Exploring a causal model in observational cohort data: The role of parents and peers in shaping substance use trajectories.

AIMS: To explore the process of applying counterfactual thinking in examining causal determinants of substance use trajectories in observational cohort data. Specifically, we examine the extent to which quality of the parent-adolescent relationship and affiliations with deviant peers are causally related to trajectories of alcohol, tobacco, and cannabis use across adolescence and into young adulthood. METHODS: Data were drawn from the Australian Temperament Project, a population-based cohort study that has followed a sample of young Australians from infancy to adulthood since 1983. Parent-adolescent relationship quality and deviant peer affiliations were assessed at age 13-14 years. Latent curve models were fitted for past month alcohol, tobacco, and cannabis use (n = 1590) from age 15-16 to 27-28 years (5 waves). Confounding factors were selected in line with the counterfactual framework. RESULTS: Following confounder adjustment, higher quality parent-adolescent relationships were associated with lower baseline cannabis use, but not alcohol or tobacco use trajectories. In contrast, affiliations with deviant peers were associated with higher baseline binge drinking, tobacco, and cannabis use, and an earlier peak in the cannabis use trajectory. CONCLUSIONS: Despite careful application of the counterfactual framework, interpretation of associations as causal is not without limitations. Nevertheless, findings suggested causal effects of both parent-adolescent relationships and deviant peer affiliations on the trajectory of substance use. Causal effects were more pervasive (i.e., more substance types) and protracted for deviant peer affiliations. The exploration of causal relationships in observational cohort data is encouraged, when relevant limitations are transparently acknowledged.

Strong inflammatory response and Th1-polarization profile in children with acute lymphoblastic leukemia without apparent infection.

Children with acute lymphoblastic leukemia (ALL) often present fever. Febrile states are usually associated with infectious processes that generate an inflammatory response involving various molecules, including cytokines. However, an inflammatory response may also occur in the absence of infection. We hypothesized that the levels of inflammatory cytokines are increased in children with ALL without apparent infection. The serum levels of 13 cytokines in 99 patients with ALL and 48 non-oncological patients without apparent infection were measured using multiplex analyte profiling technology (Luminex®). The concentration of circulating pro-inflammatory cytokines associated with fever was similar between patients with ALL and fever at diagnosis and those without fever. The levels of tumor necrosis factor α, interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and IL-10 were higher in patients with ALL vs. the control group (P<0.05). Moreover, the levels of the T helper 1 (interferon­Î³ and IL-12) cytokines were higher in patients with ALL vs. the control group. Transforming growth factor ß was lower in patients with ALL vs. the control group (P<0.05). The levels of IL-1ß, IL-2, IL-4, IL-13, and IL-17 were similar in the two groups. Our results indicate that the circulating levels of seven of the important studied cytokines are elevated in patients with newly diagnosed ALL without apparent infection, reflecting a strong and deregulated inflammatory state in this disease, with a Th1-polarization profile.

Monte-Carlo simulations of clinically realistic respiratory gated (18)F-FDG PET: application to lesion detectability and volume measurements.

In PET/CT thoracic imaging, respiratory motion reduces image quality. A solution consists in performing respiratory gated PET acquisitions. The aim of this study was to generate clinically realistic Monte-Carlo respiratory PET data, obtained using the 4D-NCAT numerical phantom and the GATE simulation tool, to assess the impact of respiratory motion and respiratory-motion compensation in PET on lesion detection and volume measurement. To obtain reconstructed images as close as possible to those obtained in clinical conditions, a particular attention was paid to apply to the simulated data the same correction and reconstruction processes as those applied to real clinical data. The simulations required 140,000h (CPU) generating 1.5 To of data (98 respiratory gated and 49 ungated scans). Calibration phantom and patient reconstructed images from the simulated data were visually and quantitatively very similar to those obtained in clinical studies. The lesion detectability was higher when the better trade-off between lesion movement limitation (compared to ungated acquisitions) and image statistic preservation is considered (respiratory cycle sampling in 3 frames). We then compared the lesion volumes measured on conventional PET acquisitions versus respiratory gated acquisitions, using an automatic segmentation method and a 40%-threshold approach. A time consuming initial manual exclusion of noisy structures needed with the 40%-threshold was not necessary when the automatic method was used. The lesion detectability along with the accuracy of tumor volume estimates was largely improved with the gated compared to ungated PET images.

Allergy and acute leukaemia in children with Down syndrome: a population study. Report from the Mexican inter-institutional group for the identification of the causes of childhood leukaemia.

