Long-term study of ovine pulmonary adenocarcinogenesis in sheep with marginal vs. sufficient nutritional selenium supply: results from computed tomography, pathology, immunohistochemistry, JSRV-PCR and lung biochemistry.

The impact of selenium (Se) in carcinogenesis is still debatable due to inconsistent results of observational studies, recent suspicion of diabetic side effects and e.g. dual roles of glutathione peroxidases (GPx). Previously, our group introduced long-term studies on lung carcinogenesis using the jaagtsiekte sheep retrovirus (JSRV) induced ovine pulmonary adenocarcinoma (OPA) as an innovative animal model. The present report describes the results of sufficient (0.2 mg Se/kg dry weight (dw)) vs. marginal (<0.05 mg Se/kg dw) nutritional Se supply on cancer progression over a two-year period in 16 animals. Computed tomography (CT) evaluation of lung cancer progression, final pathological examination, evidence of pro-viral JSRV-DNA in lung, lymph nodes and broncho-alveolar lavage cells as well as biochemical analysis of Se, GPx1 and thioredoxin reductase (TrxR) activity in lung tissue were recorded. Additionally, immunohistochemical determination of GPx1 expression in unaffected and neoplastic lung cells was implemented. The feeding regime caused significant differences in Se concentration and GPx1 activity in lung tissue between groups, whereas TrxR activity remained unaffected. JSRV was evident in broncho-alveolar lavage cells, lung tissue and lung lymph nodes. Quarterly executed CT could not demonstrate differences in lung cancer proliferation intensity. Necropsy and histopathology substantiated CT findings. Immunohistochemical analysis of GPx1 in lung tissue suggested a coherency of GPx1 immunolabelling intensity in dependence of tumour size. It was concluded that the model proved to be suitable for long-term studies of lung cancer proliferation including the impact of modifiable nutritional factors. Proliferation of OPA was unaffected by marginal vs. sufficient nutritional Se supply.

Ovine pulmonary adenocarcinoma as an animal model of progressive lung cancer and the impact of nutritional selenium supply.

Jaagsiekte sheep retrovirus (JSRV) is known to induce ovine pulmonary adenocarcinoma (OPA). Several studies have suggested an influence of selenium (Se) status on cancer progression. Thus, combining OPA with a defined Se supply might serve as a suitable animal model to study the impact of Se on lung cancer progression. 16 naturally JSRV-infected sheep were divided into 2 treatment groups receiving (a) <0.05 and (b) 0.2 mg Se/kg dry matter in diet, respectively. Computed tomography (CT) was performed repeatedly and evaluated using a CT-OPA-score system. Liver biopsies were taken three-monthly, blood samples were collected biweekly to study treatment effects on Se concentrations and glutathione peroxidase (GPx) activity. Cell pellets from bronchoalveolar lavage fluid (BALF) were tested for JSRV by PCR to approve the infection. To date, four animals of the ongoing study have been euthanised. Autopsy and histopathology were performed and correlated to CT analysis. JSRV was detected in BALF cell pellets. Progression of lung tumours was monitored successfully by repeated CT examinations, enabling the detection of even small nodules or increased lung density. Histopathology revealed bronchioloalveolar adenocarcinoma in lung areas suspicious to be OPA from CT evaluation. Score-based analysis of CT images for quantifying tumour progression proved as a valuable tool. Se concentration and GPx activity increased in liver and serum of group b and verified the efficiency of different feeding regime. In conclusion, OPA along with CT, autopsy/histopathology, trace element and enzyme activity analysis provide a suitable large animal model to examine the impact of Se supply on lung tumourigenesis.

Retrospective study on the occurrence of porcine circovirus 2 infection and associated entities in Northern Germany.

Porcine circovirus type 2 (PCV 2) represents a widespread, globally occurring pathogen with an increasing number of associated entities. To further elucidate the origin, spread and pathogenesis of PCV2 and associated changes archived material of pigs originating from Northern Germany and submitted for necropsy between 1961 and 1998 were investigated by using in situ hybridisation and polymerase chain reaction. PCV2 was first detected in a pig from 1962. However, incidence of detectable viral DNA and occurrence of PCV2-associated lesions varied substantially in the following years. The overall incidence of PCV2 infection was low between 1961 and 1984 (0-11.7%) and increased between 1985 and 1998 (14.3-53.3%). PCV2-associated pathological changes including postweaning multisystemic wasting syndrome (PMWS) and most likely porcine dermatitis and nephropathy syndrome (PDNS) were first observed in 1985. Selected sequence analyses of PCV2 DNA segments revealed high homology with current virus strains. In summary, findings showed that PCV2 has been present in the pig population in Northern Germany since 1962. This represents worldwide the earliest report about the detection of the PCV2 genome in pigs. Associated lesions such as PMWS and PDNS were not observed before 1985, indicating that virus infection alone does not seem to be sufficient enough to trigger the development of associated entities. Limited sequence analysis revealed no changes in the viral genome thus suggesting that other factors including environmental changes or co-infections with other agents might play a contributing role in the altered virulence of this pathogen and the occurrence of PCV2-associated lesions.

