Gamification of health professions education: a systematic review.

Gamification refers to using game attributes in a non-gaming context. Health professions educators increasingly turn to gamification to optimize students' learning outcomes. However, little is known about the concept of gamification and its possible working mechanisms. This review focused on empirical evidence for the effectiveness of gamification approaches and theoretical rationales for applying the chosen game attributes. We systematically searched multiple databases, and included all empirical studies evaluating the use of game attributes in health professions education. Of 5044 articles initially identified, 44 met the inclusion criteria. Negative outcomes for using gamification were not reported. Almost all studies included assessment attributes (n = 40), mostly in combination with conflict/challenge attributes (n = 27). Eight studies revealed that this specific combination had increased the use of the learning material, sometimes leading to improved learning outcomes. A relatively small number of studies was performed to explain mechanisms underlying the use of game attributes (n = 7). Our findings suggest that it is possible to improve learning outcomes in health professions education by using gamification, especially when employing game attributes that improve learning behaviours and attitudes towards learning. However, most studies lacked well-defined control groups and did not apply and/or report theory to understand underlying processes. Future research should clarify mechanisms underlying gamified educational interventions and explore theories that could explain the effects of these interventions on learning outcomes, using well-defined control groups, in a longitudinal way. In doing so, we can build on existing theories and gain a practical and comprehensive understanding of how to select the right game elements for the right educational context and the right type of student.

Molecular subtypes of systemic sclerosis in association with anti-centromere antibodies and digital ulcers.

The objective of this study was to identify molecular profiles that may distinguish clinical subtypes in systemic sclerosis (SSc). Large-scale gene expression profiling was performed on peripheral blood (PB) from 12 SSc patients and 6 healthy individuals. Significance analysis of microarrays, two-way hierarchical cluster analysis and PANTHER (Protein ANalysis THrough Evolutionary Relationships) ontology classification were used to analyze the data. Quantitative PCR was applied for validation in a cohort of 43 SSc patients. The results show that the expression of genes involved in immune defense, cell cycle and signal transduction was significantly elevated in PB of SSc patients (n=12) compared with healthy individuals (n=6). SSc patients could be stratified into subgroups based on differential expression of genes induced by type I interferon (IFN) and genes involved in antimicrobial (AM) activity. Differential expression of type I IFN or AM signature genes was validated and extended in an independent cohort of 31 patients by quantitative PCR. Low expression of IFN response genes was associated with the presence of anti-centromere antibodies, whereas increased expression was associated with the appearance of digital ulcers. In conclusion, patients with SSc can be classified on the basis of differential expression of immune defense genes. Differences in the activity of the type I IFN response program stratify patients into two clinically relevant subgroups.

[Choking caused by antipsychotics]. / Verslikking en verstikking door antipsychotica.

BACKGROUND: Asphyxia is one of the most serious types of antipsychotic-induced extrapyramidal symptoms. AIM: To study the prevalence, course, diagnostics and treatment of asphyxia and dysphagia caused by the use of antipsychotics. METHOD: The relevant literature was retrieved via Medline (1960-2005), using combinations of the (mesh) terms 'antipsychotic agents', 'dystonia', 'parkinson disease', 'secondary', 'dyskinesias', 'drug-induced', 'asphyxia' and the key words 'dysphagia' en 'respiratory'. RESULTS: Asphyxia caused by the use of antipsychotics can occur because of spasms of the respiratory muscles or because of an increased risk of choking (dysphagia). These phenomena can occur shortly after patients have started to take antipsychotics, for some time or even for a long time after. Patients who choke frequently or take rapid, irregular breaths interspersed with groans or sighs need to be observed closely. Risk factors are high doses of and long-term use of antipsychotics. Clinical examination of the gag reflex and the respiration contributes very little to an unequivocal diagnosis of swallowing disorders. However, swallowing disorders can be identified reliably by means of videofluoroscopy. Treatment that involves an adjustment of a patient's medication can often be effective. CONCLUSION: Timely recognition of asphyxia is vital for the prevention of a life-threatening complication arising from the use of antipsychotics.

