Bone disease before and after liver transplantation : clinical studies in cholestatic liver disease

Osteoporose (botontkalking) en botbreuken zijn bekende complicaties van chronische leverziektes. De meeste problemen treden op bij patiënten met galwegobstructie (cholestase). Na de benodigde levertransplantatie verliezen de patiënten nog meer botmassa, onder andere ten gevolge van hoge doseringen prednison. UMCG-onderzoeker Maureen Guichelaar onderzocht het voorkomen, de oorzaken en risicofactoren van botziekten bij 360 Amerikaanse patiënten met galwegobstructie voor en na levertransplantatie. Het onderzoek toont aan dat patiënten met eindstadium levercirrose afwijkingen hebben in botmetabolisme. Guichelaar bracht de afwijkingen nauwgezet in kaart aan de hand van analyse van botbiopten voor en na levertransplantatie. Daarnaast onderzocht zij het verloop van de botmassa en de hoeveelheid botbreuken. De eerste vier maanden na levertransplantatie neemt de botmassa snel af, en stijgt het aantal botbreuken navenant. Vanaf vier maanden na de transplantatie treedt een verbetering van het botmetabolisme op, wat leidt tot een stijging van de botmassa. Ook onderzocht Guichelaar risicofactoren voor veranderingen in botmetabolisme, botmassa, botfracturen. De resultaten van het onderzoek zijn met name van belang voor hepatologen, MDL-artsen, en transplantatiechirurgen.

Three cases of hepatocellular carcinoma in Fontan patients: Review of the literature and suggestions for hepatic screening

The Fontan procedure has been used since 1971 as a palliative treatment for various (functionally) univentricular hearts. The systemic venous blood flows passively to the pulmonary arteries, without passing through a functional ventricle. This results in chronic systemic venous congestion, which may lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. This review discusses possible screening modalities for liver fibrosis and cirrhosis in the Fontan population and proposes a screening protocol. We suggest starting screening for progression of fibrosis and cirrhosis in collaboration with the hepatologist circa 10 years after Fontan completion. The screening programme will consist of a yearly evaluation of liver laboratory tests in conjunction with imaging of the liver with ultrasound or MRI every two years. In case of liver fibrosis or cirrhosis, (reversible) causes should be ruled out (e.g. obstruction in the Fontan circuit). In case of severe fibrosis or cirrhosis, other complications of portal hypertension should be evaluated and screening for hepatocellular carcinoma is required on a regular (6-12 months) basis. As regards hepatocellular carcinoma, treatment should be discussed in a multidisciplinary team, before deciding a treatment modality. (C) 2016 Elsevier Ireland Ltd. All rights reserved

Eradication of medullary multiple myeloma by CD4+ cytotoxic human T lymphocytes directed at a single minor histocompatibility antigen

PURPOSE: The essential role of CD4(+) T cells as helpers of anticancer immunity is indisputable. Little is known, however, about their capacity to serve as effector cells in cancer treatment. Therefore, we explored the efficacy of immunotherapy with sole CD4(+) cytotoxic human T cells directed at a hematopoietic-restricted minor histocompatibility antigen (mHag). EXPERIMENTAL DESIGN: In macrophage-depleted Rag2(-/-)γc(-/-) mice, which were also devoid of T, B, and natural killer cells, mHag-specific native T cells or tetanus toxoid (TT)-specific T cells transduced with the mHag-specific T-cell receptor (TCR) were injected to treat full-blown mHag(+) human multiple myeloma tumors. RESULTS: mHag-specific antitumor responses were achieved after injection of native or mHag-TCR-transduced T cells. Although the therapy completely eradicated the primary tumors in the bone marrow, it failed to control extramedullary relapses, even after repeated T-cell injections. Detailed analyses ruled out mHag or MHC downregulation as mechanisms of extramedullary tumor escape. Impaired T-cell survival in vivo or defective homing to the tumor site were also ruled out as mechanisms behind extramedullary relapses, because injections of TT-loaded antigen presenting cells could facilitate homing of long-term surviving T cells to s.c. tumor sites. Moreover, intratumoral treatment of extramedullary tumors with 3AB11 was also ineffective. CONCLUSIONS: Taken together, these results for the first time show the feasibility of immunotherapy of primary bone marrow tumors with sole CD4(+) human T cells directed to a tumor-associated mHag. Extramedullary relapses, probably due to microenvironment-dependent inhibitory mechanisms, remain a challenging issue towards effective cellular immunotherapy of hematologic malignancies

The Effectiveness of Subjecting \u3ci\u3eBos indicus\u3c/i\u3e Crossbred Beef Carcasses to Higher Temperatures to Improve Tenderness

Many studies have evaluated changes that occur in muscle during the aging process and how they relate to meat tenderness. Other research has shown that subjecting carcasses to higher temperatures soon after slaughter speeds the aging process that ultimately results in improved tenderness. Several things may explain this effect. The higher temperature causes the pH (acidity) of the muscle to decrease faster. Also, the combination of lower pH and higher temperature could promote an earlier release of calcium into the muscle, which normally occurs in muscle tissue after slaughter. This increase in calcium concentration in turn activates the calpain enzyme system (a naturally occurring enzyme system that is found in muscle tissue). When calpain is activated by calcium, it has the potential to degrade certain muscle proteins that must be degraded for meat to be tender. A discussion of this is found in the previous article. Therefore, because meat from Bos indicus breed crosses often is less tender than meat from Bos taurus breeds, we studied whether tenderness could be altered by carcass high-temperature conditioning and, if so, what mechanisms are involved