Small bowel transplantation : immunological and functional studies

Small bowel transplantation (SBT) would be the treatment of choice for patients suffering from the short bowel syndrome. Although in some centers SBT in patients is done with a considerable degree of success (Grant et al 1990, Todo et al. 1992), it is by no means an established and widely applicable therapy for those with short bowel syndrome. The small bowel is unique among vascularized organ grafts because it not only elicits a vigorous rejection reaction, but is also capable of inducing graft-versus-host disease (GVHD). Rejection of the graft does not only lead to loss of function, but also to bacterial translocation. The risk of fatal sepsis is aggravated by the immunosuppression given to prevent rejection. This chapter describes the history of experimental and clinical SBT, and outlines recent developments and future prospects concerning this theoretically optimal treatment modality for patients who would be dependent on total parenteral nutrition (TPN) for life

The effect of immunosuppression on function of kidney allografts in the rat

Transplantation of living tissues is not a new concept. Greek mythology presents us with the Chimera in which a goat's body, a lion's head and a dragon's tail are joined to form a terrifying monster. Ancient Indian surgeons made use of local skin flaps for rhinoplasty, an art which has been practiced in Italy as early as the fifteenth century. Various transplantation experiments were performed by John Hunter in the eighteenth century. However, a systematic approach to the study of transplantation biology has only been started during the present century when technical progress in the field of surgery (Carrel and Guthrie 1905, 1906; Carrel 1908) made it possible to transplant a large variety of tissues and organs. Unfortunately, surgical problems are not the only obstacles to successful transplantation. lt has been known for a long time that tissue transplants in which the donor is also the recipient (autografts) or transplants between animals of the same inbred strain (isografts) will survive. Without complications this also applies to grafts between identical twins. On the other hand, transplants between two randomly chosen individuals of the same species called homografts or allografts, behave like autografts for a few days only, after which progressive damage occurs, leading to loss of function and destruction of the graft. This process, called rejection, is usually complete within a few weeks following transplantation and is invariably accompanied by infiltration with inflammatory cells, predominantly of the mononuclear type. In transplants exchanged between members of different species (heterografts, syn. xenografts), a much more violent and rapid rejection may take place

Small bowel transplantation: An overview

Small bowel transplantation (SBT) would, in theory, be the treatment of choice for patients suffering from the short bowel syndrome. Although SBT has been done with a considerable degree of success in some centers [36,145], it is by no means an established or widely applicable therapy for those with short bowel syndrome. The small bowel is unique among vascularized organ grafts because it not only elicits a vigorous rejection reaction but is also capable of inducing graft-versus-host disease (GVHD). Rejection of the graft does not only lead to loss of function but also to bacterial translocation. The risk of fatal sepsis is aggravated by the immunosuppression given to prevent rejection. Here, the history of SBT is described, and recent developments in experimental and clinical SBT, as well as future prospects for this theoretically optimal treatment modality for patients dependent on total parenteral nutrition (TPN) for life, are outlined

Effects of age and sex on shoulder biomechanics and relative effort during functional tasks

Age-related decline in muscle strength can compromise shoulder function, which could increase the effort needed to perform activities of daily living (ADLs). The purpose of this cross-sectional study was to determine for the first time the relative shoulder effort during ADLs in healthy young and older adults. Ten healthy young adults and ten healthy older adults were tested for maximal isokinetic torque and on a set of ADL tasks. Using inverse dynamics, the shoulder torques during ADLs were referenced to the maximal isokinetic torque and relative effort was determined. Older compared to younger adults had >40% lower isokinetic shoulder abduction strength. The ratio of peak joint torque during six ADLs over the maximal isokinetic torque, i.e., relative effort, was higher in old (similar to 52%) compared with young adults (similar to 22%, p <0.05). Relative effort in older adults was over 40% in overhead activities and particularly high in abduction and reaching tasks, over 60%. Healthy older compared with younger adults perform most ADL tasks involving the shoulder joint with nearly twice the level of relative effort. The concomitant reductions in maximal shoulder isokinetic torque and increases in relative effort may be related to the high prevalence of musculoskeletal pain and shoulder dysfunction in old age reported in epidemiological studies. (C) 2018 Elsevier Ltd. All rights reserved

Rapamycin Does Not Act as a Dietary Restriction Mimetic in the Protection against Ischemia Reperfusion Injury

