The effects of quercetin on viability and proliferation of Chinese Hamster Ovary (CHO) cells and CHO cells overexpressing human quinone reductase (CHO+NQO1) were studied to investigate the ...involvement of the pro-oxidant quinone chemistry of quercetin. The toxicity of menadione was significantly reduced in CHO+NQO1 cells compared to wild-type CHO cells, validating the NQO1-overexpression in the CHO+NQO1 transfectant. Quercetin inhibited the proliferation of wild-type CHO and CHO+NQO1 cells to a similar extent without affecting cell viability, indicating that NQO1 enrichment of CHO cells did not provide increased protection. On the other hand, inhibition of NQO1 in both types of cells by dicoumarol significantly potentiated the inhibitory effect of quercetin on cell proliferation, revealing the role of NQO1 in cellular protection against quercetin. Altogether, these results can be explained by the hypothesis that both wild-type CHO and CHO+NQO1 cells contain sufficient NQO1 activity for optimal protection against the pro-oxidant effect of quercetin on cell proliferation. The results also point at a cellular NQO1 threshold for optimal protection against quercetin. This NQO1 threshold seems to be in the range of NQO1 activities already present in various tissues.
During and after absorption in the intestine, quercetin is extensively metabolised by the phase II biotransformation system. Because the biological activity of flavonoids is dependent on the number ...and position of free hydroxyl groups, a first objective of this thesis was to investigate the consequences of phase II metabolism of quercetin for its biological activity. For this purpose, a set of analysis methods comprising HPLC-DAD, LC-MS and 1 H NMR proved to be a useful tool in the identification of the phase II metabolite pattern of quercetin in various biological systems. These studies showed that the 3'- and 4'-hydroxyl groups of quercetin, (catechol hydroxyl groups) were important targets for methylation, sulfation and glucuronidation. Methylation of a catechol hydroxyl group of quercetin proved to decrease the pH-dependent radical scavenging capacity of the compound, both by increasing its pK a for deprotonation and by decreasing its electron-donating properties. Methylation of a catechol hydroxyl group had a similar effect as replacement of the hydroxyl group by a hydrogen atom. Regarding the pro-oxidant properties of quercetin, methylation of a catechol hydroxyl group of quercetin did not eliminate the pro-oxidant chemistry of quercetin, reflected in the formation of covalent adducts with glutathione upon oxidation of quercetin by horseradish peroxidase. However, methylated quercetin proved to form only 42% of the level of DNA adducts in exposed cells as compared to a similar amount of unconjugated quercetin, indicating that methylation of quercetin attenuates also this biological reactivity towards DNA.A second objective of this thesis was to obtain more insight into the possible toxic effects of quercetin by studying various mechanisms that might be relevant in the context of carcinogenesis. Quercetin appeared to have a biphasic effect on the proliferation of cancer cell lines expressing the estrogen receptor (ER). The stimulation of cancer cell proliferation was ER-dependent and appeared to occur at concentrations that are physiologically relevant in humans. With respect to the pro-oxidant activity of quercetin, peroxidase- and tyrosinase-type oxidative enzyme activity did not play a major role in the intracellular formation of covalent adducts of quercetin with DNA and protein, indicating that the formation of covalent adducts of quercetin with cellular macromolecules might also be relevant in cell types lacking oxidative enzyme activity. Furthermore, the covalent quercetin DNA adducts were of transient nature, which may either eliminate or attenuate the adverse effects of covalent DNA adduct formation. The studies presented in this thesis provided indications for the dualistic character of quercetin, regarding its role in the process of cancer development.
Psoriasis, psoriatic arthritis (PsA), and inflammatory bowel disease (IBD) are related inflammatory immune-mediated diseases, with considerable overlap. However, it is as yet unclear whether ...co-occurrence of these diseases affects disease course and characteristics of the individual complaints. The objective of this study was to identify the prevalence of IBD and PsA in a psoriasis cohort and to examine whether patients with concurrent psoriasis and IBD carry a distinct phenotype.
