The impact of cancer and chemotherapy during pregnancy on child neurodevelopment: A multimodal neuroimaging analysis.

BACKGROUND: This study applies multimodal MRI to investigate neurodevelopment in nine-year-old children born to cancer-complicated pregnancies. METHODS: In this cohort study, children born after cancer-complicated pregnancies were recruited alongside 1:1 matched controls regarding age, sex and gestational age at birth (GA). Multimodal MRI was used to investigate whole-brain and subcortical volume, cortical structure (using surface-based morphometry), white matter microstructure (using fixel-based analysis) and functional connectivity (using resting-state blood-oxygen-level-dependant signal correlations). Graph theory probed whole-brain structural and functional organization. For each imaging outcome we conducted two group comparisons: 1) children born after cancer-complicated pregnancies versus matched controls, and 2) the subgroup of children with prenatal chemotherapy exposure versus matched controls. In both models, we used the covariate of GA and the group-by-GA interaction, using false-discovery-rate (FDR) or family-wise-error (FWE) correction for multiple comparisons. Exploratory post-hoc analyses investigated the relation between brain structure/function, neuropsychological outcome and maternal oncological/obstetrical history. FINDINGS: Forty-two children born after cancer-complicated pregnancies were included in this study, with 30 prenatally exposed to chemotherapy. Brain organization and functional connectivity were not significantly different between groups. Both cancer and chemotherapy in pregnancy, as compared to matched controls, were associated with a lower travel depth, indicating less pronounced gyrification, in the left superior temporal gyrus (pFDR ≤ 006), with post-hoc analysis indicating platinum derivatives during pregnancy as a potential risk factor (p = .028). Both cancer and chemotherapy in pregnancy were related to a lower fibre cross-section (FCS) and lower fibre density and cross-section (FDC) in the posterior corpus callosum and its tapetal fibres, compared to controls. Higher FDC in the chemotherapy subgroup and higher FCS in the whole study group were observed in the anterior thalamic radiations. None of the psycho-behavioural parameters correlated significantly with any of the brain differences in the study group or chemotherapy subgroup. INTERPRETATION: Prenatal exposure to maternal cancer and its treatment might affect local grey and white matter structure, but not functional connectivity or global organization. While platinum-based therapy was identified as a potential risk factor, this was not the case for chemotherapy in general. FUNDING: This project has received funding from the European Union's Horizon 2020 research and innovation program (European Research council, grant no 647,047), the Foundation against cancer (Stichting tegen kanker, grant no. 2014-152) and the Research Foundation Flanders (FWO, grants no. 11B9919N, 12ZV420N).

Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions.

The genetic basis of the many progressive, multi systemic, mitochondrial diseases that cause a lack of cellular ATP production is heterogeneous, with defects found both in the mitochondrial genome as well as in the nuclear genome. Many different mutations have been found in the genes encoding subunits of the enzyme complexes of the oxidative phosphorylation system. In addition, mutations in genes encoding proteins involved in the assembly of these complexes are known to cause mitochondrial disorders. Here we describe two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits. Whole exome sequencing revealed a homozygous nonsense mutation resulting in a premature stop codon in the gene encoding Pet117, a small protein that has previously been predicted to be a complex IV assembly factor. PET117 has not been identified as a mitochondrial disease gene before. Lentiviral complementation of patient fibroblasts with wild-type PET117 restored the complex IV deficiency, proving that the gene defect is responsible for the complex IV deficiency in the patients, and indicating a pivotal role of this protein in the proper functioning of complex IV. Although previous studies had suggested a possible role of this protein in the insertion of copper into complex IV, studies in patient fibroblasts could not confirm this. This case presentation thus implicates mutations in PET117 as a novel cause of mitochondrial disease.

Raised faecal calprotectin is associated with subsequent symptomatic relapse, in children and adolescents with inflammatory bowel disease in clinical remission.

BACKGROUND: Reliable data on inflammatory biomarkers for predicting relapse of paediatric inflammatory bowel disease (IBD) are lacking. AIM: To investigate the predictive value of faecal calprotectin (FC) and CRP for symptomatic relapse in pediatric IBD in clinical remission. METHODS: In this cross-sectional cohort study, patients <18 years with Crohn's disease or ulcerative colitis in clinical remission ≥3 months were included. At baseline, clinical and biochemical disease activity were assessed using the abbreviated-Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index, and FC and CRP respectively. Disease course over the subsequent 12 months was retrospectively assessed. RESULTS: In total, 114 patients (56% males; median age 14.9 years) were included. Baseline FC was higher in patients that developed symptomatic relapse [median (IQR), relapse 370 µg/g (86-1100) vs. remission 122 µg/g (40-344), P = 0.003]. Baseline FC was predictive of symptomatic relapse within 6 months [HR per 250 µg/g (95% CI): 1.46 (1.21-1.77), P < 0.001], with good predictive accuracy (AUC: 0.82). Optimal FC cut-off was 350 µg/g, with positive and negative predictive value of 41% and 96%. Baseline CRP was higher in patients that developed symptomatic relapse [median (IQR), relapse 1.0 µg/g (0.6-5.0) vs. remission 1.0 µg/g (0.4-2.0), P = 0.033]. Baseline CRP was predictive of symptomatic relapse within 6 months from baseline [HR per 1 mg/L (95% CI): 1.10 (1.02-1.19), P = 0.011], with fair predictive accuracy (AUC: 0.72). Optimal CRP cut-off was 1.0 mg/L, with positive and negative predictive value of 21% and 94%. CONCLUSIONS: Faecal calprotectin and CRP are predictive of symptomatic relapse and may be valuable in management of paediatric IBD in clinical remission.

