5. Prognostic Abilities and Quality Assessment of Models for the Prediction of 90-Day Mortality in Liver Transplant Waiting List Patients.

    PubMed

    Saldaña, Ricardo Salinas; Schrem, Harald; Barthold, Marc; Kaltenborn, Alexander

    2017-01-01

    Model of end-stage liver disease (MELD)-score and diverse variants are widely used for prognosis on liver transplant waiting-lists. 818 consecutive patients on the liver transplant waiting-list included to calculate the MELD, MESO Index, MELD-Na, UKELD, iMELD, refitMELD, refitMELD-Na, upMELD and PELD-scores. Prognostic abilities for 90-day mortality were investigated applying Receiver-operating-characteristic-curve analysis. Independent risk factors for 90-day mortality were identified with multivariable binary logistic regression modelling. Methodological quality of the underlying development studies was assessed with a systematic assessment tool. 74 patients (9%) died on the liver transplant waiting list within 90 days after listing. All but one scores, refitMELD-Na, had acceptable prognostic performance with areas under the ROC-curves (AUROCs)>0.700. The iMELD performed best (AUROC = 0.798). In pediatric cases, the PELD-score just failed to reach the acceptable threshold with an AUROC = 0.699. All scores reached a mean quality score of 72.3%. Highest quality scores could be achieved by the UKELD and PELD-scores. Studies specifically lack statistical validity and model evaluation. Inferior quality assessment of prognostic models does not necessarily imply inferior prognostic abilities. The iMELD might be a more reliable tool representing urgency of transplantation than the MELD-score. PELD-score is assumedly not accurate enough to allow graft allocation decision in pediatric liver transplantation.

  6. Fibroblasts accelerate islet revascularization and improve long-term graft survival in a mouse model of subcutaneous islet transplantation.

    PubMed

    Perez-Basterrechea, Marcos; Esteban, Manuel Martinez; Alvarez-Viejo, Maria; Fontanil, Tania; Cal, Santiago; Sanchez Pitiot, Marta; Otero, Jesus; Obaya, Alvaro Jesus

    2017-01-01

    Pancreatic islet transplantation has been considered for many years a promising therapy for beta-cell replacement in patients with type-1 diabetes despite that long-term clinical results are not as satisfactory. This fact points to the necessity of designing strategies to improve and accelerate islets engraftment, paying special attention to events assuring their revascularization. Fibroblasts constitute a cell population that collaborates on tissue homeostasis, keeping the equilibrium between production and degradation of structural components as well as maintaining the required amount of survival factors. Our group has developed a model for subcutaneous islet transplantation using a plasma-based scaffold containing fibroblasts as accessory cells that allowed achieving glycemic control in diabetic mice. Transplanted tissue engraftment is critical during the first days after transplantation, thus we have gone in depth into the graft-supporting role of fibroblasts during the first ten days after islet transplantation. All mice transplanted with islets embedded in the plasma-based scaffold reversed hyperglycemia, although long-term glycemic control was maintained only in the group transplanted with the fibroblasts-containing scaffold. By gene expression analysis and histology examination during the first days we could conclude that these differences might be explained by overexpression of genes involved in vessel development as well as in β-cell regeneration that were detected when fibroblasts were present in the graft. Furthermore, fibroblasts presence correlated with a faster graft re-vascularization, a higher insulin-positive area and a lower cell death. Therefore, this work underlines the importance of fibroblasts as accessory cells in islet transplantation, and suggests its possible use in other graft-supporting strategies.

  7. Future Economics of Liver Transplantation: A 20-Year Cost Modeling Forecast and the Prospect of Bioengineering Autologous Liver Grafts

    PubMed Central

    Habka, Dany; Mann, David; Landes, Ronald; Soto-Gutierrez, Alejandro

    2015-01-01

    During the past 20 years liver transplantation has become the definitive treatment for most severe types of liver failure and hepatocellular carcinoma, in both children and adults. In the U.S., roughly 16,000 individuals are on the liver transplant waiting list. Only 38% of them will receive a transplant due to the organ shortage. This paper explores another option: bioengineering an autologous liver graft. We developed a 20-year model projecting future demand for liver transplants, along with costs based on current technology. We compared these cost projections against projected costs to bioengineer autologous liver grafts. The model was divided into: 1) the epidemiology model forecasting the number of wait-listed patients, operated patients and postoperative patients; and 2) the treatment model forecasting costs (pre-transplant-related costs; transplant (admission)-related costs; and 10-year post-transplant-related costs) during the simulation period. The patient population was categorized using the Model for End-Stage Liver Disease score. The number of patients on the waiting list was projected to increase 23% over 20 years while the weighted average treatment costs in the pre-liver transplantation phase were forecast to increase 83% in Year 20. Projected demand for livers will increase 10% in 10 years and 23% in 20 years. Total costs of liver transplantation are forecast to increase 33% in 10 years and 81% in 20 years. By comparison, the projected cost to bioengineer autologous liver grafts is $9.7M based on current catalog prices for iPS-derived liver cells. The model projects a persistent increase in need and cost of donor livers over the next 20 years that’s constrained by a limited supply of donor livers. The number of patients who die while on the waiting list will reflect this ever-growing disparity. Currently, bioengineering autologous liver grafts is cost prohibitive. However, costs will decline rapidly with the introduction of new manufacturing

  8. Transplantation of Human Neuroblastoma Cells, Catecholaminergic and Non-Catecholaminergic: Effects on Rotational Behavoir in Parkinson's Rat Model

    PubMed Central

    Manaster, Jacob S.; Feuerman, Tony; Reynolds, C. Patrick; Markham, Charles H.

    1992-01-01

    Cultured human catecholaminergic and noncatecholaminergic donor cells were used in neural transplantation experiments in a rat model of Parkinson's disease. Using two different human catecholaminergic neuroblastoma cell lines, one control non-catecholaminergic neuroblastoma cell line, and one sham control (tissue culture medium), transplants were made into the striatum using a modified Ungerstedt hemiparkinsonian rat model. Significant decreases in apomorphine-induced rotational behavior were produced by two of three catecholaminergic cell lines. Grafted cells staining positively for tyrosine hydroxylase (TH) and catecholamine fluorescence indicated viable catecholamine activity in the two cell lines which produced reductions in rotational behavior. Catecholamine fluorescence was not detected in either of the two controls. These data suggest a link between catecholamine secretion by transplanted cells and motor improvement using a rat rotational behavior model. PMID:1355366

  9. Psychological Interventions for Irritable Bowel Syndrome and Inflammatory Bowel Diseases

    PubMed Central

    Ballou, Sarah; Keefer, Laurie

    2017-01-01

    Psychological interventions have been designed and implemented effectively in a wide range of medical conditions, including Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Diseases (IBD). The psychological treatments for IBS and IBD with the strongest evidence base include: cognitive behavioral therapy, hypnosis, and mindfulness-based therapies. The evidence for each of these therapies is reviewed here for both IBS and IBD. In general, there is a stronger and larger evidence base to support the use of psychological interventions in IBS compared with IBD. This is likely due to the high level of psychiatric comorbidity associated with IBS and the involvement of the stress-response in symptom presentation of IBS. Further research in psychosocial interventions for IBD is necessary. Finally, the importance of conceptualizing both IBS and IBD in a biopsychosocial model is discussed and several resources for accessing Clinical Health Psychology materials and referrals are provided. PMID:28102860

  10. Face transplantation in rats. Reproducibility of the experimental model in Brazil.

    PubMed

    Busnardo, Fábio de Freitas; Coltro, Pedro Soler; Olivan, Marcelo Vitoriano; Barreiro, Guilherme Cardinali; Baptista, Rachel Rossine; Ferreira, Marcus Castro; Gemperli, Rolf

    2014-08-01

    To investigate the reproducibility of the experimental model of face allotransplantation in rats in Brazil. Eighteen rats were operated, nine-nine donors recipients. Animals underwent transplantation of the left hemiface, with periorbital and scalp. Transplants were made from donor Wistar rats to recipients Lewis rats. Flaps were based on the common carotid artery and the external jugular vein of the donor animal and the anastomosis in the recipient area was performed in common carotid artery (end-to-side) and in external jugular vein (end-to-end). Of the nine recipient animals operated, six survived and three progressed to death in the first days after surgery (survival rate = 67%). The mean time of the procedure was 252 minutes and the mean time of flap ischemia was 95 minutes. The five surviving animals were sacrificed at 14 days, in good general condition and without signs of tissue rejection. The experimental model of face allotransplantation in rats is reproducible in our midst. Duration of surgery, time of flap ischemia, animal survival rate and complications observed were similar to those described in the literature.

