In vitro and in vivo downregulation of MRP1 by antisense oligonucleotides: a potential role in neuroblastoma therapy

The expression of MRP1 (multidrug resistance protein-1) is associated with chemoresistance and poor prognosis in neuroblastoma. MRP1 antisense oligonucleotides were used in an in vivo mouse-human xenograft model of neuroblastoma to downregulate MRP1. The MRP1 ASO reduced protein levels of MRP1 to an average of 40% of the nil treated controls (p = 0.007). There was significant chemosensitisation to single-agent chemotherapy, VP16 (etoposide), at 1 microg/mL (p = 0.035) and 10 microg/mL (p = 0.02) in comparison to tumours not receiving oligonucleotides. In contrast, MDR1-ASO produced significant chemosensitisation only at 10 microg/mL of VP16 (p = 0.029). No significant chemosensitisation was seen following nonsense oligonucleotides. The downregulation of MRP1 was also associated with an increase in tumour cell death (79% increase in apoptosis index p = 0.0313) and a reduction in cell turnover (42% reduction in mitotic index p = 0.0313), which was not seen with any other oligonucleotide. This new and novel perspective of MRP1 function, which is an apparent involvement in apoptosis and cell cycle progression in neuroblasts, presents a fresh avenue for investigation of the biologic consequences of MRP1 expression that occurs in many tumour cell types. Our work is the first to concurrently explore the effects of downregulation of MRP1 and MDR1 by antisense oligonucleotides in a neuroblastoma xenograft model. It provides rationale for the investigation of therapy adjuvants such as antisense oligonucleotides in the treatment of this malignancy.     

The first intermetatarsal angle in hallux valgus: an analysis of measurement reliability and the error involved

In view of the importance placed on the first intermetatarsal angle in the assessment of surgical intervention in hallux valgus, we assessed the reliability with which one measures this angle. The study involved 10 observers of varying experience measuring the angle using a standard technique on 10 weightbearing AP X-rays of the foot on three separate occasions. The margin of error in measuring the angle was +/-3.60 degrees with a 95% confidence interval. Increasing and averaging the number of readings per observer or the readings of a number of observers, reduces the error. Experience doesn't improve reliability. In conclusion, improvement in the reliability of the measurements can be achieved by careful technique, performing the measurements at least twice, and averaging them.     

Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3)GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R) action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro3)GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P < 0.05) in (Pro3)GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P < 0.05) and insulin (1.5-fold; P < 0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P < 0.05) insulin sensitivity in the (Pro3)GIP-treated group. Daily injection of (Pro3)GIP reduced pancreatic insulin content (1.3-fold; P < 0.05) and partially corrected the obesity-related islet hypertrophy and beta-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro3)GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes.     

The performance of the Clock Drawing Test in elderly medical inpatients: does it have utility in the identification of delirium?

The Clock Drawing Test is an often-used test for the detection of cognitive impairment, but the few studies that have evaluated its utility in delirium have produced rather inconsistent results. In a longitudinal study of delirium in elderly medical inpatients, we have investigated the relationships between the Clock Drawing Test, the presence and severity of delirium, and cognitive impairment. Using mixed linear model analysis we found that cognitive impairment was the major factor associated with low Clock Drawing Test scores (P < .0001): neither the presence nor the severity of delirium had additional significant effect on the Clock Drawing Test. Thus, we conclude that although the Clock Drawing Test is a good detector of cognitive impairment, it is not a suitable tool for detection of delirium in elderly medical inpatients.     

How do age and tooth loss affect oral health impacts and quality of life? A study comparing two national samples

Age and loss of teeth can be expected to have a complex relationship with oral health-related quality of life. This study aimed to explain how age and tooth loss affect the impact of oral health on daily living using the short form, 14-item Oral Health Impact Profile (OHIP-14) on national population samples of dentate adults from the UK (1998 UK Adult Dental Health Survey) and Australia (1999 National Dental Telephone Interview Survey). After correcting for key covariables, increasing age was associated with better mean impact scores in both populations. Those aged 30-49 years in Australia showed the worst (highest) scores. In the UK, those aged under 30 showed the highest scores. In both countries, adults aged 70+ showed much better scores than the rest (P < 0.001). When corrected for age, the independent effect of tooth loss was that the worst scores were found where there were fewer than 17 natural teeth in the UK and fewer than 21 teeth in Australia. People with 25 or more teeth averaged much better scores than all other groups (P < 0.001), although there were differences in pattern between countries. When Australians were analysed by region of birth, the pattern of scores by tooth loss for British/Irish immigrants was strikingly similar to that for the UK sample. First-generation immigrants from elsewhere showed much worse overall scores and a profoundly different pattern to the Australian- and British-born groups. Age, number of teeth and cultural background are important variables influencing oral health-related quality of life.     

