Targeting of Teniposide to the Mononuclear Phagocytic System (MPS) by Incorporation in Liposomes and Submicron Lipid Particles; An Autoradiographic Study in Mice

Liposomes are concentrated in the mononuclear phagocytic system in vivo and may therefore be of value as carriers of drugs when treating diseases involving phagocytic cells. Teniposide (VM-26) is a potent and lipophilic cytotoxic drug. Teniposide was incorporated in large unilamellar liposomes (LUVs) consisting of egg phosphatidylcholine and dioleoyl phosphatidic acid and into the novel submicron lipid particles containing cholesteryl oleate, cholesteryl palmitate and soybean lecithin, in order to evaluate the drug targeting effect. Radiolabelled teniposide and lipids were used and the organ distribution in mice was studied with whole-body autoradiography 20 and 90 min post i.v. injection. When the commercial formulation of teniposide (Vumon) was administered, teniposide accumulated in the liver where the drug is metabolized. Biliary excretion was rapid and considerable already after 20 min. The liposomal formulation enhanced liver uptake of teniposide slightly. The distribution of radiolabelled phosphatidyl choline differed from that of teniposide indicating instability of the liposomes in circulation. Despite this, the splenic uptake of the drug was significantly enhanced by administration in liposomes. In the red pulp of the spleen the teniposide level was 23 times higher 90 min post injection, using the liposomal formulation as compared to free drug. The submicron lipid particles were mainly accumulated in the liver and to a lesser extent in the spleen. The study shows that liposomes and lipid particles enhance splenic and liver uptake and can be used to target teniposide to the MPS.     

Detection of TP53 gene mutation in human meningiomas: A study using immunohistochemistry,polymerase chain reaction/single-strand conformation polymorphism and dna sequencing techniques on paraffin-embedded samples

Mutations in the TP53 tumor suppressor gene have been studied in different types of brain tumors. Little is known about this genetic event in human meningioma, a mostly benign tumor. To investigate the frequency of TP53 gene mutations in human tumors derived from meningeal tissues, paraffin-embedded tissues from 30 cases (including 2 malignant and 4 atypical meningiomas, as well as 2 hemangioblastomas and 3 hemangiopericytomas) were screened by immunohistochemistry. Polymerase chain reaction/single strand conformational polymorphism (PCR/SSCP) and direct DNA sequencing were thereafter performed in selected cases. Nuclear p53 staining was not seen in any of the 19 benign meningiomas tested, while atypical meningiomas, hemangioblastomas, and hemangiopericytomas displayed nuclear staining in a subpopulation of tumor cells in 4 out of 5, 2 out of 2, and 3 out of 3 cases, respectively. One malignant meningioma showed an intense nuclear staining and a band shift in SSCP. In this case, we identified a mutation in the TP53 gene at codon 161 changing GCC to ACC and resulting in an alteration of alanine to threonine in this position. Our results indicate that TP53 gene mutation may be considered as a marker for malignant transformation in meningioma. p53 immunoreactivity, even in the absence of detectable gene mutation, is also associated with atypia and does not appear in regular benign meningiomas. © 1995 Wiley-Liss, Inc.     

Ultraviolet Light and Non-Hodgkin's Lymphoma

In the beginning of this century, a Danish dermatologist, Professor Niels Finsen, received the Nobel Prize for his showing of the beneficial effects of UV-light on certain skin diseases. We have subsequently learned that UV-light is far from being only beneficial to our health. UV-light is an important risk factor for malignant melanoma and squamous cell carcinoma of the skin (1). Furthermore, UV-light appears to have immunosuppressive effects, not only on the local skin, but on the immune system in general (2-4). Recently, it was suggested that UV-light may also increase the risk of non-Hodgkin's lymphoma (NHL) (5, 6).     

