Evaluation of chemotherapy-induced nausea and vomiting in pediatric patients with high-grade glioma treated with lomustine-a case series.

PURPOSE: Although lomustine has been used as a chemotherapeutic agent for decades, no recommendation on appropriate chemotherapy-induced nausea and vomiting (CINV) prophylaxis is available. As CINV is considered one of the most bothersome side effects of chemotherapy, adequate prophylaxis is of relevance to improve quality of life during cancer treatment. The aim of this retrospective case series was to report the incidence and severity of CINV in pediatric patients with high-grade glioma treated with lomustine and to formulate recommendations for appropriate CINV prophylaxis. METHODS: Pediatric patients treated with lomustine for high-grade glioma according to the ACNS 0423 protocol were identified retrospectively. Two researchers independently reviewed and classified complaints of CINV and administered CINV prophylaxis. Treatment details, tumor localization, and response to therapy were systematically extracted from the patients' files. RESULTS: Seventeen children aged 8-18 years received a median of four cycles of lomustine. CINV complaints and administered prophylaxis were evaluable in all patients. Moderate or severe CINV was observed in 13/17 (76%) patients. Administered prophylactic CINV regimens varied from no prophylaxis to triple-agent combinations. CONCLUSION: In this case series, we identified lomustine as a highly emetogenic chemotherapeutic agent. According to the current guidelines, CINV prophylaxis with a 5-HT3 receptor antagonist in combination with dexamethasone and (fos)aprepitant is recommended.

Clinical manifestations and treatment outcomes in degos disease: a systematic review.

Degos disease (atrophic papulosis) is a rare vasculopathy with cutaneous and systemic manifestations. Although potentially fatal, the characteristics of and treatments for Degos disease variants are not adequately described. We conducted a systematic review to summarize cutaneous and systemic presentations, treatments and outcomes of malignant (MAP) and benign (BAP) variants of Degos disease. A comprehensive search was conducted on Embase, MEDLINE, CINAHL and CENTRAL on 27 October 2020, which yielded 254 original studies reporting cases of Degos disease. A total of 357 patients were included in the analysis. Mean age of onset was 33.9 years. MAP was most commonly reported (63.8%, n = 228/357), with 56.6% (n = 129/228) mortality. Cutaneous lesions were usually asymptomatic (26.3%, n = 81/308) and localized to the trunk (57.7%, n = 206/357) and extremities (56.8%, n = 203/357). Systemic involvement developed within 2 years on average, ranging from 0 to 28 years. Anti-platelet monotherapy had a complete resolution rate of 42.3% (n = 11/26) in BAP and 20.0% (n = 7/35) in MAP. Based on the findings of the study, most cases of Degos disease are malignant with high mortality, and even benign cutaneous cases may develop systemic disease in as late as 28 years. Anti-platelet monotherapies may prove effective against both variants. Further studies are needed to confirm these findings.

Testing the feasibility of a sustainable preschool obesity prevention approach: a mixed-methods service evaluation of a volunteer-led HENRY programme.

BACKGROUND: Over the last 10 years HENRY has been working to reduce and prevent child obesity by training health and early years professionals to deliver its evidence-based programme to parents. The aim and unique contribution of this study was to evaluate whether training volunteers to deliver this programme on a one-to-one basis was feasible. METHODS: Mixed-methods service evaluation with parent-reported pre- and post-programme outcomes and focus groups conducted with parents and volunteer facilitators. The programme consisted of 8 one-to-one sessions delivered weekly by volunteers (n = 18) to build food and activity-related knowledge, skills, and understanding, and improve parenting efficacy, and parent and child eating and physical activity. Programmes took place at parent's (n = 69) home or local community venues in four London boroughs, United Kingdom. Parent-reported parenting efficacy, emotional wellbeing, eating, and physical activity data were captured, alongside parent ratings of the programme and volunteer ratings of the training. Parent and volunteer focus groups explored involvement, expectations, and experiences of the programme, training and delivery, feedback, and impact. RESULTS: Parents were mostly female, had varied ethnic backgrounds, and were often not working but well educated. There were statistically significant improvements of a medium-to-large size in parent and child emotional wellbeing, parenting efficacy, fruit and vegetable consumption, family eating and food purchasing behaviours. Parent ratings of the programme were positive and qualitative data highlighted the holistic nature of the programme, which focused on more than just food, and the relationships with volunteers as key facets. Volunteers were also mostly female, had varied ethnic backgrounds, and were often well educated, but more likely to be employed than parents. Volunteers rated the training and delivery as useful in enabling them to deliver the programme confidently and for their own wellbeing. Despite finding some sessions challenging emotionally, volunteers reported positive family lifestyle improvements by parents and children and that the experience would be useful for future employment. CONCLUSIONS: It is feasible to recruit and train volunteers to deliver a structured preschool obesity prevention programme, which parents considered acceptable and enjoyable, with preliminary reports of parent and child benefits.

