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The disruption of coupling between brain areas has been suggested as the mechanism underlying loss of consciousness in anesthesia. This hypothesis has been tested previously by measuring the information transfer between brain areas, and by taking reduced information transfer as a proxy for decoupling. Yet, information transfer is a function of the amount of information available in the information source—such that transfer decreases even for unchanged coupling when less source information is available. Therefore, we reconsidered past interpretations of reduced information transfer as a sign of decoupling, and asked whether impaired local information processing leads to a loss of information transfer. An important prediction of this alternative hypothesis is that changes in locally available information (signal entropy) should be at least as pronounced as changes in information transfer. We tested this prediction by recording local field potentials in two ferrets after administration of isoflurane in concentrations of 0.0%, 0.5%, and 1.0%. We found strong decreases in the source entropy under isoflurane in area V1 and the prefrontal cortex (PFC)—as predicted by our alternative hypothesis. The decrease in source entropy was stronger in PFC compared to V1. Information transfer between V1 and PFC was reduced bidirectionally, but with a stronger decrease from PFC to V1. This links the stronger decrease in information transfer to the stronger decrease in source entropy—suggesting reduced source entropy reduces information transfer. This conclusion fits the observation that the synaptic targets of isoflurane are located in local cortical circuits rather than on the synapses formed by interareal axonal projections. Thus, changes in information transfer under isoflurane seem to be a consequence of changes in local processing more than of decoupling between brain areas. We suggest that source entropy changes must be considered whenever interpreting changes in information transfer as decoupling.
Introduction: This study reports about antenatal characteristics of Roma minority population. The study was designed to investigate data about health behaviours known to be associated with reproductive outcomes of Roma women that have very good living conditions and relatively high resource availability.
Methods: A retrospective study included 204 Roma and 408 non-Roma hospitalised singleton births that occurred in the Maternity Ward of the General Hospital Virovitica in the period from 1991 to 2010. Data about women’s age, marital status, smoking, reproductive health (abortions, delivery), antenatal care, perinatal complications and gestational age were taken from hospital records and analysed.
Results: Roma women were averagely more than three years younger than non-Roma women, only 10.8% were married. Smoking was more frequent. The average number of births of Roma and non-Roma women was similar, averagely two children per woman. The rate of induced abortions in the Roma women was higher, while the frequency of spontaneous abortions was equal. Inadequate antenatal care of Roma women was associated with two times higher incidence of perinatal complications. A higher frequency of deliveries at home without professional assistance in Roma pregnancy resulted in lower perinatal outcomes. It was confirmed that Roma mothers give birth earlier (38+6 vs. 39+4 weeks) and have a higher incidence of premature births (9.3% vs. 2.2%).
Conclusions: In the comparison of antenatal parameters between the two researched groups, poorer prenatal outcomes in the Roma population were found, despite full integration and considerable improvement in living standards of this ethnic Roma population.
Purpose: Prisoners are at a particularly high risk of suicide. In contrast to other psychosocial risk factors it remains unclear to what degree the risk of suicide differs between prisoners with local citizenship and foreigners. In order to provide more detailed information for suicide prevention in prisons, this study aims to compare suicide rates (SR) between these populations in German criminal custody.
Methods: Based on a German national database of completed suicide in custody, suicides by prisoners were analysed and compared with epidemiological data of the prison population and the general population, stratified for German and foreign citizenship. Data analysis was adjusted for differences in the age distribution of both populations by calculating standard mortality ratios (SMR) for suicide.
Results: SR were higher in prisoners with German citizenship than those with foreign citizenship (SR = 76.5 vs. SR = 42.8, P<0.01). This association was not specific to the prison population, as the higher SR in citizens compared to non-citizens (SR = 19.3 vs. SR = 9.0, P<0.01) were also found in the general population. The association between prison suicide and citizenship was comparable in juvenile and adult prisoners, indicating its relevance to both the juvenile and adult detention systems.
Conclusion: Imprisonment is associated with a substantially increased risk of suicide in both German and non-German citizens, a finding which needs to be taken into consideration by the justice system. The lower suicide risk in non-German citizens is independent of whether or not they are in custody.
