CRP-guided antibiotic treatment in acute exacerbations of COPD in hospital admissions.

The role of antibiotics in acute exacerbations of chronic obstructive pulmonary disease (COPD) is controversial and a biomarker identifying patients who benefit from antibiotics is mandatory. We performed a randomised, controlled trial in patients with acute exacerbations of COPD, comparing C-reactive protein (CRP)-guided antibiotic treatment to patient reported symptoms in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy, in order to show a reduction in antibiotic prescription.Patients hospitalised with acute exacerbations of COPD were randomised to receive antibiotics based either on the GOLD strategy or according to the CRP strategy (CRP ≥50 mg·L-1).In total, 101 patients were randomised to the CRP group and 119 to the GOLD group. Fewer patients in the CRP group were treated with antibiotics compared to the GOLD group (31.7% versus 46.2%, p=0.028; adjusted odds ratio (OR) 0.178, 95% CI 0.077-0.411, p=0.029). The 30-day treatment failure rate was nearly equal (44.5% in the CRP group versus 45.5% in the GOLD-group, p=0.881; adjusted OR 1.146, 95% CI 0.649-1.187, p=0.630), as was the time to next exacerbation (32 days in the CRP group versus 28 days in the GOLD group, p=0.713; adjusted hazard ratio 0.878, 95% CI 0.649-1.187, p=0.398). Length of stay was similar in both groups (7 days in the CRP group versus 6 days in the GOLD group, p=0.206). On day-30, no difference in symptom score, quality of life or serious adverse events was detected.Use of CRP as a biomarker to guide antibiotic treatment in severe acute exacerbations of COPD leads to a significant reduction in antibiotic treatment. In the present study, no differences in adverse events between both groups were found. Further research is needed for the generalisability of these findings.

[Rapid prototyping: a very promising method]. / Rapid prototyping: een veelbelovende methode.

Rapid prototyping is a method which makes it possible to produce a three-dimensional model based on two-dimensional imaging. Various rapid prototyping methods are available for modelling, such as stereolithography, selective laser sintering, direct laser metal sintering, two-photon polymerization, laminated object manufacturing, three-dimensional printing, three-dimensional plotting, polyjet inkjet technology,fused deposition modelling, vacuum casting and milling. The various methods currently being used in the biomedical sector differ in production, materials and properties of the three-dimensional model which is produced. Rapid prototyping is mainly usedforpreoperative planning, simulation, education, and research into and development of bioengineering possibilities.

Effects of MSC coadministration and route of delivery on cord blood hematopoietic stem cell engraftment.

Hematopoietic stem cell transplantation (HSCT) using umbilical cord blood (UCB) progenitors is increasingly being used. One of the problems that may arise after UCB transplantation is an impaired engraftment. Either intrabone (IB) injection of hematopoietic progenitors or mesenchymal stem cell (MSC) coadministration has been proposed among the strategies to improve engraftment. In the current study, we have assessed the effects of both approaches. Thus, NOD/SCID recipients were transplanted with human UCB CD34+ cells administered either intravenously (IV) or IB, receiving or not bone marrow (BM)-derived MSCs also IV or IB (in the right femur). Human HSC engraftment was measured 3 and 6 weeks after transplantation. Injected MSCs were tracked weekly by bioluminescence. Also, lodgment within the BM niche was assessed at the latter time point by immuno-fluorescence. Our study shows regarding HSC engraftment that the number of BM human CD45+ cells detected 3 weeks after transplantation was significantly higher in mice cotransplanted with human MSCs. Moreover, these mice had a higher myeloid (CD13+) engraftment and a faster B-cell (CD19+) chimerism. At the late time point evaluated (6 weeks), human engraftment was higher in the group in which both strategies were employed (IB injection of HSC and MSC coadministration). When assessing human MSC administration route, we were able to track MSCs only in the injected femurs, whereas they lost their signal in the contralateral bones. These human MSCs were mainly located around blood vessels in the subendosteal region. In summary, our study shows that MSC coadministration can enhance HSC engraftment in our xenogenic transplantation model, as well as IB administration of the CD34+ cells does. The combination of both strategies seems to be synergistic. Interestingly, MSCs were detected only where they were IB injected contributing to the vascular niche.

Human platelet lysate as a fetal bovine serum substitute improves human adipose-derived stromal cell culture for future cardiac repair applications.