The impact of HENRY on parenting and family lifestyle: Exploratory analysis of the mechanisms for change.

BACKGROUND: Childhood obesity is a major public health concern. In the United Kingdom, a quarter of children are overweight or obese at age 5 years. Overweight and obese children are more likely to develop serious health issues such as diabetes later in life. Consequently, there is an urgent need for effective, early obesity prevention and intervention. This study investigated the impact of an 8-week child obesity intervention-HENRY (Health Exercise Nutrition for the Really Young)-designed to help parents with preschool children develop the skills and knowledge needed to improve family lifestyle and well-being. We were particularly interested in exploring the potential mechanisms by which HENRY may have a positive impact. METHOD: Focus groups (n = 7, total participants = 39) were completed with mothers attending the HENRY programme at one of seven locations across England. They took place within 2 weeks of programme completion. Follow-up telephone interviews were completed with a subsample of participants (n = 10) between 17 and 21 weeks later. RESULTS: Parents consistently reported enhanced self-efficacy in terms of improved confidence in their ability to encourage healthier behaviours such as eating fruit and vegetables and increasing physical activity, and improvements to family health behaviours. Many changes were reportedly sustained at follow-up. Data provided insights into the potential mechanisms that created the conditions for the positive changes. Participants described the importance of mutual support, being listened to by facilitators, and encouragement to identify their own ideas. Their comments indicated the success of a solution-focused, strength-based, partnership approach to supporting family lifestyle change. CONCLUSION: The results of this study contribute to the body of evidence suggesting that HENRY may have a positive impact on parenting and family lifestyle behaviour. Although data were collected in 2011, the findings contribute to an understanding of the components of effective obesity prevention in young children.

Early- and late-onset preeclampsia and the tissue-specific epigenome of the placenta and newborn.

INTRODUCTION: Preeclampsia (PE) carries increased risks of cardiovascular- and metabolic diseases in mothers and offspring during the life course. While the severe early-onset PE (EOPE) phenotype originates from impaired placentation in early pregnancy, late-onset PE (LOPE) is in particular associated with pre-existing maternal cardiovascular- and metabolic risk factors. We hypothesize that PE is associated with altered epigenetic programming of placental and fetal tissues and that these epigenetic changes might elucidate the increased cardiovascular- and metabolic disease susceptibility in PE offspring. METHODS: A nested case-control study was conducted in The Rotterdam Periconceptional Cohort comprising 13 EOPE, 16 LOPE, and three control groups of 36 uncomplicated pregnancies, 27 normotensive fetal growth restricted and 20 normotensive preterm birth (PTB) complicated pregnancies. Placental tissue, newborn umbilical cord white blood cells (UC-WBC) and umbilical vein endothelial cells were collected and DNA methylation of cytosine-guanine dinucleotides was measured by the Illumina HumanMethylation450K BeadChip. An epigenome-wide analysis was performed by using multiple linear regression models. RESULTS: Epigenome-wide tissue-specific analysis between EOPE and PTB controls revealed 5001 mostly hypermethylated differentially methylated positions (DMPs) in UC-WBC and 869 mostly hypomethylated DMPs in placental tissue, situated in or close to genes associated with cardiovascular-metabolic developmental pathways. DISCUSSION: This study shows differential methylation in UC-WBC and placental tissue in EOPE as compared to PTB, identifying DMPs that are associated with cardiovascular system pathways. Future studies should examine these loci and pathways in more detail to elucidate the associations between prenatal PE exposure and the cardiovascular disease risk in offspring.

