Hydrolytic degradation of poly(carbonate)-urethanes by monocyte-derived macrophages

Polycarbonate (PCN)-based polyurethanes (PCNU) are rapidly becoming the chosen polyurethane (PU) for long-term implantation since they have shown decreased susceptibility to oxidation. However, monocyte-derived macrophages (MDM), the cell implicated in biodegradation, also contain hydrolytic activities. Hence, in this study, an activated human MDM cell system was used to assess the biostability of a PCNU, synthesized with 14C-hexane diisocyanate (HDI) and butanediol (BD), previously shown to be susceptible to hydrolysis by cholesterol esterase (CE). Monocytes, isolated from whole blood and cultured for 14 days on polystyrene (PS) to mature MDM, were gently trypsinized and seeded onto 14C-PCNU. Radiolabel release and esterase activity, as measured with p-nitrophenylbutyrate, increased for almost 2 weeks. At 1 week, the increase in radiolabel release and esterase activity were diminished by more than 50% when the protein synthesis inhibitor, cycloheximide, or the serine esterase/protease inhibitor, phenylmethylsulfonylfluoride was added to the medium. This strongly suggests that in part, it was MDM esterase activity which contributed to the PU degradation. In an effort to simulate the potential combination of oxidative and hydrolytic activities of inflammatory cells. 14C-PCNU was exposed to HOCl and then CE. Interestingly, the release of radiolabeled products by CE was significantly inhibited by the pre-treatment of PCNU with HOCl. The results of this study show that while the co-existing roles of oxidation and hydrolysis in the biodegradation of PCNUs remains to be elucidated, a clear relationship is drawn for PCNU degradation to the hydrolytic degradative activities which increase in MDM during differentiation from monocytes, and during activation in the chronic phase of the inflammatory response.     

IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis

The International Programme on Chemical Safety (IPCS) is leading an activity to harmonize approaches to cancer risk assessment as a part of its larger project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. Through a series of workshops and the evaluation of case studies, a number of key components of risk assessments relating to harmonization were identified: transparency, terminology, weight of evidence, flexibility, and accessibility/communication. A major impediment to harmonization identified in the consideration of weight of evidence was the evaluation of mode of action. To address this need, a conceptual framework was developed, based on the general principles involved in considering the chemical induction of a specific tumor in animals. This is based partly on the Bradford Hill criteria for causality as modified by Faustman et al. (1997) for developmental toxicity. The framework is described in this paper followed by a worked example. It is recognized that the framework addresses only one stage in the overall characterization of hazard to humans of chemical carcinogens. Another important but separate step is the assessment of relevance to humans. This is a priority area for future work in this project.     

Acute toxicity and first clinical results of intensive postinduction therapy using a modified busulfan and cyclophosphamide regimen with autologous bone marrow rescue in first remission of acute myeloid leukemia [see comments]

The combination of high-dose busulfan (16 mg/kg) and 200 mg/kg cyclophosphamide is gaining increasing significance as a preparative regimen prior to autologous, syngeneic, or allogeneic marrow transplantation. A new regimen of high-dose busulfan in conjunction with a reduced dose of 120 mg/kg cyclophosphamide has recently been described as a preparative regimen prior to allogeneic transplantation. To determine the drug-related nonhematologic toxic effects of this new regimen without confounding factors associated with allogeneic transplantation, we conducted a pilot study using this new regimen in 20 patients with acute myeloid leukemia (AML) in first remission prior to autologous unpurged marrow transplantation. All patients experienced transient non-life-threatening acute drug-related toxicity with skin reactions in 20 (100%), nausea and vomiting in 20 (100%), oral mucositis in 18 (90%), hepatic functional impairment in 17 (85%), hemorrhagic cystitis in three (15%), and generalized seizures in two (10%) of these patients, respectively. Two procedural, fatal complications resulted from infectious causes that were not directly related to the speed of hematopoietic reconstitution or the toxicity of the preparative regimen. The 3-year event-free survival estimate (55% +/- 11%) and probability of leukemic recurrence (38% +/- 11%) attained with this new regimen in recipients of autografts in first remission of AML are promising and challenge comparisons with preparative regimens employing combinations of cytotoxic agents or total body irradiation (TBI).     

Community‐based Residential Supports for People with Intellectual Disabilities and Challenging Behaviour: The Views of Neighbours

Background The issue of the views of neighbours of community‐based residential supports for people with intellectual disabilities and challenging behaviour has not been examined till date. This study looks at the views of neighbours of two types of community‐based residential supports: non‐congregate settings where the minority of residents have challenging behaviour; and congregate settings where the majority of residents have challenging behaviour. Materials and methods A self‐completion questionnaire was used to collect information on contact between neighbours, residents and staff, and the views of neighbours. Information was also collected by semi‐structured interview with service staff on the characteristics of settings. Results Sixty‐four questionnaires were returned. Contact between neighbours and service users was limited for both types of setting, with two‐thirds of neighbours not knowing any service users by name, and a third having had no active contact with service users. Neighbours of non‐congregate settings were more likely to think that community care was a ‘good policy’ (76%) than neighbours of congregate settings (53%) and to believe that there were benefits to the neighbourhood from having the group home in the area (46% versus 29%) but these differences were not significant. Contact with people with intellectual disabilities was associated with more positive attitudes to community care and specific characteristics of the settings. Conclusions Contact between neighbours and people with severe intellectual disabilities and challenging behaviour is limited. However, the majority of neighbours are positive about community care and the problems reported by neighbours are predominantly minor. The results point to the key role that contact plays in fostering positive attitudes. Findings regarding differences between congregate and non‐congregate settings are limited by the small number of responses from neighbours of congregate settings.     

Kr-81m ventilation imaging: clinical utility in suspected pulmonary embolism

The results of Kr-81m/Tc-99m ventilation-perfusion (VP) lung scintigraphy were correlated with the results of pulmonary angiography for 74 patients suspected of having pulmonary embolism (PE). Among patients having a diagnostic scan, the sensitivity and specificity of scintigraphy were 91% and 94%, respectively. Also, 157 consecutive cases of Kr-81m/Tc-99m VP lung scintigraphy were reviewed, and the frequency of an indeterminate scan was found to be 22%. A similar frequency was found for VP scintigraphy with xenon-133. Of eight patients who had indeterminate scans due to the presence of a single VP mismatch, four were demonstrated to have PE by angiography. Kr-81m is an excellent agent for VP scanning in cases of suspected PE, offering accuracy in diagnosis as well as favorable physical properties.     

商陆多糖Ⅱ体外对小鼠脾细胞增殖及产生集落刺激因子的影响

用[³H]TdR参入法检测小鼠脾细胞增殖能力及产生集落刺激因子(colony stimulating factor. CSF)含量.证明商陆多糖Ⅱ(PAP-Ⅱ)在31～500 μg·m^-1范围内显著促进小鼠稗细胞增殖。PAP-Ⅱ,31～125 μg·ml^-1可剂量依赖性地促进Con A(1,2.8μg·ml^-1),LPS(3,10,30 μg·ml^-1)诱导的淋巴细胞细咆增殖,随着PAP-Ⅱ剂量加大,对丝裂原诱导的淋巴细胞增殖反呈抑制作用。PAP-Ⅱ。10～500μg·ml^-1呈剂量及时间依赖性地促进脾细胞产生CSF,其最适剂量为100 μg·ml^-1。最佳时间为5 d,提示PAP-Ⅱ能增强免疫及促进造血功能。