Measuring mineralised tissue formation and resorption in a human 3D osteoblast-osteoclast co-culture model.

In vitro tissue engineered bone constructs have been developed, but models which mimic both formation and resorption in parallel are still lacking. To be used as a model for the bone remodeling process, the formation and resorption of mineralised tissue volume over time needs to be visualised, localised and quantified. The goal of this study was to develop a human 3D osteoblast-osteoclast co-culture in which 1) osteoblasts deposit mineralised matrix, 2) monocytes differentiate into resorbing osteoclasts, and 3) the formation and resorption of mineralised matrix could be quantified over time using micro-computed tomography (µCT). Mesenchymal stromal cells were seeded on silk fibroin scaffolds and differentiated towards osteoblasts to create mineralised constructs. Thereafter, monocytes were added and differentiated towards osteoclasts. The presence of osteoblasts and osteoclasts was confirmed using immunohistochemistry. Osteoclastic activity was confirmed by measuring the increased release of osteoclast marker tartrate resistant acid phosphatase (TRAP), suggesting that osteoclasts were actively resorbing mineralised tissue. Resorption pits were visualised using scanning electron microscopy. Mineralised matrix formation and resorption were quantified using µCT and subsequent scans were registered to visualise remodelling. Both formation and resorption occurred in parallel in the co-culture. The resorbed tissue volume exceeded the formed tissue volume after day 12. In conclusion, the current model was able to visualise, localise and quantify mineralised matrix formation and resorption. Such a model could be used to facilitate fundamental research on bone remodeling, facilitate drug testing and may have clinical implications in personalised medicine by allowing the use of patient cells.

Multilingualism was associated with lower cognitive outcomes in children who were born very and extremely preterm.

AIM: This study determined whether cognitive outcomes differed between very preterm (VPT) and extremely preterm (EPT) children who were monolingual or multilingual when they reached the corrected ages of two and five years. METHODS: The data were collected at the Emma Children's Hospital, Amsterdam, The Netherlands, as part of our national neonatal follow-up programme and comprised 325 VPT/EPT children born between January 1, 2007 and January 1, 2012. The study used the Third Editions of the Bayley Scales of Infant and Toddler Development and the Wechsler Preschool and Primary Scale of Intelligence. RESULTS: We compared 234 monolingual children, 65 multilingual children who spoke Dutch and at least one foreign language at home and 26 multilingual children who didn't speak Dutch at home. The best performers on the cognitive scale at two years of age and the verbal subscales at five years of age were the monolingual children, followed by the children who spoke Dutch and at least one foreign language at home, then the children who only spoke foreign languages at home. CONCLUSION: In our study cohort from The Netherlands, multilingualism lowered the cognitive and verbal outcomes of VPT/EPT children at the corrected ages of two and five years.

What is the effect of MRI with targeted biopsies on the rate of patients discontinuing active surveillance? A reflection of the use of MRI in the PRIAS study.

BACKGROUND: The reduction of overtreatment by active surveillance (AS) is limited in patients with low-risk prostate cancer (PCa) due to high rates of patients switching to radical treatment. MRI improves biopsy accuracy and could therewith affect inclusion in or continuation of AS. We aim to assess the effect of MRI with target biopsies on the total rate of patients discontinuing AS, and in particular discontinuation due to Grade Group (GG) reclassification. METHODS: Three subpopulations included in the prospective PRIAS study with GG 1 were studied. Group A consists of patients diagnosed before 2009 without MRI before or during AS. Group B consists of patients diagnosed without MRI, but all patients underwent MRI within 6 months after diagnosis. Group C consists of patients who underwent MRI before diagnosis and during follow-up. We used cumulative incidence curves to estimate the rates of discontinuation. RESULTS: In Group A (n = 500), the cumulative probability of discontinuing AS at 2 years is 27.5%; GG reclassification solely accounted for 6.9% of the discontinuation. In Group B (n = 351) these numbers are 30.9 and 22.8%, and for Group C (n = 435) 24.2 and 13.4%. The three groups were not randomized, however, baseline characteristics are highly comparable. CONCLUSIONS: Performing an MRI before starting AS reduces the cumulative probability of discontinuing AS at 2 years. Performing an MRI after already being on AS increases the cumulative probability of discontinuing AS in comparison to not performing an MRI, especially because of an increase in GG reclassification. These results suggest that the use of MRI could lead to more patients being considered unsuitable for AS. Considering the excellent long-term cancer-specific survival of AS before the MRI era, the increased diagnostic accuracy of MRI could potentially lead to more overtreatment if definitions and treatment options of significant PCa are not adapted.

Differences in plasma and tissue aluminum concentrations due to different aluminum-containing drugs in patients with renal insufficiency and with normal renal function.

The gastrointestinal absorption of aluminum from orally administered aluminum-containing drugs is well documented. Retention of the absorbed aluminum leads to elevated levels of this metal in the tissue of patients with renal failure. We studied two groups of dialysis patients who had received equal amounts of the different aluminum-containing phosphate-binders Aludrox and Antiphosphat. It has recently been shown that Antiphosphat releases only a few aluminum ions in an environment of low pH. Consistent with this finding, we found the aluminum levels to be significantly higher in the plasma, bone, and hair of patients who had received Aludrox as phosphate binder. Subjects with normal renal function excreted most of the ingested and absorbed aluminum. No data are available concerning the tissue load of the element in these subjects. We studied two groups of patients with normal renal function who had received antacid drugs prior to neurosurgery on a brain tumor. The first group of patients were treated with an aluminum-rich antacid (Maalox 70); the other group received an aluminum-poor drug (magaldrate) for 10 days prior to the operation. Analysis of the brain-tissue removed revealed twofold higher aluminum levels in the patients who had received Maalox 70. These results indicate that administration of aluminum-containing drugs leads to a tissue load of aluminum in patients with an impaired renal function as well as in those with a normal function. The extent of the aluminum load depends on the aluminum content and the liberation rate of the drug.