Effects of arginine-enriched total parenteral nutrition on inflammatory-related mediator and T-cell population in septic rats

OBJECTIVES: Previous reports have shown that oral arginine (Arg) has immune-enhancing properties in injury. However, the effects of parenterally infused Arg on sepsis are not well understood. We used a septic rat model to study Arg infusion in inflammatory-related cytokines and blood T lymphocyte population in vivo. METHODS: Rats with internal jugular catheters were assigned to one of two groups. Both groups received isonitrogenous total parenteral nutrition (TPN) supplemented with 270 mg of nitrogen per kilogram per day as Arg or glycine (Gly). TPN provided 270 kcal/kg of body weight, and the kilocalorie:nitrogen ratio was 143:1. TPN was maintained for 5 d plus 2, 4, or 6 h or 6 d, according to the scheduled deaths of the rats. On day 5, sepsis was induced by cecal ligation and puncture (CLP). After CLP for 2, 4, 6, and 24 h, rats were killed. RESULTS: The results showed that interleukin-1beta and tumor necrosis factor-alpha concentrations in peritoneal lavage fluid at 6 h and interleukin-6 levels at 24 h after CLP in the Gly group were significantly higher than those in the Arg group. The T-lymphocyte population in blood showed that CD8(+) suppressor T-cell number was significantly higher in the Gly group than in the Arg group at 6 h after CLP. The blood CD4(+):CD8(+) ratio was significantly higher in the Arg group than in the Gly group at 24 h after CLP. A negative nitrogen balance was observed in the Arg and Gly groups after CLP; there was no significant difference in nitrogen balance between the septic groups. No difference in survival rate at 24 h after CLP was observed between the groups. CONCLUSIONS: The results showed that, compared with the Gly group, TPN preinfused with Arg reduces the production of inflammatory mediators at the site of injury and that cellular immunity is enhanced at 24 h after CLP. Parenterally administered Arg had no beneficial effect in preventing nitrogen loss and improving survival in septic rats. Whether Gly has specific effects that reduce the effects of Arg require further investigation.     

Modelling death rates for carriers of hepatitis B

Hepatitis B carriers who acquired the infection perinatally die from hepatocellular carcinoma (HCC) and cirrhosis at high rates. Published cohort studies are largely limited to males and are too small to estimate the age-specific risk of death. We therefore used routinely collected Hong Kong data to estimate the risks. Deaths were partitioned between carriers and non-carriers, then current life table calculations determined life expectancy and probability of dying from HCC or cirrhosis. HCC is the dominant cause of death for male carriers in middle adulthood with a lifetime risk of 27% for HCC compared to 4% for females. Predicted life expectancy is 72 years for male carriers, compared to 79 years for non-carriers. Female carriers have a life expectancy of 81 years and non-carriers 83 years. This model probably applies to all southern Chinese populations and emigrants with similar life history, and other populations that acquired infection early in life.     

Changing incidence of non-Hodgkin lymphomas in the United States

BACKGROUND: The incidence of non-Hodgkin lymphoma (NHL) has been rising in many regions and populations during the last few decades. Data from the Surveillance, Epidemiology, and End Results (SEER) Program show that age-adjusted rates of NHL increased through the 1980s but leveled off in the 1990s. METHODS: To determine whether the incidence of NHL stabilized in all population subgroups, particularly in age-defined groups with distinctive risks of NHL, the authors investigated trends in NHL incidence among persons aged 0-14 years, 15-24 years, 25-34 years, 35-44 years, 45-54 years, 55-64 years, 65-74 years, and > 75 years by gender and race using 1973-1998 data from the SEER Program, which covered approximately 10% of the U.S. population. Joinpoint regression was used to assess changes in trends across the period. RESULTS: NHL incidence trends changed significantly among males aged 25-54 years, in whom rates began to decrease (6-16% per year) in the middle to late 1990s, as well as among most whites aged > or = 55 years, in whom rate increases slowed from 3-4% to 1-2% per year in the late 1980s. Incidence trends were steady in other groups, with uniform increases among whites aged 15-24 years (2-3% per year), women aged 25-54 years (1-6% per year), and blacks aged > or = 55 years (2-4% per year). Although recent age specific incidence rates were generally higher in males compared with females and in whites compared with blacks, among males aged 25-54 years, rates were significantly higher in black males compared with white males. CONCLUSIONS: There have been changes in the demographic groups impacted by NHL. The trends for human immunodeficiency virus probably are related to recent decreases in NHL incidence among males aged 25-54 years. The rate change in the older white population is unexplained but represents both an alleviation of the burden of NHL in this population and a potential opportunity to generate hypotheses regarding risk factors for the development of NHL.     