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells.

Small-cell lung cancers (SCLCs) initially respond to chemotherapy but are often resistant at recurrence. A potentially new method to overcome resistance is to combine classical chemotherapeutic drugs with apoptosis induction via tumour necrosis factor (TNF) death receptor family members such as Fas. The doxorubicin-resistant human SCLC cell line GLC4-Adr and its parental doxorubicin-sensitive line GLC4 were used to analyse the potential of the Fas-mediated apoptotic pathway and the mitochondrial apoptotic pathway to modulate doxorubicin resistance in SCLC. Western blotting showed that all proteins necessary for death-inducing signalling complex formation and several inhibitors of apoptosis were expressed in both lines. The proapototic proteins Bid and caspase-8, however, were higher expressed in GLC4-Adr. In addition, GLC4-Adr expressed more Fas (3.1x) at the cell membrane. Both lines were resistant to anti-Fas antibody, but plus the protein synthesis inhibitor cycloheximide anti-Fas antibody induced 40% apoptosis in GLC4-Adr. Indomethacin, which targets the mitochondrial apoptotic pathway, induced apoptosis in GLC4-Adr but not in GLC4 cells. Surprisingly, in GLC4-Adr indomethacin induced caspase-8 and caspase-9 activation as well as Bid cleavage, while both caspase-8 and caspase-9 specific inhibitors blocked indomethacin-induced apoptosis. In GLC4-Adr, doxorubicin plus indomethacin resulted in elevated caspase activity and a 2.7-fold enhanced sensitivity to doxorubicin. In contrast, no effect of indomethacin on doxorubicin sensitivity was observed in GLC4. Our findings show that indomethacin increases the cytotoxic activity of doxorubicin in a doxorubicin-resistant SCLC cell line partly via the death receptor apoptosis pathway, independent of Fas.

Modulation of death receptor pathways in oncology.

Chemotherapeutic efficacy is hampered by occurrence of drug resistance. Several mechanisms cause this phenomenon. A final common factor is the reduced capacity of resistant cells to go into apoptosis following treatment with DNA-damaging agents. It is therefore interesting to search for ways to facilitate this apoptotic process following use of chemotherapeutic drugs. The death receptor ligands tumor necrosis factor (TNF), FasL and TNF-related apoptosis-inducing ligand (TRAIL) might be interesting candidates as they are able to induce apoptosis by binding to their cell membrane receptors. Recombinant forms of these ligands potentiate chemotherapeutic drug effects in preclinical models. For the clinical application of TNF, FasL and TRAIL, it is of primary importance that their safety be guaranteed. RhTNF is the only ligand currently used in humans. However, systemic rhTNF has shown low antitumor activity and higher doses induce severe sepsis-like toxicity. Perfusion setting aimed at limb preservation with rhTNF plus melphalan is currently used in sarcoma patients. A number of options have been tested in the preclinical setting that might allow circumvention of TNF toxicity in the clinic. Systemic rhFasL administration in humans is not yet feasible because of observed severe liver toxicity in mice due to Fas-mediated apoptosis of hepatocytes. Measures to circumvent liver toxicity have not yet been exploited. Another option for using FasL in the clinic may be to identify an alternative route of administration. In the animal model, FasL appeared to be less toxic for the liver compared with anti-Fas antibodies when administered intraperitoneally. There are relatively nontoxic modulators of the Fas death pathway, such as interferon and nonsteroidal antiinflammatory drugs (NSAIDs), which might prove interesting in combination with chemotherapy. Finally, it may be possible to produce a modified FasL with a reduced toxicity profile. TRAIL, produced as soluble, zinc-stabilized rhTRAIL seems to be without preclinical toxicity. Agonistic DR4 and DR5 antibodies against their TRAIL death receptor are being studied as another potential clinical option to induce apoptosis. Due to the synergistic effect observed in the preclinical setting between death receptor ligands and other modulators of the death receptor pathways and chemotherapy, it may well be that this approach is especially of value in the clinic when combined with chemotherapy. Ideally, choices for specific (modified) death receptor ligands for the treatment of patients can be rationally made based on tumor characteristics.