Introduction: Short-term fasting protects against renal ischemia reperfusion injury (IRI). mTOR signaling is downregulated and may be involved in its protective effect. Rapamycin is considered a possible mimetic as it inhibits the mTOR pathway. This study examines the effect of rapamycin on renal IRI. Material and Methods: Mice were divided into four groups: ad libitum (AL), fasted (F), AL treated with rapamycin (AL+R), and F treated with rapamycin (F+R). Rapamycin was administered intraperitoneally 24 h before bilateral renal IRI was induced. Survival was monitored for 7 days. Renal cell death, regeneration, and mTOR activity were determined 48 h after reperfusion. Oxidative stress resistance of human renal proximal tubular and human primary tubular epithelial cells after rapamycin treatment was determined. Results: All F and F+R mice survived the experiment. Although rapamycin substantially downregulated mTOR activity, survival in the AL+R group was similar to AL (10%). Renal regeneration was significantly reduced in AL+R but not in F+R. After IRI (48 h), pS6K/S6K ratio was lower in F, F+R, and AL+R groups compared to AL fed animals (p = 0.02). In vitro, rapamycin also significantly downregulated mTOR activity (p &lt; 0.001) but did not protect against oxidative stress. Conclusion: Rapamycin pretreatment does not protect against renal IRI. Thus, protection against renal IRI by fasting is not exclusively mediated through inhibition of mTOR activity but may involve preservation of regenerative mechanisms despite mTOR downregulation. Therefore, rapamycin cannot be used as a dietary mimetic to protect against renal IRI.</p

Dietary Restriction and Fasting Arrest B and T Cell Development and Increase Mature B and T Cell Numbers in Bone Marrow

Dietary restriction (DR) delays ageing and extends life span. Both long- and short-term DR, as well as short-term fasting provide robust protection against many “neuronal and surgery related damaging phenomena” such as Parkinson’s disease and ischemia-reperfusion injury. The exact mechanism behind this phenomenon has not yet been elucidated. Its anti-inflammatory actions prompted us to thoroughly investigate the consequences of DR and fasting on B and T cell compartments in primary and secondary lymphoid organs of male C57Bl/6 mice. In BM we found that DR and fasting cause a decrease in the total B cell population and arrest early B cell development, while increasing the number of recirculating mature B cells. In the fasting group, a significant reduction in peripheral B cell counts was observed in both spleen and mesenteric lymph nodes (mLN). Thymopoiesis was arrested significantly at double negative DN2 stage due to fasting, whereas DR resulted in a partial arrest of thymocyte development at the DN4 stage. Mature CD3(+) T cell populations were increased in BM and decreased in both spleen and mLN. Thus, DR arrests B cell development in the BM but increases the number of recirculating mature B cells. DR also arrests maturation of T cells in thymus, resulting in depletion of mature T cells from spleen and mLN while recruiting them to the BM. The functional relevance in relation to protection against organ damage needs to be determined

Conserved Expression and Functionality of Furin between Chickens and Ducks as an Activating Protease of Highly Pathogenic Avian Influenza Virus Hemagglutinins

Highly pathogenic avian influenza viruses (HPAIVs) typically emerge from low-pathogenic avian influenza viruses (LPAIVs) of the H5 and H7 subtypes upon spillover from wild aquatic birds into poultry. The conversion from LPAIV to HPAIV is characterized by the acquisition of a multibasic cleavage site (MBCS) at the proteolytic cleavage site in the viral binding and fusion protein, hemagglutinin (HA), resulting in cleavage and activation of HA by ubiquitously expressed furin-like proteases. The ensuing HPAIVs disseminate systemically in gallinaceous poultry, are endotheliotropic, and cause hemorrhagic disease with high mortality. HPAIV infections in wild aquatic birds are generally milder, often asymptomatic, and generally not associated with systemic dissemination nor endotheliotropic. As MBCS cleavage by host proteases is the main virulence determinant of HPAIVs in poultry, we set out to determine whether cleavage of HPAIV HA by host proteases might influence the observed species-specific pathogenesis and tropism. Here, we sequenced, cloned, and characterized the expression and functionality of duck furin. The furin sequence was strongly conserved between chickens and ducks, and duck furin cleaved HPAIV and tetrabasic HA in an overexpression system, confirming its functionality. Furin was expressed ubiquitously and to similar extents in duck and chicken tissues, including in primary duck endothelial cells, which sustained multicycle replication of H5N1 HPAIV but not LPAIVs. In conclusion, differences in furin-like protease biology between wild aquatic birds and gallinaceous poultry are unlikely to largely determine the stark differences observed in species-specific pathogenesis of HPAIVs. IMPORTANCE HPAIV outbreaks are a global concern due to the health risks for poultry, wildlife, and humans and their major economic impact. The number of LPAIV-to-HPAIV conversions, which is associated with spillover from wild birds to poultry, has been increasing over recent decades. Furthermore, H5 HPAIVs from the A/goose/Guangdong/1/96 lineage have been circulating in migratory birds, causing increasingly frequent epizootics in poultry and wild birds. Milder symptoms in migratory birds allow for dispersion of HPAIVs over long distances, justifying the importance of understanding the pathogenesis of HPAIVs in wild birds. Here, we examined whether host proteases are a likely candidate to explain some differences in the degree of HPAIV systemic dissemination between avian species. This is the first report to show that furin function and expression is comparable between chickens and ducks, which renders the hypothesis unlikely that furin-like protease differences influence the HPAIV species-specific pathogenesis and tropism.</p