Is chronic graft rejection the reason for degenerative changes in allogeneic and xenogeneic heart valve prostheses: immunohistochemical evaluation of inflammatory factors

OBJECTIVES: After a period of 5 to 10 years, biological heart valve prostheses undergo degenerative processes, which finally lead to dysfunction and complete destruction. Although many efforts have been made to identify underlying mechanisms, many questions remain unanswered. Here we evaluate immunological factors and their potential role in biological heart valve destruction. PATIENTS AND METHODS: Allogeneic (n=10) and xenogeneic (n=3) aortic valvular prostheses, as well as aortic valves retrieved from transplanted human hearts, which had to be replaced because of chronic graft rejection (n=4) were analyzed. Aortic valves from human donor hearts (native) (n=4), which were considered not transplantable served as controls. Endothelial expression patterns of the following adhesion molecules were analyzed by immunohistochemistry: selectin family: ELAM-1, CD62, integrin family: VLA-1, -2, -3, -4, -5, and -6, immunoglobulin supergene family: PECAM-1, ICAM-1, and -2, and class I heavy chain proteins, complementary adhesion molecules: CD34, CD44 and the von Willebrand factor. RESULTS: ELAM-1, ICAM-1 and -2, CD34, CD44 and class I heavy chain proteins, all molecules which play significant roles during inflammatory processes, showed stronger expression patterns in allogeneic and xenogeneic aortic heart valve prostheses compared to native or chronically rejected valves. Furthermore, the von Willebrand factor stained positive only on allogeneic and xenogeneic valves. Only mild differences were observed regarding the expression of integrin molecules and CD62. CONCLUSIONS: Immunological reactions play a major role in the degeneration of biological heart valve prostheses. This is underlined by observations made on aortic valves from chronically rejected cardiac grafts, which did not show any degenerative alterations. Thus, since immunosuppressive therapy after heart valve replacement is no reasonable alternative, novel and future approaches in "tissue engineering" will hopefully help avoid tissue degeneration, while preserving the advantage of biological tissue origin.     

Enhanced efficacy of combined 213Bi-DTPA-F3 and paclitaxel therapy of peritoneal carcinomatosis is mediated by enhanced induction of apoptosis and G2/M phase arrest

Purpose

Targeted therapy with α-particle emitting radionuclides is a promising new option in cancer therapy. Stable conjugates of the vascular tumour-homing peptide F3 with the α-emitter ²¹³Bi specifically target tumour cells. The aim of our study was to determine efficacy of combined ²¹³Bi-diethylenetriaminepentaacetic acid (DTPA)-F3 and paclitaxel treatment compared to treatment with either ²¹³Bi-DTPA-F3 or paclitaxel both in vitro and in vivo.

Methods

Cytotoxicity of treatment with ²¹³Bi-DTPA-F3 and paclitaxel, alone or in combination, was assayed towards OVCAR-3 cells using the alamarBlue assay, the clonogenic assay and flow cytometric analyses of the mode of cell death and cell cycle arrest. Therapeutic efficacy of the different treatment options was assayed after repeated treatment of mice bearing intraperitoneal OVCAR-3 xenograft tumours. Therapy monitoring was performed by bioluminescence imaging and histopathologic analysis.

Results

Treatment of OVCAR-3 cells in vitro with combined ²¹³Bi-DTPA-F3 and paclitaxel resulted in enhanced cytotoxicity, induction of apoptosis and G2/M phase arrest compared to treatment with either ²¹³Bi-DTPA-F3 or paclitaxel. Accordingly, i.p. xenograft OVCAR-3 tumours showed the best response following repeated (six times) combined therapy with ²¹³Bi-DTPA-F3 (1.85?MBq) and paclitaxel (120?μg) as demonstrated by bioluminescence imaging and histopathologic investigation of tumour spread on the mesentery of the small and large intestine. Moreover, mean survival of xenograft mice that received combined therapy with ²¹³Bi-DTPA-F3 and paclitaxel was significantly superior to mice treated with either ²¹³Bi-DTPA-F3 or paclitaxel alone.

