Therapeutic LMP1 polyepitope vaccine for EBV-associated Hodgkin disease and nasopharyngeal carcinoma

Development of an epitope-based vaccination strategy designed to enhance Epstein-Barr virus (EBV)-specific CD8(+) cytotoxic T lymphocytes (CTLs) is increasingly being considered as a preferred approach for the treatment of EBV-associated relapsed Hodgkin disease (HD) and nasopharyngeal carcinoma (NPC). EBV-encoded latent membrane proteins, LMP1 and LMP2, are the only target antigens available for therapeutic augmentation of CTL responses in patients with HD and NPC. Here, we describe preclinical studies using a recombinant poxvirus vaccine that encodes a polyepitope protein comprising 6 HLA A2-restricted epitopes derived from LMP1. Human cells infected with this recombinant polyepitope construct were efficiently recognized by LMP1-specific CTL lines from HLA A2 healthy individuals. Furthermore, immunization of HLA A2/K(b) mice with this polyepitope vaccine consistently generated strong LMP1-specific CTL responses to 5 of the 6 epitopes, which were readily detected by both ex vivo and in vitro assays. More important, this polyepitope vaccine successfully reversed the outgrowth of LMP1-expressing tumors in HLA A2/K(b) mice. These studies provide an important platform for the development of an LMP-based polyepitope vaccine as an immunotherapeutic tool for the treatment of EBV-associated HD and NPC.     

Human enamel dissolution in citric acid as a function of pH in the range 2.30< or =pH< or =6.30--a nanoindentation study

The objective of this study was to investigate the dissolution of human enamel in citric acid solutions over a wide range of pH. The in vitro conditions are considered to be relevant to soft drink-induced enamel erosion. Nanoindentation was used to investigate changes in the nanomechanical properties of polished enamel surfaces after exposure to citric acid solutions. Solutions used had 38.1 mmol l-1 citric acid and pH greater than 2.3 but less than 6.3 (2.30 < or = pH < or = 6.30). Samples were exposed to rapidly stirred, constant composition solutions for 120 s. Statistically significant changes in enamel hardness and reduced elastic modulus were observed after exposure to all solutions. There was an approximately linear dependence of enamel hardness on solution pH for 2.90 < or = pH < or = 6.30. Below pH 2.90, enamel is thought to have reached the lowest possible hardness value. The reduction in enamel dissolution caused by an increase in pH of a soft drink is likely to be small. Product modification to reduce the erosive potential of drinks may require additional methods such as addition of calcium salts.     

Discrimination between gene expression patterns in the invasive margin and the tumour core of malignant melanomas

Genes that determine the invasive capacity of the invasive front of malignant melanomas (MM) have not yet been systematically investigated in vivo. Therefore, we combined laser pressure catapulting (LPC) microdissection with cDNA microarray technology (DermArray, Research Genetics, representing about 5700 genes) to systematically analyse differences in gene expression profiles between the invasive margin and the tumour centre in nine cases of vertical growth phase MM. Signal-to-noise statistical algorithms combined with hierarchical clustering were performed to determine class-separating genes. The gene encoding phosphoenolpyruvate carboxykinase 1 (PEPCK), the Homo sapiens gene similar to Saccharomyces cerevisiae SSM4 (TEB4), the gene encoding ribosomal protein L19, the Homo sapiens gene similar to the Aspergillus nidulans SudD (a suppressor of the bimD6 homologue), the gene encoding the interleukin-3 receptor alpha subunit, the gene encoding the inositol 1,4,5-triphosphate 3-kinase isoenzyme, and three anonymous expressed sequence tags were identified as class-separating genes. These genes significantly discriminate between the invasive front and the tumour centre. Using this set of genes, 15 out of 18 LPC-dissected MM regions could be grouped correctly. We conclude that the candidate genes identified could spark further research on MM progression and may provide novel prognostic parameters.     

Predicting abdominal adipose tissue in overweight Latino youth.

OBJECTIVES: 1) Examine associations between visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue (SAAT), and anthropometric and demographic variables; 2) generate and cross-validate prediction equations for estimating VAT and SAAT in overweight Latino children. STUDY DESIGN: Cross-sectional. PARTICIPANTS: 196 overweight 8-13-year-old Latino youth. Two-thirds (n = 131) were randomly assigned to a development group to generate prediction equations for VAT and SAAT; one-third (n = 65) was used as a cross-validation group. METHODS AND PROCEDURES: Anthropometric measurements (height, weight, skinfold thicknesses, and circumferences) were performed. VAT and SAAT were measured using magnetic resonance imaging (MRI). RESULTS: The strongest univariate correlate for VAT was waist circumference (WC) (r = 0.65, p < 0.01) while the strongest correlate for SAAT was hip circumference (r = 0.88, p < 0.001). Regression analyses showed approximately 50% of the variance in VAT was explained by WC (43.8%), Tanner stage (4.2%) and calf skinfold (1.7%). Variance in the SAAT model was explained by WC (77.8%), triceps skinfold (4.2%) and gender (2.3%). Residual analyses showed no bias in either equation. Though mean differences between measured and predicted VAT and SAAT were small, there was a large degree of variability at the individual level especially for VAT. CONCLUSIONS: Both VAT and SAAT prediction equations performed well at the group level, but the relatively high degree of variability suggests limited clinical utility of the VAT equation. MRI is currently required to derive an accurate measure of VAT at the individual level.     

