Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics

In calcific aortic valve disease (CAVD), microcalcifications originating from nanoscale calcifying vesicles disrupt the aortic valve (AV) leaflets, which consist of three (biomechanically) distinct layers: the fibrosa, spongiosa, and ventricularis. CAVD has no pharmacotherapy and lacks in vitro models as a result of complex valvular biomechanical features surrounding resident mechanosensitive valvular interstitial cells (VICs). We measured layer-specific mechanical properties of the human AV and engineered a three-dimensional (3D)-bioprinted CAVD model that recapitulates leaflet layer biomechanics for the first time. Human AV leaflet layers were separated by microdissection, and nanoindentation determined layer-specific Young’s moduli. Methacrylated gelatin (GelMA)/methacrylated hyaluronic acid (HAMA) hydrogels were tuned to duplicate layer-specific mechanical characteristics, followed by 3D-printing with encapsulated human VICs. Hydrogels were exposed to osteogenic media (OM) to induce microcalcification, and VIC pathogenesis was assessed by near infrared or immunofluorescence microscopy. Median Young’s moduli of the AV layers were 37.1, 15.4, and 26.9 kPa (fibrosa/spongiosa/ventricularis, respectively). The fibrosa and spongiosa Young’s moduli matched the 3D 5% GelMa/1% HAMA UV-crosslinked hydrogels. OM stimulation of VIC-laden bioprinted hydrogels induced microcalcification without apoptosis. We report the first layer-specific measurements of human AV moduli and a novel 3D-bioprinted CAVD model that potentiates microcalcification by mimicking the native AV mechanical environment. This work sheds light on valvular mechanobiology and could facilitate high-throughput drug-screening in CAVD

Commentaar op hoofdartikel ‘Lokale behandeling psoriasis vulgaris’ in het Geneesmiddelenbulletin, 2011;7:73-80 Onafhankelijkheid is nog geen garantie voor kwaliteit

Item does not contain fulltextHet geneesmiddelenbulletin (Drug bulletin) aims to inform about rational farmacotherapy. The bulletin uses ‘Evidence Based Medicine (EBM)’ to pursue this goal. The recently published article on topical therapy of psoriasis makes clear that an inaccurate approach and limited vision on EBM leads to incorrect positioning of drugs

[Hypersenisitivity to low molecular weight heparins: diagnostics and management.] Article in Dutch.

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De invloed van NaHCO3 in het voer op leg weakness en osteochondrosestatus bij mestvarkens

In vergelijking met een controlegroep die geen NaHCO3 kreeg, was gedurende en na afloop van de behandeling het klinische beeld met betrekking tot leg weakness significant beter in de proefgroep. Het karkasgewicht lag bij de dieren van de proefgroep iets hoger (ruim 1 kg) dan dat van de dieren van de controlegroep bij een vrijwel gelijke classificatie. Ook in het tweede onderzoek, waarbij vanaf een leeftijd van 7 weken tot aan het einde van de mestperiode 0,43% NaHCO3 via het voer werd toegediend, bleek NaHCO3 een duidelijk vertragend effect te hebben op de ontwikkeling van klinische verschijnselen van beengebreke

Measuring sensory and pain thresholds by Semmes-Weinstein monofilaments in patients with leg ulcers: a pilot study

Item does not contain fulltextOBJECTIVE: Pain is a common and disabling symptom in patients with leg ulcers. Clinical quantification of pain mostly depends on subjective pain reports, which do not reveal underlying mechanisms. The aim of this pilot study is to identify mechanisms underlying the pain in patients with leg ulcers by documenting alterations in pain processing using quantitative sensory testing. METHODS: In nine ulcer patients the mechanical sensory thresholds and the mechanical pain thresholds were determined by Semmes-Weinstein monofilaments (SWM) at three different sites: on the contralateral (unaffected) leg, on the skin of the affected leg 10cm from the ulcer margin, and on the affected leg, close (1-2cm) to the ulcer margin. Besides the mechanical sensory thresholds and mechanical pain thresholds, pain at the site of the ulcer, using an 11-point numeric rating scale (NRS), was documented. RESULTS: Mechanical sensory thresholds were increased in all subjects. Almost half (44%) of patients consistently showed allodynia at the unaffected site. The lowering of mechanical pain thresholds correlated with higher scores on the NRS. CONCLUSION: All patients showed diminished touch and/or protective sensation, which might have contributed to ulcer development via (partial) loss of protective function. The allodynia at the unaffected site suggests the presence of central sensitisation of pain processing

Dermatological exposure to coal tar and bladder cancer risk: a case-control study