  11. Irritable bowel syndrome; update on pathophysiology and management.

    PubMed

    Quigley, Eamonn M M; Craig, Orla F

    2012-08-01

    The description of the de novo development of irritable bowel syndrome following an episode of bacterial gastroenteritis (pos-infectious irritable bowel syndrome) illustrated the potential for a luminal factor (a bacterial pathogen) to cause this common gastrointestinal ailment. As a consequence of these and other observations, as well as results of experiments involving animal models, the enteric flora and the immune response that it generates in the host have, somewhat surprisingly, come centre-stage in irritable bowel syndrome research, given their potential to induce the pathophysiological changes that are associated with irritable bowel syndrome. While evidence for immune dysfunction both in the mucosa and systemically continues to accumulate, methodological limitations have hampered a full delineation of the nature of the microbiota in irritable bowel syndrome. The latter is eagerly awaited and may yet provide a firm rationale for the use of certain probiotics and antibiotics in irritable bowel syndrome, whose benefits have now been described with some consistency. Despite its prevalence, there is a striking lack of effective therapeutic options for irritable bowel syndrome. While there is reason for optimism in the management of irritable bowel syndrome with several promising new agents currently undergoing clinical trials, confirmation of the efficacy and safety of these agents in wider patient populations is awaited. A clearer understanding of the physiopathologic mechanisms underlying irritable bowel syndrome, as well as of interrelationships between irritable bowel syndrome and other gastrointestinal and non-gastrointestinal disorders, will likely be required before effective drug therapies can be found.

  12. Treatment With Tetrahydrobiopterin Overcomes Brain Death–Associated Injury in a Murine Model of Pancreas Transplantation

    PubMed Central

    Oberhuber, R.; Ritschl, P.; Fabritius, C.; Nguyen, A.‐V.; Hermann, M.; Obrist, P.; Werner, E. R.; Maglione, M.; Flörchinger, B.; Ebner, S.; Resch, T.; Pratschke, J.

    2015-01-01

    Brain death (BD) has been associated with an immunological priming of donor organs and is thought to exacerbate ischemia reperfusion injury (IRI). Recently, we showed that the essential nitric oxide synthase co‐factor tetrahydrobiopterin (BH4) abrogates IRI following experimental pancreas transplantation. We therefore studied the effects of BD in a murine model of syngeneic pancreas transplantation and tested the therapeutic potential of BH4 treatment. Compared with sham‐operated controls, donor BD resulted in intragraft inflammation reflected by induced IL‐1ß, IL‐6, VCAM‐1, and P‐selectin mRNA expression levels and impaired microcirculation after reperfusion (p < 0.05), whereas pretreatment of the BD donor with BH4 significantly improved microcirculation after reperfusion (p < 0.05). Moreover, BD had a devastating impact on cell viability, whereas BH4‐treated grafts showed a significantly higher percentage of viable cells (p < 0.001). Early parenchymal damage in pancreatic grafts was significantly more pronounced in organs from BD donors than from sham or non‐BD donors (p < 0.05), but BH4 pretreatment significantly ameliorated necrotic lesions in BD organs (p < 0.05). Pretreatment of the BD donor with BH4 resulted in significant recipient survival (p < 0.05). Our data provide novel insights into the impact of BD on pancreatic isografts, further demonstrating the potential of donor pretreatment strategies including BH4 for preventing BD‐associated injury after transplantation. PMID:26104062

  13. Graft survival and cytokine production profile after limbal transplantation in the experimental mouse model.

    PubMed

    Lenčová, Anna; Pokorná, Kateřina; Zajícová, Alena; Krulová, Magdaléna; Filipec, Martin; Holáň, Vladimír

    2011-04-15

    Limbal transplantation or limbal stem cell (LSC) transfer represents the only way to treat severe ocular surface damage or LSC deficiency. However, limbal allografts are promptly rejected in spite of extensive immunosuppressive therapy. To characterize immune response after limbal transplantation, we established an experimental model of limbal transplantation in the mouse. Syngeneic, allogeneic and xenogeneic (rat) limbal grafts were grafted orthotopically in BALB/c mice and graft survival was evaluated. The presence of graft donor cells and the expression of IL-2, IL-4, IL-10, IFN-γ and inducible nitric oxide synthase (iNOS) mRNA in the grafts were detected by real-time PCR. While syngeneic grafts survived permanently, allografts were rejected in 9.0±1.8 days and xenografts in 6.5±1.1 days. The manifestation of clinical symptoms of rejection correlated with the disappearance of donor cells in the graft and in the recipient cornea. Intragraft expression of iNOS mRNA and distinct expression patterns of Th1 (IL-2, IFN-γ) and Th2 (IL-4, IL-10) cytokines were detected during rejection of limbal allografts and xenografts. The limbal graft rejection was prevented with anti-CD4, but not anti-CD8 monoclonal antibody therapy. The results indicate that limbal grafts do not enjoy immune privilege of the eye and are promptly rejected by Th1 (allografts) or by a combined Th1 and Th2 (xenografts) type of immune response involving CD4+ cells and iNOS expression. Targeting this pathway may be an effective way to prevent and treat limbal graft rejection. Copyright © 2010 Elsevier B.V. All rights reserved.

  14. NOD-scid IL2rγnull (NSG) Mouse Model of Human Skin Transplantation and Allograft Rejection

    PubMed Central

    Racki, Waldemar J.; Covassin, Laurence; Brehm, Michael; Pino, Stephen; Ignotz, Ronald; Dunn, Raymond; Laning, Joseph; Graves, Susannah K.; Rossini, Aldo A.; Shultz, Leonard D.; Greiner, Dale L.

    2010-01-01

    Background Transplantation of human skin on immunodeficient mice that support engraftment with functional human immune systems would be an invaluable tool for investigating mechanisms involved in wound healing and transplantation. NOD-scid IL2rγnull (NSG) readily engraft with human immune systems but human skin graft integrity is poor. In contrast, human skin graft integrity is excellent on CB17-scid bg (SCID.bg) mice, but they engraft poorly with human immune systems. Methods Human skin grafts transplanted onto immunodeficient NSG, SCID.bg, and other immunodeficient strains were evaluated for graft integrity, preservation of graft endothelium and their ability to be rejected following engraftment of allogeneic peripheral blood mononuclear cells (PBMC). Results Human skin transplanted onto NSG mice develops an inflammatory infiltrate, consisting predominately of host Gr1+ cells, that is detrimental to the survival of human endothelium in the graft. Treatment of graft recipients with anti-Gr1 antibody reduces this cellular infiltrate, preserves graft endothelium, and promotes wound healing, tissue development and graft remodeling. Excellent graft integrity of the transplanted skin includes multilayered stratified human epidermis, well developed human vasculature, human fibroblasts and passenger leukocytes. Injection of unfractionated, CD4 or CD8 allogeneic human PBMC induces a rapid destruction of the transplanted skin graft. Conclusions NSG mice treated with anti-Gr1 antibody provide a model optimized for both human skin graft integrity and engraftment of a functional human immune system. This model provides the opportunity to investigate mechanisms orchestrating inflammation, wound healing, revascularization, tissue remodeling, and allograft rejection and can provide guidance for improving outcomes following clinical transplantation. PMID:20134397