BACKGROUND: Allergies have been described as protective factors against the development of childhood acute leukaemia (AL). Our objective was to investigate the associations between allergy history and the development of AL and acute lymphoblastic leukaemia (ALL) in children with Down syndrome (DS). METHODS: A case-control study was performed in Mexico City. The cases (n=97) were diagnosed at nine public hospitals, and the controls (n=222) were recruited at institutions for children with DS. Odds ratios (OR) were calculated. RESULTS: Asthma was positively associated with AL development (OR=4.18; 95% confidence interval (CI): 1.47-11.87), whereas skin allergies were negatively associated (OR=0.42; 95% CI: 0.20-0.91). CONCLUSION: Our findings suggest that allergies and AL in children with DS share biological and immune mechanisms. To our knowledge, this is the first study reporting associations between allergies and AL in children with DS.

Alelos HLA na contratura de Dupuytren

A Contratura de Dupuytren (DC) é uma doença fibroproliferativa caracterizada pela formação de nódulos e cordões fibrosos que se retraem longitudinalmente em direção aos dedos causando à contratura digital que determina o aspecto de mão em garra, sendo por isso citada como diagnóstico diferencial da hanseníase. Sua incidência é maior na raça branca de origem européia, principalmente em adultos do sexo masculino com idade superior a 50 anos. Embora existam evidências do envolvimento genético no aparecimento da DC, até o momento nenhum gene foi associado como fator de risco para a doença.

[Interest of FDG-PET for lung cancer radiotherapy]. / Intérêt de la TEP au FDG pour la radiothérapie des cancers bronchiques.

The recent advances in medical imaging have profoundly altered the radiotherapy of non-small cell lung cancers (NSCLC). A meta-analysis has confirmed the superiority of FDG PET-CT over CT for initial staging. FDG PET-CT improves the reproducibility of target volume delineation, especially close to the mediastinum or in the presence of atelectasia. Although not formally validated by a randomized trial, the reduction of the mediastinal target volume, by restricting the irradiation to FDG-avid nodes, is widely accepted. The optimal method of delineation still remains to be defined. The role of FDG PET-CT in monitoring tumor response during radiotherapy is under investigation, potentially opening the way to adapting the treatment modalities to tumor radiation sensitivity. Other tracers, such as F-miso (hypoxia), are also under clinical investigation. To avoid excessive delays, the integration of PET-CT in routine practice requires quick access to the imaging equipment, technical support (fusion and image processing) and multidisciplinary delineation of target volumes.

Influence of PET/CT on radiologists and contrast-enhanced CT on nuclear medicine physicians in patients with lymphoma.

AIM: We assessed in this study the influence of contrast-enhanced CT (ceCT) on PET/CT interpretation and PET/CT on ceCT interpretation in patients with lymphoma, before and after chemotherapy. METHODS: Fifty patients with Hodgkin disease (N.=17) or non-Hodgkin lymphomas (N.=33) were assessed before and after chemotherapy. PET/CT were performed 60 minutes after injection of FDG. Iopamidol was then injected and followed, 50 seconds later, by another CT. PET images were successively reconstructed using non-enhanced CT (PET-) and ceCT (PET+). Four nuclear physicians rated PET- and PET+ in random order. Three radiologists initially rated ceCT alone and then ceCT along with PET+. RESULTS: Before chemotherapy, global agreement (GA) was 99% (k=0.96) when PET- was compared to PET+. Nine (5%) lesions were discordant, 5 according to PET- and 4 to PET+. After chemotherapy, GA was 99% (k=0.91). Eight (15%) lesions were discordant, 3 according to PET- and 5 to PET+. Before chemotherapy, GA was 97% (k=0.91) when ceCT was compared to ceCT with PET+. Twenty-one (12%) lesions were discordant, 16 when ceCT were analyzed alone and 5 when ceCT was analyzed with PET+. After chemotherapy, GA was 95% (k=0.76). All 30 (35%) discordant lesions were positive according to ceCT alone. A significant difference between the 2 procedures was found in the pelvis and in the groin (P<0.05). CONCLUSION: PET+ did not differ from PET-, before and after chemotherapy. Fewer abnormalities were observed, when ceCT was analyzed with PET+, particularly after chemotherapy, due to residual masses that are better analyzed with functional imaging.

Long-term follow-up of patients with papillary and follicular thyroid cancer: a prospective study on 715 patients.

PURPOSE: This prospective study evaluated the recurrence rate in 715 patients with differentiated thyroid cancer who had no evidence of persistent disease after total thyroidectomy and lymph node dissection in 94% of them followed up by radioiodine ablation (30-100 mCi) and assessed the predictive value of the initial thyroglobulin (Tg) levels for detecting recurrence, both during levothyroxine (LT4) treatment and after TSH stimulation. PATIENTS AND METHODS: Patients had Tg determinations performed at 3 months on LT4 treatment (Tg1) and at 9-12 months after stimulation by either thyroid hormone withdrawal or recombinant human TSH (Tg2); the Access kit was used (functional sensitivity of 0.11 ng/ml); they had undetectable anti-Tg antibodies. Patients were followed up annually. Predictive values were calculated by comparing Tg levels (Tg1 and Tg2) and the outcome in terms of recurrence. RESULTS: During the median follow-up of 6.2 yr, 32 patients had a recurrence. Assuming a cutoff level for Tg1 at 0.27 ng/ml, Tg1 sensitivity and specificity reached 72 and 86%, respectively, whereas predictive positive and negative values were 20 and 99%, respectively. With a cutoff level for Tg2 at 1.4 ng/ml, sensitivity and specificity reached 78 and 90%, respectively, whereas positive and negative predictive values were 26 and 99%, respectively. CONCLUSION: This large prospective cohort of patients presented a low rate of recurrence. Initial Tg measurements allow to predict long-term recurrence with an excellent specificity. Stimulated Tg determination presented a slightly higher sensitivity than Tg determination on LT4. TSH stimulation may be avoided when Tg measured 3 months after ablation is less than 0.27 ng/ml during LT4 treatment.

[Prognostic value of pretherapeutic 18F-FDG PET/CT in cancer of the uterine cervix: a retrospective study of 53 patients]. / Intérêt pronostique de la TEP-TDM au 18F-FDG dans le bilan initial du cancer du col de l'utérus: étude rétrospective de 53 cas.

OBJECTIVES: Assessment of prognostic value of pretherapeutic (18)F-FDG PET/CT (PET). PATIENTS AND METHODS: Retrospective study of 53 patients with invasive uterine cervix carcinoma. Each patient has been evaluated with pretherapeutic whole-body FDG PET/CT and pelvic MRI. Minimal follow-up lasted for 1 year. On PET/CT, we have visually analyzed metabolism of primary tumor, pelvic and para-aortic lymph nodes in comparison with surrounding structures. We have compared prognostic factors as pretherapeutic haemoglobin rate, FIGO staging, MRI and PET/CT data using Mann-Whitney univariate analysis and Cox multivariate analysis. RESULTS: Para-aortic lymph node abnormal uptake on PET/CT was the only independent predictor of progression-free survival. Pelvic lymph node involvement on PET/CT was the only independent predictor of overall survival. MRI did not provide any additional information. DISCUSSION AND CONCLUSION: Lymph node involvement visually assessed by (18)F-FDG PET/CT was the most significant prognostic factor for overall and progression-free survival.

Development of a generic thresholding algorithm for the delineation of 18FDG-PET-positive tissue: application to the comparison of three thresholding models.

An iterative generic algorithm has been developed to compare three thresholding models used to delineate gross tumour volume on (18)F-FDG PET images. 3D volume was extracted and characteristic parameters were measured. Three fitting models using different parameters were studied: model 1 (volume, contrast), model 2 (contrast) and model 3 (SUV). The calibration was performed using a cylindrical phantom filled with hot spheres. To validate the models, two other phantoms were used. The calibration procedure showed a better fitting model for model 1 (R(2) from 0.94 to 1.00) than for model 3 (0.95) and model 2 (0.69). The validation study shows that model 3 yielded large volume measurement errors. Models 1 and 2 gave close results with no significant differences. Model 2 was preferred because it presents less error dispersion and needs fewer characteristic parameters, making it easier to implement. Our results show the importance of developing a generic algorithm to compare the performances of fitting models objectively and to validate results on other phantoms than the ones used during the calibration process to avoid methodological biases.

Breastfeeding and early infection in the aetiology of childhood leukaemia in Down syndrome.

BACKGROUND: For a child to develop acute leukaemia (AL), environmental exposure may not be sufficient: interaction with a susceptibility factor to the disease, such as Down syndrome (DS), may also be necessary. We assessed whether breastfeeding and early infection were associated with the risk of developing AL in children with DS. METHODS: Children with DS in Mexico City, and either with or without AL, were the cases (N=57) and controls (N=218), respectively. Population was divided in children with AL and with acute lymphoblastic leukaemia (ALL) and also in children < or = 6 and >6 years old. RESULTS: Breastfeeding and early infections showed moderate (but not significant) association for AL, whereas hospitalisation by infection during the first year of life increased the risk: odds ratios (confidence interval 95%) were 0.84 (0.43-1.61), 1.70 (0.82-3.52); and 3.57 (1.59-8.05), respectively. A similar result was obtained when only ALL was analysed. CONCLUSION: We found that breastfeeding was a protective factor for developing AL and ALL, and during the first year of life, infections requiring hospitalisation were related to a risk for developing the disease in those children with DS >6 years of age. These data do not support the Greaves's hypothesis of early infection being protective for developing ALL.