Data of all patients with psoriasis visiting a general hospital in the Netherlands between 2009 and 2014 were retrospectively retrieved from electronic patient files. In addition, clinical characteristics of patients with concurrent psoriasis and IBD (n = 40) were compared with psoriasis-only (n = 1643) and IBD-only (n = 385) cohorts.
Among 1669 hospital-based patients with psoriasis, prevalence of PsA was 12.2% (n = 203, 95% confidence interval, 10.5-13.7) and of IBD 1.6% (n = 26, 95% confidence interval, 1.0-2.2), including 12 Crohn's disease (CD) and 14 ulcerative colitis. Psoriasis-PsA patients were more likely to have IBD than psoriasis-only patients (3.0 versus 1.4%).Psoriasis-CD patients were younger at CD diagnosis (20.0 versus 32.0 yr, P = 0.001), and psoriasis diagnosis (28.0 versus 43.5 yr, P = 0.004) than psoriasis-only patients. Psoriasis-IBD patients had a mild psoriasis phenotype similar to psoriasis-only patients, but the CD-phenotype was significantly more severe than in CD-only patients.
The prevalence of IBD in psoriasis was approximately 4 times higher than that in the general population, with the highest risk for psoriasis-PsA patients. Psoriasis-CD patients have a mild (early-onset) psoriasis but an earlier-onset and severe CD-phenotype.
Background and Aims:
Psoriasis and hidradenitis suppurativa HS co-occur more often with inflammatory bowel disease IBD than expected, due to shared pathogenic and genetic features. It is known that ...IBD patients harbour an altered intestinal microbiome characterised by a depletion of Faecalibacterium prausnitzii and increase of Escherichia coli. At present, it is unclear whether a similar intestinal microbiome trend can be identified in IBD-associated skin disorders. We therefore investigated the F. prausnitzii and E. coli abundance in psoriasis and HS, with and without concomitant IBD.
Methods:
Using quantitative polymerase chain reaction , we compared the F. prausnitzii and E. coli abundances in faecal samples from healthy controls n = 33 with samples from patients with psoriasis n = 29, IBD n = 31, and concomitant IBD and psoriasis n = 13. Likewise, we analysed samples from patients with HS n = 17, and concomitant IBD and HS n = 17.
Results:
Psoriasis patients harboured a significantly lower abundance of F. prausnitzii in their stool than healthy controls p < 0.001, which was similar to IBD patients. Together with the reduced F. prausnitzii levels, the psoriasis patients had a significantly higher abundance of E. coli p < 0.001. No significant difference in F. prausnitzii or E. coli abundance was found in HS. It was apparent that patients with concomitant IBD and associated skin disorder had the greatest decrease of F. prausnitzii and increase of E. coli.
Conclusions:
The study demonstrates, for the first time, an IBD-like decrease of F. prausnitzii together with an increase of E.coli in psoriasis, supporting the presence of a gut-microbiome-skin axis in psoriasis and IBD.
This study aimed to determine the prevalence, risk factors of delirium and current practice of delirium management in intensive care units of various levels of care.
Prospective multicentre cohort ...study.
In all adult patients admitted to one of the participating intensive care units on World Delirium Awareness Day 2018, delirium point and period prevalence rates were measured between ICU admission and seven days after the index day.
In total, 28 (33%) Dutch intensive care units participated in this study. Point-prevalence was 23% (range 41), and period-prevalence was 42% (range 70). University intensive care units had a significantly higher delirium point-prevalence compared with non-university units (26% vs.15%, p = 0.02). No significant difference were found in period prevalence (50% vs. 39%, p = 0.09). Precipitating risk factors, infection and mechanical ventilation differed significantly between delirium and non-delirium patients. No differences were observed for predisposing risk factors. A delirium protocol was present in 89% of the ICUs. Mean delirium assessment compliance measured was 84% (±19) in 14 units and estimated 59% (±29) in the other 14.
