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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. [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.

  3. Fecal Microbiota Transplantation for Inflammatory Bowel Disease.

    PubMed

    Lopez, Joanna; Grinspan, Ari

    2016-06-01

    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

  4. 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

  5. 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.

  6. Basiliximab treatment for autoimmune bowel disease in a pediatric heart transplant patient.

    PubMed

    Puri, K; Kocoshis, S; Risma, K; Perez, L; Hart, C; Chin, C; Ryan, T D; Jefferies, J L; Schumacher, K R; Castleberry, C

    2015-11-01

    Autoimmune-mediated bowel disease has been reported after pediatric heart transplantation. Recognition and treatment of these patients has been difficult. We describe a patient who responded to steroids and basiliximab therapy after an inflammatory process secondary to abnormal T-cell activation. Our patient is a 28-month-old female who received a heart transplant at five wk of age. At 24 months post-transplant, she developed fever and bloody stools. Initial investigations were significant for an elevated ESR (>120) and CRP (15.2). Symptoms persisted despite bowel rest and mycophenolate discontinuation. Endoscopic evaluation revealed discontinuous ulcerative disease involving esophagus, terminal ileum, right and left colon, necessitating extensive bowel resection. She had additional airway inflammation leading to a TEF at the site of esophageal ulceration, requiring tracheostomy. Immune evaluation revealed autoimmune dysregulation that responded to parenteral methylprednisolone. Chronic basiliximab therapy allowed for successful weaning of steroids with sustained remission. She has been transitioned to sirolimus and tacrolimus maintenance immunosuppression with plans to discontinue basiliximab once off steroids. In conclusion, bowel disease in the setting of pediatric heart transplantation can be severe and refractory to traditional treatment methods. Tailoring immune therapy to activated T cells can result in remission. Basiliximab therapy was used in our patient to maintain steroid-induced remission, but long-term complications of this disease process are unknown.

  7. 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

  8. 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.

  9. Xenogeneic lung transplantation models

    PubMed Central

    Burdorf, Lars; Azimzadeh, Agnes M.; Pierson, Richard N.

    2014-01-01

    Summary Study of lung xenografts has proven useful to understand the remaining barriers to successful transplantation of other organ xenografts. In this chapter, the history and current status of lung xenotransplantation will be briefly reviewed and two different experimental models, the ex vivo porcine-to-human lung perfusion and the in vivo xenogeneic lung transplantation, will be presented. We will focus on the technical details of these lung xenograft models in sufficient detail, list the needed materials and mention analysis techniques to allow others to adopt them with minimal learning curve. PMID:22565996

  10. 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. PMID:27645751

  11. 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.

  12. 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

  13. Endoscopic biliary stent migration with small bowel perforation in a liver transplant recipient.

    PubMed

    Esterl, R M; St Laurent, M; Bay, M K; Speeg, K V; Halff, G A

    1997-03-01

    Intestinal perforation from a migrated biliary stent is a rare complication after endoscopic stent placement for benign biliary stricture. We provide the first description of stent migration and distal small-bowel perforation after stent placement for biliary anastomotic stricture in a liver transplant recipient. We review the current literature on the diagnosis and management of stent migration and intestinal perforation after endoscopic or percutaneous stent placement for benign and malignant biliary strictures. Early diagnosis and treatment of biliary stent migration and subsequent intestinal perforation are essential in transplant patients, in whom immunosuppression sometimes blunts signs and symptoms of intestinal perforation.

  14. Renal function and histology in children after small bowel transplantation.

    PubMed

    Boyer, Olivia; Noto, Cristian; De Serre, Natacha Patey-Mariaud; Gubler, Marie-Claire; Dechaux, Michèle; Goulet, Olivier; Niaudet, Patrick; Lacaille, Florence

    2013-02-01

    CKD is a frequent long-term complication after SBTx. CNIs are a well-known factor, but probably not the only cause. We assessed the incidence, risk factors, and severity of CKD in 27 children with SBTx (15 combined liver/SBTx) and prednisone/TAC-based maintenance immunosuppression. Median follow-up was seven yr (3-21). A renal biopsy was performed in 14 patients, 1-18 yr post-SBTx. A reduced GFR was observed in 17 children (63%) during the follow-up with none requiring dialysis. CNI toxicity was observed in 11/14 biopsies, as early as two yr post-transplant, and could occur with a normal mGFR. The dose of TAC was reduced by 50% in 13 patients with CKD and/or significant kidney histological lesions, and six were also given MMF. This led to a significant improvement in renal function: mGFR normalized in eight patients and improved or stabilized in five. No rejection occurred. At last follow-up, 37% had CKD stage 2 and 15% had CKD stage 3. In conclusion, CKD is frequent in children after SBTx and probably multifactorial. Less nephrotoxic immunosuppressive protocols may improve mGFR and should be further considered. The kidney histology helps in designing personalized immunosuppression strategies for patients.

  15. 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.

  16. Small bowel transplantation in children: an immunohistochemical study of intestinal grafts.

    PubMed Central

    Fromont, G; Cerf-Bensussan, N; Patey, N; Canioni, D; Rambaud, C; Goulet, O; Jan, D; Révillon, Y; Ricour, C; Brousse, N

    1995-01-01

    Seven children with short bowel syndrome underwent small bowel allografting. Episodes of early rejection were observed in five patients who received a graft from paediatric or adult donors but not in two patients who received a neonatal graft. This study aimed, firstly, to define immunohistochemical parameters accompanying rejection and, secondly, to compare immunohistochemical parameters in neonatal grafts with those in grafts from older donors. An immunohistochemical analysis was performed on 85 intestinal biopsy specimens taken for monitoring the transplant. Acute histological rejection was associated with pericryptic infiltrates of CD3+TcR alpha beta + T cells containing clusters of CD8+ cells, numerous CD25+ cells, and increased numbers of CD68+ macrophages. These changes were associated with the appearance of major histocompatibility (MHC) class II antigens on crypt enterocytes and with an appreciable increase in the expression of E-selectin on mucosal endothelial cells. Immunohistochemistry was useful in predicting rejection by showing the appearance of pericryptic CD25+ T cells 48 hours before the first histological lesions of crypt necrosis. Comparison of neonatal grafts with grafts from older donors did not show any significant difference in the density of CD68+ macrophages or in the endothelial expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, or E-selectin. In contrast to grafts from older donors, however, neonatal grafts did not express MHC class II antigens on epithelial cells and contained very low numbers of intraepithelial lymphocytes. These data indicate, firstly, that immunohistochemistry is useful for monitoring intestinal transplants and, secondly, that the better clinical tolerance of neonatal allografts may be related to the lower immunogenicity of the neonatal epithelium. Images Figure 3 Figure 4 PMID:8537048

  17. 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.

  18. Use of tissue expansion to facilitate liver and small bowel transplant in young children with contracted abdominal cavities.

    PubMed

    Vidyadharan, R; van Bommel, A C M; Kuti, K; Gupte, G L; Sharif, K; Richard, B M

    2013-11-01

    Liver and small bowel transplant is an established treatment for infants with IFALD. Despite organ reduction techniques, mortality on the waiting list remains high due to shortage of size-matched pediatric donors. Small abdominal cavity volume due to previous intestinal resection poses a significant challenge to achieve abdominal closure post-transplant. Seven children underwent tissue expansion of abdominal skin prior to multiorgan transplant. In total, 17 tissue expanders were placed subcutaneously in seven children. All seven subjects underwent re-exploration to deal with complications: hematoma, extrusion, infection, or port related. Three expanders had to be removed. Four children went on to have successful combined liver and small bowel transplant. Two children died on the waiting list of causes not related to the expander and one child died from sepsis attributed to an infected expander. Tissue expansion can generate skin to facilitate closure of abdomen post-transplant, thus allowing infants with small abdominal volumes to be considered for transplant surgery. Tissue expansion in children with end-stage liver disease and portal hypertension is associated with a very high complication rate and needs to be closely monitored during the expansion process.

  19. Ethics of emerging technologies and their transition to accepted practice: intestinal transplant for short bowel syndrome.

    PubMed

    Cummings, C L; Mercurio, M R

    2012-10-01

    Parental counseling becomes complex when considering the use of emerging technologies, especially if it is unclear whether the level of evidence is sufficient to transform the proposed therapy into accepted practice. This paper addresses ethical issues underlying medical decision-making and counseling in the setting of emerging treatments, when long-term outcomes are still in the process of being fully validated. We argue that the ethical transition of emerging technologies, ideally from ethically impermissible to permissible, to obligatory, depends primarily on two factors: outcome data (or prognosis) and treatment feasibility. To illustrate these points, we will use intestinal transplant for short bowel syndrome (SBS) as a specific example. After reviewing the data, this paper will identify the ethical justifications for both comfort care only and intestinal transplant in patients with ultra SBS, and argue that both are ethically permissible, but neither is obligatory. The approach outlined will not only be valuable as ultra SBS outcomes data continue to change, but will also be applicable to other novel therapies as they emerge in perinatal medicine. PMID:23014383

  20. 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.

  1. 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. PMID:24969143

  2. Small bowel transplantation complicated by cytomegalovirus tissue invasive disease without viremia.

    PubMed

    Avsar, Yesim; Cicinnati, Vito R; Kabar, Iyad; Wolters, Heiner; Anthoni, Christoph; Schmidt, Hartmut H J; Beckebaum, Susanne

    2014-06-01

    We report on a small bowel transplant patient, donor/recipient seropositive (D+/R+) for cytomegalovirus (CMV), with a clinical course complicated by CMV disease. Anti-CMV prophylaxis was given for 100 days. Immunosuppression consisted of alemtuzumab, tacrolimus, mycophenolate mofetil and prednisolone. Five months posttransplant, CMV tissue invasive disease of the upper gastrointestinal tract was evident without the presence of viremia, tested by quantitative polymerase chain reaction (PCR). Complete viral load suppression was achieved with intravenous ganciclovir, followed by valganciclovir for secondary prophylaxis. Mycophenolate mofetil and prednisolone were discontinued. Shortly thereafter the patient presented with recurrent CMV and candida esophagitis. While on ganciclovir and caspofungin, the patient developed CMV tissue invasive disease of the ileal graft, with persistent absence of viremia. Foscarnet and CMV immunoglobulin were added. Viral load declined to undetectable levels; however, clinical improvement did not occur due to occurrence of graft rejection. Despite infliximab and high dose prednisolone, graft rejection was progressive, requiring surgical explantation of the graft. This case highlights the importance of additional diagnostic tools such as endoscopy including PCR analysis of tissue samples. Extension of primary antiviral prophylaxis interval up to 6 months and prolonged retreatment for recurrent CMV disease may be useful to avoid severe CMV-related complications. PMID:24703746

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

    PubMed

    Kump, Patrizia; Högenauer, Christoph

    2016-01-01

    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. PMID:27548724

  4. Recombinant HLA-G as Tolerogenic Immunomodulant in Experimental Small Bowel Transplantation

    PubMed Central

    von Websky, Martin W.; Kitamura, Koji; Ludwig-Portugall, Isis; Kurts, Christian; von Laffert, Maximilian; LeMaoult, Joel; Carosella, Edgardo D.; Abu-Elmagd, Kareem; Kalff, Joerg C.; Schäfer, Nico

    2016-01-01

    The non-classical MHC I paralogue HLA-G is expressed by cytotrophoblast cells and implicated with fetomaternal tolerance by downregulating the maternal adaptive and innate immune response against the fetus. HLA-G expression correlates with favorable graft outcome in humans and recently promising immunosuppressive effects of therapeutic HLA-G in experimental transplantation (skin allograft acceptance) were shown. Consequently, we examined this novel therapeutic approach in solid organ transplantation. In this study, therapeutic recombinant HLA-G5 was evaluated for the first time in a solid organ model of acute rejection (ACR) after orthotopic intestinal transplantation (ITX). Allogenic ITX was performed in rats (Brown Norway to Lewis) with and without HLA-G treatment. It was found that HLA-G treatment significantly reduced histologically proven ACR at both an early and late postoperative timepoint (POD 4/7), concomitant to a functionally preserved graft contractility at POD 7. Interestingly, graft infiltration by myeloperoxidase+ cells was significantly reduced at POD7 by HLA-G treatment. Moreover, HLA-G treatment showed an effect on the allogenic T-cell immune response as assessed by flow cytometry: The influx of recipient-derived CD8+ T-cells into the graft mesenteric lymphnodes at POD7 was significantly reduced while CD4+ populations were not affected. As a potential mechanism of action, an induction of T-reg populations in the mesenteric lymphnodes was postulated, but flow cytometric analysis of classical CD4+/CD25+/FoxP3+Treg-cells showed no significant alteration by HLA-G treatment. The novel therapeutic approach using recombinant HLA-G5 reported herein demonstrates a significant immunosuppressive effect in this model of allogenic experimental intestinal transplantation. This effect may be mediated via inhibition of recipient-derived CD8+ T-cell populations either directly or by induction of non-classical Treg populations. PMID:27404095

  5. Bacterial translocation in acute rejection after small bowel transplantation in rats.

    PubMed

    Zou, Y; Hernandez, F; Burgos, E; Martinez, L; Gonzalez-Reyes, S; Fernandez-Dumont, V; Lopez, G; Romero, M; Lopez-Santamaria, M; Tovar, J A

    2005-03-01

    Acute rejection after small bowel transplantation (SBTx) may facilitate bacterial translocation (BT) and subsequent changes in the liver, spleen, and lungs. This study investigated whether BT occurs after acute rejection and whether this is followed by changes in the structure of the intestine and the phagocytic organs interposed between the gut and the general circulation. Orthotopic SBTx was performed in allogeneic (ALLO) rat-strain combinations (BN-Wistar, n=5). For comparison we used syngeneic SBTx (SYN) (BN-BN, n=6) controls. Animals were sacrificed on postoperative day 7. Mesenteric lymph nodes and portal and caval blood were cultured for aerobes and anaerobes. Escherichia coli beta-galactosidase DNA was assessed by polymerase chain reaction in the blood samples. Intestine, liver, spleen, and lung protein and DNA contents were measured. Histologic changes were graded according to standard criteria of acute rejection. For comparisons we used chi(2) and nonparametric Mann-Whitney test with a threshold of significance of p<0.05. ALLO rats lost more weight after SBTx than SYN rats (-13.02+/-4.39% vs. -8.04+/-5.08% of preoperative weight), although the difference was not significant (ns). A variable degree of graft rejection was histologically demonstrated in all ALLO rats, and DNA/protein content in the graft was significantly higher in this group (0.245+/-0.85 vs. 0.134+/-0.21, p<0.05). Gram-negative enteric bacteria were found in 4/5 ALLO and 4/6 SYN rats (ns), and aerobic Gram-positive bacteria in 2/5 and 3/6 (ns), respectively. Anaerobic growth occurred in mesenteric lymph nodes in one ALLO rat and in the bloodstream in another one. E. coli DNA was isolated in none of the ALLO but in two SYN rats (ns). BT was frequent after SBTx in both syngeneic and allogeneic strain combinations. Contrary to our expectations, BT after SBTx was not higher in ALLO group rats. However, anaerobic germs were isolated only in this group.

  6. Influence of Previous Inflammatory Bowel Disease on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation: A Matched-Pair Analysis.

    PubMed

    Rabian, Florence; Porcher, Raphael; Sicre de Fontbrune, Flore; Lioure, Bruno; Laplace, Anne; Nguyen, Stephanie; Tabrizi, Reza; Vigouroux, Stephane; Tomowiak, Cécile; Maillard, Nathalie; Suarez, Felipe; Delage, Jeremy; Peffault de Latour, Régis; Socié, Gérard

    2016-09-01

    The idiopathic inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis are associated with increased risk of hematologic malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) could be a curative strategy in this setting, but has been thought to be associated with increased nonrelapse mortality (NRM). We conducted a national French retrospective analysis of patients with IBD who underwent allogeneic HSCT for hematologic malignancies and were matched with 3 controls according to recipient, donor, and transplant characteristics. Between 2004 and 2015, 18 patients with IBD underwent allogeneic HSCT. With a median follow-up of 33 months for the patients with IBD and 57 months for controls, the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 39% for the patients with IBD and 40% for controls (hazard ratio [HR], 1.10; P = .82). The cumulative incidence of chronic GVHD at 48 months was 52% for the patients with IBD and 43% for controls (HR, 0.92; P = .89). Nonrelapse mortality at 48 months was 19% for the patients with IBD and 11% for controls (HR, 4.93; P = .067). Overall survival at 48 months was 59% for the patients with IBD and 60% for matched controls (HR, 1.35; P = .56). In conclusion, IBD should not be considered a contraindication for transplantation, and its impact on comorbidity indexes should be reduced. PMID:27246370

  7. 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

  8. 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

  9. 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

  10. Mouse kidney transplantation: models of allograft rejection.

    PubMed

    Tse, George H; Hesketh, Emily E; Clay, Michael; Borthwick, Gary; Hughes, Jeremy; Marson, Lorna P

    2014-01-01

    Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely replicates both the technical and pathological processes that occur in human renal transplantation. Although mouse models of allogeneic rejection in organs other than the kidney exist, and are more technically feasible, there is evidence that different organs elicit disparate rejection modes and dynamics, for instance the time course of rejection in cardiac and renal allograft differs significantly in certain strain combinations. This model is an attractive tool for many reasons despite its technical challenges. As inbred mouse strain haplotypes are well characterized it is possible to choose donor and recipient combinations to model acute allograft rejection by transplanting across MHC class I and II loci. Conversely by transplanting between strains with similar haplotypes a chronic process can be elicited were the allograft kidney develops interstitial fibrosis and tubular atrophy. We have modified the surgical technique to reduce operating time and improve ease of surgery, however a learning curve still needs to be overcome in order to faithfully replicate the model. This study will provide key points in the surgical procedure and aid the process of establishing this technique.

  11. Mouse Kidney Transplantation: Models of Allograft Rejection

    PubMed Central

    Clay, Michael; Borthwick, Gary; Hughes, Jeremy; Marson, Lorna P.

    2014-01-01

    Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely replicates both the technical and pathological processes that occur in human renal transplantation. Although mouse models of allogeneic rejection in organs other than the kidney exist, and are more technically feasible, there is evidence that different organs elicit disparate rejection modes and dynamics, for instance the time course of rejection in cardiac and renal allograft differs significantly in certain strain combinations. This model is an attractive tool for many reasons despite its technical challenges. As inbred mouse strain haplotypes are well characterized it is possible to choose donor and recipient combinations to model acute allograft rejection by transplanting across MHC class I and II loci. Conversely by transplanting between strains with similar haplotypes a chronic process can be elicited were the allograft kidney develops interstitial fibrosis and tubular atrophy. We have modified the surgical technique to reduce operating time and improve ease of surgery, however a learning curve still needs to be overcome in order to faithfully replicate the model. This study will provide key points in the surgical procedure and aid the process of establishing this technique. PMID:25350513

  12. 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

  13. Ten-Year Experience With Bowel Transplantation at Seoul St. Mary's Hospital.

    PubMed

    Chang, H K; Kim, S Y; Kim, J I; Kim, S I; Whang, J K; Choi, J Y; Park, J M; Jung, E S; Rha, S E; Kim, D G; Moon, I S; Lee, M D

    2016-03-01

    A retrospective review of intestinal transplantation (ITx) at Seoul St. Mary's Hospital was made by collecting clinical data over the past 10 years. Fifteen consecutive cases from 2004 were analyzed. Five children and 10 adults (6 months to 69 years of age) were included. Primary diseases in adults included 4 mesenteric vessel thromboses, 2 strangulations, and 1 each of visceral myopathy, malignant gastrointestinal stromal tumor (GIST), mesenteric lymphangiectasis, and injury. Pediatric cases involved 2 Hirschsprung disease, 2 visceral myopathy, and 1 necrotizing enterocolitis. Three of 7 stomas were closed using a serial transverse enteroplasty procedure before transplantation. The ITx were performed using 3 living-donor Itx, 12 deceased-donor ITx, 14 isolated Itx, and 1 modified multivisceral transplantation. Daclizumab, basiliximab, alemtusumab, or basiliximab with rabbit antithymocyte globulin (rATG) was used for the induction; tacrolimus monotherapy was used as the basic maintenance immunosuppressant; and m-TOR inhibitor was used for renal dysfunction patients. Seven cases of acute cellular rejection were treated with rATG. Three cases of antibody-mediated rejection were treated with rituximab alone or with rituximab and bortezomib combination. There were 4 cases of early mortality within 6 months after Itx. Causes of death were declamping shock, cardiac tamponade with acute cellular rejection, dysmotility, and sepsis. Surgical complications consisted of 1 feeding jejunostomy displacement, and a minor leakage at a colo-colostomy site. One-year survival of the patient and graft was 73.33% (Kaplan-Meier survival curve). Although the total number of ITx is small, its social impact has been remarkable in changing the related laws and reimbursement policy in Korea. PMID:27109981

  14. 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

  15. 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.

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

    PubMed

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

    2010-06-01

    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

  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'. PMID:22673884

  18. 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

  19. 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.

  20. 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.

  1. Autoantibodies to red blood cell antigens occur frequently with hemolysis among pediatric small bowel transplant recipients: clinical implications and management.

    PubMed

    Koepsell, Scott A; Grant, Wendy; Landmark, James D

    2015-02-01

    Reports have linked pediatric solid organ transplant recipients with the development of hemolytic autoimmune antibodies, especially in the setting of the immunosuppressant tacrolimus. This study aims to identify whether these observations also occurred at an institution that frequently performs pediatric multivisceral transplants and to characterize the treatment and outcome. Chart review was performed on all patients with RBC autoantibodies. Laboratory and clinical data were used to identify hemolysis. For transplant recipients with RBC autoantibodies, the type of transplant and outcome of the AIHA were profiled. One hundred twenty-eight patients were identified with RBC autoantibodies, of which 22 patients were solid organ transplant recipients, including 18 SB graft recipients. Sixteen of the 18 had evidence of hemolysis. The incidence rate of AIHA in this population is estimated to be 10%, resulting in significant cost. Treatment included immunosuppressant modulation, steroids, IVIG, and plasma exchange, with 12 of the 16 patients responding. RBC autoantibodies occur in up to 10% in pediatric SB transplant recipients, with high cost of obtaining compatible blood. Neither tacrolimus nor receipts of a donor spleen were associated with the development of AIHA. Treatment using steroids and IVIG appears to be effective.

  2. 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. PMID:27102447

  3. Transplantation.

    PubMed

    Faro, Albert; Weymann, Alexander

    2016-08-01

    Despite improvement in median life expectancy and overall health, some children with cystic fibrosis (CF) progress to end-stage lung or liver disease and become candidates for transplant. Transplants for children with CF hold the promise to extend and improve the quality of life, but barriers to successful long-term outcomes include shortage of suitable donor organs; potential complications from the surgical procedure and immunosuppressants; risk of rejection and infection; and the need for lifelong, strict adherence to a complex medical regimen. This article reviews the indications and complications of lung and liver transplantation in children with CF. PMID:27469184

  4. 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

  5. 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. PMID:20371236

  6. Applications of induced pluripotent stem cells in the modeling of human inflammatory bowel diseases.

    PubMed

    Liu, Jingquan; Shi, Bin; Shi, Kai; Zhang, Hongze

    2015-01-01

    Inflammatory bowel diseases (IBDs) are chronic and involve the gastrointestinal tract; the two primary IBDs are ulcerative colitis and Crohn's disease. Existing treatments for IBD include control of active inflammation and regulation of immune disorders, and commonly used drugs include salicylates, corticosteroids, and immunosuppressants. At the same time, an in-depth study of IBD pathogenesis promoted the acceptance of bioimmunotherapy by increasing numbers of people. However, long-term use of these drugs can cause adverse reactions that are difficult for patients to overcome, with limited efficacy for critically ill patients. Recent studies have found that stem cell transplantation is a new and effective therapy and IBD treatment, particularly for refractory cases. Stem cells, especially induced pluripotent stem cells (iPSCs), can differentiate into functional intestinal epithelia and their use avoids ethical issues arising from embryonic stem cells, providing a new kind of seed cell for alternative treatments for IBD. This paper reviews iPSCs as a potential new treatment for IBDs in order to provide an experimental and clinical reference.

  7. Bowel Dysfunction

    MedlinePlus

    ... PCF Spotlight Glossary African American Men Living with Prostate Cancer Bowel Dysfunction Side Effects Urinary Dysfunction Bowel Dysfunction ... rectal worse. Back to Side Effects Print | Understanding Prostate Cancer Research Faces of Prostate Cancer About PCF Take ...

  8. 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.

  9. 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. PMID:25693472

  10. 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.

  11. Human Liver Transplantation As A Model To Study HCV Pathogenesis

    PubMed Central

    Hughes, Michael G.; Rosen, Hugo R.

    2010-01-01

    Hepatitis C is a leading etiology of liver cancer and cause for liver transplantation. Although new therapies have improved the rates of sustained response, a large proportion of patients (~50%) fail to respond to antiviral treatment, thus remaining at risk for disease progression. While chimpanzees have been used to study HCV biology and treatments, their cost is quite high and their use is strictly regulated; indeed, the NIH no longer supports the breeding of chimpanzees for study. The development of HCV therapies has been hindered by the relative paucity of small animal models to study HCV pathogenesis. This review presents the strengths of the human liver transplant, highlighting the advances derived from this model, including insights into viral kinetics and quasispecies, viral receptor binding and entry, innate and adaptive immunity. Moreover, consideration is made of current and emerging antiviral therapeutic approaches based on translational research results. PMID:19877210

  12. Animal Models of Diabetes Mellitus for Islet Transplantation

    PubMed Central

    Sakata, Naoaki; Yoshimatsu, Gumpei; Tsuchiya, Haruyuki; Egawa, Shinichi; Unno, Michiaki

    2012-01-01

    Due to current improvements in techniques for islet isolation and transplantation and protocols for immunosuppressants, islet transplantation has become an effective treatment for severe diabetes patients. Many diabetic animal models have contributed to such improvements. In this paper, we focus on 3 types of models with different mechanisms for inducing diabetes mellitus (DM): models induced by drugs including streptozotocin (STZ), pancreatomized models, and spontaneous models due to autoimmunity. STZ-induced diabetes is one of the most commonly used experimental diabetic models and is employed using many specimens including rodents, pigs or monkeys. The management of STZ models is well established for islet studies. Pancreatomized models reveal different aspects compared to STZ-induced models in terms of loss of function in the increase and decrease of blood glucose and therefore are useful for evaluating the condition in total pancreatomized patients. Spontaneous models are useful for preclinical studies including the assessment of immunosuppressants because such models involve the same mechanisms as type 1 DM in the clinical setting. In conclusion, islet researchers should select suitable diabetic animal models according to the aim of the study. PMID:23346100

  13. Animal models of diabetes mellitus for islet transplantation.

    PubMed

    Sakata, Naoaki; Yoshimatsu, Gumpei; Tsuchiya, Haruyuki; Egawa, Shinichi; Unno, Michiaki

    2012-01-01

    Due to current improvements in techniques for islet isolation and transplantation and protocols for immunosuppressants, islet transplantation has become an effective treatment for severe diabetes patients. Many diabetic animal models have contributed to such improvements. In this paper, we focus on 3 types of models with different mechanisms for inducing diabetes mellitus (DM): models induced by drugs including streptozotocin (STZ), pancreatomized models, and spontaneous models due to autoimmunity. STZ-induced diabetes is one of the most commonly used experimental diabetic models and is employed using many specimens including rodents, pigs or monkeys. The management of STZ models is well established for islet studies. Pancreatomized models reveal different aspects compared to STZ-induced models in terms of loss of function in the increase and decrease of blood glucose and therefore are useful for evaluating the condition in total pancreatomized patients. Spontaneous models are useful for preclinical studies including the assessment of immunosuppressants because such models involve the same mechanisms as type 1 DM in the clinical setting. In conclusion, islet researchers should select suitable diabetic animal models according to the aim of the study. PMID:23346100

  14. [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.

  15. [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. PMID:26585110

  16. 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

  17. Preclinical modeling of hematopoietic stem cell transplantation - advantages and limitations.

    PubMed

    Stolfi, Jessica L; Pai, Chien-Chun S; Murphy, William J

    2016-05-01

    Hematopoietic stem cell transplantation, which was first successfully performed in the 1950s, remains a critical therapeutic modality for treatment of a diverse array of diseases, including a multitude of hematological malignancies, autoimmune disorders, amyloidosis and inherited genetic hematological disorders. Although great advances have been made in understanding and application of this therapy, significant complications still exist, warranting further investigation. Of critical importance, graft-versus-host disease (GVHD), in both acute and chronic forms, remains a major complication of hematopoietic stem cell transplantation, responsible for both the development of chronic illness and morbidity, as well as mortality. Use of an appropriate preclinical model may provide significant insight into the mechanistic pathways leading to the development and progression of graft-versus-host disease, as well as cancer in general. However, existing preclinical modeling systems exhibit significant limitations, and development of models that recapitulate the complex and comprehensive clinical scenario and provide a tool by which therapeutic intervention may be developed and assessed is of utmost importance. Here, we review the present status of the field of graft-versus-host disease research. We discuss and summarize the preclinical models currently in use, as well as their advantages and limitations.

  18. 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

  19. Effects of Microtus fortis lymphocytes on Schistosoma japonicum in a bone marrow transplantation model.

    PubMed

    Hu, Yuan; Xu, Yuxin; Lu, Weiyuan; Quan, Hong; Shen, Yujuan; Yuan, Zhongying; Zhang, Jing; Zang, Wei; He, Yongkang; Cao, Jianping

    2014-07-01

    Microtus fortis is a non-permissive host for Schistosoma japonicum. While M. fortis lymphocytes are known to provide natural resistance against S. japonicum, the specific mechanism remains unclear. A bone marrow transplantation (BMT) model was established using immunodeficient mice, either nude (experiment 1) or V(D)J recombination activation gene deficient mice (RAG-1(-/-)) (experiment 2) as recipients and M. fortis or C57BL/6 mice as donors. The growth and development of S. japonicum were evaluated in each group to assess the role of M. fortis lymphocytes in the response to infection. Lymphocyte ratios and S. japonicum-specific antibody production in transplanted groups increased significantly compared to those in non-transplanted group. Spleen indices and density of splenic lymphocytes in transplanted RAG-1(-/-) mice were higher than those in non-transplanted RAG-1(-/-) mice. No difference in the worm burden was observed among group A (transplants derived from M. fortis), B (transplants derived from C57BL/6 mouse) and C (non-transplanted mice), although worms in group A were shorter than those in other groups, except non-transplanted RAG-1(-/-) mice. Reproductive systems of worms in mice (nude or RAG-1(-/-)) transplanted from M. fortis were not as mature as those in mice (nude or RAG-1(-/-)) transplanted from C57BL/6 mouse and non-transplanted nude mice, but they were more mature than worms in non-transplanted RAG-1(-/-) mice. Therefore, the transplantation model using nude and RAG-1(-/-) mice was successfully established. The M. fortis lymphocytes did not appear to affect the S. japonicum worm burden, but they led to schistosome shortening and a significant reduction in parasite spawning. Thus, M. fortis cellular and humoral immunity provides a defense against schistosomes by negatively impacting the parasite growth and reproductive development.

  20. 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.

  1. Optimizing rejection readouts in a corneal allograft transplantation model

    PubMed Central

    Hildebrand, Antonia; Böhringer, Daniel; Betancor, Paola Kammrath; Schlunck, Günther; Reinhard, Thomas

    2016-01-01

    Purpose To evaluate the feasibility of anterior segment spectral domain optic coherence tomography (ASOCT) as rejection readout in a keratoplasty mouse model and to compare ASOCT against the current standard (i.e., a clinical score system). Furthermore, to compare both approaches with respect to intra- and inter-individual observer variability and to calculate a critical point that distinguishes between rejection and non-rejection in ASOCT analysis. Methods Allogeneic penetrating keratoplasties (PKs) were performed using C3H/He donor mice and BALB/c recipient mice; syngeneic transplantations served as controls using BALB/c donors and recipients. Corneal graft rejection was determined with a clinical score. ASOCT was used to determine the central thickness of the corneal grafts in the same animals. The rejection status was corroborated with histopathological examination. Results The median survival time (MST) of the corneal allografts in the wild-type BALB/c mice was 12 days. Allogeneic transplantation led to a 100% rejection rate, whereas signs of rejection after syngeneic transplantation appeared in up to 20% of the mice. Central corneal thickness (CCT) determination via customized software revealed a direct correlation with the clinical score. Receiver operating curve (ROC) analysis confirmed CCT as a valid surrogate for rejection. Calculation of the area under the curve (AUC) revealed a value of 0.88 with an optimal cut-off at 267 pixels. Conclusions An increase in the CCT during acute allogeneic corneal graft rejection significantly correlated with the clinical surrogate parameter “corneal opacity.” ASOCT not only generates source data, but also analysis of the ASOCT data shows lower readout variability and fewer interpreter variations than the clinical score commonly used to define the time point of graft rejection in mice. PMID:27777504

  2. Mathematical model for wound healing following autologous keratinocyte transplantation.

    PubMed

    Renner, Regina; Teuwen, Isabell; Gebhardt, Carl; Simon, Jan C

    2008-06-01

    In times of increasing economical pressure on the health care systems, it is important to optimise the outpatient treatment of chronic wounds. Another aim of wound healing research is to discover agents to accelerate healing. Wound healing trajectories or healing velocities can provide information to demonstrate the endpoints for wound healing. A great problem in clinical trials is to specify these parameters. Therefore, we developed a mathematical model for more transparency. In this initial project, we observed 19 wounds to construct the wound healing trajectories after transplantation of autologous keratinocytes, and the results are so encouraging that investigation in this area will continue. The developed mathematical model describes the clinical observed healing process. It was possible to find parameters to distinguish between old and young patients, retrospectively or prospectively calculate the healing rates and to determine exactly the endpoint of healing. Therefore, our model might be very useful in practices or for studies.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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. PMID:26526435

  8. Mechanical Bowel Preparation Does Not Affect Anastomosis Healing in an Experimental Rat Model

    PubMed Central

    Piroglu, Isılay; Tulgar, Serkan; Thomas, David Terence; Cakiroglu, Basri; Piroglu, Mustafa Devrim; Bozkurt, Yasin; Gergerli, Ruken; Ates, Nagihan Gozde

    2016-01-01

    Background Mechanical bowel preparation before colorectal surgery is commonly performed, but its benefits are controversial. The aim of this study was to compare the effects of mechanical bowel preparation on healing of colonic anastomosis and tissue strength. Material/Methods After institutional review board approval, 20 adult Wistar albino rats were randomly divided into 2 groups of 10 animals each. Mechanical bowel preparation including sodium phosphate was performed on the experimental group via a feeding tube, whereas no bowel preparation procedures were performed on the control group. Transverse colon resection and anastomosis were performed on all rats under general anaesthesia. On postoperative day 5, re-laparotomy was performed and the anastomotic areas were resected. Animals were killed, after which bursting pressure and tissue hydroxyproline concentrations were measured, histopathological examination was performed, and we evaluated and compared the results. Results There were no differences between control and experimental groups in bursting pressure, tissue hydroxyproline concentrations, or histopathological examination results (P>0.05). Conclusions Our study demonstrated no significant difference between bursting pressures, tissue hydroxyproline levels, or modified wound healing score at postoperative day 5 between rats undergoing and not undergoing mechanical bowel preparation. Mechanical bowel preparation is not essential for healing or strength of colonic anastomosis in rats. PMID:26725402

  9. Bowel Movement

    MedlinePlus

    A bowel movement is the last stop in the movement of food through your digestive tract. Your stool passes out ... rectum and anus. Another name for stool is feces. It is made of what is left after ...

  10. Bowel retraining

    MedlinePlus

    ... privacy as you can. Some people find that reading while sitting on the toilet helps them relax. If you do not have a bowel movement within 20 minutes, repeat the process. Try to contract the muscles of the abdomen ...

  11. 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

  12. Murine Norovirus: An Intercurrent Variable in a Mouse Model of Bacteria-Induced Inflammatory Bowel Disease

    PubMed Central

    Lencioni, Karen Chase; Seamons, Audrey; Treuting, Piper M; Maggio-Price, Lillian; Brabb, Thea

    2008-01-01

    Murine norovirus (MNV) has recently been recognized as a widely prevalent viral pathogen in mouse colonies and causes disease and mortality in mice with impaired innate immunity. We tested the hypothesis that MNV infection would alter disease course and immune responses in mice with inflammatory bowel disease (IBD). FVB.129P2-Abcb1atm1Bor N7 (Mdr1a−/−) mice develop spontaneous IBD that is accelerated by infection with Helicobacter bilis. As compared with controls, Mdr1a−/− mice coinfected with MNV4 and H. bilis showed greater weight loss and IBD scores indicative of severe colitis, demonstrating that MNV4 can modulate the progression of IBD. Compared with controls, mice inoculated with MNV4 alone had altered levels of serum biomarkers, and flow cytometric analysis of immune cells from MNV4-infected mice showed changes in both dendritic cell (CD11c+) and other nonT cell (CD4− CD8−) populations. Dendritic cells isolated from MNV4-infected mice induced higher IFNγ production by polyclonal T cells in vitro at 2 d after infection but not at later time points, indicating that MNV4 infection enhances antigen presentation by dendritic cells early after acute infection. These findings indicate that acute infection with MNV4 is immunomodulatory and alters disease progression in a mouse model of IBD. PMID:19149409

  13. [Selective bowel decontamination].

    PubMed

    Szántó, Zoltán; Pulay, István; Kotsis, Lajos; Dinka, Tibor

    2006-04-01

    Infective complications play major role in mortality of high risk patients demanding intensive care. Selective Bowel Decontamination prevents endogenous infections by reducing the number of potentially pathogen microbes (aerobic bacteria, fungi) in the oropharynx and gastrointestinal tract, saving anaerobic bacteria. It had been used 20 years ago for the first time. Authors survey it's literature ever since. Selective Bowel Decontamination is performed by the mixture of antibiotics and antimycotic drug, administered orally in hydrogel, and suspension form in nasojejunal tube. The number of Gram negative optional aerobic bacteria and fungi decrease significantly in the gut, and the microbial translocation is following this tendency. Foreign authors achieved good results in acute necrotizing pancreatitis, after liver transplant, in polytrauma, in serious burn and in haematological malignancies. According to the literature Selective Bowel Decontamination shows advantages in selected groups of high risk surgical patients. In some studies the administration took few months, but the minimum time was one week. There was no report of increasing MRSA appearance. Regular bacteriological sampling is highly recommended in order to recognize any new antibiotic resistance in time. PMID:16711371

  14. 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. PMID:26068703

  15. Neuroprotective effects of systemic cerebral endothelial cell transplantation in a rat model of cerebral ischemia.

    PubMed

    Moon, Jong-Hyun; Na, Joo-Young; Lee, Min-Cheol; Choi, Kang-Ho; Lee, Jeong-Kil; Min, Jung-Joon; Kim, Kyung-Tae; Park, Jong-Tae; Park, Man-Seok; Kim, Hyung-Seok

    2016-01-01

    Human cerebral microvascular endothelial cell line (hCMEC)/D3 cells, which are from a stable clonal cell line of human immortalized cerebral endothelial cells, were intra-arterially transplanted through the common carotid artery in a rat model of photochemical-induced cerebral ischemia. Their therapeutic effects on infarct size, blood-brain barrier (BBB) breakdown, and outcome were examined. The hCMEC/D3 cells were genetically modified with the firefly luciferase gene for in vivo imaging post-transplantation. Transplanted hCMEC/D3 cells were identified in the infarcted brain by bioluminescence imaging at 1 day after transplantation. Compared with the control group, the hCMEC/D3-transplanted group showed reduced infarct size on day 3, reduced Evans blue dye leakage on day 1 indicating decreased BBB breakdown, and early recovery from Rotarod test neurological deficits. The hCMEC/D3-transplanted group also showed decreased levels of matrix metalloproteinase (MMP)-9, which were inversely correlated with TIMP-1 levels on post-transplantation days 1 and 3. The expression of tumor necrosis factor-α and interleukin-1β were markedly diminished in the hCMEC/D3-transplanted group compared with controls. The systemically transplanted cells selectively migrated and integrated into the ischemically lesioned area, which accelerated neurological recovery. This new cerebral endothelial cell-based therapy may hold promise for clinical trials in patients with ischemic stroke. PMID:27347342

  16. Neuroprotective effects of systemic cerebral endothelial cell transplantation in a rat model of cerebral ischemia.

    PubMed

    Moon, Jong-Hyun; Na, Joo-Young; Lee, Min-Cheol; Choi, Kang-Ho; Lee, Jeong-Kil; Min, Jung-Joon; Kim, Kyung-Tae; Park, Jong-Tae; Park, Man-Seok; Kim, Hyung-Seok

    2016-01-01

    Human cerebral microvascular endothelial cell line (hCMEC)/D3 cells, which are from a stable clonal cell line of human immortalized cerebral endothelial cells, were intra-arterially transplanted through the common carotid artery in a rat model of photochemical-induced cerebral ischemia. Their therapeutic effects on infarct size, blood-brain barrier (BBB) breakdown, and outcome were examined. The hCMEC/D3 cells were genetically modified with the firefly luciferase gene for in vivo imaging post-transplantation. Transplanted hCMEC/D3 cells were identified in the infarcted brain by bioluminescence imaging at 1 day after transplantation. Compared with the control group, the hCMEC/D3-transplanted group showed reduced infarct size on day 3, reduced Evans blue dye leakage on day 1 indicating decreased BBB breakdown, and early recovery from Rotarod test neurological deficits. The hCMEC/D3-transplanted group also showed decreased levels of matrix metalloproteinase (MMP)-9, which were inversely correlated with TIMP-1 levels on post-transplantation days 1 and 3. The expression of tumor necrosis factor-α and interleukin-1β were markedly diminished in the hCMEC/D3-transplanted group compared with controls. The systemically transplanted cells selectively migrated and integrated into the ischemically lesioned area, which accelerated neurological recovery. This new cerebral endothelial cell-based therapy may hold promise for clinical trials in patients with ischemic stroke.

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

    PubMed Central

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

    2016-01-01

    Background/Aims: 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). Methods: 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. Results: 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). Conclusions: The present study demonstrated that significant and serious histopathological changes directly associated with colitis occur in the lungs in IBD. PMID:27539446

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. [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

    2016-01-01

    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. PMID:27626647

  4. [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.

  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. PMID:26814440

  6. 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

  7. Effect of metformin and adriamycin on transplantable tumor model.

    PubMed

    Kabel, Ahmed M; Omar, Mohamed S; Balaha, Mohamed F; Borg, Hany M

    2015-10-01

    Adriamycin is a cytotoxic anthracycline antibiotic used in treatment of many types of cancer. Metformin is antidiabetic drug and is under investigation for treatment of cancer. The aim of this work was to study the effect of each of adriamycin and metformin alone and in combination on solid Ehrlich carcinoma (SEC) in mice. Eighty BALB/C mice were divided into four equal groups: SEC group, SEC+adriamycin, SEC+metformin, SEC+adriamycin+metformin. Tumor volume, survival rate, tissue catalase, tissue reduced glutathione, tissue malondialdehyde, tissue sphingosine kinase 1 activity, tissue caspase 3 activity and tissue tumor necrosis factor alpha were determined. A part of the tumor was examined for histopathological and immunohistochemical study. Adriamycin or metformin alone or in combination induced significant increase in the survival rate, tissue catalase, reduced glutathione and tissue caspase 3 activity with significant decrease in tumor volume, tissue malondialdehyde, tissue sphingosine kinase 1 activity and tumor necrosis factor alpha and alleviated the histopathological changes with significant increase in Trp53 expression and apoptotic index compared to SEC group. In conclusion, the combination of adriamycin and metformin had a better effect than each of these drugs alone against transplantable tumor model in mice.

  8. 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.

  9. The Burden of Inflammatory Bowel Disease: A Patient-Reported Qualitative Analysis and Development of a Conceptual Model

    PubMed Central

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

    2014-01-01

    Background 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. Methods 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 (PRO) measures. Results 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 PRO measures. Conclusions 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. PMID:24407484

  10. 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.

  11. 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.

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

    PubMed

    Sangild, Per T; Ney, Denise M; Sigalet, David L; Vegge, Andreas; Burrin, Douglas

    2014-12-15

    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

  13. 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

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

    PubMed

    Sangild, Per T; Ney, Denise M; Sigalet, David L; Vegge, Andreas; Burrin, Douglas

    2014-12-15

    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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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,...

  16. Expression of Redox Factor-1 in Early Injury Period After Liver Transplantation in Rat Model

    PubMed Central

    Zhang, Ping; Du, Xiaohong; Sun, Zhipeng; Xu, Lijun

    2009-01-01

    The aims of this study were to observe the relationship between injury of graft and expression of redox factor-1 (Ref-1) in early period (24 h) after liver transplantation in rat model. One hundred and fifty adult male Wister rats were randomly divided into three groups including liver transplant group, sham surgery group and untreated control group. After liver transplantation, animals were sacrificed at different time points, and the changes and significance of the expression of Ref-1 were then explored by immunohistochemistry, serology and histopathology. As compared with sham surgery group and untreated control group, the expression of Ref-1 protein in transplant group was stronger in early period after liver transplantation. With pathology analysis, lots of infiltrating inflammation cells were found around the portal veins. Hepatic tissues were injury. However, the injury in sham surgery and untreated control group were comparatively slight. The serum ALT and AST levels reached the peak at 6-12 h, and decreased significantly after 12 h. These data suggested that the degree of liver injury in earlier period after transplantation peaked at 6 h and then decreased. And Ref-1 protein induced by hepatic ischemic reperfusion injury might play a critical role in repairing the injury. PMID:19728933

  17. Effects of brain-derived neurotrophic factor-pretreated neuron stem cell transplantation on Alzheimer’s disease model mice

    PubMed Central

    Li, Tong; Yu, Ying; Cai, Hongliu

    2015-01-01

    Alzheimer’s disease (AD) is a common case of dementia and its possible therapies, such as neuron stem cell (NSC) transplantation therapy, have been studied for years. In order to improve NSC transplantation effects, we were inspired to pretreat NSC using brain-derived neurotrophic factor (BDNF) before transplantation. The AD mouse model was constructed and effects of BDNF+NSC transplant group and traditional NSC transplant group were compared using the four indicators: conditions of learning and memory ability recovery tested by Morris Water Maze (MWM), number of basal forebrain cholinergic neurons, expression of synaptophysin, and number of acetylcholinesterase (ACHE)-positive fibers detected by chemical staining. Results showed all the four indicators were significantly lower in the AD model group than the control group (P < 0.05). Traditional NSC transplantation could improve these indicators to some extent but still possessed significant differences from the control group (P < 0.05). Especially, the BDNF+NSC transplant group showed significant improvements in the four indicators when compared with the AD model group (P < 0.05). Taken these data together, BDNF pretreatment improved the NSC transplantation effects, showing advantages over the traditional NSC transplantation. Our study could facilitate the application of stem cell transplantation therapy to AD treatment. PMID:26885166

  18. A new model of corneal transplantation in the miniature pig: efficacy of immunosuppressive treatment.

    PubMed

    Tavandzi, Urania; Procházka, Radek; Usvald, Dusan; Hlucílová, Jana; Vitásková, Martina; Motlík, Jan; Vítová, Andrea; Filipec, Martin; Forrester, John V; Holán, Vladimír

    2007-05-27

    Corneal allograft rejection is frequently studied in small rodent or rabbit models. To study mechanisms of rejection in a model that more closely mimics transplantation in humans, we performed orthotopic corneal transplantation in the miniature pig using a 7-mm diameter donor graft. Four groups of recipients were studied: 1) untreated naive, 2) untreated vascularized (high risk), 3) high-risk grafts treated by topical application of prednisolone, or 4) high-risk grafts treated with a combined systemic immunosuppression regime of oral prednisone, cyclosporine A, and mycophenolate mofetil. Both the clinical features and histological assessment of corneal graft rejection showed close similarities to graft rejection in humans. Interestingly, preliminary results indicated that topical steroid treatment was superior to systemic immunosuppression in significantly promoting graft survival. Thus, corneal transplantation in the pig represents an animal model most closely resembling corneal grafting in humans, and offers possibilities for testing various clinically applicable immunosuppressive treatments.

  19. Acute kidney injury following liver transplantation: a systematic review of published predictive models.

    PubMed

    Caragata, R; Wyssusek, K H; Kruger, P

    2016-03-01

    Acute kidney injury is a frequent postoperative complication amongst liver transplant recipients and is associated with increased morbidity and mortality. This systematic review analysed the existing predictive models, in order to solidify current understanding. Articles were selected for inclusion if they described the primary development of a clinical prediction model (either an algorithm or risk score) to predict AKI post liver transplantation. The database search yielded a total of seven studies describing the primary development of a prediction model or risk score for the development of AKI following liver transplantation. The models span thirteen years of clinical research and highlight a gradual change in the definitions of AKI, emphasising the need to employ standardised definitions for subsequent studies. Collectively, the models identify a diverse range of predictive factors with several common trends. They emphasise the impact of preoperative renal dysfunction, liver disease severity and aetiology, metabolic risk factors as well as intraoperative variables including measures of haemodynamic instability and graft quality. Although several of the models address postoperative parameters, their utility in predictive modelling seems to be of questionable relevance. The common risk factors identified within this systematic review provide a minimum list of variables, which future studies should address. Research in this area would benefit from prospective, multi-site studies with larger cohorts as well as the subsequent internal and external validation of predictive models. Ultimately, the ability to identify patients at high risk of post-transplant AKI may enable early intervention and perhaps prevention. PMID:27029658

  20. Population pharmacokinetic–pharmacodynamic modelling of mycophenolic acid in paediatric renal transplant recipients in the early post-transplant period

    PubMed Central

    Dong, Min; Fukuda, Tsuyoshi; Cox, Shareen; de Vries, Marij T; Hooper, David K; Goebel, Jens; Vinks, Alexander A

    2014-01-01

    Aim The purpose of this study was to develop a population pharmacokinetic and pharmacodynamic (PK−PD) model for mycophenolic acid (MPA) in paediatric renal transplant recipients in the early post-transplant period. Methods A total of 214 MPA plasma concentrations−time data points from 24 patients were available for PK model development. In 17 out of a total of 24 patients, inosine monophosphate dehydrogenase (IMPDH) enzyme activity measurements (n = 97) in peripheral blood mononuclear cells were available for PK−PD modelling. The PK−PD model was developed using non-linear mixed effects modelling sequentially by 1) developing a population PK model and 2) incorporating IMPDH activity into a PK−PD model using post hoc Bayesian PK parameter estimates. Covariate analysis included patient demographics, co-medication and clinical laboratory data. Non-parametric bootstrapping and prediction-corrected visual predictive checks were performed to evaluate the final models. Results A two compartment model with a transit compartment absorption best described MPA PK. A non-linear relationship between dose and MPA exposure was observed and was described by a power function in the model. The final population PK parameter estimates (and their 95% confidence intervals) were CL/F, 22 (14.8, 25.2) l h−1 70 kg−1; Vc/F, 45.4 (29.6, 55.6) l; Vp/F, 411 (152.6, 1472.6)l; Q/F, 22.4 (16.0, 32.5) l h−1; Ka, 2.5 (1.45, 4.93) h−1. Covariate analysis in the PK study identified body weight to be significantly correlated with CL/F. A simplified inhibitory Emax model adequately described the relationship between MPA concentration and IMPDH activity. The final population PK−PD parameter estimates (and their 95% confidence intervals) were: E0, 3.45 (2.61, 4.56) nmol h−1 mg−1 protein and EC50, 1.73 (1.16, 3.01) mg l−1. Emax was fixed to 0. There were two African-American patients in our study cohorts and both had low IMPDH baseline activities (E0) compared

  1. Five decades of progress in hematopoietic cell transplantation based on the preclinical canine model

    PubMed Central

    Lupu, Marilena; Storb, Rainer

    2009-01-01

    The preclinical canine model has proved valuable for the development of principles and techniques of hematopoietic cell transplantation (HCT) applicable to human patients. Studies in random-bred dogs concerning the impact of histocompatibility barriers on engraftment and graft-versus-host disease, the kinetics of immunological reconstitution, the efficacy of various pre-transplant conditioning regimens, post-transplantation immunosuppression protocols, treatment of malignant diseases, and graft-versus-tumor effects have advanced HCT from an investigational therapy with uncertain clinical benefit half a century ago to an important treatment choice for thousands of patients treated annually in transplantation centers worldwide. More recent preclinical canine studies have resulted in the clinical translation of nonmyeloablative, minimally invasive transplantation protocols that have extended allogeneic HCT to include older human patients with malignant and non-malignant, acquired or inherited hematological disorders, and those with comorbid conditions. Here we review the contributions of the canine model to modern HCT and describe the usefulness of HCT for the treatment of canine hematological disorders. PMID:19754798

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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

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

    PubMed

    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

  8. 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. PMID:26036495

  9. 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.

  10. The Cooperative Care model: an innovative approach to deliver blood and marrow stem cell transplant care.

    PubMed

    Schmit-Pokorny, Kim; Franco, Theresa; Frappier, Bettina; Vyhlidal, Ruth Caddy

    2003-01-01

    Competition among healthcare institutions, the need to improve outcomes, and the desire to decrease costs have motivated blood and marrow stem cell transplant centers to develop innovative care models. In an effort to meet these challenges, a major midwestern medical center adapted the transplant process to the outpatient setting. This transition created greater educational and care demands for patients and families. To address these demands and provide improved accommodations and amenities for patients and families, the center adopted an innovative model of care, Cooperative Care, for transplant recipients. Cooperative Care embraces patients and families as key members of the healthcare team. A family member serves as a primary caregiver for the patient during the acute inpatient phase of the transplant. Care becomes more personal and individualized, cost is reduced, the rate of rehospitalization potentially is decreased, and patients ultimately become more confident and competent in caring for themselves. The healthcare team shifted its care philosophy to incorporate a care partner, increase patient control and independence, and create greater emphasis on education. Outcomes, including patient satisfaction, have demonstrated success and motivated expansion of this model to other patient populations.

  11. 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.

  12. Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis.

    PubMed

    Thirunavukkarasu, Kannan; Tan, Bailin; Swearingen, Craig A; Rocha, Guilherme; Bui, Hai H; McCann, Denis J; Jones, Spencer B; Norman, Bryan H; Pfeifer, Lance A; Saha, Joy K

    2016-10-01

    Autotaxin is a secreted enzyme that catalyzes the conversion of lysophosphatidyl choline into the bioactive lipid mediator lysophosphatidic acid (LPA). It is the primary enzyme responsible for LPA production in plasma. It is upregulated in inflammatory conditions and inhibition of autotaxin may have anti-inflammatory activity in a variety of inflammatory diseases. To determine the role of autotaxin and LPA in the pathophysiology of inflammatory disease states, we used a potent and orally bioavailable inhibitor of autotaxin that we have recently identified, and characterized it in mouse models of inflammation, inflammatory bowel disease (IBD), multiple sclerosis (MS), and visceral pain. Compound-1, a potent inhibitor of autotaxin with an IC50 of ∼2 nM, has good oral pharmacokinetic properties in mice and results in a substantial inhibition of plasma LPA that correlates with drug exposure levels. Treatment with the inhibitor resulted in significant anti-inflammatory and analgesic effects in the carrageenan-induced paw inflammation and acetic acid-induced visceral pain tests, respectively. Compound-1 also significantly inhibited disease activity score in the dextran sodium sulfate-induced model of IBD, and in the experimental autoimmune encephalomyelitis model of MS. In conclusion, the present study demonstrates the anti-inflammatory and analgesic properties of a novel inhibitor of autotaxin that may serve as a therapeutic option for IBD, MS, and pain associated with inflammatory states.

  13. Transplantation tolerance.

    PubMed

    Salisbury, Emma M; Game, David S; Lechler, Robert I

    2014-12-01

    Although transplantation has been a standard medical practice for decades, marked morbidity from the use of immunosuppressive drugs and poor long-term graft survival remain important limitations in the field. Since the first solid organ transplant between the Herrick twins in 1954, transplantation immunology has sought to move away from harmful, broad-spectrum immunosuppressive regimens that carry with them the long-term risk of potentially life-threatening opportunistic infections, cardiovascular disease, and malignancy, as well as graft toxicity and loss, towards tolerogenic strategies that promote long-term graft survival. Reports of "transplant tolerance" in kidney and liver allograft recipients whose immunosuppressive drugs were discontinued for medical or non-compliant reasons, together with results from experimental models of transplantation, provide the proof-of-principle that achieving tolerance in organ transplantation is fundamentally possible. However, translating the reconstitution of immune tolerance into the clinical setting is a daunting challenge fraught with the complexities of multiple interacting mechanisms overlaid on a background of variation in disease. In this article, we explore the basic science underlying mechanisms of tolerance and review the latest clinical advances in the quest for transplantation tolerance. PMID:24213880

  14. Questions and Answers for Transplant Candidates about Model for End-Stage Liver Disease (MELD) and Pediatric End-Stage ....