Death receptor ligands, in particular TRAIL, to overcome drug resistance.

The efficacy of chemotherapeutic drugs is hampered by the occurrence of intrinsic and acquired drug resistance. A variety of mechanisms cause drug-resistance. A final common factor, however, is the reduced capacity of drug resistant cells to go into apoptosis following treatment with DNA damaging agents. This is due to defects in apoptotic pathways, for example, changes in p53. The presence of a common factor makes it of interest to search for ways that facilitate the cell to go into apoptosis following exposure to chemotherapeutic drugs. The death receptor ligands tumor necrosis factor (TNF), Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) are able to induce apoptosis by binding to their cell membrane receptors. Recombinant forms of these ligands are capable to potentiate the effect of chemotherapeutic drugs in vitro and in vivo in the animal model. Based on preclinical toxicity and activity profiling, especially TRAIL is considered to be of interest for clinical use. Systemic treatment of non-human primates with TRAIL did not result in acute toxicity. Animal studies demonstrated antitumor activity of TRAIL and potentiation of the chemotherapy efficacy by TRAIL. Phase 1 studies with TRAIL will therefore be initiated. As TRAIL is supposed to be non-toxic, it will be a major challenge to design surrogate end points to find the optimal dose in the clinic. In analogy to the herceptin therapy, it may be helpful to characterize the tumor of the patient. In addition, ex vivo exposure of the tumor may also be useful to select the proper ligand therapy for the individual patient. For optimal effect it is most likely that ligand therapy will be combined with chemotherapy, but even a combination of ligands for patient treatments can be envisioned. It is to be expected that smart, small molecules targeting these death receptors will be designed in order to lower toxicity and increase antitumor activity.

An evolutionary rearrangement of the Xp11.3-11.23 region in 3p21.3, a region frequently deleted in a variety of cancers.

In searching for a tumor suppressor gene in the 3p21.3 region, we isolated two genes, RBM5 and RBM6. Sequence analysis indicated that these genes share similarity. RBM5 and-to a lesser extent-RBM6 also have similarity to DXS8237E at Xp11.3-11.23, which maps less than 20 kb upstream of UBE1. A homologue of UBE1, UBE1L, is located at 3p21. 3. FISH analysis showed that the distance between UBE1L and RBM5 in 3p21.3 is about 265 kb. DXS8237E and UBE1 on the X chromosome have the same orientation, whereas on chromosome 3 the orientation of RBM5 and that of RBM6 are opposite to the orientation of UBE1L. Presumably, part of the Xp11.3-11.23 region has duplicated to chromosome 3. Part of this region on chromosome 3 may subsequently have duplicated again within the same chromosomal region. Inversion at some stage of the evolution of the human genome would explain the change in orientation of the genes on chromosome 3 compared with that of the genes on the X chromosome.

Comprehensive TP53-denaturing gradient gel electrophoresis mutation detection assay also applicable to archival paraffin-embedded tissue.

A comprehensive mutation detection assay is described for the entire coding region and all splice site junctions of TP53. The assay is based on denaturing gradient gel electrophoresis, which follows either multiplex polymerase chain reaction (PCR) applied to DNA extracted from fresh or frozen tissue samples or nested PCR applied to DNA extracted from paraffin-embedded tissue samples. In both instances, the analysis can be performed under a single set of conditions. When testing the assay on DNA from cultured lung cancer cell lines and from paraffin-embedded Dukes C colorectal carcinomas, significant TP53 mutations were observed at high frequencies in 15 of 16 lung cancer cell lines (94%) and in 21 of 30 paraffin-embedded tissue samples of Dukes C colorectal carcinomas (70%). A substantial proportion of these significant mutations occurred outside the evolutionary conserved region of TP53 in 4 of 16 lung cancer cell lines (25%) and in 11 of 30 paraffin-embedded colorectal carcinomas (37%). This underscores the importance of a comprehensive TP53 mutation analysis in those instances that TP53 mutation is taken into account for diagnostic and prognostic purposes.