The swing-lock denture: its use in conventional removable partial denture prosthodontics

This article describes the uses of the swing-lock retained removable partial denture in partially dentate patients where the potential for achievable retention with a conventionally designed removable partial denture is less than adequate. The article presents two case reports detailing effective use of the swing-lock concept in removable partial denture design and it is hoped that this article will increase the awareness of practitioners to the use of this prosthesis type when planning removable partial dentures.     

Preliminary development of a new individualised questionnaire measuring quality of life in older men with age-related hormonal decline: the A-RHDQoL

Background  

There is increasing interest in hormone replacement therapy to improve health and quality of life (QoL) of older men with age-related decline in hormone levels. This paper reports the preliminary development and evaluation of the psychometric properties of a new individualised questionnaire, the A-RHDQoL, measuring perceived impact of age-related hormonal decline on QoL of older men. A-RHDQoL design was based on the HDQoL for people with growth hormone (GH) deficiency and the ADDQoL (for diabetes).     

Challenges in clinical studies with multiple imaging probes

This article addresses two related issues: (a) When a new imaging agent is proposed, how does the imager integrate it with other biomarkers, either sampled or imaged? (b) When we have multiple imaging agents, is the information additive or duplicative and how is this objectively determined? Molecular biology is leading to new treatment options with reduced normal tissue toxicity, and imaging should have a role in objectively evaluating new treatments. There are two roles for molecular characterization of disease. Molecular imaging measurements before therapy help predict the aggressiveness of disease and identify therapeutic targets and, therefore, help choose the optimal therapy for an individual. Measurements of specific biochemical processes made during or after therapy should be sensitive measures of tumor response. The rules of evidence are not fully developed for the prognostic role of imaging biomarkers, but the potential of molecular imaging provides compelling motivation to push forward with convincing validation studies. New imaging procedures need to be characterized for their effectiveness under realistic clinical conditions to improve the management of patients and achieve a better outcome. The purpose of this article is to promote a critical discussion within the molecular imaging community because our future value to the overall biomedical community will be in supporting better treatment outcomes rather than in detection.     

Factors influencing the provision of removable partial dentures by dentists in Ireland

Factors influencing clinical treatment of partially dentate patients are varied, and there is a need to identify factors influencing success in the provision of removable partial dentures. The aim of this study was to assess the attitudes of general dental practitioners (GDPs) in Ireland towards tooth replacement and use of RPDs, in partially dentate older adults. The sample frame was the Register of Dentists in Ireland; data were also collected from a sample of dentists practising under NHS regulations in Northern Ireland. Validated questionnaires were sent to all dentists on the Register of Dentists in the Republic of Ireland, and dentists working under NHS regulations registered with the Central Services Agency in Northern Ireland. Content of the questionnaire included details of the dentist themselves, their dental practice and the profile of partial denture provision. They were also asked to give their views on factors influencing the success or failure of an RPD, the process of providing RPDs and their attitudes to RPD provision. A total of 1,143 responses were received, a response rate of 45%. A mean number of 61 RPDs per annum were provided, with 75% of dentures provided being acrylic based. Respondents indicate their belief that cobalt-chromium based dentures had a longer prognosis than acrylic dentures, but less than half (46%) claim to design the frameworks themselves. Patients' attitudes are considered influential in the success of RPD provision, and their influence on appearance is considered the most important factor influencing success. The most important factors influencing failure are: the patient not requesting a denture; an RPD restoring unbounded saddles; and, lower RPDs. Although considered important, approximately 60% of the sample do not routinely organise follow-up appointments for patients provided with RPDs. The fee structures in the DTSS and DTBS are considered a barrier to quality in the provision of partial dentures.