    MedlinePlus

    ... needs a liver transplant most urgently. The MELD (Model for End Stage Liver Disease) is used for ... and the PELD (Pediatric End Stage Liver Disease Model) is used for patients age 11 and younger. ...

  15. 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

  16. 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

  17. 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.

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

    PubMed

    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

    2015-11-01

    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

  19. 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.

  20. 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

  1. 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.

  2. 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. PMID:21389849

  3. 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

  4. 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

  5. Gut microbiota and allogeneic transplantation.

    PubMed

    Wang, Weilin; Xu, Shaoyan; Ren, Zhigang; Jiang, Jianwen; Zheng, Shusen

    2015-08-23

    The latest high-throughput sequencing technologies show that there are more than 1000 types of microbiota in the human gut. These microbes are not only important to maintain human health, but also closely related to the occurrence and development of various diseases. With the development of transplantation technologies, allogeneic transplantation has become an effective therapy for a variety of end-stage diseases. However, complications after transplantation still restrict its further development. Post-transplantation complications are closely associated with a host's immune system. There is also an interaction between a person's gut microbiota and immune system. Recently, animal and human studies have shown that gut microbial populations and diversity are altered after allogeneic transplantations, such as liver transplantation (LT), small bowel transplantation (SBT), kidney transplantation (KT) and hematopoietic stem cell transplantation (HTCT). Moreover, when complications, such as infection, rejection and graft versus host disease (GVHD) occur, gut microbial populations and diversity present a significant dysbiosis. Several animal and clinical studies have demonstrated that taking probiotics and prebiotics can effectively regulate gut microbiota and reduce the incidence of complications after transplantation. However, the role of intestinal decontamination in allogeneic transplantation is controversial. This paper reviews gut microbial status after transplantation and its relationship with complications. The role of intervention methods, including antibiotics, probiotics and prebiotics, in complications after transplantation are also discussed. Further research in this new field needs to determine the definite relationship between gut microbial dysbiosis and complications after transplantation. Additionally, further research examining gut microbial intervention methods to ameliorate complications after transplantation is warranted. A better understanding of the

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

    PubMed Central

    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 ortho-topic 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. PMID:26647736

  7. 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.

  8. A random effects model for multistate survival analysis with application to bone marrow transplants.

    PubMed

    Bhattacharyya, Mouchumi; Klein, John P

    2005-03-01

    We present an extension of the non-homogeneous Markov model for a bone marrow transplant recovery process which allows for possible associations between the transition intensities. The associations between intensities are modeled by a correlated gamma frailty model. Based on a parametric model for the conditional transition intensities, we obtain estimates of the model parameters. We use these estimates to make predictions of patient's eventual prognosis given the current medical history of the patient. Estimates of the uncertainty in our predictions are obtained by a modified bootstrap technique. PMID:15836863

  9. 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

  10. 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; Umbilical ...

  11. A model utilizing adult murine stem cells for creation of personalized islets for transplantation.

    PubMed

    Wang, J; Song, L J; Gerber, D A; Fair, J H; Rice, L; LaPaglia, M; Andreoni, K A

    2004-05-01

    Clinical islet cell transplantation has demonstrated great promise for diabetes treatment. Two major obstacles are the organ donor shortage and the immunoresponse. The purpose of this study was to create a model using the patient's own adult stem cell sources, possibly in combination with non-self cells, such as pancreatic, hepatic, or embryonic stem cells, to create "personalized" islets. We hypothesize that the reconstructed islets have the normal capability to produce insulin and glucagon with reduced immunoresponses after transplantation. Stem cells are a proliferating population of master cells that have the ability for self-renewal and multilineage differentiation. The recently developed photolithograph-based, biologic, microelectromechanic system (BioMEMS) technique supplies a useful tool for biomedical applications. Our lab has developed a novel method that integrates the adult stem cell and BioMEMS to reconstruct personalized islets. We selected islet-derived progenitor cells (IPC) for repairing and reconstructing STZ-diabetic islets. A6(+)/PYY(+) or A6(+)/ngn3(+) cells were selected to manipulate the neoislets. After 3 to 4 weeks in culture, the reconstructed cells formed islet-like clusters containing insulin or glucagon producing cells. The pilot results showed the ability of these reconstructed islets to correct hyperglycemia when transplanted into a STZ-diabetic isograft mouse model. Although several technical problems remain with the mouse model, namely, the difficulty to collect enough islets from a single mouse because of animal size, the mouse isograft model is suitable for personalized islet development.

  12. The role of a murine transplantation model of atherosclerosis regression in drug discovery

    PubMed Central

    Feig, Jonathan E; Quick, John S

    2015-01-01

    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. PMID:19333880

  13. Attenuation of Obliterative Bronchiolitis by a CXCR4 antagonist in the murine heterotopic tracheal transplant model

    PubMed Central

    Xu, Jianguo; Torres, Edilson; Mora, Ana; Shim, Hyunsuk; Ramirez, Allan; Neujahr, David; Brigham, Kenneth L.; Rojas, Mauricio

    2008-01-01

    Long-term success in lung transplantation is limited by obliterative bronchiolits (OB), while the mechanism for this disease is not well-understood. Chemokine SDF-1 and its receptor CXCR4 have been reported to be involved in several fibrogenic processes by recruiting inflammatory and fibroblast progenitor cells into injured tissues. We hypothesized that SDF-1/CXCR4 axis also plays a role in the pathogenesis of OB. Using the mouse heterotopic allogeneic airway transplant model, we transplanted mouse tracheas from Balb/C donors into C57BL/6 recipients. At day 10 after transplant, we found high expression of SDF-1 in cells in sub-epithelial layers of the allograft. Approximately 26% of cells infiltrating the allograft were CD45+CXCR4+ as was determined by flow cytometry analysis. Treatment of the recipients with a CXCR4 antagonist, TN 14003, decreased cell infiltration into the grafts at day 10 post implantation. At day 42 a significant reduction of the luminal occlusion was found in the TN14003 treated animals compared to controls (57.40% versus 98.21%, p<0.01). To demonstrate the relevance of SDF-1/CXCR4 axis in OB, sections of lung tissue obtained from lung transplanted patients with OB, were examined for SDF-1 and CXCR4 expression. We found higher number of CXCR4 and SDF-1 positive cells in samples from patients with OB compared with normal lungs. These findings provide new insights into the mechanisms of lung chronic rejection and may lead to new intervention tools for the treatment of OB. PMID:19059110

  14. 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.

  15. [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.

  16. 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.

  17. 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

  18. Establishment of a New Murine Elastase-Induced Aneurysm Model Combined with Transplantation

    PubMed Central

    Merx, Marc W.; Koeppel, Thomas A.

    2014-01-01

    Introduction The aim of our study was to develop a reproducible murine model of elastase-induced aneurysm formation combined with aortic transplantation. Methods Adult male mice (n = 6–9 per group) underwent infrarenal, orthotopic transplantation of the aorta treated with elastase or left untreated. Subsequently, both groups of mice were monitored by ultrasound until 7 weeks after grafting. Results Mice receiving an elastase-pretreated aorta developed aneurysms and exhibited a significantly increased diastolic vessel diameter compared to control grafted mice at 7 week after surgery (1.11±0.10 mm vs. 0.75±0.03 mm; p≤0,001). Histopathological examination revealed disruption of medial elastin, an increase in collagen content and smooth muscle cells, and neointima formation in aneurysm grafts. Conclusions We developed a reproducible murine model of elastase-induced aneurysm combined with aortic transplantation. This model may be suitable to investigate aneurysm-specific inflammatory processes and for use in gene-targeted animals. PMID:25068788

  19. A model to examine the validity of the 6-month abstinence criterion for liver transplantation.

    PubMed

    Yates, W R; Martin, M; LaBrecque, D; Hillebrand, D; Voigt, M; Pfab, D

    1998-04-01

    Six months of abstinence from alcohol is a commonly used criterion for liver transplantation eligibility for patients with alcoholic cirrhosis. There is limited evidence to document the validity of this criterion with regard to risk of alcoholism relapse. Ninety-one patients with alcoholic cirrhosis were interviewed for relapse risk using the High Risk Alcoholism Relapse (HRAR) Scale. The HRAR model can be used to predict relapse risk independent of duration of sobriety and therefore can be used to examine the validity of the 6 months of abstinence criteria in this clinical population. The two methods demonstrated poor to fair agreement. Agreement was highest with a cutoff allowing a 5% 6-month relapse risk when 79% agreement (c = 0.56) was demonstrated between the two methods. Using the 6-month abstinence criterion alone disallows a significant number of candidates who have a low relapse risk based on their HRAR score. The validity of the 6-month abstinence criterion is supported somewhat by comparison with the HRAR model. However, use of the 6-month abstinence criterion alone forces a significant number of patients with a low relapse risk by HRAR to wait for transplant listing. A relapse risk model based on an estimate of alcoholism severity in addition to duration of sobriety may more accurately select patients who are most likely to benefit from liver transplantation. PMID:9581661

  20. 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

  1. 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. PMID:24971037

  2. 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

  3. 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

  4. 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.

  5. 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. PMID:23769047

  6. Transplantation of tissue-engineered human corneal endothelium in cat models

    PubMed Central

    Ma, Xiya; Zhao, Jun; Wen, Qian; Hu, Xiuzhong; Yu, Haoze; Shi, Weiyun

    2013-01-01

    Purpose To evaluate the performance of reconstructed tissue-engineered human corneal endothelium (TE-HCE) by corneal transplantation in cat models. Methods TE-HCE reconstruction was performed by culturing 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled monoclonal HCE cells on denuded amniotic membranes (dAMs) in 20% fetal bovine serum-containing Dulbecco’s Modified Eagle’s Medium/Ham’s Nutrient Mixture F12 (1:1) medium and 5% CO2 at 37 °C on a 24-well culture plate. The reconstructed TE-HCE was transplanted into cat corneas via lamellar keratoplasty with all of the endothelium and part of Descemet’s membrane stripped. Postsurgical corneas were monitored daily with their histological properties examined during a period of 104 days after transplantation. Results The reconstructed TE-HCE at a density of 3,413.33±111.23 cells/mm2 in average established intense cell-cell and cell-dAM junctions. After lamellar keratoplasty surgery, no obvious edema was found in TE-HCE-transplanted cat corneas, which were transparent throughout the monitoring period. In contrast, intense corneal edema developed in dAM-transplanted cat corneas, which were turbid. The corneal thickness gradually decreased to 751.33±11.37 μm on day 104 after TE-HCE transplantation, while that of dAM eye was over 1,000 μm in thickness during the monitoring period. A monolayer of endothelium consisting of TE-HCE-originated cells at a density of 2,573.33±0.59 cells/mm2 attached tightly to the surface of remnant Descemet’s membrane over 104 days; this was similar to the normal eye control in cell density. Conclusions The reconstructed TE-HCE was able to function as a corneal endothelium equivalent and restore corneal function in cat models. PMID:23441111

  7. 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.

  8. 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. PMID:26758971

  9. 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.

  10. 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.

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

    PubMed Central

    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

    2016-01-01

    Background and study aims: 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. Patients and methods: Retrospective multicenter study in which Lewis score (LS) was systematically determined in 190 CE of patients diagnosed with CD between 2003 and 2014. Results: 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). Conclusions: 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. PMID:27556069

  12. Local Origin of Mesenchymal Cells in a Murine Orthotopic Lung Transplantation Model of Bronchiolitis Obliterans

    PubMed Central

    Mimura, Takeshi; Walker, Natalie; Aoki, Yoshiro; Manning, Casey M.; Murdock, Benjamin J.; Myers, Jeffery L.; Lagstein, Amir; Osterholzer, John J.; Lama, Vibha N.

    2016-01-01

    Bronchiolitis obliterans is the leading cause of chronic graft failure and long-term mortality in lung transplant recipients. Here, we used a novel murine model to characterize allograft fibrogenesis within a whole-lung microenvironment. Unilateral left lung transplantation was performed in mice across varying degrees of major histocompatibility complex mismatch combinations. B6D2F1/J (a cross between C57BL/6J and DBA/2J) (Haplotype H2b/d) lungs transplanted into DBA/2J (H2d) recipients were identified to show histopathology for bronchiolitis obliterans in all allogeneic grafts. Time course analysis showed an evolution from immune cell infiltration of the bronchioles and vessels at day 14, consistent with acute rejection and lymphocytic bronchitis, to subepithelial and intraluminal fibrotic lesions of bronchiolitis obliterans by day 28. Allografts at day 28 showed a significantly higher hydroxyproline content than the isografts (33.21 ± 1.89 versus 22.36 ± 2.33 μg/mL). At day 40 the hydroxyproline content had increased further (48.91 ± 7.09 μg/mL). Flow cytometric analysis was used to investigate the origin of mesenchymal cells in fibrotic allografts. Collagen I–positive cells (89.43% ± 6.53%) in day 28 allografts were H2Db positive, showing their donor origin. This novel murine model shows consistent and reproducible allograft fibrogenesis in the context of single-lung transplantation and represents a major step forward in investigating mechanisms of chronic graft failure. PMID:25848843

  13. 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

  14. Hair Transplants

    MedlinePlus

    ... How to Choose the Best Skin Care Products Hair Transplants What are hair transplants? In punch transplanting, a plug containing hair ... What should first be done before considering a hair transplant? Before the procedure, an ASDS doctor will ...

  15. Intrahepatic Tissue Implantation Represents a Favorable Approach for Establishing Orthotopic Transplantation Hepatocellular Carcinoma Mouse Models.

    PubMed

    Rao, Quan; You, Abin; Guo, Zhenglong; 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 0.5 cm (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

  16. Intraparenchymal Striatal Transplants Required for Maintenance of Behavioral Recovery in an Animal Model of Huntington's Disease

    PubMed Central

    Sanberg, Paul R.; Giòrdano, Magda; Henault, Mark A.; Nash, David R.; Ragozzino, Michael E.; Hagenmeyer-Houser, Starr H.

    1989-01-01

    Rats which receive injections of kainic acid (KA) into the striatum show many of the anatomical, biochemical and behavioral abnormalities seen in patients with Huntington's disease. Recently, it has been reported that fetal striatal transplants into the lesioned striatum could normalize the neurological and behavioral abnormalities produced by the KA lesion. The present study examined the issue of transplant integration in producing behavioral recovery. In one experiment, lesioned animals with transplants located within the lateral ventricle were compared against parenchymally transplanted rats. It was found that unless the ventricular transplant grew into the lesioned striatum there was no recovery. The second experiment demonstrated that electrolytic destruction of a successful fetal striatal transplant could reverse the transplant-induced behavioral recovery. These results suggest that the integrity of the transplant is important in maintaining behavioral recovery. A continuing functional interaction between the host brain and transplanted tissue may be a vital element in the success of the fetal striatal transplant. PMID:2535266

  17. 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

  18. 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

  19. Development of a transplantable glioma tumour model from genetically engineered mice: MRI/MRS/MRSI characterisation.

    PubMed

    Ciezka, Magdalena; Acosta, Milena; Herranz, Cristina; Canals, Josep M; Pumarola, Martí; Candiota, Ana Paula; Arús, Carles

    2016-08-01

    The initial aim of this study was to generate a transplantable glial tumour model of low-intermediate grade by disaggregation of a spontaneous tumour mass from genetically engineered models (GEM). This should result in an increased tumour incidence in comparison to GEM animals. An anaplastic oligoastrocytoma (OA) tumour of World Health Organization (WHO) grade III was obtained from a female GEM mouse with the S100β-v-erbB/inK4a-Arf (+/-) genotype maintained in the C57BL/6 background. The tumour tissue was disaggregated; tumour cells from it were grown in aggregates and stereotactically injected into C57BL/6 mice. Tumour development was followed using Magnetic Resonance Imaging (MRI), while changes in the metabolomics pattern of the masses were evaluated by Magnetic Resonance Spectroscopy/Spectroscopic Imaging (MRS/MRSI). Final tumour grade was evaluated by histopathological analysis. The total number of tumours generated from GEM cells from disaggregated tumour (CDT) was 67 with up to 100 % penetrance, as compared to 16 % in the local GEM model, with an average survival time of 66 ± 55 days, up to 4.3-fold significantly higher than the standard GL261 glioblastoma (GBM) tumour model. Tumours produced by transplantation of cells freshly obtained from disaggregated GEM tumour were diagnosed as WHO grade III anaplastic oligodendroglioma (ODG) and OA, while tumours produced from a previously frozen sample were diagnosed as WHO grade IV GBM. We successfully grew CDT and generated tumours from a grade III GEM glial tumour. Freezing and cell culture protocols produced progression to grade IV GBM, which makes the developed transplantable model qualify as potential secondary GBM model in mice. PMID:27324642

  20. Development of a transplantable glioma tumour model from genetically engineered mice: MRI/MRS/MRSI characterisation.

    PubMed

    Ciezka, Magdalena; Acosta, Milena; Herranz, Cristina; Canals, Josep M; Pumarola, Martí; Candiota, Ana Paula; Arús, Carles

    2016-08-01

    The initial aim of this study was to generate a transplantable glial tumour model of low-intermediate grade by disaggregation of a spontaneous tumour mass from genetically engineered models (GEM). This should result in an increased tumour incidence in comparison to GEM animals. An anaplastic oligoastrocytoma (OA) tumour of World Health Organization (WHO) grade III was obtained from a female GEM mouse with the S100β-v-erbB/inK4a-Arf (+/-) genotype maintained in the C57BL/6 background. The tumour tissue was disaggregated; tumour cells from it were grown in aggregates and stereotactically injected into C57BL/6 mice. Tumour development was followed using Magnetic Resonance Imaging (MRI), while changes in the metabolomics pattern of the masses were evaluated by Magnetic Resonance Spectroscopy/Spectroscopic Imaging (MRS/MRSI). Final tumour grade was evaluated by histopathological analysis. The total number of tumours generated from GEM cells from disaggregated tumour (CDT) was 67 with up to 100 % penetrance, as compared to 16 % in the local GEM model, with an average survival time of 66 ± 55 days, up to 4.3-fold significantly higher than the standard GL261 glioblastoma (GBM) tumour model. Tumours produced by transplantation of cells freshly obtained from disaggregated GEM tumour were diagnosed as WHO grade III anaplastic oligodendroglioma (ODG) and OA, while tumours produced from a previously frozen sample were diagnosed as WHO grade IV GBM. We successfully grew CDT and generated tumours from a grade III GEM glial tumour. Freezing and cell culture protocols produced progression to grade IV GBM, which makes the developed transplantable model qualify as potential secondary GBM model in mice.

  1. The alternative Iranian model of living renal transplantation.

    PubMed

    Delmonico, Francis L

    2012-09-01

    The experience of the Iranian model should be carefully considered by those who suggest a pilot trial of a regulated market in organ sales. Mahdavi-Mazdeh's candid report makes clear that a fixed price as the basis of regulation is not possible. Iran is proceeding with an independent program of deceased organ donation in cities such as Shiraz. Mahdavi-Mazdeh's report is encouraging for the prospect of a revitalized expansion of deceased donation.

  2. 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

  3. Treatment with tetrahydrobiopterin overcomes brain death-associated injury in a murine model of pancreas transplantation.

    PubMed

    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; Kotsch, K

    2015-11-01

    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.

  4. Fecal Microbiota Transplant Restores Mucosal Integrity in a Murine Model of Burn Injury.

    PubMed

    Kuethe, Joshua W; Armocida, Stephanie M; Midura, Emily F; Rice, Teresa C; Hildeman, David A; Healy, Daniel P; Caldwell, Charles C

    2016-06-01

    The gut microbiome is a community of commensal organisms that are known to play a role in nutrient production as well as gut homeostasis. The composition of the gut flora can be affected by many factors; however, the impact of burn injury on the microbiome is not fully known. Here, we hypothesized that burn-induced changes to the microbiome would impact overall colon health. After scald-burn injury, cecal samples were analyzed for aerobic and anaerobic colony forming units, bacterial community, and butyrate levels. In addition, colon and total intestinal permeabilities were determined. These parameters were further determined in a germ-reduced murine model. Following both burn injury and germ reduction, we observed decreases in aerobic and anaerobic bacteria, increased colon permeability and no change to small intestinal permeability. After burn injury, we further observed a significant decrease in the butyrate producing bacteria R. Gnavus, C. Eutactus, and Roseburia species as well as decreases in colonic butyrate. Finally, in mice that underwent burn followed by fecal microbiota transplant, bacteria levels and mucosal integrity were restored. Altogether our data demonstrate that burn injury can alter the microbiome leading to decreased butyrate levels and increased colon permeability. Of interest, fecal microbiota transplant treatment was able to ameliorate the burn-induced changes in colon permeability. Thus, fecal transplantation may represent a novel therapy in restoring colon health after burn injury.

  5. 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

  6. 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

  7. Inflammatory Bowel Disease

    PubMed Central

    Kaser, Arthur; Zeissig, Sebastian; Blumberg, Richard S.

    2015-01-01

    Insights into inflammatory bowel disease (IBD) are advancing rapidly owing to immunologic investigations of a plethora of animal models of intestinal inflammation, ground-breaking advances in the interrogation of diseases that are inherited as complex genetic traits, and the development of culture-independent methods to define the composition of the intestinal microbiota. These advances are bringing a deeper understanding to the genetically determined interplay between the commensal microbiota, intestinal epithelial cells, and the immune system and the manner in which this interplay might be modified by relevant environmental factors in the pathogenesis of IBD. This review examines these interactions and, where possible, potential lessons from IBD-directed, biologic therapies that may allow for elucidation of pathways that are central to disease pathogenesis in humans. PMID:20192811

  8. 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 - ...

  9. 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

  10. 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

  11. Dual Islet Transplantation Modeling of the Instant Blood-Mediated Inflammatory Reaction

    PubMed Central

    Martin, BM; Samy, KP; Lowe, MC; Thompson, PW; Cano, J; Farris, AB; Song, M; Dove, CR; Leopardi, FV; Strobert, EA; Jenkins, JB; Collins, BH; Larsen, CP; Kirk, AD

    2015-01-01

    Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations. Wild-type (WT) and α1,3-galactosyltransferase knockout (GTKO) neonatal porcine islets (NPIs) were studied in non-immunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at one and 24 hours after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages, and platelets. Insulin, complement, antibody, neutrophils, macrophages, and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 hours in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR. PMID:25702898

  12. Mechanistic Models Predict Efficacy of CCR5-Deficient Stem Cell Transplants in HIV Patient Populations.

    PubMed

    Hosseini, I; Gabhann, F Mac

    2016-02-01

    Combination antiretroviral therapy (cART) effectively suppresses viral load in HIV-infected individuals, but it is not a cure. Bone marrow transplants using HIV-resistant stem cells have renewed hope that cure is achievable but key questions remain e.g., what percentage of stem cells must be HIV-resistant to achieve cure?. As few patients have undergone transplants, we built a mechanistic model of HIV/AIDS to approach this problem. The model includes major players of infection, reproduces the complete course of the disease, and simulates crucial components of clinical treatments, such as cART, irradiation, host recovery, gene augmentation, and donor chimerism. Using clinical data from 172 cART-naïve HIV-infected individuals, we created virtual populations to predict performance of CCR5-deficient stem-cell therapies and explore interpatient variability. We validated our model against a published clinical study of CCR5-modified T-cell therapy. Our model predicted that donor chimerism must exceed 75% to achieve 90% probability of cure across patient populations.

  13. Mechanistic Models Predict Efficacy of CCR5-Deficient Stem Cell Transplants in HIV Patient Populations.

    PubMed

    Hosseini, I; Gabhann, F Mac

    2016-02-01

    Combination antiretroviral therapy (cART) effectively suppresses viral load in HIV-infected individuals, but it is not a cure. Bone marrow transplants using HIV-resistant stem cells have renewed hope that cure is achievable but key questions remain e.g., what percentage of stem cells must be HIV-resistant to achieve cure?. As few patients have undergone transplants, we built a mechanistic model of HIV/AIDS to approach this problem. The model includes major players of infection, reproduces the complete course of the disease, and simulates crucial components of clinical treatments, such as cART, irradiation, host recovery, gene augmentation, and donor chimerism. Using clinical data from 172 cART-naïve HIV-infected individuals, we created virtual populations to predict performance of CCR5-deficient stem-cell therapies and explore interpatient variability. We validated our model against a published clinical study of CCR5-modified T-cell therapy. Our model predicted that donor chimerism must exceed 75% to achieve 90% probability of cure across patient populations. PMID:26933519

  14. Insights from computational modeling in inflammation and acute rejection in limb transplantation.

    PubMed

    Wolfram, Dolores; Starzl, Ravi; Hackl, Hubert; Barclay, Derek; Hautz, Theresa; Zelger, Bettina; Brandacher, Gerald; Lee, W P Andrew; Eberhart, Nadine; Vodovotz, Yoram; Pratschke, Johann; Pierer, Gerhard; Schneeberger, Stefan

    2014-01-01

    Acute skin rejection in vascularized composite allotransplantation (VCA) is the major obstacle for wider adoption in clinical practice. This study utilized computational modeling to identify biomarkers for diagnosis and targets for treatment of skin rejection. Protein levels of 14 inflammatory mediators in skin and muscle biopsies from syngeneic grafts [n = 10], allogeneic transplants without immunosuppression [n = 10] and allografts treated with tacrolimus [n = 10] were assessed by multiplexed analysis technology. Hierarchical Clustering Analysis, Principal Component Analysis, Random Forest Classification and Multinomial Logistic Regression models were used to segregate experimental groups. Based on Random Forest Classification, Multinomial Logistic Regression and Hierarchical Clustering Analysis models, IL-4, TNF-α and IL-12p70 were the best predictors of skin rejection and identified rejection well in advance of histopathological alterations. TNF-α and IL-12p70 were the best predictors of muscle rejection and also preceded histopathological alterations. Principal Component Analysis identified IL-1α, IL-18, IL-1β, and IL-4 as principal drivers of transplant rejection. Thus, inflammatory patterns associated with rejection are specific for the individual tissue and may be superior for early detection and targeted treatment of rejection.

  15. A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation

    PubMed Central

    Xue, Jianmin; Zhu, Xuehai; George, M. Patricia; Myerburg, Michael M.; Stoner, Michael W.; Pilewski, Joseph W.; Duncan, Steven R.

    2011-01-01

    Obliterative bronchiolitis is a frequent, morbid, and usually refractory complication of lung transplantation. Mechanistic study of obliterative bronchiolitis would be aided by development of a relevant model that uses human immune effector cells and airway targets. Our objective was to develop a murine chimera model that mimics obliterative bronchiolitis of lung allograft recipients in human airways in vivo. Human peripheral blood mononuclear cells were adoptively transferred to immunodeficient mice lacking activity of T, B, and NK cells, with and without concurrent transplantations of human small airways dissected from allogeneic cadaveric lungs. Chimerism with human T cells occurred in the majority of recipient animals. The chimeric T cells became highly activated, rapidly infiltrated into the small human airway grafts, and caused obliterative bronchiolitis. In contrast, airways implanted into control mice that did not also receive human peripheral blood mononuclear cell transfers remained intact. In vitro proliferation assays indicated that the chimeric T cells had enhanced specific proliferative responses to donor airway alloantigens. This model confirms the critical role of T cells in development of obliterative bronchiolitis among human lung allograft recipients and provides a novel and easily implemented mechanism for detailed, reductionist in vivo studies of human T-cell responses to allogeneic human small airways. PMID:21801868

  16. Effect of Astragaloside IV on Neural Stem Cell Transplantation in Alzheimer's Disease Rat Models

    PubMed Central

    Haiyan, Hu; Rensong, Yang; Guoqin, Jin; Xueli, Zhang; Huaying, Xia; Yanwu, Xu

    2016-01-01

    Stem cell-based therapy is a promising treatment strategy for neurodegenerative diseases such as Alzheimer's disease (AD). However, the mechanism underlying the maintenance of renewal and replacement capabilities of endogenous progenitor cells or engrafted stem cells in a pathological environment remains elusive. To investigate the effect of astragaloside IV (ASI) on the proliferation and differentiation of the engrafted neural stem cells (NSCs), we cultured NSCs from the hippocampus of E14 rat embryos, treated the cells with ASI, and then transplanted the cells into the hippocampus of rat AD models. In vitro experimentation showed that 10−5 M ASI induced NSCs to differentiate into β-tubulin III+ and GFAP+ cells. NSCs transplantation into rat AD models resulted in improvements in learning and memory, especially in the ASI-treated groups. ASI treatment resulted in an increase in the number of β-tubulin III+ cells in the hippocampus. Further investigation showed that ASI inhibited PS1 expression in vitro and in vivo. The high-dose ASI downregulated the Notch intracellular domain, whereas the low-dose ASI increased Notch-1 and NICD. In conclusion, ASI treatment resulted in improvements in learning and memory of AD models by promoting NSC proliferation and differentiation partly through the Notch signal pathway. PMID:27034688

  17. 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

  18. 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

  19. Intestinal transplantation in children with chronic intestinal pseudo-obstruction

    PubMed Central

    Sigurdsson, L; Reyes, J; Kocoshis, S; Mazariegos, G; Abu-Elmagd, K; Bueno, J; Di, L

    1999-01-01

    BACKGROUND—Children with chronic intestinal pseudo-obstruction (CIPO) often require total parenteral nutrition (TPN) which puts them at risk of liver failure and recurrent line infections. Intestinal transplantation has become a therapeutic option for TPN dependent children with intestinal failure who are failing management with TPN.
AIMS—To investigate the outcome of children with CIPO referred for intestinal transplantation.
METHODS—A retrospective review was carried out of records and diagnostic studies from 27 patients with CIPO referred for intestinal transplantation.
RESULTS—Five children were not listed for transplantation: two because of parental decision, two because of suspicion of Munchausen syndrome by proxy, and one because he tolerated enteral nutrition. Six are still TPN dependent and awaiting transplantation. Eight children died awaiting transplantation. Eight children underwent transplantation. Three died (two months, seven months, and four years after transplant). Five children are alive with a median follow up of 2.6 years (range two months to six years). All transplanted children were able to tolerate full enteral feedings. The postoperative course was complicated by dumping syndrome, Munchausen syndrome by proxy, narcotic withdrawal, and uncovering of achalasia. Conclusion—Intestinal transplantation may be a life saving procedure in children with CIPO. Early referral and thorough pretransplant evaluation are keys to successful transplantation.


Keywords: intestinal transplantation; small bowel transplantation; children; chronic intestinal pseudo-obstruction; small bowel motility; total parenteral nutrition PMID:10486367

  20. 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 ( ...

  1. Inflammatory Bowel Disease

    PubMed Central

    Corridoni, Daniele; Arseneau, Kristen O.; Cominelli, Fabio

    2014-01-01

    Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, relapsing inflammatory condition of the gastrointestinal tract. CD and UC have distinct pathologic and clinical characteristics and despite the extensive amount of research conducted over the past decades, their pathogenesis remains still poorly understood. So far, the accepted dogma is that IBD results from dysregulated mucosal immune response to environmental factors in genetical susceptible hosts. Various components are implicated in the pathogenesis of IBD, including genetic susceptibility, environmental and microbial factors, intestinal epithelial cells and components of innate and adaptive immune system. Given the complexity of IBD, several different animal models of IBD have been developed during the last years. Animal models are very important tools to study the involvement of various factors in the pathogenesis of IBD and, importantly, to test new therapeutic options. This review examines some of the key components that have been found to be closely associated to IBD and describe the distinct features of some of the most important IBD models. PMID:24938525

  2. Transplantation of bone marrow mesenchymal stem cells for the treatment of type 2 diabetes in a macaque model.

    PubMed

    Pan, Xing-hua; Song, Qiao-qiao; Dai, Jie-jie; Yao, Xiang; Wang, Jin-xiang; Pang, Rong-qing; He, Jie; Li, Zi-an; Sun, Xiao-mei; Ruan, Guang-ping

    2013-01-01

    Bone marrow mesenchymal stem cells (BMSCs) are self-renewing, multipotent cells that can migrate to pathological sites and thereby provide a new treatment in diabetic animals. Superparamagnetic iron oxide/4',6-diamidino-2-phenylindole (DAPI) double-labeled BMSCs were transplanted into the pancreatic artery of macaques to treat type 2 diabetes mellitus (T2DM). The treatment efficiency of BMSCs was also evaluated. After successful induction of the T2DM model, the treatment group received double-labeled BMSCs via the pancreatic artery. Six weeks after BMSC transplantation, the fasting blood glucose and blood lipid levels measured in the treatment group were significantly lower (p < 0.05) than in the model group, although they were not reduced to normal levels (p < 0.05). Additionally, the serum C-peptide levels were significantly increased (p < 0.05). An intravenous glucose tolerance test and C-peptide release test had significant changes to the area under the curve. Within 14 days of the transplantation of labeled cells, the pancreatic and kidney tissue of the treatment group emitted a negative signal that was visible on magnetic resonance imaging (MRI). Six weeks after transplantation, DAPI signals appeared in the pancreatic and kidney tissue, which indicates that the BMSCs were mainly distributed in damaged tissue. Labeled stem cells can be used to track migration and distribution in vivo by MRI. In conclusion, the transplantation of BMSCs for the treatment of T2DM is safe and effective.

  3. Embryonic Chicken Transplantation is a Promising Model for Studying the Invasive Behavior of Melanoma Cells

    PubMed Central

    Jayachandran, Aparna; McKeown, Sonja J.; Woods, Briannyn L.; Prithviraj, Prashanth; Cebon, Jonathan

    2015-01-01

    Epithelial-to-mesenchymal transition is a hallmark event in the metastatic cascade conferring invasive ability to tumor cells. There are ongoing efforts to replicate the physiological events occurring during mobilization of tumor cells in model systems. However, few systems are able to capture these complex in vivo events. The embryonic chicken transplantation model has emerged as a useful system to assess melanoma cells including functions that are relevant to the metastatic process, namely invasion and plasticity. The chicken embryo represents an accessible and economical 3-dimensional in vivo model for investigating melanoma cell invasion as it exploits the ancestral relationship between melanoma and its precursor neural crest cells. We describe a methodology that enables the interrogation of melanoma cell motility within the developing avian embryo. This model involves the injection of melanoma cells into the neural tube of chicken embryos. Melanoma cells are labeled using fluorescent tracker dye, Vybrant DiO, then cultured as hanging drops for 24 h to aggregate the cells. Groups of approximately 700 cells are placed into the neural tube of chicken embryos prior to the onset of neural crest migration at the hindbrain level (embryonic day 1.5) or trunk level (embryonic day 2.5). Chick embryos are reincubated and analyzed after 48 h for the location of melanoma cells using fluorescent microscopy on whole mounts and cross-sections of the embryos. Using this system, we compared the in vivo invasive behavior of epithelial-like and mesenchymal-like melanoma cells. We report that the developing embryonic microenvironment confers motile abilities to both types of melanoma cells. Hence, the embryonic chicken transplantation model has the potential to become a valuable tool for in vivo melanoma invasion studies. Importantly, it may provide novel insights into and reveal previously unknown mediators of the metastatic steps of invasion and dissemination in melanoma

  4. In vivo model of wound healing based on transplanted tissue-engineered skin.

    PubMed

    Geer, David J; Swartz, Daniel D; Andreadis, Stelios T

    2004-01-01

    Advances in understanding the complex process of wound healing and development of novel growth factor and gene therapies would benefit from models that mimic closely the physiology of human wounds. To this end, we developed a hybrid wound-healing model based on human tissue-engineered skin transplanted onto athymic mice. Grafted tissues were infiltrated with mouse mesenchymal cells as native and foreign dermal regions fused together. Immunohistochemical staining for human involucrin revealed that the transplanted epithelium maintained its human origin, whereas the dermis was infiltrated by numerous mouse fibroblasts and blood vessels. Grafted tissues were wounded with a 4-mm punch to create full-thickness excisional wounds. At 1 and 2 weeks, the tissues were excised and assessed for reepithelialization, differentiation, and neovascularization. Interestingly, the average rate of keratinocyte migration (120 microm/day) was similar to migration rates observed in human subjects and significantly lower than migration in mouse epidermis. Immunohistochemical staining for keratin 10, laminin, and involucrin revealed a normal pattern of differentiation in the neoepidermis. Neovascularization was significantly elevated in the granulation tissue at 1 week and subsided to the level of unwounded tissue at 2 weeks postwounding. Our data suggest that skin equivalents grafted to a mouse model may serve as a realistic model of human wound regeneration. Because skin equivalents can be prepared with patient cells and genetically modified to stimulate or suppress gene expression, this model may be ideal for addressing mechanistic questions and evaluating the efficacy of biomaterials and gene therapeutics for promoting wound healing. PMID:15363158

  5. Embryonic Chicken Transplantation is a Promising Model for Studying the Invasive Behavior of Melanoma Cells.

    PubMed

    Jayachandran, Aparna; McKeown, Sonja J; Woods, Briannyn L; Prithviraj, Prashanth; Cebon, Jonathan

    2015-01-01

    Epithelial-to-mesenchymal transition is a hallmark event in the metastatic cascade conferring invasive ability to tumor cells. There are ongoing efforts to replicate the physiological events occurring during mobilization of tumor cells in model systems. However, few systems are able to capture these complex in vivo events. The embryonic chicken transplantation model has emerged as a useful system to assess melanoma cells including functions that are relevant to the metastatic process, namely invasion and plasticity. The chicken embryo represents an accessible and economical 3-dimensional in vivo model for investigating melanoma cell invasion as it exploits the ancestral relationship between melanoma and its precursor neural crest cells. We describe a methodology that enables the interrogation of melanoma cell motility within the developing avian embryo. This model involves the injection of melanoma cells into the neural tube of chicken embryos. Melanoma cells are labeled using fluorescent tracker dye, Vybrant DiO, then cultured as hanging drops for 24 h to aggregate the cells. Groups of approximately 700 cells are placed into the neural tube of chicken embryos prior to the onset of neural crest migration at the hindbrain level (embryonic day 1.5) or trunk level (embryonic day 2.5). Chick embryos are reincubated and analyzed after 48 h for the location of melanoma cells using fluorescent microscopy on whole mounts and cross-sections of the embryos. Using this system, we compared the in vivo invasive behavior of epithelial-like and mesenchymal-like melanoma cells. We report that the developing embryonic microenvironment confers motile abilities to both types of melanoma cells. Hence, the embryonic chicken transplantation model has the potential to become a valuable tool for in vivo melanoma invasion studies. Importantly, it may provide novel insights into and reveal previously unknown mediators of the metastatic steps of invasion and dissemination in melanoma.

  6. Irritable bowel syndrome - aftercare

    MedlinePlus

    Irritable bowel syndrome (IBS) may be a lifelong condition. You may be suffering from cramping and loose stools, diarrhea, constipation, or some combination of these symptoms. For some people, IBS symptoms may interfere with work, travel, and attending ...

  7. 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 ...

  8. 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 ...

  9. Are Your Bowels Moving?

    MedlinePlus

    ... how to prevent accidents in the future. continue Diarrhea Diarrhea means you have to move your bowels often, ... eat or if you're taking certain medicines. Diarrhea also can happen when you don't wash ...

  10. Daily bowel care program

    MedlinePlus

    ... a brain or spinal cord injury. People with multiple sclerosis also have problems with their bowels. Symptoms may ... PA: Elsevier Saunders; 2010:chap 17. Read More Multiple sclerosis Recovering after stroke Patient Instructions Constipation - self-care ...

  11. 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

  12. 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.

  13. 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.

  14. Choosing the Order of Deceased Donor and Living Donor Kidney Transplantation in Pediatric Recipients: A Markov Decision Process Model

    PubMed Central

    Van Arendonk, Kyle J.; Chow, Eric K.H.; James, Nathan T.; Orandi, Babak J.; Ellison, Trevor A.; Smith, Jodi M.; Colombani, Paul M.; Segev, Dorry L.

    2014-01-01

    Background Most pediatric kidney transplant recipients eventually require retransplantation, and the most advantageous timing strategy regarding deceased and living donor transplantation in candidates with only one living donor remains unclear. Methods A patient-oriented Markov decision process model was designed to compare, for a given patient with one living donor, living-donor-first followed if necessary by deceased donor retransplantation versus deceased-donor-first followed if necessary by living donor (if still able to donate) or deceased donor (if not) retransplantation. Based on Scientific Registry of Transplant Recipients data, the model was designed to account for waitlist, graft, and patient survival, sensitization, increased risk of graft failure seen during late adolescence, and differential deceased donor waiting times based upon pediatric-priority allocation policies. Based on national cohort data, the model was also designed to account for aging or disease development leading to ineligibility of the living donor over time. Results Given a set of candidate and living donor characteristics, the Markov model provides the expected patient survival over a time horizon of 20 years. For the most highly sensitized patients (PRA>80%), a deceased-donor-first strategy was advantageous, but for all other patients (PRA<80%), a living-donor-first strategy was recommended. Conclusions This Markov model illustrates how patients, families, and providers can be provided information and predictions regarding the most advantageous use of deceased donor versus living donor transplantation for pediatric recipients. PMID:25594552

  15. 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

  16. 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. PMID:27638900

  17. Transplantation of neural differentiated human mesenchymal stem cells into the cochlea of an auditory-neuropathy guinea pig model.

    PubMed

    Cho, Yong-Bum; Cho, Hyong-Ho; Jang, Sujeong; Jeong, Han-Seong; Park, Jong-Seong

    2011-04-01

    The aim of this study was to determine the effects of transplanted neural differentiated human mesenchymal stem cells (hMSCs) in a guinea pig model of auditory neuropathy. In this study, hMSCs were pretreated with a neural-induction protocol and transplanted into the scala tympani of the guinea pig cochlea 7 days after ouabain injury. A control model was made by injection of Hanks balanced salt solution alone into the scala tympani of the guinea pig cochlea 7 days after ouabain injury. We established the auditory neuropathy guinea pig model using 1 mM ouabain application to the round window niche. After application of ouabain to the round window niche, degeneration of most spiral ganglion neurons (SGNs) without the loss of hair cells within the organ of Corti and increasing the auditory brain responses (ABR) threshold were found. After transplantation of neural differentiated hMSCs, the number of SGNs was increased, and some of the SGNs expressed immunoreactivity with human nuclear antibody under confocal laser scanning microscopy. ABR results showed mild hearing recovery after transplantation. Based on an auditory neuropathy animal model, these findings suggest that it may be possible to replace degenerated SGNs by grafting stem cells into the scala tympani. PMID:21468255

  18. 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. PMID:27111656

  19. 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

  20. 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.

  1. Bone Marrow Transplantation Alters the Tremor Phenotype in the Murine Model of Globoid-Cell Leukodystrophy

    PubMed Central

    Reddy, Adarsh S.; Wozniak, David F.; Farber, Nuri B.; Dearborn, Joshua T.; Fowler, Stephen C.; Sands, Mark S.

    2012-01-01

    Tremor is a prominent phenotype of the twitcher mouse, an authentic genetic model of Globoid-Cell Leukodystrophy (GLD, Krabbe’s disease). In the current study, the tremor was quantified using a force-plate actometer designed to accommodate low-weight mice. The actometer records the force oscillations caused by a mouse’s movements, and the rhythmic structure of the force variations can be revealed. Results showed that twitcher mice had significantly increased power across a broad band of higher frequencies compared to wildtype mice. Bone marrow transplantation (BMT), the only available therapy for GLD, worsened the tremor in the twitcher mice and induced a measureable alteration of movement phenotype in the wildtype mice. These data highlight the damaging effects of conditioning radiation and BMT in the neonatal period. The behavioral methodology used herein provides a quantitative approach for assessing the efficacy of potential therapeutic interventions for Krabbe’s disease. PMID:24013457

  2. A quantitative model to predict blood use in adult orthotopic liver transplantation.

    PubMed

    Liu, Chang; Vachharajani, Neeta; Song, Shuang; Cooke, Rhonda; Kangrga, Ivan; Chapman, William C; Grossman, Brenda J

    2015-12-01

    To identify preoperative predictors for the use of any blood component during and after orthotopic liver transplantation (OLT), we performed a retrospective analysis on 602 OLT patients who were randomly split into a training set (n = 482) and a validation set (n = 120). Hemoglobin and calculated MELD score were identified as independent predictors for blood use using bootstrap aggregation. A logistic regression model constructed using both variables showed comparable performance in the training and validation sets. Predictive scores can be obtained from a nomogram, and a score above -2.328 predicted transfusion of any blood component with a positive predictive value of 97% and 96% in the training and validation sets, respectively. PMID:26297190

  3. 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.

  4. 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

  5. Hydrogen Sulfide Decreases Reactive Oxygen in a Model of Lung Transplantation

    PubMed Central

    George, Timothy J.; Arnaoutakis, George J.; Beaty, Claude A.; Jandu, Simran K.; Santhanam, Lakshmi; Berkowitz, Dan E.; Shah, Ashish S.

    2012-01-01

    Objectives Ischemia-reperfusion injury(IRI) is a common complication following lung transplantation(LTx). IRI is thought to be mediated by reactive oxygen species(ROS). Hydrogen sulfide(H2S) is a novel agent that has been previously shown to scavenge ROS and slow metabolism. We evaluated the impact of infused H2S on the presence of ROS after reperfusion in an ex vivo model of LTx. Methods Heart-Lung blocks were recovered from New Zealand White rabbits(n=12) and cold stored in Perfadex solution for 18 hours. Following storage, the heart-lung blocks were reperfused ex vivo with donor rabbit blood. In the treatment group(n=7), a bolus of sodium hydrogen sulfide was added at the beginning of reperfusion(100ug/kg) and continuously infused throughout the two hour experiment(1mg/kg/hr). The vehicle group(n=5) received an equivalent volume of saline. Serial airway and pulmonary artery pressures were measured along with arterial and venous blood gases. Results Oxygenation and pulmonary artery pressures were similar between the two groups. However, treatment with H2S resulted in a dramatic reduction in the presence of ROS after 2 hours of reperfusion(4851 ± 2139 vs. 235 ± 462 RFU/mg protein, p=0.003). There was a trend toward increased levels of cGMP in the H2S treated group(3.08 ± 1.69 vs. 1.73 ± 1.41 fmol/mg tissue, p=0.23). Conclusions After prolonged ischemia, infusion of H2S during reperfusion is associated with a significant decrease in the presence of ROS, a suspected mediator of IRI. To our knowledge, this study represents the first reported therapeutic use of H2S in an experimental model of lung transplant. PMID:22464394

  6. Endothelial cell transplantation onto polymeric arteriovenous grafts evaluated using a canine model.

    PubMed

    Williams, S K; Jarrell, B E; Kleinert, L B

    1994-01-01

    Prosthetic arteriovenous grafts (AVG) placed for hemodialysis access fail in humans due to the thrombogenicity of the flow surface and development of cellular intimal hyperplasia, particularly at the venous anastomosis. The poor patency rates of prosthetic AVG result in significant morbidity and mortality in dialysis patients. Consequently, investigators have been evaluating methods to improve the patency of prosthetic grafts by examining endothelial cell transplantation as a means of creating an antithrombogenic lining on artificial polymers. A canine model was developed to study the effects of cell transplantation of autologous, fat-derived microvessel endothelial cells (MVEC) onto the luminal surface of expanded polytetrafluoroethylene (ePTFE) grafts. Microvessel endothelial cells were isolated from falciform ligament fat, with each dog receiving its own endothelial cells. Isolated cells were subsequently placed into the lumen of the graft (4 mm by 20 cm ePTFE). The graft lumen was pressurized to 5 pounds per square inch (psi) resulting in the partial denucleation of the graft, due to the flow of buffer into the interstices of the graft, and the forced deposition of cells onto the luminal surface. Animals were maintained on aspirin and persantine during the implant phase. During the implant phase, grafts were evaluated by both duplex ultrasound and magnetic resonance angiography (MRA). At explant, gross observation of the sodded grafts revealed a glistening white flow surface with no evidence of thrombosis. Morphologic and scanning electron microscopic evaluations revealed the presence of a cellular lining on the luminal flow surface that exhibited characteristics of antithrombogenic endothelial cells. Midgraft samples were evaluated by immunocytochemistry and indicated that cells on the luminal surface react positively with antibodies to von Willebrand factor. Results from this study demonstrate that the canine model provides an excellent method of studying the

  7. Postinfectious irritable bowel syndrome.

    PubMed

    Spiller, Robin C

    2003-05-01

    A small but significant subgroup of patients with irritable bowel syndrome (IBS) report a sudden onset of their IBS symptoms after a bout of gastroenteritis. Population-based surveys show that although a history of neurotic and psychologic disorders, pain-related diseases, and gastroenteritis are all risk factors for developing IBS, gastroenteritis is the most potent. More toxigenic organisms increase the risk 11-fold, as does an initial illness lasting more than 3 weeks. Hypochondriasis and adverse life events double the risk for postinfective (PI)-IBS and may account for the increased proportion of women who develop this syndrome. PI-IBS is associated with modest increases in mucosal T lymphocytes and serotonin-containing enteroendocrine cells. Animal models and some preliminary human data suggest this leads to excessive serotonin release from the mucosa. Both the histologic changes and symptoms in humans may last for many years with only 40% recovering over a 6-year follow-up. Celiac disease, microscopic colitis, lactose intolerance, early stage Crohn's disease, and bile salt malabsorption should be excluded, as should colon cancer in those over the age of 45 years or in those with a positive family history. Treatment with Loperamide, low-fiber diets, and bile salt- binding therapy may help some patients. Serotonin antagonists are logical treatments but have yet to be evaluated. PMID:12761724

  8. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model

    PubMed Central

    Higginbotham, Laura; Mathews, Dave; Breeden, Cynthia A.; Song, Mingqing; Farris, Alton Brad; Larsen, Christian P.; Ford, Mandy L.; Lutz, Andrew J.; Tector, Matthew; Newell, Kenneth A.; Tector, A. Joseph; Adams, Andrew B.

    2016-01-01

    Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibodies are an important component of the xenogeneic immune response. To address this, we screened a cohort of 34 rhesus macaques for anti-pig antibody levels. We then selected animals with both low and high titers of anti-pig antibodies to proceed with kidney transplant from galactose-α1,3-galactose knockout/CD55 transgenic pig donors. All animals received T-cell depletion followed by maintenance therapy with costimulation blockade (either anti-CD154 mAb or belatacept), mycophenolate mofetil, and steroid. The animal with the high titer of anti-pig antibody rejected the kidney xenograft within the first week. Low-titer animals treated with anti-CD154 antibody, but not belatacept exhibited prolonged kidney xenograft survival (>133 and >126 vs. 14 and 21 days, respectively). Long-term surviving animals treated with the anti-CD154-based regimen continue to have normal kidney function and preserved renal architecture without evidence of rejection on biopsies sampled at day 100. This description of the longest reported survival of pig-to-non-human primate kidney xenotransplantation, now >125 days, provides promise for further study and potential clinical translation. PMID:25847130

  9. Efficiency is a legitimate consideration in equitable distribution of cadaveric transplants: development of an efficiency-equality model of equity.

    PubMed

    Higgins, R M; Johnson, R; Jones, M N A; Rudge, C

    2005-03-01

    It is proposed that equity is a trade-off, or compromise, between equality and efficiency. The kidney transplant allocation algorithm currently used in the United Kingdom (NAT) was tested in the efficiency-equity model. In an exercise of 2000 past UK donors and a dynamic waiting list of 5000 potential recipients, 4000 transplants were allocated according either by NAT, by equal allocation (EQ) (a lottery), or by efficiency (EF). Diabetic recipients received 7.4% of transplants in NAT, 8.6% in EQ, and 0% in EF; paediatric recipients received 6.8% in NAT, 0.6% in EQ, and 0.7% in EF model. For HLA matching, there were 77.9% favourable or 000 matches in NAT, 3.0% in EQ, and 53.1% in EF. Predicted survival showed better outcomes in EF versus NAT (P < .0001) and in NAT versus EQ (P = .05). The NAT allocation system favours paediatric recipients and does not deny diabetics the chance of a transplant, broadly in line with published public and professional opinions. The NAT scheme achieves better HLA matching than the EF model, and this suggests that the rationale for allocation based primarily on HLA matching could be reexamined.

  10. Noninvasive evaluation of the vascular response to transplantation of alginate encapsulated islets using the dorsal skin-fold model.

    PubMed

    Krishnan, Rahul; Arora, Rajan P; Alexander, Michael; White, Sean M; Lamb, Morgan W; Foster, Clarence E; Choi, Bernard; Lakey, Jonathan R T

    2014-01-01

    Alginate encapsulation reduces the risk of transplant rejection by evading immune-mediated cell injury and rejection; however, poor vascular perfusion results in graft failure. Since existing imaging models are incapable of quantifying the vascular response to biomaterial implants after transplantation, in this study, we demonstrate the use of in vivo laser speckle imaging (LSI) and wide-field functional imaging (WiFI) to monitor the microvascular environment surrounding biomaterial implants. The vascular response to two islet-containing biomaterial encapsulation devices, alginate microcapsules and a high-guluronate alginate sheet, was studied and compared after implantation into the mouse dorsal window chamber (N = 4 per implant group). Images obtained over a 14-day period using LSI and WiFI were analyzed using algorithms to quantify blood flow, hemoglobin oxygen saturation and vascular density. Using our method, we were able to monitor the changes in the peri-implant microvasculature noninvasively without the use of fluorescent dyes. Significant changes in blood flow, hemoglobin oxygen saturation and vascular density were noted as early as the first week post-transplant. The dorsal window chamber model enables comparison of host responses to transplanted biomaterials. Future experiments will study the effect of changes in alginate composition on the vascular and immune responses. PMID:24176195

  11. Inhibiting Integrin αvβ5 Reduces Ischemia-Reperfusion Injury in an Orthotopic Lung Transplant Model in Mice.

    PubMed

    Mallavia, B; Liu, F; Sheppard, D; Looney, M R

    2016-04-01

    Primary graft dysfunction after lung transplantation is the leading cause of morbidity and mortality in the immediate posttransplant period and is characterized by endothelial and epithelial barrier disruption and the leakage of protein-rich edema fluid. Integrins are cell surface receptors that have an important role in maintenance of the cell barrier, and inhibition of integrins, such as αvβ5, can diminish alveolar flooding in lung injury models. We hypothesized that inhibition of αvβ5 during donor lung cold ischemia would reduce endothelial permeability during reperfusion. Using an orthotopic single lung transplantation model with and without cold ischemia, donor lungs were perfused with αvβ5-blocking antibody (ALULA) or control antibody at the time of collection, followed by transplantation, 8 h of reperfusion, and the measurement of lung injury parameters. Prolonged cold ischemia (18 h) produced increases in extravascular lung water, protein permeability, and neutrophilic alveolitis and decreased oxygenation compared with lungs without cold ischemia. Perfusion of lungs with αvβ5 antibody versus control antibody protected donor lungs from injury and significantly improved oxygenation. In summary, αvβ5 integrin blockade protects from the development of ischemia-reperfusion lung injury and is a promising approach to preventing primary graft dysfunction in human lung transplant procedures.

  12. Noninvasive evaluation of the vascular response to transplantation of alginate encapsulated islets using the dorsal skin-fold model

    PubMed Central

    Krishnan, Rahul; Arora, Rajan P.; Alexander, Michael; White, Sean M.; Lamb, Morgan W.; Foster, Clarence E.; Choi, Bernard; Lakey, Jonathan R.T.

