Abstract
Infants developing necrotizing enterocolitis (NEC) have a different metabolomic profile compared to controls. The potential of specific metabolomics, i.e. amino acids and amino alcohols ...(AAA), as early diagnostic biomarkers for NEC is largely unexplored. In this multicenter prospective case–control study, longitudinally collected fecal samples from preterm infants (born <30 weeks of gestation) from 1–3 days before diagnosis of severe NEC (Bell’s stage IIIA/IIIB), were analyzed by targeted high-performance liquid chromatography (HPLC). Control samples were collected from gestational and postnatal age-matched infants. Thirty-one NEC cases (15 NEC IIIA;16 NEC IIIB) with 1:1 matched controls were included. Preclinical samples of infants with NEC were characterized by five increased essential amino acids—isoleucine, leucine, methionine, phenylalanine and valine. Lysine and ethanolamine ratios were lower prior to NEC, compared to control samples. A multivariate model was rendered based on isoleucine, lysine, ethanolamine, tryptophan and ornithine, modestly discriminating cases from controls (AUC 0.67;
p
< 0.001). Targeted HPLC pointed to several specific AAA alterations in samples collected 1–3 days before NEC onset, compared to controls. Whether this reflects metabolic alterations and has a role in early biomarker development for NEC, has yet to be elucidated.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Intrapartum antibiotics can impact on neonatal gut colonization.•Evidence emanates mainly from research on term vaginally born infants.•Most other studies are of low quality and are influenced by ...confounding factors.•Heterogeneity in patient characteristics limits the possibility to compare studies.•Evidence for any effect of prenatal antibiotic use on infant microbiota is limited.
The intestinal microbiota develops in early infancy and is essential for health status early and later in life. In this review we focus on the effect of prenatal and intrapartum maternally administered antibiotics on the infant intestinal microbiota.
A systematic literature search was conducted in PubMed and EMBASE. All studies reporting effect on diversity or microbiota profiles were included.
A total of 4.030 records were encountered. A total of 24 articles were included in the final analysis. Infants from mothers exposed to antibiotics during delivery showed a decreased microbial diversity compared to non-exposed infants. The microbiota of infants exposed to antibiotics was characterised by a decreased abundance of Bacteriodetes and Bifidobacteria, with a concurrent increase of Proteobacteria. These effects were most pronounced in term vaginally born infants.
Maternal administration of antibiotics seems to have profound effects on the infant gut microbiota colonisation. Interpretation of microbiota aberrations in specific populations, such as preterm and caesarean born infants, is complicated by multiple confounding factors and by lack of high quality studies and high heterogeneity in study design. Further research is needed to investigate the potential short- and long-term clinical consequences of these microbial alterations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Intestinal microbiota is considered to play a crucial role in the aetiology of inflammatory bowel disease (IBD). We aimed to describe faecal microbiota composition and dynamics in a large cohort of ...children with de novo (naïve) IBD, in comparison to healthy paediatric controls (HC).
In this prospective study, performed at two tertiary centres, faecal samples from newly diagnosed, treatment-naïve paediatric IBD patients were collected prior to bowel cleansing for colonoscopy (t0) and 1, 3 and 6 weeks and 3 months after initiation of therapy. The microbial profiles of Crohn's disease (CD) and Ulcerative colitis (UC) patients were compared with HC and linked to therapeutic response. Microbiota composition was analysed by IS-pro technology.
Microbial profiles of 104 new IBD-patients (63 CD, 41 UC, median age 14.0 years) were compared to 61 HC (median 7.8 years). IBD was mainly characterised by decreased abundance of Alistipes finegoldii and Alistipes putredinis, which characterize a healthy state microbial core. The classifier including these core species as predictors achieved an AUC of the ROC curve of .87. Core bacteria tended to regain abundance during treatment, but did not reach healthy levels.