Conclusion

Combined treatment with ²¹³Bi-DTPA-F3 and paclitaxel significantly increased mean survival of mice with peritoneal carcinomatosis of ovarian origin, thus favouring future therapeutic application.     

TAVI for pure aortic valve insufficiency in a patient with a left ventricular assist device

We report transcatheter aortic valve implantation (TAVI) for pure aortic valve insufficiency in a patient with an otherwise normal aortic valve and a long-term left ventricular assist device (LVAD). An oversized 29-mm Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA) was implanted in the 21-mm native aortic valve annulus. Despite the complete absence of aortic calcifications, the prosthesis remained stably anchored inside the annulus. The reported experience demonstrates that TAVI is feasible even in patients with pure aortic valve regurgitation and can be a reasonable option in patients with aortic regurgitation after LVAD implantation.     

The neuroprotective effect of lactate is not due to improved glutamate uptake after controlled cortical impact in rats

Abstract For many years lactate was considered to be a waste product of glycolysis. Data are accumulating that suggest that lactate is an important energy substrate for neurons during activation. In severe traumatic brain injury (TBI) glutamate release and ischemic cerebral blood flow (CBF) are major factors for a mismatch between energy demand and supply and for neuronal cell death. Although ATP and behavior could be improved by lactate treatment after TBI, no histological correlate nor any linkage to better astrocytic glutamate uptake or CBF as possible mechanisms have been described. We subjected male rats to a controlled cortical impact (CCI; 5?m/sec, 2.5?mm). To study the effects of lactate treatment on lesion volume, glutamate release, and CBF, animals were infused with either NaCl or 100?mM lactate for up to 3?h. The role of endogenous lactate was investigated by inhibiting transport with α-cyano-4-hydroxy-cinnamic acid (4-CIN; 90?mg/kg). Lactate treatment 15?min post-CCI reduced lesion volume from 21.1±2.8?mm(3) to 12.1±1.9?mm(3) at day 2 after CCI. Contusion produced a significant three- to fourfold increase of glutamate in microdialysates, but there was no significant difference between treatments that began 30?min before CCI. In this experiment lesion volume was significantly reduced by lactate at day 7 post-CCI (23.7±4 to 9.3±1-2?mm(3)). CBF increased immediately after CCI and dropped thereafter below baseline in all animals. Lactate infusion 15?min post-CCI elevated CBF for 20?min in 7 of 10 animals, whereas 7 of 8 NaCl-treated animals showed a further CBF decline. Neuroprotection was achieved by lactate treatment following contusion injury, whereas blocking of endogenous lactate transport exerted no adverse effects. Neuroprotection was not achieved by improved glutamate uptake into astrocytes, but was supported by augmented CBF following CCI. Due to its neuroprotective property, lactate might be a beneficial pharmacological treatment for TBI patients.     

Hybrid neurofibroma/schwannoma is overrepresented among schwannomatosis and neurofibromatosis patients

We analyzed the histologic features of peripheral nerve sheath tumors occurring in 14 patients with schwannomatosis. Among a total of 31 tumors, 19 tumors (61%) showed schwannoma-like nodules within a neurofibroma-like tumor, corresponding to hybrid neurofibroma/schwannoma. At least 1 hybrid tumor occurred in 10 of 14 (71%) schwannomatosis patients. We then retrieved cases of hybrid tumors without documented relation to schwannomatosis from our database and identified 41 tumors arising in 23 patients. More than half of these patients (14/23) were reported to suffer from multiple peripheral nerve sheath tumors, favoring a tumor syndrome. Indeed, analysis of clinical records revealed the diagnosis of neurofibromatosis type 2 (NF2) in 26% (6/23), neurofibromatosis type 1 (NF1) in 9% (2/23), definite schwannomatosis in 4% (1/23), and possible schwannomatosis in 13% (3/23) of patients with multiple nerve sheath tumors. Our findings suggest that hybrid neurofibroma/schwannoma represents a common tumor type in schwannomatosis and shows a striking association with neurofibromatoses.