    2014-01-01

    Alginate encapsulation reduces the risk of transplant rejection by evading immune-mediated cell injury and rejection; however, poor vascular perfusion results in graft failure. Since existing imaging models are incapable of quantifying the vascular response to biomaterial implants after transplantation, in this study, we demonstrate the use of in vivo laser speckle imaging (LSI) and wide-field functional imaging (WiFI) to monitor the microvascular environment surrounding biomaterial implants. The vascular response to two islet-containing biomaterial encapsulation devices, alginate microcapsules and a high-guluronate alginate sheet, was studied and compared after implantation into the mouse dorsal window chamber (N = 4 per implant group). Images obtained over a 14-day period using LSI and WiFI were analyzed using algorithms to quantify blood flow, hemoglobin oxygen saturation and vascular density. Using our method, we were able to monitor the changes in the peri-implant microvasculature non-invasively without the use of fluorescent dyes. Significant changes in blood flow, hemoglobin oxygen saturation and vascular density were noted as early as the first week post-transplant. The dorsal window chamber model enables comparison of host responses to transplanted biomaterials. Future experiments will study the effect of changes in alginate composition on the vascular and immune responses. PMID:24176195

  13. Effect of Prophylactic Antifungal Protocols on the Prognosis of Liver Transplantation: A Propensity Score Matching and Multistate Model Approach

    PubMed Central

    Chen, Yi-Chan; Wang, Yu-Chao; Lee, Chen-Fang; Wu, Ting-Jun; Chou, Hong-Shiue; Chan, Kun-Ming; Lee, Wei-Chen

    2016-01-01

    Background. Whether routine antifungal prophylaxis decreases posttransplantation fungal infections in patients receiving orthotopic liver transplantation (OLT) remains unclear. This study aimed to determine the effectiveness of antifungal prophylaxis for patients receiving OLT. Patients and Methods. This is a retrospective analysis of a database at Chang Gung Memorial Hospital. We have been administering routine antibiotic and prophylactic antifungal regimens to recipients with high model for end-stage liver disease scores (>20) since 2009. After propensity score matching, 402 patients were enrolled. We conducted a multistate model to analyze the cumulative hazards, probability of fungal infections, and risk factors. Results. The cumulative hazards and transition probability of “transplantation to fungal infection” were lower in the prophylaxis group. The incidence rate of fungal infection after OLT decreased from 18.9% to 11.4% (p = 0.052); overall mortality improved from 40.8% to 23.4% (p < 0.001). In the “transplantation to fungal infection” transition, prophylaxis was significantly associated with reduced hazards for fungal infection (hazard ratio: 0.57, 95% confidence interval: 0.34–0.96, p = 0.033). Massive ascites, cadaver transplantation, and older age were significantly associated with higher risks for mortality. Conclusion. Prophylactic antifungal regimens in high-risk recipients might decrease the incidence of posttransplant fungal infections. PMID:27747235

  14. Noninvasive evaluation of the vascular response to transplantation of alginate encapsulated islets using the dorsal skin-fold model.

    PubMed

    Krishnan, Rahul; Arora, Rajan P; Alexander, Michael; White, Sean M; Lamb, Morgan W; Foster, Clarence E; Choi, Bernard; Lakey, Jonathan R T

    2014-01-01

    Alginate encapsulation reduces the risk of transplant rejection by evading immune-mediated cell injury and rejection; however, poor vascular perfusion results in graft failure. Since existing imaging models are incapable of quantifying the vascular response to biomaterial implants after transplantation, in this study, we demonstrate the use of in vivo laser speckle imaging (LSI) and wide-field functional imaging (WiFI) to monitor the microvascular environment surrounding biomaterial implants. The vascular response to two islet-containing biomaterial encapsulation devices, alginate microcapsules and a high-guluronate alginate sheet, was studied and compared after implantation into the mouse dorsal window chamber (N = 4 per implant group). Images obtained over a 14-day period using LSI and WiFI were analyzed using algorithms to quantify blood flow, hemoglobin oxygen saturation and vascular density. Using our method, we were able to monitor the changes in the peri-implant microvasculature noninvasively without the use of fluorescent dyes. Significant changes in blood flow, hemoglobin oxygen saturation and vascular density were noted as early as the first week post-transplant. The dorsal window chamber model enables comparison of host responses to transplanted biomaterials. Future experiments will study the effect of changes in alginate composition on the vascular and immune responses.

  15. [Research progress of fecal microbiota transplantation].

    PubMed

    Dai, Ting; Tang, Tongyu

    2015-07-01

    Intestinal microbial ecosystem is the most complex and the largest micro-ecosystem of the mammals. The use of antibiotics can lead to a lot of major changes of the flora, making the intestinal flora damaged and impacted, even developing Clostridium difficile infection. Fecal microbiota transplantation (FMT) as a special organ transplant therapy, which can rebuild the intestinal flora, has raised the clinical concerns. It has been used in the refractory Clostridium difficile, inflammatory bowel disease, irritable bowel syndrome, chronic fatigue syndrome, and some non-intestinal diseases related to the metabolic disorders. But this method of treatment has not become a normal treatment, and many clinicians and patients can not accept it. This paper reviews relevant literature in terms of origin, indications, mechanism, production process, current situation and future research, and provide a reference for the clinical application of the treatment of fecal microbiota transplantation.

  16. [Small-Bowel Cancer].

    PubMed

    Kagaya, Yuka; Sakamoto, Hirotsugu; Yamamoto, Hironori

    2016-05-01

    Diagnosis of small-bowel cancer has become easier thanks to the development of both balloon-assisted endoscopy and capsule endoscopy. Balloon-assisted endoscopy allows not only for observation of the deep intestine but also for biopsies and for establishing a histological diagnosis. Although endoscopic diagnosis is reported to improve the prognosis of small-bowel cancer by early detection, it is still difficult and the prognosis in general is poor. Surgery and chemotherapy protocols for this disease are similar to those for colon cancer. At present, the response rate to chemotherapy for small-bowel cancer is low. There is an urgent need in this patient population to establish a new diagnostic and therapeutic algorithm using balloon-assisted endoscopy and capsule endoscopy. PMID:27210079

  17. PPARγ in Inflammatory Bowel Disease

    PubMed Central

    Annese, Vito; Rogai, Francesca; Settesoldi, Alessia; Bagnoli, Siro

    2012-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is member of a family of nuclear receptors that interacts with nuclear proteins acting as coactivators and corepressors. The colon is a major tissue which expresses PPARγ in epithelial cells and, to a lesser degree, in macrophages and lymphocytes and plays a role in the regulation of intestinal inflammation. Indeed, both natural and synthetic PPARγ ligands have beneficial effects in different models of experimental colitis, with possible implication in the therapy of inflammatory bowel disease (IBD). This paper will specifically focus on potential role of PPARγ in the predisposition and physiopathology of IBD and will analyze its possible role in medical therapy. PMID:22997506

  18. State of deceased donor transplantation in India: A model for developing countries around the world.

    PubMed

    Abraham, Georgi; Vijayan, Madhusudan; Gopalakrishnan, Natarajan; Shroff, Sunil; Amalorpavanathan, Joseph; Yuvaraj, Anand; Nair, Sanjeev; Sundarrajan, Saravanan

    2016-06-24

    Renal replacement therapy (RRT) resources are scarce in India, with wide urban-rural and interstate disparities. The burden of end-stage renal disease is expected to increase further due to increasing prevalence of risk factors like diabetes mellitus. Renal transplantation, the best RRT modality, is increasing in popularity, due to improvements made in public education, the deceased donor transplantation (DDT) programme and the availability of free and affordable transplant services in government hospitals and certain non-governmental philanthropic organizations. There are about 120000 haemodialysis patients and 10000 chronic peritoneal dialysis patients in India, the majority of them waiting for a donor kidney. Shortage of organs, lack of transplant facilities and high cost of transplant in private facilities are major barriers for renal transplantation in India. The DDT rate in India is now 0.34 per million population, among the lowest in the world. Infrastructural development in its infancy and road traffic rules not being strictly implemented by the authorities, have led to road traffic accidents being very common in urban and rural India. Many patients are declared brain dead on arrival and can serve as potential organ donors. The DDT programme in the state of Tamil Nadu has met with considerable success and has brought down the incidence of organ trade. Government hospitals in Tamil Nadu, with a population of 72 million, provide free transplantation facilities for the underprivileged. Public private partnership has played an important role in improving organ procurement rates, with the help of trained transplant coordinators in government hospitals. The DDT programmes in the southern states of India (Tamil Nadu, Kerala, Pondicherry) are advancing rapidly with mutual sharing due to public private partnership providing vital organs to needy patients. Various health insurance programmes rolled out by the governments in the southern states are effective in

  19. State of deceased donor transplantation in India: A model for developing countries around the world

    PubMed Central

    Abraham, Georgi; Vijayan, Madhusudan; Gopalakrishnan, Natarajan; Shroff, Sunil; Amalorpavanathan, Joseph; Yuvaraj, Anand; Nair, Sanjeev; Sundarrajan, Saravanan

    2016-01-01

    Renal replacement therapy (RRT) resources are scarce in India, with wide urban-rural and interstate disparities. The burden of end-stage renal disease is expected to increase further due to increasing prevalence of risk factors like diabetes mellitus. Renal transplantation, the best RRT modality, is increasing in popularity, due to improvements made in public education, the deceased donor transplantation (DDT) programme and the availability of free and affordable transplant services in government hospitals and certain non-governmental philanthropic organizations. There are about 120000 haemodialysis patients and 10000 chronic peritoneal dialysis patients in India, the majority of them waiting for a donor kidney. Shortage of organs, lack of transplant facilities and high cost of transplant in private facilities are major barriers for renal transplantation in India. The DDT rate in India is now 0.34 per million population, among the lowest in the world. Infrastructural development in its infancy and road traffic rules not being strictly implemented by the authorities, have led to road traffic accidents being very common in urban and rural India. Many patients are declared brain dead on arrival and can serve as potential organ donors. The DDT programme in the state of Tamil Nadu has met with considerable success and has brought down the incidence of organ trade. Government hospitals in Tamil Nadu, with a population of 72 million, provide free transplantation facilities for the underprivileged. Public private partnership has played an important role in improving organ procurement rates, with the help of trained transplant coordinators in government hospitals. The DDT programmes in the southern states of India (Tamil Nadu, Kerala, Pondicherry) are advancing rapidly with mutual sharing due to public private partnership providing vital organs to needy patients. Various health insurance programmes rolled out by the governments in the southern states are effective in

  20. State of deceased donor transplantation in India: A model for developing countries around the world.

    PubMed

    Abraham, Georgi; Vijayan, Madhusudan; Gopalakrishnan, Natarajan; Shroff, Sunil; Amalorpavanathan, Joseph; Yuvaraj, Anand; Nair, Sanjeev; Sundarrajan, Saravanan

    2016-06-24

    Renal replacement therapy (RRT) resources are scarce in India, with wide urban-rural and interstate disparities. The burden of end-stage renal disease is expected to increase further due to increasing prevalence of risk factors like diabetes mellitus. Renal transplantation, the best RRT modality, is increasing in popularity, due to improvements made in public education, the deceased donor transplantation (DDT) programme and the availability of free and affordable transplant services in government hospitals and certain non-governmental philanthropic organizations. There are about 120000 haemodialysis patients and 10000 chronic peritoneal dialysis patients in India, the majority of them waiting for a donor kidney. Shortage of organs, lack of transplant facilities and high cost of transplant in private facilities are major barriers for renal transplantation in India. The DDT rate in India is now 0.34 per million population, among the lowest in the world. Infrastructural development in its infancy and road traffic rules not being strictly implemented by the authorities, have led to road traffic accidents being very common in urban and rural India. Many patients are declared brain dead on arrival and can serve as potential organ donors. The DDT programme in the state of Tamil Nadu has met with considerable success and has brought down the incidence of organ trade. Government hospitals in Tamil Nadu, with a population of 72 million, provide free transplantation facilities for the underprivileged. Public private partnership has played an important role in improving organ procurement rates, with the help of trained transplant coordinators in government hospitals. The DDT programmes in the southern states of India (Tamil Nadu, Kerala, Pondicherry) are advancing rapidly with mutual sharing due to public private partnership providing vital organs to needy patients. Various health insurance programmes rolled out by the governments in the southern states are effective in

  1. Inflammatory Bowel Disease.

    PubMed

    2016-01-01

    Inflammation response plays an important role in host survival, and it also leads to acute and chronic inflammatory diseases such as rheumatoid arthritis, bowel diseases, allergic rhinitis, asthma, atopic dermatitis and various neurodegenerative diseases. During the course of inflammation, the ROS level increases. In addition to ROS, several inflammatory mediators produced at the site lead to numerous cell-mediated damages. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal disorder resulting from a dysfunctional epithelial, innate and adaptive immune response to intestinal microorganisms. The methods involving indomethacin-induced enterocolitis in rats with macroscopic changes of IBD, myeloperoxidase assay, microscopic (histologic) characters and biochemical parameters are discussed.

  2. Cyclosporine pharmacokinetics in pancreas transplant recipients.

    PubMed

    Munda, R; Schroeder, T J; Pedersen, S A; Clardy, C W; Wadhwa, N K; Myre, S A; Stephens, G W; Pesce, A J; Alexander, J W; First, M R

    1988-04-01

    Ten CsA pharmacokinetic studies were performed on five pancreas transplant recipients to determine proper doses and dosing intervals. These cadaver pancreas transplants were performed with exocrine ductal drainage into the urinary tract through a bladder anastomosis in four cases and into the bowel in one case. Four CsA pharmacokinetic studies were performed on diabetic renal transplant recipients and an additional six studies were performed while with pancreas transplant patients taking metoclopramide in an effort to enhance absorption of CsA. Mean CsA dose was 3.7 mg/kg/dose (range 2.1 to 7.5 mg/kg/dose). All patients but one were on twice daily dosing intervals yielding an average daily dose of 7.4 mg/kg/d. Noncompartmental pharmacokinetic analyses were used. The adequacy of a 1-, 2-, or 3-exponential model was determined by breakpoint analysis of the log concentration v time curve using the F statistic. The terminal rate constant was calculated by nonlinear regression analysis. The AUC and AUMC were calculated by the trapezoidal method with exponential extrapolation and these were used to calculate the MRT and Vdss. The unknown fractional absorption, F, was used to correct the oral data. The average CsA concentration maximum (Cmax) was 528 ng/mL with an average time to maximum concentration (Tmax) of 4.7 hours, a mean residence time of 7.75 hours, with a Vdss/%F of 9.61 L/kg in the pancreas transplant recipients. Additional studies of six patients receiving metoclopramide with CsA revealed an average Cmax of 723 ng/mL, an average Tmax of 2.3 hours, an average MRT of 6.08 hours, and an average Vdss/%F of 5.7% L/kg. These results indicate that coexistent gastroparesis in diabetic recipients of either pancreatic or renal transplants may result in reduced bioavailability of CsA. PMID:3284095

  3. Development of a Minor Histocompatibility Antigen Vaccine Regimen in the Canine Model of Hematopoietic Cell Transplantation

    PubMed Central

    Rosinski, Steven L.; Stone, Brad; Graves, Scott S.; Fuller, Deborah H.; De Rosa, Stephen C.; Spies, Gregory A.; Mize, Gregory J.; Fuller, James T.; Storb, Rainer

    2015-01-01

    Background Minor histocompatibility (miHA) antigen 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 MHC-matched allogeneic hematopoietic cell transplantation (HCT) as a platform to develop a miHA vaccination regimen. Methods We engineered DNA plasmids and replication-deficient human adenovirus type 5 (rAd5) constructs encoding large sections of canine SMCY and the entire canine SRY gene. Results Priming with rAd5 constructs and boosting with ex vivo plasmid-transfected dendritic cells and cutaneous delivery of plasmids with a particle-mediated epidermal delivery device (PMED) in two female dogs induced antigen-specific T cell responses. Similar responses were observed following a prime-boost vaccine regimen in three female HCT donors. Subsequent donor lymphocyte infusion resulted in a significant change of chimerism in 1 of 3 male recipients without any signs of GVHD. 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. Conclusions 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. PMID:25965411

  4. Inclusion of CYP3A5 genotyping in a nonparametric population model improves dosing of tacrolimus early after transplantation

    PubMed Central

    Åsberg, Anders; Midtvedt, Karsten; van Guilder, Mike; Størset, Elisabet; Bremer, Sara; Bergan, Stein; Jelliffe, Roger; Hartmann, Anders; Neely, Michael N

    2013-01-01

    Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C0 concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three-compartment model with first-order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat-free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3-4 tacrolimus concentrations were known. After this, a model without CYP3A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation. PMID:24118301

  5. Hair transplantation.

    PubMed

    Avram, Marc R

    2012-12-01

    Hair transplantation is a purely dermatologic surgical procedure that dermatologists should be able to perform in appropriate candidates with hair loss. Hair transplantation techniques performed in the 1960s through the 1990s utilized large grafts that created an unfortunate public image of unnatural-appearing transplanted hair. Over the last 15 years, hair transplantation has been performed using follicular units to create consistently natural-looking transplanted hair in both men and women. This article provides an overview of candidate selection and state-of-the-art techniques for performing hair transplantation.

  6. Primordial Follicle Transplantation within Designer Biomaterial Grafts Produce Live Births in a Mouse Infertility Model

    PubMed Central

    Kniazeva, E.; Hardy, A. N.; Boukaidi, S. A.; Woodruff, T. K.; Jeruss, J. S.; Shea, L. D.

    2015-01-01

    The gonadotoxic effects of chemotherapy and radiation may result in premature ovarian failure in premenopausal oncology patients. Although autotransplantation of ovarian tissue has led to successful live births, reintroduction of latent malignant cells inducing relapse is a significant concern. In this report, we investigated the design of biomaterial grafts for transplantation of isolated ovarian follicles as a means to preserve fertility. Primordial and primary ovarian follicles from young female mice were extracted and encapsulated into biomaterials for subsequent transplantation into adult mice. Among the formulations tested, aggregated follicles encapsulated within fibrin had enhanced survival and integration with the host tissue following transplantation relative to the fibrin-alginate and fibrin-collagen composites. All mice transplanted with fibrin-encapsulated follicles resumed cycling, and live births were achieved only for follicles transplanted within VEGF-loaded fibrin beads. The extent to which these procedures reduce the presence of metastatic breast cancer cells among the isolated follicles was evaluated, with significantly reduced numbers of cancer cells present relative to intact ovaries. This ability to obtain live births by transplanting isolated primordial and primary follicles, while also reducing the risk of re-seeding disease relative to ovarian tissue transplantation, may ultimately provide a means to preserve fertility in premenopausal oncology patients. PMID:26633657

  7. Neural stem cell transplantation enhances mitochondrial biogenesis in a transgenic mouse model of Alzheimer's disease-like pathology.

    PubMed

    Zhang, Wei; Gu, Guo-Jun; Shen, Xing; Zhang, Qi; Wang, Gang-Min; Wang, Pei-Jun

    2015-03-01

    Mitochondrial dysfunction, especially a defect in mitochondrial biogenesis, is an early and prominent feature of Alzheimer's disease (AD). Previous studies demonstrated that the number of mitochondria is significantly reduced in susceptible hippocampal neurons from AD patients. Neural stem cell (NSC) transplantation in AD-like mice can compensate for the neuronal loss resulting from amyloid-beta protein deposition. The effects of NSC transplantation on mitochondrial biogenesis and cognitive function in AD-like mice, however, are poorly understood. In this study, we injected NSCs or vehicle into 12-month-old amyloid precursor protein (APP)/PS1 transgenic mice, a mouse model of AD-like pathology. The effects of NSC transplantation on cognitive function, the amount of mitochondrial DNA, the expression of mitochondrial biogenesis factors and mitochondria-related proteins, and mitochondrial morphology were investigated. Our results show that in NSC-injected APP/PS1 (Tg-NSC) mice, the cognitive function, number of mitochondria, and expression of mitochondria-related proteins, specifically the mitochondrial fission factors (dynamin-related protein 1 [Drp1] and fission 1 [Fis1]) and the mitochondrial fusion factor optic atrophy 1 (OPA1), were significantly increased compared with those in age-matched vehicle-injected APP/PS1 (Tg-Veh) mice, whereas the expression of mitochondrial fusion factors mitofusion 1 (Mfn1) and Mfn2 was significantly decreased. These data indicate that NSC transplantation may enhance mitochondria biogenesis and further rescue cognitive deficits in AD-like mice. PMID:25582749

  8. Neural stem cell transplantation enhances mitochondrial biogenesis in a transgenic mouse model of Alzheimer's disease-like pathology.

    PubMed

    Zhang, Wei; Gu, Guo-Jun; Shen, Xing; Zhang, Qi; Wang, Gang-Min; Wang, Pei-Jun

    2015-03-01

    Mitochondrial dysfunction, especially a defect in mitochondrial biogenesis, is an early and prominent feature of Alzheimer's disease (AD). Previous studies demonstrated that the number of mitochondria is significantly reduced in susceptible hippocampal neurons from AD patients. Neural stem cell (NSC) transplantation in AD-like mice can compensate for the neuronal loss resulting from amyloid-beta protein deposition. The effects of NSC transplantation on mitochondrial biogenesis and cognitive function in AD-like mice, however, are poorly understood. In this study, we injected NSCs or vehicle into 12-month-old amyloid precursor protein (APP)/PS1 transgenic mice, a mouse model of AD-like pathology. The effects of NSC transplantation on cognitive function, the amount of mitochondrial DNA, the expression of mitochondrial biogenesis factors and mitochondria-related proteins, and mitochondrial morphology were investigated. Our results show that in NSC-injected APP/PS1 (Tg-NSC) mice, the cognitive function, number of mitochondria, and expression of mitochondria-related proteins, specifically the mitochondrial fission factors (dynamin-related protein 1 [Drp1] and fission 1 [Fis1]) and the mitochondrial fusion factor optic atrophy 1 (OPA1), were significantly increased compared with those in age-matched vehicle-injected APP/PS1 (Tg-Veh) mice, whereas the expression of mitochondrial fusion factors mitofusion 1 (Mfn1) and Mfn2 was significantly decreased. These data indicate that NSC transplantation may enhance mitochondria biogenesis and further rescue cognitive deficits in AD-like mice.

  9. Adipose-derived stromal cell autologous transplantation ameliorates pulmonary arterial hypertension induced by shunt flow in rat models.

    PubMed

    Liu, Kai; Liu, Ruifang; Cao, Guangqing; Sun, Hourong; Wang, Xuping; Wu, Shuming

    2011-06-01

    Hyperkinetic pulmonary arterial hypertension (PAH) severely influences the success of operation for congenital heart disease and deteriorates the prognosis of disease. Adipose-derived stromal cell (ADSC) is a good alternative multipotent stem cell for regeneration medicine. PAH rat models were established by arteriovenous shunt and ADSCs were isolated, cultured, and labeled in vitro. Twelve weeks after shunt operation, rats received an injection of 5 × 10(7) ADSCs. Two weeks after transplantation, hemodynamic abnormality induced by the shunt flow and the hypertrophy of right ventricle were reversed, which was confirmed by invasive measurement and echocardiography examination. The PAH rats receiving cell transplantation demonstrated decreased remodeling of small arteries in the lung; immunohistochemistry analysis showed augmented expression of hepatocyte growth factor (HGF) and increased number of pulmonary small arteries. Western blot and real-time reverse transcriptase-polymerase chain reaction indicated that the protein and mRNA levels of HGF and endothelial nitric oxide synthase increased, respectively, in the lung after cell transplantation. Our results suggested that ADSC transplantation can ameliorate PAH induced by shunt flow by enhancing the expression of HGF and subsequently promoting angiogenesis in the injured lung tissue. PMID:20828291

  10. Development and Validation of Predictive Models of Cardiac Mortality and Transplantation in Resynchronization Therapy

    PubMed Central

    Rocha, Eduardo Arrais; Pereira, Francisca Tatiana Moreira; Abreu, José Sebastião; Lima, José Wellington O.; Monteiro, Marcelo de Paula Martins; Rocha Neto, Almino Cavalcante; Goés, Camilla Viana Arrais; Farias, Ana Gardênia P.; Rodrigues Sobrinho, Carlos Roberto Martins; Quidute, Ana Rosa Pinto; Scanavacca, Maurício Ibrahim

    2015-01-01

    Background 30-40% of cardiac resynchronization therapy cases do not achieve favorable outcomes. Objective This study aimed to develop predictive models for the combined endpoint of cardiac death and transplantation (Tx) at different stages of cardiac resynchronization therapy (CRT). Methods Prospective observational study of 116 patients aged 64.8 ± 11.1 years, 68.1% of whom had functional class (FC) III and 31.9% had ambulatory class IV. Clinical, electrocardiographic and echocardiographic variables were assessed by using Cox regression and Kaplan-Meier curves. Results The cardiac mortality/Tx rate was 16.3% during the follow-up period of 34.0 ± 17.9 months. Prior to implantation, right ventricular dysfunction (RVD), ejection fraction < 25% and use of high doses of diuretics (HDD) increased the risk of cardiac death and Tx by 3.9-, 4.8-, and 5.9-fold, respectively. In the first year after CRT, RVD, HDD and hospitalization due to congestive heart failure increased the risk of death at hazard ratios of 3.5, 5.3, and 12.5, respectively. In the second year after CRT, RVD and FC III/IV were significant risk factors of mortality in the multivariate Cox model. The accuracy rates of the models were 84.6% at preimplantation, 93% in the first year after CRT, and 90.5% in the second year after CRT. The models were validated by bootstrapping. Conclusion We developed predictive models of cardiac death and Tx at different stages of CRT based on the analysis of simple and easily obtainable clinical and echocardiographic variables. The models showed good accuracy and adjustment, were validated internally, and are useful in the selection, monitoring and counseling of patients indicated for CRT. PMID:26559987

  11. Liver fibrosis impairs hepatic pharmacokinetics of liver transplant drugs in the rat model.

    PubMed

    Zou, Yu-Hong; Liu, Xin; Khlentzos, Alexander M; Asadian, Peyman; Li, Peng; Thorling, Camilla A; Robertson, Thomas A; Fletcher, Linda M; Crawford, Darrell H G; Roberts, Michael S

    2010-01-01

    This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl(4)-induced fibrotic perfused rat livers and the results were compared to those in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single-pass-perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl(4)-treated rats compared to controls (p<0.05). The extraction ratios (E) for all drugs were significantly lower (p<0.05) in fibrotic than in normal livers and the decrease in E was consistent with the decrease in intrinsic clearance and permeability-surface area product. In addition, other than for furosemide, the mean transit times for all drugs were significantly longer (p<0.01) in the fibrotic livers than in normal livers. Pharmacokinetic model and stepwise regression analyses suggest that these differences arise from a reduction in both the transport of drugs across the basolateral membrane and their metabolic clearance and were in a manner similar to those previously found for another group of drugs.

  12. Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms

    PubMed Central

    Asai, Takashi; Hatlen, Megan A.; Lossos, Chen; Ndiaye-Lobry, Delphine; Deblasio, Anthony; Murata, Kazunori; Fleisher, Martin; Cortizas, Elena M.; Verdun, Ramiro E.; Petrini, John; Nimer, Stephen D.

    2016-01-01

    Multiple myeloma is a plasma cell neoplasm with an extremely variable clinical course. Animal models are needed to better understand its pathophysiology and for preclinical testing of potential therapeutic agents. Hematopoietic cells expressing the hypermorphic Rad50s allele show hematopoietic failure, which can be mitigated by the lack of a transcription factor, Mef/Elf4. However, we find that 70% of Mef−/−Rad50s/s mice die from multiple myeloma or other plasma cell neoplasms. These mice initially show an abnormal plasma cell proliferation and monoclonal protein production, and then develop anemia and a decreased bone mineral density. Tumor cells can be serially transplanted and according to array CGH and whole exome sequencing, the pathogenesis of plasma cell neoplasms in these mice is not linked to activation of a specific oncogene, or inactivation of a specific tumor suppressor. This model recapitulates the systemic manifestations of human plasma cell neoplasms, and implicates cooperativity between the Rad50s and Mef/Elf4 pathways in initiating myelomagenic mutations that promote plasma cell transformation. PMID:26961797

  13. Benign small bowel tumor.

    PubMed Central

    Wilson, J M; Melvin, D B; Gray, G; Thorbjarnarson, B

    1975-01-01

    The clinical record and histologic sections of 84 cases of benign small bowel tumor are reviewed. Manifestations of systemic diseases, congenital anomalies, and lesions of either the ileocecal valve or periampullary region were excluded. In the same time span there were 96 small bowel malignancies. Clinical presentation, pathologic findings, management and result are compared to the collected published experience of about 2000 cases. There were 36 leiomyomas, 22 lipomas, 9 angiomas, 6 neurofibromas and 4 fibromas. Thirty-six men and 48 women were affected; the majority in their fifth and sixth decade. Seventy-eight were operative and 6 autopsy diagnoses. The most common symptom was obstruction (42%) followed by hemorrhage (34%) and pain (22%), relative frequency differing for the various specific tumors. There were rarely significant physical findings. A diagnosis of small bowel tumor was made radiologically in 30 patients. Because of the nonspecificity of other signs and symptoms, an acute awareness of the possibility of small bowel tumor is mandatory for preoperative anticipation of the diagnosis. Local resection was performed in all with no deaths or significant postoperative complications. PMID:1078626

  14. Small bowel obstruction- a surprise.

    PubMed

    Mathew, Jeffrey Daniel; Cp, Ganesh Babu; M, Balachandar; M, Ramanathan

    2015-01-01

    Trans - omental hernia is very rare, accounting to 1-4% of all internal hernias which is an unusual cause of small bowel obstruction. Here we present a case report of a small bowel obstruction in a female due to trans - omental hernia presenting with central abdominal pain, distension and bilious vomiting. She had no previous history of trauma, surgery. Plain X-ray abdomen erect showed multiple air fluid levels with dilated small bowel loops. Emergency laparotomy revealed a segment of congested small bowel loop (ileum) through a defect in greater omentum. On table the herniated bowel loop was reduced and the defect in greater omentum was closed primarily. There was no necessity for bowel resection as it regained normal colour after reduction. Postoperative period was uneventful with complete resolution of symptoms. This case is presented for its rarity and its importance in clinical differential diagnosis of acute abdomen due to small bowel obstruction.

  15. Small Bowel Obstruction- A Surprise

    PubMed Central

    CP, Ganesh Babu; M, Balachandar; M, Ramanathan

    2015-01-01

    Trans - omental hernia is very rare, accounting to 1-4% of all internal hernias which is an unusual cause of small bowel obstruction. Here we present a case report of a small bowel obstruction in a female due to trans - omental hernia presenting with central abdominal pain, distension and bilious vomiting. She had no previous history of trauma, surgery. Plain X-ray abdomen erect showed multiple air fluid levels with dilated small bowel loops. Emergency laparotomy revealed a segment of congested small bowel loop (ileum) through a defect in greater omentum. On table the herniated bowel loop was reduced and the defect in greater omentum was closed primarily. There was no necessity for bowel resection as it regained normal colour after reduction. Postoperative period was uneventful with complete resolution of symptoms. This case is presented for its rarity and its importance in clinical differential diagnosis of acute abdomen due to small bowel obstruction. PMID:25738033

  16. Therapeutic effect of transplanted human Wharton's jelly stem cell-derived oligodendrocyte progenitor cells (hWJ-MSC-derived OPCs) in an animal model of multiple sclerosis.

    PubMed

    Mikaeili Agah, Elmira; Parivar, Kazem; Joghataei, Mohammad Taghi

    2014-04-01

    Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS). A potential new therapeutic approach for MS is cell transplantation which may promote remyelination. We transplanted human Wharton's jelly stem cell-derived oligodendrocyte progenitor cells (hWJ-MSC-derived OPCs) into the brain ventricles of mice induced with experimental autoimmune encephalomyelitis (EAE), the animal model of MS. We studied the effect of the transplanted OPCs on the functional and pathological manifestations of the disease. Transplanted hWJ-MSC-derived OPCs significantly reduced the clinical signs of EAE. Histological examinations showed that remyelination was significantly increased after transplantation. These results suggest that hWJ-MSC-derived OPCs promote the regeneration of myelin sheaths in the brain.

  17. Transplant services

    MedlinePlus

    ... diseased body part with a healthy one. SOLID ORGAN TRANSPLANTS Auto islet cell transplant is done after a ... selected experts, including: Surgeons who specialize in performing ... doctors Radiologists and medical imaging technologists Nurses ...

  18. Pancreas Transplantation

    MedlinePlus

    ... Text Size: A A A Listen En Español Pancreas Transplantation Some patients with type 1 diabetes have ... weigh the potential benefits and risks. Benefits of Pancreas Transplants You may be able to maintain a ...

  19. Evaluation of stem cell reserve using serial bone marrow transplantation and competitive repopulation in a murine model of chronic hemolytic anemia

    SciTech Connect

    Maggio-Price, L.; Wolf, N.S.; Priestley, G.V.; Pietrzyk, M.E.; Bernstein, S.E.

    1988-09-01

    Serial transplantation and competitive repopulation were used to evaluate any loss of self-replicative capacity of bone marrow stem cells in a mouse model with increased and persistent hemopoietic demands. Congenic marrows from old control and from young and old mice with hereditary spherocytic anemia (sphha/sphha) were serially transplanted at 35-day intervals into normal irradiated recipients. Old anemic marrow failed or reverted to recipient karyotype at a mean of 3.5 transplants, and young anemic marrow reverted at a mean of 4.0 transplants, whereas controls did so at a mean of 5.0 transplants. In a competitive assay in which a mixture of anemic and control marrow was transplanted, the anemic marrow persisted to 10 months following transplantation; anemic marrow repopulation was greater if anemic marrow sex matched with the host. It is possible that lifelong stress of severe anemia decreases stem cell reserve in the anemic sphha/sphha mouse marrow. However, marginal differences in serial transplantation number and the maintenance of anemic marrow in a competition assay would suggest that marrow stem cells, under prolonged stress, are capable of exhibiting good repopulating and self-replicating abilities.

  20. Ethical issues in transplantation.

    PubMed

    Sells, R A

    1994-09-01

    The transplantation of gastrointestinal organs has relied on cadaver donors for its successful development. The fact that success has been achieved is largely due to the certainty with which brain death can be diagnosed, and the acceptance of these criteria as signifying actual death by doctors, in particular, intensivists. If continuing goodwill leads to further co-operative effort, cadaveric liver, pancreas and eventually, small bowel transplants, should become more frequent. At present the numbers of recipients requiring these operations are considerably less than those in need of kidneys. There are grounds for believing therefore that the pressure to subvert good ethical standards in acquiring these organs (that pressure imposed by long waiting lists and a high death rate on those waiting lists) should be avoidable. The solution to the problem of deficits in cadaveric liver and pancreatic grafts will be achieved only by better education of nurses and doctors, professionalization and expansion of co-ordinator organizations, legal reform, and cultural change. Only by such progress, achieved at medical, governmental, and societal levels can we avoid the insidious tendency to commercialism which we have witnessed with disquiet in renal transplantation.

  1. A medaka model of cancer allowing direct observation of transplanted tumor cells in vivo at a cellular-level resolution.

    PubMed

    Hasegawa, Sumitaka; Maruyama, Kouichi; Takenaka, Hikaru; Furukawa, Takako; Saga, Tsuneo

    2009-08-18

    The recent success with small fish as an animal model of cancer with the aid of fluorescence technique has attracted cancer modelers' attention because it would be possible to directly visualize tumor cells in vivo in real time. Here, we report a medaka model capable of allowing the observation of various cell behaviors of transplanted tumor cells, such as cell proliferation and metastasis, which were visualized easily in vivo. We established medaka melanoma (MM) cells stably expressing GFP and transplanted them into nonirradiated and irradiated medaka. The tumor cells were grown at the injection sites in medaka, and the spatiotemporal changes were visualized under a fluorescence stereoscopic microscope at a cellular-level resolution, and even at a single-cell level. Tumor dormancy and metastasis were also observed. Interestingly, in irradiated medaka, accelerated tumor growth and metastasis of the transplanted tumor cells were directly visualized. Our medaka model provides an opportunity to visualize in vivo tumor cells "as seen in a culture dish" and would be useful for in vivo tumor cell biology. PMID:19666513

  2. Diet-induced increase in plasma oxidized LDL promotes early fibrosis in a renal porcine auto-transplantation model

    PubMed Central

    2014-01-01

    Background In kidney transplantation, the prevalence of hypercholesterolemia as a co-morbidity factor known to affect graft function, is rising due to the increased number of older donors in response to organ shortage as well as to the hyperlipidemic effects of immunosuppressors in recipient. This study aimed to characterize the effects of hypercholesterolemia on renal graft outcome, investigating the role of oxidized low-density lipoprotein (OxLDL). Methods In vivo, we used a porcine preclinical model of renal auto-transplantation modulated by two experimental diets: a normal (n = 6) or a hyperlipidemic diet (n = 5) maintained during the 3 month follow-up after the surgical procedure. Kidney function and OxLDL levels were monitored as well as fibrosis, LOX-1 and TGF beta signaling pathways. In vitro, we used human artery endothelial cells subjected to OxLDL to investigate the TGF beta profibrotic pathway and the role of the scavenger receptor LOX-1. Results Hyperlipidemic diet-induced increase in plasma OxLDL levels at the time of surgery correlated with an increase in proteinuria 3 months after transplantation, associated with an early graft fibrosis combined with an activation of renal TGF beta signaling. These data suggest a direct involvement of OxLDL in the hyperlipidemic diet-induced activation of the pro-fibrotic TGF beta pathway which seems to be activated by LOX-1 signaling. These results were supported by studies with endothelial cells incubated in culture medium containing OxLDL promoting TGF beta expression inhibited by LOX-1 antibody. Conclusions These results implicate OxLDL in the hyperlipidemic diet-promoted fibrosis in transplanted kidneys, suggesting LOX-1 as a potential therapeutic target and reinforce the need to control cholesterol levels in kidney transplant recipients. PMID:24655356

  3. Enhanced Ghrelin Levels and Hypothalamic Orexigenic AgRP and NPY Neuropeptide Expression in Models of Jejuno-Colonic Short Bowel Syndrome

    PubMed Central

    Gillard, Laura; Billiauws, Lore; Stan-Iuga, Bogdan; Ribeiro-Parenti, Lara; Jarry, Anne-Charlotte; Cavin, Jean-Baptiste; Cluzeaud, Françoise; Mayeur, Camille; Thomas, Muriel; Freund, Jean-Noël; Lacorte, Jean-Marc; Le Gall, Maude; Bado, André; Joly, Francisca; Le Beyec, Johanne

    2016-01-01

    Short bowel syndrome (SBS) patients developing hyperphagia have a better outcome. Gastrointestinal endocrine adaptations help to improve intestinal functions and food behaviour. We investigated neuroendocrine adaptations in SBS patients and rat models with jejuno-ileal (IR-JI) or jejuno-colonic (IR-JC) anastomosis with and without parenteral nutrition. Circulating levels of ghrelin, PYY, GLP-1, and GLP-2 were determined in SBS rat models and patients. Levels of mRNA for proglucagon, PYY and for hypothalamic neuropeptides were quantified by qRT-PCR in SBS rat models. Histology and immunostaining for Ki67, GLP-1 and PYY were performed in SBS rats. IR-JC rats, but not IR-JI, exhibited significantly higher crypt depths and number of Ki67-positive cells than sham. Fasting and/or postprandial plasma ghrelin and PYY concentrations were higher, or tend to be higher, in IR-JC rats and SBS-JC patients than in controls. Proglucagon and Pyy mRNA levels were significantly enhanced in IR-JC rats. Levels of mRNA coding hypothalamic orexigenic NPY and AgRP peptides were significantly higher in IR-JC than in sham rats. We demonstrate an increase of plasma ghrelin concentrations, major changes in hypothalamic neuropeptides levels and greater induction of PYY in SBS-JC rats and patients suggesting that jejuno-colonic continuity creates a peculiar environment promoting further gut-brain adaptations. PMID:27323884

  4. Enhanced Ghrelin Levels and Hypothalamic Orexigenic AgRP and NPY Neuropeptide Expression in Models of Jejuno-Colonic Short Bowel Syndrome.

    PubMed

    Gillard, Laura; Billiauws, Lore; Stan-Iuga, Bogdan; Ribeiro-Parenti, Lara; Jarry, Anne-Charlotte; Cavin, Jean-Baptiste; Cluzeaud, Françoise; Mayeur, Camille; Thomas, Muriel; Freund, Jean-Noël; Lacorte, Jean-Marc; Le Gall, Maude; Bado, André; Joly, Francisca; Le Beyec, Johanne

    2016-01-01

    Short bowel syndrome (SBS) patients developing hyperphagia have a better outcome. Gastrointestinal endocrine adaptations help to improve intestinal functions and food behaviour. We investigated neuroendocrine adaptations in SBS patients and rat models with jejuno-ileal (IR-JI) or jejuno-colonic (IR-JC) anastomosis with and without parenteral nutrition. Circulating levels of ghrelin, PYY, GLP-1, and GLP-2 were determined in SBS rat models and patients. Levels of mRNA for proglucagon, PYY and for hypothalamic neuropeptides were quantified by qRT-PCR in SBS rat models. Histology and immunostaining for Ki67, GLP-1 and PYY were performed in SBS rats. IR-JC rats, but not IR-JI, exhibited significantly higher crypt depths and number of Ki67-positive cells than sham. Fasting and/or postprandial plasma ghrelin and PYY concentrations were higher, or tend to be higher, in IR-JC rats and SBS-JC patients than in controls. Proglucagon and Pyy mRNA levels were significantly enhanced in IR-JC rats. Levels of mRNA coding hypothalamic orexigenic NPY and AgRP peptides were significantly higher in IR-JC than in sham rats. We demonstrate an increase of plasma ghrelin concentrations, major changes in hypothalamic neuropeptides levels and greater induction of PYY in SBS-JC rats and patients suggesting that jejuno-colonic continuity creates a peculiar environment promoting further gut-brain adaptations. PMID:27323884

  5. Chronic Psychological Stress Disrupted the Composition of the Murine Colonic Microbiota and Accelerated a Murine Model of Inflammatory Bowel Disease

    PubMed Central

    Watanabe, Yohei; Arase, Sohei; Nagaoka, Noriko; Kawai, Mitsuhisa; Matsumoto, Satoshi

    2016-01-01

    The effect of psychological stress on the gastrointestinal microbiota is widely recognized. Chronic psychological stress may be associated with increased disease activity in inflammatory bowel disease, but the relationships among psychological stress, the gastrointestinal microbiota, and the severity of colitis is not yet fully understood. Here, we examined the impact of 12-week repeated water-avoidance stress on the microbiota of two inbred strains of T cell receptor alpha chain gene knockout mouse (background, BALB/c and C57BL/6) by means of next-generation sequencing of bacterial 16S rRNA genes. In both mouse strains, knockout of the T cell receptor alpha chain gene caused a loss of gastrointestinal microbial diversity and stability. Chronic exposure to repeated water-avoidance stress markedly altered the composition of the colonic microbiota of C57BL/6 mice, but not of BALB/c mice. In C57BL/6 mice, the relative abundance of genus Clostridium, some members of which produce the toxin phospholipase C, was increased, which was weakly positively associated with colitis severity, suggesting that expansion of specific populations of indigenous pathogens may be involved in the exacerbation of colitis. However, we also found that colitis was not exacerbated in mice with a relatively diverse microbiota even if their colonic microbiota contained an expanded phospholipase C-producing Clostridium population. Exposure to chronic stress also altered the concentration of free immunoglobulin A in colonic contents, which may be related to both the loss of bacterial diversity in the colonic microbiota and the severity of the colitis exacerbation. Together, these results suggest that long-term exposure to psychological stress induces dysbiosis in the immunodeficient mouse in a strain-specific manner and also that alteration of microbial diversity, which may be related to an altered pattern of immunoglobulin secretion in the gastrointestinal tract, might play a crucial role in the

  6. Chronic Psychological Stress Disrupted the Composition of the Murine Colonic Microbiota and Accelerated a Murine Model of Inflammatory Bowel Disease.

    PubMed

    Watanabe, Yohei; Arase, Sohei; Nagaoka, Noriko; Kawai, Mitsuhisa; Matsumoto, Satoshi

    2016-01-01

    The effect of psychological stress on the gastrointestinal microbiota is widely recognized. Chronic psychological stress may be associated with increased disease activity in inflammatory bowel disease, but the relationships among psychological stress, the gastrointestinal microbiota, and the severity of colitis is not yet fully understood. Here, we examined the impact of 12-week repeated water-avoidance stress on the microbiota of two inbred strains of T cell receptor alpha chain gene knockout mouse (background, BALB/c and C57BL/6) by means of next-generation sequencing of bacterial 16S rRNA genes. In both mouse strains, knockout of the T cell receptor alpha chain gene caused a loss of gastrointestinal microbial diversity and stability. Chronic exposure to repeated water-avoidance stress markedly altered the composition of the colonic microbiota of C57BL/6 mice, but not of BALB/c mice. In C57BL/6 mice, the relative abundance of genus Clostridium, some members of which produce the toxin phospholipase C, was increased, which was weakly positively associated with colitis severity, suggesting that expansion of specific populations of indigenous pathogens may be involved in the exacerbation of colitis. However, we also found that colitis was not exacerbated in mice with a relatively diverse microbiota even if their colonic microbiota contained an expanded phospholipase C-producing Clostridium population. Exposure to chronic stress also altered the concentration of free immunoglobulin A in colonic contents, which may be related to both the loss of bacterial diversity in the colonic microbiota and the severity of the colitis exacerbation. Together, these results suggest that long-term exposure to psychological stress induces dysbiosis in the immunodeficient mouse in a strain-specific manner and also that alteration of microbial diversity, which may be related to an altered pattern of immunoglobulin secretion in the gastrointestinal tract, might play a crucial role in the

  7. Identification of CD68(+) neutrophil granulocytes in in vitro model of acute inflammation and inflammatory bowel disease.

    PubMed

    Amanzada, Ahmad; Malik, Ihtzaz Ahmed; Blaschke, Martina; Khan, Sajjad; Rahman, Hazir; Ramadori, Giuliano; Moriconi, Federico

    2013-01-01

    CD-68 is widely regarded as a selective marker for human monocytes and macrophages and is commonly used in human pathology studies. The purpose of this study was to investigate the expression of CD-68 in human peripheral blood mononuclear cells (PBMCs), neutrophil granulocytes (NGs) and in inflamed intestinal tissue samples for comparison. PBMCs and NGs were isolated from heparinized human blood samples. Intestinal biopsies were obtained during routine endoscopic procedures from patients with inflammatory bowel disease (IBD), e.g. ulcerative colitis and Crohn's disease. Gene and protein expression was analyzed by real-time RT-PCR, Western blot and immunohistochemistry. Both PBMCs and NGs preparations contained cells that were positive for CD-68 and either neutrophil elastase (NE), or myeloperoxidase (MPO). CD-68(+)/NE(-)/MPO(-) cells were regarded as monocytes. CD-68 mRNA expression was detected in PBMCs and NGs preparations. With Western blot and by performing immunoprecipitation of cell lysate, we could clearly detect CD-68 in NGs, U-937, THP-1, Hep-G2, Jurkat cells and PBMCs. Identification of inflammatory cells in acutely inflamed colonic mucosa obtained from patients with IBD revealed a strong accumulation of CD-68(+)/MPO(+) cells compared to normal colonic mucosa. The uptake of the marker by phagocytosis was excluded by performing a double staining with CD-163/NE and CD-163/MPO in PBMCs, NGs cultures and in inflamed colonic mucosa. These results identify CD-68(+) NGs in peripheral blood and inflamed colonic mucosa. CD-68 is not only a marker for the macrophages-monocytes but also for NGs.

  8. Characterization of a novel transplantable orthotopic rat bladder transitional cell tumour model.

    PubMed

    Xiao, Z; McCallum, T J; Brown, K M; Miller, G G; Halls, S B; Parney, I; Moore, R B

    1999-10-01

    An animal tumour model that mimics the human counterpart is essential for preclinical evaluation of new treatment modalities. The objective of this study was to develop and characterize such a model. To accomplish this, the established AY-27 rat bladder transitional cell carcinoma (TCC) cell line was transplanted orthotopically into Fischer CDF344 female rats. AY-27 TCC cells were grown in monolayer cell culture and instilled intravesically as single cell suspensions into bladders that had been conditioned with mild acid washing. Tumour growth was assessed weekly by subjecting the rats to magnetic resonance imaging (MRI). At intervals following implantation and MRI tumour detection, the animals were sacrificed for necropsy, histological examination and immunocytochemical studies. Flow cytometry was also performed for detection of Fas or Fas-ligand expression on AY-27 cells. The overall tumour establishment was 95% (97/102 rats) at 12-50 days, while in a subgroup of animals sacrificed at 16 days, 80 out of 82 animals (97%) developed TCC, the majority of which was superficial. Tumour stage was assessed by gross pathology and light microscopy. Histological examination of the tumour specimens confirmed the presence of grade II-III TCC. Immunocytochemistry confirmed that the tumour model maintained the features of TCC. The changes seen on MRI correlated well with the extent of tumour invasion identified histologically. Patchy carcinoma in situ could be detected histologically 12-13 days post-inoculation, and progressed to papillary tumour or invasive disease thereafter. Neither Fas nor Fas-ligand was expressed on AY-27 cells. The orthotopic AY-27 TCC model is highly reproducible and is ideal for preclinical studies on experimental intravesical therapies.

  9. Cardiac transplantation.

    PubMed

    Shanewise, Jack

    2004-12-01

    Cardiac transplantation is a proven, accepted mode of therapy for selected patients with end-stage heart failure, but the inadequate number of suitable donor hearts available ultimately limits its application. This chapter reviews adult cardiac transplantation, with an emphasis on the anesthetic considerations of the heart transplant operation itself.

  10. Hepatocyte transplantation in the Long Evans Cinnamon rat model of Wilson's disease.

    PubMed

    Park, Seon Mee; Vo, Kim; Lallier, Michel; Cloutier, Alexis-Simon; Brochu, Pierre; Alvarez, Fernando; Martin, Steven R

    2006-01-01

    Wilson's disease (WD), caused by a mutation in the P-type copper transporting ATPase (Atp7b) gene, results in excessive accumulation of copper in the liver. Long Evans Cinnamon rats (LEC) bear a mutation in the atp7b gene and share clinical characteristics of human WD. To explore hepatocyte transplantation (HT) as therapy for metabolic liver diseases, 8-week-old LEC rats (n = 12) were transplanted by intrasplenic injection of hepatocytes from donor Long Evans (LE) rats. Immunosuppression was maintained with intraperitoneal tacrolimus. The success of HT was monitored at 24 weeks of life. Serum aminotransferases and bilirubin peaked at 14-21 weeks in both HT rats and nontransplanted controls, but at 24 weeks, survival was 97% in LEC-HT versus 63% in controls. All transplanted rats showed restored biliary copper excretion and reduced liver iron concentration associated with increased ceruloplasmin oxidase activity. Liver tissue expressed atp7b mRNA (11.9 +/- 13.6%) indicative of engraftment of normal cells in 7 of 12 HT rats, associated with a reduced liver copper concentration compared to untreated LEC rats. Periportal islets of normal appearing hepatocytes, recognized by atp7b antibody, were observed in transplanted livers while lobular host cells showed persistent pleomorphic changes and inflammatory infiltrates. In conclusion, transplantation of normal hepatocytes prevented fulminant hepatitis, reduces chronic inflammation, and improved 6-month survival in LEC rats. Engraftment of transplanted cells, which express atp7b mRNA, repopulated the recipient liver with normal functional capacity.

  11. Hepatitis C: liver transplantation.

    PubMed

    Metts, Julius; Carmichael, Lesley; Kokor, Winfred; Scharffenberg, Robert

    2014-12-01

    Hepatitis C virus (HCV)-related cirrhosis and hepatocellular carcinoma account for approximately 40% of the 6,000 adult liver transplantations performed each year in the United States. Survival rates are 76% to 83% at 2 years and 69% to 72% at 5 years. If eligible for surgery and in the absence of contraindications, any patient with HCV infection who develops decompensated liver disease or hepatocellular carcinoma is a candidate for liver transplantation. Most transplantation programs require that a patient with a history of alcohol or drug abuse be abstinent for at least 6 months and active in a substance abuse rehabilitation program. Prioritization for transplantation is based primarily on a patient's model for end-stage liver disease score, though other factors are considered. Complications after liver transplantation include recurrence of HCV infection, rejection of the transplanted liver, and an increased rate of infection because of immunosuppression. Various drugs are used to prevent infection and organ rejection. Liver transplant recipients also develop diabetes, hypertension, hyperlipidemia, renal dysfunction, osteopenia, and cancers at high rates, likely because of the effects of immunosuppressive drugs, particularly steroids and calcineurin inhibitors. The family physician's role in caring for liver transplant recipients often involves detection and management of these conditions. PMID:25478647

  12. A new microvascular model for noninvasive nuclear magnetic resonance spectroscopy of the transplanted kidney.

    PubMed

    Haug, C E; Shapiro, J I; Chan, L; Weil, R

    1988-03-01

    The cellular biology of graft rejection is not well understood. Phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy is a new noninvasive technique for the measurement of intracellular pH and relative amounts of phosphorus-containing compounds, such as adenosine triphosphate (ATP), inorganic phosphate, phosphocreatine, and sugar phosphates, in any tissue from which a clear signal can be obtained. Biochemical analysis of such precision, without the need for tissue destruction, represents an unusual opportunity for analysis of in vivo cellular metabolism under varying conditions, including graft rejection. 31P NMR study of intra-abdominal viscera has not been feasible in most laboratories without laparotomy because of signal interference from abdominal wall muscle. In this study, to eliminate this interference, a rat kidney was transplanted to the groin, where it could be serially studied without overlying skeletal muscle. This new vascular technique was successful in 11 of 11 attempts and maintained normal serum creatinines in 10 chronic survivors after removal of both native kidneys. The 31P NMR spectroscopic signal from the groin kidney is clear and highly reproducible. This new microvascular model will make it possible to carry out noninvasive long-term spectroscopic studies that could potentially identify a reliable marker for allograft rejection. PMID:3278404

  13. Fecal Microbiota Transplantation Eliminates Clostridium difficile in a Murine Model of Relapsing Disease.

    PubMed

    Seekatz, Anna M; Theriot, Casey M; Molloy, Caitlyn T; Wozniak, Katherine L; Bergin, Ingrid L; Young, Vincent B

    2015-10-01

    Recurrent Clostridium difficile infection (CDI) is of particular concern among health care-associated infections. The role of the microbiota in disease recovery is apparent given the success of fecal microbiota transplantation (FMT) for recurrent CDI. Here, we present a murine model of CDI relapse to further define the microbiota recovery following FMT. Cefoperazone-treated mice were infected with C. difficile 630 spores and treated with vancomycin after development of clinical disease. Vancomycin treatment suppressed both C. difficile colonization and cytotoxin titers. However, C. difficile counts increased within 7 days of completing treatment, accompanied by relapse of clinical signs. The administration of FMT immediately after vancomycin cleared C. difficile and decreased cytotoxicity within 1 week. The effects of FMT on the gut microbiota community were detectable in recipients 1-day posttransplant. Conversely, mice not treated with FMT remained persistently colonized with high levels of C. difficile, and the gut microbiota in these mice persisted at low diversity. These results suggest that full recovery of colonization resistance against C. difficile requires the restoration of a specific community structure.

  14. Photoacoustic imaging of angiogenesis in a subcutaneous islet transplant site in a murine model

    NASA Astrophysics Data System (ADS)

    Shi, Wei; Pawlick, Rena; Bruni, Antonio; Rafiei, Yasmin; Pepper, Andrew R.; Gala-Lopez, Boris; Choi, Min; Malcolm, Andrew; Zemp, Roger J.; Shapiro, A. M. James

    2016-06-01

    Islet transplantation (IT) is an established clinical therapy for select patients with type-1 diabetes. Clinically, the hepatic portal vein serves as the site for IT. Despite numerous advances in clinical IT, limitations remain, including early islet cell loss posttransplant, procedural complications, and the inability to effectively monitor islet grafts. Hence, alternative sites for IT are currently being explored, with the subcutaneous space as one potential option. When left unmodified, the subcutaneous space routinely fails to promote successful islet engraftment. However, when employing the previously developed subcutaneous "deviceless" technique, a favorable microenvironment for islet survival and function is established. In this technique, an angiocatheter was temporarily implanted subcutaneously, which facilitated angiogenesis to promote subsequent islet engraftment. This technique has been employed in preclinical animal models, providing a sufficient means to develop techniques to monitor functional aspects of the graft such as angiogenesis. Here, we utilize photoacoustic imaging to track angiogenesis during the priming of the subcutaneous site by the implanted catheter at 1 to 4 weeks postcatheter. Quantitative analysis on vessel densities shows gradual growth of vasculature in the implant position. These results demonstrate the ability to track angiogenesis, thus facilitating a means to optimize and assess the pretransplant microenvironment.