  15. Effects of ischemic preconditioning in a pig model of large-for-size liver transplantation

    PubMed Central

    Leal, Antonio José Gonçalves; Tannuri, Ana Cristina Aoun; Belon, Alessandro Rodrigo; Guimarães, Raimundo Renato Nunes; Coelho, Maria Cecília Mendonça; de Oliveira Gonçalves, Josiane; Serafini, Suellen; de Melo, Evandro Sobroza; Tannuri, Uenis

    2015-01-01

    : Ischemia-reperfusion injury in this model of large-for-size liver transplantation could be partially attenuated by ischemic preconditioning. PMID:25789522

  16. Small Bowel Adenocarcinoma.

    PubMed

    Aparicio, Thomas; Zaanan, Aziz; Mary, Florence; Afchain, Pauline; Manfredi, Sylvain; Evans, Thomas Ronald Jeffry

    2016-09-01

    Small bowel adenocarcinomas (SBAs) are rare tumors, but their incidence is increasing. The most common primary location is the duodenum. Even though SBAs are more often sporadic, some diseases are risk factors. Early diagnosis of small bowel adenocarcinoma remains difficult, despite significant radiologic and endoscopic progress. After R0 surgical resection, the main prognostic factor is lymph node invasion. An international randomized trial (BALLAD [Benefit of Adjuvant Chemotherapy For Small Bowel Adenocarcinoma] study) will evaluate the benefit of adjuvant chemotherapy. For metastatic disease, retrospectives studies suggest that platinum-based chemotherapy is the most effective treatment. Phase II studies are ongoing to evaluate targeted therapy in metastatic SBA.

  17. Bioengineering a 3D integumentary organ system from iPS cells using an in vivo transplantation model

    PubMed Central

    Takagi, Ryoji; Ishimaru, Junko; Sugawara, Ayaka; Toyoshima, Koh-ei; Ishida, Kentaro; Ogawa, Miho; Sakakibara, Kei; Asakawa, Kyosuke; Kashiwakura, Akitoshi; Oshima, Masamitsu; Minamide, Ryohei; Sato, Akio; Yoshitake, Toshihiro; Takeda, Akira; Egusa, Hiroshi; Tsuji, Takashi

    2016-01-01

    The integumentary organ system is a complex system that plays important roles in waterproofing, cushioning, protecting deeper tissues, excreting waste, and thermoregulation. We developed a novel in vivo transplantation model designated as a clustering-dependent embryoid body transplantation method and generated a bioengineered three-dimensional (3D) integumentary organ system, including appendage organs such as hair follicles and sebaceous glands, from induced pluripotent stem cells. This bioengineered 3D integumentary organ system was fully functional following transplantation into nude mice and could be properly connected to surrounding host tissues, such as the epidermis, arrector pili muscles, and nerve fibers, without tumorigenesis. The bioengineered hair follicles in the 3D integumentary organ system also showed proper hair eruption and hair cycles, including the rearrangement of follicular stem cells and their niches. Potential applications of the 3D integumentary organ system include an in vitro assay system, an animal model alternative, and a bioengineered organ replacement therapy. PMID:27051874

  18. Bioengineering a 3D integumentary organ system from iPS cells using an in vivo transplantation model.

    PubMed

    Takagi, Ryoji; Ishimaru, Junko; Sugawara, Ayaka; Toyoshima, Koh-Ei; Ishida, Kentaro; Ogawa, Miho; Sakakibara, Kei; Asakawa, Kyosuke; Kashiwakura, Akitoshi; Oshima, Masamitsu; Minamide, Ryohei; Sato, Akio; Yoshitake, Toshihiro; Takeda, Akira; Egusa, Hiroshi; Tsuji, Takashi

    2016-04-01

    The integumentary organ system is a complex system that plays important roles in waterproofing, cushioning, protecting deeper tissues, excreting waste, and thermoregulation. We developed a novel in vivo transplantation model designated as a clustering-dependent embryoid body transplantation method and generated a bioengineered three-dimensional (3D) integumentary organ system, including appendage organs such as hair follicles and sebaceous glands, from induced pluripotent stem cells. This bioengineered 3D integumentary organ system was fully functional following transplantation into nude mice and could be properly connected to surrounding host tissues, such as the epidermis, arrector pili muscles, and nerve fibers, without tumorigenesis. The bioengineered hair follicles in the 3D integumentary organ system also showed proper hair eruption and hair cycles, including the rearrangement of follicular stem cells and their niches. Potential applications of the 3D integumentary organ system include an in vitro assay system, an animal model alternative, and a bioengineered organ replacement therapy.

  19. Small bowel and colon perforation.

    PubMed

    Brown, Carlos V R

    2014-04-01

    For patients with small bowel and colonic perforations, a definitive diagnosis of the cause of perforation is not necessary before operation. Bowel obstruction and inflammatory bowel disease are the most common causes of nontraumatic intestinal perforations in industrialized countries, whereas infectious causes of intestinal perforations are more common in developing countries. Treatment of small bowel and colonic perforations generally includes intravenous antibiotics and fluid resuscitation, but the specific management of the bowel depends on the underlying cause of the perforation.

  20. Intrathecal Transplantation of Autologous Adherent Bone Marrow Cells Induces Functional Neurological Recovery in a Canine Model of Spinal Cord Injury.

    PubMed

    Gabr, Hala; El-Kheir, Wael Abo; Farghali, Haithem A M A; Ismail, Zeinab M K; Zickri, Maha B; El Maadawi, Zeinab M; Kishk, Nirmeen A; Sabaawy, Hatem E

    2015-01-01

    Spinal cord injury (SCI) results in demyelination of surviving axons, loss of oligodendrocytes, and impairment of motor and sensory functions. We have developed a clinical strategy of cell therapy for SCI through the use of autologous bone marrow cells for transplantation to augment remyelination and enhance neurological repair. In a preclinical large mammalian model of SCI, experimental dogs were subjected to a clipping contusion of the spinal cord. Two weeks after the injury, GFP-labeled autologous minimally manipulated adherent bone marrow cells (ABMCs) were transplanted intrathecally to investigate the safety and efficacy of autologous ABMC therapy. The effects of ABMC transplantation in dogs with SCI were determined using functional neurological scoring, and the integration of ABMCs into the injured cords was determined using histopathological and immunohistochemical investigations and electron microscopic analyses of sections from control and transplanted spinal cords. Our data demonstrate the presence of GFP-labeled cells in the injured spinal cord for up to 16 weeks after transplantation in the subacute SCI stage. GFP-labeled cells homed to the site of injury and were detected around white matter tracts and surviving axons. ABMC therapy in the canine SCI model enhanced remyelination and augmented neural regeneration, resulting in improved neurological functions. Therefore, autologous ABMC therapy appears to be a safe and promising therapy for spinal cord injuries.

  1. Intraocular transplantation of human adipose-derived mesenchymal stem cells in a rabbit model of experimental retinal holes.

    PubMed

    Xuqian, W; Kanghua, L; WeiHong, Y; Xi, Y; Rongping, D; Qin, H; Fangtian, D; Chunhua Zhao, Robert

    2011-10-01

    To investigate whether human adipose-derived mesenchymal stem cell (hAD-MSC) transplantation would ameliorate the healing process of a rabbit model of retinal holes. Retinal holes were made in the left eyes of 20 New Zealand white rabbits and randomly filled by hAD-MSCs (transplantation group) or phosphate-buffered saline (control group), respectively. Frequency-domain optical coherence tomography (OCT) scan was performed on days 2, 4, 12, 20 and 32 postoperatively, and immunofluorescence was performed on days 12 and 32 to further identify the cell types of the injured area. Frequency-domain OCT scan showed that the mean center thickness of the reconstructed tissue reached a normal level on day 12 in the transplantation group, while in the control group, the mean center thickness was normal on day 32. Furthermore, compared to the control group where only anti-glial fibrillary acidic protein-labeled glial-like cells were detected, donor-derived opsin-positive photoreceptor-like cells and protein kinase C-positive bipolar-like cells were sporadically found in the transplantation group. Transplanted hAD-MSCs could engraft in the retinal hole of a rabbit model, and clearly accelerated the healing process and ameliorated injury recovery. Copyright © 2011 S. Karger AG, Basel.