Adipose-derived stromal cells (ASC) are promising candidates for cell therapy, for example to treat myocardial infarction. Commonly, fetal bovine serum (FBS) is used in ASC culturing. However, FBS has several disadvantages. Its effects differ between batches and, when applied clinically, transmission of pathogens and antibody development against FBS are possible. In this study, we investigated whether FBS can be substituted by human platelet lysate (PL) in ASC culture, without affecting functional capacities particularly important for cardiac repair application of ASC. We found that PL-cultured ASC had a significant 3-fold increased proliferation rate and a significantly higher attachment to tissue culture plastic as well as to endothelial cells compared with FBS-cultured ASC. PL-cultured ASC remained a significant 25% smaller than FBS-cultured ASC. Both showed a comparable surface marker profile, with the exception of significantly higher levels of CD73, CD90, and CD166 on PL-cultured ASC. PL-cultured ASC showed a significantly higher migration rate compared with FBS-cultured ASC in a transwell assay. Finally, FBS- and PL-cultured ASC had a similar high capacity to differentiate towards cardiomyocytes. In conclusion, this study showed that culturing ASC is more favorable in PL-supplemented medium compared with FBS-supplemented medium.

Expansion of human mesenchymal stromal cells on microcarriers: growth and metabolism.

Adult stem cells, or mesenchymal stromal cells (MSCs), are of great potential for cell therapy and tissue-engineering applications. However, for therapeutic use, these cells need to be isolated from tissue or a biopsy and efficiently expanded, as they cannot be harvested in sufficient quantities from the body. In our opinion, efficient expansion of MSCs can be achieved in a microcarrier-based cultivation system. This study selected a suitable microcarrier for human bone marrow-derived stromal cells (HBMSCs), optimized cell-seeding strategies by varying serum concentrations, and optimized dynamic expansion of the HBMSCs in a microcarrier-based spinner flask cultivation system by applying various feeding regimes. Cytodex 1 microcarriers in combination with a low-serum concentration (0-5%) in the medium resulted in the highest seeding efficiency for the HBMSCs. Subsequently, significant expansion of the HBMSCs on these carriers has been observed. The highest number of HBMSCs population doublings (4.8 doublings) was obtained by a combination of 50% medium refreshment combined with addition of 30% medium containing microcarriers every 3 days. Exponential cell growth was observed for at least 9 days after seeding, provided that sufficient nutrients (such as glucose) were present, metabolite concentrations (such as ammonia) were kept below growth-inhibitory concentrations and adequate surface area was present for the cells. After dynamic expansion of the HBMSCs, the cells retained their differentiation potential and their cell surface markers, indicating that HBMSCs expansion on Cytodex 1 microcarriers did not alter the phenotypic properties of the cells.

The Hollow Fibre Assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells.

The Hollow Fibre Assay (HFA) is usually applied as an early in vivo model for anti-cancer drug screening, but is potentially an excellent model for short-term in vivo pharmacodynamic studies. We used the model to study the in vivo role of thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) in the cytotoxicity and pharmacodynamics of TAS-102 in colon cancer cells. TAS-102 is a new oral drug formulation, which is composed of trifluorothymidine (TFT) and thymidine phosphorylase inhibitor (TPI), which prevents TFT degradation. We compared the activity with Xeloda (capecitabine), which is activated by TP into 5FU. Hollow fibres filled with human Colo320 or Colo320TP1 colorectal cancer cells with deficient or high TP expression, respectively, were implanted subcutaneously (s.c.) at both flanks of BALB/c mice. The mice were treated orally over 5 days with TAS-102, TFT alone, 5'DFUR+/-TPI or capecitabine at their maximum tolerated dose (MTD). The cells were retrieved from the fibres and assayed for growth (MTT assay), cell cycle distribution (flow cytometry) and apoptosis induction (FragEL method). TAS-102 induced considerable growth inhibition (50%, P<0.01) to both cell lines, which was completely abolished in the absence of TPI. Capecitabine and its metabolite 5'DFUR reduced proliferation of Colo320TP1 cells in the fibres significantly (down to 25-40%), but much less in Colo320 cells, whereas addition of TPI reduced the effect of 5'DFUR, although not completely. These differences in cytotoxic effects were reflected in the pharmacodynamic evaluation. TAS-102 induced a G2M-phase arrest (from 25 to 40%) and apoptosis (>8-fold), which was more pronounced in Colo320 than in Colo320TP1. Again, omission of TPI neutralised the effect of TAS-102. Similarly, 5'DFUR and capecitabine induced a significant G2M-phase arrest (up to 45%) in the Colo320TP1 cell line, but less pronounced in the parental Colo320. Addition of TPI to 5'DFUR reduced this effect to control levels. Also induction of apoptosis was reduced in the presence of TPI. The data demonstrated that the HFA is excellently suited for studying short-term pharmacodynamic effects of fluoropyrimidines in vivo. TAS-102 is only effective in inducing cytotoxicity when systemic TPI is present, but acts against both low and high TP expressing colon cancer cells, while 5'DFUR needs cellular TP to exert significant activity.