  15. Effects of Adoptive Transfer of Tolerogenic Dendritic Cells on Allograft Survival in Organ Transplantation Models: An Overview of Systematic Reviews

    PubMed Central

    Shan, Juan; Guo, Yingjia; Li, Shengfu; Long, Dan

    2016-01-01

    Objective. To dissect the efficacy of Tol-DC therapy with or without IS in multiple animal models of transplantation. Methods and Results. PubMed, Medline, Embase, and the Cochrane Library were searched for reviews published up to April 2015. Six systematic reviews and a total of 61 articles were finally included. Data were grouped by organ transplantation models and applied to meta-analysis. Our meta-analysis shows that Tol-DC therapy successfully prolonged allograft survival to varying extents in all except the islet transplantation models and with IS drugs further prolonged the survival of heart, skin, and islet allografts in mice, but not of heart allografts in rats. Compared with IS drugs alone, Tol-DC therapy with IS extended islet allograft survival in rats but failed to influence the survival of skin, small intestine, and heart allografts in rats or of heart and skin allografts in mice. Conclusion. Tol-DC therapy significantly prolonged multiple allograft survival and further prolonged survival with IS. However, standardized protocols for modification of Tol-DC should be established before its application in clinic. PMID:27547767

  16. Textbooks, Transitions, and Transplants

    ERIC Educational Resources Information Center

    Callahan, Leroy G.; Passi, Sneh Lata

    1972-01-01

    Three popular textbooks were analyzed for level of cognitive processes used, and implications were drawn regarding supplementary activities if the English primary school model is to be transplanted" in America. (MM)

  17. Transgenic animals in experimental xenotransplantation models: orthotopic heart transplantation in the pig-to-baboon model.

    PubMed

    Brandl, U; Michel, S; Erhardt, M; Brenner, P; Burdorf, L; Jöckle, H; Bittmann, I; Rössle, M; Mordstein, V; Baschnegger, H; Bauer, A; Hammer, C; Reichart, B; Schmoeckel, M

    2007-03-01

    Pig organs are at risk for hyperacute and acute vascular rejection mediated by anti-pig antibodies, mainly binding to the Galalpha(1,3)Gal epitope. Acute cellular rejection is characterized by progressive infiltration of mononuclear cells. There is an ongoing search for immunosuppressive regimens that provide adequate protection against all patterns of xenograft rejection, but have no severe impact on the condition of xenograft recipients. Herein orthotopic heart transplantations were performed from hDAF or hCD46 piglets to nonsplenectomized baboons. Basic immunosuppression consisted of tacrolimus, sirolimus, GAS914, steroids, and ATG. Group 1 received basic immunosuppression. Group 2 was additionally treated with rituximab and group 3 with half-dose cyclophosphamide. Group 4 received cyclophosphamide and an anti-HLA-DR antibody. Three baboons received GAS914 and TPC. Monitoring included the regular assessment of anti-porcine antibodies, blood counts, therapeutic drug monitoring, and graft histology. Two grafts failed due to technical mistakes. In group 1, baboons died after 1 and 9 days. In group 2, maximum survival was 30 hours. In group 3, baboons lived 20 hours, 25 days, and 14 days. Group 4 survival times were 9.5 hours, 5.5 hours, 4 days, 34 hours, and 3 days. An increase of non-Galalpha(1,3)Gal antibodies was observed. Depositions of immunoglobulins and complement revealed a humoral rejection process. No cellular infiltration could be observed. In conclusion, suppressing cellular rejection with half-dose cyclophosphamide together with tacrolimus and sirolimus produced longer graft survival with a good general condition. Prevention of acute xenograft rejection further needs inhibition of non-Galalpha(1,3)Gal cytotoxicity by sufficient depression of B-cell activation.

  18. Physiological relevance of food grade microcapsules: Impact of milk protein based microcapsules on inflammation in mouse models for inflammatory bowel diseases.

    PubMed

    Würth, Rebecca; Lagkouvardos, Ilias; Clavel, Thomas; Wilke, Julia; Foerst, Petra; Kulozik, Ulrich; Haller, Dirk; Hörmannsperger, Gabriele

    2015-08-01

    In order to increase beneficial effects of bioactive compounds in functional food and dietary supplements, enormous efforts are put in the technological development of microcapsules. Although these products are often tailor-made for disease susceptible consumer, the physiological impact of microcapsule uptake on the respective target consumer has never been addressed. The present study aimed to assess the relevance of this aspect by analyzing the impact of milk protein based microcapsules on experimental inflammatory bowel disease. Long-term feeding of sodium caseinate or rennet gel microcapsules resulted in significant alterations in the intestinal microbiota of healthy mice. In TNFΔARE/wt mice, a model for chronic ileal inflammation, rennet gel microcapsules resulted in further increased splenomegaly, whereas ileal inflammation was unchanged. In IL10(-/-) mice, a model for chronic colitis, both types of microcapsules induced a local increase of the intestinal inflammation. The present study is the first to demonstrate that, independent of their cargo, microcapsules have the potential to affect the intestinal microbiota and to exert unprecedented detrimental effects on disease-susceptible individuals. In conclusion, the impact of microcapsule uptake on the respective target consumer groups should be thoroughly investigated in advance to their commercial use in functional food or dietary supplements.

  19. Suppression of MAPK and NF-κ B pathways by schisandrin B contributes to attenuation of DSS-induced mice model of inflammatory bowel disease.

    PubMed

    Liu, Weidong; Liu, Yang; Wang, Zhi; Yu, Ting; Lu, Qin; Chen, Hong

    2015-09-01

    Schisandrin B (Sch B), the most abundant dibenzocyclooctadiene lignan isolated from the traditional Chinese medicinal herb Schisandra chinensis (Turcz.) Baill, possesses various biological activities, such as hepatic protection, anti-tumor, anti-inflammatory and anti-cardiovascular properties. However, the effect of Sch B on inflammatory bowel disease (IBD) is not yet known. The aim of this study was to investigate whether Sch B has protective effect against dextran sulfate sodium (DSS)-induced colitis in a mouse model. The acute mouse model of IBD was induced by drinking 2.5% DSS water for 5 days. Sch B was administered orally in doses of 10, 40, and 100 mg/kg respectively. It significantly reduced concentration of TNF-α, IL-1β, INF-γ and IL-6 in colon tissue as well as the mRNA expression levels. In addition, we demonstrated that Sch B blocked the phosphorylation of IκBα, nuclear factor-κB (NF-κB) p65, p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, and extracellular signal regulated kinase in DSS-induced acute colitis. In conclusion, these results indicated that Sch B could exert beneficial effects on experimental IBD induced by DSS and may represent a novel treatment strategy for IBD.

  20. Hair transplantation.

    PubMed

    Al-Khair, Y M

    2000-09-01

    Hair transplantation is a technique in which hair follicles are harvested from the occipital area and re-transplanted in the frontal bald area. Hair transplantation is the most common cosmetic procedure in the United States nowadays despite the fact that it is expensive. Usually, patients need more than one session to receive a cosmetically acceptable result and patients need to be understanding and have realistic expectations. Although most of our patients are males, females represent about 10-15% of our new patients. This article reviews the basic principals of hair transplantation and describes new and improved techniques of hair transplantation. PMID:11376357

  1. Simultaneous transplantation.

    PubMed

    Sala, P

    1993-01-01

    1. Thoracic organ transplantation requires extensive preparation with little advance notice. 2. A single organ transplant requires a team of various staff members, and may include one or two circulating nurses, two scrub technologists or nurses, one perfusionist, one surgeon's assistant, two surgeons, and one anesthesiologist. 3. Timing is important in organ transplantation because thoracic organs ideally should be transplanted within four hours after cross-clamping the aorta of the donor. 4. The dedication, expertise, and thorough follow-up care provided by transplant surgeons, nurse transplant coordinators, organ procurement coordinators, and the CICU and coronary care nurses/departments directly relate to the success of a thoracic organ transplant program. PMID:8493710

  2. The Semaphorin 3A Inhibitor SM-345431 Accelerates Peripheral Nerve Regeneration and Sensitivity in a Murine Corneal Transplantation Model

    PubMed Central

    Miyashita, Hideyuki; Kawakita, Tetsuya; Yoshida, Kenji; Kishino, Akiyoshi; Kimura, Toru; Shibata, Shinsuke; Tsubota, Kazuo; Okano, Hideyuki; Shimmura, Shigeto

    2012-01-01

    Background Peripheral nerve damage of the cornea is a complication following surgery or infection which may lead to decreased visual function. We examined the efficacy of the semaphorin 3A inhibitor, SM-345431, in promoting regeneration of peripheral nerves in a mouse corneal transplantation model. Methodology/Principal Findings P0-Cre/Floxed-EGFP mice which express EGFP in peripheral nerves cells were used as recipients of corneal transplantation with syngeneic wild-type mouse cornea donors. SM-345431 was administered subconjunctivally every 2 days while control mice received vehicle only. Mice were followed for 3 weeks and the length of regenerating nerves was measured by EGFP fluorescence and immunohistochemistry against βIII tubulin. Cornea sensitivity was also measured by the Cochet-Bonnet esthesiometer. CD31 staining was used to determine corneal neovascularization as a possible side effect of SM-345431. Regeneration of βIII tubulin positive peripheral nerves was significantly higher in SM-345431 treated mice compared to control. Furthermore, corneal sensitivity significantly improved in the SM-345431 group by 3 weeks after transplantation. Neovascularization was limited to the peripheral cornea with no difference between SM-345431 group and control. Conclusions/Significance Subconjunctival injections of SM-345431 promoted a robust network of regenerating nerves as well as functional recovery of corneal sensation in a mouse keratoplasty model, suggesting a novel therapeutic strategy for treating neurotrophic corneal disease. PMID:23152758

  3. Ischemic bowel disease

    PubMed Central

    Castelli, M. F.; Qizilbash, A. H.; Salem, S.; Fyshe, T. G.

    1974-01-01

    The clinical, radiologic and pathologic features of 25 cases of ischemic bowel disease are presented. The majority of patients presented with the triad of abdominal pain, diarrhea and vomiting. In 13 patients the diarrhea was associated with the passage of bright red blood per rectum. There were 10 cases of infarction, 11 of enterocolitis and 4 had resulted in stricture formation. In five cases of enterocolitis the lesion was transient; symptoms improved with conservative medical management and the radiologic findings returned to normal. Barium enema examination yielded abnormal findings in the majority of the cases in which it was performed. Plain films of the abdomen, however, were not helpful. The actual mortality in this group of patients was 44%, 80% in those with infarction of the bowel and 20% in the other two groups. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5FIG. 6FIG. 7 PMID:4419659

  4. Bioluminescence imaging of transplanted human endothelial colony-forming cells in an ischemic mouse model.

    PubMed

    Ding, Jie; Zhao, Zhen; Wang, Chao; Wang, Cong-Xiao; Li, Pei-Cheng; Qian, Cheng; Teng, Gao-Jun

    2016-07-01

    Ischemic strokes are devastating events responsible for high mortality and morbidity worldwide each year. Endothelial colony-forming cell (ECFC) therapy holds promise for stroke treatment; however, grafted ECFCs need to be monitored better understand their biological behavior in vivo, so as to evaluate their safety and successful delivery. The objectives of this study are to visualize the fate of infused human cord blood derived ECFCs via bioluminescence imaging (BLI) in an ischemic stroke mouse model and to determine the therapeutic effects of ECFC transplantation. ECFCs derived from human umbilical cord blood were infected with lentivirus carrying enhanced green fluorescent protein (eGFP) and firefly luciferase (Luc2) double fusion reporter gene. Labeled ECFCs were grafted into a photothrombotic ischemic stroke mouse model via intra-arterial injection though the left cardiac ventricle. The homing of infused cells and functional recovery of stroke mice were evaluated using BLI, neurological scoring, and immunohistochemistry. Significantly, BLI signals were highest in the brain on day 1 and decreased steadily until day 14. GFP-positive cells were also found surrounding infarct border zones in brain sections using immunohistochemical staining, suggesting that ECFCs properly homed to the ischemic brain tissue. Using a modified neurological severity score assay and histological analysis of brain slices with CD31 immunostaining in brain tissue, double cortin analysis, and the TdT-mediated dUTP nick end labeling (TUNEL) assay, we demonstrated functional restoration, improved angiogenesis, neurogenesis, and decreased apoptosis in ischemic mice after ECFC infusion. Collectively, our data support that ECFCs may be a promising therapeutic agent for stroke. PMID:27038754

  5. Bioluminescence imaging of transplanted human endothelial colony-forming cells in an ischemic mouse model.

    PubMed

    Ding, Jie; Zhao, Zhen; Wang, Chao; Wang, Cong-Xiao; Li, Pei-Cheng; Qian, Cheng; Teng, Gao-Jun

    2016-07-01

    Ischemic strokes are devastating events responsible for high mortality and morbidity worldwide each year. Endothelial colony-forming cell (ECFC) therapy holds promise for stroke treatment; however, grafted ECFCs need to be monitored better understand their biological behavior in vivo, so as to evaluate their safety and successful delivery. The objectives of this study are to visualize the fate of infused human cord blood derived ECFCs via bioluminescence imaging (BLI) in an ischemic stroke mouse model and to determine the therapeutic effects of ECFC transplantation. ECFCs derived from human umbilical cord blood were infected with lentivirus carrying enhanced green fluorescent protein (eGFP) and firefly luciferase (Luc2) double fusion reporter gene. Labeled ECFCs were grafted into a photothrombotic ischemic stroke mouse model via intra-arterial injection though the left cardiac ventricle. The homing of infused cells and functional recovery of stroke mice were evaluated using BLI, neurological scoring, and immunohistochemistry. Significantly, BLI signals were highest in the brain on day 1 and decreased steadily until day 14. GFP-positive cells were also found surrounding infarct border zones in brain sections using immunohistochemical staining, suggesting that ECFCs properly homed to the ischemic brain tissue. Using a modified neurological severity score assay and histological analysis of brain slices with CD31 immunostaining in brain tissue, double cortin analysis, and the TdT-mediated dUTP nick end labeling (TUNEL) assay, we demonstrated functional restoration, improved angiogenesis, neurogenesis, and decreased apoptosis in ischemic mice after ECFC infusion. Collectively, our data support that ECFCs may be a promising therapeutic agent for stroke.

  6. Allogeneic Transplantation of Periodontal Ligament-Derived Multipotent Mesenchymal Stromal Cell Sheets in Canine Critical-Size Supra-Alveolar Periodontal Defect Model.

    PubMed

    Tsumanuma, Yuka; Iwata, Takanori; Kinoshita, Atsuhiro; Washio, Kaoru; Yoshida, Toshiyuki; Yamada, Azusa; Takagi, Ryo; Yamato, Masayuki; Okano, Teruo; Izumi, Yuichi

    2016-01-01

    Periodontitis is a chronic inflammatory disease that induces the destruction of tooth-supporting tissues, followed by tooth loss. Although several approaches have been applied to periodontal regeneration, complete periodontal regeneration has not been accomplished. Tissue engineering using a combination of cells and scaffolds is considered to be a viable alternative strategy. We have shown that autologous transplantation of periodontal ligament-derived multipotent mesenchymal stromal cell (PDL-MSC) sheets regenerates periodontal tissue in canine models. However, the indications for autologous cell transplantation in clinical situations are limited. Therefore, this study evaluated the safety and efficacy of allogeneic transplantation of PDL-MSC sheets using a canine horizontal periodontal defect model. Canine PDL-MSCs were labeled with enhanced green fluorescent protein (EGFP) and were cultured on temperature-responsive dishes. Three-layered cell sheets were transplanted around denuded root surfaces either autologously or allogeneically. A mixture of β-tricalcium phosphate and collagen gel was placed on the bone defects. Eight weeks after transplantation, dogs were euthanized and subjected to microcomputed tomography and histological analyses. RNA and DNA were extracted from the paraffin sections to verify the presence of EGFP at the transplantation site. Inflammatory markers from peripheral blood sera were quantified using an enzyme-linked immunosorbent assay. Periodontal regeneration was observed in both the autologous and the allogeneic transplantation groups. The allogeneic transplantation group showed particularly significant regeneration of newly formed cementum, which is critical for the periodontal regeneration. Serum levels of inflammatory markers from peripheral blood sera showed little difference between the autologous and allogeneic groups. EGFP amplicons were detectable in the paraffin sections of the allogeneic group. These results suggest that

  7. Allogeneic Transplantation of Periodontal Ligament-Derived Multipotent Mesenchymal Stromal Cell Sheets in Canine Critical-Size Supra-Alveolar Periodontal Defect Model

    PubMed Central

    Tsumanuma, Yuka; Iwata, Takanori; Kinoshita, Atsuhiro; Washio, Kaoru; Yoshida, Toshiyuki; Yamada, Azusa; Takagi, Ryo; Yamato, Masayuki; Okano, Teruo; Izumi, Yuichi

    2016-01-01

    Abstract Periodontitis is a chronic inflammatory disease that induces the destruction of tooth-supporting tissues, followed by tooth loss. Although several approaches have been applied to periodontal regeneration, complete periodontal regeneration has not been accomplished. Tissue engineering using a combination of cells and scaffolds is considered to be a viable alternative strategy. We have shown that autologous transplantation of periodontal ligament-derived multipotent mesenchymal stromal cell (PDL-MSC) sheets regenerates periodontal tissue in canine models. However, the indications for autologous cell transplantation in clinical situations are limited. Therefore, this study evaluated the safety and efficacy of allogeneic transplantation of PDL-MSC sheets using a canine horizontal periodontal defect model. Canine PDL-MSCs were labeled with enhanced green fluorescent protein (EGFP) and were cultured on temperature-responsive dishes. Three-layered cell sheets were transplanted around denuded root surfaces either autologously or allogeneically. A mixture of β-tricalcium phosphate and collagen gel was placed on the bone defects. Eight weeks after transplantation, dogs were euthanized and subjected to microcomputed tomography and histological analyses. RNA and DNA were extracted from the paraffin sections to verify the presence of EGFP at the transplantation site. Inflammatory markers from peripheral blood sera were quantified using an enzyme-linked immunosorbent assay. Periodontal regeneration was observed in both the autologous and the allogeneic transplantation groups. The allogeneic transplantation group showed particularly significant regeneration of newly formed cementum, which is critical for the periodontal regeneration. Serum levels of inflammatory markers from peripheral blood sera showed little difference between the autologous and allogeneic groups. EGFP amplicons were detectable in the paraffin sections of the allogeneic group. These results suggest

  8. Infections Following Orthotopic Liver Transplantation

    PubMed Central

    Arnow, Paul M.

    1991-01-01

    The epidemiology of infections associated with orthotopic liver transplantation is summarized herein, and approaches to prophylaxis are outlined. Infection is a major complication following orthotopic liver transplantation, and more than half of transplant recipients develop at least one infection. The risk of infection is highest in the first month after transplantation, and the most common pathogens are bacteria and cytomegalovirus (CMV). Bacterial infections usually occur in the first month, arise in the abdomen, and are caused by aerobes. The peak incidence of CMV infection is late in the first month and early in the second month after transplantationn. CMV syndromes include fever and neutropenia, hepatitis, pneumonitis, gut ulceration, and disseminated infection. Other significant problems are Candida intraabdominal infection, Herpes simplex mucocutaneous infection or hepatitis, adenovirus hepatitis, and Pneumocystis carinii pneumonia. Prophylaxis of infection in liver transplant recipients has not been well-studied. Several different regimens of parenteral, oral absorbable, and/or oral non-absorbable antibiotics active against bacteria and yeast have been used at various centers, but no randomized controlled trials have been conducted. Selective bowel decontamination appears to be a promising approach to the prevention of bacterial and Candida infections, while oral acyclovir may be a relatively convenient and effective agent for CMV prophylaxis. PMID:1650245

  9. Overview of pediatric short bowel syndrome.

    PubMed

    Duro, Debora; Kamin, Daniel; Duggan, Christopher

    2008-08-01

    Short bowel syndrome (SBS) is a malabsorptive state occuring as a result of surgical resection or congenital disease of a significant portion of the small intestine . The amount of resection or remaining bowel generally dictates the degree of malabsorption and consequentely the need for specialized enteral nutrition or parenteral nutrition (PN). Intestinal failure in the context of SBS is defined as a dependence on PN to maintain minimal energy and fluid requirement for growth in children. Common causes of SBS in infants and children include necrotizing enterocolitis, midgut volvulus, intestinal atresia, and gastroschisis. Early identification of patients at risk for long-term PN dependency is the first step toward avoiding severe complications. Close monitoring of nutritional status, steady and early introduction of enteral nutrition, and aggressive prevention, diagnosis, and treatment of infections such as central venous catheter sepsis and bacterial overgrowth can significantly improve the prognosis. Intestinal transplantation is an emerging treatment that may be considered when intestinal failure is irreversible and children are experiencing serious complications related to TPN administration. PMID:18667916

  10. Lung transplantation

    PubMed Central

    Afonso, José Eduardo; Werebe, Eduardo de Campos; Carraro, Rafael Medeiros; Teixeira, Ricardo Henrique de Oliveira Braga; Fernandes, Lucas Matos; Abdalla, Luis Gustavo; Samano, Marcos Naoyuki; Pêgo-Fernandes, Paulo Manuel

    2015-01-01

    ABSTRACT Lung transplantation is a globally accepted treatment for some advanced lung diseases, giving the recipients longer survival and better quality of life. Since the first transplant successfully performed in 1983, more than 40 thousand transplants have been performed worldwide. Of these, about seven hundred were in Brazil. However, survival of the transplant is less than desired, with a high mortality rate related to primary graft dysfunction, infection, and chronic graft dysfunction, particularly in the form of bronchiolitis obliterans syndrome. New technologies have been developed to improve the various stages of lung transplant. To increase the supply of lungs, ex vivo lung reconditioning has been used in some countries, including Brazil. For advanced life support in the perioperative period, extracorporeal membrane oxygenation and hemodynamic support equipment have been used as a bridge to transplant in critically ill patients on the waiting list, and to keep patients alive until resolution of the primary dysfunction after graft transplant. There are patients requiring lung transplant in Brazil who do not even come to the point of being referred to a transplant center because there are only seven such centers active in the country. It is urgent to create new centers capable of performing lung transplantation to provide patients with some advanced forms of lung disease a chance to live longer and with better quality of life. PMID:26154550

  11. Ulcerative colitis has an aggressive course after orthotopic liver transplantation for primary sclerosing cholangitis

    PubMed Central

    Papatheodoridis, G; Hamilton, M; Mistry, P; Davidson, B; Rolles, K; Burroughs, A

    1998-01-01

    Background—The course of inflammatory bowel disease after liver transplantation has been reported as variable with usually no change or improvement, but there may be an increased risk of early colorectal neoplasms. In many centres steroids are often withdrawn early after transplantation and this may affect inflammatory bowel disease activity. 
Aims—To evaluate the course of inflammatory bowel disease in primary sclerosing cholangitis transplant patients who were treated without long term steroids. 
Methods—Between 1989 and 1996, there were 30 patients transplanted for primary sclerosing cholangitis who survived more than 12 months. Ulcerative colitis was diagnosed in 18 (60%) patients before transplantation; two had previous colectomy. All patients underwent colonoscopy before and after transplantation and were followed for 38 (12-92) months. All received cyclosporin or tacrolimus with or without azathioprine as maintenance immunosuppression. 
Results—Ulcerative colitis course after transplantation compared with that up to five years before transplantation was the same in eight (50%) and worse in eight (50%) patients. It remained quiescent in eight and worsened in four of the 12 patients with pretransplant quiescent course, whereas it worsened in all four patients with pretransplant active course (p=0.08). New onset ulcerative colitis developed in three (25%) of the 12 patients without inflammatory bowel disease before transplantation. No colorectal cancer has been diagnosed to date. 
Conclusions—Preexisting ulcerative colitis often has an aggressive course, while de novo ulcerative colitis may develop in patients transplanted for primary sclerosing cholangitis and treated without long term steroids. 

 Keywords: liver transplantation; inflammatory bowel disease; ulcerative colitis; primary sclerosing cholangitis; immunosuppression PMID:9824344

  12. From Child-Pugh to Model for End-Stage Liver Disease: Deciding Who Needs a Liver Transplant.

    PubMed

    Reddy, Sheela S; Civan, Jesse M

    2016-05-01

    This article reviews the historical evolution of the liver transplant organ allocation policy and the indications/contraindications for liver transplant, and provides an overview of the liver transplant evaluation process. The article is intended to help internists determine whether and when referral to a liver transplant center is indicated, and to help internists to counsel patients whose initial evaluation at a transplant center is pending. PMID:27095638

  13. [History of organ transplantation in the field of pediatric surgery in Japan].

    PubMed

    Inomata, Yukihiro

    2014-11-01

    In Japan, liver transplantation was first attempted 50 years ago, around the same time as the development of pediatric surgery. In 1989, clinical liver transplantation in Japan started with a living related-donor transplantation in a boy with biliary atresia. In the early years, the majority of recipients were children worldwide, which is why pediatric surgeons played a major role in the establishment of liver transplantation in Japan. From 1998, most of the indications for pediatric patients needing liver transplantation have been covered by governmental health insurance. Since that year, the annual number of pediatric liver transplantations, mainly living-donor transplantations, has remained stable at around 130. Biliary atresia is still the most common indication, but others like metabolic disease and hepatoblastoma have been increasing. Deceased-donor liver transplantation started in 1999 in Japan, but pediatric donors are very rare. Intestinal transplantation in Japan also started in a pediatric patient with short bowel syndrome in 1996. Deceased-donor intestinal transplantation is also performed, but the number of those on the waiting list for bowel transplantations in Japan has been very limited, probably due to financial constraints and relatively poor long-term results. With the change in the Organ Transplant Law in 2010, organ donations in Japan have increased slightly. Cadaveric split-liver transplantation has the potential to expand the benefit to pediatric recipients. A universal system for the long-term follow-up of pediatric recipients should be established to manage their transition to adulthood.

  14. [History of organ transplantation in the field of pediatric surgery in Japan].

    PubMed

    Inomata, Yukihiro

    2014-11-01

    In Japan, liver transplantation was first attempted 50 years ago, around the same time as the development of pediatric surgery. In 1989, clinical liver transplantation in Japan started with a living related-donor transplantation in a boy with biliary atresia. In the early years, the majority of recipients were children worldwide, which is why pediatric surgeons played a major role in the establishment of liver transplantation in Japan. From 1998, most of the indications for pediatric patients needing liver transplantation have been covered by governmental health insurance. Since that year, the annual number of pediatric liver transplantations, mainly living-donor transplantations, has remained stable at around 130. Biliary atresia is still the most common indication, but others like metabolic disease and hepatoblastoma have been increasing. Deceased-donor liver transplantation started in 1999 in Japan, but pediatric donors are very rare. Intestinal transplantation in Japan also started in a pediatric patient with short bowel syndrome in 1996. Deceased-donor intestinal transplantation is also performed, but the number of those on the waiting list for bowel transplantations in Japan has been very limited, probably due to financial constraints and relatively poor long-term results. With the change in the Organ Transplant Law in 2010, organ donations in Japan have increased slightly. Cadaveric split-liver transplantation has the potential to expand the benefit to pediatric recipients. A universal system for the long-term follow-up of pediatric recipients should be established to manage their transition to adulthood. PMID:25702514

  15. Gamma-Irradiated Sterile Cornea for Use in Corneal Transplants in a Rabbit Model

    PubMed Central

    Yoshida, Junko; Heflin, Thomas; Zambrano, Andrea; Pan, Qing; Meng, Huan; Wang, Jiangxia; Stark, Walter J.; Daoud, Yassine J.

    2015-01-01

    Purpose: Gamma irradiated corneas in which the donor keratocytes and endothelial cells are eliminated are effective as corneal lamellar and glaucoma patch grafts. In addition, gamma irradiation causes collagen cross inking, which stiffens collagen fibrils. This study evaluated gamma irradiated corneas for use in corneal transplantations in a rabbit model comparing graft clarity, corneal neovascularization, and edema. Methods: Penetrating keratoplasty was performed on rabbits using four types of corneal grafts: Fresh cornea with endothelium, gamma irradiated cornea, cryopreserved cornea, and fresh cornea without endothelium. Slit lamp examination was performed at postoperative week (POW) one, two, and four. Corneal clarity, edema, and vascularization were graded. Confocal microscopy and histopathological evaluation were performed. A P < 0.05 was statistically significant. Results: For all postoperative examinations, the corneal clarity and edema were statistically significantly better in eyes that received fresh cornea with endothelium compared to the other three groups (P < 0.05). At POW 1, gamma irradiated cornea scored better than the cryopreserved and fresh cornea without endothelium groups in clarity (0.9 vs. 1.5 and 2.6, respectively), and edema (0.6 vs. 0.8 and 2.0, respectively). The gamma irradiated corneas, cryopreserved corneas and the fresh corneas without endothelium, developed haze and edema after POW 2. Gamma irradiated cornea remained statistically significantly clearer than cryopreserved and fresh cornea without endothelium during the observation period (P < 0.05). Histopathology indicated an absence of keratocytes in gamma irradiated cornea. Conclusion: Gamma irradiated corneas remained clearer and thinner than the cryopreserved cornea and fresh cornea without endothelium. However, this outcome is transient. Gamma irradiated corneas are useful for lamellar and patch grafts, but cannot be used for penetrating keratoplasty. PMID:26180475

  16. The imbalanced expression of adenosine receptors in an epilepsy model corrected using targeted mesenchymal stem cell transplantation.

    PubMed

    Huicong, Kang; Zheng, Xue; Furong, Wang; Zhouping, Tang; Feng, Xu; Qi, Hu; Xiaoyan, Liu; Xiaojiang, Huang; Na, Zhang; Ke, Xu; Zheng, Zeng; Suiqiang, Zhu

    2013-12-01

    Adenosine inhibits epileptic episodes by interacting with G-protein-coupled receptors. This study examined the mechanism by which the inhibitory effect of adenosine becomes impaired during epileptogenesis. Dynamic changes in adenosine A1 receptors (A1Rs) and A2a receptors (A2aRs) were investigated in a kindling model of epilepsy. RT-PCR, Western blotting, and immunofluorescence results indicated that expression of A1Rs was increased in the hippocampus 24 h after kindling, but progressively decreased 1 and 6 months after kindling. Opposite changes were seen in the expression of A2aRs. This bidirectional change resulted in an imbalance between A1Rs and A2aRs and dysregulation of the adenosine system. Autologous mesenchymal stem cell (MSC) transplantation was used to correct this disorder and avoid side effects of systematic adenosine therapy. Paramagnetic iron oxide particles were used to mark and track the MSCs in vivo using MRI. The results indicated that the transplanted cells migrated along the callosum and settled at the ependymal layer. The MSCs displayed a relatively long survival time, at least 3 months. The improved AR expression and EEG findings suggested that MSC transplantation was a potentially effective means of treating refractory epilepsy.

  17. Biodistribution and in vivo efficacy of genetically modified human mesenchymal stem cells systemically transplanted into a mouse bone fracture model.

    PubMed

    Kang, Jin Wook; Park, Ki Dae; Choi, Youngju; Baek, Dae Hyun; Cho, Wan-Seob; Choi, Mina; Park, Jae Hyun; Choi, Kyoung Suk; Kim, Hyung Soo; Yoo, Tae Moo

    2013-08-01

    Human mesenchymal stem cells (hMSCs) have generated a great deal of interest in clinical application due to their ability to undergo multi-lineage differentiation. Recently, ex vivo genetic modification of hMSCs was attempted to increase their differentiation potential. The present study was conducted to evaluate the biodistribution and in vivo efficacy of genetically modified hMSCs. To accomplish this, Runx2, which is a key transcription factor associated with osteoblast differentiation, was transduced into hMSCs using lentiviral vectors expressing green fluorescent protein (GFP) or luciferase. Here, we developed an experimental fracture in mice femur to investigate the effects of Runx2-transduced hMSCs on bone healing and migration into injury site. We conducted bio-luminescence imaging (BLI) using luciferase-tagged vector and quantitative real-time PCR using GFP probe to investigate the biodistribution of Runx2-transduced hMSCs in the fracture model. The biodistribution of hMSC cells in the fractured femur was observed at 14 days post-transplantation upon both BLI imaging and real-time PCR. Moreover, the fractured mice transplanted with Runx2-transduced hMSCs showed superior bone healing when compared to mock-transduced hMSC and MRC5 fibroblasts which were used as control. These data suggested that transplanted genetically modified hMSCs systemically migrate to the fractured femur, where they contribute to bone formation in vivo.

  18. CD47 Blockade Reduces Ischemia/Reperfusion Injury and Improves Survival in a Rat Liver Transplantation Model

    PubMed Central

    Jia, Jianluo; Manning, Pamela T.; Hiebsch, Ronald R.; Gunasekaran, Muthukumar; Upadhya, Gundumi A.; Frazier, William A.; Mohanakumar, Thalachallour; Lin, Yiing; Chapman, William C.

    2015-01-01

    Orthotopic liver transplantation (OLT) remains the standard treatment option for nonresponsive liver failure. Because ischemia/reperfusion injury (IRI) is an important impediment to the success of OLT, new therapeutic strategies are needed to reduce IRI. We investigated whether blocking the CD47/thrombospondin-1 inhibitory action on nitric oxide signaling with a monoclonal antibody specific to CD47 (CD47mAb400) would reduce IRI in liver grafts. Syngeneic OLT was performed with Lewis rats. Control immunoglobulin G or CD47mAb400 was administered to the donor organ at procurement or to both the organ and the recipient at the time of transplant. Serum transaminases, histological changes of the liver, and animal survival were assessed. Oxidative stress, inflammatory responses, and hepatocellular damage were also quantified. A significant survival benefit was not achieved when CD47mAb400 was administered to the donor alone. However, CD47mAb400 administration to both the donor and the recipient increased animal survival afterward. The CD47mAb400-treated group showed lower serum transaminases, bilirubin, oxidative stress, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining, caspase-3 activity, and proinflammatory cytokine expression of tumor necrosis factor α, interleukin-1β, and interleukin-6. Thus, CD47 blockade with CD47mAb400 administered both to the donor and the recipient reduced liver graft IRI in a rat liver transplantation model. This may translate to decreased liver dysfunction and increased survival of liver transplant recipients. PMID:25482981

  19. Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model.

    PubMed Central

    Jones-Hughes, Tracey; Snowsill, Tristan; Haasova, Marcela; Coelho, Helen; Crathorne, Louise; Cooper, Chris; Mujica-Mota, Ruben; Peters, Jaime; Varley-Campbell, Jo; Huxley, Nicola; Moore, Jason; Allwood, Matt; Lowe, Jenny; Hyde, Chris; Hoyle, Martin; Bond, Mary; Anderson, Rob

    2016-01-01

    BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation. METHODS Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI

  20. Fecal microbiota transplantation: in perspective

    PubMed Central

    Gupta, Shaan; Allen-Vercoe, Emma; Petrof, Elaine O.

    2016-01-01

    There has been increasing interest in understanding the role of the human gut microbiome to elucidate the therapeutic potential of its manipulation. Fecal microbiota transplantation (FMT) is the administration of a solution of fecal matter from a donor into the intestinal tract of a recipient in order to directly change the recipient’s gut microbial composition and confer a health benefit. FMT has been used to successfully treat recurrent Clostridium difficile infection. There are preliminary indications to suggest that it may also carry therapeutic potential for other conditions such as inflammatory bowel disease, obesity, metabolic syndrome, and functional gastrointestinal disorders. PMID:26929784

  1. A Mouse Model of Inducible Liver Injury Caused by Tet-On Regulated Urokinase for Studies of Hepatocyte Transplantation

    PubMed Central

    Song, Xijun; Guo, Yushan; Duo, Shuguang; Che, Jie; Wu, Chen; Ochiya, Takahiro; Ding, Mingxiao; Deng, Hongkui

    2009-01-01

    Mouse models of liver injury provide useful tools for studying hepatocyte engraftment and proliferation. A representative model of liver injury is the albumin-urokinase (Alb-uPA) transgenic model, but neonatal lethality hampers its widespread application. To overcome this problem, we generated a transgenic mouse in which transcription of the reverse tetracycline transactivator was (rtTA) driven by the mouse albumin promoter, and backcrossed the rtTA mice onto severe combined immunodeficient (SCID)/bg mice to generate immunodeficient rtTA/SCID mice. We then produced recombinant adenoviruses Ad.TRE-uPA, in which the urokinase was located downstream of the tetracycline response element (TRE). The rtTA/SCID mouse hepatocytes were then infected with Ad.TRE-uPA to establish an inducible liver injury mouse model. In the presence of doxycycline, uPA was exclusively expressed in endogenous hepatocytes and caused extensive liver injury. Enhanced green fluorescent protein-labeled mouse hepatocytes selectively repopulated the rtTA/SCID mouse liver and replaced over 80% of the recipient liver mass after repeated administration of Ad.TRE-uPA. Compared with the original uPA mice, rtTA/SCID mice did not exhibit problems regarding breeding efficiency, and the time window for transplantation was flexible. In addition, we could control the extent of liver injury to facilitate transplantation surgery by regulating the dose of Ad.TRE-uPA. Our inducible mouse model will be convenient for studies of hepatocyte transplantation and hepatic regeneration, and this system will facilitate screening for potential genetic factors critical for engraftment and proliferation of hepatocytes in vivo. PMID:19808649

  2. Mycoses in the transplanted patient.

    PubMed

    Dictar, M O; Maiolo, E; Alexander, B; Jacob, N; Verón, M T

    2000-01-01

    The incidence of invasive fungal infection (IFI) has increased considerably over the past 20 years, and transplant recipients are at especially high risk for fungal infections owing to their overall immunosuppressed condition. Organ transplantation procedures were incorporated as a therapeutic option for many patients who lacked the normal functions of organs such as the heart, liver, kidney, lung, pancreas and small bowel. The prevalence of IFI in solid organ transplant (SOTR) patients ranges from 5 to 50% in kidney and liver transplants, respectively. In bone marrow transplant (BMT) patients, IFI are major causes of morbidity and mortality due to the protracted neutropenic period and graft-versus-host disease. Candida spp. and Aspergillus spp. account for >80% of fungal episodes in both SOTR and BMT. The development of new immunosuppressive agents, new prophylaxis strategies (as pre-emptive therapy) and the improvement in surgical techniques led to increase survival of transplant recipients. In this session, a clear and concise update of the recent advances in the laboratory diagnosis of candidiasis and aspergillosis in this kind of patients was presented. However, we still need to establish more rapid, sensitive and specific methods for IFI diagnosis. Representatives of the 'Subcomision de Infecciones en el Paciente Neutropenico y Transplantado (SIPNYT)' de la Sociedad Argentina de Infectologia (SADI), presented the results of an unusual multicenter study both retrospective and descriptive studies of IFI in SOTR and BMT patients in Argentina. In addition, a study of IFI in 1,861 SOTR patients from four centers and the analysis of IFI in 2,066 BMT patients from all 12 BMT centers from Argentina was presented. From these studies it can be concluded that 'all transplant recipients are not the same' and that they should be stratified according to their different risk degrees in order to determine the best prophylaxis and treatment strategies.

  3. Estradiol worsens the syndrome of ischemia-reperfusion injury in an experimental lung transplantation model.

    PubMed

    Santana-Rodríguez, Norberto; Clavo, Bernardino; Llontop, Pedro; López, Ana; García-Castellano, José Manuel; Machín, Rubén P; Ponce, Miguel A; Fiuza, María D; García-Herrera, Ricardo; Brito, Yanira; Yordi, Nagib Atallah; Chirino, Ricardo

    2011-06-01

    Ischemia-reperfusion injury (IRI) is a common complication after lung transplantation. There is evidence that reactive oxygen species are involved in its pathogenesis. We designed an experimental study to evaluate whether the administration of antioxidants to lung transplantation recipients protects against IRI and early acute rejection (AR). Twenty-five rats received left lung transplants after 6 h of ischemia. Fifty minutes before the reperfusion, groups of five rats received a single dose of desferrioxamine (20 mg/kg), estradiol (25 mg/kg), or melatonin (10 mg/kg). The animals were killed 48 h after surgery and the postoperative outcome, IRI, and AR were evaluated. The frequency of severe injury and of moderate-to-severe edema was higher in animals treated with estradiol than in the control group (P = 0.022 and P = 0.026, respectively). No significant changes in the degree of IRI or AR were observed in the groups treated with desferrioxamine or melatonin. In our study, treatment with the antioxidants melatonin or desferrioxamine before reperfusion had no effects on IRI damage or on AR frequency or severity. However, treatment with estradiol resulted in a worse postoperative outcome and in severe edema. Therefore, despite the antioxidant capacity of estradiol, it is recommended that an evaluation of these adverse effects of estradiol in human lung transplant recipients be performed.

  4. Introduction of a Framework for Dynamic Knowledge Representation of the Control Structure of Transplant Immunology: Employing the Power of Abstraction with a Solid Organ Transplant Agent-Based Model

    PubMed Central

    An, Gary

    2015-01-01

    Agent-based modeling has been used to characterize the nested control loops and non-linear dynamics associated with inflammatory and immune responses, particularly as a means of visualizing putative mechanistic hypotheses. This process is termed dynamic knowledge representation and serves a critical role in facilitating the ability to test and potentially falsify hypotheses in the current data- and hypothesis-rich biomedical research environment. Importantly, dynamic computational modeling aids in identifying useful abstractions, a fundamental scientific principle that pervades the physical sciences. Recognizing the critical scientific role of abstraction provides an intellectual and methodological counterweight to the tendency in biology to emphasize comprehensive description as the primary manifestation of biological knowledge. Transplant immunology represents yet another example of the challenge of identifying sufficient understanding of the inflammatory/immune response in order to develop and refine clinically effective interventions. Advances in immunosuppressive therapies have greatly improved solid organ transplant (SOT) outcomes, most notably by reducing and treating acute rejection. The end goal of these transplant immune strategies is to facilitate effective control of the balance between regulatory T cells and the effector/cytotoxic T-cell populations in order to generate, and ideally maintain, a tolerant phenotype. Characterizing the dynamics of immune cell populations and the interactive feedback loops that lead to graft rejection or tolerance is extremely challenging, but is necessary if rational modulation to induce transplant tolerance is to be accomplished. Herein is presented the solid organ agent-based model (SOTABM) as an initial example of an agent-based model (ABM) that abstractly reproduces the cellular and molecular components of the immune response to SOT. Despite its abstract nature, the SOTABM is able to qualitatively reproduce acute

  5. Inclusion of Dynamic Clinical Data Improves the Predictive Performance of a 30-Day Readmission Risk Model in Kidney Transplantation

    PubMed Central

    Taber, David J; Palanisamy, Arun P; Srinivas, Titte R; Gebregziabher, Mulugeta; Odeghe, John; Chavin, Kenneth D; Egede, Leonard E; Baliga, Prabhakar K

    2015-01-01

    Background 30-day readmissions (30DRA) are a highly scrutinized measure of healthcare quality and relatively frequent among kidney transplants (KTX). Development of predictive risk models are critical to reducing 30DRA and improving outcomes. Current approaches rely on fixed variables derived from administrative data. These models may not capture clinical evolution that is critical to predicting outcomes. Methods We directed a retrospective analysis towards: 1) developing parsimonious risk models for 30DRA and 2) comparing efficiency of models based on the use of immutable versus dynamic data. Baseline and in-hospital clinical and outcomes data were collected from adult KTX recipients between 2005 – 12. Risk models were developed using backward logistic regression and compared for predictive efficacy using ROC Curves. Results Of 1,147 KTX patients, 123 had 30DRA. Risk factors for 30DRA included recipient comorbidities, transplant factors, and index hospitalization patient level clinical data. The initial fixed variable model included 9 risk factors and was modestly predictive (AUC 0.64, 95% CI 0.58–0.69). The model was parsimoniously reduced to 6 risks, which remained modestly predictive (AUC 0.63, 95% CI 0.58–0.69). The initial predictive model using 13 fixed and dynamic variables was significantly predictive (AUC 0.73, 95% CI 0.67–0.80), with parsimonious reduction to 9 variables maintaining predictive efficacy (AUC 0.73, 95% CI 0.67–0.79). The final model using dynamically evolving clinical data outperformed the model using static variables (p=0.009). Internal validation demonstrated the final model was stable with minimal bias. Conclusion We demonstrate that modeling dynamic clinical data outperformed models utilizing immutable data in predicting 30DRA. PMID:25594549

  6. New model for cardiomyocyte sheet transplantation using a virus-cell fusion technique

    PubMed Central

    Takahashi, Yuto; Tomotsune, Daihachiro; Takizawa, Sakiko; Yue, Fengming; Nagai, Mika; Yokoyama, Tadayuki; Hirashima, Kanji; Sasaki, Katsunori

    2015-01-01

    AIM: To facilitate close contacts between transplanted cardiomyocytes and host skeletal muscle using cell fusion mediated by hemagglutinating virus of Japan envelope (HVJ-E) and tissue maceration. METHODS: Cardiomyocytes (1.5 × 106) from fetal rats were first cultured. After proliferation, some cells were used for fusion with adult muscle fibers using HVJ-E. Other cells were used to create cardiomyocyte sheets (area: about 3.5 cm2 including 2.1 × 106 cells), which were then treated with Nile blue, separated, and transplanted between the latissimus dorsi and intercostal muscles of adult rats with four combinations of HVJ-E and/or NaOH maceration: G1: HVJ-E(+), NaOH(+), Cardiomyocytes(+); G2: HVJ-E(-), NaOH(+), Cardiomyocytes(+); G3: HVJ-E(+), NaOH(-), Cardiomyocytes(+); G4: HVJ-E(-), NaOH(-), Cardiomyocytes(-). At 1 and 2 wk after transplantation, the four groups were compared by detection of beating domains, motion images using moving target analysis software, action potentials, gene expression of MLC-2v and Mesp1 by reverse transcription-polymerase chain reaction, hematoxylin-eosin staining, and immunostaining for cardiac troponin and skeletal myosin. RESULTS: In vitro cardiomyocytes were fused with skeletal muscle fibers using HVJ-E. Cardiomyocyte sheets remained in the primary transplanted sites for 2 wk. Although beating domains were detected in G1, G2, and G3 rats, G1 rats prevailed in the number, size, motion image amplitudes, and action potential compared with G2 and G3 rats. Close contacts were only found in G1 rats. At 1 wk after transplantation, the cardiomyocyte sheets showed adhesion at various points to the myoblast layer in the latissimus dorsi muscle. At 2 wk after transplantation, close contacts were seen over a broad area. Part of the skeletal muscle sarcoplasma seemed to project into the myocardiocyte plasma and some nuclei appeared to share both sarcoplasmas. CONCLUSION: The present results show that close contacts were acquired and facilitated

  7. Transplantation of goat bone marrow stromal cells to the degenerating intervertebral disc in a goat disc-injury model

    PubMed Central

    Zhang, Yejia; Drapeau, Susan; An, Howard S.; Thonar, Eugene J-M.A.; Anderson, D. Greg

    2010-01-01

    Study Design In vivo randomized controlled study in the goat intervertebral disc (IVD) injury model. Objective To define the effects of allogeneic bone marrow-derived stromal cell injected into the degenerating goat IVDs. Summary of Background Data Transplantation of bone marrow stromal cells to the degenerating disc has been suggested as a means to correct the biologic incompetence of the disc. However, large animal models with IVDs similar in shape and size to those of humans are needed to define the efficacy and safety of this approach. Methods Goat IVD degeneration was induced by stabbing with a #15 blade. One month after disc injury, the injured discs were randomly selected to receive goat bone marrow-derived stromal cell (suspended in hydrogel), saline (control), or hydrogel (control) injections. Three and 6 months after stem cell transplantation, goats were euthanized and the IVD were examined for biochemical content and tissue morphology. MR images at 3- and 6-month time points were also examined. Results The goat large animal model shows early degenerative changes following disc injury. Degenerating IVDs injected with bone marrow stromal cells showed significantly increased proteoglycan (PG) accumulation within their nucleus pulposus (NP) region. However, collagen content, MRI grade and histology did not show statistically significant differences between the cell-treated and control IVDs. Conclusions Following transplantation of bone marrow stromal cells, NP tissue contained more PG than control discs. Although this result was promising, the rate and severity of degeneration in this goat disc injury were modest, suggesting that a more severe injury and a larger sample size is indicated for future studies to better define the utility of cell therapies in this model. PMID:20890267

  8. Acellular allogeneic nerve grafting combined with bone marrow mesenchymal stem cell transplantation for the repair of long-segment sciatic nerve defects: biomechanics and validation of mathematical models

    PubMed Central

    Li, Ya-jun; Zhao, Bao-lin; Lv, Hao-ze; Qin, Zhi-gang; Luo, Min

    2016-01-01

    We hypothesized that a chemically extracted acellular allogeneic nerve graft used in combination with bone marrow mesenchymal stem cell transplantation would be an effective treatment for long-segment sciatic nerve defects. To test this, we established rabbit models of 30 mm sciatic nerve defects, and treated them using either an autograft or a chemically decellularized allogeneic nerve graft with or without simultaneous transplantation of bone marrow mesenchymal stem cells. We compared the tensile properties, electrophysiological function and morphology of the damaged nerve in each group. Sciatic nerves repaired by the allogeneic nerve graft combined with stem cell transplantation showed better recovery than those repaired by the acellular allogeneic nerve graft alone, and produced similar results to those observed with the autograft. These findings confirm that a chemically extracted acellular allogeneic nerve graft combined with transplantation of bone marrow mesenchymal stem cells is an effective method of repairing long-segment sciatic nerve defects. PMID:27651781

  9. Acellular allogeneic nerve grafting combined with bone marrow mesenchymal stem cell transplantation for the repair of long-segment sciatic nerve defects: biomechanics and validation of mathematical models

    PubMed Central

    Li, Ya-jun; Zhao, Bao-lin; Lv, Hao-ze; Qin, Zhi-gang; Luo, Min

    2016-01-01

    We hypothesized that a chemically extracted acellular allogeneic nerve graft used in combination with bone marrow mesenchymal stem cell transplantation would be an effective treatment for long-segment sciatic nerve defects. To test this, we established rabbit models of 30 mm sciatic nerve defects, and treated them using either an autograft or a chemically decellularized allogeneic nerve graft with or without simultaneous transplantation of bone marrow mesenchymal stem cells. We compared the tensile properties, electrophysiological function and morphology of the damaged nerve in each group. Sciatic nerves repaired by the allogeneic nerve graft combined with stem cell transplantation showed better recovery than those repaired by the acellular allogeneic nerve graft alone, and produced similar results to those observed with the autograft. These findings confirm that a chemically extracted acellular allogeneic nerve graft combined with transplantation of bone marrow mesenchymal stem cells is an effective method of repairing long-segment sciatic nerve defects.

  10. Carrageenan Gum and Adherent Invasive Escherichia coli in a Piglet Model of Inflammatory Bowel Disease: Impact on Intestinal Mucosa-associated Microbiota

    PubMed Central

    Munyaka, Peris M.; Sepehri, Shadi; Ghia, Jean-Eric; Khafipour, Ehsan

    2016-01-01

    Inflammatory bowel diseases (IBD) including Crohn's disease (CD), and ulcerative colitis (UC), are chronic conditions characterized by chronic intestinal inflammation. Adherent invasive Escherichia coli (AIEC) pathotype has been increasingly implicated in the etiopathogenesis of IBD. In a 21-day study, we investigated the effects of AIEC strain UM146 inoculation on microbiota profile of the ileal, cecal, ascending and descending colon in a pig model of experimental colitis. Carrageenan gum (CG) was used to induce colitis in weaner piglets whereas AIEC strain UM146 previously isolated from a CD patient was included to investigate a cause or consequence effect in IBD. Treatments were: (1) control; (2) CG; (3) AIEC strain UM146; and (4) CG+UM146. Pigs in groups 2 and 4 received 1% CG in drinking water from day 1 of the study while pigs in groups 3 and 4 were inoculated with UM146 on day 8. Following euthanization on day 21, tissue mucosal scrapings were collected and used for DNA extraction. The V4 region of bacterial 16S rRNA gene was then subjected to Illumina sequencing. Microbial diversity, composition, and the predicted functional metagenome were determined in addition to short chain fatty acids profiles in the digesta and inflammatory cytokines in the intestinal tissue. CG-induced colitis decreased bacterial species richness and shifted community composition. At the phylum level, an increase in Proteobacteria and Deferribacteres and a decrease in Firmicutes, Actinobacteria, and Bacteroidetes were observed in CG and CGUM146 compared to control and UM146. The metabolic capacity of the microbiome was also altered in CG and CGUM146 compared to UM146 and control in the colon. We demonstrated that CG resulted in bacterial dysbiosis and shifted community composition similar to what has been previously observed in IBD patients. However, AIEC strain UM146 alone did not cause any clear changes compared to CG or control in our experimental IBD pig model. PMID:27092122

  11. Five-year update on the mouse model of orthotopic lung transplantation: Scientific uses, tricks of the trade, and tips for success

    PubMed Central

    Lin, Xue; Li, Wenjun; Lai, Jiaming; Okazaki, Mikio; Sugimoto, Seiichiro; Yamamoto, Sumiharu; Wang, Xingan; Gelman, Andrew E.; Kreisel, Daniel

    2012-01-01

    It has been 5 years since our team reported the first successful model of orthotopic single lung transplantation in the mouse. There has been great demand for this technique due to the obvious experimental advantages the mouse offers over other large and small animal models of lung transplantation. These include the availability of mouse-specific reagents as well as knockout and transgenic technology. Our laboratory has utilized this mouse model to study both immunological and non-immunological mechanisms of lung transplant physiology while others have focused on models of chronic rejection. It is surprising that despite our initial publication in 2007 only few other laboratories have published data using this model. This is likely due to the technical complexity of the surgical technique and perioperative complications, which can limit recipient survival. As two of the authors (XL and WL) have a combined experience of over 2500 left and right single lung transplants, this review will summarize their experience and delineate tips and tricks necessary for successful transplantation. We will also describe technical advances made since the original description of the model. PMID:22754663

  12. Inhaled Hydrogen Sulfide Improves Graft Function in an Experimental Model of Lung Transplantation

    PubMed Central

    George, Timothy J.; Arnaoutakis, George J.; Beaty, Claude A.; Jandu, Simran K.; Santhanam, Lakshmi; Berkowitz, Dan E.; Shah, Ashish S.

    2014-01-01

    Objectives: Ischemia-reperfusion(IRI) is a common complication of lung transplantation(LTx). Hydrogen sulfide(H2S) is a novel agent previously shown to slow metabolism and scavenge reactive oxygen species, potentially mitigating IRI. We hypothesized that pre-treatment with inhaled H2S would improve graft function in an ex vivo model of LTx. Methods: Rabbits(n=10) were ventilated for 2 hours prior to heart-lung bloc procurement. The treatment group(n=5) inhaled room air(21% O2) supplemented with 150 ppm H2S while the control group(n=5) inhaled room air alone. Both groups were gradually cooled to 34 C. All heart-lung blocs were then recovered and cold-stored in low potassium dextran solution for 18 hours. Following storage, the blocs were reperfused with donor rabbit blood in an ex vivo apparatus. Serial clinical parameters were assessed and serial tissue biochemistry was examined. Results: Prior to heart-lung bloc procurement, rabbits pre-treated with H2S exhibited similar oxygenation(p=0.1), ventilation(p=0.7), and heart rate(p=0.5); however, treated rabbits exhibited consistently higher mean arterial blood pressures(p=0.01). During reperfusion, lungs pre-treated with H2S had better oxygenation(p<0.01) and ventilation(p=0.02) as well as lower pulmonary artery pressures(p<0.01). Reactive oxygen species levels were lower in treated lungs during reperfusion(p=0.01). Additionally, prior to reperfusion, treated lungs demonstrated more preserved mitochondrial cytochrome c oxidase activity(p=0.01). Conclusions: To our knowledge, this study represents the first reported therapeutic use of inhaled H2S in an experimental model of LTx. After prolonged ischemia, lungs pre-treated with inhaled H2S exhibited improved graft function during reperfusion. Donor pre-treatment with inhaled H2S represents a potentially novel adjunct to conventional preservation techniques and merits further exploration. PMID:22771242

  13. [Diagnosis of functional bowel diseases].

    PubMed

    Kruis, W

    2007-02-28

    Functional bowel disorders cause frequent doctor visits. The term comprises various disease entities. Most frequent are the irritable bowel syndrome, functional constipation and functional diarrhea. An exact history plays an outstanding role for the diagnosis of all these entities. History either confirms a positive diagnosis or initiates some complementary investigations. Redundant and dangerous technical procedures should be avoided in the diagnostic work up.