A cylinder-shaped double ribbon structure formed by an amyloid hairpin peptide derived from the beta-sheet of murine PrP: an X-ray and molecular dynamics simulation study.

A structural model of the murine PrP small beta-sheet was obtained by synthesizing the RGYMLGSADPNGNQVYYRG peptide comprising the two beta-strands 127-133 and 159-164 linked by a four-residue sequence of high turn propensity. The DPNG turn sequence is a "short circuit" replacing the original protein sequence between the two strands. This 19-residue peptide spontaneously forms very long single fibrils as observed by electron microscopy. The X-ray diffraction patterns of a partially oriented sample reveals an average arrangement of the hairpin peptides into a structure which can be geometrically approximated by an empty-core cylinder. The hairpins are oriented perpendicular to the cylinder axis and a 130 A helix period is observed. Based on X-ray diffraction constraints and on more indirect general protein structure considerations, a precise and consistent fibril model was built. The structure consists of two beta-sheet ribbons wound around a cylinder and assembled into a single fibril with a hairpin orientation perpendicular to the fibril axis. Subsequent implicit and explicit solvent molecular dynamics simulations provided the final structure at atomic resolution and further insights into the stabilizing interactions. Particularly important are the zipper-like network of polar interactions between the edges of the two ribbons, including the partially buried water molecules. The hydrophobic core is not optimally compact explaining the low density of this region seen by X-ray diffraction. The present findings provide also a simple model for further investigating the sequence-stability relationship using a mutational approach with a quasi-independent consideration of the polar and apolar interactions.

A multicentre report from the Mexican Retinoblastoma Group.

BACKGROUND: Retinoblastoma (RB) is a relatively uncommon tumour in childhood. The incidence of retinoblastoma in Mexico is probably higher than the incidence reported worldwide, however there is not enough information about the characteristics of this illness in Mexico. This report aims to present the results of a multicentre clinical survey of RB in Mexico. METHODS: A retrospective study was carried out on all RB cases treated in 16 institutions during the last six years. The variables analysed were age at diagnosis, sex, affected eyes, treatment modalities, and pathological staging. Overall survival was obtained. RESULTS: The authors analysed 500 cases; age range was 0-182 months. There were 364 unilateral cases (72.8%). Enucleation was performed in 84.9% of the patients. The St Jude's staging was: 7.4% stage I, 52.8% stage II, 18.0% stage III, 11.4% stage IV, 7.2% not evaluated, and 3.2% missing data. Chemotherapy was used in 74.4% of the patients. Disease free survival was 89% at 73 months follow up. CONCLUSIONS: The paper presents a great number of cases and pioneers multicentre studies in paediatric ophthalmology and oncology in this country. Given the great number of patients in advanced stages and the variability on treatment schemes, it is evident that it is mandatory to work in a cooperative group and develop a national early detection programme as well as a treatment protocol which include all specialists involved in the care of patients with RB.

Pediatric oncology at Hospital Infantil de Mexico: fifty-five years of accomplishment.

The Department of Oncology at Hospital Infantil de México Federico Gómez (HIMFG) was the first unit in our country, and one of the first in Latin America, to specialize in the management of children with cancer. The HIMFG is part of the National Institutes of Health of Mexico, and is a reference hospital with research, educative, and tertiary care medical function. To date, the HIMFG and the Instituto Nacional de Pediatria are the principal medical centers in which children with cancer receive comprehensive care.

Concerted influence of key amino acids on the lipid binding properties of a single-spanning membrane protein: NMR and mutational analysis.

Finding the combinations of key amino acids involved in the interaction network underlying the interfacial features of membrane proteins would contribute to a better understanding of their sequence-structure-function relationships and the role of anionic phospholipids. To further address these questions, we performed mutational analysis associated with NMR experiments on synthetic fragments of the single-spanning membrane protein PMP1 that exhibit binding specificity for phosphatidylserine (PS). The aromatic and glutamine residues of the helix part of the PMP1 cytoplasmic domain were mutated. (1)H NMR experiments were carried out using perdeuterated DPC micelles as a membrane-like environment, in the absence and presence of small amounts of either POPC or POPS lipids. From intermolecular NOEs and chemical shift data, specific and nonspecific aspects of peptide-phospholipid interactions were distinguished. The major finding of our study is to reveal the concerted influence of a tryptophan and a glutamine residue on the interfacial conformation and lipid binding specificity of the PMP1 cytoplasmic domain.

