Stable trichimerism after marrow grafting from 2 DLA-identical canine donors and nonmyeloablative conditioning

Although hematopoietic cell transplantation (HCT) is generally accomplished using a single donor, multiple donors have been used to enhance the speed of engraftment, particularly in the case of umbilical cord blood grafts. Here we posed the question in the canine HCT model whether stable dual-donor chimerism could be established using 2 DLA-identical donors. We identified 8 DLA-identical littermate triplets in which the marrow recipients received 2 Gy total body irradiation followed by marrow infusions from 2 donors and postgrafting immunosuppression. All 8 dogs showed initial "trichimerism," which was sustained in 5 dogs, while 2 dogs rejected one of the allografts and remained mixed chimeras, and 1 dog rejected both allografts. Immune function in one trichimeric dog, as tested by mixed leukocyte culture response and antibody response to sheep red blood cells, was found to be normal. Five dogs received kidney grafts from one of their respective marrow donors at least 6 months after HCT without immunosuppressive drugs, and grafts in 4 dogs are surviving without rejection. In summary, following nonmyeloablative conditioning, simultaneous administration of marrow grafts from 2 DLA-identical littermates could result in sustained trichimerism, and immunologic tolerance could include a kidney graft from one of the marrow donors.     

Surgical animal models of heart failure related to coronary heart disease

Coronary heart disease is caused by atherosclerotic narrowing of coronary arteries. It accounts for about two-thirds of heart failure cases, which are frequently secondary to myocardial infarction. Despite considerable progress in the understanding and management of heart failure, its incidence, prevalence and economic burden are steadily increasing. Therefore, efficient preventive and therapeutic measures are urgently needed. In order to investigate the mechanisms involved in the pathogenesis of coronary heart disease-related heart failure and to develop therapies, appropriate animal models are indispensable. According to the aetiology of this disorder, surgical models are based on various methods allowing for the narrowing or occlusion of coronary arteries. Depending on the duration and extent of the impairment of coronary blood flow and its consequences for cardiac tissue, these are classified as models of myocardial infarction, cardiac ischemia/reperfusion injury, or chronic cardiac ischemia. In addition, factors such as species, strain, and gender of the laboratory animals also significantly contribute to the pathophysiology of the induced disorder and, therefore, have to be taken into consideration thoroughly when an animal model is to be established.     

Feasibility of high activity rhenium-188-microsphere in hepatic radioembolization

BACKGROUND: This paper describes the feasibility of intra-arterial high-activity administration of (188)Re-microspheres. METHODS: Patients with unresectable colorectal liver metastases or hepatocellular cancer (HCC) received single treatments with (188)Re-microspheres. The administered activity was calculated to give a liver dose of 100 Gy. From post-therapeutic scans and urine sampling, the dose to the liver, metastases and bladder was calculated. Toxicity was assessed up to 3 months after administration by means of the Common Terminology Criteria for Adverse Events v3.0 (Trotti et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13(3):176-81). Response was evaluated on CT. RESULTS: 13.6 +/- 4.7 GBq (188)Re-microspheres was administered selective in the feeding artery of the tumour to 10 patients (3 x HCC and 7 x colorectal liver metastases). There was a low urinary excretion rate of 8.9 +/- 3.8% of administered activity within 96 h. The absorbed dose to the tumour, normal liver (excluding the tumour) and bladder was 10.24 +/- 5.02 Gy/GBq (128 +/- 47 Gy), 3.94 +/- 2.52 Gy/GBq (50 +/- 33 Gy) and 0.27 +/- 0.20 Gy/GBq (2.4 +/- 1.9 Gy), respectively. There was an acceptable rate of toxicity in 30% of grades I and II, respectively, and 10% with grade III. There was reversible in the most patients within 14 days after treatment. The response was assessed on CT: two patients had a partial response (PR), five patients had stable disease and three patients had disease progression. CONCLUSION: Treatment of colorectal liver metastases or HCC using high activities of (188)Re-microspheres was well tolerated and a PR was seen in 2 of 10 patients. The treatment represents a therapeutic option in these patients.     

Model for the response of radiographic films and implications for quality assurance

The present paper describes the development of a model linking the optical density of a radiographic film to the applied dose. This model takes into account the kind of bremsstrahlung used in radiotherapy, and uses fewer parameters compared with the models developed so far. The measurements showed an influence of the field size on the model parameters. Monte Carlo simulations showed that different field sizes and depths in solid water can change the spectral distributions. The spectrum hardens with decreasing field size and increasing depth in phantom material. This has an influence on the model parameters. Nevertheless, the model can still be used to describe the relation between optical density and applied dose for films that are irradiated with fields of different size. A dose-rate dependence was not observed. The size and form of the fields used in calibration and application can therefore cause a systematic error in verification with film.     