Faecal microbiota profiles of children with de novo CD and UC can be discriminated from HC with high accuracy, mainly driven by a decreased abundance of species shaping the microbial core in the healthy state. Paediatric IBD can therefore be characterized by decreased abundance of certain bacterial species reflecting the healthy state rather than by the introduction of pathogens.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Ten percent of patients with autoimmune hepatitis (AIH) are nonresponsive or intolerant to thiopurine therapy. A skewed metabolism, leading to the preferential generation of ...(hepato)toxic thiopurine metabolites (6‐MMPs) instead of the metabolic active 6‐tioguanine (thioguanine) nucleotides (6‐TGNs), may explain this unfavourable outcome. Co‐administration of allopurinol to low‐dose thiopurine therapy may effectively revert this deviant metabolism, as has been shown in inflammatory bowel disease.
Aim
To describe the effect of adding allopurinol to low‐dose thiopurine therapy in patients with AIH with intolerance or nonresponse to normal thiopurine dosages due to a skewed metabolism.
Methods
We describe the clinical efficacy and tolerability of allopurinol–thiopurine combination therapy with allopurinol 100 mg and low‐dose thiopurine (25–33% of the original dosage) in eight AIH patients with a skewed thiopurine metabolism. Patients were switched because of dose‐limiting intolerance (n = 3), nonresponse (n = 3) or loss of response (n = 2) to conventional thiopurine treatment.
Results
All eight patients showed biochemical improvement with a reduction in median alanine aminotransferase (ALT) levels of 62 U/L at start to 35 U/L at 1 month (P = 0.03). This clinical benefit was sustained in seven patients. Allopurinol–thiopurine combination therapy effectively bypassed thiopurine side effects in four of five patients. Median 6‐tioguanine nucleotides levels increased from 100 to 200 pmol/8 × 108 red blood cells (RBC) at 3 months (P = 0.04). Median 6‐MMP levels decreased in all patients from 6090 to 175 pmol/8 × 108 RBC (P = 0.01).
Conclusion
Allopurinol safely and effectively optimises thiopurine therapy in patients with autoimmune hepatitis with intolerance and/or nonresponse due to an unfavourable thiopurine metabolism.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Fecal volatile organic compounds (VOCs) are increasingly considered to be potential noninvasive, diagnostic biomarkers for various gastrointestinal diseases. Knowledge of the influence of sampling ...conditions on VOC outcomes is limited. We aimed to evaluate the effects of sampling conditions on fecal VOC profiles and to assess under which conditions an optimal diagnostic accuracy in the discrimination between pediatric inflammatory bowel disease (IBD) and controls could be obtained. Fecal samples from de novo treatment-naïve pediatric IBD patients and healthy controls (HC) were used to assess the effects of sampling conditions compared to the standard operating procedure (reference standard), defined as 500 mg of sample mass diluted with 10 mL tap water, using field asymmetric ion mobility spectrometry (FAIMS). A total of 17 IBD (15 CD (Crohn's disease) and 2 UC (ulcerative colitis)) and 25 HC were included. IBD and HC could be discriminated with high accuracy (accuracy = 0.93, AUC = 0.99, p < 0.0001). A smaller fecal sample mass resulted in a decreased diagnostic accuracy (300 mg accuracy = 0.77, AUC = 0.69, p = 0.02; 100 mg accuracy = 0.70, AUC = 0.74, p = 0.003). A loss of diagnostic accuracy was seen toward increased numbers of thaw–freeze cycles (one cycle, accuracy = 0.61, AUC = 0.80, p = 0.0004; two cycles, accuracy = 0.64, AUC = 0.56, p = 0.753; and three cycles, accuracy = 0.57, AUC = 0.50, p = 0.5101) and when samples were kept at room temperature for 180 min prior to analysis (accuracy = 0.60, AUC = 0.51, p = 0.46). Diagnostic accuracy of VOC profiles was not significantly influenced by storage duration differences of 20 months. The application of a 500 mg sample mass analyzed after one thaw–freeze cycle showed the best discriminative accuracy for the differentiation of IBD and HC. VOC profiles and diagnostic accuracy were significantly affected by sampling conditions, underlining the need for the implementation of standardized protocols in fecal VOC analysis.
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IJS, KILJ, NUK, PNG, UL, UM
Summary
Background
Inflammatory bowel disease (IBD) affects a substantial number of female patients in their reproductive years. Therefore, many physicians face the dilemma whether thiopurines, ...prescribed to maintain remission, can be taken safely during pregnancy. Data on long‐term development outcome of children exposed to maternal thiopurine therapy are very limited.
