T-2 toxin is a cytochrome P450 1A1 inducer and leads to MAPK/p38- but not aryl hydrocarbon receptor-dependent interleukin-8 secretion in the human intestinal epithelial cell line Caco-2

T-2 toxin (T-2) is a secondary metabolite produced by various mould species of the genus Fusarium and a common contaminant detectable in staple foods of cereal origin. In the present study the impact of this mycotoxin on the inflammatory response of the intestinal epithelial cell line Caco-2 was examined by measuring interleukin (IL)-8 secretion. A T-2 concentration dependent IL-8 up-regulation was detected in IL-1β stimulated and unstimulated Caco-2 cells. To elucidate the possible underlying molecular mechanism of this conditional T-2-provoked IL-8 induction, a possible involvement of the aryl hydrocarbon receptor (AHR) and the mitogen-activated protein kinase (MAPK) pathway was investigated. Like benzo-[a]-pyrene (B[a]P), a well known AHR ligand, T-2 led to cytochrome P450 1A1 (CYP1A1) mRNA expression in Caco-2 cells, which could be inhibited by the AHR antagonist resveratrol. However, resveratrol did not influence T-2-dependent IL-8 induction. Since T-2 did not lead to AHR-translocation in stably GFP-AHR-transfected cells, an AHR dependency of T-2-triggered IL-8 induction could be excluded. But finally, up to a total inhibition of T-2-induced IL-8 was obtained using p38 inhibitors. Therefore, we conclude that p38 MAPK is responsible for mediating the inflammatory properties of the type A trichothecene T-2.     

Pharmacokinetics of two formulations of omeprazole administered through a gastrostomy tube in patients with severe neurodevelopmental problems

AIMS

Omeprazole is often administered through a gastrostomy tube as either (i) a Multiple Unit Pellet System (MUPS®) tablet disintegrated in water (MUPS® formulation), or (ii) a suspension in 8.4% sodium bicarbonate (suspension formulation). This bioavailability study evaluates this practice in tube-fed patients with severe neurodevelopmental problems.

METHODS

Nonblinded, two-phase cross-over trial.

RESULTS

In seven of 10 patients, bioavailability was higher for the suspension formulation than for the MUPS® formulation. Median (90% confidence interval) area under the plasma concentration–time curve ratio (MUPS® over suspension) was 0.5 (0.06–2.37).

CONCLUSIONS

In this population, omeprazole MUPS® formulation has no apparent advantage over the more easily administered suspension formulation.     

Combined CADM1 and MAL promoter methylation analysis to detect (pre-)malignant cervical lesions in high-risk HPV-positive women

Given the lower specificity for high-grade cervical lesions of high-risk human papillomavirus (hrHPV) testing compared to cytology, additional triage testing for hrHPV test-positive women is needed to detect high-grade cervical lesions. Here, we tested whether combined methylation analysis for cell adhesion molecule 1 (CADM1) and T-lymphocyte maturation associated protein (MAL), both functionally involved in cervical carcinogenesis, could serve as such a triage marker. Four quantitative methylation-specific PCRs (qMSP), two for CADM1 (regions M12 and M18) and MAL (regions M1 and M2) each, were applied to 261 cervical tissue specimens ranging from no neoplasia to carcinoma. When qMSPs were combined and positivity for at least one of the qMSPs in the combination was taken into account, the highest positivity rates for cervical intraepithelial neoplasia grade 3 (CIN3) lesions (97%) and squamous cell- and adeno-carcinomas (99%) were obtained by combining a single CADM1 marker with a single MAL marker. Subsequent qMSP analysis of 70 GP5+/6+-PCR hrHPV-positive scrapings revealed that a two-marker panel consisting of CADM1-M18 and MAL-M1 was most discriminative, detecting 90% of women with CIN3 (n = 30), whereas it showed a positive result in only 13.5% of women without cervical disease (n = 40). Finally, we applied hrHPV GP5+/6+-PCR testing followed by CADM1-M18/MAL-M1 methylation analysis to a cohort of 79 women visiting the outpatient colposcopy clinic. hrHPV testing revealed a sensitivity of 97% and a specificity of 33% for CIN3+. Additional CADM1-M18/MAL-M1 methylation analysis on the hrHPV-positive women increased the specificity to 78% with a sensitivity of 70%. In conclusion, the methylation marker panel CADM1-M18 and MAL-M1 may serve as an alternative molecular triage tool for hrHPV-positive women.     