Cancer is characterized by a remarkable intertumoral, intratumoral, and cellular heterogeneity that might be explained by the cancer stem cell (CSC) and/or the clonal evolution models. CSCs have the ability to generate all different cells of a tumor and to reinitiate the disease after remission. In the clonal evolution model, a consecutive accumulation of mutations starting in a single cell results in competitive growth of subclones with divergent fitness in either a linear or a branching succession. Acute lymphoblastic leukemia (ALL) is a highly malignant cancer of the lymphoid system in the bone marrow with a dismal prognosis after relapse. However, stabile phenotypes and functional data of CSCs in ALL, the so-called leukemia-initiating cells (LICs), are highly controversial and the question remains whether there is evidence for their existence. This review discusses the concepts of CSCs and clonal evolution in respect to LICs mainly in B-ALL and sheds light onto the technical controversies in LIC isolation and evaluation. These aspects are important for the development of strategies to eradicate cells with LIC capacity. Common properties of LICs within different subclones need to be defined for future ALL diagnostics, treatment, and disease monitoring to improve the patients’ outcome in ALL.
Local treatment of unresectable colorectal liver metastases : results of a randomized phase II trial
(2017)
Background: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach.
Methods: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection. Previously, we reported that the primary end point (30-month overall survival [OS] > 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat.
Results: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm.
Conclusions: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases.
Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting that nucleolar dysfunction could be a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human α-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1. We showed that overexpressed hA53T-SNCA localizes to the nucleolus. Moreover, these mutants show a progressive reduction of rDNA transcription linked to a reduced mouse lifespan. By contrast, rDNA transcription is preserved in DJ-1/PINK1 double knockout (DKO) mice. mRNA levels of the nucleolar transcription initiation factor 1A (TIF-IA, also known as RRN3) decrease in the substantia nigra of individuals with PD. Because loss of TIF-IA, as a tool to mimic nucleolar stress, increases oxidative stress and because DJ-1 and PINK1 mutations result in higher vulnerability to oxidative stress, we further explored the synergism between these PD-associated genes and impaired nucleolar function. By the conditional ablation of TIF-IA, we blocked ribosomal RNA (rRNA) synthesis in adult dopaminergic neurons in a DJ-1/PINK1 DKO background. However, the early phenotype of these triple knockout mice was similar to those mice exclusively lacking TIF-IA. These data sustain a model in which loss of DJ-1 and PINK1 does not impair nucleolar activity in a pre-symptomatic stage. This is the first study to analyse nucleolar function in digenic PD models. We can conclude that, at least in these models, the nucleolus is not as severely disrupted as previously shown in DA neurons from PD patients and neurotoxin-based PD mouse models. The results also show that the early increase in rDNA transcription and nucleolar integrity may represent specific homeostatic responses in these digenic pre-symptomatic PD models.
Development of single-port cholecystectomy : results of a case-control study matched to one surgeon
(2012)
Background: Single-port laparoscopic cholecystectomy is an evolving technique which is now widely established. Up until now, the safety of the procedure and a respective learning curve have not been adequately reported in most studies. The aim of this study was to demonstrate that single-port cholecystectomy is a safe procedure, with a positive learning curve from a case-control study matched to one surgeon.
Methods: One hundred single-port cholecystectomies performed by one surgeon (AB) were retrospectively matched to 100 patients who underwent conventional laparoscopic cholecystectomy carried out by the same surgeon. The two groups were matched in respect of surgical indication, gender, age, and body mass index. The groups were compared with respect to operation time, use of additional trocars, analgesics required in the post anesthesia care unit, postoperative complications, and duration of hospital stay.
Results: No significant difference was found between the two groups with respect to postoperative complications and stay in hospital. The operation time increased slightly in the single-port group. Directly after the operation, the analgesic use required in the post anesthesia care unit was higher in the single-port group. Consumption of analgesics on the surgical ward was very similar in each group. In respect to the learning curve, the operation time and use of additional trocars showed a positive trend, starting with the thirtieth operation.
Conclusion: Single-port cholecystectomy is a feasible and safe procedure in a specialist setting. The procedure can be done under the same safety rules as those for conventional laparoscopic cholecystectomy. Considering the learning curve, starting with the thirtieth operation, a positive trend was seen. Long-term studies will be needed to establish the incidence and rate of incisional hernias.
This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28-d cycles of 85 mg/m2 pixantrone dimaleate (equivalent to 50 mg/m2 in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2–6) with pixantrone and 3 (2–6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression-free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26–1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B-cell NHL in the 3rd or 4th line setting, independently of previous rituximab.
Objective: Loss of function mutations in PINK1 typically lead to early onset Parkinson disease (PD). Zebrafish (Danio rerio) are emerging as a powerful new vertebrate model to study neurodegenerative diseases. We used a pink1 mutant (pink−/−) zebrafish line with a premature stop mutation (Y431*) in the PINK1 kinase domain to identify molecular mechanisms leading to mitochondrial dysfunction and loss of dopaminergic neurons in PINK1 deficiency.
