Potential limitations in using minor histocompatibility antigen-specific cytotoxic T cells for targeting solid tumor cells

We have shown previously that KIAA0223, a gene encoding a minor histocompatibility antigen, HA-1, whose expression was believed to be restricted to the hematopoietic cells, is aberrantly expressed in some solid tumor cell lines. However, its significance in tumor immunity needs to be determined. Cytotoxic activity of HA-1(H)-specific cytotoxic T lymphocytes (CTLs) was assessed against solid tumor cell lines expressing KIAA0223 using (51)Cr release assays. Five of seven cell lines were lysed when HLA-A*0201 was adequately expressed. One of the two CTL-resistant cell lines became susceptible after treatment with IFN-gamma and TNF-alpha, while the other was lysed only after pulsing with HA-1(H) peptide. In most cell lines tested, HA-1(H) peptide was properly generated and presented for recognition by the CTL. However, impaired antigen processing and presentation observed in this study may result in escape from CTL recognition in vivo, as well as in vitro, as observed in this study.     

Comparison of effectiveness of two urinary drainage systems in intensive care unit: a prospective,randomized clinical trial

Objective In a previous nonrandomized study we observed no difference in the rate of acquisition of bacteriuria between a complex closed drainage system (CCDS) and a two-chamber drainage system (TCDS) in ICU patients. To confirm this result we performed a statistically powerful study assessing the effectiveness of the CCDS and the TCDS in ICU patients.Design and setting Randomized, prospective, and controlled study in the medicosurgical intensive care unit (16 beds) in a teaching hospital.Patients and interventions We assigned 311 patients requiring indwelling urinary catheter for longer than 48 h to TCDS or CCDS to compare the rate of acquisition of bacteriuria.Measurements and results Patients did not receive prophylactic antibiotics during placement management or catheter withdrawal. Urine samples were obtained weekly for the duration of catheterization and within 24 h after catheter removal, and each time symptoms of urinary infection were suspected. There was no statistical difference in the rate of bacteriuria between the two groups: 8% with TCDS and 8.5% with CCDS. Rates of urinary tract infection were 12.1 episodes with TCDS and 12.8 episodes with CCDS per 1000 days of catheter.Conclusions This randomized study on the effectiveness of TCDS and CCDS in ICU patients confirms the findings of our previous study. No differences were noted between the two systems. The higher cost of CCDS is not justified for ICU patients.An erratum to this article can be found at     

Down-regulation of deoxycytidine kinase in human leukemic cell lines resistant to cladribine and clofarabine and increased ribonucleotide reductase activity contributes to fludarabine resistance

Mechanisms of acquired resistance to three purine analogues, 2-chloro-2'-deoxyadenosine (cladribine, CdA), 9-beta-D-arabinofuranosyl-2-fluoroadenine (fludarabine, Fara-A), and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (clofarabine, CAFdA) were investigated in a human T-lymphoblastic leukemia cell line (CCRF-CEM). These analogues are pro-drugs and must be activated by deoxycytidine kinase (dCK). The CdA and CAFdA resistant cell lines exhibited increased resistance to the other nucleoside analogues activated by dCK. This was also the case for the Fara-A resistant cells, except that they were sensitive to CAFdA and guanosine analogues. The CdA and CAFdA resistant cells displayed a deficiency in dCK activity (to <5%) while the Fara-A resistant cells showed only a minor reduction of dCK activity (20% reduction). The activity of high K(m) 5'-nucleotidase (5'-NT) (cN-II) using IMP as substrate, was 2-fold elevated in the resistant cell lines. The amount of the small subunit R2 of ribonucleotide reductase (RR) was higher in the Fara-A resistant cells, which translated into a higher RR activity, while CdA and CAFdA cells had decreased activity compared to the parental cells. Expression of the recently identified RR subunit, p53R2 full-size protein, in CAFdA cells was low compared to parental cells, but a protein of lower molecular weight was detected in CdA and CAFdA cells. Co-incubation of Fara-A with the RR inhibitor 3,4-dihydroxybenzohydroxamic acid (didox) enhanced cytotoxicity in the Fara-A resistant cells by a factors of 20. Exposure of the cells to the nucleoside analogues studied here also caused structural and numerical instability of the chromosomes; the most profound changes were recorded for CAFdA cells, as demonstrated by SKY and CGH analysis. We conclude that down-regulation of dCK in cells resistant to CdA and CAFdA and increased activity of RR in cells resistant to Fara-A contribute to resistance.     