Health status in Swedish burn patients. Assessment utilising three variants of the Burn Specific Health Scale

Perceived health in a consecutive group of major burn patients treated at the Uppsala University Hospital Burn Unit from 1980 to 1995 is reported. The three published variants of the Burn Specific Health Scale (BSHS), i.e. BSHS-Abbreviated (BSHS-A); BSHS-Revised (BSHS-R); BSHS-Brief (BSHS-B) were used in concert for this purpose in order to allow for a comparison of the instruments. Two hundred and forty-eight of 350 former patients (response rate 70.9%; mean total body surface area (TBSA) 23.1% (S.D.=16.2%)) responded to 94 items from previous versions of the BSHS at a mean of 9.3 (S.D.=4.8) years after injury. All three versions of the BSHS gave similar results with respect to global outcome on a group level. Correlations among the three different instruments were high, but were strongest between BSHS-B and BSHS-R (r=0.99). The largest impact on health was seen for Role Activities in BSHS-A, and Heat Sensitivity and Work in both BSHS-R and BSHS-B. There were significant relationships between sociodemographic variables (e.g. work, partnership and living) and self-reported outcome. Men reported better overall outcome than women did. The presence of a full thickness burn was associated with worse outcome with respect to several domains. The apparent variability in outcome pattern between different domains underscores the importance of utilising a broad instrument with adequate content validity.     

Kinematics and laxity of the knee joint after anterior cruciate ligament reconstruction: pre- and postoperative radiostereometric studies

BACKGROUND: Injury of the anterior cruciate ligament changes the kinematics of the knee joint. In studies of cadaveric knees, investigators have examined the effect of anterior cruciate ligament reconstruction on knee kinematics, but the effect on dynamic knee motion is not known. HYPOTHESIS: Reconstruction of the anterior cruciate ligament restores knee kinematics to normal. STUDY DESIGN: Prospective cohort study. METHODS: Nine patients were examined preoperatively and 1 year after reconstruction. Continuous radiostereometric exposures were performed at a speed of two to four exposures per second while the patients ascended an 8-cm high platform. Tibial rotation and tibial and femoral translation were measured with radiostereometric analysis. RESULTS: Tibial rotation and tibial and femoral translation were not significantly different after anterior cruciate ligament reconstruction compared with preoperative measurements. A radiostereometric evaluation of anterior knee laxity revealed restoration to within 1 mm of that on the uninjured side. Further evaluation of knee function using the Lysholm score, the Tegner activity level score, the International Knee Documentation Committee evaluation system score, and measurements of laxity using the KT-1000 arthrometer revealed significant improvements after reconstruction. CONCLUSION: Kinematics of the anterior cruciate ligament injured knee did not change significantly after ligament reconstruction, but the functional results were satisfactory and knee laxity was diminished.     

Immune deviation and the hygiene hypothesis: A review of the epidemiological evidence

The epidemiological evidence for the proposal that early life immune deviation is the principal mechanism by which microbial agents prevent the development of atopy has been reviewed. Seven criteria are proposed which should ideally be fulfilled. The majority of studies only fulfill two or three criteria. For mycobacteria, measles and respiratory viruses there are studies that demonstrate a significant increase in atopy or allergic disease. Parasite infections, which provide a strong TH2 stimulus, are associated with reduced rather than enhanced allergen sensitization. The available epidemiological evidence does not provide support for a mechanism of early life immune deviation. The principal environmental influences on atopic disease are likely to occur throughout life and involve interactions between microbes and other non-infective and lifestyle factors.     

Environmental influences on brain neurotrophins in rats

Environmental factors can have profound influences on the brain. Enriching environments with physical, social and sensory stimuli are now established to be beneficial to brain development and ageing. A multitude of responses from cellular and molecular mechanisms to macroscopic changes in neural morphology and neurogenesis have been considered in the context for evidences that environmental inputs can regulate brain plasticity in the rat at all stages of life. Data from our laboratory have revealed that enriched environment increased nerve growth factor (NGF) gene expression and protein levels in the hippocampus, and this may contribute to events underlying environmentally induced neural plasticity. Because neurotrophic factors are essential for neural development and survival, they are likely to be involved in the cerebral consequences modified by enriched experiences.     

Therapy with radiopharmaceuticals

In an investigation by the Swedish Cancer Society, an expert group described the present status, critical issues and future aspects and potentials for each of nine major areas of radiation therapy research. The present report deals with therapy with radiopharmaceuticals.     

Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease

BACKGROUND: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use. METHODS: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided. RESULTS: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment. CONCLUSIONS: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco.