CYP3A5 and NAT2 gene polymorphisms: role in childhood acute lymphoblastic leukemia risk and treatment outcome

Susceptibility to acute lymphoblastic leukemia can be highly influenced by genetic polymorphisms in metabolizing enzyme genes of environmental carcinogens. This study aimed to evaluate the impact of the CYP3A5 and NAT2 metabolizing enzyme polymorphisms on the risk of childhood acute lymphoblastic leukemia. The analysis was conducted on 204 ALL patients and in 364 controls from a Brazilian population, using PCR-RFLP. The CYP3A5*3 polymorphic homozygous genotype was more frequent among ALL patients and the *3 allele variant was significantly associated with increased risk of childhood ALL (OR = 0.29; 95% CI, 0.14-0.60). The homozygous polymorphic genotype for the *6 allele variant was extremely rare and found in only two individuals. The heterozygous frequencies were similar for the ALL group and the control group. No significant differences were observed between the groups analyzed regarding NAT2 variant polymorphisms. None of the polymorphisms analyzed was related to treatment outcome. The results suggest that CYP3A5*3 polymorphism may play an important role in the risk of childhood ALL.

Characterization of Ectonucleotidases in Human Medulloblastoma Cell Lines: ecto-5 ' NT/CD73 in Metastasis as Potential Prognostic Factor

Medulloblastoma (MB) is the most common malignant brain tumor in children and occurs mainly in the cerebellum. Important intracellular signaling molecules, such those present in the Sonic Hedgehog and Wnt pathways, are involved in its development and can also be employed to determine tumor grade and prognosis. Ectonucleotidases, particularly ecto-5'NT/CD73, are important enzymes in the malignant process of different tumor types regulating extracellular ATP and adenosine levels. Here, we investigated the activity of ectonucleotidases in three malignant human cell lines: Daoy and ONS76, being representative of primary MB, and the D283 cell line, derived from a metastatic MB. All cell lines secreted ATP into the extracellular medium while hydrolyze poorly this nucleotide, which is in agreement with the low expression and activity of pyrophosphate/phosphodiesterase, NTPDases and alkaline phosphatase. The analysis of AMP hydrolysis showed that Daoy and ONS76 completely hydrolyzed AMP, with parallel adenosine production (Daoy) and inosine accumulation (ONS76). On the other hand, D283 cell line did not hydrolyze AMP. Moreover, primary MB tumor cells, Daoy and ONS76 express the ecto-5'NT/CD73 while D283 representative of a metastatic tumor, revealed poor expression of this enzyme, while the ecto-adenosine deaminase showed higher expression in D283 compared to Daoy and ONS76 cells. Nuclear beta-catenin has been suggested as a marker for MB prognosis. Further it can promotes expression of ecto-5'NT/CD73 and suppression of adenosine deaminase. It was observed that Daoy and ONS76 showed greater nuclear beta-catenin immunoreactivity than D283, which presented mainly cytoplasmic immunoreactivity. In summary, the absence of ecto-5'NT/CD73 in the D283 cell line, a metastatic MB phenotype, suggests that high expression levels of this ectonucleotidase could be correlated with a poor prognosis in patients with MB.

Cost-effectiveness of introducing the 10-valent pneumococcal conjugate vaccine into the universal immunisation of infants in Brazil

Background Cost-effectiveness studies have been increasingly part of decision processes for incorporating new vaccines into the Brazilian National Immunisation Program. This study aimed to evaluate the cost-effectiveness of 10-valent pneumococcal conjugate vaccine (PCV10) in the universal childhood immunisation programme in Brazil. Methods A decision-tree analytical model based on the ProVac Initiative pneumococcus model was used, following 25 successive cohorts from birth until 5 years of age. Two strategies were compared: (1) status quo and (2) universal childhood immunisation programme with PCV10. Epidemiological and cost estimates for pneumococcal disease were based on National Health Information Systems and literature. A 'top-down' costing approach was employed. Costs are reported in 2004 Brazilian reals. Costs and benefits were discounted at 3%. Results 25 years after implementing the PCV10 immunisation programme, 10 226 deaths, 360 657 disability-adjusted life years (DALYs), 433 808 hospitalisations and 5 117 109 outpatient visits would be avoided. The cost of the immunisation programme would be R$10 674 478 765, and the expected savings on direct medical costs and family costs would be R$1 036 958 639 and R$209 919 404, respectively. This resulted in an incremental cost-effectiveness ratio of R$778 145/death avoided and R$22 066/DALY avoided from the society perspective. Conclusion The PCV10 universal infant immunisation programme is a cost-effective intervention (1-3 GDP per capita/DALY avoided). Owing to the uncertain burden of disease data, as well as unclear long-term vaccine effects, surveillance systems to monitor the long-term effects of this programme will be essential.

Orbital Hemangiopericytoma/Solitary Fibrous Tumor in Childhood

A 12-year-old girl had a 6-year history of a large soft-tissue mass in her left orbit. The tumor biopsy was previously performed elsewhere when she was 7 years old, but no treatment was offered at that time. Later, the tumor was completely excised, and histologic examination revealed a mesenchymal neoplasia with typical hemangiopericytoma features. At 9 months of follow up, no evidence of local recurrence or metastasis was seen.

Acoustic analyses of diadochokinesis in fluent and stuttering children

OBJECTIVES: The purpose of the study was to acoustically compare the performance of children who do and do not stutter on diadochokinesis tasks in terms of syllable duration, syllable periods, and peak intensity. METHODS: In this case-control study, acoustical analyses were performed on 26 children who stutter and 20 aged-matched normally fluent children (both groups stratified into preschoolers and school-aged children) during a diadochokinesis task: the repetition of articulatory segments through a task testing the ability to alternate movements. Speech fluency was assessed using the Fluency Profile and the Stuttering Severity Instrument. RESULTS: The children who stutter and those who do not did not significantly differ in terms of the acoustic patterns they produced in the diadochokinesis tasks. Significant differences were demonstrated between age groups independent of speech fluency. Overall, the preschoolers performed poorer. These results indicate that the observed differences are related to speech-motor age development and not to stuttering itself. CONCLUSIONS: Acoustic studies demonstrate that speech segment durations are most variable, both within and between subjects, during childhood and then gradually decrease to adult levels by the age of eleven to thirteen years. One possible explanation for the results of the present study is that children who stutter presented higher coefficients of variation to exploit the motor equivalence to achieve accurate sound production (i.e., the absence of speech disruptions).

Exercise training in childhood-onset systemic lupus erythematosus: a controlled randomized trial

Abstract Introduction Exercise training has emerged as a promising therapeutic strategy to counteract physical dysfunction in adult systemic lupus erythematosus. However, no longitudinal studies have evaluated the effects of an exercise training program in childhood-onset systemic lupus erythematosus (C-SLE) patients. The objective was to evaluate the safety and the efficacy of a supervised aerobic training program in improving the cardiorespiratory capacity in C-SLE patients. Methods Nineteen physically inactive C-SLE patients were randomly assigned into two groups: trained (TR, n = 10, supervised moderate-intensity aerobic exercise program) and non-trained (NT, n = 9). Gender-, body mass index (BMI)- and age-matched healthy children were recruited as controls (C, n = 10) for baseline (PRE) measurements only. C-SLE patients were assessed at PRE and after 12 weeks of training (POST). Main measurements included exercise tolerance and cardiorespiratory measurements in response to a maximal exercise (that is, peak VO2, chronotropic reserve (CR), and the heart rate recovery (ΔHRR) (that is, the difference between HR at peak exercise and at both the first (ΔHRR1) and second (ΔHRR2) minutes of recovery after exercise). Results The C-SLE NT patients did not present changes in any of the cardiorespiratory parameters at POST (P > 0.05). In contrast, the exercise training program was effective in promoting significant increases in time-to-exhaustion (P = 0.01; ES = 1.07), peak speed (P = 0.01; ES = 1.08), peak VO2 (P = 0.04; ES = 0.86), CR (P = 0.06; ES = 0.83), and in ΔHRR1 and ΔHRR2 (P = 0.003; ES = 1.29 and P = 0.0008; ES = 1.36, respectively) in the C-SLE TR when compared with the NT group. Moreover, cardiorespiratory parameters were comparable between C-SLE TR patients and C subjects after the exercise training intervention, as evidenced by the ANOVA analysis (P > 0.05, TR vs. C). SLEDAI-2K scores remained stable throughout the study. Conclusion A 3-month aerobic exercise training was safe and capable of ameliorating the cardiorespiratory capacity and the autonomic function in C-SLE patients. Trial registration NCT01515163.

The informal market of education in Egypt: Private tutoring and its implications /// Arbeitspapiere / Institut für Ethnologie und Afrikastudien ; 88