  14. Inflammatory bowel disease

    PubMed Central

    Beattie, R M; Croft, N M; Fell, J M; Afzal, N A; Heuschkel, R B

    2006-01-01

    Twenty five per cent of inflammatory bowel disease presents in childhood. Growth and nutrition are key issues in the management with the aim of treatment being to induce and then maintain disease remission with minimal side effects. Only 25% of Crohn's disease presents with the classic triad of abdominal pain, weight loss, and diarrhoea. Most children with ulcerative colitis have blood in the stool at presentation. Inflammatory markers are usually although not invariably raised at presentation (particularly in Crohn's disease). Full investigation includes upper gastrointestinal endoscopy and ileocolonoscopy. Treatment requires multidisciplinary input as part of a clinical network led by a paediatrician with special expertise in the management of the condition. PMID:16632672

  15. Toxoplasmosis in organ transplant recipients: Evaluation, implication, and prevention

    PubMed Central

    Khurana, Sumeeta; Batra, Nitya

    2016-01-01

    Toxoplasmosis in organ transplant patients can be a result of donor-transmitted infection, or reactivation of latent infection, or de novo infection. Solid organ transplants including heart, liver, kidney, pancreas and small bowel, and hematogenous stem cell transplants have been implicated in the risk of acquiring infection. In contrast to a benign course in immunocompetent individuals, the spectrum of illness is severe in transplant recipients. Clinical manifestations usually occur within the first 3 months of transplant and may present as encephalitis, pneumonitis, chorioretinitis, meningitis, and disseminated toxoplasmosis with multi-organ involvement. The diagnosis of toxoplasmosis in organ transplant patients is often difficult and is an integration of clinical, radiological, and microbiological workup. Preventive measures include pretransplant evaluation and chemoprophylaxis in view of rapidly progressing and fatal outcome of toxoplasmosis in immunocompromised individuals. PMID:27722100

  16. Identification of a Functional TPH1 Polymorphism Associated with Irritable Bowel Syndrome Bowel Habit Subtypes

    PubMed Central

    Grasberger, Helmut; Chang, Lin; Shih, Wendy; Presson, Angela P.; Sayuk, Gregory S.; Newberry, Rodney D.; Karagiannides, Iordanis; Pothoulakis, Charalabos; Mayer, Emeran; Merchant, Juanita L.

    2014-01-01

    Background & Aims Alterations in 5-hydroxytryptamine (5-HT) signaling have been implicated as a factor contributing to the altered bowel habit of irritable bowel syndrome (IBS) patients. Tryptophan hydroxylase 1 (TPH1) is the rate–limiting enzyme in enterochromaffin cell 5-HT biosynthesis. We hypothesized that genetic variants affecting TPH1 gene expression might alter intestinal 5-HT bioavailability and subsequently the propensity for distinct bowel habit subtypes in IBS. In this study, we assessed the only common TPH1 proximal promoter variant (-347C/A; rs7130929) and its association with bowel habit predominance in IBS. Methods Electrophoretic mobility shift assays were performed to assess whether the -347C/A allele variant affects the DNA-binding of nuclear factors. Genotype distribution was determined for 422 IBS patients subtyped using Rome III criteria and for 495 healthy controls recruited from two university medical centers. Association with bowel habit was tested using a multinomial logistic regression model controlling for race, anxiety, depression, and study site. Results Early growth response factor 1 (EGR-1) bound with higher affinity to a site comprising the minor A-allele of SNP -347C/A. TPH1 genotype frequencies did not differ between IBS patients and controls overall. The CC genotype was more prevalent in the IBS-D subtype (47%) than in the IBS-C (25%) and IBS-M (37%) subtypes (P=0.039) after adjusting for race and other covariates. Colonic biopsies from a small cohort of IBS patients from one center were tested for higher TPH1 mRNA expression in samples with CC compared to CA genotype, but the results did not reach statistical significance. Conclusions The TPH1 promoter SNP -347C/A differentially binds EGR1, correlates with IBS bowel habit subtypes and possibly colonic TPH1 expression consistent with its role in modulating intestinal 5-HT signaling. PMID:24060757

  17. Continuum of therapy in progressive renal diseases (from predialysis to transplantation): analysis of a new organizational model.

    PubMed

    Piccoli, Giuseppe; Piccoli, Giorgina Barbara; Mezza, Elisabetta; Burdese, Manuel; Rosetti, Maura; Guarena, Cesare; Messina, Maria; Pacitti, Alfonso; Thea, Alessandra; Malfi, Bernardo; Soragna, Giorgio; Gai, Massimo; Mangiarotti, Giovanni; Jeantet, Alberto; Segoloni, Giuseppe Paolo

    2004-09-01

    In the aging of Western populations, decreased mortality is counterbalanced by an increase in morbidity, particularly involving chronic diseases such as most renal diseases. The price of the successful care of chronic conditions, such as cardiovascular diseases or diabetes, is a continuous increase in new dialysis patients. However, the increased survival of patients on chronic renal replacement therapies poses new challenges to nephrologists and calls for new models of care. Since its split from internal medicine, nephrology has seen a progressive trend toward super specialization and the differentiation into at least 3 major branches (nephrology, dialysis, and transplantation), following a path common to several other fields of internal medicine. The success in the care of chronic patients is owed not only to a careful technical prescription, but also to the ability to teach self-care and attain compliance; this requires good medical practice and a sound patient-physician relationship. In this context, the usual models of care may fail to provide adequate coordination and, despite valuable single elements, could end up as an orchestra without a conductor. We propose an integrated model of care oriented to the type of patient (tested in our area especially for diabetic patients): the patient is followed-up by the same team from the first signs of renal disease to eventual dialysis or transplantation. This model offers an interesting alternative both for patients, who usually seek continuity of care, and for nephrologists who prefer a holistic and integrated patient-physician approach. PMID:15490421

  18. Psychosocial factors in peptic ulcer and inflammatory bowel disease.

    PubMed

    Levenstein, Susan

    2002-06-01

    Over the past decade, while gastroenterologists' interest in mind-body interactions in organic disorders dwindled, stronger evidence has linked psychosocial factors with the incidence and recurrence of peptic ulcer and with the course of inflammatory bowel disease. Psychological-behavioral approaches to treatment continue to be disappointing. Psychosocial factors may affect ulcer by increasing duodenal acid load, altering local circulation or motility, intensifying Helicobacter pylori infection, stimulating corticosteroid secretion, and affecting health risk behaviors; possible mechanisms for inflammatory bowel disease include immune deregulation, gut permeability changes, and poor medication adherence. Both belong to the growing category of diseases thought to have an infectious component: for peptic ulcer the bacterium Helicobacter pylori, for inflammatory bowel disease an exaggerated immune response to gut bacteria. Peptic ulcer and inflammatory bowel disease, which present unique interactions among psychological, immunologic, endocrine, infectious, and behavioral factors, are splendid paradigms of the biopsychosocial model.

  19. Organ Transplantation

    MedlinePlus

    ... recipients to reduce the risk of transplant rejection. Rejection happens when your immune system attacks the new organ. If you have a transplant, you must take drugs the rest of your life to help keep your body from rejecting the new organ.

  20. Transplant rejection

    MedlinePlus

    ... Wood K, Shankar S, Mittal S. Concepts and challenges in organ transplantation. In: Rich RR, Fleisher TA, Shearer WT, et ... A.M. Editorial team. Related MedlinePlus Health Topics Organ Transplantation Browse the Encyclopedia A.D.A.M., Inc. ...

  1. Intestine Transplant

    MedlinePlus

    ... intestine segment, most intestine transplants involve a whole organ from a deceased donor. In addition, most intestine transplants are performed in ... blood before surgery. I am looking for ... allocation About UNOS Being a living donor Calculator - CPRA Calculator - KDPI Calculator - LAS Calculator - MELD ...

  2. Intrastriatal transplantation of neurotrophic factor-secreting human mesenchymal stem cells improves motor function and extends survival in R6/2 transgenic mouse model for Huntington's disease

    PubMed Central

    Sadan, Ofer; Melamed, Eldad; Offen, Daniel

    2012-01-01

    Stem cell-based treatment for Huntington's disease (HD) is an expanding field of research. Although various stem cells have been shown to be beneficial in vivo, no long standing clinical effect has been demonstrated. To address this issue, we are developing a stem cell-based therapy designed to improve the microenvironment of the diseased tissue via delivery of neurotrophic factors (NTFs). Previously, we established that bone marrow derived human mesenchymal stem cells (MSCs) can be differentiated using medium based cues into NTF-secreting cells (NTF+ cells) that express astrocytic markers. NTF+ cells were shown to alleviate neurodegeneration symptoms in several disease models in vitro and in vivo, including the model for excitotoxicity. In the present study, we explored if the timing of intrastriatal transplantation of hNTF+ cells into the R6/2 transgenic mouse model for HD influences motor function and survival. One hundred thousand cells were transplanted bilaterally into the striatum of immune-suppressed mice at 4.5, 5.5 and 6.5 weeks of age. Contrary to our expectations, early transplantation of NTF+ cells did not improve motor function or overall survival. However, late (6.5 weeks) transplantation resulted in a temporary improvement in motor function and an extension of life span relative to that observed for PBS treated mice. We conclude that late transplantation of NTF+ cells induces a beneficial effect in this transgenic model for HD. Since no transplanted NTF+ cells could be detected in vivo, we suspect that the temporary nature of the beneficial effect is due to poor survival of transplanted cells. In general, we submit that NTF+ cells should be further evaluated for the therapy of HD. PMID:22953237

  3. Irritable bowel syndrome

    PubMed Central

    Enck, Paul; Aziz, Qasim; Barbara, Giovanni; Farmer, Adam D.; Fukudo, Shin; Mayer, Emeran A.; Niesler, Beate; Quigley, Eamonn M. M.; Rajilić-Stojanović, Mirjana; Schemann, Michael; Schwille-Kiuntke, Juliane; Simren, Magnus; Zipfel, Stephan; Spiller, Robin C.

    2016-01-01

    Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with a high population prevalence. The disorder can be debilitating in some patients, whereas others may have mild or moderate symptoms. The most important single risk factors are female sex, younger age and preceding gastrointestinal infections. Clinical symptoms of IBS include abdominal pain or discomfort, stool irregularities and bloating, as well as other somatic, visceral and psychiatric comorbidities. Currently, the diagnosis of IBS is based on symptoms and the exclusion of other organic diseases, and therapy includes drug treatment of the predominant symptoms, nutrition and psychotherapy. Although the underlying pathogenesis is far from understood, aetiological factors include increased epithelial hyperpermeability, dysbiosis, inflammation, visceral hypersensitivity, epigenetics and genetics, and altered brain–gut interactions. IBS considerably affects quality of life and imposes a profound burden on patients, physicians and the health-care system. The past decade has seen remarkable progress in our understanding of functional bowel disorders such as IBS that will be summarized in this Primer. PMID:27159638

  4. Cecal volvulus following laparoscopic nephrectomy and renal transplantation.

    PubMed

    Eng, Mary; Ravindra, Kadiyala

    2009-01-01

    Cecal volvulus is a rare cause of bowel obstruction that carries a high mortality. Recent surgery is known to be a risk factor for the development of cecal volvulus. We present a case of cecal volvulus following laparoscopic nephrectomy and renal transplantation.

  5. A transplantable TH-MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma.

    PubMed

    Kroesen, Michiel; Nierkens, Stefan; Ansems, Marleen; Wassink, Melissa; Orentas, Rimas J; Boon, Louis; den Brok, Martijn H; Hoogerbrugge, Peter M; Adema, Gosse J

    2014-03-15

    Current multimodal treatments for patients with neuroblastoma (NBL), including anti-disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well-explored autologous mouse model for NBL is the TH-MYCN model. However, the immunobiology of the TH-MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH-MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH-MYCN-derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.1+ cells resulted in enhanced tumor outgrowth in both wild-type and Rag1(-/-) mice, showing an important role for NK cells in the natural anti-NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti-GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH-MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients.

  6. Insights Into Normal and Disordered Bowel Habits From Bowel Diaries

    PubMed Central

    Bharucha, Adil E.; Seide, Barbara M.; Zinsmeister, Alan R.; Melton, L. Joseph

    2008-01-01

    Background While symptom questionnaires provide a snapshot of bowel habits, they may not reflect day-to-day variations or the relationship between bowel symptoms and stool form. Aim To assess bowel habits by daily diaries in women with and without functional bowel disorders. Method From a community-based survey among Olmsted County, MN, women, 278 randomly selected subjects were interviewed by a gastroenterologist, who completed a bowel symptom questionnaire. Subjects also maintained bowel diaries for 2 wk. Results Among 278 subjects, questionnaires revealed diarrhea (26%), constipation (21%), or neither (53%). Asymptomatic subjects reported bowel symptoms (e.g., urgency) infrequently (i.e., <25% of the time) and generally for hard or loose stools. Urgency for soft, formed stools (i.e., Bristol form = 4) was more prevalent in subjects with diarrhea (31%) and constipation (27%) than in normals (16%). Stool form, straining to begin (odds ratio [OR] 4.1, 95% confidence interval [CI] 1.7–10.2) and end (OR 4.7, 95% CI 1.6–15.2) defecation increased the odds for constipation. Straining to end defecation (OR 3.7, 95% CI 1.2–12.0), increased stool frequency (OR 1.9, 95% CI 1.02–3.7), incomplete evacuation (OR 2.2, 95% CI 1.04–4.6), and rectal urgency (OR 3.1, 95% CI 1.4–6.6) increased the odds for diarrhea. In contrast, variations in stool frequency and form were not useful for discriminating between health and disease. Conclusions Bowel symptoms occur in association with, but are only partly explained by, stool form disturbances. These observations support a role for other pathophysiological mechanisms in functional bowel disorders. PMID:18021288

  7. Modeling intraspecific adaptation of Abies sachalinensis to local altitude and responses to global warming, based on a 36-year reciprocal transplant experiment.

    PubMed

    Ishizuka, Wataru; Goto, Susumu

    2012-04-01

    Intraspecific adaptation in Abies sachalinensis was examined using models based on long-term monitoring data gathered during a reciprocal transplant experiment with eight seed source populations and six transplantation sites along an altitudinal gradient. The consequence of local adaptation was evaluated by testing the home-site advantage for upslope and downslope transplants at five ages. The populations' fitness-linked trait was set as their productivity (tree height × survival rate) at each age. The effects of global warming were evaluated on the basis of the 36-year performance of downslope transplants. Evidence was found for adaptive genetic variation affecting both height and survival from an early age. Increasing the distance between seed source and planting site significantly reduced productivity for both upslope and downslope transplantation, demonstrating the existence of a significant home-site advantage. The decrease in productivity was most distinct for upslope transplantations, indicating strong local adaptation to high altitudes. Global warming is predicted to increase the productivity of high-altitude populations. However, owing to their existing local adaptation, all tested populations exhibited lower productivity under warming than demes that were optimal for the new climate. These negative predictions should be considered when planning the management of locally adapted plant species such as A. sachalinensis.

  8. Efficient liver repopulation of transplanted hepatocyte prevents cirrhosis in a rat model of hereditary tyrosinemia type I

    PubMed Central

    Zhang, Ludi; Shao, Yanjiao; Li, Lu; Tian, Feng; Cen, Jin; Chen, Xiaotao; Hu, Dan; Zhou, Yan; Xie, Weifen; Zheng, Yunwen; Ji, Yuan; Liu, Mingyao; Li, Dali; Hui, Lijian

    2016-01-01

    Hereditary tyrosinemia type I (HT1) is caused by a deficiency in the enzyme fumarylacetoacetate hydrolase (Fah). Fah-deficient mice and pigs are phenotypically analogous to human HT1, but do not recapitulate all the chronic features of the human disorder, especially liver fibrosis and cirrhosis. Rats as an important model organism for biomedical research have many advantages over other animal models. Genome engineering in rats is limited till the availability of new gene editing technologies. Using the recently developed CRISPR/Cas9 technique, we generated Fah−/− rats. The Fah−/− rats faithfully represented major phenotypic and biochemical manifestations of human HT1, including hypertyrosinemia, liver failure, and renal tubular damage. More importantly, the Fah−/− rats developed remarkable liver fibrosis and cirrhosis, which have not been observed in Fah mutant mice or pigs. Transplantation of wild-type hepatocytes rescued the Fah−/− rats from impending death. Moreover, the highly efficient repopulation of hepatocytes in Fah−/− livers prevented the progression of liver fibrosis to cirrhosis and in turn restored liver architecture. These results indicate that Fah−/− rats may be used as an animal model of HT1 with liver cirrhosis. Furthermore, Fah−/− rats may be used as a tool in studying hepatocyte transplantation and a bioreactor for the expansion of hepatocytes. PMID:27510266

  9. Efficient liver repopulation of transplanted hepatocyte prevents cirrhosis in a rat model of hereditary tyrosinemia type I.

    PubMed

    Zhang, Ludi; Shao, Yanjiao; Li, Lu; Tian, Feng; Cen, Jin; Chen, Xiaotao; Hu, Dan; Zhou, Yan; Xie, Weifen; Zheng, Yunwen; Ji, Yuan; Liu, Mingyao; Li, Dali; Hui, Lijian

    2016-01-01

    Hereditary tyrosinemia type I (HT1) is caused by a deficiency in the enzyme fumarylacetoacetate hydrolase (Fah). Fah-deficient mice and pigs are phenotypically analogous to human HT1, but do not recapitulate all the chronic features of the human disorder, especially liver fibrosis and cirrhosis. Rats as an important model organism for biomedical research have many advantages over other animal models. Genome engineering in rats is limited till the availability of new gene editing technologies. Using the recently developed CRISPR/Cas9 technique, we generated Fah(-/-) rats. The Fah(-/-) rats faithfully represented major phenotypic and biochemical manifestations of human HT1, including hypertyrosinemia, liver failure, and renal tubular damage. More importantly, the Fah(-/-) rats developed remarkable liver fibrosis and cirrhosis, which have not been observed in Fah mutant mice or pigs. Transplantation of wild-type hepatocytes rescued the Fah(-/-) rats from impending death. Moreover, the highly efficient repopulation of hepatocytes in Fah(-/-) livers prevented the progression of liver fibrosis to cirrhosis and in turn restored liver architecture. These results indicate that Fah(-/-) rats may be used as an animal model of HT1 with liver cirrhosis. Furthermore, Fah(-/-) rats may be used as a tool in studying hepatocyte transplantation and a bioreactor for the expansion of hepatocytes. PMID:27510266

  10. Complete rat spinal cord transection as a faithful model of spinal cord injury for translational cell transplantation.

    PubMed

    Lukovic, Dunja; Moreno-Manzano, Victoria; Lopez-Mocholi, Eric; Rodriguez-Jiménez, Francisco Javier; Jendelova, Pavla; Sykova, Eva; Oria, Marc; Stojkovic, Miodrag; Erceg, Slaven

    2015-01-01

    Spinal cord injury (SCI) results in neural loss and consequently motor and sensory impairment below the injury. There are currently no effective therapies for the treatment of traumatic SCI in humans. Various animal models have been developed to mimic human SCI. Widely used animal models of SCI are complete or partial transection or experimental contusion and compression, with both bearing controversy as to which one more appropriately reproduces the human SCI functional consequences. Here we present in details the widely used procedure of complete spinal cord transection as a faithful animal model to investigate neural and functional repair of the damaged tissue by exogenous human transplanted cells. This injury model offers the advantage of complete damage to a spinal cord at a defined place and time, is relatively simple to standardize and is highly reproducible. PMID:25860664

  11. Complete rat spinal cord transection as a faithful model of spinal cord injury for translational cell transplantation.

    PubMed

    Lukovic, Dunja; Moreno-Manzano, Victoria; Lopez-Mocholi, Eric; Rodriguez-Jiménez, Francisco Javier; Jendelova, Pavla; Sykova, Eva; Oria, Marc; Stojkovic, Miodrag; Erceg, Slaven

    2015-04-10

    Spinal cord injury (SCI) results in neural loss and consequently motor and sensory impairment below the injury. There are currently no effective therapies for the treatment of traumatic SCI in humans. Various animal models have been developed to mimic human SCI. Widely used animal models of SCI are complete or partial transection or experimental contusion and compression, with both bearing controversy as to which one more appropriately reproduces the human SCI functional consequences. Here we present in details the widely used procedure of complete spinal cord transection as a faithful animal model to investigate neural and functional repair of the damaged tissue by exogenous human transplanted cells. This injury model offers the advantage of complete damage to a spinal cord at a defined place and time, is relatively simple to standardize and is highly reproducible.

  12. Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation

    PubMed Central

    Ashraf, M. I.; Schwelberger, H. G.; Brendel, K. A.; Feurle, J.; Andrassy, J.; Kotsch, K.; Regele, H.; Pratschke, J.; Maier, H. T.

    2016-01-01

    Abstract Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor–recipient combinations (C57Bl/6 wild‐type and Lcn2−/−, Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation. PMID:26595644

  13. Increasing access to renal transplantation in India through our single-center kidney paired donation program: a model for the developing world to prevent commercial transplantation.

    PubMed

    Kute, Vivek B; Shah, Priyadarshini S; Vanikar, Aruna V; Gumber, Manoj R; Patel, Himanshu V; Engineer, Divyesh P; Shah, Pankaj R; Modi, Pranjal R; Shah, Veena R; Rizvi, Syed Jamal; Trivedi, Hargovind L

    2014-10-01

    Because access to transplantation with HLA-desensitization protocols and ABO incompatible transplantation is very limited due to high costs and increased risk of infections from more intense immunosuppression, kidney paired donation (KPD) promises hope to a growing number of end-stage renal disease (ESRD) patient in India. We present a government and institutional ethical review board approved study of 56 ESRD patients [25 two-way and 2 three-way pairs] who consented to participate in KPD transplantation at our center in 2013, performed to avoid blood group incompatibility (n = 52) or positive cross-match (n = 4). All patients had anatomic, functional, and immunologically comparable donors. The waiting time in KPD was short as compared to deceased donor transplantation. Laparoscopic donor nephrectomy was performed in 54 donors. Donor relationships were spousal (n = 40), parental (n = 13), others (n = 3), with median HLA match of 1. Graft survival was 97.5%. Three patients died with functioning graft. 16% had biopsy-proven acute rejection. Mean serum creatinine was 1.2 mg/dl at 0.73 ± 0.32 months follow-up. KPD is a viable, legal, and rapidly growing modality for facilitating LDRT for patients who are incompatible with their healthy, willing living donor. To our knowledge, this is the largest single-center report from India.

  14. A new simplified volume-loaded heterotopic rabbit heart transplant model with improved techniques and a standard operating procedure

    PubMed Central

    Lu, Wei; Zheng, Jun; Pan, Xu-Dong; Li, Bing; Zhang, Jin-Wei; Wang, Long-Fei

    2015-01-01

    Background The classic non-working (NW) heterotopic heart transplant (HTX) model in rodents had been widely used for researches related to immunology, graft rejection, evaluation of immunosuppressive therapies and organ preservation. But unloaded models are considered not suitable for some researches. Accordingly, We have constructed a volume-loaded (VL) model by a new and simple technique. Methods Thirty male New Zealand White rabbits were randomly divided into two groups, group NW with 14 rabbits and group VL with 16 rabbits, which served as donors and recipients. We created a large and nonrestrictive shunt to provide left heart a sufficient preload. The donor superior vena cave and ascending aorta (AO) were anastomosed to the recipient abdominal aorta (AAO) and inferior vena cava (IVC), respectively. Results No animals suffered from paralysis, pneumonia and lethal bleeding. Recipients’ mortality and morbidity were 6.7% (1/15) and 13.3% (2/15), respectively. The cold ischemia time in group VL is slight longer than that in group NW. The maximal aortic velocity (MAV) of donor heart was approximately equivalent to half that of native heart in group VL. Moreover, the similar result was achieved in the parameter of late diastolic mitral inflow velocity between donor heart and native heart in group VL. The echocardiography (ECHO) showed a bidirectional flow in donor SVC of VL model, inflow during diastole and outflow during systole. PET-CT imaging showed the standard uptake value (SUV) of allograft was equal to that of native heart in both groups on the postoperative day 3. Conclusions We have developed a new VL model in rabbits, which imitates a native heart hemodynamically while only requiring a minor additional procedure. Surgical technique is simple compared with currently used HTX models. We also developed a standard operating procedure that significantly improved graft and recipient survival rate. This study may be useful for investigations in transplantation

  15. Endoscopic Delivery of Fecal Biotherapy in Inflammatory Bowel Disease.

    PubMed

    Kerman, David H

    2016-10-01

    The intestinal microbiome plays an important role in the pathogenesis of inflammatory bowel disease (IBD). We are able to use the microbiome as a therapeutic target with use of fecal microbiota transplantation (FMT) for cure of recurrent Clostridium difficile infection. Given our ability to target the dysbiotic state with FMT, its use as therapy in IBD has tremendous potential. This overview discusses the practical considerations of FMT therapy with respect to our current understanding of safety and efficacy in IBD, screening for donors and recipients, specimen handling and storage, methods of delivery, and regulatory considerations. PMID:27633598

  16. Gene array analysis of a rat model of liver transplant tolerance identifies increased complement C3 and the STAT-1/IRF-1 pathway during tolerance induction.

    PubMed

    Cordoba, Shaun P; Wang, Chuanmin; Williams, Rohan; Li, Jian; Smit, Lynn; Sharland, Alexandra; Allen, Richard; McCaughan, Geoffrey; Bishop, Alex

    2006-04-01

    This study aimed to define the molecular mechanism during induction of spontaneous liver transplant tolerance using microarrays and to focus on molecular pathways associated with tolerance by meta-analysis with published studies. The differences in the early immune response between PVG to DA liver transplant recipients that are spontaneously tolerant (TOL) and PVG to Lewis liver transplants that reject (REJ) were examined. Spleens from TOL and REJ on days 1 and 3 were compared by 2 color microarray. Forty-six of 199 genes differentially expressed between TOL and REJ had an immunological function. More immune genes were increased in TOL vs. REJ on day 1, including STAT-1, IRF-1 and complement C3. Differential expression of selected genes was confirmed by quantitative RT-PCR. The results were compared to two published high-throughput studies of rat liver transplant tolerance and showed that C3 was increased in all three models, while STAT-1 and IRF-1 were increased in two models. The early increases in immune genes in TOL confirmed previous reports of an active early immune response in TOL. In conclusion, the increase in STAT-1, IRF-1 and complement component C3 in several models of liver transplant tolerance suggests that the STAT-1/IRF-1 apoptotic pathway and C3 may be involved in the tolerogenic mechanism.

  17. The Role of Lysophosphatidic Acid on Airway Epithelial Cell Denudation in a Murine Heterotopic Tracheal Transplant Model

    PubMed Central

    Tando, Yukiko; Ota, Chiharu; Yamada, Mitsuhiro; Kamata, Satoshi; Yamaya, Mutsuo; Kano, Kuniyuki; Okudaira, Shinichi; Aoki, Junken; Kubo, Hiroshi

    2015-01-01

    Background Chronic rejection is the major leading cause of morbidity and mortality after lung transplantation. Obliterative bronchiolitis (OB), a fibroproliferative disorder of the small airways, is the main manifestation of chronic lung allograft rejection. However, there is currently no treatment for the disease. We hypothesized that lysophosphatidic acid (LPA) participates in the progression of OB. The aim of this study was to reveal the involvement of LPA on the lesion of OB. Methods Ki16198, an antagonist specifically for LPA1 and LPA3, was daily administered into the heterotopic tracheal transplant model mice at the day of transplantation. At days 10 and 28, the allografts were isolated and evaluated histologically. The messenger RNA levels of LPAR in microdissected mouse airway regions were assessed to reveal localization of lysophosphatidic acid receptors. The human airway epithelial cell was used to evaluate the mechanism of LPA-induced suppression of cell adhesion to the extracellular matrix (ECM). Results The administration of Ki16198 attenuated airway epithelial cell loss in the allograft at day 10. Messenger RNAs of LPA1 and LPA3 were detected in the airway epithelial cells of the mice. Lysophosphatidic acid inhibited the attachment of human airway epithelial cells to the ECM and induced cell detachment from the ECM, which was mediated by LPA1 and Rho-kinase pathway. However, Ki16198 did not prevent obliteration of allograft at day 28. Conclusions The LPA signaling is involved in the status of epithelial cells by distinct contribution in 2 different phases of the OB lesion. This finding suggests a role of LPA in the pathogenesis of OB. PMID:27500235

  18. Abate Cytochrome C induced apoptosome to protect donor liver against ischemia reperfusion injury on rat liver transplantation model

    PubMed Central

    Zhuang, Zhuonan; Lian, Peilong; Wu, Xiaojuan; Shi, Baoxu; Zhuang, Maoyou; Zhou, Ruiling; Zhao, Rui; Zhao, Zhen; Guo, Sen; Ji, Zhipeng; Xu, Kesen

    2016-01-01

    Objective: Aim of this study is to protect donor liver against ischemia-reperfusion injury by abating Cytochrome C induced apoptosome on rat model. Methods: A total of 25 clean SD inbred male rats were used in this research. The rats in ischemia-reperfusion injury group (I/R group, n=5) were under liver transplantation operation; rats in dichloroacetate diisopropylamine group (DADA group, n=5) were treated DADA before liver transplantation; control group (Ctrl group, n=5); other 10 rats were used to offer donor livers. Results: In DADA therapy group, Cytochrome C expression in donor hepatocellular cytoplasm was detected lower than that in I/R group. And the Cytochrome C induced apoptosome was also decreased in according to the lower expressions of Apaf-1 and Caspase3. Low level of cleaved PARP expression revealed less apoptosis in liver tissue. The morphology of donor liver mitochondria in DADA group was observed to be slightly edema but less than I/R group after operation 12 h. The liver function indexes of ALT and AST in serum were tested, and the results in DADA group showed it is significantly lower than I/R group after operation 12 h. The inflammation indexes of IL-6 and TNF-α expressions in DADA group were significantly lower than that in I/R group after operation 24 h. Conclusion: The dichloroacetate diisopropylamine treatment could protect the hepatocellular mitochondria in case of the spillage of Cytochrome C induced apoptosome, and protect the liver against ischemia-reperfusion injury. Thus, it may be a method to promote the recovery of donor liver function after transplantation. PMID:27186297

  19. Facial Transplantation.

    PubMed

    Russo, Jack E; Genden, Eric M

    2016-08-01

    Reconstruction of severe facial deformities poses a unique surgical challenge: restoring the aesthetic form and function of the face. Facial transplantation has emerged over the last decade as an option for reconstruction of these defects in carefully selected patients. As the world experience with facial transplantation grows, debate remains regarding whether such a highly technical, resource-intensive procedure is warranted, all to improve quality of life but not necessarily prolong it. This article reviews the current state of facial transplantation with focus on the current controversies and challenges, with particular attention to issues of technique, immunology, and ethics. PMID:27400850

  20. Inflammatory bowel disease.

    PubMed Central

    Van Rosendaal, G M

    1989-01-01

    An increasing number of options are available for the treatment of inflammatory bowel disease; the selection depends on the extent and severity of the disease. Experience with sulfasalazine and corticosteroids has led to a proliferation of 5-aminosalicylic acid (5-ASA) compounds and experimentation with alternative corticosteroid preparations. Given rectally 5-ASA is particularly effective in the treatment of distal ulcerative colitis, and experience is accumulating with several oral formulations. Metronidazole is useful in some cases, and immunosuppressive agents have a role in some patients with chronic refractory disease. A variety of measures, such as nutritional therapy, surgery and psychosocial support, are important elements of therapy. Further therapeutic innovations are expected as the etiology and pathogenesis are clarified. PMID:2568163

  1. Prenatal Intestinal Obstruction Affects the Myenteric Plexus and Causes Functional Bowel Impairment in Fetal Rat Experimental Model of Intestinal Atresia

    PubMed Central

    Khen-Dunlop, Naziha; Sarnacki, Sabine; Victor, Anais; Grosos, Celine; Menard, Sandrine; Soret, Rodolphe; Goudin, Nicolas; Pousset, Maud; Sauvat, Frederique; Revillon, Yann; Cerf-Bensussan, Nadine; Neunlist, Michel

    2013-01-01

    Background Intestinal atresia is a rare congenital disorder with an incidence of 3/10 000 birth. About one-third of patients have severe intestinal dysfunction after surgical repair. We examined whether prenatal gastrointestinal obstruction might effect on the myenteric plexus and account for subsequent functional disorders. Methodology/Principal Findings We studied a rat model of surgically induced antenatal atresia, comparing intestinal samples from both sides of the obstruction and with healthy rat pups controls. Whole-mount preparations of the myenteric plexus were stained for choline acetyltransferase (ChAT) and nitric oxide synthase (nNOS). Quantitative reverse transcription PCR was used to analyze mRNAs for inflammatory markers. Functional motility and permeability analyses were performed in vitro. Phenotypic studies were also performed in 8 newborns with intestinal atresia. In the experimental model, the proportion of nNOS-immunoreactive neurons was similar in proximal and distal segments (6.7±4.6% vs 5.6±4.2%, p = 0.25), but proximal segments contained a higher proportion of ChAT-immunoreactive neurons (13.2±6.2% vs 7.5±4.3%, p = 0.005). Phenotypic changes were associated with a 100-fold lower concentration-dependent contractile response to carbachol and a 1.6-fold higher EFS-induced contractile response in proximal compared to distal segments. Transcellular (p = 0.002) but not paracellular permeability was increased. Comparison with controls showed that modifications involved not only proximal but also distal segments. Phenotypic studies in human atresia confirmed the changes in ChAT expression. Conclusion Experimental atresia in fetal rat induces differential myenteric plexus phenotypical as well as functional changes (motility and permeability) between the two sides of the obstruction. Delineating these changes might help to identify markers predictive of motility dysfunction and to define guidelines for post-surgical care. PMID:23667464

  2. Protective effects of heat-killed Lactococcus lactis subsp. lactis BF3, isolated from the intestine of chum salmon, in a murine model of DSS-induced inflammatory bowel disease.

    PubMed

    Nakata, Toru; Hirano, Shino; Yokota, Yasushi; Takahashi, Hajime; Kimura, Bon; Kuda, Takashi; Eto, Tadashi; Kato, Michiko

    2016-01-01

    Oxidative stress is considered an etiological factor responsible for several symptoms of inflammatory bowel disease (IBD). In vitro anti-inflammatory activities of heat-killed Lactococcus lactis subsp. lactis BF3 have been reported. In this study, the anti-inflammatory effect of these cells was examined using a dextran sodium sulphate (DSS)-induced murine IBD model. Administration of heat-killed L. lactis BF3 via drinking water suppressed the IBD symptoms, such as shortening of colon length, damage to the colon mucosa as observed under the microscope, and spleen enlargement. This result suggests that heat-killed L. lactis BF3 has the potential to treat IBD. PMID:27508115

  3. Protective effects of heat-killed Lactococcus lactis subsp. lactis BF3, isolated from the intestine of chum salmon, in a murine model of DSS-induced inflammatory bowel disease

    PubMed Central

    NAKATA, Toru; HIRANO, Shino; YOKOTA, Yasushi; TAKAHASHI, Hajime; KIMURA, Bon; KUDA, Takashi; ETO, Tadashi; KATO, Michiko

    2016-01-01

    Oxidative stress is considered an etiological factor responsible for several symptoms of inflammatory bowel disease (IBD). In vitro anti-inflammatory activities of heat-killed Lactococcus lactis subsp. lactis BF3 have been reported. In this study, the anti-inflammatory effect of these cells was examined using a dextran sodium sulphate (DSS)-induced murine IBD model. Administration of heat-killed L. lactis BF3 via drinking water suppressed the IBD symptoms, such as shortening of colon length, damage to the colon mucosa as observed under the microscope, and spleen enlargement. This result suggests that heat-killed L. lactis BF3 has the potential to treat IBD. PMID:27508115

  4. Slope Estimation for Bivariate Longitudinal Outcomes Adjusting for Informative Right Censoring Using Discrete Survival Model: Application to the Renal Transplant Cohort.

    PubMed

    Jaffa, Miran A; Woolson, Robert F; Lipsitz, Stuart R

    2011-04-01

    Patients undergoing renal transplantation are prone to graft failure which causes lost of follow-up measures on their blood urea nitrogen and serum creatinine levels. These two outcomes are measured repeatedly over time to assess renal function following transplantation. Loss of follow-up on these bivariate measures results in informative right censoring, a common problem in longitudinal data that should be adjusted for so that valid estimates are obtained. In this study, we propose a bivariate model that jointly models these two longitudinal correlated outcomes and generates population and individual slopes adjusting for informative right censoring using a discrete survival approach. The proposed approach is applied to the clinical dataset of patients who had undergone renal transplantation. A simulation study validates the effectiveness of the approach.

  5. Hematopoietic Stem Cells Transplantation Can Normalize Thyroid Function in a Cystinosis Mouse Model.

    PubMed

    Gaide Chevronnay, H P; Janssens, V; Van Der Smissen, P; Rocca, C J; Liao, X H; Refetoff, S; Pierreux, C E; Cherqui, S; Courtoy, P J

    2016-04-01

    Hypothyroidism is the most frequent and earliest endocrine complication in cystinosis, a multisystemic lysosomal storage disease caused by defective transmembrane cystine transporter, cystinosin (CTNS gene). We recently demonstrated in Ctns(-/-) mice that altered thyroglobulin biosynthesis associated with endoplasmic reticulum stress, combined with defective lysosomal processing, caused hypothyroidism. In Ctns(-/-) kidney, hematopoietic stem cell (HSC) transplantation provides long-term functional and structural protection. Tissue repair involves transfer of cystinosin-bearing lysosomes from HSCs differentiated as F4/80 macrophages into deficient kidney tubular cells, via tunneling nanotubes that cross basement laminae. Here we evaluated the benefit of HSC transplantation for cystinotic thyroid and investigated the underlying mechanisms. HSC engraftment in Ctns(-/-) thyroid drastically decreased cystine accumulation, normalized the TSH level, and corrected the structure of a large fraction of thyrocytes. In the thyroid microenvironment, HSCs differentiated into a distinct, mixed macrophage/dendritic cell lineage expressing CD45 and major histocompatibility complex II but low CD11b and F4/80. Grafted HSCs closely apposed to follicles and produced tunneling nanotube-like extensions that crossed follicular basement laminae. HSCs themselves further squeezed into follicles, allowing extensive contact with thyrocytes, but did not transdifferentiate into Nkx2.1-expressing cells. Our observations revealed significant differences of basement lamina porosity between the thyroid and kidney and/or intrinsic macrophage invasive properties once in the thyroid microenvironment. The contrast between extensive thyrocyte protection and low HSC abundance at steady state suggests multiple sequential encounters and/or remanent impact. This is the first report demonstrating the potential of HSC transplantation to correct thyroid disease and supports a major multisystemic benefit of stem

  6. Berberine Improves Intestinal Motility and Visceral Pain in the Mouse Models Mimicking Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D) Symptoms in an Opioid-Receptor Dependent Manner

    PubMed Central

    Pan, Qiuhui; Fichna, Jakub; Zheng, Lijun; Wang, Kesheng; Yu, Zhen; Li, Yongyu; Li, Kun; Song, Aihong; Liu, Zhongchen; Song, Zhenshun; Kreis, Martin

    2015-01-01

    Background and Aims Berberine and its derivatives display potent analgesic, anti-inflammatory and anticancer activity. Here we aimed at characterizing the mechanism of action of berberine in the gastrointestinal (GI) tract and cortical neurons using animal models and in vitro tests. Methods The effect of berberine was characterized in murine models mimicking diarrhea-predominant irritable bowel syndrome (IBS-D) symptoms. Then the opioidantagonists were used to identify the receptors involved. Furthermore, the effect of berberineon opioid receptors expression was established in the mouse intestine and rat fetal cortical neurons. Results In mouse models, berberine prolonged GI transit and time to diarrhea in a dose-dependent manner, and significantly reduced visceral pain. In physiological conditions the effects of berberine were mediated by mu- (MOR) and delta- (DOR) opioidreceptors; hypermotility, excessive secretion and nociception were reversed by berberine through MOR and DOR-dependent action. We also found that berberine increased the expression of MOR and DOR in the mouse bowel and rat fetal cortical neurons. Conclusion Berberine significantly improved IBS-D symptoms in animal models, possibly through mu- and delta- opioid receptors. Berberine may become a new drug candidate for the successful treatment of IBS-D in clinical conditions. PMID:26700862

  7. Lung transplant

    MedlinePlus

    Solid organ transplant - lung ... the new lung Have severe disease of other organs Cannot reliably take their medicines Are unable to ... medicines Damage to your kidneys, liver, or other organs from anti-rejection medicines Future risk of certain ...

  8. Corneal transplant

    MedlinePlus

    ... transplant are: Bleeding Cataracts Infection of the eye Glaucoma (high pressure in the eye that can cause ... clot (blood thinners) for 10 days before the surgery. Some of these are aspirin, ibuprofen (Advil, Motrin), ...

  9. Pancreas Transplantation

    MedlinePlus

    The pancreas is a gland behind your stomach and in front of your spine. It produces the juices that ... hormones that help control blood sugar levels. A pancreas transplant is surgery to place a healthy pancreas ...

  10. Liver transplant

    MedlinePlus

    ... toxins in the blood Storing sugars, fats, iron, copper, and vitamins The most common reason for a ... cirrhosis or primary sclerosing cholangitis Metabolic disorders of copper or iron ( Wilson's disease and hemochromatosis ) Liver transplant ...

  11. Heart transplant

    MedlinePlus

    ... PA: Elsevier Saunders; 2014:chap 28. Bernstein D. Pediatric heart and heart-lung transplantation. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics . 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap ...

  12. The chick/quail transplantation model: discovery of the isthmic organizer center.

    PubMed

    Alvarado-Mallart, Rosa-Magda

    2005-09-01

    This paper summarizes chick/quail transplantation experiments performed in the INSERM U106 by Alvarado-Mallart's group from 1989 to 2002. First, it will present the various steps leading us to demonstrate that, at stage 10 of Hamburger and Hamilton, the avian neuroepithelium is still competent to change its fate influenced by environmental inductive factors and that these factors emanate from the cerebellar neuroepithelium; then, it will be briefly reported, experiments aimed to characterize the genetic cascade involved in the formation of the midbrain/hindbrain boundary and the specification of the meso-isthmic-cerebellar domain. PMID:16111542

  13. Complications of inflammatory bowel disease.

    PubMed

    Gasche, C

    2000-01-01

    Complications in inflammatory bowel disease determine the severity of disease as well as the complexities of medical or surgical treatment opportunities. Therefore, in known inflammatory bowel disease, the prevention, the early detection and the adequate therapeutic response to certain complications are important goals in the follow-up of inflammatory bowel disease patients. Disease complications are separated into intestinal and extraintestinal complications. Intestinal complications are somewhat disease specific, which means that they occur exclusively in either Crohn's disease or ulcerative colitis (e.g., enteric fistulas are particularly found in Crohn's disease and toxic megacolon in ulcerative colitis). Most extraintestinal complications occur in both forms of inflammatory bowel disease (e.g., anemia, thromboembolic events or osteoporosis). The current knowledge on pathogenesis, diagnostic tools, prevention and treatment of certain intestinal and extraintestinal complications is reviewed. PMID:10690585

  14. Multiple systemic transplantations of human amniotic mesenchymal stem cells exert therapeutic effects in an ALS mouse model.

    PubMed

    Sun, Haitao; Hou, Zongliu; Yang, Huaqiang; Meng, Mingyao; Li, Peng; Zou, Qingjian; Yang, Lujun; Chen, Yuxin; Chai, Huihui; Zhong, Huilin; Yang, Zara Zhuyun; Zhao, Jing; Lai, Liangxue; Jiang, Xiaodan; Xiao, Zhicheng

    2014-09-01

    Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease involving degeneration of motor neurons in the central nervous system. Stem cell treatment is a potential therapy for this fatal disorder. The human amniotic membrane (HAM), an extremely rich and easily accessible tissue, has been proposed as an attractive material in cellular therapy and regenerative medicine because of its advantageous characteristics. In the present study, we evaluate the long-term effects of a cellular treatment by intravenous administration of human amniotic mesenchymal stem cells (hAMSCs) derived from HAM into a hSOD1(G93A) mouse model. The mice received systemic administration of hAMSCs or phosphate-buffered saline (PBS) at the onset, progression and symptomatic stages of the disease. hAMSCs were detected in the spinal cord at the final stage of the disease, in the form of isolates or clusters and were negative for β-tubulin III and GFAP. Compared with the treatment with PBS, multiple hAMSC transplantations significantly retarded disease progression, extended survival, improved motor function, prevented motor neuron loss and decreased neuroinflammation in mice. These findings demonstrate that hAMSC transplantation is a promising cellular treatment for ALS.

  15. Moderate swimming suppressed the growth and metastasis of the transplanted liver cancer in mice model: with reference to nervous system.

    PubMed

    Zhang, Q-B; Zhang, B-H; Zhang, K-Z; Meng, X-T; Jia, Q-A; Zhang, Q-B; Bu, Y; Zhu, X-D; Ma, D-N; Ye, B-G; Zhang, N; Ren, Z-G; Sun, H-C; Tang, Z-Y

    2016-08-01

    Physical activity has been shown to suppress tumor initiation and progression. The neurotransmitter dopamine (DA) is closely related to movement and exhibits antitumor properties. However, whether the suppressive effects of physical activity on tumors was mediated by the nervous system via increased DA level remains unknowns. Here we show that regular moderate swimming (8 min/day, 9 weeks) raised DA levels in the prefrontal cortex, serum and tumor tissue, suppressed growth, reduced lung metastasis of transplanted liver cancer, and prolonged survival in a C57BL/6 mouse model, while overload swimming (16 and 32 min/day, 9 weeks) had the opposite effect. In nude mice that were orthotopically implanted with human liver cancer cell lines, DA treatment significantly suppressed growth and lung metastasis by acting on the D2 receptor (DR2). Furthermore, DR2 blockade attenuated the suppressive effect of moderate swimming on liver cancer. Both moderate swimming and DA treatment suppressed the transforming growth factor-beta (TGF-β1)-induced epithelial-mesenchymal transition of transplanted liver cancer cells. At the molecular level, DR2 signaling inhibited extracellular signal-regulated kinase phosphorylation and expression of TGF-β1 in vitro. Together, these findings demonstrated a novel mechanism by which the moderate exercise suppressed liver cancer through boosting DR2 activity, while overload exercise had the opposite effect, highlighting the possible importance of the dopaminergic system in tumor growth and metastasis of liver cancer. PMID:26686088

  16. One-year results from cryopreserved mitral allograft transplantation into the tricuspid position in a sheep experimental model.

    PubMed

    Mokracek, A; Canadyova, J; Simunkova, Z; Fiala, R; Hmirak, M; Sulda, M; Burkert, J; Tintera, J; Kobylka, P; Spatenka, J

    2015-01-01

    Mitral allografts are still used only exceptionally in the mitral or tricuspid position. The main indication remains infectious endocarditis of atrioventricular valves for its flexibility and low risk of infection. The aim of our study was to evaluate 1-year results of mitral allografts transplantation into the tricuspid position in a sheep model. Mitral allografts were processed, cryopreserved, and transplanted into the tricuspid position anatomically (Group I - 11 animals) or antianatomically (Group II - 8 animals). All survivors (4 from Group I, and 3 from Group II) were checked at 3, 6, and 12 months by echocardiography with the exception of one survivor from Group II (which was examinated only visually). Examination throughout follow-up included for mitral allograft regurgitation and annuli dilatation. At postmortem, the papillary muscles were healed and firmly anchored to the right ventricular wall in all subjects. Transventricular fixation of the papillary muscles with buttressed sutures was proven to be a stable, reproducible, and safe method for anchoring mitral allograft leaflets. There were no significant differences between the two implantation methods. Annulus support of mitral allografts might be very useful in this type of operation and could prevent annular dilatation.

  17. Transplants of adult mesenchymal and neural stem cells provide neuroprotection and behavioral sparing in a transgenic rat model of Huntington's disease.

    PubMed

    Rossignol, Julien; Fink, Kyle; Davis, Kendra; Clerc, Steven; Crane, Andrew; Matchynski, Jessica; Lowrance, Steven; Bombard, Matthew; Dekorver, Nicholas; Lescaudron, Laurent; Dunbar, Gary L

    2014-02-01

    Stem cells have gained significant interest as a potential treatment of neurodegenerative diseases, including Huntington's disease (HD). One source of these cells is adult neural stem cells (aNSCs), which differentiate easily into neuronal lineages. However, these cells are vulnerable to immune responses following transplantation. Another source is bone-marrow-derived mesenchymal stem cells (MSCs), which release neurotrophic factors and anti-inflammatory cytokines following transplantation, and are less vulnerable to rejection. The goal of this study was to compare the efficacy of transplants of MSCs, aNSCs, or cotransplants of MSCs and aNSCs for reducing deficits in a transgenic rat model of HD. HD rats received intrastriatal transplantations of 400,000 MSCs, aNSCs, or a combination of MSCs/aNSCs, while wild-type and HD controls were given vehicle. Rats were tested on the rotarod over the course of 20 weeks. The results indicated that transplants of: (a) aNSCs produced a strong immune response and conferred short-term behavioral benefits; (b) MSCs elicited a relatively weak immune response, and provided a longer term behavioral benefit; and (c) combined MSCs and aNSCs conferred long-term behavioral benefits and increased survival of the transplanted aNSCs. The finding that cotransplanting MSCs with aNSCs can prolong aNSC survival and provide greater behavioral sparing than when the transplants contains only aNSCs suggests that MSCs are capable of creating a more suitable microenvironment for aNSC survival. This cotransplantation strategy may be useful as a future therapeutic option for treating HD, especially if long-term survival of differentiated cells proves to be critically important for preserving lasting functional outcomes.

  18. Development and Preclinical Application of an Immunocompetent Transplant Model of Basal Breast Cancer with Lung, Liver and Brain Metastases

    PubMed Central

    Hoenerhoff, Mark; Hixon, Julie A.; Durum, Scott K.; Qiu, Ting-hu; He, Siping; Burkett, Sandra; Liu, Zi-Yao; Swanson, Steven M.; Green, Jeffrey E.

    2016-01-01

    Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with a poor prognosis and for which no targeted therapies currently exist. In order to improve preclinical testing for TNBC that relies primarily on using human xenografts in immunodeficient mice, we have developed a novel immunocompetent syngeneic murine tumor transplant model for basal-like triple-negative breast cancer. The C3(1)/SV40-T/t-antigen (C3(1)/Tag) mouse mammary tumor model in the FVB/N background shares important similarities with human basal-like TNBC. However, these tumors or derived cell lines are rejected when transplanted into wt FVB/N mice, likely due to the expression of SV40 T-antigen. We have developed a sub-line of mice (designated REAR mice) that carry only one copy of the C3(1)/Tag-antigen transgene resulting from a spontaneous transgene rearrangement in the original founder line. Unlike the original C3(1)/Tag mice, REAR mice do not develop mammary tumors or other phenotypes observed in the original C3(1)/Tag transgenic mice. REAR mice are more immunologically tolerant to SV40 T-antigen driven tumors and cell lines in an FVB/N background (including prostate tumors from TRAMP mice), but are otherwise immunologically intact. This transplant model system offers the ability to synchronously implant the C3(1)/Tag tumor-derived M6 cell line or individual C3(1)/Tag tumors from various stages of tumor development into the mammary fat pads or tail veins of REAR mice. C3(1)/Tag tumors or M6 cells implanted into the mammary fat pads spontaneously metastasize at a high frequency to the lung and liver. M6 cells injected by tail vein can form brain metastases. We demonstrate that irradiated M6 tumor cells or the same cells expressing GM-CSF can act as a vaccine to retard tumor growth of implanted tumor cells in the REAR model. Preclinical studies performed in animals with an intact immune system should more authentically replicate treatment responses in

  19. Neonatal bone marrow transplantation prevents bone pathology in a mouse model of mucopolysaccharidosis type I.

    PubMed

    Pievani, Alice; Azario, Isabella; Antolini, Laura; Shimada, Tsutomu; Patel, Pravin; Remoli, Cristina; Rambaldi, Benedetta; Valsecchi, Maria Grazia; Riminucci, Mara; Biondi, Andrea; Tomatsu, Shunji; Serafini, Marta

    2015-03-01

    Neonatal bone marrow transplantation (BMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept in mucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of α-l-iduronidase. MPS IH is characterized by a broad spectrum of clinical manifestations, including severe progressive skeletal abnormalities. Although BMT increases the life span of patients with MPS IH, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal BM into newborn MPS I mice soon after birth can prevent skeletal dysplasia. We observed that neonatal BMT was effective at restoring α-l-iduronidase activity and clearing elevated glycosaminoglycans in blood and multiple organs. At 37 weeks of age, we observed an almost complete normalization of all bone tissue parameters, using radiographic, microcomputed tomography, biochemical, and histological analyses. Overall, the magnitude of improvements correlated with the extent of hematopoietic engraftment. We conclude that BMT at a very early stage in life markedly reduces signs and symptoms of MPS I before they appear.

  20. MODEL SYSTEMS AND EXPERIMENTAL CONDITIONS THAT LEAD TO EFFECTIVE REPOPULATION OF THE LIVER BY TRANSPLANTED CELLS

    PubMed Central

    Shafritz, David A.; Oertel, Michael

    2010-01-01

    In recent years, there has been substantial progress in transplanting cells into the liver with the ultimate goal of restoring liver mass and function in both inherited and acquired liver diseases. The basis for considering that this might be feasible is that the liver is a highly regenerative organ. After massive liver injury or surgical removal of two-thirds or more of the liver tissue, the organ can restore its mass with completely normal morphologic structure and function. It has also been found under highly selective conditions that transplanted hepatocytes can fully repopulate the liver and cure a metabolic disorder or deficiency state. Fetal liver cells can also substantially repopulate the normal liver, and it is hoped in the future that effective repopulation will be achievable with cultured cells or cell lines, pluripotent stem cells from other somatic tissues, embryonic stem cells, or induced pluripotent stem cells, which can now be generated in vitro by a variety of methods. The purpose of this review is to present the major systems that have been used for liver repopulation, the variables involved in obtaining successful repopulation and what has been achieved in these various systems to date with different cell types. PMID:20080205

  1. Pancreatic islet transplantation: utility of ductular obstruction and exocrine atrophy model?

    PubMed

    Verma, A; Dinda, A; Sarkar, C; Fotedar, R; Dhawan, I K; Sharma, L K; Khetarpal, K; Fotedar, A; Srikanta, S; Kochupillai, N

    1990-01-01

    Introduction of 'silent' exocrine atrophy (and endocrine 'enrichment') in pancreatic grafts following ductular blockade may have a role in human diabetes by circumventing currently elusive islet isolation/purification protocols. To explore this potential, pancreatic isografts were performed in 12 pairs of inbred Wistar NIN rats. Donor pancreatectomy was performed after distal clamping and canulation of common bile duct and injection of 0.5 ml. polyacrylamide gel (blocked n = 7) or normal saline (un-blocked n = 5) respectively. One to 2 m.m. fragments of the resulting mildly distended pancreases were transplanted in to 2 sites (renal capsule and iliac fossa subcutaneously) of cach recipient. Post-operative biopsies of the transplanted grafts (unilateral nephrectomy and iliac fossa biopsies) revealed macroscopic and microscopic evidence of necrotizing pancreatitis in both the groups at both the sites (histiocytic and giant cell infiltration, fat necrosis and focal calcification with destruction of exocrine and endocrine cells) as early as 1 and 3 weeks. Possible detrimental factors include: volume and pressure of ductal injection, graft sites (confined spaces), post-operative wound infection and bio-compatibility of the material used for ductular blockade.