  2. Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I.

    PubMed

    Azario, Isabella; Pievani, Alice; Del Priore, Federica; Antolini, Laura; Santi, Ludovica; Corsi, Alessandro; Cardinale, Lucia; Sawamoto, Kazuki; Kubaski, Francyne; Gentner, Bernhard; Bernardo, Maria Ester; Valsecchi, Maria Grazia; Riminucci, Mara; Tomatsu, Shunji; Aiuti, Alessandro; Biondi, Andrea; Serafini, Marta

    2017-08-25

    Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases.

  3. Administration of a DPP-IV Inhibitor Enhances the Intestinal Adaptation in a Mouse Model of Short Bowel Syndrome

    PubMed Central

    Okawada, Manabu; Holst, Jens J.; Teitelbaum, Daniel H.

    2011-01-01

    Background Glucagon-like peptide-2(GLP-2) induces small intestine mucosal epithelial cell (EC) proliferation; and may have benefit for patients suffering from short bowel syndrome (SBS). However, GLP-2 is rapidly inactivated in vivo by dipeptidyl peptidase IV (DPPIV). Therefore, we hypothesized that selectively inhibiting DPPIV would prolong the circulating life of GLP-2 and lead to increased intestinal adaptation after development of SBS. Methods 8-week old C57BL/6J mice underwent a 50% proximal small bowel resection and were treated with either sitagliptin, a DPPIV-inhibitor (DPPIV-I), starting 1 day before surgery versus placebo. DPPIV-I efficacy was assessed 3 days after resection, including intestinal morphology, EC apoptosis and EC proliferation. Adaptive mechanisms were assessed with quantitative real-time PCR, and plasma bioactive GLP-2 was measured by radioimmunoassay. RESULT Body weight loss and peripheral blood glucose levels did not change compared to SBS controls. DPPIV-I treatment led to significant increases in villus height and crypt depth. DPPIV-I treatment did not significantly change EC apoptosis rates, but significantly increased crypt EC proliferation versus placebo-SBS controls. DPPIV-I treatment markedly increased mRNA expression of β-catenin and c-myc in ileal mucosa. Plasma GLP-2 levels significantly increased(~40.9%) in DPPIV-I-SBS mice. Conclusions DPPIV- I treatment increased SBS adaptation, and may potentially be useful for SBS patients. PMID:21719060

  4. Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease.

    PubMed

    Hale, Laura P; Greer, Paula K; Trinh, Chau T; Gottfried, Marcia R

    2005-08-01

    Bromelain is a mixture of proteinases derived from pineapple stem that is marketed in health food stores as a "digestive aid". Orally administered bromelain was anecdotally reported to induce clinical and endoscopic remission of ulcerative colitis in two patients whose disease was refractory to multi-agent conventional medical therapy. However, the potential efficacy of bromelain in colitis has not yet been tested rigorously in either animals or humans. In this study, the clinical and histologic severity of inflammatory bowel disease (IBD) was determined in IL-10-/- mice treated orally with bromelain in vivo. Daily treatment with oral bromelain beginning at age 5 weeks decreased the incidence and severity of spontaneous colitis in C57BL/6 IL-10-/- mice. Bromelain also significantly decreased the clinical and histologic severity of colonic inflammation when administered to piroxicam-exposed IL-10-/- mice with established colitis. Proteolytically active bromelain was required for anti-inflammatory effects in vivo. Adverse effects of dermatitis, hair loss, and weight loss due to mucositis were rare, dose related, and were not seen in wild-type mice treated orally with up to 1000 mg bromelain/kg/day for 18 weeks. Although the exact mechanisms by which exogenous proteinases affect bowel inflammation have not yet been determined, the results justify additional studies of this complementary biologically based approach to treatment of IBD.

  5. A Prognostic Model Predicting Autologous Transplantation Outcomes in Children, Adolescents and Young Adults with Hodgkin Lymphoma

    PubMed Central

    Satwani, Prakash; Ahn, Kwang Woo; Carreras, Jeanette; Abdel-Azim, Hisham; Cairo, Mitchell S.; Cashen, Amanda; Chen, Andy I.; Cohen, Jonathon B.; Costa, Luciano J.; Dandoy, Christopher; Fenske, Timothy S.; Freytes, César O.; Ganguly, Siddhartha; Gale, Robert Peter; Ghosh, Nilanjan; Hertzberg, Mark S.; Hayashi, Robert J.; Kamble, Rummurti T.; Kanate, Abraham S.; Keating, Armand; Kharfan-Dabaja, Mohamed A.; Lazarus, Hillard M.; Marks, David I.; Nishihori, Taiga; Olsson, Richard F.; Prestidge, Tim D.; Rolon, Juliana Martinez; Savani, Bipin N.; Vose, Julie M.; Wood, William A.; Inwards, David J.; Bachanova, Veronika; Smith, Sonali M.; Maloney, David G.; Sureda, Anna; Hamadani, Mehdi

    2015-01-01

    Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pre-transplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995–2010. The probabilities of progression free survival (PFS) at 1, 5 and 10 years were 66% (95% CI: 62–70), 52% (95% CI: 48–57) and 47% (95% CI: 42–51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ≥90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low, intermediate and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64–80), 53% (95% CI: 47–59) and 23% (95% CI: 9–36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk for progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT. PMID:26237164

  6. Induction of psoriasiform inflammation by a bacterial superantigen in the SCID-hu xenogeneic transplantation model.

    PubMed

    Boehncke, W H; Zollner, T M; Dressel, D; Kaufmann, R

    1997-01-01

    Psoriasis is a chronic skin disease affecting about 2% of the Caucasian population, characterized by co-existing inflammation and epidermal hyperproliferation. A T-lymphocyte-mediated autoimmune reaction induced by bacterial superantigens might be central in its pathogenesis. To model psoriasiform inflammation, we transplanted clinically uninvolved skin from psoriatic patients onto SCID mice. Repetitive intradermal injections with a bacterial superantigen and simultaneous intraperitoneal injections with the patients superantigen-stimulated peripheral mononuclear blood cells resulted in an inflammatory reaction exhibiting some of the hallmarks of psoriasis, e.g. epidermal hyperproliferation, papillomatosis, focal neo-expression of ICAMI, and an exocytotic T-lymphocytic infiltrate characterized by the expression of the cutaneous lymphocyte-associated antigen. These observations document the potential of superantigens to trigger psoriasiform dermatitis and provide a model to study lymphocyte homing.

  7. Multistate Models on Pleural Effusion after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Lee, Joohyoung; Modi, Dipenkumar; Jang, Hyejeong; Uberti, Joseph P.

    2017-01-01

    A multistate model is more complicated than competing risk models and composed of finite number of states and transitions between states. Unlike competing risk models, this model has the ability to assess the effect of occurrence order of time-to-event data. Pleural effusion (PE) is a severe complication that often occurs after allogeneic hematopoietic stem cell transplantation (HSCT). Many patients develop pleural effusion during the first 100 days after allogeneic HSCT and graft-versus-host disease (GVHD) occurs either before or after the development of PE, implying that the occurrence order of PE and GVHD (i.e., PE after GVHD vs. GVHD after PE) would influence on the incidence, risk factors and mortality of pleural effusion. One can use either Cox proportional models or competing risk models to evaluate these values, but neither method is able to incorporate the occurrence order of incidence into the model. To resolve this difficulty, we developed a multistate model describing several possible events and event-related dependences and applied to a retrospective study of 606 patients, including eight covariates. PMID:28428936