Aim
To assess the long‐term effects of in utero exposure to thiopurines during pregnancy on infant health status.
Methods
A prospective multicentre follow‐up study was performed in children exposed intrauterine to maternal thiopurine therapy. Physical, cognitive and social aspects of infant health status were assessed with the 43‐item TNO‐AZL Preschool Children Quality of Life Questionnaire (TAPQOL). Furthermore, information on visits to general practitioner and medical specialists, and physician's advice regarding lactation was evaluated. Data were compared with normative data from a control group consisting of 340 children.
Results
Thirty children were included in this study median 3.8 years (IQR 2.9–4.7). No differences on global medical and psychosocial health status were found between children exposed to intrauterine thiopurines and the reference group. Exposure to intrauterine thiopurines was not associated with increased susceptibility to infection or immunodeficiency in childhood. Twenty‐one of 30 children were exclusively formula‐fed based on a negative advice of medical specialists directed at thiopurine use during lactation.
Conclusions
Thiopurine use during pregnancy did not affect long‐term development or immune function of children up to 6 years of age. Our results underscore the present notion that mothers, even those using thiopurines, should be encouraged to breastfeed their infants.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Aim
Early detection and removal of colorectal cancer (CRC) and advanced adenomas (AAs) decreases the incidence of and mortality from the disease. We aimed to evaluate the potential of faecal volatile ...organic compounds (VOCs) for detection and follow‐up of colorectal adenoma using advanced electronic nose technology.
Method
This was a prospective multi‐centre case–control cohort including two district hospitals and one tertiary referral hospital. Patients undergoing colonoscopy were instructed to collect a faecal sample prior to bowel cleansing and were included in the study when CRC, AAs, large adenomas (LAs; 0.5–1.0 cm), small adenomas (SAs; 0.1–0.5 cm) or no endoscopic abnormalities (controls) were observed. Patients undergoing polypectomy and controls were asked for a second sample after 3 months. Faecal VOCs were measured with gas chromatography–ion mobility spectrometry. Random forest, support vector machine, Gaussian process and neural net classification were used to evaluate accuracy.
Results
In total, 14 patients with CRC, 64 with AAs, 69 with LAs, 127 with SAs and 227 controls were included. A second sample was collected from 32 polypectomy patients and 32 controls. Faecal VOCs discriminated CRC and adenomas from control AUC (95% CI): CRC vs control 0.96 (0.89–1); AA vs control 0.96 (0.93–1); LA vs control 0.96 (0.92–0.99); SA vs control 0.96 (0.94–0.99). There were no significant differences between CRC and adenoma groups. Patients with adenomas and controls were discriminated prior to polypectomy, whereas 3 months after polypectomy VOC profiles were similar T0 adenoma vs control 0.98 (0.95–1); T1 adenoma vs control 0.55 (0.40–0.69).
Conclusions
Faecal VOC profiles may be useful for early detection of CRC and adenomas and the timing of polyp surveillance as polypectomy led to a normalization of the VOC profile.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Letter: thiopurines ‐ is less really more? Meijer, B.; Boer, N. K. H.
Alimentary pharmacology & therapeutics,
January 2018, 2018-01-00, 20180101, Volume:
47, Issue:
1
Journal Article
Peer reviewed
Open access
Linked Content
This article is linked to Roblin et al papers. To view these articles visit https://doi.org/10.1111/apt.14106 and https://doi.org/10.1111/apt.14385.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Therapeutic drug monitoring (TDM) has the potential to improve efficacy and diminish side effects. Measuring methotrexate-polyglutamate (MTX-PG) in erythrocytes might enable TDM for methotrexate in ...patients with Crohn's disease (CD).
To investigate the relationship between MTX-PGs and methotrexate drug survival, efficacy and toxicity METHODS: In a multicentre prospective cohort study, patients with CD starting subcutaneous methotrexate without biologics were included and followed for 12 months. Primary outcome was subcutaneous methotrexate discontinuation or requirement for step-up therapy. Secondary outcomes included faecal calprotectin (FCP), Harvey Bradshaw Index (HBI), hepatotoxicity and gastrointestinal intolerance. Erythrocyte MTX-PGs were analysed at weeks 8, 12, 24 and 52 or upon treatment discontinuation.