Effectiveness of pertussis vaccination in New South Wales,Australia, 1996-1998

Pertussis notifications have increased over the past decade in Australia and other industrialised countries. This study estimates the effectiveness of pertussis vaccination in one Australian State (New South Wales, NSW) among children aged less than 14 years, during a period when an Australian whole-cell pertussis vaccine was in routine use. Cases notified with pertussis between 1996 and 1998 and pertussis vaccine coverage estimates from the Australian Childhood Immunisation Register were used. Vaccine effectiveness (VE) was calculated using the screening method, with adjustment for age group, year of disease onset and area of residence. VE was highest (91%) in the youngest age group (8–23 months) and lowest (78%) in the oldest age group (9–13 years). Pertussis vaccination is highly effective at preventing pertussis in NSW children, as measured by notified cases. Ongoing monitoring will be important to evaluate VE following Australia's change to an acellular vaccine based program.     

Public opponents of vaccination: a case study

Opposition to mass childhood vaccination is a world-wide phenomenon, particularly in industrialised countries. Unfounded claims about vaccination are perpetuated by parental lobby groups and individual spokespeople, some of whom have a medical or scientific background. This article focuses on one such spokesperson who has achieved particular notoriety. Dr. Viera Scheibner is a retired micropalaeontologist, without any formal training in health-related sciences, who tours the world claiming that vaccines are ineffective and dangerous and lead to a host of ills such as cancer and asthma. Professionals in public health or the clinical arena are from time to time called upon to publicly respond to her, or similar, claims disseminated during tours of Europe, North America or Australasia and in books and articles. Health professionals have expressed at how such spokespersons misrepresent the evidence on vaccine safety, resulting in the potential to undermine public confidence in immunisation. Media coverage, or proposed coverage, particularly of her more extreme claims, often makes health professionals engaged in immunisation feel obliged to respond. This paper describes Viera Scheibner’s approach, which follows a repetitious path and is representative of that taken by other public opponents of immunisation. We conclude by suggesting how health professionals might respond in the public arena.     

表达HPV16 E6和E7蛋白的非复制型重组痘苗病毒诱发的抗肿瘤免疫反应

目的　观察表达人乳头瘤病毒 (HPV) 16E6和E7蛋白的非复制型重组痘苗病毒的抗肿瘤免疫效果。方法　以重组痘苗病毒NTVJmE6E7免疫C5 7BL/ 6小鼠 ,检测特异性的细胞毒性T淋巴细胞 (CTL)活性 ;经免疫后的小鼠以TC 1肿瘤细胞攻击 ,观察免疫保护效果 ;荷瘤小鼠切除肿瘤后接种重组痘苗病毒 ,观察肿瘤复发情况。结果　以重组痘苗病毒NTVJmE6E7免疫小鼠 ,可诱导产生针对TC 1细胞的特异性的CTL反应 ;加强免疫后的小鼠能耐受 1× 10 4TC 1细胞的攻击 ;以重组痘苗病毒NTVJmE6E7免疫肿瘤术后小鼠 ,能有效地预防肿瘤复发。结论　非复制型重组痘苗病毒NTVJmE6E7可作为HPV16的相关肿瘤及其癌前病变免疫治疗的候选疫苗。     

Regulation of proliferation, survival and apoptosis by members of the TNF superfamily

Tumor necrosis factor (TNF) was first identified in 1984 as a cytokine with anti-tumor effects in vitro and in vivo. Extensive research since then has shown that there are at least 18 distinct members of the TNF super family and they exhibit 15-25% amino acid sequence homology with each other. These family members bind to distinct receptors, which are homologous in their extracellular domain. These cytokines have been implicated in a wide variety of diseases including tumorigenesis, septic shock, viral replication, bone resorption, rheumatoid arthritis, diabetes, and other inflammatory diseases. TNF blockers have been approved for human use in treating some of these conditions in the United States and other countries. Various members of the TNF super family mediate either proliferation, survival, or apoptosis of cells. Although distinct receptors, all members share a common cell signaling pathway that mediates the activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (e.g. c-jun N-terminal kinase). Regulation of cell growth and activation of NF-kappaB and of c-jun N-terminal kinase by the TNF super family is mediated through sequential activation/association of a set of cell signaling proteins named TNF receptor-associated factors, Fas-associated death domain and FADD-like ICE, caspases, receptor-interacting protein, NF-kappaB-inducing kinases, and IkappaBalpha kinases. Both apoptotic and antiapoptotic signals are activated simultaneously by the same cytokine in the same cell. Together these cytokines regulate cell growth/survival/apoptosis in a complex dance of changing partners and overlapping steps.     