Change in psychological resources of younger and older cancer patients during chemotherapy

Psychological resources were investigated in 150 recently diagnosed adult cancer patients and in 150 healthy control group members. Before the start of chemotherapy, cancer patients reported higher levels of optimism, purpose in life than their healthy peers, and self-esteem (only younger patients) whereas no between-group differences emerged for internal locus of control. However, the mobilization of psychological resources was limited to younger patients, and varied by item content. Over a 9-month period, most psychological resources of cancer patients showed a small but significant decline, and patients with higher illness-related stressors (e.g. stronger functional impairments, low perceived success of therapy) were more likely to decline in resources. We conclude that in line with cognitive adaptation theory cancer diagnosis leads to an initial mobilization of psychological resources in younger patients, but that over the course of therapy psychological resources decline to a level that would be expected in healthy adults.     

Long-term tolerance to kidney allografts in a preclinical canine model

Durable immune tolerance supporting vascularized allotransplantation offers the possibility of extending graft survival and avoiding harmful complications of chronic immunosuppression. Immune tolerance to renal allografts was induced in a preclinical canine model through engraftment of donor hematopoietic cells using a combination of low-dose total body irradiation and a short course of immunosuppression. Subsequently, donor renal allografts were transplanted accompanied by bilateral native nephrectomies. With 5-year follow up, we found normal renal function in all recipients and no histological evidence of acute or chronic rejection. This tolerance does not extend universally to donor skin grafts, however, with two of four animals rejecting delayed donor skin grafts. Hematopoietic chimerism produces durable and robust immune tolerance to kidney allografts, although incomplete tolerance to donor skin grafting.     

An extract from the medicinal plant Phyllanthus acidus and its isolated compounds induce airway chloride secretion: A potential treatment for cystic fibrosis

According to previous reports, flavonoids and nutraceuticals correct defective electrolyte transport in cystic fibrosis (CF) airways. Traditional medicinal plants from China and Thailand contain phytoflavonoids and other bioactive compounds. We examined herbal extracts of the common Thai medicinal euphorbiaceous plant Phyllanthus acidus for their potential effects on epithelial transport. Functional assays by Ussing chamber, patch-clamping, double-electrode voltage-clamp and Ca2+ imaging demonstrate activation of Cl- secretion and inhibition of Na+ absorption by P. acidus. No cytotoxic effects of P. acidus could be detected. Mucosal application of P. acidus to native mouse trachea suggested transient and steady-state activation of Cl- secretion by increasing both intracellular Ca2+ and cAMP. These effects were mimicked by a mix of the isolated components adenosine, kaempferol, and hypogallic acid. Additional experiments in human airway cells and CF transmembrane conductance regulator (CFTR)-expressing BHK cells and Xenopus laevis oocytes confirm the results obtained in native tissues. Cl- secretion was also induced in tracheas of CF mice homozygous for Phe508del-CFTR and in Phe508del-CFTR homozygous human airway epithelial cells. Taken together, P. acidus corrects defective electrolyte transport in CF airways by parallel mechanisms including 1) increasing the intracellular levels of second messengers cAMP and Ca2+, thereby activating Ca2+-dependent Cl- channels and residual CFTR-Cl- conductance; 2) stimulating basolateral K+ channels; 3) redistributing cellular localization of CFTR; 4) directly activating CFTR; and 5) inhibiting ENaC through activation of CFTR. These combinatorial effects on epithelial transport may provide a novel complementary nutraceutical treatment for the CF lung disease.     

Acute or subchronic clozapine treatment does not ameliorate prepulse inhibition (PPI) deficits in CPB-K mice with low levels of hippocampal NMDA receptor density

Introduction The hypo-glutamatergic hypothesis of schizophrenia is based on clinical similarities between schizophrenia and phencyclidine (PCP)-induced psychosis in mentally healthy humans. Sensorimotor gating, as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR), is impaired in schizophrenic patients. In animals, noncompetitive N-methyl-d-aspartate (NMDA) antagonists such as PCP disrupt PPI in a way that resembles the defect seen in schizophrenia. In a previous study with inbred mouse strains, low PPI levels have been demonstrated in CPB-K mice possessing low levels of hippocampal NMDA receptor densities. The present study was performed to test whether the low magnitude of PPI in CPB-K mice can be reversed by the atypical antipsychotic drug clozapine (CLZ). Results Before any treatment, CPB-K mice displayed a significant (p < 0.001) lower level in PPI and a significant (p < 0.001) higher ASR when compared to BALB/cJ mice known to have high hippocampal NMDA receptor densities. Acute and subchronic effects of a 2-week treatment with CLZ at daily doses of 5 and 10 mg/kg intraperitoneally, respectively, did not reveal any significant alteration of PPI levels in CPB-K mice. Nevertheless, the examination of motor behavior during nonstimulus trials provided a positive control for the drug’s effectiveness. Conclusion In summary, (1) this study confirmed our working hypothesis: Lower levels of hippocampal glutamatergic receptor densities correspond to lower sensorimotor gating in CPB-K mice, and (2) acute or subchronic treatment with CLZ did not elevate low PPI levels in CPB-K mice. Thus, further experiments will concentrate on other antipsychotic drugs to prove the predictive validity of this animal model.