  2. Enhanced Efficacy of Human Brain-Derived Neural Stem Cells by Transplantation of Cell Aggregates in a Rat Model of Parkinson's Disease

    PubMed Central

    Shin, Eun Sil; Hwang, Onyou; Hwang, Yu-Shik; Suh, Jun-Kyo Francis; Chun, Young Il

    2014-01-01

    Objective Neural tissue transplantation has been a promising strategy for the treatment of Parkinson's disease (PD). However, transplantation has the disadvantages of low-cell survival and/or development of dyskinesia. Transplantation of cell aggregates has the potential to overcome these problems, because the cells can extend their axons into the host brain and establish synaptic connections with host neurons. In this present study, aggregates of human brain-derived neural stem cells (HB-NSC) were transplanted into a PD animal model and compared to previous report on transplantation of single-cell suspensions. Methods Rats received an injection of 6-OHDA into the right medial forebrain bundle to generate the PD model and followed by injections of PBS only, or HB-NSC aggregates in PBS into the ipsilateral striatum. Behavioral tests, multitracer (2-deoxy-2-[18F]-fluoro-D-glucose ([18F]-FDG) and [18F]-N-(3-fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl)nortropane ([18F]-FP-CIT) microPET scans, as well as immunohistochemical (IHC) and immunofluorescent (IF) staining were conducted to evaluate the results. Results The stepping test showed significant improvement of contralateral forelimb control in the HB-NSC group from 6-10 weeks compared to the control group (p<0.05). [18F]-FP-CIT microPET at 10 weeks posttransplantation demonstrated a significant increase in uptake in the HB-NSC group compared to pretransplantation (p<0.05). In IHC and IF staining, tyrosine hydroxylase and human β2 microglobulin (a human cell marker) positive cells were visualized at the transplant site. Conclusion These results suggest that the HB-NSC aggregates can survive in the striatum and exert therapeutic effects in a PD model by secreting dopamine. PMID:25535514

  3. Liver transplantation in Germany.

    PubMed

    Tacke, Frank; Kroy, Daniela C; Barreiros, Ana Paula; Neumann, Ulf P

    2016-08-01

    Liver transplantation (LT) is a well-accepted procedure for end-stage liver disease in Germany. In 2015, 1489 patients were admitted to the waiting list (including 1308 new admissions), with the leading etiologies being fibrosis and cirrhosis (n = 349), alcoholic liver disease (n = 302), and hepatobiliary malignancies (n = 220). Organ allocation in Germany is regulated within the Eurotransplant system based on urgency as expressed by the Model for End-Stage Liver Disease score. In 2015, only 894 LTs (n = 48 from living donors) were performed at 23 German transplant centers, reflecting a shortage of organs. Several factors may contribute to the low number of organ donations. The German transplant legislation only accepts donation after brain death (not cardiac death), whereas advances in neurosurgery and a more frequently requested "palliative care" approach render fewer patients suitable as potential donors. The legislation further requires the active consent of the donor or first-degree relatives before donation. Ongoing debates within the German transplant field address the optimal management of patients with alcoholic liver cirrhosis, hepatocellular carcinoma (HCC), and cholangiocarcinoma and measures to increase living donor transplantations. As a result of irregularities at mainly 4 German transplant centers that were exposed in 2012, guiding principles updated by the German authorities have since implemented strict rules (including internal and external auditing, the 8-eyes principle, mandatory repeated testing for alcohol consumption) to prohibit any manipulations in organ allocation. In conclusion, we will summarize important aspects on the management of LT in Germany, discuss legal and organizational aspects, and highlight challenges mainly related to the relative lack of organ donations, increasing numbers of extended criteria donors, and the peculiarities of the recipient patients. Liver Transplantation 22 1136-1142 2016 AASLD.

  4. Liver transplantation in Germany.

    PubMed

    Tacke, Frank; Kroy, Daniela C; Barreiros, Ana Paula; Neumann, Ulf P

    2016-08-01

    Liver transplantation (LT) is a well-accepted procedure for end-stage liver disease in Germany. In 2015, 1489 patients were admitted to the waiting list (including 1308 new admissions), with the leading etiologies being fibrosis and cirrhosis (n = 349), alcoholic liver disease (n = 302), and hepatobiliary malignancies (n = 220). Organ allocation in Germany is regulated within the Eurotransplant system based on urgency as expressed by the Model for End-Stage Liver Disease score. In 2015, only 894 LTs (n = 48 from living donors) were performed at 23 German transplant centers, reflecting a shortage of organs. Several factors may contribute to the low number of organ donations. The German transplant legislation only accepts donation after brain death (not cardiac death), whereas advances in neurosurgery and a more frequently requested "palliative care" approach render fewer patients suitable as potential donors. The legislation further requires the active consent of the donor or first-degree relatives before donation. Ongoing debates within the German transplant field address the optimal management of patients with alcoholic liver cirrhosis, hepatocellular carcinoma (HCC), and cholangiocarcinoma and measures to increase living donor transplantations. As a result of irregularities at mainly 4 German transplant centers that were exposed in 2012, guiding principles updated by the German authorities have since implemented strict rules (including internal and external auditing, the 8-eyes principle, mandatory repeated testing for alcohol consumption) to prohibit any manipulations in organ allocation. In conclusion, we will summarize important aspects on the management of LT in Germany, discuss legal and organizational aspects, and highlight challenges mainly related to the relative lack of organ donations, increasing numbers of extended criteria donors, and the peculiarities of the recipient patients. Liver Transplantation 22 1136-1142 2016 AASLD. PMID:27082951

  5. Transplantation of GABAergic cells derived from bioreactor-expanded human neural precursor cells restores motor and cognitive behavioral deficits in a rodent model of Huntington's disease.

    PubMed

    McLeod, Marcus C; Kobayashi, Nao R; Sen, Arindom; Baghbaderani, Behnam A; Sadi, Damaso; Ulalia, Ruperto; Behie, Leo A; Mendez, Ivar

    2013-01-01

    Huntington's disease (HD) is a neurodegenerative disorder that is characterized by progressive dementia, choreiform involuntary movements, and emotional deterioration. Neuropathological features include the progressive degeneration of striatal γ-aminobutyric acid (GABA) neurons. New therapeutic approaches, such as the transplantation of human neural precursor cells (hNPCs) to replace damaged or degenerated cells, are currently being investigated. The aim of this study was to investigate the potential for utilizing telencephalic hNPCs expanded in suspension bioreactors for cell restorative therapy in a rodent model of HD. hNPCs were expanded in a hydrodynamically controlled and homogeneous environment under serum-free conditions. In vitro analysis revealed that the bioreactor-expanded telencephalic (BET)-hNPCs could be differentiated into a highly enriched population of GABAergic neurons. Behavioral assessments of unilateral striatal quinolinic acid-lesioned rodents revealed a significant improvement in motor and memory deficits following transplantation with GABAergic cells differentiated from BET-hNPCs. Immunohistochemical analysis revealed that transplanted BET-hNPCs retained a GABAergic neuronal phenotype without aberrant transdifferentiation or tumor formation, indicating that BET-hNPCs are a safe source of cells for transplantation. This preclinical study has important implications as the transplantation of GABAergic cells derived from predifferentiated BET-hNPCs may be a safe and feasible cell replacement strategy to promote behavioral recovery in HD.

  6. Age Is the Only Predictor of Poor Bowel Preparation in the Hospitalized Patient.

    PubMed

    McNabb-Baltar, Julia; Dorreen, Alastair; Al Dhahab, Hisham; Fein, Michael; Xiong, Xin; O' Byrne, Mike; Ait, Imene; Martel, Myriam; Barkun, Alan N

    2016-01-01

    We examine the impact of key variables on the likelihood of inpatient poor bowel preparation for colonoscopy. Records of inpatients that underwent colonoscopy at our institution between January 2010 and December 2011 were retrospectively extracted. Univariable and multivariable logistic regression models were fitted to assess the effect of clinical variables on the odds of poor preparation. Tested predictors included age; gender; use of narcotics; heavy medication burden; comorbidities; history of previous abdominal surgery; neurological disorder; product used for bowel preparation, whether or not the bowel regimen was given as split or standard dose; and time of endoscopy. Overall, 244 patients were assessed including 83 (34.0%, 95% CI: 28.1-39.9%) with poor bowel preparation. Cecal intubation was achieved in 81.1% of patients (95% CI: 76.2-86.0%). When stratified by quality of bowel preparation, cecal intubation was achieved in only 65.9% (95% CI: 60.0-71.9%) of patients with poor bowel preparation and 89.9% (95% CI: 86.1-93.7%) of patient with good bowel preparation. In multivariate logistic regression analysis, only advancing age was an independent predictor of poor bowel preparation (OR = 1.026, CI: 1.006 to 1.045, and p = 0.008). Age is the only independent predictor of poor bowel preparation amongst hospitalized patients. PMID:27446828

  7. Transplant nephrectomy

    PubMed Central

    Akoh, Jacob A

    2011-01-01

    About 10% of all renal allografts fail during the first year of transplantation and thereafter approximately 3%-5% yearly. Given that approximately 69 400 renal transplants are performed worldwide annually, the number of patients returning to dialysis following allograft failure is increasing. A failed transplant kidney, whether maintained by low dose immunosuppression or not, elicits an inflammatory response and is associated with increased morbidity and mortality. The risk for transplant nephrectomy (TN) is increased in patients who experienced multiple acute rejections prior to graft failure, develop chronic graft intolerance, sepsis, vascular complications and early graft failure. TN for late graft failure is associated with greater morbidity and mortality, bleeding being the leading cause of morbidity and infection the main cause of mortality. TN appears to be beneficial for survival on dialysis but detrimental to the outcome of subsequent transplantation by virtue of increased level of antibodies to mismatched antigens, increased rate of primary non function and delayed graft function. Many of the studies are characterized by a retrospective and univariate analysis of small numbers of patients. The lack of randomization in many studies introduced a selection bias and conclusions drawn from such studies should be applied with caution. Pending a randomised controlled trial on the role of TN in the management of transplant failure patients, it is prudent to remove failed symptomatic allografts and all grafts failing within 3 mo of transplantation, monitor inflammatory markers in patients with retained failed allografts and remove the allograft in the event of a significant increase in levels. PMID:24175187

  8. Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients 2014 Data Report: Intestine.

    PubMed

    Cai, Junchao; Wu, Guosheng; Qing, Annie; Everly, Matthew; Cheng, Elaine; Terasaki, Paul

    2014-01-01

    As of September 19, 2014, 2441 cases of intestinal transplantation have been performed in 46 centers (2400 deceased, 41 living). Eight centers did more than 100 transplants. Annual case numbers peaked in 2007 (N = 198) and steadily decreased to 109 cases in 2013. Short gut syndrome (68%) and functional bowel problems (15%) are two major indications for intestinal transplantation. The 3 major types of transplants involving the intestine include: isolated intestine transplant (I); simultaneous intestine, liver, and pancreas transplant (I+L+P); and, combined intestine and liver (I+L) transplant. Graft survival has significantly improved in recent years, mainly due to improved first year graft survival. The 1-, 5-, and 10-year graft survivals were: 74%, 42%,and 26%, respectively (I); 70%, 50%, and 40%, respectively (I+L+P); and 61%, 46%, and 40%, respectively (I+L). The longest graft survivals for I, l+L+P, and l+L were 19 years, 16 years, and 23 years, respectively. Steroids, Thymoglobulin, and rituximab are 3 major induction agents used in recent years. Prograf, steroids, and Cellcept are 3 major maintenance agents. Induction recipients (68% of all patients) had a significantly lower acute rejection rate than nonrecipients before discharge (60% versus 75%, p < 0.001). Most of the patients received 2 (53%) or 3 (25%) maintenance immunosuppressants. Acute rejection episodes were usually treated with one (60%) or two agents (27%). Steroids were most commonly used (50-60%). OKT3 has been replaced with antithymocyte globulin (since 1999) and rituximab (since 2006). During 1990-2000, 94% (N = 445) of patients received ABO identical intestinal transplants, while 6% (N = 29) received ABO compatible transplants. ABO identical transplant recipients had a significantly higher 5-year graft survival rate than ABO compatible recipients (39% versus 21%, p < 0.0001). In recent years (2001- 2012), more patients received ABO compatible (N = 188, 11%) than in the early decade (p < 0

  9. Transplantation of Achilles Tendon Treated With Bone Morphogenetic Protein 7 Promotes Meniscus Regeneration in a Rat Model of Massive Meniscal Defect

    PubMed Central

    Ozeki, Nobutake; Muneta, Takeshi; Koga, Hideyuki; Katagiri, Hiroki; Otabe, Koji; Okuno, Makiko; Tsuji, Kunikazu; Kobayashi, Eiji; Matsumoto, Kenji; Saito, Hirohisa; Saito, Tomoyuki; Sekiya, Ichiro

    2013-01-01

    Objective This study was undertaken to examine whether bone morphogenetic protein 7 (BMP-7) induces ectopic cartilage formation in the rat tendon, and whether transplantation of tendon treated with BMP-7 promotes meniscal regeneration. Additionally, we analyzed the relative contributions of host and donor cells on the healing process after tendon transplantation in a rat model. Methods BMP-7 was injected in situ into the Achilles tendon of rats, and the histologic findings and gene profile were evaluated. Achilles tendon injected with 1 μg of BMP-7 was transplanted into a meniscal defect in rats. The regenerated meniscus and articular cartilage were evaluated at 4, 8, and 12 weeks. Achilles tendon from LacZ-transgenic rats was transplanted into the meniscal defect in wild-type rats, and vice versa. Results Injection of BMP-7 into the rat Achilles tendon induced the fibrochondrocyte differentiation of tendon cells and changed the collagen gene profile of tendon tissue to more closely approximate meniscal tissue. Transplantation of the rat Achilles tendon into a meniscal defect increased meniscal size. The rats that received the tendon treated with BMP-7 had a meniscus matrix that exhibited increased Safranin O and type II collagen staining, and showed a delay in articular cartilage degradation. Using LacZ-transgenic rats, we determined that the regeneration of the meniscus resulted from contribution from both donor and host cells. Conclusion Our findings indicate that BMP-7 induces ectopic cartilage formation in rat tendons. Transplantation of Achilles tendon treated with BMP-7 promotes meniscus regeneration and prevents cartilage degeneration in a rat model of massive meniscal defect. Native cells in the rat Achilles tendon contribute to meniscal regeneration. PMID:23897174

  10. Irritable bowel syndrome.

    PubMed

    Drossman, D A

    1994-12-01

    Irritable bowel syndrome (IBS) is a common medical disorder that is associated with significant disability and health care costs. A practical approach to diagnosis and management of patients afflicted by this disorder has previously been hampered due to incomplete understanding of its pathophysiology, lack of diagnostic precision, and absence of specific treatments. Over the last decade, epidemiological, physiological, and psychosocial data have emerged to improve our understanding of this disorder and its treatment. IBS is currently believed to result from dysregulation of intestinal motor, sensory, and central nervous system function. Symptoms are due to both disturbances in intestinal motility and enhanced visceral sensitivity. Psychosocial factors, although not part of IBS per se, have an important role in modulating the illness experience and its clinical outcome. Use of multinational symptom-based "Rome" criteria has increased diagnostic specificity and has helped to minimize studies done to exclude other disease. Finally, treatment involves an integrated pharmacological and behavioral approach that is determined by the severity of the illness and its physiological and psychosocial determinants. PMID:7866739

  11. Irritable bowel syndrome

    PubMed Central

    2010-01-01

    Introduction The prevalence of irritable bowel syndrome (IBS) varies depending on the criteria used to diagnose it, but it ranges from about 5% to 20%. IBS is associated with abnormal gastrointestinal motor function and enhanced visceral perception, as well as psychosocial and genetic factors. People with IBS often have other bodily and psychiatric symptoms, and have an increased likelihood of having unnecessary surgery compared with people without IBS. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments in people with IBS? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: 5HT3 receptor antagonists (alosetron and ramosetron); 5HT4 receptor agonists (tegaserod); antidepressants (tricyclic antidepressants and selective serotonin reuptake inhibitors [SSRIs]); antispasmodics (including peppermint oil); cognitive behavioural therapy (CBT); hypnotherapy; soluble and insoluble fibre supplementation; and loperamide. PMID:21718578

  12. Irritable bowel syndrome

    PubMed Central

    2012-01-01

    Introduction The prevalence of irritable bowel syndrome (IBS) varies depending on the criteria used to diagnose it, but it ranges from about 5% to 20%. IBS is associated with abnormal gastrointestinal motor function and enhanced visceral perception, as well as psychosocial and genetic factors. People with IBS often have other bodily and psychiatric symptoms, and have an increased likelihood of having unnecessary surgery compared with people without IBS. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments in people with IBS? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 27 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: 5HT3 receptor antagonists (alosetron and ramosetron), 5HT4 receptor agonists (tegaserod), antidepressants (tricyclic antidepressants and selective serotonin reuptake inhibitors [SSRIs]), antispasmodics (including peppermint oil), cognitive behavioural therapy (CBT), hypnotherapy, loperamide, and soluble and insoluble fibre supplementation. PMID:22296841

  13. Anti-aging Effect of Transplanted Amniotic Membrane Mesenchymal Stem Cells in a Premature Aging Model of Bmi-1 Deficiency.

    PubMed

    Xie, Chunfeng; Jin, Jianliang; Lv, Xianhui; Tao, Jianguo; Wang, Rong; Miao, Dengshun

    2015-09-15

    To determine whether transplanted amniotic membrane mesenchymal stem cells (AMSCs) ameliorated the premature senescent phenotype of Bmi-1-deficient mice, postnatal 2-day-old Bmi-1(-/-) mice were injected intraperitoneally with the second-passage AMSCs from amniotic membranes of β-galactosidase (β-gal) transgenic mice or wild-type (WT) mice labeled with DiI. Three reinjections were given, once every seven days. Phenotypes of 5-week-old β-gal(+) AMSC-transplanted or 6-week-old DiI(+) AMSC-transplanted Bmi-1(-/-) mice were compared with vehicle-transplanted Bmi-1(-/-) and WT mice. Vehicle-transplanted Bmi-1(-/-) mice displayed growth retardation and premature aging with decreased cell proliferation and increased cell apoptosis; a decreased ratio and dysmaturity of lymphocytic series; premature osteoporosis with reduced osteogenesis and increased adipogenesis; redox imbalance and DNA damage in multiple organs. Transplanted AMSCs carried Bmi-1 migrated into multiple organs, proliferated and differentiated into multiple tissue cells, promoted growth and delayed senescence in Bmi-1(-/-) transplant recipients. The dysmaturity of lymphocytic series were ameliorated, premature osteoporosis were rescued by promoting osteogenesis and inhibiting adipogenesis, the oxidative stress and DNA damage in multiple organs were inhibited by the AMSC transplantation in Bmi-1(-/-) mice. These findings indicate that AMSC transplantation ameliorated the premature senescent phenotype of Bmi-1-deficient mice and could be a novel therapy to delay aging and prevent aging-associated degenerative diseases.

  14. Risk Factors of Graft Survival After Diagnosis of Post-kidney Transplant Malignancy: Using Cox Proportional Hazard Model

    PubMed Central

    Rahimi Foroushani, Abbas; Salesi, Mahmoud; Rostami, Zohreh; Mehrazmay, Ali Reza; Mohammadi, Jamile; Einollahi, Behzad; Eshraghian, Mohammad Reza

    2015-01-01

    Background: All recipients of kidney transplantation, especially those with posttransplant malignancy, are at risk of long-term graft failure. Objectives: The purpose of our study was to evaluate the risk factors associated with graft survival after diagnosis of malignancy. Patients and Methods: To reach this purpose, we conducted a historical cohort study in Iran and 266 cases with posttransplant malignancy were followed up from diagnosis of malignancy until long-term graft loss or the date of last visit. These patients were taken as a census from 16 Transplant Centers in Iran during 22 years follow-up period since October 1984 to December 2008. A Cox proportional hazards model was performed to determine the important independent predictors of graft survival after malignancy. Results: At the end of the study, long-term graft failure was seen in 27 (10.2%) cases. One-year and 2-year graft survival after diagnosis of cancer were 93.6% and 91.7%, respectively. The univariate analysis showed that the incidence of chronic graft loss was significantly higher in male patients with solid cancers, withdrawal of immunosuppressant regimen, no response to treatment, and tumor metastasis. In continuation, the Cox model indicated that the significant risk factors associated with graft survival were type of cancer (P < 0.0001), response to treatment (P < 0.0001, HR = 0.14, 95% CI: 0.06 - 0.32), metastasis (P < 0.0001, HR = 5.68, 95% CI: 2.24 - 14.42), and treatment modality (P = 0.0001). Conclusions: By controlling the modifiable risk factors and modality of treatment in our study, physicians can reach more effective treatment. PMID:26734477

  15. Neural differentiation of transplanted neural stem cells in a rat model of striatal lacunar infarction: light and electron microscopic observations

    PubMed Central

    Muñetón-Gómez, Vilma C.; Doncel-Pérez, Ernesto; Fernandez, Ana P.; Serrano, Julia; Pozo-Rodrigálvarez, Andrea; Vellosillo-Huerta, Lara; Taylor, Julian S.; Cardona-Gómez, Gloria P.; Nieto-Sampedro, Manuel; Martínez-Murillo, Ricardo

    2012-01-01

    The increased risk and prevalence of lacunar stroke and Parkinson's disease (PD) makes the search for better experimental models an important requirement for translational research. In this study we assess ischemic damage of the nigrostriatal pathway in a model of lacunar stroke evoked by damaging the perforating arteries in the territory of the substantia nigra (SN) of the rat after stereotaxic administration of endothelin-1 (ET-1), a potent vasoconstrictor peptide. We hypothesized that transplantation of neural stem cells (NSCs) with the capacity of differentiating into diverse cell types such as neurons and glia, but with limited proliferation potential, would constitute an alternative and/or adjuvant therapy for lacunar stroke. These cells showed neuritogenic activity in vitro and a high potential for neural differentiation. Light and electron microscopy immunocytochemistry was used to characterize GFP-positive neurons derived from the transplants. 48 h after ET-1 injection, we characterized an area of selective degeneration of dopaminergic neurons within the nigrostriatal pathway characterized with tissue necrosis and glial scar formation, with subsequent behavioral signs of Parkinsonism. Light microscopy showed that grafted cells within the striatal infarction zone differentiated with a high yield into mature glial cells (GFAP-positive) and neuron types present in the normal striatum. Electron microscopy revealed that NSCs-derived neurons integrated into the host circuitry establishing synaptic contacts, mostly of the asymmetric type. Astrocytes were closely associated with normal small-sized blood vessels in the area of infarct, suggesting a possible role in the regulation of the blood brain barrier and angiogenesis. Our results encourage the use of NSCs as a cell-replacement therapy for the treatment of human vascular Parkinsonism. PMID:22876219

  16. Therapeutic potential of fecal microbiota transplantation.

    PubMed

    Smits, Loek P; Bouter, Kristien E C; de Vos, Willem M; Borody, Thomas J; Nieuwdorp, Max

    2013-11-01

    There has been growing interest in the use of fecal microbiota for the treatment of patients with chronic gastrointestinal infections and inflammatory bowel diseases. Lately, there has also been interest in its therapeutic potential for cardiometabolic, autoimmune, and other extraintestinal conditions that were not previously considered to be associated with the intestinal microbiota. Although it is not clear if changes in the microbiota cause these conditions, we review the most current and best methods for performing fecal microbiota transplantation and summarize clinical observations that have implicated the intestinal microbiota in various diseases. We also discuss case reports of fecal microbiota transplantations for different disorders, including Clostridium difficile infection, irritable bowel syndrome, inflammatory bowel diseases, insulin resistance, multiple sclerosis, and idiopathic thrombocytopenic purpura. There has been increasing focus on the interaction between the intestinal microbiome, obesity, and cardiometabolic diseases, and we explore these relationships and the potential roles of different microbial strains. We might someday be able to mine for intestinal bacterial strains that can be used in the diagnosis or treatment of these diseases.

  17. The Morphofunctional Effect of the Transplantation of Bone Marrow Stromal Cells and Predegenerated Peripheral Nerve in Chronic Paraplegic Rat Model via Spinal Cord Transection.

    PubMed

    Buzoianu-Anguiano, Vinnitsa; Orozco-Suárez, Sandra; García-Vences, Elisa; Caballero-Chacón, Sara; Guizar-Sahagún, Gabriel; Chavez-Sanchez, Luis; Grijalva, Israel

    2015-01-01

    Functional recovery following spinal cord injury (SCI) is limited by poor axonal and cellular regeneration as well as the failure to replace damaged myelin. Employed separately, both the transplantation of the predegenerated peripheral nerve (PPN) and the transplantation of bone marrow stromal cells (BMSCs) have been shown to promote the regrowth and remyelination of the damaged central axons in SCI models of hemisection, transection, and contusion injury. With the aim to test the effects of the combined transplantation of PPN and BMSC on regrowth, remyelination, and locomotor function in an adult rat model of spinal cord (SC) transection, 39 Fischer 344 rats underwent SC transection at T9 level. Four weeks later they were randomly assigned to traumatic spinal cord injury (TSCI) without treatment, TSCI + Fibrin Glue (FG), TSCI + FG + PPN, and TSCI + FG + PPN + BMSCs. Eight weeks after, transplantation was carried out on immunofluorescence and electron microscope studies. The results showed greater axonal regrowth and remyelination in experimental groups TSCI + FG + PPN and TSCI + FG + PPN + BMSCs analyzed with GAP-43, neuritin, and myelin basic protein. It is concluded that the combined treatment of PPN and BMSCs is a favorable strategy for axonal regrowth and remyelination in a chronic SC transection model. PMID:26634157

  18. The Morphofunctional Effect of the Transplantation of Bone Marrow Stromal Cells and Predegenerated Peripheral Nerve in Chronic Paraplegic Rat Model via Spinal Cord Transection

    PubMed Central

    Buzoianu-Anguiano, Vinnitsa; Orozco-Suárez, Sandra; García-Vences, Elisa; Caballero-Chacón, Sara; Guizar-Sahagún, Gabriel; Chavez-Sanchez, Luis; Grijalva, Israel

    2015-01-01

    Functional recovery following spinal cord injury (SCI) is limited by poor axonal and cellular regeneration as well as the failure to replace damaged myelin. Employed separately, both the transplantation of the predegenerated peripheral nerve (PPN) and the transplantation of bone marrow stromal cells (BMSCs) have been shown to promote the regrowth and remyelination of the damaged central axons in SCI models of hemisection, transection, and contusion injury. With the aim to test the effects of the combined transplantation of PPN and BMSC on regrowth, remyelination, and locomotor function in an adult rat model of spinal cord (SC) transection, 39 Fischer 344 rats underwent SC transection at T9 level. Four weeks later they were randomly assigned to traumatic spinal cord injury (TSCI) without treatment, TSCI + Fibrin Glue (FG), TSCI + FG + PPN, and TSCI + FG + PPN + BMSCs. Eight weeks after, transplantation was carried out on immunofluorescence and electron microscope studies. The results showed greater axonal regrowth and remyelination in experimental groups TSCI + FG + PPN and TSCI + FG + PPN + BMSCs analyzed with GAP-43, neuritin, and myelin basic protein. It is concluded that the combined treatment of PPN and BMSCs is a favorable strategy for axonal regrowth and remyelination in a chronic SC transection model. PMID:26634157

  19. Quantitative survival model for short-term survival after adult-to-adult living donor liver transplantation.

    PubMed

    Tsunematsu, Ichiro; Ogura, Yasuhiro; Inoue, Kayoko; Koizumi, Akio; Tanigawa, Nobuhiko; Tanaka, Koichi

    2006-06-01

    Adult-to-adult living donor liver transplantation (ALDLT) has been accepted as an important option for end-stage liver disease, but information regarding the risk factors remains fragmentary. We aimed to establish a predictive model for 90-day survival. In the first step, a total of 286 cases who had received primary ALDLT using a right lobe graft between 1998 and 2004 were randomly divided into 2 cohorts at a ratio of 2:1 (191 vs. 95 recipients). The larger cohort of patients was used to develop a model. The outcome was defined as 90-day survival, and a total of 39 preoperative and operative variables, including the period of surgery (1998-2001 vs. 2002-2004), were included using Cox's proportional hazard regression model. Two mismatches of human leukocyte antigen (HLA) type DR (hazard ratio [HR] = 4.45; confidence interval [CI] = 1.96-10.1), log(e)[blood loss volume] (HR = 2.43; CI = 1.64-3.60), period of surgery (1998-2001 vs. 2002-2004) (HR = 2.41; CI = 1.04-5.57), and log(e)[serum C-reactive protein or CRP] (HR = 1.64; CI = 1.13-2.38) were found to be independent risk factors. In the second step, we tried to establish a realistic survival model. In this step, we created 2 models, 1 that used all 4 variables (model 1) and 1 (model 2) in which blood loss volume was replaced with the past history of upper abdominal surgery and Model for End-Stage Liver Disease (MELD) score (> or =25), both of which showed associations with blood loss volume. These models were applied to the smaller cohort of 95 patients. Receiver operating characteristic analyses demonstrated that both models showed similar significant c-statistics (0.63 and 0.62, respectively). In conclusion, model 2 can provide a rough estimation of the 90-day survival after ALDLT.

  20. THEMES OF LIVER TRANSPLANTATION

    PubMed Central

    Starzl, Thomas E.; Fung, John J.

    2010-01-01

    Liver transplantation was the product of 5 interlocking themes. These began in 1958-59 with canine studies of then theoretical hepatotrophic molecules in portal venous blood (Theme I) and with the contemporaneous parallel development of liver and multivisceral transplant models (Theme II). Further Theme I investigations showed that insulin was the principal, although not the only, portal hepatotrophic factor. In addition to resolving long-standing controversies about the pathophysiology of portacaval shunt, the hepatotrophic studies blazed new trails in the regulation of liver size, function, and regeneration. They also targeted inborn metabolic errors (e.g. familial hyperlipoproteinemia) whose palliation by portal diversion presaged definitive correction with liver replacement. Clinical use of the Theme II transplant models depended on multiple drug immunosuppression (Theme III, Immunology), guided by an empirical algorithm of pattern recognition and therapeutic response. Successful liver replacement was first accomplished in 1967 with azathioprine, prednisone, and ALG. With this regimen, the world’s longest surviving liver recipient is now 40 years postoperative. Incremental improvements in survival outcome occurred (Theme IV) when azathioprine was replaced by cyclosporine (1979) which was replaced in turn by tacrolimus (1989). However, the biologic meaning of alloengraftment remained enigmatic until multilineage donor leukocyte microchimerism was discovered in 1992 in long surviving organ recipients. Seminal mechanisms were then identified (clonal exhaustion-deletion and immune ignorance) that linked organ engraftment and the acquired tolerance of bone marrow transplantation and eventually clarified the relationship of transplantation immunology to the immunology of infections, neoplasms, and autoimmune disorders. With this insight, better strategies of immunosuppression have evolved. As liver and other kinds of organ transplantation became accepted as

  1. The Role of Animal Models in the Study of Hematopoietic Stem Cell Transplantation and GvHD: A Historical Overview.

    PubMed

    Boieri, Margherita; Shah, Pranali; Dressel, Ralf; Inngjerdingen, Marit

    2016-01-01

    Bone marrow transplantation (BMT) is the only therapeutic option for many hematological malignancies, but its applicability is limited by life-threatening complications, such as graft-versus-host disease (GvHD). The last decades have seen great advances in the understanding of BMT and its related complications; in particular GvHD. Animal models are beneficial to study complex diseases, as they allow dissecting the contribution of single components in the development of the disease. Most of the current knowledge on the therapeutic mechanisms of BMT derives from studies in animal models. Parallel to BMT, the understanding of the pathophysiology of GvHD, as well as the development of new treatment regimens, has also been supported by studies in animal models. Pre-clinical experimentation is the basis for deep understanding and successful improvements of clinical applications. In this review, we retrace the history of BMT and GvHD by describing how the studies in animal models have paved the way to the many advances in the field. We also describe how animal models contributed to the understanding of GvHD pathophysiology and how they are fundamental for the discovery of new treatments. PMID:27625651

  2. The Role of Animal Models in the Study of Hematopoietic Stem Cell Transplantation and GvHD: A Historical Overview

    PubMed Central

    Boieri, Margherita; Shah, Pranali; Dressel, Ralf; Inngjerdingen, Marit

    2016-01-01

    Bone marrow transplantation (BMT) is the only therapeutic option for many hematological malignancies, but its applicability is limited by life-threatening complications, such as graft-versus-host disease (GvHD). The last decades have seen great advances in the understanding of BMT and its related complications; in particular GvHD. Animal models are beneficial to study complex diseases, as they allow dissecting the contribution of single components in the development of the disease. Most of the current knowledge on the therapeutic mechanisms of BMT derives from studies in animal models. Parallel to BMT, the understanding of the pathophysiology of GvHD, as well as the development of new treatment regimens, has also been supported by studies in animal models. Pre-clinical experimentation is the basis for deep understanding and successful improvements of clinical applications. In this review, we retrace the history of BMT and GvHD by describing how the studies in animal models have paved the way to the many advances in the field. We also describe how animal models contributed to the understanding of GvHD pathophysiology and how they are fundamental for the discovery of new treatments.

  3. The Role of Animal Models in the Study of Hematopoietic Stem Cell Transplantation and GvHD: A Historical Overview

    PubMed Central

    Boieri, Margherita; Shah, Pranali; Dressel, Ralf; Inngjerdingen, Marit

    2016-01-01

    Bone marrow transplantation (BMT) is the only therapeutic option for many hematological malignancies, but its applicability is limited by life-threatening complications, such as graft-versus-host disease (GvHD). The last decades have seen great advances in the understanding of BMT and its related complications; in particular GvHD. Animal models are beneficial to study complex diseases, as they allow dissecting the contribution of single components in the development of the disease. Most of the current knowledge on the therapeutic mechanisms of BMT derives from studies in animal models. Parallel to BMT, the understanding of the pathophysiology of GvHD, as well as the development of new treatment regimens, has also been supported by studies in animal models. Pre-clinical experimentation is the basis for deep understanding and successful improvements of clinical applications. In this review, we retrace the history of BMT and GvHD by describing how the studies in animal models have paved the way to the many advances in the field. We also describe how animal models contributed to the understanding of GvHD pathophysiology and how they are fundamental for the discovery of new treatments. PMID:27625651

  4. Co- transplantation of Bone Marrow Stromal Cells with Schwann Cells Evokes Mechanical Allodynia in the Contusion Model of Spinal Cord Injury in Rats

    PubMed Central

    Pourheydar, Bagher; Joghataei, Mohammad Taghi; Bakhtiari, Mehrdad; Mehdizadeh, Mehdi; Yekta, Zahra; Najafzadeh, Norooz

    2012-01-01

    Objective: Several studies have shown that, although transplantation of neural stem cells into the contusion model of spinal cord injury (SCI) promotes locomotor function and improves functional recovery, it induces a painful response, Allodynia. Different studies indicate that bone marrow stromal cells (BMSCs) and Schwann cells (SCs) can improve locomotor recovery when transplanted into the injured rat spinal cord. Since these cells are commonly used in cell therapy, we investigated whether co-transplantation of these cells leads to the development of Allodynia. Materials and Methods: In this experimental research, the contusion model of SCI was induced by laminectomy at the T8-T9 level of the spinal cord in adult female wistar rats (n=40) weighting (250-300g) using the New York University Device. BMSCs and SCs were cultured and prelabeled with 5-bromo-2-deoxyuridine (BrdU) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) respectively. The rats were divided into five groups of 8 including: a control group (laminectomy only), three experimental groups (BMSC, SC and Co-transplant) and a sham group. The experimental groups received BMSCs, SCs, and BMSCs and SCs respectively by intraspinal injection 7 days after injury and the sham group received serum only. Locomotion was assessed using Basso, Beattie and Bresnahan (BBB) test and Allodynia by the withdrawal threshold test using Von Frey Filaments at 1, 7, 14, 21, 28, 35, 42, 49 and 56 days after SCI. The statistical comparisons between groups were carried out by using repeated measures analysis of variances (ANOVA). Results: Significant differences were observed in BBB scores in the Co- transplant group compared to the BMSC and SC groups (p< 0.05). There were also significant differences in the withdrawal threshold means between animals in the sham group and the BMSC, SC and the Co-transplant groups (p<0.05).BBB scores and withdrawal threshold means showed that co-transplation improved

  5. Pregnancy and inflammatory bowel disease.

    PubMed

    Zeldis, J B

    1989-08-01

    Conclusions about the relationship between the pathophysiology and treatment of inflammatory bowel disease and the physiology and management of pregnancy are based on the results of several large physician surveys and retrospective chart reviews. Patients with active disease fare worse than those with inactive disease. There is little evidence that pregnancy affects the course of inflammatory bowel disease or that inactive inflammatory bowel disease affects the course of pregnancy. Judicious medical therapy is effective in controlling inflammatory bowel disease during pregnancy. Sulfasalazine or steroid therapy should not be withdrawn in a patient who needs it to achieve or maintain a quiescent state of inflammatory bowel disease during the course of pregnancy. Immunosuppressive therapy should be avoided. Aggressive medical therapy with total parenteral nutrition in a team approach with a gastroenterologist, surgeon, and perinatologist usually avoids the need for surgical intervention during pregnancy with a good fetal outcome in a patient whose disease is active. Contraception against pregnancy need only be considered in those patients whose disease is so severe that operative therapy is imminent.

  6. [Irritable bowel syndrome in adolescence].

    PubMed

    Shimada, A; Takano, M

    1992-11-01

    We studied seventy patients, 23 males and 47 females with irritable bowel syndrome in adolescence aged 13-19 yrs, who visited the department of psychosomatic medicine in Takano Hospital during about six year period of April, 1986-July, 1992. Takano Hospital is a coloproctological center in Kumamoto. In the clinical pattern of adolescent patients with irritable bowel syndrome the "gas" pattern was dominant (51.4%). Patients with the gas pattern have severe symptoms of flatus, fullness, rumbling sound and abdominal pain as well as bowel dysfunction, constipation and diarrhea in a classroom. Next, the diarrheal pattern occurred in 20.0%. Diarrheal patients complained of frequent bowel movements and retention feelings before attending school. Recurrent abdominal pain-like pattern was found in 7.1% patients. Clinical symptoms in the adolescent patients seem to derived from a mental tension and stress in a close classroom or before attending school. Many adolescenct patients (67.1%) with irritable bowel syndrome are embarrassed in school-maladjustment; leaving class early, late coming, a long absence, and a withdrawal. PMID:1363122

  7. Inflammatory Bowel Disease (IBD) and Pregnancy

    MedlinePlus

    ... Inflammatory Bowel Disease? Inflammatory bowel disease (IBD) includes Crohn’s disease (CD) and ulcerative colitis (UC). Symptoms include abdominal ... become pregnant? Women with ulcerative colitis and inactive Crohn’s disease are as likely to become pregnant as women ...

  8. Mouth cancer in inflammatory bowel diseases.

    PubMed

    Giagkou, E; Christodoulou, D K; Katsanos, K H

    2016-05-01

    Mouth cancer is a major health problem. Multiple risk factors for developing mouth cancer have been studied and include history of tobacco and alcohol abuse, age over 40, exposure to ultraviolet radiation, human papilloma virus infection (HPV), nutritional deficiencies, chronic irritation, and existence or oral potentially malignant lesions such as leukoplakia and lichen planus. An important risk factor for mouth cancer is chronic immunosuppression and has been extensively reported after solid organ transplantation as well as HIV-infected patients. Diagnosis of inflammatory bowel disease (IBD) is not yet considered as a risk factor for oral cancer development. However, a significant number of patients with IBD are receiving immunosuppressants and biological therapies which could represent potential oral oncogenic factors either by direct oncogenic effect or by continuous immunosuppression favoring carcinogenesis, especially in patients with HPV(+) IBD. Education on modifiable risk behaviors in patients with IBD is the cornerstone of prevention of mouth cancer. Oral screening should be performed for all patients with IBD, especially those who are about to start an immunosuppressant or a biologic. PMID:26671147

  9. In Vivo Kinetics of Mesenchymal Stem Cells Transplanted into the Knee Joint in a Rat Model Using a Novel Magnetic Method of Localization.

    PubMed

    Ikuta, Yasunari; Kamei, Naosuke; Ishikawa, Masakazu; Adachi, Nobuo; Ochi, Mitsuo

    2015-10-01

    We have developed a magnetic system for targeting cells in minimally invasive cell transplantation. Magnetically labeled MSCs (m-MSCs) with nanoscale iron particles can be guided into the desired region by magnetic force from an extracorporeal device. We reported that magnetic targeting of m-MSCs enhances cartilage repair in a mini-pig model. However, the detailed kinetics of these magnetically targeted m-MSCs remain unknown. For clinical use, this aspect should be clarified from a safety standpoint. We therefore investigated the spatial and temporal distribution of the fluorescently-labeled m-MSCs transplanted into the knee joint using in vivo fluorescence combined with three-dimensional computed tomographic imaging in a rat model. Although the intraarticularly injected m-MSCs were spread throughout the joint cavity in the absence of magnetic force, the magnetic force caused the injected m-MSCs to accumulate around the chondral lesion. Further examinations including ex vivo imaging, histological assessments and reverse transcription polymerase chain reaction revealed that transplanted MSCs were not present in any major organs after intraarticular administration, regardless of magnetic targeting. Our data suggest that m-MSCs can be accumulated efficiently into a chondral lesion using our magnetic targeting system, while none of the intraarticularly transplanted MSCs migrate to other major organs. PMID:25963065

  10. In Vivo Kinetics of Mesenchymal Stem Cells Transplanted into the Knee Joint in a Rat Model Using a Novel Magnetic Method of Localization.

    PubMed

    Ikuta, Yasunari; Kamei, Naosuke; Ishikawa, Masakazu; Adachi, Nobuo; Ochi, Mitsuo

    2015-10-01

    We have developed a magnetic system for targeting cells in minimally invasive cell transplantation. Magnetically labeled MSCs (m-MSCs) with nanoscale iron particles can be guided into the desired region by magnetic force from an extracorporeal device. We reported that magnetic targeting of m-MSCs enhances cartilage repair in a mini-pig model. However, the detailed kinetics of these magnetically targeted m-MSCs remain unknown. For clinical use, this aspect should be clarified from a safety standpoint. We therefore investigated the spatial and temporal distribution of the fluorescently-labeled m-MSCs transplanted into the knee joint using in vivo fluorescence combined with three-dimensional computed tomographic imaging in a rat model. Although the intraarticularly injected m-MSCs were spread throughout the joint cavity in the absence of magnetic force, the magnetic force caused the injected m-MSCs to accumulate around the chondral lesion. Further examinations including ex vivo imaging, histological assessments and reverse transcription polymerase chain reaction revealed that transplanted MSCs were not present in any major organs after intraarticular administration, regardless of magnetic targeting. Our data suggest that m-MSCs can be accumulated efficiently into a chondral lesion using our magnetic targeting system, while none of the intraarticularly transplanted MSCs migrate to other major organs.

  11. Future Therapeutic Approaches for Inflammatory Bowel Diseases

    PubMed Central

    Plevy, Scott E.; Targan, Stephan R.

    2016-01-01

    In this review, we speculate about future therapeutic approaches for inflammatory bowel diseases (IBDs), focusing on the need for better preclinical and clinical models and approaches beyond small molecules and systemically administered biologics. We offer ideas to change clinical trial programs and to use immunologic and genetic biomarkers to personalize medicine. We attempt to reconcile past therapeutic successes and failures to improve future approaches. Some of our ideas might be provocative, but we hope that the examples we provide will stimulate discussion about what will advance the field of IBD therapy. PMID:21530750

  12. Transplant production

    Technology Transfer Automated Retrieval System (TEKTRAN)

    For field pepper (Capsicum spp.) production, plants can be established from direct seed or transplants depending on the location and cultural practices for the specific pepper type grown. Direct seeding can result in slow, variable, and reduced plant stands due to variations in soil temperature, wat...

  13. Transplantation tolerance

    PubMed Central

    Muller, Yannick D; Seebach, Jörg D; Bühler, Leo H; Pascual, Manuel

    2011-01-01

    The major challenge in transplantation medicine remains long-term allograft acceptance, with preserved allograft function under minimal chronic immunosuppression. To safely achieve the goal of sustained donor-specific T and B cell non-responsiveness, research efforts are now focusing on therapies based on cell subsets with regulatory properties. In particular the transfusion of human regulatory T cells (Treg) is currently being evaluated in phase I/II clinical trials for the treatment of graft versus host disease following hematopoietic stem cell transplantation, and is also under consideration for solid organ transplantation. The purpose of this review is to recapitulate current knowledge on naturally occurring as well as induced human Treg, with emphasis on their specific phenotype, suppressive function and how these cells can be manipulated in vitro and/or in vivo for therapeutic purposes in transplantation medicine. We highlight the potential but also possible limitations of Treg-based strategies to promote long-term allograft survival. It is evident that the bench-to-beside translation of these protocols still requires further understanding of Treg biology. Nevertheless, current data already suggest that Treg therapy alone will not be sufficient and needs to be combined with other immunomodulatory approaches in order to induce allograft tolerance. PMID:21776332

  14. Heart Transplantation

    MedlinePlus

    A heart transplant removes a damaged or diseased heart and replaces it with a healthy one. The healthy heart comes from a donor who has died. It is the last resort for people with heart failure when all other treatments have failed. The ...

  15. Pancreas transplant

    MedlinePlus

    ... evidence that the complications of diabetes, such as diabetic retinopathy, may not get worse and may even improve after a pancreas-kidney transplant. More than 95% of people survive ... of the donated pancreas and kidney for the rest of your life.

  16. Small Bowel Imaging: an Update.

    PubMed

    Rimola, Jordi; Panés, Julián

    2016-07-01

    Bowel imaging had experienced relevant technical advances during the last decade. The developments in the field of cross-sectional imaging had a particular impact on the assessment of Crohn's disease. The purpose of this manuscript is to provide a review of the main progress of cross-sectional imaging in the assessment of Crohn's disease and other small bowel diseases with relevance in clinical practice and in research. Also, we outline the technical advances, trends, and potential contributions of new technological cross-sectional imaging improvements that may have potential impact and contribution in the near future. PMID:27315216

  17. Intestinal microbiota transplant - current state of knowledge.

    PubMed

    Leszczyszyn, Jarosław Jerzy; Radomski, Marek; Leszczyszyn, Anna Maria

    2016-01-01

    Faecal microbiota transplantation (FMT) has induced a lot scientific interest and hopes for the last couple of years. FMT has been approved as a treatment of recurrent Clostridium difficile colitis. Highly sophisticated molecular DNA identification methods have been used to assess the healthy human microbiome as well as its disturbances in several diseases. The metabolic and immunologic functions of the microbiome have become more clear and understandable. A lot of pathological changes, such as production of short-chain fatty acids or components of the inflammatory cascade, caused by changes in microbiome diversity, variability and richness have been observed among patients suffering from inflammatory bowel diseases, irritable bowel syndrome, type 2 diabetes or rheumatoid arthritis. The published clinical results are encouraging, but still there is huge demand for FMT controlled clinical trials. PMID:27407273

  18. Intestinal microbiota transplant - current state of knowledge.

    PubMed

    Leszczyszyn, Jarosław Jerzy; Radomski, Marek; Leszczyszyn, Anna Maria

    2016-01-01

    Faecal microbiota transplantation (FMT) has induced a lot scientific interest and hopes for the last couple of years. FMT has been approved as a treatment of recurrent Clostridium difficile colitis. Highly sophisticated molecular DNA identification methods have been used to assess the healthy human microbiome as well as its disturbances in several diseases. The metabolic and immunologic functions of the microbiome have become more clear and understandable. A lot of pathological changes, such as production of short-chain fatty acids or components of the inflammatory cascade, caused by changes in microbiome diversity, variability and richness have been observed among patients suffering from inflammatory bowel diseases, irritable bowel syndrome, type 2 diabetes or rheumatoid arthritis. The published clinical results are encouraging, but still there is huge demand for FMT controlled clinical trials.

  19. Inflammatory Bowel Disease and Mutations Affecting the Interleukin-10 Receptor

    PubMed Central

    Glocker, Erik-Oliver; Kotlarz, Daniel; Boztug, Kaan; Gertz, E. Michael; Schäffer, Alejandro A.; Noyan, Fatih; Perro, Mario; Diestelhorst, Jana; Allroth, Anna; Murugan, Dhaarini; Hätscher, Nadine; Pfeifer, Dietmar; Sykora, Karl-Walter; Sauer, Martin; Kreipe, Hans; Lacher, Martin; Nustede, Rainer; Woellner, Cristina; Baumann, Ulrich; Salzer, Ulrich; Koletzko, Sibylle; Shah, Neil; Segal, Anthony W.; Sauerbrey, Axel; Buderus, Stephan; Snapper, Scott B.; Grimbacher, Bodo; Klein, Christoph

    2009-01-01

    BACKGROUND The molecular cause of inflammatory bowel disease is largely unknown. METHODS We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease. We screened six additional patients with early-onset colitis for mutations in two candidate genes and carried out functional assays in patients’ peripheral-blood mononuclear cells. We performed an allogeneic hematopoietic stem-cell transplantation in one patient. RESULTS In four of nine patients with early-onset colitis, we identified three distinct homozygous mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a heterotetramer to make up the interleukin-10 receptor. The mutations abrogate interleukin-10–induced signaling, as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10. Consistent with this observation was the increased secretion of tumor necrosis factor α and other proinflammatory cytokines from peripheral-blood mononuclear cells from patients who were deficient in IL10R subunit proteins, suggesting that interleukin-10–dependent “negative feedback” regulation is disrupted in these cells. The allogeneic stem-cell transplantation performed in one patient was successful. CONCLUSIONS Mutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis, involving hyperinflammatory immune responses in the intestine. Allogeneic stem-cell transplantation resulted in disease remission in one patient. PMID:19890111

  20. Allogeneic Transplantation of Müller-Derived Retinal Ganglion Cells Improves Retinal Function in a Feline Model of Ganglion Cell Depletion.

    PubMed

    Becker, Silke; Eastlake, Karen; Jayaram, Hari; Jones, Megan F; Brown, Robert A; McLellan, Gillian J; Charteris, David G; Khaw, Peng T; Limb, G Astrid

    2016-02-01

    Human Müller glia with stem cell characteristics (hMGSCs) have been shown to improve retinal function upon transplantation into rat models of retinal ganglion cell (RGC) depletion. However, their translational potential may depend upon successful engraftment and improvement of retinal function in experimental models with anatomical and functional features resembling those of the human eye. We investigated the effect of allogeneic transplantation of feline Müller glia with the ability to differentiate into cells expressing RGC markers, following ablation of RGCs by N-methyl-d-aspartate (NMDA). Unlike previous observations in the rat, transplantation of hMGSC-derived RGCs into the feline vitreous formed aggregates and elicited a severe inflammatory response without improving visual function. In contrast, allogeneic transplantation of feline MGSC (fMGSC)-derived RGCs into the vitrectomized eye improved the scotopic threshold response (STR) of the electroretinogram (ERG). Despite causing functional improvement, the cells did not attach onto the retina and formed aggregates on peripheral vitreous remnants, suggesting that vitreous may constitute a barrier for cell attachment onto the retina. This was confirmed by observations that cellular scaffolds of compressed collagen and enriched preparations of fMGSC-derived RGCs facilitated cell attachment. Although cells did not migrate into the RGC layer or the optic nerve, they significantly improved the STR and the photopic negative response of the ERG, indicative of increased RGC function. These results suggest that MGSCs have a neuroprotective ability that promotes partial recovery of impaired RGC function and indicate that cell attachment onto the retina may be necessary for transplanted cells to confer neuroprotection to the retina. Significance: Müller glia with stem cell characteristics are present in the adult human retina, but they do not have regenerative ability. These cells, however, have potential for

  1. Allogeneic Transplantation of Müller-Derived Retinal Ganglion Cells Improves Retinal Function in a Feline Model of Ganglion Cell Depletion

    PubMed Central

    Becker, Silke; Eastlake, Karen; Jayaram, Hari; Jones, Megan F.; Brown, Robert A.; McLellan, Gillian J.; Charteris, David G.; Khaw, Peng T.

    2016-01-01

    Human Müller glia with stem cell characteristics (hMGSCs) have been shown to improve retinal function upon transplantation into rat models of retinal ganglion cell (RGC) depletion. However, their translational potential may depend upon successful engraftment and improvement of retinal function in experimental models with anatomical and functional features resembling those of the human eye. We investigated the effect of allogeneic transplantation of feline Müller glia with the ability to differentiate into cells expressing RGC markers, following ablation of RGCs by N-methyl-d-aspartate (NMDA). Unlike previous observations in the rat, transplantation of hMGSC-derived RGCs into the feline vitreous formed aggregates and elicited a severe inflammatory response without improving visual function. In contrast, allogeneic transplantation of feline MGSC (fMGSC)-derived RGCs into the vitrectomized eye improved the scotopic threshold response (STR) of the electroretinogram (ERG). Despite causing functional improvement, the cells did not attach onto the retina and formed aggregates on peripheral vitreous remnants, suggesting that vitreous may constitute a barrier for cell attachment onto the retina. This was confirmed by observations that cellular scaffolds of compressed collagen and enriched preparations of fMGSC-derived RGCs facilitated cell attachment. Although cells did not migrate into the RGC layer or the optic nerve, they significantly improved the STR and the photopic negative response of the ERG, indicative of increased RGC function. These results suggest that MGSCs have a neuroprotective ability that promotes partial recovery of impaired RGC function and indicate that cell attachment onto the retina may be necessary for transplanted cells to confer neuroprotection to the retina. Significance Müller glia with stem cell characteristics are present in the adult human retina, but they do not have regenerative ability. These cells, however, have potential for

  2. Excretion of ciprofloxacin into the large bowel of the rabbit.

    PubMed Central

    Ramon, J; Dautrey, S; Farinoti, R; Carbon, C; Rubinstein, E

    1996-01-01

    The intestinal elimination of ciprofloxacin in the large bowel was studied in a rabbit model. Segments from the cecum, colon, and sigmoid colon along with their intact blood vessels were isolated and perfused, and their contents were collected over a 90-min period following the administration of a single parenteral dose of 27 mg of ciprofloxacin per kg of body weight. The elimination rates of ciprofloxacin were 0.126 +/- 0.084 micrograms.min-1.cm-2 in the cecum and 0.264 +/- 0.126, 0.11 +/- 0.07, and 0.21 +/- 0.141 micrograms.min-1.cm-2 in the proximal colon, distal colon, and sigmoid colon, respectively. The calculated fraction of ciprofloxacin eliminated in the large bowel was 3% of the parenteral dose administered. The elimination pattern of ciprofloxacin in the large bowel may explain the unusual activity of this fluoroquinolone in modifying the colonic flora. PMID:8787870

  3. Irritable bowel syndrome, inflammatory bowel disease and the microbiome

    PubMed Central

    Major, Giles; Spiller, Robin

    2014-01-01

    Purpose of review The review aims to update the reader on current developments in our understanding of how the gut microbiota impact on inflammatory bowel disease and the irritable bowel syndrome. It will also consider current efforts to modulate the microbiota for therapeutic effect. Recent findings Gene polymorphisms associated with inflammatory bowel disease increasingly suggest that interaction with the microbiota drives pathogenesis. This may be through modulation of the immune response, mucosal permeability or the products of microbial metabolism. Similar findings in irritable bowel syndrome have reinforced the role of gut-specific factors in this ‘functional’ disorder. Metagenomic analysis has identified alterations in pathways and interactions with the ecosystem of the microbiome that may not be recognized by taxonomic description alone, particularly in carbohydrate metabolism. Treatments targeted at the microbial stimulus with antibiotics, probiotics or prebiotics have all progressed in the past year. Studies on the long-term effects of treatment on the microbiome suggest that dietary intervention may be needed for prolonged efficacy. Summary The microbiome represents ‘the other genome’, and to appreciate its role in health and disease will be as challenging as with our own genome. Intestinal diseases occur at the front line of our interaction with the microbiome and their future treatment will be shaped as we unravel our relationship with it. PMID:24296462

  4. Cellular Origins of Regenerating Nodules and Malignancy in the FAH Model of Liver Injury after Bone Marrow Cell Transplantation

    PubMed Central

    Wang, Pei-Rong; Li, Yi

    2016-01-01

    In previous reports, we and other groups have shown that proliferating hepatocytes are formed by the fusion of donor hematopoietic cells with host hepatocytes in the Fah−/− model. Thus, it would be interesting to determine whether cell fusion occurs during malignancy. However, it is difficult to demonstrate such processes using this model. Therefore, we established a new strain to study the processes of regenerating nodules and malignancy and their origins. The FAH−/− mouse model was crossed with the ROSAnZ strain and their offspring was genotyped for FAH−/− and ROSAnZ mutations to create a new strain (Fah−/−-ROSAnZ). Using this strain as recipients, we performed bone marrow transplantation experiments. As a result, we could not demonstrate the presence of any epithelial cells except hepatocytes that were of donor origin in regenerating tissue, and no evidence of cell fusion was found in tumors. The hepatic malignancy was of host origin in these mice. There was higher expression of extracellular matrix proteins and more inflammatory cells in liver tumor nodules than in regenerating normal liver nodules. Hepatocytes generated by fusion with bone marrow cells did not form malignant tumors. Extracellular matrix and inflammatory cells had significantly accumulated in liver tumors. PMID:26962307

  5. Busulfan in infants to adult hematopoietic cell transplant recipients: A population pharmacokinetic model for initial and Bayesian dose personalization

    PubMed Central

    McCune, Jeannine S.; Bemer, Meagan J.; Barrett, Jeffrey S.; Baker, K. Scott; Gamis, Alan S.; Holford, Nicholas H.G.