Trumpets of attack: collaborative efforts between nursing and philanthropies to care for the child crippled with polio 1930 to 1959

The purpose of this historical inquiry research was to explore (a) the relationship of nursing and foundations focusing on polio from 1930 to 1959; (b) the employment and educational opportunities arising from the polio epidemics for white and black nurses, as well as the obstacles encountered; (c) the role of nursing leaders in the care of the crippled child; and (d) the effects of the resolution of the polio epidemics resulting from the polio vaccine on public attitude and on the philanthropic organizations. Relevant journals, primary and secondary sources, and personal interviews were the methods used for data collection. Because of the extraordinary community support for work related to polio, nurses were able to obtain support from foundations. This support resulted in employment and educational opportunities for bedside nursing, primarily for white nurses. Middle and upper class fear of polio enabled the development of powerful and successful private organizations to supplement the available governmental services. This research illustrates the advances that nursing has made and reminds nurses to develop and maintain strong praxis relationships, alliances with philanthropies, referrals for clients with local organizations, and a strong voice in the planning arena.     

Estrogen alters amyloid precursor protein as well as dendritic and cholinergic markers in a mouse model of Down syndrome

Individuals with Down syndrome (DS) develop the pathological hallmarks of Alzheimer's disease at an early age, later followed by memory decline and dementia. Women with DS are twice as likely to undergo early menopause, and levels of estradiol correlate with onset of cognitive decline in these women. We have demonstrated that a mouse model of DS, mice with segmental trisomy of chromosome 16 (Ts65Dn), develop a significant deficit in both reference and working memory as young adults (6-10 months of age), coupled with phenotypic loss of cholinergic neurons in the basal forebrain and altered growth factor levels. In the present study we examined cholinergic and dendritic markers in the hippocampal formation and levels of the amyloid precursor protein (APP) in different brain regions of Ts65Dn mice treated with estradiol for 60 days. The density of the dendritic marker Map2 was significantly decreased in the hippocampal formation of middle-aged trisomic mice (9-15 months old), and the density of cholinergic neurites (acetylcholinesterase [AChE] histochemistry) was also decreased in specific layers of the hippocampus. Treatment with 17beta-estradiol alleviated the decreases in Map2 and AChE staining, but had no effect on full-length APP levels in the hippocampus. In contrast, a main effect of treatment on APP levels in the striatum was noted, with significant elevations observed in controls and trisomics. These findings demonstrate that estrogen can alleviate deficits in cholinergic and dendritic elements in the hippocampal formation and further strengthens the rationale to explore estrogen replacement therapy in women with DS.     

Tracking superparamagnetic iron oxide labeled monocytes in brain by high-field magnetic resonance imaging

Inflammatory cells, most notably mononuclear phagocytes (MP; macrophages and microglia), play a critical role in brain homeostasis, repair and disease. One important event in cellular biodynamics is how MP move in and throughout the nervous system. Prior studies have focused principally on cell migration across the blood-brain barrier during neuroinflammatory processes with little work done on cell movement within the brain. During the past decade our laboratories have studied the role of MP in HIV-1-associated dementia (HAD). In HAD MP incite sustained glial inflammatory reactions causing significant neuronal damage. To extend these works we investigated cell movement in brain and its influence for disease in a novel co-registration system integrating neuropathology with high-field magnetic resonance imaging (MRI). Human monocytes labeled with superparamagnetic iron oxide particles were injected into the brain of severe combined immunodeficient (SCID) mice. MRI was recorded 1, 7, and 14 days after cell injection. MRI co-registered with histology verified that the MRI signal modification was due to the labeled cells. MRI showed human monocyte-derived macrophages along the injection site, the corpus callosum, the ventricular system and in other brain sites. These data support the idea that cell migration can be monitored in vivo and provides an opportunity to assess monocyte mobility in brain and its affects on neurodegenerative processes and notably HAD.