The role of 18F-FDG-PET in the local/regional evaluation of women with breast cancer

Purpose. In women with breast cancer, knowledge of the local/regional extent of the tumor is essential for staging, treatment planning, monitoring response to therapy, and follow-up. Positron emission tomography (PET) is an important imaging test which can detect tumor at multiple sites in women with breast cancer. We compared the ability of PET to provide a comprehensive view of the local/regional extent of tumor in women with stage I, II and stage III, IV breast cancer. Materials and methods. Forty-six women with breast cancer underwent PET using ¹⁸F-FDG. ¹⁸FDG uptake in the breast primary tumor, associated skin, axillary and internal mammary lymph nodes, and the contralateral breast was determined qualitatively, and correlated with histologic, clinical and radiographic findings. Results. Twenty-four patients were premenopausal and 22 were postmenopausal, with the following distribution according to clinical stage: stage I – 2 patients, stage II – 16, stage III – 16, stage IV – 12 patients. Among stage I, II patients, the sensitivity for detection of the primary tumor was 83.3%, and for detection of axillary lymph node metastases was 42.9%. ¹⁸FDG-PET was negative for the breast skin, contralateral breast, and internal mammary lymph nodes in all stage I, II patients, in agreement with clinical and radiographic findings. Among 28 stage III, IV patients, the sensitivity of ¹⁸FDG-PET for detection of the primary tumor was 90.5%, and for detection of axillary lymph node metastases 83.3%. Fourteen patients had clinically advanced changes in the skin, and the sensitivity of PET for detection of skin changes was 76.9%. ¹⁸FDG-PET was positive in the internal mammary lymph nodes in 25.0%, and negative in the contralateral breast in all patients with stage III, IV breast cancer. ¹⁸FDG-PET was studied in 10 patients following neoadjuvant chemotherapy, and showed a strong correlation with clinical response, and with clinical and pathological findings post-treatment at multiple local/regional sites. Conclusion. ¹⁸FDG-PET can provide a comprehensive image of local/regional tumor in women with breast cancer. ¹⁸FDG-PET may play a greater role in women with stage III, IV breast cancer because of increased sensitivity and the increased involvement of multiple local/regional sites with tumor.     

Thyroid hormone receptor alpha 1 (c-erb A alpha 1) suppressed transforming phenotype of nasopharyngeal carcinoma cell line

Only three thyroid hormone receptor (TR) isoforms, alpha 1, beta 1, and beta 2, bind thyroid hormone (TH) and are considered to be true TRs. TR alpha 2, unable to bind TH, binds to TH response element on DNA and has been shown to exert dominant negative action on TR alpha1. TR alphas regulate many important processes such as proliferation, differentiation and apoptosis. To find out if TR alphas played roles in growth control of nasopharyngeal carcinoma cells, transfectant with inducible expression of TR alpha 1 was generated from NPC-TW 04 cell lines. Induced expression of TR alpha 1 in nasopharyngeal carcinoma cell reduced proliferation and colony-formation ability in agar. Tumor formation ability in nude mice was reduced in NPC cells with TR alpha 1 expression than those without expression or vector-transfected cells. Our results supported the hypothesis that TR alpha 1 functions as a tumor suppressor gene in nasopharyngeal carcinoma tumorigenesis.     

Assessment of growth inhibition and morphological changes in in vitro and in vivo hepatocellular carcinoma models post treatment with dl1520 adenovirus

BACKGROUND AND AIMS: E1B-deleted virus dl1520 (ONYX-015) has been previously used in clinical trials mainly for treatment of head and neck tumors, and has been shown to have beneficial effects independent of p53 status. The main aim of this investigation was to carry out a preclinical study for assessment of the use of dl1520 in in vitro and in vivo hepatocellular carcinoma (HCC) models with various p53 status (deleted, mutant, and wild type), and study the ultrastructural changes in the carcinoma cells during and following treatment with dl1520. METHODS: dl1520 (ONYX-015) virus was used for treatment of three HCC cell lines in culture, then for treatment of developed xenografts in SCID mice. The effects of dl1520 on HCC cell growth and accompanied morphological changes were assessed by various techniques including transmission electron microscopy. dl1520 infection was confirmed using polymerase chain reaction and immunolabeling at transmission electron microscopy level. RESULTS: dl1520 was effective in killing cells and inhibiting HCC cell growth both in vitro and in vivo. The cell killing was at higher levels in cells possessing abnormal p53. Survival rates in SCID mice treated with dl1520 were statistically significantly higher in HCC tumors with deleted and mutant p53, than in tumors with wild-type p53. CONCLUSIONS: The findings in this study suggest that dl1520 could be safely and effectively used for treatment of HCC dependent on the p53 status of the cells in vivo. Characteristic morphological changes that took place in the dl1520-treated HCC cells/tumors were distinct at transmission electron microscopy level and are the first of their kind to be reported.     

Mutations in conserved regions 1, 2, and 3 of Raf-1 that activate transforming activity

To investigate the role of Raf-1 in v-Ha-ras transformation, we have isolated and characterized a number of Raf-1 mutants that display increased transforming activity in Rat2 fibroblasts. A dipeptide deletion (Delta144-145) in the cysteine-rich domain (CRD) of conserved region (CR) 1 increased the interaction between Raf-1 and v-Ha-ras effector loop mutants in the yeast two-hybrid system, supporting the proposal that the CRD serves as a secondary ras-binding domain. Many activating mutations were located in CR2. Two representative CR2 mutants (Delta250-258 and S257L) displayed increased interaction with v-Ha-ras effector loop mutants and with mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) 1 in the two-hybrid system. One novel mutation in CR3 was recovered; G361S affected the third glycine of the GXGXXG protein kinase motif involved in ATP binding. Expression of G361S Raf-1 in Rat2 fibroblasts activated MEK and ERK. The CR1, CR2, and CR3 activating mutations, when combined in cis, cooperated in transforming Rat2 fibroblasts. Conversely, Raf-1 transforming activity was decreased when the S257L or G361S mutation was combined in cis with the R89E substitution, which disrupts ras-Raf interaction. This mutant analysis provides additional information about the distinct functions of individual Raf-1 regions and documents a novel genetic mechanism for activating an oncogenic kinase.