Education is generally perceived as a public good which should be provided by the state. In Egypt, free and equal access to education has been guaranteed to all citizens since President Nasser’s socialist reforms in the 1950s. However, due to high population growth rates and a lack of financial resources, the public education system has been struggling to accommodate rapidly increasing numbers of students. While enrolment rates have risen steadily, the quality of state-provided services has deteriorated. Teachers and students have to cope with high class densities, insufficient facilities, a rigid syllabus and a centralized examination system. Today, teaching is among the lowest-paying occupations in the public sector. One strategy to cope with this situation is the widespread practice of private tutoring, which usually takes place at students’ homes or in commercial tutoring centers. Based on research carried out in Cairo in 2004/05 and 2006, I use an actor-centered approach to analyze the motivations of Egyptian teachers and students for participating in private tutoring and the impact that this practice has on the relationship between teachers and students. Students of all socio-economic backgrounds resort to tutoring in order to succeed in a highly competitive and exam-oriented education system. However, the form and quality of tutoring that can be accessed depends on the financial means of the family. For teachers, tutoring provides a good opportunity not only to supplement their income, but also, in the case of renowned “star teachers”, to improve their professional status and autonomy. On the informal “market of education” that has developed in Egypt during the last decades, the educational responsibilities of the state are increasingly being taken over by private actors, i.e. the process of teaching and learning is dissociated from the direct control of the state and from school as an institution. At the same time, education is turned into a marketable commodity. Despite the government’s efforts to provide free education to all citizens, the quality of social services that can be accessed in Egypt, thus, depends mainly on the financial means of the individual or the family.

Properdin in childhood and its association with wheezing and atopy

Properdin, a serum glycoprotein, is an important component of innate immunity, the only known positive regulator of complement, acting as an initiation point for alternative pathway activation. As an X-linked protein, we hypothesized that properdin may play a modulatory role in the pathogenesis of viral wheeze in children, which tends to be more common and more severe in boys. We aimed to determine properdin levels in a community-based paediatric sample, and to assess whether levels of properdin were associated with childhood wheeze phenotypes and atopy. We studied 137 school-children aged 8-12 yrs, a nested sample from a cohort study. Properdin was measured by a commercial enzyme-linked immunoabsorbant assay. We assessed wheeze by questionnaire, validated it by a nurse-led interview and performed skin prick tests and a methacholine challenge in all children. Forty children (29%) reported current wheeze. Serum properdin levels ranged between 18 and 40 microg/ml. Properdin was not associated with age, gender, atopy, bronchial responsiveness, current wheeze (neither the viral wheeze nor multiple-trigger wheeze phenotype) or severity of wheeze, but was slightly lower in south Asian (median 21.8 microg/ml) compared with white children (23.3 microg/ml; p = 0.006). Our data make it unlikely that properdin deficiency is common in healthy children or that levels of properdin are a major risk factor for wheeze or atopy.

Assessing the efficiency of a pharmacokinetic-based algorithm for target-controlled infusion of ketamine in ponies

The objective of this study was to assess a pharmacokinetic algorithm to predict ketamine plasma concentration and drive a target-controlled infusion (TCI) in ponies. Firstly, the algorithm was used to simulate the course of ketamine enantiomers plasma concentrations after the administration of an intravenous bolus in six ponies based on individual pharmacokinetic parameters obtained from a previous experiment. Using the same pharmacokinetic parameters, a TCI of S-ketamine was then performed over 120 min to maintain a concentration of 1 microg/mL in plasma. The actual plasma concentrations of S-ketamine were measured from arterial samples using capillary electrophoresis. The performance of the simulation for the administration of a single bolus was very good. During the TCI, the S-ketamine plasma concentrations were maintained within the limit of acceptance (wobble and divergence <20%) at a median of 79% (IQR, 71-90) of the peak concentration reached after the initial bolus. However, in three ponies the steady concentrations were significantly higher than targeted. It is hypothesized that an inaccurate estimation of the volume of the central compartment is partly responsible for that difference. The algorithm allowed good predictions for the single bolus administration and an appropriate maintenance of constant plasma concentrations.

Prognostic importance of anaemia in patients with acute pulmonary embolism

Although associated with adverse outcomes in other cardiopulmonary diseases, limited evidence exists on the prognostic value of anaemia in patients with acute pulmonary embolism (PE). We sought to examine the associations between anaemia and mortality and length of hospital stay in patients with PE. We evaluated 14,276 patients with a primary diagnosis of PE from 186 hospitals in Pennsylvania, USA. We used random-intercept logistic regression to assess the association between anaemia at the time of presentation and 30-day mortality and discrete-time logistic hazard models to assess the association between anaemia and time to hospital discharge, adjusting for patient (age, gender, race, insurance type, clinical and laboratory variables) and hospital (region, size, teaching status) factors. Anaemia was present in 38.7% of patients at admission. Patients with anaemia had a higher 30-day mortality (13.7% vs. 6.3%; p <0.001) and a longer length of stay (geometric mean, 6.9 vs. 6.6 days; p <0.001) compared to patients without anaemia. In multivariable analyses, anaemia remained associated with an increased odds of death (OR 1.82, 95% CI: 1.60-2.06) and a decreased odds of discharge (OR 0.85, 95% CI: 0.82-0.89). Anaemia is very common in patients presenting with PE and is independently associated with an increased short-term mortality and length of stay.