    2014-01-01

    Purpose Personalizing intravenous (IV) busulfan doses to a target plasma concentration at steady state (Css) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict IV busulfan doses over a wide age spectrum (0.1 – 66 years) that accounts for differences in age and body size. Experimental design A population pharmacokinetic model based on normal fat mass and maturation based on post-menstrual age was built from 12,380 busulfan concentration-time points obtained after IV busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target Css with this model were compared with pediatric-only models. Results A two-compartment model with first-order elimination best fit the data. The population busulfan clearance was 12.4 L/h for an adult male with 62kg normal fat mass (equivalent to 70kg total body weight). Busulfan clearance, scaled to body size – specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years post-natal age. With a target Css of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size-dependent model (72%) compared to dosing recommended by the Food and Drug Administration (57%) or the European Medicines Agency (70%). Conclusion This is the first population pharmacokinetic model developed to predict initial IV busulfan doses and personalize to a target Css over a wide age spectrum, ranging from infants to adults. PMID:24218510

  6. A model of donors' decision-making in adult-to-adult living donor liver transplantation in Japan: having no choice.

    PubMed

    Fujita, Misao; Akabayashi, Akira; Slingsby, Brian Taylor; Kosugi, Shinji; Fujimoto, Yasuhiro; Tanaka, Koichi

    2006-05-01

    This study examined the decision-making processes of donors in adult-to-adult living donor liver transplantation. Twenty-two donors were interviewed using a semi-structured format. Interview contents were transcribed verbatim and analyzed qualitatively using grounded theory. A decision-making model was developed consisting of 5 stages: (1) recognition, (2) digestion, (3) decision-making, (4) reinforcement, and (5) resolution. The second and the third stages described donors' experiences of "reaching a decision"; the fourth and fifth stages described those of "facing transplantation." The central theme of this model was "having no choice," which consisted of 4 codes: (1) priority of life, (2) only LDLT, (3) for family, and (4) only me. In conclusion, this model can help health care professionals to understand the donor experience and, based on that understanding, to provide sufficient support to the donor.

  7. The role of bone marrow-derived cells during the bone healing process in the GFP mouse bone marrow transplantation model.

    PubMed

    Tsujigiwa, Hidetsugu; Hirata, Yasuhisa; Katase, Naoki; Buery, Rosario Rivera; Tamamura, Ryo; Ito, Satoshi; Takagi, Shin; Iida, Seiji; Nagatsuka, Hitoshi

    2013-03-01

    Bone healing is a complex and multistep process in which the origin of the cells participating in bone repair is still unknown. The involvement of bone marrow-derived cells in tissue repair has been the subject of recent studies. In the present study, bone marrow-derived cells in bone healing were traced using the GFP bone marrow transplantation model. Bone marrow cells from C57BL/6-Tg (CAG-EGFP) were transplanted into C57BL/6 J wild mice. After transplantation, bone injury was created using a 1.0-mm drill. Bone healing was histologically assessed at 3, 7, 14, and 28 postoperative days. Immunohistochemistry for GFP; double-fluorescent immunohistochemistry for GFP-F4/80, GFP-CD34, and GFP-osteocalcin; and double-staining for GFP and tartrate-resistant acid phosphatase were performed. Bone marrow transplantation successfully replaced the hematopoietic cells into GFP-positive donor cells. Immunohistochemical analyses revealed that osteoblasts or osteocytes in the repair stage were GFP-negative, whereas osteoclasts in the repair and remodeling stages and hematopoietic cells were GFP-positive. The results indicated that bone marrow-derived cells might not differentiate into osteoblasts. The role of bone marrow-derived cells might be limited to adjustment of the microenvironment by differentiating into inflammatory cells, osteoclasts, or endothelial cells in immature blood vessels.

  8. BK virus-associated urinary bladder carcinoma in transplant recipients: report of 2 cases, review of the literature, and proposed pathogenetic model.

    PubMed

    Alexiev, Borislav A; Randhawa, Parmjeet; Vazquez Martul, Eduardo; Zeng, Gang; Luo, Chunqing; Ramos, Emilio; Drachenberg, Cinthia B; Papadimitriou, John C

    2013-05-01

    Despite strong experimental evidence, BK polyomavirus involvement in human cancers has been controversial. We report 2 cases of kidney ± pancreas transplant recipients with evidence of BK polyomavirus reactivation, who developed aggressive urinary bladder urothelial carcinomas with adenocarcinomatous and/or micropapillary differentiation. Diffuse strong nuclear positivity for viral T antigen, p53, Ki-67, and p16 was observed in both malignancies. The BK polyomavirus role in promoting urothelial neoplasia in transplant recipients may be partly indirect, based on the demonstration by polymerase chain reaction in both tumors of BK polyomavirus with intact open reading frames and close phylogenetic clustering with known replication-competent strains, and viral capsid protein VP1 messenger RNA and intranuclear virions by electron microscopy in 1 tumor. No unique cancer-associated mutations were found, but some viral T antigen mutations were potentially associated with increased rate of viral replication and risk for "rare" carcinogenic events. The BK polyomavirus-induced profound effects on cell activation, cell cycle shift to proliferation, and apoptosis inhibition, in the context of marked immunosuppression, constitute a potentially ideal background for malignant transformation. The long time lapse between transplantation and tumor manifestation, 7 and 11 years, respectively, further supports the concept of multistep carcinogenesis cascade and long-term risk for these patients. We propose a model of changes ranging from viral reactivation to dysplasia to invasive carcinoma. Clinical vigilance is warranted for early diagnosis of BK polyomavirus-related urothelial malignancies in transplant recipients.

  9. Effects of stem cell transplantation on cognitive decline in animal models of Alzheimer’s disease: A systematic review and meta-analysis

    PubMed Central

    Wang, Zhe; Peng, Weijun; Zhang, Chunhu; Sheng, Chenxia; Huang, Wei; Wang, Yang; Fan, Rong

    2015-01-01

    Alzheimer’s disease (AD), an irreversible progressive neurodegenerative disease, causes characteristic cognitive impairment, and no curative treatments are currently available. Stem cell transplantation offers a powerful tool for the treatment of AD. We conducted a systematic review and meta-analysis of data from controlled studies to study the impact of stem cell biology and experimental design on learning and memory function following stem cell transplantation in animal models of AD. A total of 58 eligible controlled studies were included by searching PubMed, EMBASE, and Web of Science up to April 13, 2015. Meta-analysis showed that stem cell transplantation could promote both learning and memory recovery. Stratified meta-analysis was used to explore the influence of the potential factors on the estimated effect size, and meta-regression analyses were undertaken to explore the sources of heterogeneity for learning and memory function. Publication bias was assessed using funnel plots and Egger’s test. The present review reinforces the evidence supporting stem cell transplantation in experimental AD. However, it highlights areas that require well-designed and well-reported animal studies. PMID:26159750

  10. Patient selection for cardiac transplant in 2012.

    PubMed

    Kinkhabwala, Mona Parikh; Mancini, Donna

    2013-02-01

    Heart transplantation is the treatment of choice for many patients with advanced heart failure who remain symptomatic despite optimal medical therapy. Although heart transplantation results have improved over the past 10 years, careful patient selection and risk stratification of patients with advanced heart failure is paramount given limited allograft resources. Moreover, as alternative therapies to heart transplant, such as mechanical circulatory support, continue to improve in terms of patient outcomes, the selection strategy for those patients who would benefit from device support as destination therapy or bridge-to-transplant versus those patients who should proceed directly to transplant will continue to evolve. This review focuses on the optimal timing for heart transplant, risk stratification models for patient selection, as well as examining factors that continue to provoke controversy during the candidate selection process and factors that have changed from absolute to relative contraindications as the authors experience with cardiac transplantation continues to increase. PMID:23405839

  11. Neoplasms of the Small Bowel

    PubMed Central

    Silberman, Howard; Crichlow, Robert W.; Caplan, Howard S.

    1974-01-01

    Small bowel tumors are unusual lesions exhibiting nonspecific clinical features often diagnosed at an advanced stage. In the cases studied at the Hospital of the University of Pennsylvania nearly all the 32 patients with malignancies were symptomatic whereas in the 34 patients with benign lesions the condition was discovered as an incidental finding in about half of the patients. Weight loss, palpable mass or anemia usually indicated malignancy. Small bowel radiography was the most useful diagnostic aid in the present series. While the etiology of these lesions is unknown, villous adenomas probably bear a relationship to carcinoma. The association between chronic regional enteritis and small bowel tumors is unestablished but suggestive. An analysis of reported series reveals a disproportionate incidence of additional primary tumors in patients with small bowel neoplasms. Surgical extirpation is indicated for curative treatment. In the present series, resection in hope of cure was carried out in 25 of 32 malignant tumors resulting in eight five-year survivals. One of these latter lived nine years with disseminated malignant carcinoid reflecting the occasional indolent course of this tumor. PMID:4842978

  12. Biomarker versus environmental factors: seasonal variations and modelling multixenobiotic defence (MXD) transport activity in transplanted zebra mussels.

    PubMed

    Pain, Sandrine; Devin, Simon; Parant, Marc

    2007-02-01

    The occurrence of biomarker temporal variations linked to environmental factors makes it difficult to distinguish the specific effect of pollution. The present work aims to investigate the seasonal variations of the transport activity of the multixenobiotic defence (MXD), which is used as a biological tool for the monitoring of pollution in aquatic ecosystems. The MXD transport activity was monitored monthly from August 2001 to October 2002 in zebra mussels (Dreissena polymorpha) transplanted to three sites in the Moselle River. The 'efflux method' was used to evaluate functional activity of MXD by assessing rhodamine B efflux with or without an inhibitor (verapamil). Environmental parameters were provided by a French regulatory agency (Water Agency) that monitors river water quality. The results of a principal components analysis describe the seasonal cycle of water characteristics and demonstrate that MXD activity is subjected to significant temporal variations. These data were described with a generalised linear model that enables it to link MXD variability to the seasonal variations of environmental parameters such as temperature or levels of organic contamination. This work proposes a modelling approach and highlights that the occurrence of seasonal variations in MXD response has to be taken into account in the interpretation of in situ monitoring studies. PMID:17210171

  13. Transplantation of NGF-gene-modified bone marrow stromal cells into a rat model of Alzheimer' disease.

    PubMed

    Li, Li-Yan; Li, Jin-Tao; Wu, Qing-Ying; Li, Jin; Feng, Zhong-Tang; Liu, Su; Wang, Ting-Hua

    2008-02-01

    It is well known that bone marrow stromal cells (BMSC) grafted into the hippocampus of the rat model of Alzheimer's disease (AD) could survive and differentiate into cholinergic neurons as well as contribute towards functional restoration. The present study evaluated the effects of BMSC as a seed cell modified by nerve growth factor (NGF) gene into the hippocampus of AD rats. The beta-amyloid protein was injected bilaterally into the rat hippocampus to reproduce the AD model. After the human total RNA was extracted, the NGF gene was amplified by reverse transcription-polymerase chain reaction, then cloned into the pcDNA3. BMSC derived from a green fluorescence protein transgenic mouse were isolated, cultured, identified, and transfected by the NGF recombinant. The NGF-gene-modified BMSC were then transplanted into the hippocampus of AD rats. The results showed that implanted BMSC survived, migrated and expressed NGF as well as differentiated into ChAT-positive neurons. A significant improvement in learning and memory in AD rats was also seen in NGF-gene-modified BMSC group, when compared with the BMSC group. The present findings suggested that BMSC provided an effective carrier for delivery of NGF into AD rats, and the administration of NGF-gene-modified BMSC may be considered as a potential strategy for the development of effective therapies for the treatment of AD.

  14. Biomarker versus environmental factors: seasonal variations and modelling multixenobiotic defence (MXD) transport activity in transplanted zebra mussels.

    PubMed

    Pain, Sandrine; Devin, Simon; Parant, Marc

    2007-02-01

    The occurrence of biomarker temporal variations linked to environmental factors makes it difficult to distinguish the specific effect of pollution. The present work aims to investigate the seasonal variations of the transport activity of the multixenobiotic defence (MXD), which is used as a biological tool for the monitoring of pollution in aquatic ecosystems. The MXD transport activity was monitored monthly from August 2001 to October 2002 in zebra mussels (Dreissena polymorpha) transplanted to three sites in the Moselle River. The 'efflux method' was used to evaluate functional activity of MXD by assessing rhodamine B efflux with or without an inhibitor (verapamil). Environmental parameters were provided by a French regulatory agency (Water Agency) that monitors river water quality. The results of a principal components analysis describe the seasonal cycle of water characteristics and demonstrate that MXD activity is subjected to significant temporal variations. These data were described with a generalised linear model that enables it to link MXD variability to the seasonal variations of environmental parameters such as temperature or levels of organic contamination. This work proposes a modelling approach and highlights that the occurrence of seasonal variations in MXD response has to be taken into account in the interpretation of in situ monitoring studies.

  15. Human tonsil-derived mesenchymal stromal cells enhanced myelopoiesis in a mouse model of allogeneic bone marrow transplantation

    PubMed Central

    Ryu, Jung-Hwa; Park, Minhwa; Kim, Bo-Kyung; Kim, Yu-Hee; Woo, So-Youn; Ryu, Kyung-Ha

    2016-01-01

    Mesenchymal stromal cells (MSCs) have therapeutic potential for repairing tissue damage and are involved in immune regulation. MSCs are predominantly isolated from bone marrow (BM), adipose tissue or placental tissue. Further to these well-known sources, the isolation of MSCs from human tonsils was previously reported. The aim of the present study was to investigate a potential role for tonsil-derived MSCs (T-MSCs) in BM reconstitution and application towards supplementing hematopoiesis in a mouse model of BM transplantation (BMT). Eight-week-old BALB/c female mice received 80 mg/kg busulfan (Bu)/200 mg/kg cyclophosphamide (Cy) conditioning chemotherapy for BM ablation. Subsequently, human T-MSCs were injected into the Bu/Cy-treated mice with or without BM cells (BMCs) obtained from allogeneic C57BL/6 male mice. After 3 weeks, peripheral blood and BM was collected for analysis. The red blood cell count in the group that received BMCs had almost returned to normal, whereas mononuclear cell counts and BM cellularity were most improved in the T-MSCs + BMCs group. These results indicate that the T-MSCs enhanced myelopoiesis in the allogeneic BMT mouse model, as evidenced by the restoration of BM with hematopoietic cells, as well as increased myeloid colony formation in vitro. Therefore, T-MSCs may provide a source of MSCs to facilitate myelopoiesis and megakaryocytosis following BMT. PMID:27511380

  16. Underlying molecular and cellular mechanisms in childhood irritable bowel syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Irritable bowel syndrome (IBS) affects a large number of children throughout the world. The symptom expression of IBS is heterogeneous, and several factors which may be interrelated within the IBS biopsychosocial model play a role. These factors include visceral hyperalgesia, intestinal permeability...

  17. [Percutaneous Nephrolithotripsy for Renal Transplant Lithiasis: A Case Report].

    PubMed

    Oida, Takeshi; Kanemitsu, Toshiyuki; Hayashi, Tetsuya; Fujimoto, Nobumasa; Koide, Takuo

    2016-02-01

    A 54-year-old man was introduced to our hospital for follow-up examinations after renal transplantation. At the initial visit, a 25 mm renal transplant stone was noted, which had enlarged to 32 mm at an examination 1 year later. We first attempted transurethral lithotripsy (TUL), but failed due to ureteral stricture. However, we could completely remove the stone in 2 sessions of percutaneous nephrolithotripsy (PNL). The incidence of urinary lithiasis after renal transplantation ranges from 0.17-1.8%, for which PNL and TUL are frequently used. Although considered to be accompanied with risks of bleeding, bowel injury, and renal dysfunction, PNL is effective for urinary lithiasis after renal transplantation. TUL is less invasive, but access may be difficult when the ureter has an unusual course or ureteral stricture exists, as in our patient. PMID:27018408

  18. Vitamin D and inflammatory bowel disease.

    PubMed

    Ardesia, Marco; Ferlazzo, Guido; Fries, Walter

    2015-01-01

    Vitamin D deficiency has been recognized as an environmental risk factor for Crohn's disease since the early 80s. Initially, this finding was correlated with metabolic bone disease. Low serum 25-hydroxyvitamin D levels have been repeatedly reported in inflammatory bowel diseases together with a relationship between vitamin D status and disease activity. Subsequently, low serum vitamin D levels have been reported in various immune-related diseases pointing to an immunoregulatory role. Indeed, vitamin D and its receptor (VDR) are known to interact with different players of the immune homeostasis by controlling cell proliferation, antigen receptor signalling, and intestinal barrier function. Moreover, 1,25-dihydroxyvitamin D is implicated in NOD2-mediated expression of defensin-β2, the latter known to play a crucial role in the pathogenesis of Crohn's disease (IBD1 gene), and several genetic variants of the vitamin D receptor have been identified as Crohn's disease candidate susceptibility genes. From animal models we have learned that deletion of the VDR gene was associated with a more severe disease. There is a growing body of evidence concerning the therapeutic role of vitamin D/synthetic vitamin D receptor agonists in clinical and experimental models of inflammatory bowel disease far beyond the role of calcium homeostasis and bone metabolism. PMID:26000293

  19. Establishment of an orthotopic transplantation tumor model in nude mice using a drug-resistant human ovarian cancer cell line with a high expression of c-Kit.

    PubMed

    Yi, Cunjian; Zhang, Lei; Li, Li; Liu, Xiangqiong; Ling, Shengrong; Zhang, Fayun; Liang, Wei

    2014-12-01

    The resistance of ovarian cancer to platinum-based chemotherapy is a critical issue in the clinical setting. The present study aimed to establish animal models to replicate this clinical condition, as well as to investigate the resistance mechanisms of ovarian cancer. A cisplatin (DDP)-resistant human ovarian cancer cell line, SKOV3/DDP, was screened, validated and injected subcutaneously into the neck of female nude mice. Following tumor establishment, the tumor was collected and cut into small sections, which were subsequently implanted into the ovaries of other nude mice. The growth of the orthotopic tumors was observed and the tumor-bearing mice were sacrificed and dissected. The orthotopic and metastatic tumor tissues were collected, sectioned, stained with hematoxylin and eosin and analyzed. In the present study, 16 nude mice underwent orthotopic transplantation surgery and a tumor model was successfully established in 14/16 of the mice, with an in situ tumor formation rate of 87.5%. Following euthanasia, a laparotomy demonstrated the tumor formation at the site of transplantation, as well as varying degrees of metastasis to additional organs and tissues. Therefore, the present study successfully established an orthotopic tumor transplantation model in nude mice using a c-Kit-positive DDP-resistant human ovarian cancer cell line. This model may represent a useful tool for investigating the resistance mechanism of ovarian cancer, as well as evaluating the efficacy of therapeutic strategies.

  20. Co-transplantation of GDNF-overexpressing neural stem cells and fetal dopaminergic neurons mitigates motor symptoms in a rat model of Parkinson's disease.

    PubMed

    Deng, Xingli; Liang, Yuanxin; Lu, Hua; Yang, Zhiyong; Liu, Ru'en; Wang, Jinkun; Song, Xiaobin; Long, Jiang; Li, Yu; Lei, Deqiang; Feng, Zhongtang

    2013-01-01

    Striatal transplantation of dopaminergic (DA) neurons or neural stem cells (NSCs) has been reported to improve the symptoms of Parkinson's disease (PD), but the low rate of cell survival, differentiation, and integration in the host brain limits the therapeutic efficacy. We investigated the therapeutic effects of intracranial co-transplantation of mesencephalic NSCs stably overexpressing human glial-derived neurotrophic factor (GDNF-mNSCs) together with fetal DA neurons in the 6-OHDA rat model of PD. Striatal injection of mNSCs labeled by the contrast enhancer superparamagnetic iron oxide (SPIO) resulted in a hypointense signal in the striatum on T2-weighted magnetic resonance images that lasted for at least 8 weeks post-injection, confirming the long-term survival of injected stem cells in vivo. Co-transplantation of GDNF-mNSCs with fetal DA neurons significantly reduced apomorphine-induced rotation, a behavioral endophenotype of PD, compared to sham-treated controls, rats injected with mNSCs expressing empty vector (control mNSCs) plus fetal DA neurons, or rats injected separately with either control mNSCs, GDNF-mNSCs, or fetal DA neurons. In addition, survival and differentiation of mNSCs into DA neurons was significantly greater following co-transplantation of GDNF-mNSCs plus fetal DA neurons compared to the other treatment groups as indicated by the greater number of cell expressing both the mNSCs lineage tracer enhanced green fluorescent protein (eGFP) and the DA neuron marker tyrosine hydroxylase. The success of cell-based therapies for PD may be greatly improved by co-transplantation of fetal DA neurons with mNSCs genetically modified to overexpress trophic factors such as GDNF that support differentiation into DA cells and their survival in vivo.

  1. Meniscal allograft transplantation

    MedlinePlus

    Meniscus transplant; Surgery - knee - meniscus transplant; Surgery - knee - cartilage; Arthroscopy - knee - meniscus transplant ... the lab for any diseases and infection. Other surgeries, such as ligament or cartilage repairs, may be ...

  2. Pancreatic Islet Transplantation

    MedlinePlus

    ... allo-transplantation?" For each pancreatic islet allo-transplant infusion, researchers use specialized enzymes to remove islets from ... in a lab. Transplant patients typically receive two infusions with an average of 400,000 to 500, ...

  3. Lung Transplantation for Hypersensitivity Pneumonitis

    PubMed Central

    Singer, Jonathan P.; Koth, Laura; Mooney, Joshua; Golden, Jeff; Hays, Steven; Greenland, John; Wolters, Paul; Ghio, Emily; Jones, Kirk D.; Leard, Lorriana; Kukreja, Jasleen; Blanc, Paul D.

    2015-01-01

    BACKGROUND: Hypersensitivity pneumonitis (HP) is an inhaled antigen-mediated interstitial lung disease (ILD). Advanced disease may necessitate the need for lung transplantation. There are no published studies addressing lung transplant outcomes in HP. We characterized HP outcomes compared with referents undergoing lung transplantation for idiopathic pulmonary fibrosis (IPF). METHODS: To identify HP cases, we reviewed records for all ILD lung transplantation cases at our institution from 2000 to 2013. We compared clinical characteristics, survival, and acute and chronic rejection for lung transplant recipients with HP to referents with IPF. We also reviewed diagnoses of HP discovered only by explant pathology and looked for evidence of recurrent HP after transplant. Survival was compared using Kaplan-Meier methods and Cox proportional hazard modeling. RESULTS: We analyzed 31 subjects with HP and 91 with IPF among 183 cases undergoing lung transplantation for ILD. Survival at 1, 3, and 5 years after lung transplant in HP compared with IPF was 96%, 89%, and 89% vs 86%, 67%, and 49%, respectively. Subjects with HP manifested a reduced adjusted risk for death compared with subjects with IPF (hazard ratio, 0.25; 95% CI, 0.08-0.74; P = .013). Of the 31 cases, the diagnosis of HP was unexpectedly made at explant in five (16%). Two subjects developed recurrent HP in their allografts. CONCLUSIONS: Overall, subjects with HP have excellent medium-term survival after lung transplantation and, relative to IPF, a reduced risk for death. HP may be initially discovered only by review of the explant pathology. Notably, HP may recur in the allograft. PMID:25412059

  4. The Intravenous Route of Injection Optimizes Engraftment and Survival in the Murine Model of In Utero Hematopoietic Cell Transplantation.

    PubMed

    Boelig, Matthew M; Kim, Aimee G; Stratigis, John D; McClain, Lauren E; Li, Haiying; Flake, Alan W; Peranteau, William H

    2016-06-01

    In utero hematopoietic cell transplantation (IUHCT) has the potential to treat a number of congenital hematologic disorders. Clinical application is limited by low levels of donor engraftment. Techniques that optimize donor cell delivery to the fetal liver (FL), the hematopoietic organ at the time of IUHCT, have the potential to enhance engraftment and the clinical success of IUHCT. We compared the 3 clinically applicable routes of injection (intravenous [i.v.], intraperitoneal [i.p.], and intrahepatic [i.h.]) and assessed short- and long-term donor cell engraftment and fetal survival in the murine model of IUHCT. We hypothesized that the i.v. route would promote direct donor cell homing to the FL, resulting in increased engraftment and allowing for larger injectate volumes without increased fetal mortality. We demonstrate that the i.v. route results in (1) rapid diffuse donor cell population of the FL compared with delayed diffuse engraftment after the i.p. and i.h. routes; (2) higher FL and spleen engraftment at early prenatal time points; (3) enhanced stable long-term peripheral blood donor cell engraftment; and (4) improved survival at higher injectate volumes, allowing for higher donor cell doses and increased long-term engraftment. These findings support the use of an i.v. route for clinical protocols of IUHCT. PMID:26797401

  5. Living donor liver transplantation for high model for end-stage liver disease score: What have we learned?

    PubMed Central

    Dabbous, Hany; Sakr, Mohammad; Abdelhakam, Sara; Montasser, Iman; Bahaa, Mohamed; Said, Hany; El-Meteini, Mahmoud

    2016-01-01

    AIM To assess the impact of model for end-stage liver disease (MELD) score on patient survival and morbidity post living donor liver transplantation (LDLT). METHODS A retrospective study was performed on 80 adult patients who had LDLT from 2011-2013. Nine patients were excluded and 71 patients were divided into two groups; Group 1 included 38 patients with a MELD score < 20, and Group 2 included 33 patients with a MELD score > 20. Comparison between both groups was done regarding operative time, intra-operative blood requirement, intensive care unit (ICU) and hospital stay, infection, and patient survival. RESULTS Eleven patients died (15.5%); 3/38 (7.9%) patients in Group 1 and 8/33 (24.2%) in Group 2 with significant difference (P = 0.02). Mean operative time, duration of hospital stay, and ICU stay were similar in both groups. Mean volume of blood transfusion and cell saver re-transfusion were 8 ± 4 units and 1668 ± 202 mL, respectively, in Group 1 in comparison to 10 ± 6 units and 1910 ± 679 mL, respectively, in Group 2 with no significant difference (P = 0.09 and 0.167, respectively). The rates of infection and systemic complications (renal, respiratory, cardiovascular and neurological complications) were similar in both groups. CONCLUSION A MELD score > 20 may predict mortality after LDLT. PMID:27574548

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

    PubMed

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

    2013-05-01

    Despite aggressive chemotherapy combined with hematopoietic stem cell transplantation (HSCT), many patients with acute myeloid leukemia (AML) relapse. Radioimmunotherapy (RIT) using monoclonal antibodies labeled with β-emitting radionuclides has been explored to reduce relapse. β emitters are limited by lower energies and nonspecific cytotoxicity from longer path lengths compared with α emitters such as (211)At, which has a higher energy profile and shorter path length. We evaluated the efficacy and toxicity of anti-CD45 RIT using (211)At in a disseminated murine AML model. Biodistribution studies in leukemic SJL/J mice showed excellent localization of (211)At-anti-murine CD45 mAb (30F11) to marrow and spleen within 24 hours (18% and 79% injected dose per gram of tissue [ID/g], respectively), with lower kidney and lung uptake (8.4% and 14% ID/g, respectively). In syngeneic HSCT studies, (211)At-B10-30F11 RIT improved the median survival of leukemic mice in a dose-dependent fashion (123, 101, 61, and 37 days given 24, 20, 12, and 0 µCi, respectively). This approach had minimal toxicity with nadir white blood cell counts >2.7 K/µL 2 weeks after HSCT and recovery by 4 weeks. These data suggest that (211)At-anti-CD45 RIT in conjunction with HSCT may be a promising therapeutic option for AML. PMID:23471305

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

    PubMed Central

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

    2013-01-01

    Despite aggressive chemotherapy combined with hematopoietic stem cell transplantation (HSCT), many patients with acute myeloid leukemia (AML) relapse. Radioimmunotherapy (RIT) using monoclonal antibodies labeled with β-emitting radionuclides has been explored to reduce relapse. β emitters are limited by lower energies and nonspecific cytotoxicity from longer path lengths compared with α emitters such as 211At, which has a higher energy profile and shorter path length. We evaluated the efficacy and toxicity of anti-CD45 RIT using 211At in a disseminated murine AML model. Biodistribution studies in leukemic SJL/J mice showed excellent localization of 211At-anti-murine CD45 mAb (30F11) to marrow and spleen within 24 hours (18% and 79% injected dose per gram of tissue [ID/g], respectively), with lower kidney and lung uptake (8.4% and 14% ID/g, respectively). In syngeneic HSCT studies, 211At-B10-30F11 RIT improved the median survival of leukemic mice in a dose-dependent fashion (123, 101, 61, and 37 days given 24, 20, 12, and 0 µCi, respectively). This approach had minimal toxicity with nadir white blood cell counts >2.7 K/µL 2 weeks after HSCT and recovery by 4 weeks. These data suggest that 211At-anti-CD45 RIT in conjunction with HSCT may be a promising therapeutic option for AML. PMID:23471305

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

    PubMed

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

    2013-05-01

    Despite aggressive chemotherapy combined with hematopoietic stem cell transplantation (HSCT), many patients with acute myeloid leukemia (AML) relapse. Radioimmunotherapy (RIT) using monoclonal antibodies labeled with β-emitting radionuclides has been explored to reduce relapse. β emitters are limited by lower energies and nonspecific cytotoxicity from longer path lengths compared with α emitters such as (211)At, which has a higher energy profile and shorter path length. We evaluated the efficacy and toxicity of anti-CD45 RIT using (211)At in a disseminated murine AML model. Biodistribution studies in leukemic SJL/J mice showed excellent localization of (211)At-anti-murine CD45 mAb (30F11) to marrow and spleen within 24 hours (18% and 79% injected dose per gram of tissue [ID/g], respectively), with lower kidney and lung uptake (8.4% and 14% ID/g, respectively). In syngeneic HSCT studies, (211)At-B10-30F11 RIT improved the median survival of leukemic mice in a dose-dependent fashion (123, 101, 61, and 37 days given 24, 20, 12, and 0 µCi, respectively). This approach had minimal toxicity with nadir white blood cell counts >2.7 K/µL 2 weeks after HSCT and recovery by 4 weeks. These data suggest that (211)At-anti-CD45 RIT in conjunction with HSCT may be a promising therapeutic option for AML.

  9. Video capsule endoscopy: is bowel preparation necessary?

    PubMed

    Catalano, Carmine; Companioni, Rafael Antonio Ching; Khankhanian, Pouya; Vyas, Neil; Patel, Ishan; Bansal, Raghav; Walfish, Aaron

    2016-08-01

    There is no standardized protocol for bowel preparation prior to video capsule endoscopy, although one is strongly recommended. The purpose of our study was to see if there was a statistical significance between small bowel mucosal visualization rates for those who received bowel preparation and those who did not. We retrospectively analyzed all patients who had a video capsule endoscopy from August 2014 to January 2016 at a tertiary care center. All patients fasted prior to the procedure. Bowel preparation when used consisted of polyethylene glycol. A long fast consisted of 12 or more hours. The grading system used to assess the small bowel was adapted from a previously validated system from Esaki et al Statistical analyses were performed using Fisher's exact test or Welch's 2-sample t-test and statistical significance was present if the p value was ≤0.05. 76 patients were carried forward for analysis. Small bowel mucosal visualization rates were similar between those who received bowel preparation and those who did not (92.5% vs 88.9%, p=0.44). Small bowel mucosal visualization rates were significantly better in those patients who had a long fast compared with those who had a short fast (97.7% vs 81.3%, p=0.019). Our study demonstrates that the addition of bowel preparation prior to video capsule endoscopy does not significantly improve small bowel mucosal visualization rates and, in addition, there is a statistically significant relationship between increased fasting time and improved small bowel mucosal visualization. A prolonged fast without bowel preparation might be satisfactory for an adequate small bowel visualization but further randomized, prospective studies are necessary to confirm these findings. PMID:27271277

  10. New diagnosis and therapy model for ischemic-type biliary lesions following liver transplantation--a retrospective cohort study.

    PubMed

    Zhang, Ying-cai; Qu, En-ze; Ren, Jie; Zhang, Qi; Zheng, Rong-qin; Yang, Yang; Chen, Gui-hua

    2014-01-01

    Ischemic-type biliary lesions (ITBLs) are a major cause of graft loss and mortality after orthotopic liver transplantation (OLT). Impaired blood supply to the bile ducts may cause focal or extensive damage, resulting in intra- or extrahepatic bile duct strictures or dilatations that can be detected by ultrasonography, computed tomography, magnetic resonance cholangiopancreatography, and cholangiography. However, the radiographic changes occur at an advanced stage, after the optimal period for therapeutic intervention. Endoscopic retrograde cholangio-pancreatography (ERCP) and percutaneous transhepatic cholangiodrainage (PTCD) are the gold standard methods of detecting ITBLs, but these procedures cannot be used for continuous monitoring. Traditional methods of follow-up and diagnosis result in delayed diagnosis and treatment of ITBLs. Our center has used the early diagnosis and intervention model (EDIM) for the diagnosis and treatment of ITBLs since February 2008. This model mainly involves preventive medication to protect the epithelial cellular membrane of the bile ducts, regular testing of liver function, and weekly monitor of contrast-enhanced ultrasonography (CEUS) to detect ischemic changes to the bile ducts. If the liver enzyme levels become abnormal or CEUS shows low or no enhancement of the wall of the hilar bile duct during the arterial phase, early ERCP and PTCD are performed to confirm the diagnosis and to maintain biliary drainage. Compared with patients treated by the traditional model used prior to February 2008, patients in the EDIM group had a lower incidence of biliary tract infection (28.6% vs. 48.6%, P = 0.04), longer survival time of liver grafts (24±9.6 months vs. 17±12.3 months, P = 0.02), and better outcomes after treatment of ITBLs.

  11. The Intestinal Microbiota in Inflammatory Bowel Disease.

    PubMed

    Becker, Christoph; Neurath, Markus F; Wirtz, Stefan

    2015-01-01

    The intestinal microbiota has important metabolic and host-protective functions. Conversely to these beneficial functions, the intestinal microbiota is thought to play a central role in the etiopathogenesis of inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), a chronic inflammation of the gut mucosa. Genetic screens and studies in experimental mouse models have clearly demonstrated that IBD can develop due to excessive translocation of bacteria into the bowel wall or dysregulated handling of bacteria in genetically susceptible hosts. In healthy individuals, the microbiota is efficiently separated from the mucosal immune system of the gut by the gut barrier, a single layer of highly specialized epithelial cells, some of which are equipped with innate immune functions to prevent or control access of bacterial antigens to the mucosal immune cells. It is currently unclear whether the composition of the microbial flora or individual bacterial strains or pathogens induces or supports the pathogenesis of IBD. Further research will be necessary to carefully dissect the contribution of individual bacterial species to this disease and to ascertain whether specific modulation of the intestinal microbiome may represent a valuable further option for future therapeutic strategies.

  12. Projected outcomes of 6-month delay in exception points versus an equivalent Model for End-Stage Liver Disease score for hepatocellular carcinoma liver transplant candidates.

    PubMed

    Alver, Sarah K; Lorenz, Douglas J; Marvin, Michael R; Brock, Guy N

    2016-10-01

    The United Network for Organ Sharing (UNOS) recently implemented a 6-month delay before granting exception points to liver transplantation candidates with hepatocellular carcinoma (HCC) to address disparity in transplantation access between HCC and non-HCC patients. An HCC-specific scoring scheme, the Model for End-Stage Liver Disease equivalent (MELDEQ ), has also been developed. We compared projected dropout and transplant probabilities and posttransplant survival for HCC and non-HCC patients under the 6-month delay and the MELDEQ using UNOS data from October 1, 2009, to June 30, 2014, and multistate modeling. Overall (combined HCC and non-HCC) wait-list dropout was similar under both schemes and slightly improved (though not statistically significant) compared to actual data. Projected HCC wait-list dropout was similar between the MELDEQ and 6-month delay at 6 months but thereafter started to differ, with the 6-month delay eventually favoring HCC patients (3-year dropout 10.0% [9.0%-11.0%] for HCC versus 14.1% [13.6%-14.6%]) for non-HCC) and the MELDEQ favoring non-HCC patients (3-year dropout 16.0% [13.2%-18.8%] for HCC versus 12.3% [11.9%-12.7%] for non-HCC). Projected transplant probabilities for HCC patients were substantially lower under the MELDEQ compared to the 6-month delay (26.6% versus 83.8% by 3 years, respectively). Projected HCC posttransplant survival under the 6-month delay was similar to actual, but slightly worse under the MELDEQ (2-year survival 82.9% [81.7%-84.2%] versus actual of 85.5% [84.3%-86.7%]). In conclusion, although the 6-month delay improves equity in transplant and dropout between HCC and non-HCC candidates, disparity between the 2 groups may still exist after 6 months of wait-list time. Projections under the MELDEQ , however, appear to disadvantage HCC patients. Therefore, modification to the exception point progression or refinement of an HCC prioritization score may be warranted. Liver Transplantation 22 1343-1355 2016 AASLD.

  13. Irritable Bowel Syndrome.

    PubMed

    Wald

    1999-02-01

    I believe there are four essential elements in the management of patients with irritable bowel syndrome (IBS): to establish a good physician-patient relationship; to educate patients about their condition; to emphasize the excellent prognosis and benign nature of the illness; and to employ therapeutic interventions centering on dietary modifications, pharmacotherapy, and behavioral strategies tailored to the individual. Initially, I establish the diagnosis, exclude organic causes, educate patients about the disease, establish realistic expectations and consistent limits, and involve patients in disease management. I find it critical to determine why the patient is seeking assistance (eg, cancer phobia, disability, interpersonal distress, or exacerbation of symptoms). Most patients can be treated by their primary care physician. However, specialty consultations may be needed to reinforce management strategies, perform additional diagnostic tests, or institute specialized treatment. Psychological co-morbidities do not cause symptoms but do affect how patients respond to them and influence health care-seeking behavior. I find that these issues are best explored over a series of visits when the physician-patient relationship has been established. It can be helpful to have patients fill out a self-administered test to identify psychological co-morbidities. I often use these tests as a basis for extended inquiries into this area, resulting in the initiation of appropriate therapies. I encourage patients to keep a 2-week diary of food intake and gastrointestinal symptoms. In this way, patients become actively involved in management of their disease, and I may be able to obtain information from the diary that will be valuable in making treatment decisions. I do not believe that diagnostic studies for food intolerances are cost-effective or particularly helpful; however, exclusion diets may be beneficial. I introduce fiber supplements gradually and monitor them for

  14. Intracoronary artery transplantation of cardiomyoblast-like cells from human adipose tissue-derived multi-lineage progenitor cells improve left ventricular dysfunction and survival in a swine model of chronic myocardial infarction

    SciTech Connect

    Okura, Hanayuki; Saga, Ayami; Soeda, Mayumi; Miyagawa, Shigeru; Sawa, Yoshiki; Daimon, Takashi; Ichinose, Akihiro; Matsuyama, Akifumi

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer We administered human CLCs in a swine model of MI via intracoronary artery. Black-Right-Pointing-Pointer Histological studies demonstrated engraftment of hCLCs into the scarred myocardium. Black-Right-Pointing-Pointer Echocardiography showed rescue of cardiac function in the hCLCs transplanted swine. Black-Right-Pointing-Pointer Transplantation of hCLCs is an effective therapeutics for cardiac regeneration. -- Abstract: Transplantation of human cardiomyoblast-like cells (hCLCs) from human adipose tissue-derived multi-lineage progenitor cells improved left ventricular function and survival of rats with myocardial infarction. Here we examined the effect of intracoronary artery transplantation of human CLCs in a swine model of chronic heart failure. Twenty-four pigs underwent balloon-occlusion of the first diagonal branch followed by reperfusion, with a second balloon-occlusion of the left ascending coronary artery 1 week later followed by reperfusion. Four weeks after the second occlusion/reperfusion, 17 of the 18 surviving animals with severe chronic MI (ejection fraction <35% by echocardiography) were immunosuppressed then randomly assigned to receive either intracoronary artery transplantation of hCLCs hADMPCs or placebo lactic Ringer's solution with heparin. Intracoronary artery transplantation was followed by the distribution of DiI-stained hCLCs into the scarred myocardial milieu. Echocardiography at post-transplant days 4 and 8 weeks showed rescue and maintenance of cardiac function in the hCLCs transplanted group, but not in the control animals, indicating myocardial functional recovery by hCLCs intracoronary transplantation. At 8 week post-transplantation, 7 of 8 hCLCs transplanted animals were still alive compared with only 1 of the 5 control (p = 0.0147). Histological studies at week 12 post-transplantation demonstrated engraftment of the pre DiI-stained hCLCs into the scarred myocardium and their expression of

  15. Amniotic Fluid-Derived Mesenchymal Stem Cells Prevent Fibrosis and Preserve Renal Function in a Preclinical Porcine Model of Kidney Transplantation

    PubMed Central

    Baulier, Edouard; Favreau, Frederic; Le Corf, Amélie; Jayle, Christophe; Schneider, Fabrice; Goujon, Jean-Michel; Feraud, Olivier; Bennaceur-Griscelli, Annelise; Turhan, Ali G.

    2014-01-01

    It is well known that ischemia/reperfusion injuries strongly affect the success of human organ transplantation. Development of interstitial fibrosis and tubular atrophy is the main deleterious phenomenon involved. Stem cells are a promising therapeutic tool already validated in various ischemic diseases. Amniotic fluid-derived mesenchymal stem cells (af-MSCs), a subpopulation of multipotent cells identified in amniotic fluid, are known to secrete growth factors and anti-inflammatory cytokines. In addition, these cells are easy to collect, present higher proliferation and self-renewal rates compared with other adult stem cells (ASCs), and are suitable for banking. Consequently, af-MSCs represent a promising source of stem cells for regenerative therapies in humans. To determine the efficiency and the safety of af-MSC infusion in a preclinical porcine model of renal autotransplantation, we injected autologous af-MSCs in the renal artery 6 days after transplantation. The af-MSC injection improved glomerular and tubular functions, leading to full renal function recovery and abrogated fibrosis development at 3 months. The strong proof of concept generated by this translational porcine model is a first step toward evaluation of af-MSC-based therapies in human kidney transplantation. PMID:24797827

  16. Allogeneic Transplantation of an Adipose-Derived Stem Cell Sheet Combined With Artificial Skin Accelerates Wound Healing in a Rat Wound Model of Type 2 Diabetes and Obesity.

    PubMed

    Kato, Yuka; Iwata, Takanori; Morikawa, Shunichi; Yamato, Masayuki; Okano, Teruo; Uchigata, Yasuko

    2015-08-01

    One of the most common complications of diabetes is diabetic foot ulcer. Diabetic ulcers do not heal easily due to diabetic neuropathy and reduced blood flow, and nonhealing ulcers may progress to gangrene, which necessitates amputation of the patient's foot. This study attempted to develop a new cell-based therapy for nonhealing diabetic ulcers using a full-thickness skin defect in a rat model of type 2 diabetes and obesity. Allogeneic adipose-derived stem cells (ASCs) were harvested from the inguinal fat of normal rats, and ASC sheets were created using cell sheet technology and transplanted into full-thickness skin defects in Zucker diabetic fatty rats. The results indicate that the transplantation of ASC sheets combined with artificial skin accelerated wound healing and vascularization, with significant differences observed 2 weeks after treatment. The ASC sheets secreted large amounts of several angiogenic growth factors in vitro, and transplanted ASCs were observed in perivascular regions and incorporated into the newly constructed vessel structures in vivo. These results suggest that ASC sheets accelerate wound healing both directly and indirectly in this diabetic wound-healing model. In conclusion, allogeneic ASC sheets exhibit potential as a new therapeutic strategy for the treatment of diabetic ulcers.

  17. [Blastocystis hominis and bowel diseases].

    PubMed

    Ustün, Sebnem; Turgay, Nevin

    2006-01-01

    Blastocystis hominis (B. hominis) is a parasite of uncertain role in human disease. It may be identified during a workup for gastrointestinal symptoms, usually in stools. The clinical consequences of B. hominis infection are mainly diarrhea and abdominal pain as well as nonspecific gastrointestinal symptoms such as nausea, anorexia, vomiting, weight loss, lassitude, dizziness, and flatulence. Case reports and series have suggested a pathogenic role of B. hominis in causing intestinal inflammation. Also some studies have suggested that inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are associated with B. hominis infection. The investigators indicate that the stools of all patients presenting with IBD or IBS should be examined, and culture methods for B. hominis carried out. Invasion and mucosal inflammation of the intestine with B. hominis have been observed in studies of gnotobiotic guinea pigs. The transmission, pathogenicity, culture characteristics, taxonomy, life cycle, biochemistry and molecular biology of B. hominis remain unclear. More studies are necessary for this parasite. PMID:17106862

  18. Costs in inflammatory bowel diseases

    PubMed Central

    Witczak, Izabela

    2016-01-01

    Variables influencing total direct medical costs in inflammatory bowel diseases include country, diagnosis (generally, patients with Crohn's disease generated higher costs compared with patients with ulcerative colitis), and year since diagnosis. In all studies the mean costs were higher than the median costs, which indicates that a relatively small group of the most severely ill patients significantly affect the total cost of treatment of these diseases. A major component of direct medical costs was attributed to hospitalisation, ranging from 49% to 80% of the total. The costs of surgery constituted 40–61% of inpatient costs. Indirect costs in inflammatory bowel diseases, unappreciated and often underestimated (considered by few authors and as a loss of work), are in fact important and may even exceed direct medical costs. PMID:27110304

  19. Human Biomarker Discovery and Predictive Models for Disease Progression for Idiopathic Pneumonia Syndrome Following Allogeneic Stem Cell Transplantation*

    PubMed Central

    Schlatzer, Daniela M.; Dazard, Jean-Eudes; Ewing, Rob M.; Ilchenko, Serguei; Tomcheko, Sara E.; Eid, Saada; Ho, Vincent; Yanik, Greg; Chance, Mark R.; Cooke, Kenneth R.

    2012-01-01

    Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative therapy for many malignant and nonmalignant conditions. Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication that limits successful outcomes. Preclinical models suggest that IPS represents an immune mediated attack on the lung involving elements of both the adaptive and the innate immune system. However, the etiology of IPS in humans is less well understood. To explore the disease pathway and uncover potential biomarkers of disease, we performed two separate label-free, proteomics experiments defining the plasma protein profiles of allogeneic SCT patients with IPS. Samples obtained from SCT recipients without complications served as controls. The initial discovery study, intended to explore the disease pathway in humans, identified a set of 81 IPS-associated proteins. These data revealed similarities between the known IPS pathways in mice and the condition in humans, in particular in the acute phase response. In addition, pattern recognition pathways were judged to be significant as a function of development of IPS, and from this pathway we chose the lipopolysaccaharide-binding protein (LBP) protein as a candidate molecular diagnostic for IPS, and verified its increase as a function of disease using an ELISA assay. In a separately designed study, we identified protein-based classifiers that could predict, at day 0 of SCT, patients who: 1) progress to IPS and 2) respond to cytokine neutralization therapy. Using cross-validation strategies, we built highly predictive classifier models of both disease progression and therapeutic response. In sum, data generated in this report confirm previous clinical and experimental findings, provide new insights into the pathophysiology of IPS, identify potential molecular classifiers of the condition, and uncover a set of markers potentially of interest for patient stratification as a basis for individualized therapy. PMID:22337588

  20. Trends in kidney transplantation rates and disparities.

    PubMed Central

    Stolzmann, Kelly L.; Bautista, Leonelo E.; Gangnon, Ronald E.; McElroy, Jane A.; Becker, Bryan N.; Remington, Patrick L.

    2007-01-01

    OBJECTIVE: To examine the likelihood of transplantation and trends over time among persons with end-stage renal disease (ESRD) in Wisconsin. METHODS: We examined the influence of patient- and community-level characteristics on the rate of kidney transplantation in Wisconsin among 22,387 patients diagnosed with ESRD between January 1, 1982 and October 30, 2005. We grouped patients by the year of ESRD onset in order to model the change in transplantation rates over time. RESULTS: After multivariate adjustment, all other racial groups were significantly less likely to be transplanted compared with whites, and the racial disparity increased over calendar time. Older patients were less likely to be transplanted in all periods. Higher community income and education level and a greater distance from patients' residence to the nearest dialysis center significantly increased the likelihood of transplantation. Males also had a significantly higher rate of transplantation than females. CONCLUSION: These results demonstrate a growing disparity in transplantation rates by demographic characteristics and a consistent disparity in transplantation by socioeconomic characteristics. Future studies should focus on identifying specific barriers to transplantation among different subpopulations in order to target effective interventions. PMID:17722672

  1. Transplanted fibroblast cell sheets promote migration of hepatic progenitor cells in the incised host liver in allogeneic rat model.

    PubMed

    Muraoka, Izumi; Takatsuki, Mitsuhisa; Sakai, Yusuke; Tomonaga, Tetsuo; Soyama, Akihiko; Hidaka, Masaaki; Hishikawa, Yoshitaka; Koji, Takehiko; Utoh, Rie; Ohashi, Kazuo; Okano, Teruo; Kanematsu, Takashi; Eguchi, Susumu

    2015-11-01

    Cell sheet engineering has been noted as a new and valuable approach in the tissue-engineering field. The objective of this study was to explore a procedure to induce hepatic progenitor cells and biliary duct structures in the liver. Sprague-Dawley rat dermal fibroblast (DF) sheets were transplanted into the incised surface of the liver of F344 nude rats. In the control group, an incision was made without transplantation of the DF sheets. Bile duct (BD)-like structures and immature hepatocyte-like cells were observed in the DF sheet transplant sites. These BD-like structures were cytokeratin-8-positive, while the hepatocyte-like cells were both OV-6-positive and α-fetoprotein-positive as well. The proliferation and differentiation of liver progenitor cells were not influenced by hepatectomy. We also transplanted DF sheets transfected with a plasmid encoding the enhanced yellow fluorescent protein target to mitochondria (pEYFP-Mito) by electroporation, and found that the new structures were pEYFP-Mito-negative. We observed new BD-like structures and immature hepatocytes after transplantation of DF sheets onto incised liver surfaces, and clarified that the origin of these BD-like structures and hepatocyte-like cells was the recipient liver. The present study described an aspect of the hepatic differentiation process induced at the site of liver injury.

  2. Transplantation of Human Neural Stem Cells in a Parkinsonian Model Exerts Neuroprotection via Regulation of the Host Microenvironment.

    PubMed

    Zuo, Fu-Xing; Bao, Xin-Jie; Sun, Xi-Cai; Wu, Jun; Bai, Qing-Ran; Chen, Guo; Li, Xue-Yuan; Zhou, Qiang-Yi; Yang, Yuan-Fan; Shen, Qin; Wang, Ren-Zhi

    2015-11-05

    Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons and consequent dopamine (DA) deficit, and current treatment still remains a challenge. Although neural stem cells (NSCs) have been evaluated as appealing graft sources, mechanisms underlying the beneficial phenomena are not well understood. Here, we investigate whether human NSCs (hNSCs) transplantation could provide neuroprotection against DA depletion by recruiting endogenous cells to establish a favorable niche. Adult mice subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were transplanted with hNSCs or vehicle into the striatum. Behavioral and histological analyses demonstrated significant neurorescue response observed in hNSCs-treated animals compared with the control mice. In transplanted animals, grafted cells survived, proliferated, and migrated within the astrocytic scaffold. Notably, more local astrocytes underwent de-differentiation, acquiring the properties of NSCs or neural precursor cells (NPCs) in mice given hNSCs. Additionally, we also detected significantly higher expression of host-derived growth factors in hNSCs-transplanted mice compared with the control animals, together with inhibition of local microglia and proinflammatory cytokines. Overall, our results indicate that hNSCs transplantation exerts neuroprotection in MPTP-insulted mice via regulating the host niche. Harnessing synergistic interaction between the grafts and host cells may help optimize cell-based therapies for PD.

  3. The Effects of Exendin-4 Treatment on Graft Failure: An Animal Study Using a Novel Re-Vascularized Minimal Human Islet Transplant Model

    PubMed Central

    Sahraoui, Afaf; Winzell, Maria Sörhede; Gorman, Tracy; Smith, Dave M.; Skrtic, Stanko; Hoeyem, Merete; Abadpour, Shadab; Johansson, Lars; Korsgren, Olle; Foss, Aksel; Scholz, Hanne

    2015-01-01

    Islet transplantation has become a viable clinical treatment, but is still compromised by long-term graft failure. Exendin-4, a glucagon-like peptide 1 receptor agonist, has in clinical studies been shown to improve insulin secretion in islet transplanted patients. However, little is known about the effect of exendin-4 on other metabolic parameters. We therefore aimed to determine what influence exendin-4 would have on revascularized minimal human islet grafts in a state of graft failure in terms of glucose metabolism, body weight, lipid levels and graft survival. Introducing the bilateral, subcapsular islet transplantation model, we first transplanted diabetic mice with a murine graft under the left kidney capsule sufficient to restore normoglycemia. After a convalescent period, we performed a second transplantation under the right kidney capsule with a minimal human islet graft and allowed for a second recovery. We then performed a left-sided nephrectomy, and immediately started treatment with exendin-4 with a low (20μg/kg/day) or high (200μg/kg/day) dose, or saline subcutaneously twice daily for 15 days. Blood was sampled, blood glucose and body weight monitored. The transplanted human islet grafts were collected at study end point and analyzed. We found that exendin-4 exerts its effect on failing human islet grafts in a bell-shaped dose-response curve. Both doses of exendin-4 equally and significantly reduced blood glucose. Glucagon-like peptide 1 (GLP-1), C-peptide and pro-insulin were conversely increased. In the course of the treatment, body weight and cholesterol levels were not affected. However, immunohistochemistry revealed an increase in beta cell nuclei count and reduced TUNEL staining only in the group treated with a low dose of exendin-4 compared to the high dose and control. Collectively, these results suggest that exendin-4 has a potential rescue effect on failing, revascularized human islets in terms of lowering blood glucose, maintaining beta

  4. Opposite effects of bone marrow-derived cells transplantation in MPTP-rat model of Parkinson's disease: a comparison study of mononuclear and mesenchymal stem cells.

    PubMed

    Capitelli, Caroline Santos; Lopes, Carolina Salomão; Alves, Angélica Cristina; Barbiero, Janaína; Oliveira, Lucas Felipe; da Silva, Valdo José Dias; Vital, Maria Aparecida Barbato Frazão

    2014-01-01

    The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model is a useful tool to study Parkinson's disease (PD) and was used in the present study to investigate the potential beneficial as well as deleterious effects of systemic bone-marrow mononuclear cell (BMMC) or mesenchymal stem cell (BM-MSC) transplantation. MPTP administration resulted in a breakdown of the blood-brain barrier and motor impairment in the open field test 24 h after surgery. Three and 7 days after receiving the lesion, the injured animals showed remaining motor impairment compared to the sham groups along with a significant loss of tyrosine hydroxylase-immunoreactive (TH-ir) cells in the substantia nigra pars compacta (SNpc). The MPTP-lesioned rats treated with BMMCs immediately after lesioning exhibited motor impairment similar to the MPTP-saline group, though they presented a significantly higher loss of TH-ir cells in the SNpc compared to the MPTP-saline group. This increased loss of TH-ir cells in the SNpc was not observed when BMMC transplantation was performed 24 h after MPTP administration. In contrast, in the MPTP animals treated early with systemic BM-MSCs, no loss of TH-ir cells was observed. BMMCs and BM-MSCs previously labeled with CM-DiI cell tracker were found in brain sections of all transplanted animals. In addition, cells expressing CD45, an inflammatory white blood cell marker, were found in all brain sections analyzed and were more abundant in the MPTP-BMMC animals. In these animals, Iba1+ microglial cells showed also marked morphological changes indicating increased microglial activation. These results show that systemic BMMC transplantation did not ameliorate or prevent the lesion induced by MPTP. Instead, BMMC transplantation in MPTP-lesioned rats accelerated dopaminergic neuronal damage and induced motor impairment and immobility behavior. These findings suggest that caution should be taken when considering cell therapy using BMMCs to treat PD. However, systemic

  5. Heart transplantation.

    PubMed

    Nakatani, Takeshi

    2009-06-01

    A total of 59 heart transplantations (HTx) have been performed in Japan as of September, 2008, since the Organ Transplantation Law was settled in October 1997. The majority of recipients were suffered from dilated cardiomyopathy and waiting condition of all recipients were status 1. The mean waiting time was 777 day; 50 patients (85%) were supported by several types of left ventricular assist systems (LVAS) and the mean duration of support was 780 days. The majority of patients underwent operation by modified bicaval method with Celsior solution for cardiac preservation, and 64% of recipients were administered triple therapy with cyclosporine, mycophenolate mofetil, and steroid as the initial immunosuppressive regimen. The 9-year survival rate was 94%, which was superior to that of the international registry. HTx in Japan has been very limited by a severe shortage of donors, but the results have been excellent even though the majority of recipients were waiting for long-term with a LVAS as a bridge to HTx.

  6. [Establishment of a keloid model by transplanting human keloid onto the backs of nude mice].