Interventional atrial septal defect closure using a totally bioresorbable occluder matrix: development and preclinical evaluation of the BioSTAR device.

OBJECTIVES: We sought to test the hypothesis that interventional atrial septal defect (ASD) closure can be performed safely and effectively using a bioresorbable occluder matrix. BACKGROUND: The ideal septal occluder scaffold should promote the healthiest and most complete healing response while eventually facilitating the full resorption of the material and leaving "native" tissue behind, thus minimizing the potential for future complications from chronic foreign body and maintaining the possibility for later unobstructed transseptal access to the left atrium. METHODS: The STARFlex occluders (NMT Medical Inc., Boston, Massachusetts) were modified by substituting the conventional polyester fabric for a bioengineered, acellular type-I collagen matrix derived from porcine submucosa with a heparin-coated surface (BioSTAR occluder, NMT Medical Inc.). Comparative transcatheter closure of ASDs was performed in young sheep (n = 36). Gross pathology and histopathology were obtained after follow-up periods ranging from 7 days to 2 years. RESULTS: The STARFlex (control) devices were encapsulated time-dependently by ingrown fibrous tissue. Histology showed a mild but chronically persisting foreign body reaction. By contrast, BioSTAR devices exhibited a mild-to-moderate transient cellular immune response. Heparin coating of the BioSTAR surface improved the biocompatibility of the device by reducing surface thrombogencity. A remodeling process of the collagen scaffold, starting after 30 days in vivo, resulted in the full replacement of the matrix by host tissue after 2 years of follow-up. CONCLUSIONS: The BioSTAR device is the first septal occluder with a totally bioresorbable matrix that is fully replaced by host tissue during the healing process. The promising results of this study support testing of the BioSTAR device in clinical trials.

A new biological matrix for septal occlusion.

The ideal septal occluder scaffold should promote the healthiest and most complete healing response possible while eventually facilitating the full resorption of the material, leaving "native" tissue behind. An excellent biocompatibility of the scaffold tissue is a prerequisite for quick, complete, and firm ingrowth of the device, optimizing outcomes and minimizing the potential for complications. Intestinal collagen layer (ICL) is a highly purified (acellular) bioengineered type-1 collagen derived from porcine submucosa. It is gradually resorbed by the host organism and subsequently replaced by the host tissue. CardioSEAL occluders were modified by substituting the conventional polyester fabric for an intestinal collagen layer (ICL). Percutaneous transcatheter closure of interventionally created atrial septal defects was performed in lambs using these modified occluders. A complete pathomorphological investigation including histology was carried out after 2, 4, and 12 weeks follow-up. Standard CardioSEAL implants served as a control group. After 2 weeks in vivo the devices were already covered completely by neo-endothelium. Compared with the conventional synthetic scaffold, ICL devices showed a quicker endothelialization, decreased thrombogenicity, and superior biocompatibility with no significant cellular infiltration observed in the histology of explants with ICL fabrics. After 3 months in vivo the collagen layer remained mechanically intact, but began to show the first histological signs of mild disintegration, gradual resorption, and remodeling. In conclusion, short-term results from preliminary in vivo experiments using a bioengineered collagen matrix as the occluder tissue scaffold showed excellent biocompatibility. This resulted in superior overall results: quicker endothelialization, a decreased thrombogenicity, and decreased immunological host response.

Degradation of tungsten coils implanted into the subclavian artery of New Zealand white rabbits is not associated with local or systemic toxicity.

OBJECTIVE: To assess whether corrosion of tungsten coils is related to residual shunting and to evaluate whether elevated tungsten serum levels are associated with local or systemic toxicity. METHODS: Tungsten coils (SPI, Balt, France) were implanted into the subclavian artery of New Zealand white rabbits leading to a residual high-flow shunt in 5/10 rabbits. Serial serum tungsten levels, complete blood count and clinical chemistry were analysed prior to the implantation as well as 15 min, 2 and 4 months thereafter. After 4 months the rabbits underwent repeat angiography before they were sacrificed and the internal organs were evaluated histopathologically. RESULTS: Mean tungsten levels rose from 0.48 microg/l prior to the implantation to 12.4 microg/l 4 months post-implantation. The rise in serum tungsten levels was neither associated with residual shunting present at the time of implantation nor with residual shunting at the time of explantation. One animal had to be sacrificed because of non-resolving palsy of the upper extremity. The remaining animals had an uneventful clinical course with no signs of toxicity of the elevated tungsten levels. Histological examination revealed no evidence of local or systemic toxicity of the tungsten coils. CONCLUSION: Tungsten coils corrode and lead to a steady increase in serum tungsten levels starting as early as 15 min after implantation. Residual shunting does not seem to influence the kinetics of corrosion of tungsten coils. Despite markedly elevated serum tungsten levels 4 months after implantation degradation of tungsten coils is not associated with local or systemic toxicity.