Differential effects of chlorpromazine on the in vitro generation and effector function of cytotoxic lymphocytes

Allograft rejection represents a cytotoxic response mediated to a large degree by thymus-derived T lymphocytes (1). The study of such cell-mediated cytotoxic phenomena has been greatly facilitated by the discovery first noted by Hayry and Defendi (2) and Wunderlich and Cany (3), that a natural consequence of allogeneic stimulation in an unidirectional mixed lymphocyte culture (MLC) was the appearance of cytotoxic lymphocytes specific for antigens present on the stimulator cells. Subsequent studies have shown that such in vitro generation of cytotoxic lymphocytes was dependent on the proliferative response in an MLC (4), was genetically determined (5), and possibly required the interaction of several subpopulations of T cells (6). We now report that the surface active agent chlorpromazine: (a) inhibits allogeneic stimulation of the proliferative response in an MLC; (b) inhibits the MLC generation of cytotoxic lymphocytes, (c) has no effect on the recognition, binding, or lysis of target cells by already sensitized lymphocytes; and (d) blocks a postproliferative membrane-mediated event, independent of proliferation, and necessary for the MLC generation of cytotoxic lymphocytes.     

Lithium inhibits internalization and endosomal processing of both neuropeptide Y (NPY) Y1 and transferrin receptors

Low concentrations of Li+ reduce the rate of internalization of neuropeptide Y (NPY) Y1 receptors [M.S. Parker, S.L. Parker, J.K. Kane, Internalization of neuropeptide Y Y1 and Y5 and of pancreatic polypeptide Y4 receptors is inhibited by lithium in preference to sodium and potassium ions, Regul. Pept., 118 (2004) 67-74]. This Li+-induced decrease in Y1 receptor internalization could be alleviated by Y1 receptor agonists. As shown by fractionation on Percoll gradients, lithium treatment induces a concentration-related decrease of intermediate and higher endosomal densities that contain the internalized Y1 ligand-receptor complex. This indicates an inhibition of endosome processing and maturation. Internalization of human transferrin shows [Li+] sensitivity similar to that of the Y1 receptor, and a similar Li+-induced decrease in endosomal processing. Lithium treatment thus decreases activity of the endosome system shared in the recycling endocytosis of the Y1 and transferrin receptors.     

Cell density alters matrix accumulation in two distinct fractions and the mechanical integrity of alginate-chondrocyte constructs

Chondrocyte density in articular cartilage is known to change with the development and growth of the tissue and may play an important role in the formation of a functional extracellular matrix (ECM). The objective of this study was to determine how initial chondrocyte density in an alginate hydrogel affects the matrix composition, its distribution between the cell-associated (CM) and further removed matrix (FRM) fractions, and the tensile mechanical properties of the developing engineered cartilage. Alginate constructs containing primary bovine chondrocytes at densities of 0, 4, 16, and 64 million cells/ml were fabricated and cultured for 1 or 2 weeks, at which time structural, biochemical, and mechanical properties were analyzed. Both matrix content and distribution varied with the initial cell density. Increasing cell density resulted in an increasing content of collagen and sulfated-glycosaminoglycan (GAG) and an increasing proportion of these molecules localized in the CM. While the equilibrium tensile modulus of cell-free alginate did not change with time in culture, the constructs with highest cell density were 116% stiffer than cell-free controls after 2 weeks of culture. The equilibrium tensile modulus was positively correlated with total collagen (r² = 0.47, p < 0.001) and GAG content (r² = 0.68, p < 0.001), and these relationships were enhanced when analyzing only those matrix molecules in the CM fraction (r² = 0.60 and 0.72 for collagen and GAG, respectively, each p < 0.001). Overall, the results of this study indicate that initial cell density has a considerable effect on the developing composition, structure, and function of alginate–chondrocyte constructs.     

可调节式人工砧骨的颞骨实验研究

目的 :对中耳听力重建手术来说 ,合适的人工听骨张力是至关重要的 ,而刚性人工听骨的张力与其长度直接相关。本文目的为探讨人工听骨的长度发生细微变化 (即听骨链的张力发生微小变化 )时 ,中耳的声音传输特点。方法 :7个成人颞骨冰冻标本被采用 ,将一可调节长度钛质人工砧骨植入到颞骨标本中 ,用多普勒激光测振系统 (HL V- 10 0 0型 ,Polytec,PI,Costa Mesa,CA)测量镫骨底板的位移 ,声刺激为 0 .1～ 10 k Hz间的 4 0 6个纯音 ,鼓膜表面的声刺激强度为80 d B SPL。首先测量听骨链完整时镫骨底板的位移 (即基线 ) ,然后摘除砧骨 ,将人工砧骨植入到镫骨头与槌骨柄尖端之间。调节砧骨的长度 ,使其处于最佳长度状态 (即最合适张力 )以及在此基础上分别增加 0 .2 mm和 0 .4 mm,再分别测量这三种状态时镫骨底板的位移。结果 :当人工砧骨处于最佳长度时 ,与听骨链完整时的基线相比 ,在 1.0 k Hz以下声音传输相差 0 .2 d B;1.0～ 3.0 k Hz之间 ,平均听力降低 1.7d B;3.0 k Hz以上 ,声音传输比基线好。当人工砧骨的长度增加0 .2 mm(一个刻度 )时 ,与基线相比 ,1.0 k Hz以下 ,平均降低 6 .0 d B,1.0 k Hz以上 ,平均降低 3.0 d B。当人工砧骨的长度再增加 0 .2 mm(共增加 2个刻度 ) ,与基线相比 ,1.0 k Hz以下降低     