Expanding the Klebsiella pneumoniae volatile metabolome using advanced analytical instrumentation for the detection of novel metabolites.

AIMS: The purpose of this study was to identify the volatile molecules produced by the pathogenic Gram-negative bacterium Klebsiella pneumoniae (ATCC 13883) during in vitro growth using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS). METHODS AND RESULTS: Klebsiella pneumoniae ATCC 13883 was incubated in lysogeny broth to mid-exponential and stationary growth phases. Headspace volatile molecules from culture supernatants were concentrated using solid-phase microextraction (SPME) and analysed via GC×GC-TOFMS. Ninety-two K. pneumoniae-associated volatile molecules were detected, of which 78 (85%) were detected at both phases of growth and 14 (15%) were detected at either mid-exponential or stationary growth phases. CONCLUSIONS: This study has increased the total number of reported K. pneumoniae-associated volatile molecules from 77 to 150, demonstrating the sensitivity and resolution achieved by employing GC×GC-TOFMS for the analysis of bacterial headspace volatiles. SIGNIFICANCE AND IMPACT OF THE STUDY: This study represents an early-stage comprehensive volatile metabolomic analysis of an opportunistic bacterial pathogen. Characterizing the volatile molecules produced by K. pneumoniae during in vitro growth could provide us with a better understanding of this organisms' metabolism, an area that has not been extensively studied to date.

The microbiome of diabetic foot osteomyelitis.

The purpose of this investigation was to evaluate the diversity of bacteria in diabetic foot osteomyelitis using a 16S rRNA sequencing approach and to compare the results with conventional culture techniques. In this prospective observational study, we obtained 34 bone samples from patients admitted to our hospital with a moderate-severe diabetic foot infection. We analysed the distribution of the 16S rRNA gene sequences in the bone samples, using an Illumina MiSeq Personal Sequencer. We compared the genera that were detected with the cultured pathogens in the bone samples with conventional techniques. In the 23 samples that had positive results with both techniques, Staphylococcus, Corynebacterium, Streptococcus and Propionibacterium spp. were detected in 20, 18, 13 and 11 samples, respectively. Significantly more anaerobes were detected with 16S rRNA sequencing compared to conventional techniques (86.9 % vs. 23.1 %, p = 0.001) and more Gram-positive bacilli were present (78.3 % vs. 3.8 %, p < 0.001). Staphylococcus spp. were identified in all of the sequenced bone samples that were negative with conventional techniques. Mixed genera were present in 83.3 % (5 of 6) of the negative samples. Anaerobic and fastidious organisms may play a more significant role in osteomyelitis than previously reported. Further studies with larger populations are needed in order to fully understand the clinical importance of the microbial diversity of diabetic foot osteomyelitis.

Mitigating yield-scaled greenhouse gas emissions through combined application of soil amendments: A comparative study between temperate and subtropical rice paddy soils.