Contains fulltext : 154955.pdf (Publisher’s version ) (Open Access)OBJECTIVE: Coal tar ointments are used as treatment of various skin diseases, especially psoriasis and eczema. These ointments contain several carcinogenic polycyclic aromatic hydrocarbons. Metabolites of these polycyclic aromatic hydrocarbons are excreted in the urine and therefore, dermatological use of coal tar may be associated with an increased risk of bladder cancer. The objective of this study was to evaluate the association between dermatological use of coal tar ointments and bladder cancer. MATERIAL AND METHODS: A population-based case-control study was conducted including 1,387 cases diagnosed with bladder cancer and 5,182 population controls. Information on the use of coal tar, history of skin disease, and known risk factors for bladder cancer was obtained through postal questionnaires. Logistic regression analyses were performed to estimate the risk of bladder cancer after coal tar treatment, adjusted for age, gender, smoking status, duration of smoking, and intensity of smoking. RESULTS: The use of coal tar ointments was approximately equal among cases and controls (3.8% vs. 3.0%, respectively). Dermatological application of coal tar was not significantly associated with bladder cancer (adjusted odds ratio = 1.37, 95% CI: 0.93-2.01). An inverse association between bladder cancer and a history of skin disease was observed (adjusted odds ratio = 0.74, 95% CI: 0.61-0.90). CONCLUSION: This is the first study with a specific aim to study the association between the use of coal tar preparations and bladder cancer. The results suggest that there is no reason for safety concerns with respect to the risk of bladder cancer after the use of coal tar preparations in dermatological practice

Spongy white matter changes, MR appearances, differential diagnosis and description of a new disease

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[Integrated care for patients with hand eczema: results of a randomized, controlled trial]

Item does not contain fulltextOBJECTIVE: To evaluate the effectiveness of integrated, transmural multidisciplinary care compared with usual care for patients with moderate to severe, chronic hand eczema after 26 weeks follow-up. DESIGN: Randomized, controlled study. METHOD: Patients who visited their dermatologist were randomized to integrated care or usual care. Integrated transmural care was carried out by a multidisciplinary team and consisted of a combination of clinical and occupational care to optimize treatment, the patient's quality of life and social functioning. Outcome variables were clinical assessment of hand eczema using the Hand Eczema Severity Index (HECSI) (primary outcome), quality of life, patient's global assessment of hand eczema and sick leave. RESULTS: Average improvement on the HECSI was 22.4 points in the integrated care group and 11.7 points in the control group. The mean difference in improvement on the HECSI between both groups after 26 weeks was 10.7 points in favour of the integrated care group (SE: 5.3; 95% CI: 0.3-21.1; p = 0.04). No differences between the groups were found for any of the other outcomes. CONCLUSION: The integrated care program significantly improved clinical outcome measures compared with usual care and was effective in treating patients with chronic hand eczema

Astroglial PGC-1alpha increases mitochondrial antioxidant capacity and suppresses inflammation: implications for multiple sclerosis

Recent evidence suggests that reactive oxygen species (ROS) produced by inflammatory cells drive axonal degeneration in active multiple sclerosis (MS) lesions by inducing mitochondrial dysfunction. Mitochondria are endowed with a variety of antioxidant enzymes, including peroxiredoxin-3 and thioredoxin-2, which are involved in limiting ROS-induced damage. In this study, we explored the distribution and role of the mitochondrial antioxidants peroxiredoxin-3 and thioredoxin-2 as well as their regulator peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1α) in MS pathogenesis. Immunohistochemical analysis of a large cohort of MS patients revealed a striking upregulation of PGC-1α and downstream mitochondrial antioxidants in active demyelinating MS lesions. Enhanced expression was predominantly observed in reactive astrocytes. To elucidate the functional role of astrocytic PGC-1α in MS pathology, we generated human primary astrocytes that genetically overexpressed PGC-1α. Upon an oxidative insult, these cells were shown to produce less ROS and were found to be more resistant to ROS-induced cell death compared to control cells. Intriguingly, also neuronal cells co-cultured with PGC-1α-overexpressing astrocytes were protected against an exogenous oxidative attack compared to neuronal cells co-cultured with control astrocytes. Finally, enhanced astrocytic PGC-1α levels markedly reduced the production and secretion of the pro-inflammatory mediators interleukin-6 and chemokine (C-C motif) ligand 2. Our findings suggest that increased astrocytic PGC-1α in active MS lesions might initially function as an endogenous protective mechanism to dampen oxidative damage and inflammation thereby reducing neurodegeneration. Activation of PGC-1α therefore represents a promising therapeutic strategy to improve mitochondrial function and repress inflammation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-014-0170-2) contains supplementary material, which is available to authorized users

A Clinical Investigation Of Removable Partial Dentures

We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic. There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involvement of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known