Negative life events predict performance on an executive function task in young adults with developmental disabilities.

BACKGROUND: Recent research with typically developing children indicates that chronic stress can be detrimental to the development of executive function. This study extends this work to individuals with developmental disabilities and examines the longitudinal relationship between an indicator of chronic stress, negative life events, and performance on a task of executive function within a group of 30 individuals with early identified developmental disabilities. METHODS: Multilevel modelling was used to analyse the relationship between cumulative negative life events and response time on a Flanker task. RESULTS: As hypothesized, individuals who had experienced more cumulative negative life events in their families demonstrated longer response time, an indicator of less efficient executive function. CONCLUSIONS: The association between cumulative negative life events and executive function for children with developmental disabilities suggests the prominent role of the environment for development in this domain. These findings also suggest the importance of providing services, resources, and interventions that will help families adaptively cope with stressful circumstances.

'Will I be able to have a baby?' Results from online focus group discussions with childhood cancer survivors in Sweden.

STUDY QUESTION: What do adolescent and young adult survivors of childhood cancer think about the risk of being infertile? SUMMARY ANSWER: The potential infertility, as well as the experience of having had cancer, affects well-being, intimate relationships and the desire to have children in the future. WHAT IS KNOWN ALREADY: Many childhood cancer survivors want to have children and worry about possible infertility. STUDY DESIGN, SIZE, DURATION: For this qualitative study with a cross-sectional design, data were collected through 39 online focus group discussions during 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cancer survivors previously treated for selected diagnoses were identified from The Swedish Childhood Cancer Register (16-24 years old at inclusion, ≥5 years after diagnosis) and approached regarding study participation. Online focus group discussions of mixed sex (n = 133) were performed on a chat platform in real time. Texts from the group discussions were analysed using qualitative content analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The analysis resulted in the main category Is it possible to have a baby? including five generic categories: Risk of infertility affects well-being, Dealing with possible infertility, Disclosure of possible infertility is a challenge, Issues related to heredity and Parenthood may be affected. The risk of infertility was described as having a negative impact on well-being and intimate relationships. Furthermore, the participants described hesitation about becoming a parent due to perceived or anticipated physical and psychological consequences of having had cancer. LIMITATIONS, REASONS FOR CAUTION: Given the sensitive topic of the study, the response rate (36%) is considered acceptable. The sample included participants who varied with regard to received fertility-related information, current fertility status and concerns related to the risk of being infertile. WIDER IMPLICATIONS OF THE FINDINGS: The results may be transferred to similar contexts with other groups of patients of childbearing age and a risk of impaired fertility due to disease. The findings imply that achieving parenthood, whether or not with biological children, is an area that needs to be addressed by health care services. STUDY FUNDING/COMPETING INTERESTS: The study was financially supported by The Cancer Research Foundations of Radiumhemmet, The Swedish Childhood Cancer Foundation and the Doctoral School in Health Care Science, Karolinska Institutet. The authors report no conflicts of interest.

Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).

Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. By some estimates, the disorder may account for upwards of 10% of hereditary deafness. Previous genetic linkage studies localized the gene to a broad interval on human chromosome 7q22-31.1. Using a positional cloning strategy, we have identified the gene (PDS) mutated in Pendred syndrome and found three apparently deleterious mutations, each segregating with the disease in the respective families in which they occur. PDS produces a transcript of approximately 5 kb that was found to be expressed at significant levels only in the thyroid. The predicted protein, pendrin, is closely related to a number of known sulphate transporters. These studies provide compelling evidence that defects in pendrin cause Pendred syndrome thereby launching a new area of investigation into thyroid physiology, the pathogenesis of congenital deafness and the role of altered sulphate transport in human disease.

Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program.

PURPOSE: The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies. PATIENTS AND METHODS: This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses. RESULTS: From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient. CONCLUSION: The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.

T-cell acute lymphoblastic leukemia in patients 1-45 years treated with the pediatric NOPHO ALL2008 protocol.

The NOPHO ALL2008 is a population-based study using an unmodified pediatric protocol in patients 1-45 years of age with acute lymphoblastic leukemia. Patients with T-ALL were given a traditional pediatric scheme if fast responding (minimal residual disease (MRD) < 0.1% day 29), or intensive block-based chemotherapy if slow responding (MRD > 0.1% day 29). Both treatment arms included pediatric doses of high-dose methotrexate and asparaginase. If MRD ≥ 5% on day 29 or ≥0.1% after consolidation, patients were assigned to allogeneic hematopoietic stem cell transplantation. The 5-year overall survival of the 278 T-ALL patients was 0.75 (95% CI 0.69-0.81), being 0.82 (0.74-0.88) for patients 1.0-9.9 years, 0.76 (0.66-0.86) for those 10.0-17.9 years, and 0.65 (0.55-0.75) for the older patients. The risk of death in first remission was significantly higher in adults (12%) compared with the 1-9 years group (4%). The MRD responses in the three age groups were similar, and only a nonsignificant increase in relapse risk was found in adults. In conclusion, an unmodified pediatric protocol in patients 1-45 years is effective in all age groups. The traditional pediatric treatment schedule was safe for all patients, but the intensive block therapy led to a high toxic death rate in adults.

Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia.

Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P=0.53). Event-free survival rates (pEFS5y) were 89±1% (A), 80±3% (B) and 74±4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.

Venous thrombosis in children and adolescents with Hodgkin lymphoma in Sweden.