Delirium prevalence in Dutch intensive care units is substantial and occurs with a large variation, with the highest prevalence in university units. Precipitating risk factors were more frequent in patients with delirium. In the majority of units a delirium management protocol is in place.
•Assessment of vertebra specific fracture risk can be helpful in spinal care.•Gender, ISS stage 2 and 3 and back pain are patient-specific risk factors for VCFs.•Many radiographic vertebra-specific ...characteristics are predictive for VCFs.•CT Hounsfield Units can be used to assess vertebral bone mineral density.
Vertebral compression fractures (VCFs) are a common complication for patients with multiple myeloma. These fractures are associated with significant morbidity and mortality due to severe back pain, spinal instability, increased risk of new fractures, neurologic dysfunction, and other physical symptoms.
To identify risk factors associated with the development of VCFs which may help to predict them in future patients.
A retrospective multicenter cohort study.
Patients with multiple myeloma diagnosed between 2012 and 2018 and appropriate baseline- and follow-up imaging studies (>6 months after diagnosis) were included.
Individual odds ratios for each of the fifteen potential risk factors including patient factors and radiographical characteristics.
Relevant clinical baseline data were extracted from the patient charts. Computed tomography (CT) scans were used to score all radiographic variables. VCFs were graded following the Genant grading system. General Linear Mixed Models were used to analyze risk factors associated with vertebral fractures.
A total of 143 patients with 1,605 eligible vertebrae were included in the study with a mean follow-up time of 25 months. Mean age at diagnosis was 65 years and 39% were female. Among 1,605 vertebrae, there were 192 (12%) VCFs (Genant grade 1 or higher) at the time of diagnosis and 111 (7%) occurred during follow-up. In a General Linear Mixed Model, significant predictors were gender (odds ratio OR=1.5), International Staging System stage 2 and 3 (OR=3.6 and OR=4.1 respectively), and back pain (OR=2.7). Furthermore, lower Hounsfield Unit score, lytic lesions and abnormal alignment were risk factors for (the development of) VCFs.
This study investigated both patient characteristics and vertebra-specific risk factors for VFCs in multiple myeloma patients. The factors found in this study might be useful for identifying patients at higher risk of VFCs to help clinical management to prevent vertebral collapse and the development of spinal deformities.
Background
Regular colonoscopic surveillance for detection of dysplasia is recommended in longstanding inflammatory bowel disease (IBD), however, its sensitivity is disputed. Screening accuracy may ...increase by using a biomarker-based surveillance strategy.
Methods
A case-control study was performed to determine the prognostic value of DNA ploidy and p53 in IBD-related neoplasia. Cases with IBD-related colorectal cancer (CRC), detected in our surveillance program between 1985-2008, were selected and matched with two controls, for age, gender, disease characteristics, interval of follow-up, PSC, and previous surgery. Biopsies were assessed for DNA ploidy, p53, grade of inflammation and neoplasia. Progression to neoplasia was analyzed with Cox regression analysis, adjusting for potentially confounding variables.
Results
Adjusting for age, we found statistically significant Hazard ratios (HR) between development of CRC, and low grade dysplasia (HR5.5; 95%CI 2.6-11.5), abnormal DNA ploidy (DNA index (DI) 1.06-1.34, HR4.7; 95%CI 2.9-7.8 and DI>1.34, HR6.6; 95%CI 3.7-11.7) and p53 immunopositivity (HR3.0; 95%CI 1.9-4.7) over time. When adjusting for all confounders, abnormal DNA ploidy (DI 1.06-1.34, HR4.7; 95%CI 2.7-7.9 and DI>1.34, HR5.0; 95%CI 2.5-10.0) and p53 immunopositivity (HR1.7; 95%CI 1.0-3.1) remained statistically significant predictive of neoplasia.
Conclusion
In longstanding IBD, abnormal DNA ploidy and p53 immunopositivity are important risk factors of developing CRC. The yield of surveillance may potentially increase by adding these biomarkers to the routine assessment of biopsies.
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