Risk of high-grade cervical intra-epithelial neoplasia based on cytology and high-risk HPV testing at baseline and at 6-months

Adding a test for high-risk human papillomavirus (hrHPV) to cytological screening enhances the detection of high-grade cervical intraepithelial neoplasia (>or=CIN2), but data are required that enable long-term evaluation of screening. We investigated the >or=CIN2 risk for women participating in population-based screening as a function of hrHPV and cytology testing results at baseline and at 6 months. We included 2,193 women aged 30-60 years participating in a population-based screening trial who received colposcopy or a repeat testing advice at baseline. The main endpoint was histologically confirmed >or=CIN2 diagnosed within 36 months. hrHPV testing was more sensitive than cytology for >or=CIN2 (relative sensitivity 1.4, 95%CI: 1.3-1.5; absolute sensitivity 94.1 and 68.0%, respectively). The 18-month >or=CIN2 risks in women with a hrHPV-positive smear and in women with abnormal cytology were similar (relative risk 0.9, 95%CI: 0.8-1.1). Women with HPV16 and/or HPV18 had a higher >or=CIN2 risk than other hrHPV-positive women irrespective of the cytological grade. Repeat testing showed that both cytological regression and viral clearance were strongly associated with a decrease in >or=CIN2 risk. Notably, women who had a double negative repeat test at 6 months had a >or=CIN2 risk of only 0.2% (95%CI: 0.0-1.1) and hrHPV-negative women with baseline borderline or mild dyskaryosis and normal cytology at 6 months had a >or=CIN2 risk of 0% (95%CI: 0.0-0.8). Using hrHPV and/or cytology testing, risk of >or=CIN2 can be assessed more accurately by repeat testing than single visit testing. Hence, when hrHPV testing is implemented, patient management with repeat testing is a promising strategy to control the number of referrals for colposcopy.     

Quality of integrated care for patients with nonsmall cell lung cancer: variations and determinants of care

BACKGROUND: In the current study, the authors focused on determinants influencing the quality of care and variations in the actual quality of integrated care for patients with nonsmall cell lung cancer (NSCLC) to estimate whether there is room for improvement. METHODS: The authors tested the quality of integrated care for 276 NSCLC patients with 14 quality indicators of professional (4 indicators), organizational (3 indicators), and patient-oriented quality (7 indicators). Patient characteristics and actual care data were derived from medical record data, patient-oriented care was derived from patient questionnaires, and professional and hospital characteristics were derived from questionnaires for professionals. The performance measure was the proportion of patients to whom the indicator applied who had positive scores on the indicator. Multilevel logistic regression analysis determined the influence of patient, professional, and hospital characteristics on care. RESULTS: With regard to professional quality, the proportions of patients who underwent fluorodeoxyglucose-positron emission tomography or cervical mediastinoscopy according to the guideline criteria were 88% and 84%, respectively. Only 50% of the biopsies were adequately obtained during mediastinoscopy, and in 3% of the patients with clinical stage III disease (based on the TNM classification) there was a search for brain metastases before the initiation of combination therapy. With regard to organizational quality, the diagnostic route of 79% of the patients was completed within 21 days; 51% of patients began therapy within 35 days and 57% were discussed during multidisciplinary consultation. All but 1 patient-oriented quality indicator scored /=20% with regard to 11 of the 14 indicators. The patient-related determinants "stage of disease," "age," and "comorbidity" were found to influence the indicator scores the most. CONCLUSIONS: The quality of integrated care (especially patient-oriented care) for NSCLC patients needs improvement. Patient characteristics appear to influence performance more than professional or hospital characteristics.     

A Simple Risk Score for the Assessment of Absolute Fracture Risk in General Practice Based on Two Longitudinal Studies