Celiac disease: an overview from pathophysiology to treatment.

Celiac disease (CD) is one of the most common immune-mediated diseases with a worldwide prevalence of around 1%, although a couple of decades ago the disease was thought to be very rare. CD is characterized by an inadequate inflammatory response to gluten in genetically susceptible individuals. In this inflammatory response both the adaptive and innate immunity are involved. The clinical picture of CD is variable ranging from severe malabsorption syndrome to silent cases. Disease specific antibodies can aid in selecting patients for a small intestinal biopsy, which is thought to be the gold standard investigation to diagnose CD. However, in selected patients, serology can be sufficient to confirm the diagnosis and a biopsy is not needed. Hitherto, the only treatment for CD is adherence to a lifelong strict gluten-free diet. The purpose of this review was to summarize current literature on the epidemiology and pathophysiology of CD and to discuss diagnostic and therapeutic approaches.

Immunoglobulin G antibodies against deamidated-gliadin-peptides outperform anti-endomysium and tissue transglutaminase antibodies in children <2 years age.

To investigate the usefulness of deamidated-gliadin-peptides-antibodies in the diagnosis of celiac disease, serology was tested in 212 children suspected with celiac disease who had undergone a small-intestinal-biopsy. For deamidated-gliadin-peptides-antibodies, two kits were tested. Positive and negative predictive values for IgA deamidated-gliadin-peptides-antibodies using the Bindazyme-kit were 89% and 74%, while the Quanta-Lite-kit had values of 89% and 85%, respectively. For the IgG subtype using the Bindazyme-kit, these values were 85% and 89%, while they were 85% and 91% for the Quanta-Lite-kit. The positive predictive values for endomysium and tissue-transglutaminase antibodies were disappointing (77% and 87%), although the negative predictive values were better (97% and 96%). When the analysis was restricted to the 41 children aged <2 years, no misclassifications occurred with IgG deamidated-gliadin-peptides-antibodies giving 100% accuracy in both kits. The positive predictive value reached 100% for tissue-transglutaminase antibodies and both kits for IgA deamidated-gliadin-peptides-antibodies, while the negative predictive value was 94% in these assays. Positive and negative predictive values for endomysium antibodies were 96% and 93%, respectively. In conclusion, although deamidated-gliadin-peptides-antibodies do not outperform anti-endomysium antibodies in the total study population, the IgG subtype seems to be the best test in children aged <2 years, reaching 100% accuracy.

Hepatitis C infection in children with haemophilia: a pilot study.

Many haemophilia patients were infected with hepatitis C virus (HCV) in childhood after transfusion with inadequately or non-virus inactivated clotting factor products. Limited information is available on the clinical course of HCV infection in children. To assess the clinical consequences of hepatitis C in these young patients we performed a pilot study of 31 patients with haemophilia, infected with HCV before the age of 13. Current median age was 20 years. Nineteen (61%) patients had chronic hepatitis C, whereas the remaining 12 patients spontaneously cleared HCV. The median duration of infection was 17 years. Among patients chronically infected with HCV, an enlarged liver and/or spleen on ultrasound was present in 59%, whereas 63% had abnormal aminotransferases and/or gamma-GT values. In conclusion, 39% of the patients infected in childhood cleared HCV spontaneously. The majority of the patients with chronic hepatitis C had ultrasound and/or laboratory abnormalities and these findings may be associated with the presence of chronic liver disease.

Treatment of patients with long-standing unexplained subfertility with in vitro fertilization.