  8. An Extraperitoneal Technique for Murine Heterotopic Cardiac Transplantation.

    PubMed

    Nowocin, A K; Brown, K; Edwards, L A; Meader, L; Hill, J I; Wong, W

    2015-09-01

    The mouse heterotopic cardiac transplantation model has been used extensively by investigators in the field of organ transplantation to study the rejection process, test new antirejection treatments, tolerance induction protocols or to understand basic immunological principles. Due to its extensive use, any small refinement of the technique would have a major impact on replacement, reduction and refinement (commonly known as the 3Rs). Here, we describe a novel approach to refine this model. The donor aorta and pulmonary artery are anastomosed peripherally to the femoral artery and vein of the recipient, respectively. The technical success rate is comparable to the conventional abdominal site, but it avoids a laparotomy and handling of the bowels making it less invasive method. As a result, recipients recover faster and require less postoperative analgesia. It is a major refinement under one of the 3Rs and would represent an advance in animal welfare in scientific research. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  9. Transplantation of epidermal cell sheets by endoscopic balloon dilatation to avoid esophageal re-strictures: initial experience in a porcine model

    PubMed Central

    Kobayashi, Shinichiro; Kanai, Nobuo; Tanaka, Nobuyuki; Maeda, Masanori; Hosoi, Takahiro; Fukai, Fumio; Eguchi, Susumu; Yamato, Masayuki

    2016-01-01

    Background and study aims: Epidermal cell sheet (ECS) transplantation immediately after aggressive endoscopic submucosal dissection (ESD) has been shown to be safe and effective in the prevention of esophageal strictures. This study evaluated the feasibility of ECS transplantation after endoscopic balloon dilation (EBD) in a porcine model. Methods: Six pigs underwent circumferential esophageal ESD under general anesthesia. Two weeks later, two pigs underwent EBD and transplantation of an autologous ECS, two underwent EBD alone, and two underwent endoscopic observation only (control). Results: The two pigs in the transplantation group underwent six ECS transplants after EBD with five of the six (83 %) being successful, as shown by engraftment of transplanted ECSs after 7 days. No adverse events were observed. Stricture rates were lower in the two transplanted pigs (55 % and 60 %) than in the control (92.2 % and 87.7 %) and EBD-treated (71.7 % and 78.2 %) pigs. Infiltration of inflammatory cells was significantly lower in the transplanted pigs than in the control and EBD-treated pigs. Conclusion: Preliminary results indicate the stability of the ECS transplantation procedure and the engraftment of transplanted ECS in the tears after EBD. This proof-of-concept study suggests that covering tears with ECSs after EBD may avoid re-strictures. PMID:27853736

  10. Kidney Transplant

    MedlinePlus

    Kidney transplant Overview By Mayo Clinic Staff A kidney transplant is a surgical procedure to place a healthy kidney ... bloodstream via a machine (dialysis) or a kidney transplant to stay alive. Mayo Clinic's approach . Mayo Clinic ...

  11. Lung Transplant

    MedlinePlus

    Lung transplant Overview By Mayo Clinic Staff A lung transplant is a surgical procedure to replace a diseased or ... lung, usually from a deceased donor. A lung transplant is reserved for people who have tried other ...

  12. Kidney transplant

    MedlinePlus

    Renal transplant; Transplant - kidney ... Barry JM, Conlin MJ. In: Renal transplantation. Wein AJ, ed. Campbell-Walsh Urology . 10th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 44. Kidney Disease: Improving Global Outcomes ( ...

  13. Inflammatory bowel disease - slideshow

    MedlinePlus

    ... presentations/100171.htm Inflammatory bowel disease - series—Normal anatomy To ... gastrointestinal tract starts at the mouth, which leads to the esophagus, stomach, small intestine, colon, and finally, the rectum and ...

  14. Accidental Bowel Leakage

    MedlinePlus

    Member Login Join Pay Dues Follow us: Women's Health Care Physicians Contact Us My ACOG ACOG Departments Donate ... underwear or pads Diarrhea Constipation How will my health care provider diagnose the cause of my accidental bowel ...

  15. Large bowel resection - discharge

    MedlinePlus

    ... 26. Read More Colon cancer Colostomy Crohn disease Intestinal obstruction Large bowel resection Ulcerative colitis Patient Instructions Bland ... Diseases Colonic Polyps Colorectal Cancer Diverticulosis and Diverticulitis Intestinal Obstruction Ulcerative Colitis Browse the Encyclopedia A.D.A. ...

  16. Small bowel resection - discharge

    MedlinePlus

    ... chap 26. Read More Colon cancer Crohn disease Intestinal obstruction Small bowel resection Patient Instructions Bland diet Crohn ... Editorial team. Related MedlinePlus Health Topics Intestinal Cancer Intestinal Obstruction Small Intestine Disorders Browse the Encyclopedia A.D. ...

  17. Short bowel syndrome

    MedlinePlus

    Small intestine insufficiency; Short gut syndrome; Necrotizing enterocolitis - short bowel ... The small intestine absorbs much of the nutrients found in foods we eat. When one half or more of our small ...

  18. Small bowel resection

    MedlinePlus

    Small intestine surgery; Bowel resection - small intestine; Resection of part of the small intestine; Enterectomy ... her hand inside your belly to feel the intestine or remove the diseased segment. Your belly is ...

  19. Daily bowel care program

    MedlinePlus

    ... a brain or spinal cord injury. People with multiple sclerosis also have problems with their bowels. Those with ... PA: Elsevier Saunders; 2016:chap 18. Read More Multiple sclerosis Recovering after stroke Patient Instructions Constipation - self-care ...

  20. Irritable Bowel Syndrome

    MedlinePlus

    ... cause inflammation that can alter function of the gastrointestinal system. Stress can also play a part in IBS. ... Disease (GERD) Lactose Intolerance Inflammatory Bowel Disease Ulcers Digestive System Eating Well While Eating Out Constipation Celiac Disease ...

  1. Hearing restoration in a deaf animal model with intravenous transplantation of mesenchymal stem cells derived from human umbilical cord blood.

    PubMed

    Choi, Mi Young; Yeo, Sang Won; Park, Kyoung Ho

    2012-10-26

    This study was performed to confirm the effect of transplantation of human umbilical cord blood mesenchymal stem cells (UCB-MSCs) on hearing restoration in a sensorineural hearing loss (SNHL) animal model. UCB was collected from pregnant women after obtaining consent, and mesenchymal stem cells (MSCs) were extracted. We established an SNHL model and transplanted UCB-MSCs through the brachial vein of the guinea pigs. The animals were divided into 4 groups: animals with normal hearing, animals with SNHL, animals with SNHL and injected with saline, and animals with SNHL and transplanted with UCB-MSCs. Hearing tests were conducted at 1, 3, and 5 weeks, and the results were compared by grading auditory brainstem response (ABR) recordings and distortion product otoacoustic emissions (DPOAEs) for each treatment. Lastly, cochlear pathological features were examined, and surface preparations and morphological changes in each animal model were compared using hematoxylin and eosin staining and light microscopy studies. In SNHL group, decreased DPOAEs and increased ABR threshold were noted. Furthermore, in the SNHL group, ABR hearing thresholds were unconverted and were similar to those observed in deafness. The transplanted UCB-MSC group showed a significant improvement in hearing threshold (40 dB) compared to that in all the SNHL group (80-90 dB). Examination of the SNHL animals' cochlear morphological features demonstrated a noticeable lack of spiral ganglion cells and also showed degenerated outer hair cells. However, the transplanted UCB-MSCs showed an increase in spiral ganglion and hair cells. Intravenous transplantation of UCB-MSCs can enhance hearing thresholds, outer-hair cells and increase the number of spiral ganglion neurons (SGNs). Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Prediction at First Year of Incident New-Onset Diabetes After Kidney Transplantation by Risk Prediction Models

    PubMed Central

    Rodrigo, Emilio; Santos, Lidia; Piñera, Celestino; Ruiz San Millán, Juan Carlos; Quintela, Maria Estrella; Toyos, Carmen; Allende, Natalia; Gómez-Alamillo, Carlos; Arias, Manuel

    2012-01-01

    OBJECTIVE Our aim was to analyze the performance of two scores developed for predicting diabetes in nontransplant populations for identifying kidney transplant recipients with a higher new-onset diabetes mellitus after transplantation (NODAT) risk beyond the first year after transplantation. RESEARCH DESIGN AND METHODS We analyzed 191 kidney transplants, which had at least 1-year follow-up posttransplant. First-year posttransplant variables were collected to estimate the San Antonio Diabetes Prediction Model (SADPM) and Framingham Offspring Study–Diabetes Mellitus (FOS-DM) algorithm. RESULTS Areas under the receiver operating characteristic curve of FOS-DM and SADPM scores to predict NODAT were 0.756 and 0.807 (P < 0.001), respectively. FOS-DM and SADPM scores over 75 percentile (hazard ratio 5.074 and 8.179, respectively, P < 0.001) were associated with NODAT. CONCLUSIONS Both scores can be used to identify kidney recipients at higher risk for NODAT beyond the first year. SADPM score detects some 25% of kidney transplant patients with an eightfold risk for NODAT. PMID:22279030

  3. Optimization of Cultured Human Corneal Endothelial Cell Sheet Transplantation and Post-Operative Sheet Evaluation in a Rabbit Model.