Effects of different soil amendments were investigated on methane (CH4) and nitrous oxide (N2O) emissions, global warming potential (GWP) and yield scaled GWPs in paddy soils of Republic of Korea, Japan and Bangladesh. The experimental treatments were NPK only, NPK+fly ash, NPK+silicate slag, NPK+phosphogypsum(PG), NPK+blast furnace slag (BFS), NPK+revolving furnace slag (RFS), NPK+silicate slag (50%)+RFS (50%), NPK+biochar, NPK+biochar+Azolla-cyanobacteria, NPK+silicate slag+Azolla-cyanobacteria, NPK+phosphogypsum (PG)+Azolla-cyanobacteria. The maximum decrease in cumulative seasonal CH4 emissions was recorded 29.7% and 32.6% with Azolla-cyanobacteria plus phospho-gypsum amendments in paddy soils of Japan and Bangladesh respectively, followed by 22.4% and 26.8% reduction with silicate slag plus Azolla-cyanobacteria application. Biochar amendments in paddy soils of Japan and Bangladesh decreased seasonal cumulative N2O emissions by 31.8% and 20.0% respectively, followed by 26.3% and 25.0% reduction with biochar plus Azolla-cyanobacteria amendments. Although seasonal cumulative CH4 emissions were significantly increased by 9.5-14.0% with biochar amendments, however, global warming potentials were decreased by 8.0-12.0% with cyanobacterial inoculation plus biochar amendments. The maximum decrease in GWP was calculated 22.0-30.0% with Azolla-cyanobacteria plus silicate slag amendments. The evolution of greenhouse gases per unit grain yield (yield scaled GWP) was highest in the NPK treatment, which was decreased by 43-50% from the silicate slag and phosphogypsum amendments along with Azolla-cyanobacteria inoculated rice planted soils. Conclusively, it is recommended to incorporate Azolla-cyanobacteria with inorganic and organic amendments for reducing GWP and yield scaled GWP from the rice planted paddy soils of temperate and subtropical countries.

Periconceptional parental conditions and perimembranous ventricular septal defects in the offspring.

BACKGROUND: The perimembranous ventricular septal (pVSD) defect is the most common congenital heart disease phenotype. Several parental factors are associated with pVSD risk in the offspring. To contribute to the future prevention of pVSDs, we investigated associations with nongenetic parental conditions. METHODS: In a case-control study with standardized data collection at 17 months after birth, 115 parents of a child with pVSD and 484 parents of a healthy child completed questionnaires about periconceptional nongenetic conditions. Univariable and multivariable logistic regression analyses were used to estimate odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: Complete data were available for 588 families (98%). Maternal risk conditions associated with pVSD offspring were a positive family history of congenital heart disease (OR, 2.61; 95%CI, 0.98-6.91), medication use (OR, 1.80; 95%CI, 1.13-2.85) and advanced age (OR, 1.07; 95%CI, 1.02-1.12). Exposure to phthalates (OR, 1.93; 95%CI, 1.05-3.54) was the only paternal risk condition associated with pVSD offspring. CONCLUSION: Four periconceptional parental conditions contributed to pVSD risk in the offspring. Couples planning pregnancy should be counseled on these risk conditions which are partially modifiable to contribute to the future prevention of pVSDs.

Intrinsic hyporesponsiveness of invariant natural killer T cells precedes the onset of lupus.

Patients with systemic lupus erythematosus (SLE) display reduced numbers and functions of invariant natural killer T (iNK T) cells, which are restored upon treatment with corticosteroids and rituximab. It is unclear whether the iNK T cell insufficiency is a consequence of disease or is a primary abnormality that precedes the onset of disease. To address this, we analysed iNK T cell function at different stages of disease development using the genetically lupus-susceptible NZB × NZW F1 (BWF(1)) model. We found that iNK T cell in-vivo cytokine responses to an iNK T cell ligand α-galactosylceramide (α-GalCer) were lower in BWF(1) mice than in non-autoimmune BALB/c and major histocompatibility complex (MHC)-matched NZB × N/B10.PL F1 mice, although iNK T cell numbers in the periphery were unchanged in BWF(1) mice compared to control mice. Such iNK T cell hyporesponsiveness in BWF(1) mice was detected at a young age long before the animals exhibited any sign of autoimmunity. In-vivo activation of iNK T cells is known to transactivate other immune cells. Such transactivated T and B cell activation markers and/or cytokine responses were also lower in BWF(1) mice than in BALB/c controls. Finally, we show that iNK T cell responses were markedly deficient in the NZB parent but not in NZW parent of BWF(1) mice, suggesting that BWF(1) might inherit the iNK T cell defect from NZB mice. Thus, iNK T cells are functionally insufficient in lupus-prone BWF(1) mice. Such iNK T cell insufficiency precedes the onset of disease and may play a pathogenic role during early stages of disease development in SLE.

Effect of limited nickel availability on methane emission from EDTA treated soils: coenzyme M an alternative biomarker for methanogens.