The peroxisome proliferators are hepatocyte mitogens in chemically- defined media: glucocorticoid-induced PPAR alpha is linked to peroxisome proliferator mitogenesis

Peroxisome proliferator-induced mitogenesis is believed to play a role in hepatocarcinogenesis, but it has not been possible to demonstrate high level induction of DNA synthesis by peroxisome proliferators in cultured hepatocytes. We now show that four structurally dissimilar peroxisome proliferators (methylclofenapate, Wy-14 643, tetradecyl-3- thia acetic acid and clofibrate) cause high level induction of DNA synthesis in primary cultures of rat hepatocytes, routinely 7-9 fold above control, with up to 29% of cells undergoing S-phase. Peroxisome proliferators induce DNA synthesis rapidly, with maximal response 24 h after dosing [compared with 48 h for epidermal growth factor (EGF)]; indeed, peroxisome proliferators were mitogenic in a chemically defined medium, i.e. with no added exogenous growth factors. EGF-treated hepatocytes that had undergone DNA synthesis comprised 23% binucleated cells, whereas hepatocytes induced into S-phase by peroxisome proliferators contained only 3% binucleated cells, demonstrating a distinct response of hepatocytes to peroxisome proliferators and EGF. The presence of a glucocorticoid was essential for peroxisome proliferator-induced DNA synthesis, but not for EGF-induced DNA synthesis, demonstrating that the requirement for glucocorticoids is selective for peroxisome proliferators. Hydrocortisone was shown to induce the expression of peroxisome proliferator activated receptor- alpha (PPAR alpha), and we propose that it is the glucocorticoid- induced expression of PPAR alpha that is essential for peroxisome proliferator mitogenesis. This in vitro system provides a powerful tool for investigating the mechanism and role of peroxisome proliferator- induced mitogenesis in liver growth and carcinogenesis.      

Pediatric home health care in King County, Washington

BACKGROUND: Pediatric home health care is one of the fastest growing segments of our health care system. However, our knowledge of the extent and quality of the services provided in this field is generally limited. Despite this shortcoming, pediatric health care providers are increasingly expected to participate in the home health care of their patients. OBJECTIVE: To describe the agencies and services that constitute pediatric home health care in a large metropolitan setting. METHODS: During the summer of 1995, home health care agencies in King County, WA, were surveyed if they had provided any pediatric services within the preceding 6 months. The agencies were queried about their characteristics and services provided, as well as referral and reimbursement sources. Survey data were supplemented by interviews with agency and state health personnel. RESULTS: Fourteen (88%) of the 16 agencies providing pediatric home health care services completed the survey. Agencies were predominantly for-profit, free-standing, and in business fewer than 10 years. Although there were uniform licensing requirements for agencies, no pediatric-specific regulations existed. In addition, many agencies lacked internal methods to ensure the provision of quality pediatric care. Eighty percent of all pediatric home health care services were provided by only 5 agencies. For intermittent (acute) services, agencies served approximately 450 children per month. The average number of visits per child was two, with 40% receiving only one visit. Services included skilled nursing (60%), infusion (27%), and respiratory therapy (9%). Maintenance (chronic) home health care services, for 156 chronically ill children, were provided almost exclusively by skilled nursing for an average of 9 hours per patient per day. The majority of referrals to agencies (75%) originated from health care providers, although a small number came from insurance companies or individual families. Reimbursement for intermittent care services was divided among commercial insurance (35%), captitated contracts (35%), and Medicaid (20%). In contrast, 90% of reimbursement for the chronically ill was from Medicaid. CONCLUSIONS: In King County, WA, pediatric home health care is predominantly an unregulated, for-profit industry, with most agencies having little actual experience in pediatric home health care. In addition, the unique features of pediatric home health care necessitate both a greater understanding of this field and the consideration of more specific guidelines.     

Enhanced drug metabolism in young children with cystic fibrosis

The effect of cystic fibrosis on caffeine metabolism was studied in young children using the caffeine breath test. Eight children with cystic fibrosis aged 2-6 years and nine age matched controls were studied on a single occasion, and the cumulative percentage of labelled caffeine exhaled as carbon dioxide measured over two hours. This was significantly higher in the patients with cystic fibrosis than in controls, suggesting an increase in the CYP1A2 metabolic pathway in the former. The fact that these were young children with minimal lung and liver disease suggests that enhanced drug metabolism in children with cystic fibrosis is hereditary rather than secondary to lung and liver damage.     

Nasal cerebral heterotopia: a case report

Nasal cerebral heterotopia (nasal glioma) are rare congenital benign masses of neurogenic origin with intranasal location, or both. An extranasal case is reported in a 2-year-old-boy without any bony defect or connection with brain. Histology and immunohistochemistry confirmed the diagnosis.