    PubMed

    Yamaguchi, Masahiro; Shima, Nobuyuki; Kimoto, Miwa; Ebihara, Nobuyuki; Murakami, Akira; Yamagami, Satoru

    2016-09-01

    To optimize cultured human corneal endothelial cell (cHCEC) sheet transplantation technique for maintenance of cHCEC viability. cHCEC sheets cultured on a collagen scaffold were covered with or without Viscoat® and exposed to humidified air in the incubator. cHCEC sheets with or without Viscoat® were transplanted into cadaveric porcine eyes by the DSAEK technique with full air tamponade and incubated for various time periods. Then cell viability was determined by using the live/dead assay kit. cHCEC sheets with Viscoat® were transplanted into rabbit eyes and the sheets were histologically evaluated before and 14 days after transplantation. A collagen scaffold and Viscoat® were effective for protecting cHCEC from damage due to air exposure in vitro. All cells died after 18 hours of air exposure in porcine eyes in Viscoat® untreated control. In contrast, Viscoat® treatment sustained full cell viability following 2 hours and could maintain approximately 80% viability after 18 hours. In a rabbit model, transplanted cHCEC sheet with Viscoat® maintained cell density at 2803 ± 229 mm(2) (18% cell loss) and expression of N-cadherin, zonula occludens-1, and actin-filament localized to cell boundary as similar as donor HCEC. Viscoat® can contribute to cHCEC protection from damage caused by exposure to air.

  4. Use of a novel docosahexaenoic acid formulation vs control in a neonatal porcine model of short bowel syndrome leads to greater intestinal absorption and higher systemic levels of DHA

    USDA-ARS?s Scientific Manuscript database

    Infants with short bowel syndrome (SBS) are at high risk for malabsorption, malnutrition, and failure to thrive. The objective of this study was to evaluate in a porcine model of SBS, the systemic absorption of a novel enteral Docosahexaenoic acid (DHA) formulation that forms micelles independent of...

  5. Short Bowel Syndrome and Intestinal Failure in Crohn's Disease.

    PubMed

    Limketkai, Berkeley N; Parian, Alyssa M; Shah, Neha D; Colombel, Jean-Frédéric

    2016-05-01

    Crohn's disease is a chronic and progressive inflammatory disorder of the gastrointestinal tract. Despite the availability of powerful immunosuppressants, many patients with Crohn's disease still require one or more intestinal resections throughout the course of their disease. Multiple resections and a progressive reduction in bowel length can lead to the development of short bowel syndrome, a form of intestinal failure that compromises fluid, electrolyte, and nutrient absorption. The pathophysiology of short bowel syndrome involves a reduction in intestinal surface area, alteration in the enteric hormonal feedback, dysmotility, and related comorbidities. Most patients will initially require parenteral nutrition as a primary or supplemental source of nutrition, although several patients may eventually wean off nutrition support depending on the residual gut anatomy and adherence to medical and nutritional interventions. Available surgical treatments focus on reducing motility, lengthening the native small bowel, or small bowel transplantation. Care of these complex patients with short bowel syndrome requires a multidisciplinary approach of physicians, dietitians, and nurses to provide optimal intestinal rehabilitation, nutritional support, and improvement in quality of life.

  6. Uterus transplantation: From animal models through the first heart beating pregnancy to the first human live birth.

    PubMed

    Ozkan, Omer; Dogan, Nasuh Utku; Ozkan, Ozlenen; Mendilcioglu, Inanc; Dogan, Selen; Aydinuraz, Batu; Simsek, Mehmet

    2016-07-01

    Absolute uterine factor infertility affects 3-5% of the general population, and unfortunately this condition is untreatable. There are some available options, including surrogacy or adoption, but neither of these suits each and every woman who desires to have her own genetic child. With recent advances in surgery and transplant immunology, uterus transplantation may be a source of hope for these women with uterine infertility. In the last decade, a number of animal species including rats, mice, rabbits, pigs, sheep, and primates have been used as experimental models, and pregnancies were achieved in some of these. Human data consist of 11 subjects yielding positive pregnancy results with no live births in the second trial from Turkey and, more fortunately, live births from the latest trial from Sweden. In the light of all these studies, uterus transplantation has been proven to be a viable option for women with uterine factor infertility.

  7. Transplantation of Adult Monkey Neural Stem Cells into A Contusion Spinal Cord Injury Model in Rhesus Macaque Monkeys

    PubMed Central

    Hajinasrollah, Mostafa; Zare Mehrjerdi, Nargess; Azizi, Hossein; Hemmesi, Katayoun; Moghiminasr, Reza; Azhdari, Zahra; Talebi, Ardeshir; Mohitmafi, Soroush; Vosough Taqi Dizaj, Ahmad; Sharifi, Giuve; Baharvand, Hossein; Rezaee, Omidvar; Kiani, Sahar

    2014-01-01

    Objective Currently, cellular transplantation for spinal cord injuries (SCI) is the subject of numerous preclinical studies. Among the many cell types in the adult brain, there is a unique subpopulation of neural stem cells (NSC) that can self-renew and differentiate into neurons. The study aims, therefore, to explore the efficacy of adult monkey NSC (mNSC) in a primate SCI model. Materials and Methods In this experimental study, isolated mNSCs were analyzed by flow cytometry, immunocytochemistry, and RT-PCR. Next, BrdU-labeled cells were transplanted into a SCI model. The SCI animal model was confirmed by magnetic resonance imaging (MRI) and histological analysis. Animals were clinically observed for 6 months. Results Analysis confirmed homing of mNSCs into the injury site. Transplanted cells expressed neuronal markers (TubIII). Hind limb performance improved in trans- planted animals based on Tarlov’s scale and our established behavioral tests for monkeys. Conclusion Our findings have indicated that mNSCs can facilitate recovery in contusion SCI models in rhesus macaque monkeys. Additional studies are necessary to determine the im- provement mechanisms after cell transplantation. PMID:24567941

  8. A synthesis of transplant experiments and ecological niche models suggests that range limits are often niche limits.

    PubMed

    Lee-Yaw, Julie A; Kharouba, Heather M; Bontrager, Megan; Mahony, Colin; Csergő, Anna Mária; Noreen, Annika M E; Li, Qin; Schuster, Richard; Angert, Amy L

    2016-06-01

    Global change has made it important to understand the factors that shape species' distributions. Central to this area of research is the question of whether species' range limits primarily reflect the distribution of suitable habitat (i.e. niche limits) or arise as a result of dispersal limitation. Over-the-edge transplant experiments and ecological niche models are commonly used to address this question, yet few studies have taken advantage of a combined approach for inferring the causes of range limits. Here, we synthesise results from existing transplant experiments with new information on the predicted suitability of sites based on niche models. We found that individual performance and habitat suitability independently decline beyond range limits across multiple species. Furthermore, inferences from transplant experiments and niche models were generally concordant within species, with 31 out of 40 cases fully supporting the hypothesis that range limits are niche limits. These results suggest that range limits are often niche limits and that the factors constraining species' ranges operate at scales detectable by both transplant experiments and niche models. In light of these findings, we outline an integrative framework for addressing the causes of range limits in individual species.