Methanogens utilize simple carbon compounds to produce methane (CH(4)) under strictly anaerobic condition. During methanogenesis, methyl coenzyme M (MeCoM) is reduced by MeCoM reductase enzyme to CH(4) involving a nickel-containing cofactor F(430). In this experiment, strong chelating agent like ethylenediaminetetraacetic acid (EDTA) was applied in soil to study its feasibility for suppressing methanogen activity and CH(4) production in soil. Application of EDTA significantly (P≤0.05) reduced CH(4) production in soil. Application of 60 ppm EDTA (soil weight basis) was the most effective among all treatments. Applied EDTA forms complex compounds with heavy metals like nickel (Ni) and increases Ni concentration in soil solution. Since methanogenesis is intracellular process, it is necessary for methanogens to assimilate those Ni-EDTA complexes inside cell to utilize Ni in EDTA treated soils. Results indicated that methanogens cannot utilize Ni in the presence of EDTA and that significantly (P≤0.05) reduced mcrA gene (coding MeCoM reductase enzyme) copy number and Co-M concentration in soil. Due to high correlation (r=0.901(*)) between Co-M concentration and mcrA gene copy numbers, Co-M concentration could be used as an alternative biomarker for methanogens. Therefore, it could be propose that 60 ppm EDTA could be an optimum dose to suppress CH(4) emission from soil by restricting Ni availability to methanogens.

Disparate effects of depletion of CD1d-reactive T cells during early versus late stages of disease in a genetically susceptible model of lupus.

Some T cells react with lipid antigens bound to antigen-presenting molecule CD1d. Numbers and functions of a subset of such lipid-reactive T cells are reduced in patients with systemic lupus erythematosus (SLE) and their relatives, as well as in genetically susceptible and chemically induced animal models of lupus-like disease. We have reported that the germline deletion of CD1d exacerbates lupus, suggesting a protective role of these cells in the development of lupus. The use of a knockout mouse model in this study, however, did not allow examination of the role of these cells at different stages of disease. Here, we describe an approach to deplete CD1d-dependent T cells, which allowed us to investigate the role of these cells at different stages of disease in genetically lupus-prone NZB/NZW F1 (BWF1) mice. Repeated intravenous injections of large numbers of CD1d-transfected cells resulted in ∼50-75% reduction in these cells, as defined by the expression of CD4, NK1.1 and CD122, and lack of expression of CD62 ligand. TCR γδ (+)NK1.1(+) cells were also reduced in the recipients of CD1d-transfected cells as compared with control recipients. Such depletion of CD1d-reactive T cells in preclinical BWF1 mice resulted in disease acceleration with a significant increase in proteinuria and mortality. In older BWF1 mice having advanced nephritis, however, such depletion of CD1d-reactive T cells resulted in some disease improvement. Taken together, these data as well as our published studies suggest that CD1d-reactive T cells protect against the development of lupus in animal models. However, these cells appear to be unable to suppress established lupus nephritis in these animals, and might even play a disease aggravating role in late stages of disease.

Contrast echocardiography: finding its place in stem cell therapy.

To date, the underlying mechanism responsible for the restoration of the injured myocardium following transplantation of stem cells has not been clearly identified. Molecular imaging is essential to the continued progress of stem cell therapy by elucidating the biology of transplanted stem cells in vivo. Currently, several imaging modalities are in development in the rapidly evolving field of molecular imaging. Contrast echocardiography has the potential to define its role in shaping the future development of stem cell therapy. We describe the current state of contrast echocardiography and its future direction herein.

Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53.

The inhibitor of apoptosis protein survivin has been implicated in both cell cycle control and apoptosis resistance. To discriminate between these different roles, we used transgenic expression of survivin in the skin as a model for cell proliferation, differentiation, and apoptosis. Transgenic mice expressing survivin under the control of a keratin-14 promoter developed normally, without histologic abnormalities of the skin or hair, epidermal hyperplasia, or developmental abnormalities of basal or suprabasal epidermis. Keratinocyte proliferation assessed under basal conditions, or after ultraviolet-B (UVB) irradiation, or phorbol ester stimulation was unchanged in survivin transgenic mice. In contrast, survivin expression inhibited UVB-induced apoptosis in vitro and in vivo (i.e., sunburn cell formation), whereas it did not affect Fas-induced cell death. When crossed with p53 knockout mice, transgenic expression of survivin in a p53(+/-) background substituted for the loss of a second p53 allele and further inhibited UVB-induced apoptosis. These data provide the first in vivo evidence that survivin inhibits apoptosis and suggest that this pathway may oppose the elimination of cancerous cells by p53.