The aim of this prospective study was to develop a risk score, based on putative risk factors in current guidelines, which can be used to identify women at high risk of fractures in general practice. The study sample included 4157 women ≥60 yr of age (mean ± SD: 74.1 ± 9.1 yr), with a median follow‐up of 8.9 yr of the Rotterdam Study (ERGO), and 762 women ≥65 yr of age (mean ± SD: 76.0 ± 6.7.yr), with a median follow‐up of 6.0 yr of the Longitudinal Aging Study Amsterdam (LASA). Potential risk factors were those proposed in risk scores of three recent guidelines on osteoporosis: age, family history of fractures, prior fracture, low body weight/body mass index (BMI), serious immobility, rheumatoid arthritis, current smoking, alcohol consumption >2 units daily, prevalent vertebral fracture, and systemic corticosteroid use. Five‐year absolute risk of hip fracture was 3.9% in the Rotterdam Study and 3.1% in LASA, and 10‐yr absolute risk of hip fracture was 8.4% in the Rotterdam Study. Using Cox regression analysis, age (70–79 and 80+ versus <60–69) and four other risk factors were included in the risk profiles of hip fractures and fragility fractures: any prior fracture after age 50, body weight <64 kg, use of a walking aid as a proxy measure of serious immobility, and current smoking. Estimated 10‐yr absolute risk of hip fracture ranged from 1.4% in women, age 60–69 years, without any of these predictors to 29% in women, ≥80 yr of age, having two or more positive risk factors. A simple risk score can satisfactorily identify older women at high risk of osteoporotic fractures in general practice. Future studies are needed to validate this score.     

Vitamin D Status,Parathyroid Function,Bone Turnover,and BMD in Postmenopausal Women With Osteoporosis: Global Perspective

Poor vitamin D status is common in the elderly and is associated with bone loss and fractures. The aim was to assess worldwide vitamin D status in postmenopausal women with osteoporosis according to latitude and economic status, in relation to parathyroid function, bone turnover markers, and BMD. The study was performed in 7441 postmenopausal women from 29 countries participating in a clinical trial on bazedoxifene (selective estrogen receptor modulator), with BMD T‐score at the femoral neck or lumbar spine ≤ ?2.5 or one to five mild or moderate vertebral fractures. Serum 25(OH)D, PTH, alkaline phosphatase (ALP), bone turnover markers osteocalcin (OC) and C‐terminal cross‐linked telopeptides of type I collagen (CTX), and BMD of the lumbar spine, total hip, femoral neck, and trochanter were measured. The mean serum 25(OH)D level was 61.2 ± 22.4 nM. The prevalence of 25(OH)D <25, 25–50, 50–75, and >75 nM was 5.9%, 29.4%, 43.5%, and 21.2%, respectively, in winter and 3.0%, 22.2%, 47.2%, and 27.5% in summer. Worldwide, a negative correlation between 25(OH)D and latitude was observed. With increasing 25(OH)D categories of <25, 25–50, 50–75, and >75 nM, mean PTH, OC, and CTX were decreasing (p < 0.001), whereas BMD of all sites was increasing (p < 0.001). A threshold in the positive relationship between 25(OH)D and different BMD parameters was visible at a 25(OH)D level of 50 nM. Our study showed a high prevalence of low 25(OH)D in postmenopausal women with osteoporosis worldwide. Along with latitude, affluence seems to be an important factor for serum 25(OH)D level, especially in Europe, where it is strongly correlated with latitude.     

Complete remission of nephrotic syndrome in an infant with focal segmental glomerulosclerosis: is it renin–angiotensin blockade?

Nephrotic syndrome presenting in the first year of life is often challenging, with substantial risk of progression to end-stage renal disease (ESRD). Focal segmental glomerulosclerosis (FSGS) comprises up to 20% of biopsy-proven glomerular disease in children and adults. We report on a 9-month-old infant who presented with nephrotic syndrome, hypertension and progressive deterioration of renal function due to FSGS. As immunosuppressive agents are often unsuccessful in treating this condition, we adopted renoprotection as the mainstay treatment for this patient, through rigorous control of blood pressure and proteinuria with a multi-drug regimen including renin-angiotensin axis blockade. Initially, there was partial improvement, with a gradual decline in proteinuria and a concomitant rise in the glomerular filtration rate, before the disease eventually passed into complete clinical and laboratory remission. We speculate that infants with steroid-resistant nephrotic syndrome due to FSGS may benefit from tight control of hypertension, mainly though early blockade of the renin-angiotensin axis. We believe that its renoprotecive mechanism counteracts the deleterious effects of both hypertension and proteinuria, thereby not only preventing progressive renal disease, but even paving the way for a remission, as in our patient. To the best of our knowledge, this is the first report of an infant with nephrotic syndrome (NS) due to FSGS that passed into complete remission while the patient was on renoprotective measures including the use of angiotensin-converting enzyme inhibitors (ACEis).