PMP1 18-38, a yeast plasma membrane protein fragment, binds phosphatidylserine from bilayer mixtures with phosphatidylcholine: a (2)H-NMR study.

PMP1 is a 38-residue plasma membrane protein of the yeast Saccharomyces cerevisiae that regulates the activity of the H(+)-ATPase. The cytoplasmic domain conformation results in a specific interfacial distribution of five basic side chains, thought to strongly interact with anionic phospholipids. We have used the PMP1 18-38 fragment to carry out a deuterium nuclear magnetic resonance ((2)H-NMR) study for investigating the interactions between the PMP1 cytoplasmic domain and phosphatidylserines. For this purpose, mixed bilayers of 1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphoserine (POPS) were used as model membranes (POPC/POPS 5:1, m/m). Spectra of headgroup- and chain-deuterated POPC and POPS phospholipids, POPC-d4, POPC-d31, POPS-d3, and POPS-d31, were recorded at different temperatures and for various concentrations of the PMP1 fragment. Data obtained from POPS deuterons revealed the formation of specific peptide-POPS complexes giving rise to a slow exchange between free and bound PS lipids, scarcely observed in solid-state NMR studies of lipid-peptide/protein interactions. The stoichiometry of the complex (8 POPS per peptide) was determined and its significance is discussed. The data obtained with headgroup-deuterated POPC were rationalized with a model that integrates the electrostatic perturbation induced by the cationic peptide on the negatively charged membrane interface, and a "spacer" effect due to the intercalation of POPS/PMP1f complexes between choline headgroups.

Diagnosis of bone marrow metastases in children with solid tumors and lymphomas. Aspiration, or unilateral or bilateral biopsy?

BACKGROUND: Malignancies are among the most common causes of death in children. The present study was undertaken to evaluate and compare bone marrow aspiration and unilateral biopsy to detect bone marrow metastases in pediatric patients, using bilateral biopsy as the gold standard. METHODS: During a 6-month period, 63 consecutive newly diagnosed children with confirmed malignant diseases other than leukemia were evaluated for bone marrow metastases or infiltration. Biopsies were obtained from both right and left posterior iliac crests whereas aspiration was performed only at the right crest. Interpretation to the right-side biopsy was considered as the unilateral biopsy result, whereas the bilateral biopsy result was as follows: positively was accepted if one or both of the two-side samples were qualified as positive, while a negative result was considered only if both sides were negative. The bilateral biopsy was considered the gold standard, and sensitivity, specificity, positive and negative predictive value, and false positive and negative rates were computed for the unilateral biopsy and aspiration procedure. RESULTS: We identified bone marrow metastases in 11 (17.5%) patients. The sensitivity was the only significant difference (p <0.05) observed between unilateral biopsy and aspiration. Finally, of the 63 patients, unilateral biopsy was reported as inadequate in one patient (1.6%), while aspiration was inadequate in two (3.2%). CONCLUSION: Unilateral biopsy was better than bone marrow aspiration. However, because bilateral biopsy is the gold standard, we recommend using this and bone marrow aspiration simultaneously to evaluate a pediatric patient with any malignancy potentially infiltrating bone marrow.

Dodecylphosphocholine micelles as a membrane-like environment: new results from NMR relaxation and paramagnetic relaxation enhancement analysis.

To further examine to what extent a dodecyl-phosphocholine (DPC) micelle mimics a phosphatidylcholine bilayer environment, we performed 13C, 2H, and 31P NMR relaxation measurements. Our data show that the dynamic behavior of DPC phosphocholine groups at low temperature (12 degrees C) corresponds to that of a phosphatidylcholine interface at high temperature (51 degrees C). In the presence of helical peptides, a PMP1 fragment, or an annexin fragment, the DPC local dynamics are not affected whereas the DPC aggregation number is increased to match an appropriate area/volume ratio for accommodating the bound peptides. We also show that quantitative measurements of paramagnetic relaxation enhancements induced by small amounts of spin-labeled phospholipids on peptide proton signals provide a meaningful insight on the location of both PMP1 and annexin fragments in DPC micelles. The paramagnetic contributions to the relaxation were extracted from intra-residue cross-peaks of NOESY spectra for both peptides. The location of each peptide in the micelles was found consistent with the corresponding relaxation data. As illustrated by the study of the PMP1 fragment, paramagnetic relaxation data also allow us to supply the missing medium-range NOEs and therefore to complete a standard conformational analysis of peptides in micelles.