Nuclear localization of beta-catenin is an important prognostic factor in hepatoblastoma.

In this study, mutational and immunohistochemical analyses of beta-catenin were performed in 30 hepatoblastomas, to assess the prevalence of alterations of the Wnt pathway with respect to clinicopathological parameters and survival. Four missense mutations of beta-catenin (13.3%) were detected and there was strong immunoreactivity for beta-catenin in the cytoplasm and/or the nucleus in 97% of hepatoblastomas. Nuclear and cytoplasmic staining was demonstrated in 19 of 30 tumours (63%), while ten revealed only cytoplasmic staining. Statistically, this nuclear beta-catenin staining was significantly higher in the embryonal (Fisher exact test; p=0.00393) or undifferentiated type (p=0.00156) of hepatoblastoma than in the fetal type, but there was no difference between clinical stages I and II and clinical stages III and IV (p=0.175). Cumulative survival curves showed that nuclear beta-catenin staining (generalized Wilcoxon test; p=0.0088), undifferentiated histological type (p=0.0305), and clinical stages III and IV (p=0.0107) were significantly correlated with shorter survival time in these patients. Moreover, Cox multivariate analysis provides evidence that nuclear beta-catenin staining is the most important prognostic factor for survival (p=0.0090). It is therefore concluded that immunohistochemical analysis of beta-catenin might be a useful clinical tool for estimating the prognosis for patients with hepatoblastoma.

Somatic mutations in the death domain of the Fas (Apo-1/CD95) gene in gastric cancer.

It is now believed that genes regulating apoptosis are also important variables in cancer development. Fas, a transmembrane protein of the tumour necrosis factor receptor family, is a key molecule for cell death signalling. The mutation of the primary structure of the Fas gene might also be one of the possible mechanisms that disrupt Fas-mediated apoptosis in tumour cells. The purpose of this study was to determine whether somatic mutation of the Fas gene could be involved in the tumourigenesis of gastric cancer. Polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) analysis with two intragenic polymorphic markers, and mutation analysis for the entire coding regions of the Fas gene were performed in 43 cases of gastric cancer, using PCR-single-strand conformational polymorphism sequencing. Five (11.6%) missense mutations were detected, only in the death domain of the Fas gene. Although these mutations were observed only in intestinal-type gastric cancers, there was no statistically significant difference in the frequency of Fas mutation between intestinal- and diffuse-type gastric cancer (p=0.068). Nine LOH out of 22 informative cases were also detected with one or both markers (41%). Three of them demonstrated a somatic mutation in the remaining allele, indicating the inactivation of both alleles. These results suggest that genetic alterations of the Fas gene may not only be limited to gastric cancer cell protection through Fas resistance, but may also play an important role in tumour promotion and/or progression in a subset of gastric cancer.

Inhibition of melanoma tumor growth in vivo by survivin targeting.

A role of apoptosis (programmed cell death) in tumor formation and growth was investigated by targeting the apoptosis inhibitor survivin in vivo. Expression of a phosphorylation-defective survivin mutant (Thr(34)-->Ala) triggered apoptosis in several human melanoma cell lines and enhanced cell death induced by the chemotherapeutic drug cisplatin in vitro. Conditional expression of survivin Thr(34)-->Ala in YUSAC2 melanoma cells prevented tumor formation upon s.c. injection into CB.17 severe combined immunodeficient-beige mice. When induced in established melanoma tumors, survivin Thr(34)-->Ala inhibited tumor growth by 60-70% and caused increased apoptosis and reduced proliferation of melanoma cells in vivo. Manipulation of the antiapoptotic pathway maintained by survivin may be beneficial for cancer therapy.