Methods: The effect of PINK1 deficiency on the number of dopaminergic neurons, mitochondrial function, and morphology was assessed in both zebrafish embryos and adults. Genome-wide gene expression studies were undertaken to identify novel pathogenic mechanisms. Functional experiments were carried out to further investigate the effect of PINK1 deficiency on early neurodevelopmental mechanisms and microglial activation.
Results: PINK1 deficiency results in loss of dopaminergic neurons as well as early impairment of mitochondrial function and morphology in Danio rerio. Expression of TigarB, the zebrafish orthologue of the human, TP53-induced glycolysis and apoptosis regulator TIGAR, was markedly increased in pink−/− larvae. Antisense-mediated inactivation of TigarB gave rise to complete normalization of mitochondrial function, with resulting rescue of dopaminergic neurons in pink−/− larvae. There was also marked microglial activation in pink−/− larvae, but depletion of microglia failed to rescue the dopaminergic neuron loss, arguing against microglial activation being a key factor in the pathogenesis.
Interpretation: Pink1−/− zebrafish are the first vertebrate model of PINK1 deficiency with loss of dopaminergic neurons. Our study also identifies TIGAR as a promising novel target for disease-modifying therapy in PINK1-related PD. Ann Neurol 2013;74:837–847
Stroke is a major public health issue worldwide. The prevalence of stroke in 2010 was 33 million, with 16.9 million people having a first stroke.1 Stroke was the second‐leading cause of death behind heart disease globally, accounting for over 10% of total deaths worldwide.
Stroke is a heterogeneous condition that can be due to rupture of a blood vessel (hemorrhagic) or to blockage of a vessel (ischemic). About 85% of strokes are ischemic in origin and these are often classified by mechanism. This should be distinguished from risk factors such as hypertension, diabetes, smoking, etc. Risk factors increase the risk of stroke but do not necessarily explain the mechanism of a particular stroke. About 25% of ischemic strokes have a radiographic appearance similar to that seen in patients with cardioembolic sources (such as atrial fibrillation [AF], prosthetic valves, valvular prolapse, or mitral valve regurgitation), but no embolic source is found. These "cryptogenic strokes" (CS; also called embolic strokes of undetermined source) pose a particular clinical challenge in that the optimal antithrombotic therapy to reduce recurrence is uncertain. Since there are currently no data to support long‐term oral anticoagulation (OAC) in CS, but also no specific trials that have addressed this question, guidelines recommend antiplatelet therapy. Identification of AF in these patients changes the most likely mechanism to cardioembolism, and thus changes the recommended antithrombotic therapy to OAC, which is extremely effective in preventing stroke in patients with AF.
This report is based on discussions held at The Diagnostics and Monitoring Stroke Focus Group, a meeting held on January 15 to 17, 2015. The meeting focused on CS as a healthcare issue, and the utility of extended cardiac monitoring for AF in patients with strokes of unknown origin. The objectives of the meeting were to review existing information on the subject, define areas where knowledge was lacking or limited, and discuss study designs by which information gaps might be filled.
Aims: The purpose of this study was to analyze the prevalence of depression, anxiety, adjustment disorders, and somatoform disorders in patients diagnosed with age-related macular degeneration (AMD) in Germany.
Methods: This study included 7,580 patients between the ages of 40 and 90 diagnosed with AMD between January 2011 and December 2014 in 1,072 primary care practices (index date). The last follow-up was in July 2016. We also included 7,580 controls without AMD, which were matched (1:1) to the AMD cases by age, sex, type of health insurance (private or statutory), physician, and Charlson comorbidity score as a generic marker of comorbidity. The outcome of the study was the prevalence of depression, anxiety, adjustment disorders, and somatoform disorders recorded in the database between the index date and the end of follow-up.
Results: The mean age among subjects was 75.7 years (SD=10.1 years), 34.0% were men, and 7.8% had private health insurance coverage. The Charlson comorbidity index was 2.0 (SD=1.8). Depression was the most frequent disease (33.7% in AMD patients versus 27.3% in controls), followed by somatoform disorders (19.6% and 16.7%), adjustment disorders (14.8% and 10.5%), and anxiety disorders (11.7% and 8.2%). Depression (OR=1.37, 95% CI: 1.27–1.47), anxiety (OR=1.50, 95% CI: 1.35–1.67), adjustment disorders (OR=1.50, 95% CI: 1.36–1.65), and somatoform disorders (OR=1.22, 95% CI: 1.12–1.32) were all positively associated with AMD.