We included 80 patients with CD (mean age 55 ± 13y, 35% male) with a median FCP of 268 μg/g (IQR 73-480). After the 12-month visit, 21 patients (26%) were still on subcutaneous methotrexate monotherapy. Twenty-one patients stopped because of disease activity, 29 because of toxicity, and four for both reasons. Five patients ended study participation or stopped methotrexate for another reason. A higher MTX-PG
concentration was associated with a higher rate of methotrexate drug survival (HR 0.86, 95% CI 0.75-0.99), lower FCP (β -3.7, SE 1.3, p < 0.01) and with biochemical response (FCP ≤250 if baseline >250 μg/g; OR 1.1, 95% CI 1.0-1.3). Higher MTX-PGs were associated with less gastrointestinal intolerance. There was no robust association between MTX-PGs and HBI or hepatotoxicity.
Higher MTX-PG
concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX-PG
could be used for TDM if a target concentration can be established.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
10.
The Miocene: The Future of the Past Steinthorsdottir, M.; Coxall, H. K.; de Boer, A. M. ...
Paleoceanography and Paleoclimatology,
April 2021, Volume:
36, Issue:
4
Journal Article
Peer reviewed
Open access
The Miocene epoch (23.03–5.33 Ma) was a time interval of global warmth, relative to today. Continental configurations and mountain topography transitioned toward modern conditions, and many flora and ...fauna evolved into the same taxa that exist today. Miocene climate was dynamic: long periods of early and late glaciation bracketed a ∼2 Myr greenhouse interval—the Miocene Climatic Optimum (MCO). Floras, faunas, ice sheets, precipitation, pCO2, and ocean and atmospheric circulation mostly (but not ubiquitously) covaried with these large changes in climate. With higher temperatures and moderately higher pCO2 (∼400–600 ppm), the MCO has been suggested as a particularly appropriate analog for future climate scenarios, and for assessing the predictive accuracy of numerical climate models—the same models that are used to simulate future climate. Yet, Miocene conditions have proved difficult to reconcile with models. This implies either missing positive feedbacks in the models, a lack of knowledge of past climate forcings, or the need for re‐interpretation of proxies, which might mitigate the model‐data discrepancy. Our understanding of Miocene climatic, biogeochemical, and oceanic changes on broad spatial and temporal scales is still developing. New records documenting the physical, chemical, and biotic aspects of the Earth system are emerging, and together provide a more comprehensive understanding of this important time interval. Here, we review the state‐of‐the‐art in Miocene climate, ocean circulation, biogeochemical cycling, ice sheet dynamics, and biotic adaptation research as inferred through proxy observations and modeling studies.
Plain Language Summary
During the Miocene time period (∼23–5 million years ago), Planet Earth looked similar to today, with some important differences: the climate was generally warmer and highly variable, while atmospheric CO2 was not much higher. Continental‐sized ice sheets were only present on Antarctica, but not in the northern hemisphere. The continents drifted to near their modern‐day positions, and plants and animals evolved into the many (near) modern species. Scientists study the Miocene because present‐day and projected future CO2 levels are in the same range as those reconstructed for the Miocene. Therefore, if we can understand climate changes and their biotic responses from the Miocene past, we are able to better predict current and future global changes. By comparing Miocene climate reconstructions from fossil and chemical data to climate simulations produced by computer models, scientists are able to test their understanding of the Earth system under higher CO2 and warmer conditions than those of today. This helps in constraining future warming scenarios for the coming decades. In this study, we summarize the current understanding of the Miocene world from data and models. We also identify gaps in our understanding that need further research attention in the future.
Key Points
Miocene floras, faunas, and paleogeography were similar to today and provide plausible analogs for future climatic warming
The Miocene saw great dynamism in biotic and climate systems, but the reasons for these shifts are still not well understood
The pCO2‐temperature‐ice relationships during major Miocene climate oscillations and transitions warrant further research
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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