A comparison of genomic structures and expression patterns of two closely related flanking genes in a critical lung cancer region at 3p21.3.

In the search for a tumour suppressor gene in the 3p21.3 region we isolated two genes, RBM5 and RBM6. Gene RBM5 maps to the region which is homozygously deleted in the small cell lung cancer cell line GLC20; RBM6 crosses the telomeric breakpoint of this deletion. Sequence comparison revealed that at the amino acid level both genes show 30% identity. They contain two zinc finger motifs, a bipartite nuclear signal and two RNA binding motifs, suggesting that the proteins for which RBM5 and RBM6 are coding have a DNA/RNA binding function and are located in the nucleus. Northern and Southern analysis did not reveal any abnormalities. By SSCP analysis of 16 lung cancer cell lines we found only in RBM5 a single presumably neutral mutation. By RT-PCR we demonstrated the existence of two alternative splice variants of RBM6, one including and one excluding exon 5, in both normal lung tissue and lung cancer cell lines. Exclusion of exon 5 results in a frameshift which would cause a truncated protein of 520 amino acids instead of 1123 amino acids. In normal lung tissue, the relative amount of the shorter transcript was much greater than that in the lung tumour cell lines, which raises the question whether some tumour suppressor function may be attributed to the derived shorter protein.

Investigation of the genes for RET and its ligand complex, GDNF/GFR alpha-I, in small cell lung carcinoma.

RET is a receptor tyrosine kinase expressed in neuroendocrine cells and in tumors of these cell types. RET activation may be mediated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF family receptor alpha-1 (GFR alpha-1). Activating RET mutations are found in the inherited cancer syndrome multiple endocrine neoplasia type 2 and in a subset of the related sporadic tumors, medullary thyroid carcinoma and pheochromocytoma, both being derived from neuroendocrine tissues. In one small study, mutations were identified in another tumor with neuroendocrine features, small cell lung carcinoma (SCLC). To determine whether RET mutations contribute to the pathogenesis of SCLC, we examined a panel of 54 SCLC cell lines. No mutations were identified in RET exons 10, 11, and 13-16, regions previously implicated in SCLC or other neuroendocrine tumors. We further examined the expression pattern of RET and the genes encoding the components of its ligand complex GDNF and GFR alpha-1, in 21 SCLC lines by using RT-PCR. Although we found no consistent pattern of expression for these three genes, RET was expressed in 57% of SCLC lines. Thus, although RET mutations appear unlikely to be an important step in the tumorigenesis of SCLC, the frequent expression of this gene suggests that RET may have a mitogenic role in a subset of SCLC cell lines.

Normal FHIT transcripts in renal cell cancer- and lung cancer-derived cell lines, including a cell line with a homozygous deletion in the FRA3B region.

The recently identified FHIT gene encompasses the FRA3B region and the breakpoint of a constitutive t(3;8) occurring in a family with hereditary renal cell cancer. Occurrence of aberrant transcripts in different types of tumours has led to the suggestion that FHIT might play a critical role in the development of various types of cancer. We have analyzed the gene and its transcripts in lung cancers and renal cell cancer-derived cell lines. A lung adenocarcinoma cell line, GLC-A2, appeared to have a homozygous deletion in intron 5 of FHIT. RT-PCR analysis revealed a normal-sized PCR product in all of the cell lines: Including GLC-A2. A number of them had an additional aberrant product. Analysis of a great number of control cell lines and tissues showed that the majority of these also had aberrant PCR products in addition to a normal-sized PCR product. Different specimens of the same cell type showed variable additional RT-PCR products. Normal-sized PCR products had a sequence identical to the FHIT sequence. PCR products longer than normal had insertions of different sizes at different positions. With three exceptions, PCR products shorter than normal represented FHIT sequences missing one or more entire exons. Thus, the presence of aberrant transcripts is not cancer-specific. Conceivably, sequence responsible for the instability of the FRA3B region are being transcribed into FHIT pre-mRNA and may cause the abnormal splicing and processing of the transcripts.