Conclusion: Overall, a significant association was found between AMD and depression, anxiety, adjustment disorders, and somatoform disorders.
Green tea (GT) and green tea extracts (GTE) have been postulated to decrease cancer incidence. In vitro results indicate a possible effect; however, epidemiological data do not support cancer chemoprevention. We have performed a PubMED literature search for green tea consumption and the correlation to the common tumor types lung, colorectal, breast, prostate, esophageal and gastric cancer, with cohorts from both Western and Asian countries. We additionally included selected mechanistical studies for a possible mode of action. The comparability between studies was limited due to major differences in study outlines; a meta analysis was thus not possible and studies were evaluated individually. Only for breast cancer could a possible small protective effect be seen in Asian and Western cohorts, whereas for esophagus and stomach cancer, green tea increased the cancer incidence, possibly due to heat stress. No effect was found for colonic/colorectal and prostatic cancer in any country, for lung cancer Chinese studies found a protective effect, but not studies from outside China. Epidemiological studies thus do not support a cancer protective effect. GT as an indicator of as yet undefined parameters in lifestyle, environment and/or ethnicity may explain some of the observed differences between China and other countries.
Das Buch "Qualitative Evaluation" zeigt Schritt für Schritt die Vorgehensweise und stellt damit in sehr anwendungsorientierter Form das Handwerkszeug für eine qualitative Evaluation zur Verfügung. So werden Lesende in die Lage versetzt, eine solche Evaluation auch bei geringen Vorkenntnissen durchzuführen, wobei damit das Risiko verbunden sein kann, dass bei der Interpretation der Befunde wichtige Voraussetzungen für das Gelingen einer qualitativen Studie wie Verwurzelung der Interpretation im tatsächlich aufgezeichneten Text vernachlässigt werden.
Osteoid osteoma is a benign bone tumor of undetermined etiology, composed of a central zone named nidus which is an atypical bone completely enclosed within a wellvascularized stroma and a peripheral sclerotic reaction zone. There are three types of radiographic features: cortical, medullary and subperiosteal. Forty-four patients with osteoid osteoma were studied retrospectively. In plain films, 35 patients presented as the cortical type, six cases were located in the medullary zone and three had subperiosteal osteoid osteoma. In all the cases, the nidus was visualized on computed tomography (CT) scan. The nidus was visible in four out of five patients who had also undergone magnetic resonance imaging (MRI). Double-density sign, seen on radionuclide bone scans was positive in all patients. MRI is more sensitive in the diagnosis of bone marrow and soft tissue abnormalities adjacent to the lesion, and in the nidus that is located closer to the medullary zone. On the other hand, CT is more specific when it comes to detecting the lesion’s nidus.
Die Entwicklungen in der Medizinischen Ausbildung der letzten Jahre konfrontieren Lehrende zunehmend mit neuen didaktischen Herausforderungen. An zahlreichen Standorten im deutschsprachigen Raum werden bereits Qualifizierungsangebote für Lehrende angeboten, jedoch fehlt bisher ein Orientierungsrahmen für medizindidaktische Kompetenzen, der ein Qualifikationsprofil für Lehrende darstellt.
Vor dem Hintergrund der Diskussion um die Kompetenzorientierung des Medizinstudiums und auf Grundlage aktueller internationaler Literatur wurde durch den GMA Ausschuss für Personal- und Organisationsentwicklung in der Lehre ein Kernkompetenzmodell für Lehrende in der Medizin entwickelt. Das Modell soll nicht nur den Lehrenden Orientierung zu ihrem Qualifikationsprofil geben, sondern auch die inhaltliche Ausrichtung hochschuldidaktischer (Aus-) Weiter- und Fortbildungen sowie die Evaluation von Fakultätsentwicklungsprozessen erleichtern und nicht zuletzt einheitliche Kriterien für die Beurteilung der Lehrqualifikation in deutschsprachigen Raum definieren.
Das Modell besteht aus sechs Kompetenzfeldern, für die jeweils Teilkompetenzen definiert und Lernziele beschrieben wurden. Anwendungsbeispiele sollen die jeweiligen Kompetenzen verdeutlichen.
Das Modell ist für die praktische Anwendung konzipiert und soll in einem nächsten Schritt durch spezifische Kompetenzen für Lehrende mit besonderen Aufgaben ergänzt werden.