    PubMed

    Philandrianos, C; Gonnelli, D; Andrac-Meyer, L; Bruno, M; Magalon, G; Mordon, S

    2014-08-01

    Keloid scar is a proliferative healing dysfunction formed by an excessive build-up of collagen fibers on the dermis. It is responsible of aesthetic and functional disabilities. There is no ideal treatment and recurrence occurs very often. Keloid scars occur only to human, that's why animal model needs to be made to study this pathology and new treatments. Few models have been described using human keloid scars implanted into subcutaneous tissue of nude mice or rat. To allow study of topical and laser treatment we have developed a new animal model using human keloid scar fragment with epidermal and dermal tissue implanted into back of nude mice like a full thickness skin graft. Keloid fragments from five donors have been grafted onto 40 nudes mice. Macroscopic and microscopic studies have been made at day 28, 56, 84 and 112. We observed integration of the fragments in all cases. Hyalinized collagen bundles were observed in all implant biopsies confirming the stability of the keloid architecture within 112 days. This model is easily reproducible and allows the study of topical treatment and laser due to the accessibility of the keloid.

  7. Hair transplantation in mice: Challenges and solutions.

    PubMed

    Asgari, Azar Z; Rufaut, Nicholas W; Morrison, Wayne A; Dilley, Rodney J; Knudsen, Russle; Jones, Leslie N; Sinclair, Rodney D

    2016-07-01

    Hair follicle cells contribute to wound healing, skin circulation, and skin diseases including skin cancer, and hair transplantation is a useful technique to study the participation of hair follicle cells in skin homeostasis and wound healing. Although hair follicle transplantation is a well-established human hair-restoration procedure, follicular transplantation techniques in animals have a number of shortcomings and have not been well described or optimized. To facilitate the study of follicular stem and progenitor cells and their interaction with surrounding skin, we have established a new murine transplantation model, similar to follicular unit transplantation in humans. Vibrissae from GFP transgenic mice were harvested, flip-side microdissected, and implanted individually into needle hole incisions in the back skin of immune-deficient nude mice. Grafts were evaluated histologically and the growth of transplanted vibrissae was observed. Transplanted follicles cycled spontaneously and newly formed hair shafts emerged from the skin after 2 weeks. Ninety percent of grafted vibrissae produced a hair shaft at 6 weeks. After pluck-induced follicle cycling, growth rates were equivalent to ungrafted vibrissae. Transplanted vibrissae with GFP-positive cells were easily identified in histological sections. We established a follicular vibrissa transplantation method that recapitulates human follicular unit transplantation. This method has several advantages over current protocols for animal hair transplantation. The method requires no suturing and minimizes the damage to donor follicles and recipient skin. Vibrissae are easier to microdissect and transplant than pelage follicles and, once transplanted, are readily distinguished from host pelage hair. This facilitates measurement of hair growth. Flip-side hair follicle microdissection precisely separates donor follicular tissue from interfollicular tissue and donor cells remain confined to hair follicles. This makes it

  8. Anti-inflammatory Effect of Mesenchymal Stromal Cell Transplantation and Quercetin Treatment in a Rat Model of Experimental Cerebral Ischemia.

    PubMed

    Zhang, Lan-Lan; Zhang, Hong-Tian; Cai, Ying-Qian; Han, Yan-Jiang; Yao, Fang; Yuan, Zhao-Hu; Wu, Bing-Yi

    2016-10-01

    Here, we have investigated the synergistic effect of quercetin administration and transplantation of human umbilical cord mesenchymal stromal cells (HUMSCs) following middle cerebral artery occlusion in rat. Combining quercetin treatment with delayed transplantation of HUMSCs after local cerebral ischemia significantly (i) improved neurological functional recovery; (ii) reduced proinflammatory cytokines (interleukin(IL)-1β and IL-6), increased anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor-β1), and reduced ED-1 positive areas; (iii) inhibited cell apoptosis (caspase-3 expression); and (iv) improved the survival rate of HUMSCs in the injury site. Altogether, our results demonstrate that combined HUMSC transplantation and quercetin treatment is a potential strategy for reducing secondary damage and promoting functional recovery following cerebral ischemia.

  9. Utility-based criteria for selecting patients with hepatocellular carcinoma for liver transplantation: A multicenter cohort study using the alpha-fetoprotein model as a survival predictor.

    PubMed

    Vitale, Alessandro; Farinati, Fabio; Burra, Patrizia; Trevisani, Franco; Giannini, Edoardo G; Ciccarese, Francesca; Piscaglia, Fabio; Rapaccini, Gian Lodovico; Di Marco, Mariella; Caturelli, Eugenio; Zoli, Marco; Borzio, Franco; Cabibbo, Giuseppe; Felder, Martina; Sacco, Rodolfo; Morisco, Filomena; Missale, Gabriele; Foschi, Francesco Giuseppe; Gasbarrini, Antonio; Svegliati Baroni, Gianluca; Virdone, Roberto; Chiaramonte, Maria; Spolverato, Gaya; Cillo, Umberto

    2015-10-01

    The lifetime utility of liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) is still controversial. The aim of this study was to ascertain when LT is cost-effective for HCC patients, with a view to proposing new transplant selection criteria. The study involved a real cohort of potentially transplantable Italian HCC patients (n = 2419 selected from the Italian Liver Cancer group database) who received nontransplant therapies. A non-LT survival analysis was conducted, the direct costs of therapies were calculated, and a Markov model was used to compute the cost utility of LT over non-LT therapies in Italian and US cost scenarios. Post-LT survival was calculated using the alpha-fetoprotein (AFP) model on the basis of AFP values and radiological size and number of nodules. The primary endpoint was the net health benefit (NHB), defined as LT survival benefit in quality-adjusted life years minus incremental costs (US $)/willingness to pay. The calculated median cost of non-LT therapies per patient was US $53,042 in Italy and US $62,827 in the United States. On Monte Carlo simulation, the NHB of LT was always positive for AFP model values ≤ 3 and always negative for values > 7 in both countries. A multivariate model showed that nontumor variables (patient's age, Child-Turcotte-Pugh [CTP] class, and alternative therapies) had the potential to shift the AFP model threshold of LT cost-ineffectiveness from 3 to 7. LT proved always cost-effective for HCC patients with AFP model values ≤ 3, whereas the cost-ineffectiveness threshold ranged between 3 and 7 using nontumor variables. PMID:26183802

  10. Utility-based criteria for selecting patients with hepatocellular carcinoma for liver transplantation: A multicenter cohort study using the alpha-fetoprotein model as a survival predictor.

    PubMed

    Vitale, Alessandro; Farinati, Fabio; Burra, Patrizia; Trevisani, Franco; Giannini, Edoardo G; Ciccarese, Francesca; Piscaglia, Fabio; Rapaccini, Gian Lodovico; Di Marco, Mariella; Caturelli, Eugenio; Zoli, Marco; Borzio, Franco; Cabibbo, Giuseppe; Felder, Martina; Sacco, Rodolfo; Morisco, Filomena; Missale, Gabriele; Foschi, Francesco Giuseppe; Gasbarrini, Antonio; Svegliati Baroni, Gianluca; Virdone, Roberto; Chiaramonte, Maria; Spolverato, Gaya; Cillo, Umberto

    2015-10-01

    The lifetime utility of liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) is still controversial. The aim of this study was to ascertain when LT is cost-effective for HCC patients, with a view to proposing new transplant selection criteria. The study involved a real cohort of potentially transplantable Italian HCC patients (n = 2419 selected from the Italian Liver Cancer group database) who received nontransplant therapies. A non-LT survival analysis was conducted, the direct costs of therapies were calculated, and a Markov model was used to compute the cost utility of LT over non-LT therapies in Italian and US cost scenarios. Post-LT survival was calculated using the alpha-fetoprotein (AFP) model on the basis of AFP values and radiological size and number of nodules. The primary endpoint was the net health benefit (NHB), defined as LT survival benefit in quality-adjusted life years minus incremental costs (US $)/willingness to pay. The calculated median cost of non-LT therapies per patient was US $53,042 in Italy and US $62,827 in the United States. On Monte Carlo simulation, the NHB of LT was always positive for AFP model values ≤ 3 and always negative for values > 7 in both countries. A multivariate model showed that nontumor variables (patient's age, Child-Turcotte-Pugh [CTP] class, and alternative therapies) had the potential to shift the AFP model threshold of LT cost-ineffectiveness from 3 to 7. LT proved always cost-effective for HCC patients with AFP model values ≤ 3, whereas the cost-ineffectiveness threshold ranged between 3 and 7 using nontumor variables.

  11. Exocrine drainage in vascularized pancreas transplantation in the new millennium

    PubMed Central

    El-Hennawy, Hany; Stratta, Robert J; Smith, Fowler

    2016-01-01

    The history of vascularized pancreas transplantation largely parallels developments in immunosuppression and technical refinements in transplant surgery. From the late-1980s to 1995, most pancreas transplants were whole organ pancreatic grafts with insulin delivery to the iliac vein and diversion of the pancreatic ductal secretions to the urinary bladder (systemic-bladder technique). The advent of bladder drainage revolutionized the safety and improved the success of pancreas transplantation. However, starting in 1995, a seismic change occurred from bladder to bowel exocrine drainage coincident with improvements in immunosuppression, preservation techniques, diagnostic monitoring, general medical care, and the success and frequency of enteric conversion. In the new millennium, pancreas transplants are performed predominantly as pancreatico-duodenal grafts with enteric diversion of the pancreatic ductal secretions coupled with iliac vein provision of insulin (systemic-enteric technique) although the systemic-bladder technique endures as a preferred alternative in selected cases. In the early 1990s, a novel technique of venous drainage into the superior mesenteric vein combined with bowel exocrine diversion (portal-enteric technique) was designed and subsequently refined over the next ≥ 20 years to re-create the natural physiology of the pancreas with first-pass hepatic processing of insulin. Enteric drainage usually refers to jejunal or ileal diversion of the exocrine secretions either with a primary enteric anastomosis or with an additional Roux limb. The portal-enteric technique has spawned a number of newer and revisited techniques of enteric exocrine drainage including duodenal or gastric diversion. Reports in the literature suggest no differences in pancreas transplant outcomes irrespective of type of either venous or exocrine diversion. The purpose of this review is to examine the literature on exocrine drainage in the new millennium (the purported

  12. [INFLUENCE OF AUTOLOGOUS CHONDROCYTES TRANSPLANTATION ON THE INTERVERTEBRAL DISC STATE IN EXPERIMENTAL MODEL OF OSTEOCHONDROSIS].

    PubMed

    Khyzhnyak, M V

    2015-07-01

    The degenerative changes in the nucleus pulposus and fibrous ring of the intervertebral discs are the basis of spinal osteochondrosis. A large number of models, including biological, where some mechanisms of their development were worked out and studied, was used to study the morphogenesis and pathogenesis of degenerative spinal changes. The deserved place in the comparative experiments and especially the different methods of therapeutic effects on the tissues of the intervertebral discs in degenerative spinal changes is taken by the experimental methods. The biochemical changes of the intervertebral disc structures were analyzed under the administration of cultured autologous cell of nucleus pulposus suspension against a background of experimental model of rat osteochondrosis. PMID:26591226

  13. New construction of an animal model for the orthotopic transplantation of an ovarian tumor

    PubMed Central

    2014-01-01

    A new technique has successfully established the non-obese diabetic/severely combined immunodeficiency (NOD/SCID) mouse model of ovarian cancer. Under 4% chloral hydrate (0.1 mL/g dose) anesthesia, female mice were inoculated with tumor-cell suspension. The expression rate of OVCAR3 to CA125 was assessed using flow cytometry. The inoculated site was hand palpated and the signs and symptoms related to tumor growth were observed with the naked eye. The allophycocyanin (APC) indirectly labeled mouse-antihuman CA125 and fluorescein isothiocyanate (FITC)-labeled anti-mouse MHC Class I molecule (H-2Kd/H-2Dd) were observed using a confocal laser scanning microscope. The animal model of ovarian cancer constructed using this method can more directly reflect the characteristics of cancer cells. It provides reliable experimental results and presents a technical platform for the research of ovarian cancer stem cells. PMID:24955132

  14. Chimerism and tolerance in transplantation.

    PubMed

    Starzl, Thomas E

    2004-10-01

    Studies in experimental models (1953-1956) demonstrated that acquired donor-specific allotolerance in immunologically immature or irradiated animals is strongly associated with donor leukocyte chimerism. Bone marrow transplantation in immune-deficient or cytoablated human recipients was a logical extension (1968). In contrast, clinical (1959) and then experimental organ transplantation was systematically accomplished in the apparent absence of leukocyte chimerism. Consequently, it was assumed for many years that success with organ and bone marrow transplantation involved fundamentally different mechanisms. With the discovery in 1992 of small numbers of donor leukocytes in the tissues or blood of long-surviving organ recipients (microchimerism), we concluded that organ engraftment was a form of leukocyte chimerism-dependent partial tolerance. In this initially controversial paradigm, alloengraftment after both kinds of transplantation is the product of a double immune reaction in which responses, each to the other, of coexisting donor and recipient immune systems results in variable reciprocal clonal exhaustion, followed by peripheral clonal deletion. It was proposed with Rolf Zinkernagel that the individual alloresponses are the equivalent of the MHC-restricted T cell recognition of, and host response to, intracellular parasites and that the mechanisms of immune responsiveness, or nonresponsiveness, are governed by the migration and localization of the respective antigens. Elucidation of the mechanisms of nonresponsiveness (clonal exhaustion-deletion and immune ignorance) and their regulation removed much of the historical mystique of transplantation. The insight was then applied to improve the timing and dosage of immunosuppression of current human transplant recipients.

  15. Insulin sensitivity index in type 1 diabetes and following human islet transplantation: comparison of the minimal model to euglycemic clamp measures.

    PubMed

    Rickels, Michael R; Kong, Stephanie M; Fuller, Carissa; Dalton-Bakes, Cornelia; Ferguson, Jane F; Reilly, Muredach P; Teff, Karen L; Naji, Ali

    2014-05-15

    Insulin sensitivity is impaired in type 1 diabetes (T1D) and may be enhanced by islet transplantation, an effect best explained by improved metabolic control. While the minimal model index of insulin sensitivity, SI, has been used in studies of T1D, it has not before been evaluated against gold-standard measures derived from the euglycemic clamp. We sought to determine how well minimal model SI derived from an insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test compared with total body and peripheral insulin sensitivity estimates derived from the hyperinsulinemic-euglycemic clamp in subjects with T1D and following islet transplantation. Twenty-one T1D subjects were evaluated, including a subgroup (n = 12) studied again after intrahepatic islet transplantation, with results compared with normal controls (n = 11 for the FSIGT). The transplant recipients received 9,648 ± 666 islet equivalents/kg with reduction in HbA1c from 7.1 ± 0.2 to 5.5 ± 0.1% (P < 0.01) and 10/12 were insulin independent. FSIGT-derived SI was reduced in T1D pre- compared with posttransplant and with normal [1.76 ± 0.45 vs. 4.21 ± 0.34 vs. 4.45 ± 0.81 × 10(-4)(μU/ml)(-1)·min(-1); P < 0.01 for both]. Similarly, clamp-derived total body, and by the isotopic dilution method with [6,6-(2)H2]glucose, peripheral insulin sensitivity increased in T1D from pre- to posttransplant (P < 0.05 for both). The predictive power (r(2)) between volume-corrected SIC and measures of total and peripheral insulin sensitivity was 0.66 and 0.70, respectively (P < 0.00001 for both). That the minimal model SIC is highly correlated to the clamp-derived measures indicates that the FSIGT is an appropriate methodology for the determination of insulin sensitivity in T1D and following islet transplantation.

  16. Fast-track surgery and exclusive enteral nutrition applied to a rat model of heterotopic intestinal transplantation

    PubMed Central

    XU, XINGWEI; FENG, TAO; GAO, XIN; ZHAO, XIN; LIAO, YANNIAN; JI, WU

    2016-01-01

    The present study applied fast-track surgery (FTS) concepts and exclusive enteral nutrition (EEN) to a rat model of heterotopic intestinal transplantation (HIT). A total of 96 pairs of Sprague-Dawley rats were randomly distributed into three groups, as follows: i) The conventional group (group 1); ii) the FTS group (group 2); and iii) the FTS with EEN group (EEN group). FTS alterations to the HIT protocol were as follows: i) The use of sevoflurane as an anesthetic; ii) alterations to the order of the procedure and iii) a modified suturing technique. In addition, the EEN group rats underwent an early EEN gavage. The operation time, success rate, recovery state and morphological characteristics of the grafts were compared among the groups. The average operative time was significantly decreased in the group 2 and EEN group rats (137.44±16.03 and 139.67±15.25 min, respectively), as compared with the group 1 rats (169.36±13.72 min; P<0.05). In addition, the percentage of rats surviving >14 days was significantly increased in the group 2 (87.5%) and EEN group (90.6%) rats, as compared with the group 1 rats (68.7%; P<0.05). Furthermore, the villi of graft in EEN group appeared longer, and exhibited narrower interspaces. The ischemia-reperfusion injury and mononuclear cell infiltration were attenuated at postoperative day 7. The results of the present study suggested that the application of FTS concepts and EEN gavage to HIT may accelerate recovery and ameliorate graft damage following surgery. PMID:26998015

  17. Intramuscular Transplantation of Pig Amniotic Fluid-Derived Progenitor Cells Has Therapeutic Potential in a Mouse Model of Myocardial Infarction.

    PubMed

    Peng, Shao-Yu; Chou, Chih-Jen; Cheng, Po-Jen; Tseng, Tse-Yang; Cheng, Winston Teng-Kui; Shaw, S W Steven; Wu, Shinn-Chih

    2015-01-01

    Acute myocardial infarction (MI) is a fatal event that causes a large number of deaths worldwide. MI results in pathological remodeling and decreased cardiac function, which could lead to heart failure and fatal arrhythmia. Cell therapy is a potential strategy to repair the damage through enhanced angiogenesis or by modulation of the inflammatory process via paracrine signaling. Amniotic fluid-derived progenitor cells (AFPCs) have been reported to differentiate into several lineages and can be used without ethical concerns or risk of teratoma formation. Since pigs are anatomically, physiologically, and genetically similar to humans, and pregnant pigs can be an abundant source of AFPCs, we used porcine AFPCs (pAFPCs) as our target cells. Intramyocardial injection of AFPCs has been shown to cure MI in animal models. However, intramuscular transplantation of cells has not been extensively investigated. In this study, we investigated the therapeutic potential of intramuscular injection of pAFPCs on acute MI. MI mice were divided into 1) PBS control, 2) medium cell dose (1 × 10(6) cells per leg; cell-M), and 3) high cell dose (4 × 10(6) cells per leg; cell-H) groups. Cells or PBS were directly injected into the hamstring muscle 20 min after MI surgery. Four weeks after MI surgery, the cell-M and cell-H groups exhibited significantly better ejection fraction, significantly greater wall thickness, smaller infarct scar sizes, and lower LV expansion index compared to the PBS group. Using in vivo imaging, we showed that the hamstring muscles from animals in the cell-M and cell-H groups had RFP-positive signals. In summary, intramuscular injection of porcine AFPCs reduced scar size, reduced pathological remodeling, and preserved heart function after MI. PMID:24667157

  18. Does the model for end-stage liver disease score predict transfusion amount, acid-base imbalance, haemodynamic and oxidative abnormalities during living donor liver transplantation?

    PubMed

    Lee, J; Chung, M Y

    2011-01-01

    The model for end-stage liver disease (MELD) score is associated with the severity of liver failure in transplant patients. This study examined whether life-threatening stress factors during liver transplantation differed according to the patients' preoperative MELD scores. Forty-four patients who underwent living donor liver transplantation were divided into a high MELD group (MELD score ≥ 20) (n = 25) and a low MELD group (MELD score < 20) (n = 19). The volume of blood components transfused, acid-base homeostasis variables, and haemodynamic and oxidative variables were measured at each stage of the surgery. The systemic vascular resistance index was significantly lower in the high MELD group than in the low MELD group at all time points. The oxygen utility index and the oxygen extraction ratio were all significantly lower in the high MELD group than in the low MELD group only at the preanhepatic stage and not at later stages of surgery. Intraoperative transfusion volume and the severity of metabolic acidosis were not associated with the preoperative MELD score.

  19. Inhibition of IL-32 activation by α-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model

    PubMed Central

    Li, Xiang; Tabellini, Laura; Bartenstein, Matthias; Kabacka, Julia; Sale, George E.; Hansen, John A.; Dinarello, Charles A.; Deeg, H. Joachim

    2011-01-01

    Interleukin (IL)–32 was originally identified in natural killer cells and IL-2–activated human T lymphocytes. As T cells are activated in allogeneic transplantation, we determined the role of IL-32 in human mixed lymphocyte cultures (MLCs) and GVHD. In allogeneic MLCs, IL-32 increased two-fold in responding T cells, accompanied by five-fold increases of TNFα, IL-6, and IL-8. After allogeneic hematopoietic cell transplantation, IL-32 mRNA levels in blood leukocytes were statistically significantly higher in patients with acute GVHD (n = 10) than in serial samples from patients who did not develop acute GVHD (n = 5; P = .02). No significant changes in IL-32 levels were present in patients with treated (n = 14) or untreated (n = 8) chronic GVHD, compared with healthy controls (n = 8; P = .5, and P = .74, respectively). As IL-32 is activated by proteinase-3 (PR3), we determined the effect of the serine protease inhibitor α-1 antitrypsin (AAT) on IL-32 levels and showed suppression of IL-32 and T-lymphocyte proliferation in MLCs. In an MHC-minor antigen disparate murine transplant model, preconditioning and postconditioning treatment with AAT resulted in attenuation or prevention of GVHD and superior survival compared with albumin-treated controls (80% vs 44%; P = .04). These findings suggest that AAT modulates immune and inflammatory functions and may represent a novel approach to prevent or treat GVHD. PMID:21900190

  20. Neural stem cell transplants improve cognitive function without altering amyloid pathology in an APP/PS1 double transgenic model of Alzheimer's disease.

    PubMed

    Zhang, Wei; Wang, Pei-Jun; Sha, Hong-ying; Ni, Jiong; Li, Ming-hua; Gu, Guo-jun

    2014-10-01

    Neural stem cells (NSCs) are capable of self-renewal and are multipotent. Transplantation of NSCs may represent a promising approach for treating neurodegenerative disorders associated with cognitive decline, such as Alzheimer disease (AD) characterized by extensive loss of neurons. In this study, we investigated the effect of NSC transplantation on cognitive function in the amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mouse, an AD mouse model with age-dependent cognitive deficits. We found that NSCs bilaterally transplanted into hippocampal regions improved spatial learning and memory function in these mice, but did not alter Aβ pathology. Immunohistochemical analyses determined that NSCs proliferated, migrated, and differentiated into three neuronal cell types. The improvement in cognitive function was correlated with enhanced long-term potentiation (LTP) and an increase in the neuron expression of proteins related to cognitive function: N-methyl-D-aspartate (NMDA) 2B unit, synaptophysin (SYP), protein kinase C ζ subtypes (PKCζ), tyrosine receptor kinase B (TrkB), and brain-derived neurotrophic factor (BDNF). Taken together, our data indicated that injected NSCs can rescue cognitive deficits in APP/PS1 transgenic mice by replacing neuronal cell types expressing multiple cognition-related proteins that enhance LTP.

  1. Plasmacytoma-like Posttransplant Lymphoproliferative Disorder in a Pediatric Heart Transplant Recipient.

    PubMed

    Proctor Short, Sara Rhodes; Cook, Steven L; Kim, Andrew S; Lamour, Jacqueline M; Lowe, Eric J; Petersen, William C

    2016-03-01

    Posttransplant lymphoproliferative disorder (PTLD) is a diversely manifesting group of lymphoid or plasmacytic proliferations found in solid organ and bone marrow transplant recipients. PTLD occurs as a result of immunosuppression and is often driven by the Epstein Barr virus. Although most commonly of B-cell origin, similar to B-cell lymphomas, PTLD can rarely present as a plasmacytic process, resembling multiple myeloma. Although more common in adults, 8 cases of plasmacytoma-like PTLD have been reported in pediatric renal and combined small bowel-liver transplant recipients. Here, we present a rare report of a plasmacytoma-like PTLD case in a pediatric heart transplant recipient.

  2. Transplantation of neural stem cells expressing hypoxia-inducible factor-1alpha (HIF-1alpha) improves behavioral recovery in a rat stroke model.

    PubMed

    Wu, Wanfu; Chen, Xiu; Hu, Changlin; Li, Jinfang; Yu, Zhen; Cai, Wenqin

    2010-01-01

    We explored the possibility that hypoxia-inducible factor-1alpha (HIF-1alpha) might contribute to the therapeutic effect of neural stem cell (NSC) transplantation in cerebral ischemia. The relative efficacy of modified NSC to promote behavioral recovery was investigated in a rat model of stroke induced by a transient middle cerebral artery occlusion (MCAO). A recombinant adenovirus (Ad-HIF-1alpha) was engineered to express HIF-1alpha. Control NSC infected with control adenovirus (NSC-Ad), recombinant adenovirus Ad-HIF-1alpha, or NSC infected by Ad-HIF-1alpha (NSC-Ad-HIF-1alpha), were used for intraventricular transplantion into rat brain 24 hours after MCAO. Neurological deficits were assessed over 4 weeks using the modified neurological severity scale (NSS) score. Long-term in vivo expression of HIF-1alpha was demonstrated by Western blotting and immunocytochemistry, and derivatives of nestin-positive transplanted cells contributed to both neuronal (neurofilament-positive) and astroglial (glial fibrillary acidic protein-positive) lineages. All animals showed functional improvement. Improvement was accelerated in animals receiving either NSC-Ad or Ad-HIF-1alpha, while improvement at all times between 7 days and 28 days post MCAO was significantly greater in animals transplanted with NSC-Ad-HIF-1alpha than for other treated animals. NSC-Ad-HIF-1alpha cells also increased the number of factor VIII-positive cells in the region of ischemic injury, indicating that HIF-1alpha expression can promote angiogenesis. Gene-modified NSC expressing HIF-1alpha have therapeutic potential in ischemic stroke.

  3. Recipient's unemployment restricts access to renal transplantation.

    PubMed

    Sandhu, Gurprataap S; Khattak, Muhammad; Pavlakis, Martha; Woodward, Robert; Hanto, Douglas W; Wasilewski, Marcy A; Dimitri, Noelle; Goldfarb-Rumyantzev, Alexander

    2013-01-01

    Equitable distribution of a scarce resource such as kidneys for transplantation can be a challenging task for transplant centers. In this study, we evaluated the association between recipient's employment status and access to renal transplantation in patients with end-stage renal disease (ESRD). We used data from the United States Renal Data System (USRDS). The primary variable of interest was employment status at ESRD onset. Two outcomes were analyzed in Cox model: (i) being placed on the waiting list for renal transplantation or being transplanted (whichever occurred first); and (ii) first transplant in patients who were placed on the waiting list. We analyzed 429 409 patients (age of ESRD onset 64.2 ± 15.2 yr, 55.0% males, 65.1% White). Compared with patients who were unemployed, patients working full time were more likely to be placed on the waiting list/transplanted (HR 2.24, p < 0.001) and to receive a transplant once on the waiting list (HR 1.65, p < 0.001). Results indicate that recipient's employment status is strongly associated with access to renal transplantation, with unemployed and partially employed patients at a disadvantage. Adding insurance status to the model reduces the effect size, but the association still remains significant, indicating additional contribution from other factors.

  4. Recipient's unemployment restricts access to renal transplantation.

    PubMed

    Sandhu, Gurprataap S; Khattak, Muhammad; Pavlakis, Martha; Woodward, Robert; Hanto, Douglas W; Wasilewski, Marcy A; Dimitri, Noelle; Goldfarb-Rumyantzev, Alexander

    2013-01-01

    Equitable distribution of a scarce resource such as kidneys for transplantation can be a challenging task for transplant centers. In this study, we evaluated the association between recipient's employment status and access to renal transplantation in patients with end-stage renal disease (ESRD). We used data from the United States Renal Data System (USRDS). The primary variable of interest was employment status at ESRD onset. Two outcomes were analyzed in Cox model: (i) being placed on the waiting list for renal transplantation or being transplanted (whichever occurred first); and (ii) first transplant in patients who were placed on the waiting list. We analyzed 429 409 patients (age of ESRD onset 64.2 ± 15.2 yr, 55.0% males, 65.1% White). Compared with patients who were unemployed, patients working full time were more likely to be placed on the waiting list/transplanted (HR 2.24, p < 0.001) and to receive a transplant once on the waiting list (HR 1.65, p < 0.001). Results indicate that recipient's employment status is strongly associated with access to renal transplantation, with unemployed and partially employed patients at a disadvantage. Adding insurance status to the model reduces the effect size, but the association still remains significant, indicating additional contribution from other factors. PMID:23808849

  5. Radiation Dose-Volume Effects in the Stomach and Small Bowel

    SciTech Connect

    Kavanagh, Brian D.; Pan, Charlie C.; Dawson, Laura A.; Das, Shiva K.; Li, X. Allen; Ten Haken, Randall K.; Miften, Moyed

    2010-03-01

    Published data suggest that the risk of moderately severe (>=Grade 3) radiation-induced acute small-bowel toxicity can be predicted with a threshold model whereby for a given dose level, D, if the volume receiving that dose or greater (VD) exceeds a threshold quantity, the risk of toxicity escalates. Estimates of VD depend on the means of structure segmenting (e.g., V15 = 120 cc if individual bowel loops are outlined or V45 = 195 cc if entire peritoneal potential space of bowel is outlined). A similar predictive model of acute toxicity is not available for stomach. Late small-bowel/stomach toxicity is likely related to maximum dose and/or volume threshold parameters qualitatively similar to those related to acute toxicity risk. Concurrent chemotherapy has been associated with a higher risk of acute toxicity, and a history of abdominal surgery has been associated with a higher risk of late toxicity.

  6. Flavonoids in Inflammatory Bowel Disease: A Review

    PubMed Central

    Vezza, Teresa; Rodríguez-Nogales, Alba; Algieri, Francesca; Utrilla, Maria Pilar; Rodriguez-Cabezas, Maria Elena; Galvez, Julio

    2016-01-01

    Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestine that compromises the patients’ life quality and requires sustained pharmacological and surgical treatments. Since their etiology is not completely understood, non-fully-efficient drugs have been developed and those that have shown effectiveness are not devoid of quite important adverse effects that impair their long-term use. In this regard, a growing body of evidence confirms the health benefits of flavonoids. Flavonoids are compounds with low molecular weight that are widely distributed throughout the vegetable kingdom, including in edible plants. They may be of great utility in conditions of acute or chronic intestinal inflammation through different mechanisms including protection against oxidative stress, and preservation of epithelial barrier function and immunomodulatory properties in the gut. In this review we have revised the main flavonoid classes that have been assessed in different experimental models of colitis as well as the proposed mechanisms that support their beneficial effects. PMID:27070642

  7. Flavonoids in Inflammatory Bowel Disease: A Review.

    PubMed

    Vezza, Teresa; Rodríguez-Nogales, Alba; Algieri, Francesca; Utrilla, Maria Pilar; Rodriguez-Cabezas, Maria Elena; Galvez, Julio

    2016-01-01

    Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestine that compromises the patients' life quality and requires sustained pharmacological and surgical treatments. Since their etiology is not completely understood, non-fully-efficient drugs have been developed and those that have shown effectiveness are not devoid of quite important adverse effects that impair their long-term use. In this regard, a growing body of evidence confirms the health benefits of flavonoids. Flavonoids are compounds with low molecular weight that are widely distributed throughout the vegetable kingdom, including in edible plants. They may be of great utility in conditions of acute or chronic intestinal inflammation through different mechanisms including protection against oxidative stress, and preservation of epithelial barrier function and immunomodulatory properties in the gut. In this review we have revised the main flavonoid classes that have been assessed in different experimental models of colitis as well as the proposed mechanisms that support their beneficial effects. PMID:27070642

  8. GENETICS AND PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE

    PubMed Central

    Liu, Ta-Chiang; Stappenbeck, Thaddeus S.

    2016-01-01

    We are currently in an exciting time where our understanding of genetic underpinnings of inflammatory bowel disease (IBD) has undergone a revolution, based in large part by novel genotyping and sequencing technologies. With >160 susceptible loci identified for IBD, the goals now are to understand at a fundamental level, the function of these susceptibility alleles. Clinical relevance of how these susceptible genes shape the development of IBD is also a high priority. The main challenge is to understand how the environment and microbiome play a role in triggering disease in genetically susceptible individual, as the interactions may be complex. To advance the field, novel in vitro and mouse models that are designed to interrogate complex genetics and be able to functionally test hypotheses are needed. Ultimately, the goal of genetics studies will be to translate genetics to the patients with IBD and improve their care. PMID:26907531

  9. Differentiation of Apical Bud Cells in a Newly Developed Apical Bud Transplantation Model Using GFP Transgenic Mice as Donor

    PubMed Central

    Sakagami, Ryuji; Yoshinaga, Yasunori; Okamura, Kazuhiko

    2016-01-01

    Rodent mandibular incisors have a unique anatomical structure that allows teeth to grow throughout the lifetime of the rodent. This report presents a novel transplantation technique for studying the apical bud differentiation of rodent mandibular incisors. Incisal apical end tissue with green fluorescent protein from transgenic mouse was transplanted to wild type mice, and the development of the transplanted cells were immunohistologically observed for 12 weeks after the transplantation. Results indicate that the green fluorescent apical end tissue replaced the original tissue, and cells from the apical bud differentiated and extended toward the incisal edge direction. The immunostaining with podoplanin also showed that the characteristics of the green fluorescent tissue were identical to those of the original. The green fluorescent cells were only found in the labial side of the incisor up to 4 weeks. After 12 weeks, however, they were also found in the lingual side. Here the green fluorescent cementocyte-like cells were only present in the cementum close to the dentin surface. This study suggests that some of the cells that form the cellular cementum come from the apical tissue including the apical bud in rodent incisors. PMID:26978064

  10. Neural stem cell transplantation at critical period improves learning and memory through restoring synaptic impairment in Alzheimer's disease mouse model.

    PubMed

    Kim, J A; Ha, S; Shin, K Y; Kim, S; Lee, K J; Chong, Y H; Chang, K-A; Suh, Y-H

    2015-06-18

    Alzheimer's disease (AD) is characterized by neuronal loss in several regions of the brain. Recent studies have suggested that stem cell transplantation could serve as a potential therapeutic strategy to halt or ameliorate the inexorable disease progression. However, the optimal stage of the disease for stem cell transplantation to have a therapeutic effect has yet to be determined. Here, we demonstrated that transplantation of neural stem cells into 12-month-old Tg2576 brains markedly improved both cognitive impairments and neuropathological features by reducing β-amyloid processing and upregulating clearance of β-amyloid, secretion of anti-inflammatory cytokines, endogenous neurogenesis, as well as synapse formation. In contrast, the stem cell transplantation did not recover cognitive dysfunction and β-amyloid neuropathology in Tg2576 mice aged 15 months when the memory loss is manifest. Overall, this study underscores that stem cell therapy at optimal time frame is crucial to obtain maximal therapeutic effects that can restore functional deficits or stop the progression of AD.

  11. Intervention Effect of Electroacupuncture Combined with EPCs Transplantation on the Mice in Aging Model

    PubMed Central

    Wen, Mei

    2015-01-01

    The results of this experiment suggested that electroacupuncture promotes the endothelialization of liver endothelial progenitor cells (EPCs) for mice in D-gal model and improves the repair of vascular endothelial function, as well as increasing the vascular endothelial growth factor (VEGF) expression in liver tissue fluorescence and KL protein levels. Also, it reduces the malondialdehyde (MDA) activity and delays vascular aging and even overall aging. Results showed that the in vivo fluorescence intensity for D-gal EA group was significantly lower than that of D-gal group, P < 0.05; VEGF fluorescence expression in liver tissue for D-gal EA group was significantly higher than that for D-gal group, P < 0.05; KL protein content in liver tissue for D-gal EA group was significantly higher than that for D-gal group, P < 0.05; MDA activity for D-gal EA group was significantly lower than that for D-gal group, P < 0.05. PMID:26379754

  12. Survival and functional restoration of human fetal ventral mesencephalon following transplantation in a rat model of Parkinson's disease.

    PubMed

    Rath, Anika; Klein, Alexander; Papazoglou, Anna; Pruszak, Jan; Garcia, Joanna; Krause, Martin; Maciaczyk, Jaroslaw; Dunnett, Stephen B; Nikkhah, Guido

    2013-01-01

    Cell replacement therapy by intracerebral transplantation of fetal dopaminergic neurons has become a promising therapeutic option for patients suffering from Parkinson's disease during the last decades. However, limited availability of human fetal tissue as well as ethical issues, lack of alternative nonfetal donor cells, and the absence of standardized transplantation protocols have prevented neurorestorative therapies from becoming a routine procedure in patients suffering from neurodegenerative diseases. Improvement of graft survival, surgery techniques, and identification of the optimal target area are imperative for further optimization of this novel treatment. In the present study, human primary fetal ventral mesencephalon-derived tissue from 7- to 9-week-old human fetuses was transplanted into 6-hydroxydopamine-lesioned adult Sprague-Dawley rats. Graft survival, fiber outgrowth, and drug-induced rotational behavior up to 14 weeks posttransplantation were compared between different intrastriatal transplantation techniques (full single cell suspension vs. partial tissue pieces suspension injected by glass capillary or metal cannula) and the intranigral glass capillary injection of a full (single cell) suspension. The results demonstrate a higher survival rate of dopamine neurons, a greater reduction in amphetamine-induced rotations (overcompensation), and more extensive fiber outgrowth for the intrastriatally transplanted partial (tissue pieces) suspension compared to all other groups. Apomorphine-induced rotational bias was significantly reduced in all groups including the intranigral group. The data confirm that human ventral mesencephalon-derived cells serve as a viable cell source, survive in a xenografting paradigm, and functionally integrate into the host tissue. In contrast to rat donor cells, keeping the original (fetal) neuronal network by preparing only a partial suspension containing tissue pieces seems to be beneficial for human cells, although a

  13. Erythroblast transformation-specific 2 correlates with vascular smooth muscle cell apoptosis in rat heterotopic heart transplantation model

    PubMed Central

    Liu, Xiaojuan; Yan, Daliang; Li, Yangcheng; Sha, Xilin; Wu, Kunpeng; Zhao, Jianhua; Yang, Chen; Zhang, Chao

    2016-01-01

    Background Cardiac allograft vasculopathy (CAV) decreases the long-term survival of heart transplantation recipients. Vascular smooth muscle cell (VSMC) apoptosis is an important pathological feature of CAV. Erythroblast transformation-specific 2 (Ets-2), as a transcription factor, participates in cell apoptosis and plays an important role in organ transplantation. Methods Hearts from Wistar-Furth (WF:RT1u) rats were heterotopically transplanted into Lewis (Lew:RT1l) rats without immunosuppression. Additional syngeneic heterotopic cardiac transplantations were performed in Lewis rats. HE staining was used to identify CAV. Ets-2 expression was examined by western blot. Ets-2 tissue location was examined by immunohistochemical assay and double immunostaining. Cleaved caspase 3 expression was detected by western blot. Co-localization of Ets-2 and cleaved caspase 3 was detected by double immunostaining. Ets-2, p53, cleaved caspase 3 and Bcl-xl expression in rat VSMC line A7R5 was examined after Ets-2 siRNA transfection. TUNEL assay was applied to detect A7R5 apoptosis with or without ETS-2 siRNA transfection. Immunoprecipitation was performed to explore the interaction between Ets-2 and p53. Results Ets-2 expression decreased in the allograft group but had no obvious change in the isograft group. Meanwhile, the phenomenon of CAV was observed in the allograft group and there is neointima formation in the isograft group which is not obvious compared with allograft group. Additionally, Ets-2 expression was opposite to VSMC apoptosis in the allograft group. In vitro, Ets-2 siRNA transfection in A7R5cells resulted in enhanced cell apoptosis. Finally, Ets-2 interacted with p53. Conclusions Ets-2 might inhibit VSMC apoptosis via p53 pathway. The results further elucidate the molecular mechanism of VSMC apoptosis after heart transplantation during CAV and provide theoretical basis for seeking new specific drug targets for CAV prevention and treatment.

  14. Erythroblast transformation-specific 2 correlates with vascular smooth muscle cell apoptosis in rat heterotopic heart transplantation model

    PubMed Central

    Liu, Xiaojuan; Yan, Daliang; Li, Yangcheng; Sha, Xilin; Wu, Kunpeng; Zhao, Jianhua; Yang, Chen; Zhang, Chao

    2016-01-01

    Background Cardiac allograft vasculopathy (CAV) decreases the long-term survival of heart transplantation recipients. Vascular smooth muscle cell (VSMC) apoptosis is an important pathological feature of CAV. Erythroblast transformation-specific 2 (Ets-2), as a transcription factor, participates in cell apoptosis and plays an important role in organ transplantation. Methods Hearts from Wistar-Furth (WF:RT1u) rats were heterotopically transplanted into Lewis (Lew:RT1l) rats without immunosuppression. Additional syngeneic heterotopic cardiac transplantations were performed in Lewis rats. HE staining was used to identify CAV. Ets-2 expression was examined by western blot. Ets-2 tissue location was examined by immunohistochemical assay and double immunostaining. Cleaved caspase 3 expression was detected by western blot. Co-localization of Ets-2 and cleaved caspase 3 was detected by double immunostaining. Ets-2, p53, cleaved caspase 3 and Bcl-xl expression in rat VSMC line A7R5 was examined after Ets-2 siRNA transfection. TUNEL assay was applied to detect A7R5 apoptosis with or without ETS-2 siRNA transfection. Immunoprecipitation was performed to explore the interaction between Ets-2 and p53. Results Ets-2 expression decreased in the allograft group but had no obvious change in the isograft group. Meanwhile, the phenomenon of CAV was observed in the allograft group and there is neointima formation in the isograft group which is not obvious compared with allograft group. Additionally, Ets-2 expression was opposite to VSMC apoptosis in the allograft group. In vitro, Ets-2 siRNA transfection in A7R5cells resulted in enhanced cell apoptosis. Finally, Ets-2 interacted with p53. Conclusions Ets-2 might inhibit VSMC apoptosis via p53 pathway. The results further elucidate the molecular mechanism of VSMC apoptosis after heart transplantation during CAV and provide theoretical basis for seeking new specific drug targets for CAV prevention and treatment. PMID:27621856

  15. Neural stem cells transplanted in a mouse model of Parkinson's disease differentiate to neuronal phenotypes and reduce rotational deficit.

    PubMed

    Ziavra, Despina; Makri, Georgia; Giompres, Panagiotis; Taraviras, Stavros; Thomaidou, Dimitra; Matsas, Rebecca; Mitsacos, Ada; Kouvelas, Elias D

    2012-11-01

    The most prominent pathological feature in Parkinson's disease (PD) is the progressive and selective loss of mesencephalic dopaminergic neurons of the nigrostriatal tract. The present study was conducted in order to investigate whether naive and or genetically modified neural stem/precursor cells (NPCs) can survive, differentiate and functionally integrate in the lesioned striatum. To this end, stereotaxic injections of 6-OHDA in the right ascending nigrostriatal dopaminergic pathway of mice and subsequent NPC transplantations were performed, followed by apomorphine-induced rotations and double-immunofluorescence experiments. Our results demonstrate that transplanted embryonic NPCs derived from the cortical ventricular zone of E14.5 transgenic mouse embryos expressing the green fluorescent protein (GFP) under control of the beta-actin promoter and cultured as neurospheres can survive in the host striatum for at least three weeks after transplantation. The percentage of surviving GFP-positive cells in the host striatum ranges from 0.2% to 0.6% of the total transplanted NPCs. Grafted cells functionally integrate in the striatum, as indicated by the statistically significant decrease of contralateral rotations after apomorphine treatment. Furthermore, we show that within the striatal environment GFP-positive cells differentiate into beta-III tubulin-expressing neurons, but not glial cells. Most importantly, GFP-positive cells further differentiate to dopaminergic (TH-positive) and medium size spiny (DARPP-32- positive) neuronal phenotypes. Over-expression of the cell cycle exit and neuronal differentiation protein Cend1 in NPCs enhances the generation of GABAergic, but not dopaminergic, neuronal phenotypes after grafting in the lesioned striatum. Our results encourage the development of strategies involving NPC transplantation for the treatment of neurodegenerative diseases.

  16. Surgical techniques in short bowel syndrome.

    PubMed

    Waag, K L; Heller, K

    1990-01-01

    An operation according to Bianchi in a 2-year-old girl is described and indications as well as technical procedure are discussed. The girl was born with a gastroschisis. There was a jejunal perforation 10 cm below the ligament of Treitz caused by a volvulus. Only 20 cm of the jejunum remained. Moreover, only the left part of the colon was present. Total parenteral nutrition for 2 years was necessary. The principle of the operation is based on a longitudinal division of the remaining bowel and a creation of two separate bowel tubes out of the divided bowel halves, thus effecting an isoperistaltic serial connection by means of two anastomoses. This is technically possible since each half of the bowel wall has its own blood supply. The vessels originating from the mesenterium branch off before they reach the bowel wall so that the mesenteric dissection line can be anastomosed longitudinally with the antimesenteric border. This results in doubling of the bowel length, narrowing of the preoperatively dilated bowel diameter, closer contact of bowel contents with the mucosa, prolonged transit time and a Bacteroides colonization which is reduced by more effective peristalsis. Indications, time of operation and our own experiences are discussed and three cases are described. All children are alive and show marked improvement in nutrition. PMID:2105523

  17. Hypertrophic osteoarthropathy of chronic inflammatory bowel disease

    SciTech Connect

    Oppenheimer, D.A.; Jones, H.H.

    1982-12-01

    The case of a 14-year old girl with painful periostitis and ulcerative colitis is reported. The association of chronic inflammatory bowel disease with osteoarthropathy is rare and has previously been reported in eight patients. The periosteal reaction found in association with inflammatory bowel disease is apparently related to a chronic disease course and may cause extreme localized pain.

  18. Transplant benefit for patients with hepatocellular carcinoma.

    PubMed

    Vitale, Alessandro; Volk, Michael; Cillo, Umberto

    2013-12-28

    Although liver transplantation is theoretically the best treatment for hepatocellular carcinoma (HCC), it is limited by the realities of perioperative complications, and the shortage of donor organs. Furthermore, in many cases there are available alternative treatments such as resection or locoregional therapy. Deciding upon the best option for a patient with HCC is complicated, involving numerous ethical principles including: urgency, utility, intention-to-treat survival, transplant benefit, harm to candidates on waiting list, and harm to living donors. The potential contrast between different principles is particularly relevant for patients with HCC for several reasons: (1) HCC candidates to liver transplantation are increasing; (2) the great prognostic heterogeneity within the HCC population; (3) in HCC patients tumor progression before liver transplantation may significantly impair post transplant outcome; and (4) effective alternative therapies are often available for HCC candidates to liver transplantation. In this paper we suggest that allocating organs by transplant benefit could help balance these competing principles, and also introduce equity between patients with HCC and nonmalignant liver disease. We also propose a triangular equipoise model to help decide between deceased donor liver transplantation, living donor liver transplantation, or alternative therapies. PMID:24409046

  19. Overview of inflammatory bowel disease.

    PubMed

    Myer, S A

    1984-03-01

    Ulcerative colitis and Crohn's disease have been on the increase in terms of incidence, prevalence, and virulence. The young adult population is affected most frequently and most severely. The cause of inflammatory bowel disease is unknown, but many misconceptions exist about its etiology. Nurses need to be familiar with the similarities and differences between the two illnesses, the treatment, and the prognosis in order to be effective care givers. Good health care can make a significant contribution to the quality of life the patient subsequently has. PMID:6560534

  20. [Inflammatory bowel disease and pregnancy].

    PubMed

    Parfenov, A I

    2012-01-01

    Inflammatory bowel disease (IBD) in pregnant women in their characteristics do not differ from general population, unless they had operations on the pelvic organs. Women with a first pregnancy, regardless of the activity of IBD have an increased risk of adverse pregnancy and high risk births. Most treatment methods are compatible with pregnancy and breastfeeding. Women affected by IBD should discuss their plans for pregnancy with the doctor first in order to know the possible dangers. Every patient in the IBD during pregnancy must be observed by a gastroenterologist, accoucheur and pediatrician to ensure peace of mother and child.

  1. Pharmacogenetics in irritable bowel syndrome.

    PubMed

    Acosta, Andres; Camilleri, Michael

    2015-01-01

    Irritable bowel syndrome (IBS) is a chronic disease characterized by complex interactions between genetic predisposition and the environment. Current treatments for IBS are characterized by a highly variable response. Gene variations may result from insertions or deletions, gene rearrangements, splice variants or copy number variants, or, more commonly, from substitutions in the DNA of one (single nucleotide polymorphism [SNPs]) or more than one nucleotide. The objective of this editorial is to review the potential importance of pharmacogenetics in the treatment of IBS based on current evidence.

  2. Irritable bowel syndrome: contemporary nutrition management strategies.

    PubMed

    Mullin, Gerard E; Shepherd, Sue J; Chander Roland, Bani; Ireton-Jones, Carol; Matarese, Laura E

    2014-09-01

    Irritable bowel syndrome is a complex disorder whose pathophysiology involves alterations in the enteric microbiota, visceral hypersensitivity, gut immune/barrier function, hypothalamic-pituitary-adrenal axis regulation, neurotransmitters, stress response, psychological factors, and more. The importance of diet in the management of irritable bowel syndrome has taken center stage in recent times as the literature validates the relationship of certain foods with the provocation of symptoms. Likewise, a number of elimination dietary programs have been successful in alleviating irritable bowel syndrome symptoms. Knowledge of the dietary management strategies for irritable bowel syndrome will help guide nutritionists and healthcare practitioners to deliver optimal outcomes. This tutorial reviews the nutrition management strategies for irritable bowel syndrome.

  3. Organ transplantation in Tunisia.

    PubMed

    El Matri, Aziz; Ben Abdallah, Taieb

    2015-04-01

    Kidney transplants were first performed in Tunisia in 1986, and transplants soon extended to other organs including the heart, liver, and pancreas. Live-related donor and deceased-donor kidney transplants were both began in the summer of 1986. An organ procurement and transplant law was passed in March 1991, and the National Centre for Advancement of Organ Transplantation was created in 1995. The number of transplantation units has increased to 7 throughout the country, and the yearly transplant number has progressively increased to 139 in 2010, including 20% from deceased kidney donors. Despite these gains, the need continues to grow. Heart transplants began in January 1993, and Tunisia and Jordan are currently the only Arab countries where it is practiced. However, only 16 patients have received a heart transplant as of 2004, and the number of recipients has decreased in the past 10 years. Liver transplants are rare in other Arab countries, but began in Tunisia in January 1998. Over 10 years, 38 patients benefited from this procedure. After a few years of stagnation, the number of liver transplants is increasing. While all types of transplantation are needed, kidney transplantation is a priority in Tunisia. The target is to perform 400 transplants annually, which would require a long-term strategy to provide full financial coverage using the National Health Insurance Funds in both the public and private sectors.

  4. The myeloid differentiation factor 88 (MyD88) is required for CD4+ T cell effector function in a murine model of inflammatory bowel disease1

    PubMed Central

    Fukata, Masayuki; Breglio, Keith; Chen, Anli; Vamadevan, Arunan S.; Goo, Tyralee; Hsu, David; Conduah, Daisy; Xu, Ruliang; Abreu, Maria T.

    2009-01-01

    Abnormal T cell responses to commensal bacteria are involved in the pathogenesis of inflammatory bowel disease (IBD). MyD88 is an essential signal transducer for TLRs in response to the microflora. We hypothesized that TLR signaling via MyD88 was important for effector T cell responses in the intestine. TLR expression on murine T cells was examined by flow cytometry. CD4+CD45Rbhigh T cells and/or CD4+CD45RblowCD25+ regulatory T cells (Tregs) were isolated and adoptively transferred to RAG1−/− mice. Colitis was assessed by changes in body weight and histology score. Cytokine production was assessed by ELISA. In vitro proliferation of T cells was assessed by [3H]thymidine assay. In vivo proliferation of T cells was assessed by BrdU and CFSE labeling. CD4+CD45Rbhigh T cells expressed TLR2, TLR4, TLR9, and TLR3 and TLR ligands could act as co-stimulatory molecules. MyD88−/− CD4+ T cells showed decreased proliferation compared with WT CD4+ T cells both in vivo and in vitro. CD4+CD45Rbhigh T cells from MyD88−/− mice did not induce wasting disease when transferred into RAG1−/− recipients. Lamina propria CD4+ T cell expression of IL-2 and IL-17 and colonic expression of IL-6 and IL-23 were significantly lower in mice receiving MyD88−/− cells than mice receiving WT cells. In vitro, MyD88−/− T cells were blunted in their ability to secrete IL-17 but not IFN-γ. Absence of MyD88 in CD4+CD45Rbhigh cells results in defective T cell function, especially Th17 differentiation. These results suggest a role for TLR signaling by T cells in the development of IBD. PMID:18209086

  5. The use of jejunal transplants to treat a genetic enzyme deficiency.

    PubMed Central

    Jaffe, B M; Burgos, A A; Martinez-Noack, M

    1996-01-01

    INTRODUCTION: The Gunn rat is an excellent animal model of Crigler-Najjar syndrome, type 1. The liver and small intestine synthesize no functional bilirubin uridine diphosphoglucuronosyl transferase and, consequently, the animals cannot conjugate bilirubin. In prior studies, the authors have shown that 15- to 20-cm jejunal transplants from normal Wistar rats lowered but did not normalize serum bilirubin levels. Phenobarbital has been used to increase enzyme conjugation of bilirubin. HYPOTHESIS: Phenobarbital treatment of Gunn recipients of jejunal transplants from Wistar rats normalizes serum bilirubin levels. METHODS: Forty-three Gunn recipients of jejunal transplants from Wistar rats were divided into four groups: 1) heterotopically placed grafts (Thiry-Vella loops), saline-treated, n = 14; 2) heterotopically placed grafts, phenobarbital-treated (80 mg/kg/day), n = 17; 3) orthotopically placed (in intestinal continuity) grafts, saline-treated, n = 5; and 4) orthotopically placed grafts, phenobarbital-treated, n = 7. Serum was collected before operation and weekly for 8 weeks for measurement of serum total, indirect, and direct bilirubin levels. Animals received cyclosporine, 5 micrograms/kg, daily intramuscularly. RESULTS: Phenobarbital significantly augmented the bilirubin-lowering effect of heterotopic jejunal transplants (group 2). Mean total serum bilirubin fell from 9.14 +/- 0.01 to a nadir of 1.63 +/- 0.11 mg/dL at 6 weeks, after which time, levels began to rise toward baseline (as noted previously). Serum indirect bilirubin levels behaved in a similar fashion. Phenobarbital treatment "normalized" serum bilirubin levels in recipients of orthotopic Wistar jejunal grafts (group 4). Mean total serum bilirubin plummeted from 8.41 +/- 0.20 to 0.76 +/- 0.15 mg/dL at 1 week, and levels remained within the normal range for the entire 8-week study period. Identical changes were observed for serum indirect bilirubin levels. CONCLUSIONS: The combination of

  6. A model to predict survival at one month, one year, and five years after liver transplantation based on pretransplant clinical characteristics.

    PubMed

    Thuluvath, Paul J; Yoo, Hwan Y; Thompson, Richard E

    2003-05-01

    Reliable models that could predict outcome of liver transplantation (LT) may guide physicians to advise their patients of immediate and late survival chances and may help them to optimize organ use. The objective of this study was to develop user-friendly models to predict short and long-term mortality after LT in adults based on pre-LT recipient characteristics. The United Network for Organ Sharing (UNOS) transplant registry (n = 38,876) from 1987 to 2001 was used to develop and validate the model. Two thirds of patients were randomized to develop the model (the modeling group), and the remaining third was randomized to cross-validate (the cross-validation group) it. Three separate models, using multivariate logistic regression analysis, were created and validated to predict survival at 1 month, 1 year, and 5 years. Using the total severity scores of patients in the modeling group, a predictive model then was created, and the predicted probability of death as a function of total score then was compared in the cross-validation group. The independent variables that were found to be very significant for 1 month and 1 year survival were age, body mass index (BMI), UNOS status 1, etiology, serum bilirubin (for 1 month and 1 year only), creatinine, and race (only for 5 years). The actual deaths in the cross-validation group followed very closely the predicted survival graph. The chi-squared goodness-of-fit test confirmed that the model could predict mortality reliably at 1 month, 1 year, and 5 years. We have developed and validated user-friendly models that could reliably predict short-term and long-term survival after LT. PMID:12740799