Contributions of mucosal immune cells to methotrexate-induced mucositis

The use of high doses of the anti-cancer drug methotrexate (MTX) is associated with intestinal damage. As a result, mucosal immune cells become increasingly exposed to a vast amount of microbial stimuli. We aimed at determining whether these cells are still functional during MTX treatment. Furthermore, we assessed if activation of the mucosal immune system would play a role in the pathogenesis of mucositis. A contributive role to mucositis for the adaptive immune system was established by showing that mucosal lymphocytes from MTX-treated mice secreted enhanced amounts of cytokines upon ex vivo polyclonal stimulation. Next, in vitro experiments revealed that macrophages were not affected by MTX in the capacity to produce tumor necrosis factor-alpha (TNF-alpha) and IL-10 after LPS exposure. Moreover, peritoneal macrophages from MTX-treated mice produced more IL-10 and TNF-alpha upon LPS stimulation, compared with cells derived from control mice. These data indicate a persistence of both innate and adaptive immune responses in this model. The clinical relevance of these findings was further established by the fact that LPS exposure prior to MTX treatment aggravated the course of mucositis. Furthermore, LPS-responsive mice recovered more slowly compared with LPS-unresponsive mice from MTX treatment. Finally, we found an increase in weight loss and intestinal damage upon MTX treatment in IL-10-deficient mice in comparison to wild-type controls, suggesting a protective role for IL-10 in mucositis. We conclude that mucosal immune responses remain resilient during MTX-induced mucositis. Whereas TNF-alpha production may contribute to mucosal damage, IL-10 may regulate by restricting excessive mucositis.     

Phenotypic and genotypic characterization of orthotopic human glioma models and its relevance for the study of anti-glioma therapy

Most human gliomas are characterized by diffuse infiltrative growth in the brain parenchyma. Partly because of this characteristic growth pattern, gliomas are notorious for their poor response to current therapies. Many animal models for human gliomas, however, do not display this diffuse infiltrative growth pattern. Furthermore, there is a need for glioma models that represent adequate genocopies of different subsets of human gliomas (e.g., oligodendrogliomas). Here, we assessed the intracerebral growth patterns and copy number changes [using multiplex ligation-dependent probe amplification (MLPA)/comparative genomic hybridization (CGH)] of 15 human glioma lines in nude mice. Most xenografts present with compact growing lesions intracerebrally. Only the E98 and, to a lesser degree, E106 xenograft lines (propagated through subcutaneous growth) consistently produced intracerebral tumors, displaying diffuse infiltrative growth in the brain parenchyma. In contrast, four xenograft lines (E434, E468, E473 and E478), established by direct intracerebral inoculation of human glioma cells and serially propagated intracerebrally, consistently showed extensive diffuse infiltration throughout the brain. After several passages, the neoplastic cells still carry typical chromosomal aberrations [(-1p/-19q in oligodendroglioma, +7/-10 in glioblastoma multiforme (GBM)]. Especially these latter four models and the E98 line thus represent adequate geno- and phenocopies of human gliomas and form an attractive platform to investigate different therapeutic approaches in a preclinical setting.     

Visual assessment of segmental muscle ultrasound images in spina bifida aperta

In spina bifida aperta (SBA), spinal MRI provides a surrogate marker to estimate muscle damage caudal to the myelomeningocele (MMC). This muscle damage by the MMC can be quantified by intra-individual comparison of muscle ultrasound density (MUD) caudal versus cranial to the MMC (dMUD = [MUD(caudal-to-the-MMC)] - [MUD(cranial-to-the-MMC)]). Quantitative dMUD assessment requires time, equipment and expertise, whereas it could also be visually determined by differences in muscle echodensity caudal vs. cranial to the MMC (visual-dMUD). If visual and quantitative dMUD correspond, visual dMUD assessment could provide a clinical screening parameter. In 100 SBA muscle ultrasound recordings of patients with various MMC levels, we aimed to compare quantitative dMUD (dMUD = [MUD(calf-muscle/S1)] - [MUD(quadriceps-muscle/L2-L4)]) with visual dMUD assessments by 20 different observers. Results indicate that quantitative dMUD can be visually detected (sensitivity 86%; specificity 57%), implicating that visual dMUD screening could provide a quick, clinical screening tool for muscle impairment by the MMC.     

Home visits for frail older people: a qualitative study on the needs and preferences of frail older people and their informal caregivers

Background

A number of studies have examined the effects of home visits and showed inconsistent results on physical functioning, institutionalisation, and mortality. Despite continuing interest from professionals in home visits for older people, reports on older people’s needs and preferences for such visits are scarce.

Aim

This qualitative study aims to explore the views and needs of community-dwelling frail older people concerning home visits.

Design and setting

A qualitative study including interviews with frail older persons and their informal caregivers living in the area of Nijmegen, the Netherlands.

Method

Semi-structured interviews were conducted with frail older people and informal caregivers. A grounded theory approach was used for data-analysis.

Results

Eleven frail older people and 11 informal caregivers were included. Most participants emphasised the importance of home visits for frail older people. They felt that it would give older people the personal attention they used to receive from GPs but miss nowadays. Most stated that this would give them more trust in GPs. Participants stated that trust is one of the most important factors in a good patient–professional relationship. Further, participants preferred home visits to focus on the psychosocial context of the patient. They stated that more knowledge of the psychosocial context and a good patient–professional relationship would enable the professional to provide better and more patient-centred care.

Conclusion

Patients’ expectations of home visits are quite different from the actual purpose of home visiting programmes; that is, care and wellbeing versus cure and prevention. This difference may partly explain why the effectiveness of home visits remains controversial. Future studies on home visits should involve patients in the development of home visiting programmes.     

A three-part, mixed-effects model to estimate the habitual total vitamin D intake distribution from food and dietary supplements in Dutch young children

Statistical modeling of habitual micronutrient intake from food and dietary supplements using short-term measurements is hampered by heterogeneous variances and multimodality. Summing short-term intakes from food and dietary supplements prior to simple correction for within-person variation (first add then shrink) may produce estimates of habitual total micronutrient intake so badly biased as to be smaller than estimates of habitual intake from food sources only. A 3-part model using a first shrink then add approach is proposed to estimate the habitual micronutrient intake from food among nonsupplement users, food among supplement users, and supplements. The population distribution of habitual total micronutrient intake is estimated by combining these 3 habitual intake distributions, accounting for possible interdependence between Eq. 2 and 3. The new model is an extension of a model developed by the USA National Cancer Institute. Habitual total vitamin D intake among young children was estimated using the proposed model and data from the Dutch food consumption survey (n = 1279). The model always produced habitual total intakes similar to or higher than habitual intakes from food sources only and also preserved the multimodal shape of the observed total vitamin D intake distribution. This proposed method incorporates several sources of covariate information that should provide more precise estimates of the habitual total intake distribution and the proportion of the population with intakes below/above cutpoint values. The proposed methodology could be useful for other complex situations, e.g. where high concentrations of micronutrients appear in episodically consumed foods.