[Arthritis as a consequence of diabetes mellitus or haemochromatosis]. / Artritis ten gevolge van diabetes mellitus of hemochromatose.

Four patients with arthritis appeared to have this as a consequence of an internal disorder: a 60-year-old woman and a 20-year-old man with diabetes mellitus and arthritis of an ankle had Charcot arthropathy, whilst a 53-year-old woman and a 60-year-old man with polyarthritis had previously undiagnosed haemochromatosis. Patients were then adequately treated. Charcot arthropathy and haemochromatosis are not uncommon. Early diagnosis is important with respect to preventive and therapeutic measures. In patients with Charcot arthropathy immobilisation allows healing of the fractures. Bisphosphonates may be given in order to decrease bone resorption. In patients with haemochromatosis therapeutic bleeding may limit further damage to the joints and to the internal organs.

Testicular microlithiasis, a premalignant condition: prevalence, histopathologic findings, and relation to testicular tumor.

OBJECTIVES: To perform a retrospective analysis concerning the prevalence of testicular microlithiasis (TM). In patients with TM, the association of TM with testicular tumor, histopathologic findings, and follow-up were studied. METHODS: During a 6-year period at the Central Military Hospital or the University Medical Center in Utrecht, The Netherlands, ultrasonography of the testis was performed in 1535 patients. Patient records, ultrasound images, and histopathologic specimens were reviewed. Follow-up was performed in patients with TM. RESULTS: In 63 patients (4.1%), with a mean age of 35.4 years (range 19 to 74), TM was diagnosed at ultrasonography. In 29 of these patients (46%), a concomitant testicular tumor was diagnosed. A statistically significant correlation was found between TM and the presence of a testicular tumor (P <0.001; chi-square test). No significant correlation was found concerning the respective positions of the TM and the tumor in the testis, type of calcification, and histologic type of the tumor. In 34 patients, TM was found without a malignancy at diagnosis (mean age 39.2 years; range 19 to 69). Follow-up was possible in 31 patients. During the follow-up period (median 61.8 months), 1 patient developed a testicular tumor. CONCLUSIONS: A correlation was found between TM and testicular tumor. Because an increasing number of studies have reported patients with TM who developed a testicular tumor, TM should be regarded as a premalignant condition, which necessitates follow-up. Urologists should consider testis biopsy in patients with TM.

MR diagnosis of paraganglioma of the head and neck: value of contrast enhancement.

OBJECTIVE: Contrast enhancement with gadopentetate dimeglumine has been advocated to increase the efficacy of MR imaging for paragangliomas of the head and neck. However, contrast media are expensive, time-consuming to use, and involve minimal but not negligible risks. The purpose of this study was to determine if the use of contrast material is warranted in patients undergoing MR imaging for the diagnosis of paragangliomas of the head and neck. MATERIALS AND METHODS: Unenhanced MR images were compared with images obtained after administration of gadopentetate dimeglumine in 23 healthy subjects and 37 patients who had a total of 71 tumors. Three combinations of sequences were reviewed independently and in a random order by four observers who had no clinical information. Combination A comprised enhanced and unenhanced T1-weighted sequences, combination B comprised unenhanced T1- and T2-weighted sequences, and combination C was a combination of all sequences. A four-point scale of certainty was used. CT, scintigraphic, angiographic, and surgicopathologic findings were used as the standard of reference. Results were subjected to alternative free-response receiver-operating-characteristic (AFROC) scoring and statistical analysis. RESULTS: The mean areas under the AFROC curve for combinations A, B, and C were 0.761, 0.856, and 0.827, respectively. Mean sensitivity/specificity values after dichotomizing the scoring results were 0.73/0.94, 0.79/0.95, and 0.78/0.94 for combinations A, B, and C, respectively. The performance of combinations B and C did not differ markedly, but both combinations were significantly better than combination A. In a relatively large percentage (36%) of small postoperative tumor residues not detected on unenhanced images, however, gadopentetate dimeglumine allowed detection. CONCLUSION: The results of this study indicate that, in general, the use of gadopentetate dimeglumine is not necessary for the detection of head and neck paragangliomas. The addition of contrast-enhanced imaging does not increase the sensitivity or specificity compared with imaging without enhancement. Only when searching for small postoperative tumor residues is the addition of gadopentetate dimeglumine warranted.

Lumbar myelography with metrizamide.

Experiences with lumbar myelography with metrizamide (Amipaque) are reported. A less strict post-examination routine is presented. The subjective side effects do not seem to differ from those reported after lumbar puncture alone.