PC-based visual stimuli for behavioural and electrophysiological studies of optic flow field detection

A PC-based visual-stimulus-generation package for behavioural and electrophysiological studies of responses to optic flow is described. Developed for studies of crab vision, the package is particularly well suited for use with animals that have very large fields of view, i.e. +/-120 degrees. Programs, written in the Borland Delphi language, use the OpenGL graphics library to create realistic representations of motion in a three dimensional environment. Large-field stimuli include simulations of self-motion (rotation and translation, separately or in combination) relative to a square-wave grating or other, user-selected, background. The package also includes representations of approaching and receding objects, and rotating spiral patterns for the investigation of neural responses to looming/anti-looming. Additionally, the package provides local motion stimuli, translating or rotating targets presented at many points in the receptive field, which can be used to derive response maps of large-field motion-sensitive interneurones. In all these stimuli, inconsistencies in animation timing that have hitherto hindered the use of standard PCs running Microsoft Windows for such applications have been minimised by using an improved real-time clock to control the animation cycle.     

Intensity-modulated radiation therapy: First reported treatment in Australasia

Intensity-modulated radiation therapy (IMRT) is an exciting new advance in the practice of radiation oncology. It is the use of non-uniform radiation beams to achieve conformal dose distributions. As a result of the high initial capital costs and the time and complexity of planning, IMRT is not yet a widely available clinical treatment option. We describe the process involved in applying this new technology to a case of locally advanced nasopharyngeal cancer.     

The relationship between lesion and normal appearing brain tissue abnormalities in early relapsing remitting multiple sclerosis

Background In multiple sclerosis (MS), pathological changes have been found both in macroscopic lesions and normal appearing tissue. Magnetisation transfer ratio (MTR) and T1 relaxation time are abnormal in normal appearing tissues in established MS. This study used these MR techniques in early MS to study normal appearing tissues and lesions. The purpose was to determine whether abnormalities are already detectable in normal appearing tissues in early MS, and if so how they correlate with lesion characteristics. Methods Twenty two patients with early relapsing remitting (RR) MS (median disease duration 2 years, range 7 months–3 years) and 11 age-matched controls were studied. MTR and T1 relaxation times were measured in 9 regions of normal appearing white matter (NAWM) and 7 of normal appearing grey matter (NAGM). Gadolinium enhancing, T1-hypointense and T2 lesion loads were measured in all patients. Results When all regions were combined, there was a significant difference between patient and control NAWM for both T1 and MTR; T1 was abnormal in 6/9 and MTR in 3/9 NAWM regions. Global assessment of NAGM revealed a significant difference between patients and controls for T1 but not for MTR; T1 was significantly abnormal only in frontal NAGM. There was no significant correlation between NAWM T1 or MTR and any of the lesion load measurements. Conclusions This study reveals quantitative MR abnormalities in both NAWM and NAGM in early RR MS, with more extensive changes in the former. The lack of correlation between NAWM and lesion abnormalities suggests that they have developed by at least partly independent mechanisms. T1 may be more sensitive than MTR in detecting subtle pathological changes in NAWM and NAGM. Received: 3 April 2001, Received in revised form: 15 June 2001, Accepted: 18 June 2001     

Parent influences in the transmission of eating and weight related values and behaviors

Early adolescent boys (n = 587) and girls (n = 619) and a parent completed questionnaires, that assessed child dieting behaviors, body dissatisfaction and tendency to overeat, child's current and ideal size, mother and father dieting, and encouragement of the child to diet.     

Difficult tracheal intubation induced by maxillary distraction devices in craniosynostosis syndromes

BACKGROUND: Difficult intubation occurred during anaesthesia for removal of maxillary distraction devices in five of seven children with syndromal craniosynostoses (four with Apert, two with Pfeiffer and one with Crouzon syndrome). METHODS: Intubation was assessed in terms of laryngeal view and an established intubation difficulty score and had been straightforward before device insertion. Difficulty was induced by trismus due to device insertion and by increased maxillary prominence. This was compounded by preexisting mandibular hypoplasia. Cephalometric analysis, with each child acting as their own control, demonstrated anterior displacement of the maxilla and increased maxillary vertical height, as well as increased protuberance of the maxillary incisors. RESULTS: All five difficult tracheal intubations were associated with preoperative Mallampati scores of 3 or 4 and the nine straightforward intubations with scores of 1 or 2. Maximal interincisor distance was less than the lower 95% confidence limit for age in all five children who were difficult to intubate at the time of device removal. No child had a failed intubation, but all had significantly increased intubation difficulty. CONCLUSIONS: In view of the risks of trauma, hypoxia and aspiration associated with difficult direct laryngoscopy, we recommend elective fibreoptic intubation at anaesthesia for removal of maxillary distraction osteogenesis devices in these children.