Recent developments in medical education have created increasing challenges for medical teachers which is why the majority of German medical schools already offer educational and instructional skills trainings for their teaching staff. However, to date no framework for educational core competencies for medical teachers exists that might serve as guidance for the qualification of the teaching faculty. Against the background of the discussion about competency based medical education and based upon the international literature, the GMA Committee for Faculty and Organizational Development in Teaching developed a model of core teaching competencies for medical teachers. This framework is designed not only to provide guidance with regard to individual qualification profiles but also to support further advancement of the content, training formats and evaluation of faculty development initiatives and thus, to establish uniform quality criteria for such initiatives in German-speaking medical schools. The model comprises a framework of six competency fields, subdivided into competency components and learning objectives. Additional examples of their use in medical teaching scenarios illustrate and clarify each specific teaching competency. The model has been designed for routine application in medical schools and is thought to be complemented consecutively by additional competencies for teachers with special duties and responsibilities in a future step.
Objective: The glucose stimulation of insulin secretion (GSIS) by pancreatic β-cells critically depends on increased production of metabolic coupling factors, including NADPH. Nicotinamide nucleotide transhydrogenase (NNT) typically produces NADPH at the expense of NADH and ΔpH in energized mitochondria. Its spontaneous inactivation in C57BL/6J mice was previously shown to alter ATP production, Ca2+ influx, and GSIS, thereby leading to glucose intolerance. Here, we tested the role of NNT in the glucose regulation of mitochondrial NADPH and glutathione redox state and reinvestigated its role in GSIS coupling events in mouse pancreatic islets.
Methods: Islets were isolated from female C57BL/6J mice (J-islets), which lack functional NNT, and genetically close C57BL/6N mice (N-islets). Wild-type mouse NNT was expressed in J-islets by adenoviral infection. Mitochondrial and cytosolic glutathione oxidation was measured with glutaredoxin 1-fused roGFP2 probes targeted or not to the mitochondrial matrix. NADPH and NADH redox state was measured biochemically. Insulin secretion and upstream coupling events were measured under dynamic or static conditions by standard procedures.
Results: NNT is largely responsible for the acute glucose-induced rise in islet NADPH/NADP+ ratio and decrease in mitochondrial glutathione oxidation, with a small impact on cytosolic glutathione. However, contrary to current views on NNT in β-cells, these effects resulted from a glucose-dependent reduction in NADPH consumption by NNT reverse mode of operation, rather than from a stimulation of its forward mode of operation. Accordingly, the lack of NNT in J-islets decreased their sensitivity to exogenous H2O2 at non-stimulating glucose. Surprisingly, the lack of NNT did not alter the glucose-stimulation of Ca2+ influx and upstream mitochondrial events, but it markedly reduced both phases of GSIS by altering Ca2+-induced exocytosis and its metabolic amplification.
Conclusion: These results drastically modify current views on NNT operation and mitochondrial function in pancreatic β-cells.
Photodynamic treatment of oral squamous cell carcinoma cells with low curcumin concentrations
(2017)
Objective: Curcumin is known for its anti-oxidative, anti-inflammatory and anti-tumorigenic qualities at concentrations ranging from 3.7µg/ml to 55µg/ml. Therefore it is pre-destined for tumour therapy. Due to high oral doses that have to be administered and the low bioavailability of curcumin new therapy concepts have to be developed. One of these therapy concepts is the combination of low curcumin concentrations and UVA or visible light. Aim of our study was to investigate the influence of this treatment regime on oral squamous cell carcinoma cells.
Materials and Methods: A human oral squamous cell carcinoma cell line (HN) was pre-incubated with low curcumin concentrations (0.01µg/ml to 1µg/ml). Thereafter cell cultures were either left un-irradiated or were irradiated either with 1J/cm2 UVA or for 5min with visible light. Quantitative analysis of proliferation, membrane integrity, oxidative potential and DNA fragmentation were done.
Results: It could be shown that low curcumin concentrations neither influenced proliferation, nor cell morphology, nor cell integrity nor apoptosis. When combining these curcumin concentrations with UVA or visible light irradiation cell proliferation as well as development of reactive oxygen species was reduced whereas DNA fragmentation was increased. Concentration as well as light entity specific effects could be observed.
Conclusions: The present findings substantiate the potential of the combination of low curcumin concentrations and light as a new therapeutic concept to increase the efficacy of curcumin in the treatment of cancer of the oral mucosa.