OBJECTIVE: To evaluate whether IVF is an effective treatment for long-standing unexplained subfertility. DESIGN: Retrospective cohort study. SETTING: Tertiary care infertility center in a university hospital. PATIENT(S): Two hundred two couples with unexplained subfertility of 2 years' duration or more who attended the center for their first IVF attempt. INTERVENTION(S): Couples were placed on a waiting list for IVF. They received no treatment until IVF was started. MAIN OUTCOME MEASURE(S): Pregnancy rate (PR) while on the waiting list and PR after IVF treatment. RESULT(S): Complete data sets were available for 131 couples. Seventeen of 131 women became pregnant while waiting for IVF treatment (PR 0.9% per exposure cycle), whereas 45 of 119 receiving IVF treatment became pregnant (PR 17% per IVF attempt). CONCLUSION(S): IVF treatment has substantial added value over waiting and is an efficient treatment for long-standing unexplained subfertility.

Effects of high doses of toluene on color vision.

High exposure to toluene may cause optic neuropathy and retinopathy, both associated with dyschromatopsia. Another solvent, ethanol, is known to induce acute blue-yellow dyschromatopsia. This study investigated the acute effects of high doses of toluene on color vision. Eight male printshop workers were examined before and after cleaning printing containers with pure toluene. After cleaning, concentrations of toluene in blood were between 3.61 and 7.37 mg/l. Color vision was tested with the Farnsworth panel D-15 test, the Lanthony desaturated panel D-15 test, and the Standard Pseudoisochromatic Plates part 2. For control of possible acute effects, eight workers of a metal-working factory without any neurotoxic exposure were tested according to the same procedure. Acute exposure to toluene did not cause impairment of color vision. However, statistical power is limited due to the small number of exposed subjects. Color vision of the printshop workers tested before cleaning was slightly impaired (statistically not significant) when compared with unexposed subjects.

Effect of subacute occupational exposure to toluene on color vision.

The subacute effect of toluene on color vision was examined in 59 rotogravure workers exposed to toluene. Toluene and ethanol were determined in blood and color vision testing was performed on Monday before shift and on Friday after shift. The battery included the Ishihara plates, the Velhagen plates, the Standard Pseudoisochromatic Plates part 2, the Farnsworth panel D-15 test, and the Lanthony desaturated panel D-15 test. The concentrations of toluene in blood ranged from < 0.22 to 7.37 mg/l. No effect of toluene on color vision could be observed even in a subgroup of highly exposed workers. So their ability to judge colored products was not impaired.

The influence of omnivorous elaterid larvae on the microbial carbon cycle in different forest soils.

Data are presented on the influence of Athous subfuscus larvae (Coleoptera, Elateridae) on the microbial carbon cycle in the biotically most active horizons of three contrasting beech forest soils: the Ah horizon of a mull soil on limestone (Göttinger Wald, FRG), the F/H horizon of a moder soil on new red sandstone (Solling area, FRG) and in the F/H horizon of a lime ameliorated area close to the second site. Gut content analyses demonstrated that the larvae of A. subfuscus are humiphagous and that this unspecific feeding behaviour is widely independent of soil conditions. Differences in 14C incorporation demonstrated that only the larvae in the F/H horizon of the limed moder soil directly affected primary decomposer organisms. However, the burrowing activity of the larvae in the topsoil indirectly modified the time course of beech leaf-litter decomposition in the litter layer of all three soils. The microflora of the mull soil contained 2.6%, that of the moder soil 0.7% and that of the limed moder soil 2.2% of total C. The metabolic quotient (qCO2, 10°C) of the soil microflora was 0.0010 (mgCO2-C·mg-1 biomass-C·h-1) in the mull soil, 0.0034 in the moder soil and 0.0012 in the limed moder soil. The A. subfuscus larvae generally reduced the size of the microbial C pool (<-30%) and increased the metabolic quotient of the microflora (>+50%). Considering these soil-independent effects of A. subfuscus on the C turnover of the soil microflora, the burrowing activity of humiphagous soil arthropods may generally increase nutrient availability to primary producers. The results of this study reveal that some of the micro- and mesoscale effects of humiphagous arthropods on the microbial carbon turnover in beech forest soils are surprisingly similar, even under very different soil conditions. The long-term modification of the time course of leaf litter decomposition, in contrast, indicates that the influence of humiphagous arthropods on the formation of the humus layer is soil-specific. There are profound differences in the role of humiphagous arthropods in limed moder soils and in naturally base-rich soils. It is concluded that liming increases competition within the microfloral population due to accelerated humification. The negative effect of A. subfuscus on 14C mineralization in the limed substrate could thus be explained by its effects on a microflora that was strongly limited by the availability of carbon.

[Partial resection of the tongue (author's transl)]. / La résection partielle de la langue.

An improved simplified technique is described for reducing the volume of the tongue by operation. A plastic support has been designed on which the tongue can be spread out symmetrically and fixed in position. Gallbladder forceps are applied to the base of the tongue to avoid hemorrhage. An initial incision is made through the whole thickness of the tongue down to the support, and a partial resectomy performed, followed by apposition of the wound edges. The results obtained with this procedure are far superior to those previously reported using other techniques: the operation takes less time and there is almost no loss of blood.