Disabling c-Myc in childhood medulloblastoma and atypical teratoid/rhabdoid tumor cells by the potent G-quadruplex interactive agent S2T1-6OTD

We investigated here the effects of S2T1-6OTD, a novel telomestatin derivative that is synthesized to target G-quadruplex-forming DNA sequences, on a representative panel of human medulloblastoma (MB) and atypical teratoid/rhabdoid (AT/RT) childhood brain cancer cell lines. S2T1-6OTD proved to be a potent c-Myc inhibitor through its high-affinity physical interaction with the G-quadruplex structure in the c-Myc promoter. Treatment with S2T1-6OTD reduced the mRNA and protein expressions of c-Myc and hTERT, which is transcriptionally regulated by c-Myc, and decreased the activities of both genes. In remarkable contrast to control cells, short-term (72-hour) treatment with S2T1-6OTD resulted in a dose- and time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC(50), 0.25-0.39 micromol/L). Under conditions where inhibition of both proliferation and c-Myc activity was observed, S2T1-6OTD treatment decreased the protein expression of the cell cycle activator cyclin-dependent kinase 2 and induced cell cycle arrest. Long-term treatment (5 weeks) with nontoxic concentrations of S2T1-6OTD resulted in a time-dependent (mainly c-Myc-dependent) telomere shortening. This was accompanied by cell growth arrest starting on day 28 followed by cell senescence and induction of apoptosis on day 35 in all of the five cell lines investigated. On in vivo animal testing, S2T1-6OTD may well represent a novel therapeutic strategy for childhood brain tumors.

Preference for formulations containing calcium and vitamin D(3) in childhood: a randomized-sequence, open-label trial

Children who experience adverse reactions to cow's milk or who have diseases predisposing them to low bone mass are often prescribed a supplementation of calcium and vitamin D(3), but adherence can be poor. Age-specific preferences for different formulations may exist and at least partially explain poor compliance.

Vasculitides associated with IgG antineutrophil cytoplasmic autoantibodies in childhood

Immunoglobulin (Ig)G antineutrophil cytoplasmic autoantibodies are causally associated with necrotizing vasculitides that are characterized immunopathologically by little or no deposition of immunoreactants, such as Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss angiitis, "renal-limited" vasculitis and a number of drug-induced vasculitides. Clinical routine testing targets the antigens myeloperoxidase and proteinase 3. However, in all of the conditions mentioned, the renal histopathologic findings are indistinguishable. Churg-Strauss angiitis (characterized by necrotizing vasculitis, granulomatous inflammation and tissue eosinophilia), Wegener granulomatosis (characterized by necrotizing vasculitis and granulomatous inflammation) and microscopic polyangiitis (characterized by necrotizing vasculitis) often present with fever, weight loss and a multisystem involvement (ear, nose, throat, lung, eyes, peripheral nerve and heart). Fifty years ago these conditions were very often fatal within 6 months of diagnosis. The introduction of corticosteroids and cyclophosphamide has resulted in a dramatic clinical benefit. Patients who develop treatment-related morbidity can be switched from cyclophosphamide to azathioprine after achieving remission. In patients with less severe disease, methotrexate achieves remission with a success rate similar to that of cyclophosphamide. Plasma exchange, in association with immunosuppression, is likely to be a beneficial therapy for patients with severe kidney disease or pulmonary hemorrhage.

Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumor in children. It is known that overexpression and/or amplification of the MYC oncogene is associated with poor clinical outcome, but the molecular mechanisms and the MYC downstream effectors in MB remain still elusive. Besides contributing to elucidate how progression of MB takes place, most importantly, the identification of novel MYC-target genes will suggest novel candidates for targeted therapy in MB. A group of 209 MYC-responsive genes was obtained from a complementary DNA microarray analysis of a MB-derived cell line, following MYC overexpression and silencing. Among the MYC-responsive genes, we identified the members of the bone morphogenetic protein (BMP) signaling pathway, which have a crucial role during the development of the cerebellum. In particular, the gene BMP7 was identified as a direct target of MYC. A positive correlation between MYC and BMP7 expression was documented by analyzing two distinct sets of primary MB samples. Functional studies in vitro using a small-molecule inhibitor of the BMP/SMAD signaling pathway reproduced the effect of the small interfering RNA-mediated silencing of BMP7. Both approaches led to a block of proliferation in a panel of MB cells and to inhibition of SMAD phosphorylation. Altogether, our findings indicate that high MYC levels drive BMP7 overexpression, promoting cell survival in MB cells. This observation suggests the potential relevance of targeting the BMP/SMAD pathway as a novel therapeutic approach for the treatment of childhood MB.