  9. Diaphragmatic Hernia After Pediatric Liver Transplant.

    PubMed

    Kirnap, Mahir; Akdur, Aydincan; Ozcay, Figen; Soy, Ebru; Coskun, Mehmet; Moray, Gokhan; Haberal, Mehmet

    2015-10-01

    Diaphragmatic hernia is an unusual complication after pediatric liver transplant. Nearly half of bowel obstruction cases, which require surgical intervention in liver transplant patients, are caused by diaphragmatic hernia. The smaller patients are at risk for higher rates of diaphragmatic complication after pediatric liver transplant, but diaphragmatic hernia has not been reported as a unique occurrence. Here, we report 3 cases of diaphragmatic hernia after liver transplant and discuss the possible contributing factors. Diaphragmatic hernia should nevertheless be added to the list of potential complications after liver transplant in the pediatric population. Pediatric transplant physicians and surgeons should be aware of this complication so that it is recognized promptly in both acute and nonacute settings and appropriate action is taken.

  10. Effectiveness of pure argon for renal transplant preservation in a preclinical pig model of heterotopic autotransplantation.

    PubMed

    Faure, Alice; Bruzzese, Laurie; Steinberg, Jean-Guillaume; Jammes, Yves; Torrents, Julia; Berdah, Stephane V; Garnier, Emmanuelle; Legris, Tristan; Loundou, Anderson; Chalopin, Matthieu; Magalon, Guy; Guieu, Regis; Fenouillet, Emmanuel; Lechevallier, Eric

    2016-02-04

    In kidney transplantation, the conditions of organ preservation following removal influence function recovery. Current static preservation procedures are generally based on immersion in a cold-storage solution used under atmospheric air (approximately 78 kPa N2, 21 kPa O2, 1 kPa Ar). Research on static cold-preservation solutions has stalled, and modifying the gas composition of the storage medium for improving preservation was considered. Organoprotective strategies successfully used noble gases and we addressed here the effects of argon and xenon on graft preservation in an established preclinical pig model of autotransplantation. The preservation solution Celsior saturated with pure argon (Argon-Celsior) or xenon (Xenon-Celsior) at atmospheric pressure was tested versus Celsior saturated with atmospheric air (Air-Celsior). The left kidney was removed, and Air-Celsior (n = 8 pigs), Argon-Celsior (n = 8) or Xenon-Celsior (n = 6) was used at 4 °C to flush and store the transplant for 30 h, a duration that induced ischemic injury in our model when Air-Celsior was used. Heterotopic autotransplantation and contralateral nephrectomy were performed. Animals were followed for 21 days. The use of Argon-Celsior vs. Air-Celsior: (1) improved function recovery as monitored via creatinine clearance, the fraction of excreted sodium and tubulopathy duration; (2) enabled diuresis recovery 2-3 days earlier; (3) improved survival (7/8 vs. 3/8 pigs survived at postoperative day-21); (4) decreased tubular necrosis, interstitial fibrosis, apoptosis and inflammation, and preserved tissue structures as observed after the natural death/euthanasia; (5) stimulated plasma antioxidant defences during the days following transplantation as shown by monitoring the "reduced ascorbic acid/thiobarbituric acid reactive substances" ratio and Hsp27 expression; (6) limited the inflammatory response as shown by expression of TNF-alpha, IL1-beta and IL6 as observed after the natural death

  11. Human cytomegalovirus infection leads to elevated levels of transplant arteriosclerosis in a humanized mouse aortic xenograft model.

    PubMed

    Abele-Ohl, S; Leis, M; Wollin, M; Mahmoudian, S; Hoffmann, J; Müller, R; Heim, C; Spriewald, B M; Weyand, M; Stamminger, T; Ensminger, S M

    2012-07-01

    Recent findings emphasized an important role of human cytomegalovirus (HCMV) infection in the development of transplant arteriosclerosis. Therefore, the aim of this study was to develop a human peripheral blood lymphocyte (hu-PBL)/Rag-2(-/-) γc(-/-) mouse-xenograft-model to investigate both immunological as well as viral effector mechanisms in the progression of transplant arteriosclerosis. For this, sidebranches from the internal mammary artery were recovered during coronary artery bypass graft surgery, tissue-typed and infected with HCMV. Then, size-matched sidebranches were implanted into the infrarenal aorta of Rag-2(-/-) γc(-/-) mice. The animals were reconstituted with human peripheral blood mononuclear cells (PBMCs) 7 days after transplantation. HCMV-infection was confirmed by Taqman-PCR and immunofluorescence analyses. Arterial grafts were analyzed by histology on day 40 after transplantation. PBMC-reconstituted Rag-2(-/-) γc(-/-) animals showed splenic chimerism levels ranging from 1-16% human cells. After reconstitution, Rag-2(-/-) γc(-/-) mice developed human leukocyte infiltrates in their grafts and vascular lesions that were significantly elevated after infection. Cellular infiltration revealed significantly increased ICAM-1 and PDGF-R-β expression after HCMV-infection of the graft. Arterial grafts from unreconstituted Rag-2(-/-) γc(-/-) recipients showed no vascular lesions. These data demonstrate a causative relationship between HCMV-infection as an isolated risk factor and the development of transplant-arteriosclerosis in a humanized mouse arterial-transplant-model possibly by elevated ICAM-1 and PDGF-R-β expression.

  12. Cell Sheet Transplantation for Esophageal Stricture Prevention after Endoscopic Submucosal Dissection in a Porcine Model

    PubMed Central

    Pidial, Laetitia; Camilleri, Sophie; Bellucci, Alexandre; Casanova, Amaury; Viel, Thomas; Tavitian, Bertrand; Cellier, Christophe; Clement, Olivier

    2016-01-01

    Background & Aims Extended esophageal endoscopic submucosal dissection (ESD) is highly responsible for esophageal stricture. We conducted a comparative study in a porcine model to evaluate the effectiveness of adipose tissue-derived stromal cell (ADSC) double cell sheet transplantation. Methods Twelve female pigs were treated with 5 cm long hemi-circumferential ESD and randomized in two groups. ADSC group (n = 6) received 4 double cell sheets of allogenic ADSC on a paper support membrane and control group (n = 6) received 4 paper support membranes. ADSC were labelled with PKH-67 fluorophore to allow probe-based confocal laser endomicroscopie (pCLE) monitoring. After 28 days follow-up, animals were sacrificed. At days 3, 14 and 28, endoscopic evaluation with pCLE and esophagography were performed. Results One animal from the control group was excluded (anesthetic complication). Animals from ADSC group showed less frequent alimentary trouble (17% vs 80%; P = 0.08) and higher gain weight on day 28. pCLE demonstrated a compatible cell signal in 4 animals of the ADSC group at day 3. In ADSC group, endoscopy showed that 1 out of 6(17%) animals developed a severe esophageal stricture comparatively to 100% (5/5) in the control group; P = 0.015. Esophagography demonstrated a decreased degree of stricture in the ADSC group on day 14 (44% vs 81%; P = 0.017) and day 28 (46% vs 90%; P = 0.035). Histological analysis showed a decreased fibrosis development in the ADSC group, in terms of surface (9.7 vs 26.1 mm²; P = 0.017) and maximal depth (1.6 vs 3.2 mm; P = 0.052). Conclusion In this model, transplantation of allogenic ADSC organized in double cell sheets after extended esophegeal ESD is strongly associated with a lower esophageal stricture’s rate. PMID:26930409

  13. A novel model for studies of blood-mediated long-term responses to cellular transplants

    PubMed Central

    Lindblom, Susanne; Hong, Jaan; Nilsson, Bo; Korsgren, Olle; Ronquist, Gunnar

    2015-01-01

    Aims Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h. Methods Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability. Results Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen. Conclusion A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions. PMID:25322825

  14. Development of a Colon Cancer GEMM-Derived Orthotopic Transplant Model for Drug Discovery and Validation

    PubMed Central

    Martin, Eric S.; Belmont, Peter J.; Sinnamon, Mark J.; Richard, Larissa Georgeon; Yuan, Jing; Coffee, Erin M.; Roper, Jatin; Lee, Lydia; Heidari, Pedram; Lunt, Sophia Y.; Goel, Gautam; Ji, Christy; Xie, Julie; Xie, Tao; Lamb, John; Weinrich, Scott; VanArsdale, Todd; Bronson, Roderick T.; Xavier, Ramnik J.; Vander Heiden, Matthew G.; Kan, Julie L. C.; Mahmood, Umar; Hung, Kenneth E.

    2014-01-01

    Purpose Effective therapies for KRAS mutant colorectal cancer (CRC) are a critical unmet clinical need. Previously, we described GEMMs for sporadic Kras mutant and non-mutant CRC suitable for preclinical evaluation of experimental therapeutics. To accelerate drug discovery and validation, we sought to derive low-passage cell lines from GEMM Kras mutant and wild-type tumors for in vitro screening and transplantation into the native colonic environment of immunocompetent mice for in vivo validation. Experimental Design Cell lines were derived from Kras mutant and non-mutant GEMM tumors under defined media conditions. Growth kinetics, phosphoproteomes, transcriptomes, drug sensitivity, and metabolism were examined. Cell lines were implanted in mice and monitored for in vivo tumor analysis. Results Kras mutant cell lines displayed increased proliferation, MAPK signaling, and PI3K signaling. Microarray analysis identified significant overlap with human CRC-related gene signatures, including KRAS mutant and metastatic CRC. Further analyses revealed enrichment for numerous disease-relevant biological pathways, including glucose metabolism. Functional assessment in vitro and in vivo validated this finding and highlighted the dependence of Kras mutant CRC on oncogenic signaling and on aerobic glycolysis. Conclusions We have successfully characterized a novel GEMM-derived orthotopic transplant model of human KRAS mutant CRC. This approach combines in vitro screening capability using low-passage cell lines that recapitulate human CRC and potential for rapid in vivo validation using cell line-derived tumors that develop in the colonic microenvironment of immunocompetent animals. Taken together, this platform is a clear advancement in preclinical CRC models for comprehensive drug discovery and validation efforts. PMID:23403635

  15. Cell Sheet Transplantation for Esophageal Stricture Prevention after Endoscopic Submucosal Dissection in a Porcine Model.

    PubMed

    Perrod, Guillaume; Rahmi, Gabriel; Pidial, Laetitia; Camilleri, Sophie; Bellucci, Alexandre; Casanova, Amaury; Viel, Thomas; Tavitian, Bertrand; Cellier, Christophe; Clement, Olivier

    2016-01-01

    Extended esophageal endoscopic submucosal dissection (ESD) is highly responsible for esophageal stricture. We conducted a comparative study in a porcine model to evaluate the effectiveness of adipose tissue-derived stromal cell (ADSC) double cell sheet transplantation. Twelve female pigs were treated with 5 cm long hemi-circumferential ESD and randomized in two groups. ADSC group (n = 6) received 4 double cell sheets of allogenic ADSC on a paper support membrane and control group (n = 6) received 4 paper support membranes. ADSC were labelled with PKH-67 fluorophore to allow probe-based confocal laser endomicroscopie (pCLE) monitoring. After 28 days follow-up, animals were sacrificed. At days 3, 14 and 28, endoscopic evaluation with pCLE and esophagography were performed. One animal from the control group was excluded (anesthetic complication). Animals from ADSC group showed less frequent alimentary trouble (17% vs 80%; P = 0.08) and higher gain weight on day 28. pCLE demonstrated a compatible cell signal in 4 animals of the ADSC group at day 3. In ADSC group, endoscopy showed that 1 out of 6 (17%) animals developed a severe esophageal stricture comparatively to 100% (5/5) in the control group; P = 0.015. Esophagography demonstrated a decreased degree of stricture in the ADSC group on day 14 (44% vs 81%; P = 0.017) and day 28 (46% vs 90%; P = 0.035). Histological analysis showed a decreased fibrosis development in the ADSC group, in terms of surface (9.7 vs 26.1 mm²; P = 0.017) and maximal depth (1.6 vs 3.2 mm; P = 0.052). In this model, transplantation of allogenic ADSC organized in double cell sheets after extended esophegeal ESD is strongly associated with a lower esophageal stricture's rate.

  16. Bone marrow transplantation reverses new-onset immunoinflammatory diabetes in a mouse model.

    PubMed

    Lv, Cheng-Lan; Wang, Jing; Xie, Ting; Ouyang, Jian

    2014-01-01

    Bone marrow transplantation might be an effective method to cure type 1 diabetes mellitus. This study aimed to investigate whether bone marrow transplantation could reverse hyperglycemia in diabetic mice and whether high-dose total body irradiation followed by high-dose bone marrow mononuclear cell infusion could improve the efficiency of bone marrow transplantation in treating diabetic mice. Diabetic mice after multiple low doses of streptozotocin injection were irradiated followed by infusion with approximately 1×10(7) bone marrow mononuclear cells intravenously. Before and after bone marrow transplantation, fasting blood glucose, intraperitoneal glucose tolerance test, serum insulin, pancreatic histology, and the examination of insulin and glucagon in islets were processed. All recipients returned to near euglycemic within 1 week after undergoing bone marrow transplantation. No mice became hyperglycemia again during investigation period. The change of serum insulin, glucose tolerance test, pancreatic histology and the expression of insulin and glucagon in recipient islets after bone marrow transplantation all revealed islets regeneration and significant amelioration when compared respectively with those of diabetic mice without bone marrow transplantation. Bone marrow transplantation contributed to reduce blood glucose, prevent further blood glucose hike in diabetic recipients, and promote islets regeneration. High-dose total body irradiation in combination with high-dose bone marrow monoclear cell infusion could improve the efficiency of bone marrow transplantation in treating streptozotocin-induced diabetes.

  17. Budget-impact model for colonoscopy cost calculation and comparison between 2 litre PEG+ASC and sodium picosulphate with magnesium citrate or sodium phosphate oral bowel cleansing agents.

    PubMed

    Gruss, H-J; Cockett, A; Leicester, R J

    2012-01-01

    With the availability of several bowel cleansing agents, physicians and hospitals performing colonoscopies will often base their choice of cleansing agent purely on acquisition cost. Therefore, an easy to use budget impact model has been developed and established as a tool to compare total colon preparation costs between different established bowel cleansing agents. The model was programmed in Excel and designed as a questionnaire evaluating information on treatment costs for a range of established bowel cleansing products. The sum of costs is based on National Health Service reference costs for bowel cleansing products. Estimations are made for savings achievable when using a 2-litre polyethylene glycol with ascorbate components solution (PEG+ASC) in place of other bowel cleansing solutions. Test data were entered into the model to confirm validity and sensitivity. The model was then applied to a set of audit cost data from a major hospital colonoscopy unit in the UK. Descriptive analysis of the test data showed that the main cost drivers in the colonoscopy process are the procedure costs and costs for bed days rather than drug acquisition costs, irrespective of the cleansing agent. Audit data from a colonoscopy unit in the UK confirmed the finding with a saving of £107,000 per year in favour of PEG+ASC when compared to sodium picosulphate with magnesium citrate solution (NaPic+MgCit). For every patient group the model calculated overall cost savings. This was irrespective of the higher drug expenditure associated with the use of PEG+ASC for bowel preparation. Savings were mainly realized through reduced costs for repeat colonoscopy procedures and associated costs, such as inpatient length of stay. The budget impact model demonstrated that the primary cost driver was the procedure cost for colonoscopy. Savings can be realized through the use of PEG+ASC despite higher drug acquisition costs relative to the comparator products. From a global hospital funding

  18. Serial transverse enteroplasty for short bowel syndrome: a case report.

    PubMed

    Kim, Heung Bae; Lee, Patricia W; Garza, Jennifer; Duggan, Christopher; Fauza, Dario; Jaksic, Tom

    2003-06-01

    The patient is a 2-year-old boy born with gastroschi