INTRODUCTION: Pediatric patients with Hodgkin lymphoma (HL) have several risk factors for venous thromboembolism (VTE). Although these patients are occasionally treated with thromboprophylaxis, no guidelines are implemented in Sweden. Scarce data from adult patients indicate an increased risk of VTE, but pediatric data is largely missing. Given the favorable overall survival of HL, there should reasonably be more focus on preventing complications. MATERIALS AND METHODS: We conducted a retrospective cohort study, including all patients registered in the Childhood Cancer Registry under the age of 18years diagnosed with HL between January 2005 and December 2015 in Sweden. RESULTS: Data was retrieved from the medical records of all 163 patients (100%) at six Swedish pediatric cancer centers. The incidence of VTE was 7.7% (symptomatic VTE 3.9%). The median follow-up was 3.4years (range 0.3-10.5). Only five patients (3.1%) were treated with thromboprophylaxis. All VTE events occurred in the older age category (11-17years) and all but one (92.7%) had a mediastinal mass. While the VTE did not significantly affect the treatment of HL, it caused increased morbidity and 2/12 developed a post-thrombotic syndrome. No significant risk factors for VTE were identified. CONCLUSIONS: VTE is a relatively common complication of HL and its treatment, causing increased acute and long-term morbidity. However, due to limited number of events we could not demonstrate risk-factors for VTE that would identify patients who might benefit from thromboprophylaxis.

Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol.

Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence=6.8%) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting >72 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P=0.001). Pseudocysts developed in 28%. Of the 20 re-exposed to ASP, 9 (45%) developed a second AAP. After a median follow-up of 2.3 years, 8% needed permanent insulin therapy, and 7% had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P=5.8 × 10-7; odds ratio (OR)=6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P=0.015) and had lower risk of AAP-related complications (15% vs 43%; P=0.13) compared with cases without this variant. Among 45 cases and 517 controls <10 years, the strongest associations with AAP were found for RGS6 variant rs17179470 (P=9.8 × 10-9; OR=7.3). Rs281366 is located in the ULK2 gene involved in autophagy, and RGS6 regulates G-protein signaling regulating cell dynamics. More than 50% of AAP cases <10 years carried one or both risk alleles.

Autologous stem cell transplantation followed by consolidation chemotherapy for patients with multiple myeloma.

Although high-dose therapy and autologous stem cell transplant (ASCT) is superior to conventional chemotherapy for treatment of myeloma, most patients relapse and the time to relapse depends upon the initial prognostic factors. The administration of non-cross-resistant chemotherapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after single autologous peripheral blood stem cell transplant (auto-PBSCT) in 103 mostly newly diagnosed myeloma patients (67 patients were < or =6 months from the initial treatment). Patients received conditioning with BCNU, melphalan+/-gemcitabine and auto-PBSCT followed by two cycles of the DCEP+/-G regimen (dexamethasone, cyclophosphamide, etoposide, cisplatin+/-gemcitabine) at 3 and 9 months post-transplant and alternating with two cycles of DPP regimen (dexamethasone, cisplatin, paclitaxel) at 6 and 12 months post-transplant. With a median follow-up of 61.2 months, the median event-free survival (EFS) and overall survival (OS) are 26 and 54.1 months, respectively. The 5-year EFS and OS are 23.1 and 42.5%, respectively. Overall, 51 (49.5%) patients finished all CC, suggesting that a major limitation of this approach is an inability to deliver all planned treatments. In order to improve results following autotransplantation, novel agents or immunologic approaches should be studied in the post-transplant setting.

Acute lymphoblastic leukemia in adolescents between 10 and 19 years of age in Denmark--secondary publication.

INTRODUCTION: Data seem to indicate that young adults with acute lymphoblastic leukemia (ALL) have a better survival when treated with pediatric protocols compared with adult ALL protocols. The purpose of the study was to report the clinical characteristics and outcome of all children and young adults 10-19 years of age diagnosed with ALL in Denmark between 1992 and 2001. MATERIAL: The study includes 99 patients 10-19 years of age with ALL in Denmark during a ten year period found in the complete NOPHO (Nordic Society of Pediatric Hematology and Oncology) registry and through the Danish Cancer Registry and local pathology databases. Data were retrieved by reviewing medical charts of the patients. A total of 61 children (10-14 years) treated on pediatric protocols and 38 young adults (15-19 years) were diagnosed with ALL. Data were reported as of January 1st 2005. RESULTS: There were no difference with respect to the distribution of T-ALL, CNS-leukemia, total white blood count and high risk chromosomal abnormalities between the two groups. There was a statistical significant lower event free survival (p<0.01) and lower overall survival (p<0.01) in young adults compared with 10-14 year-old children (0.38 vs 0.60 and 0.47 vs 0.67). There were more transplant-related deaths in the young adults. Higher treatment intensity in children may be an additional explanatory factor. Children received more prednisone, vincristine and high-dose methotrexate than young adults. CONCLUSION: Young adult patients with ALL might benefit from therapy with pediatric NOPHO ALL protocols.

Cord blood telomere length in Latino infants: relation with maternal education and infant sex.

OBJECTIVE: Telomere length (TL) has important consequences for early disease and lifelong health. However, few studies have examined determinants of TL at birth. STUDY DESIGN: Here we test associations between cord blood TL and parental and birth factors associated with exposure to stress and indicative of healthy intrauterine life in Latino infants. We tested associations that were significant in bivariate analysis in a multivariate regression model to identify independent predictors for shorter TL at birth. RESULT: Two novel and independent predictors emerged in our analysis of 54 infants. Female gender was associated with longer TL by ~350 base pairs (adjusted ß-coefficient for male gender=-369.57, (95% confidence interval, -718.21 to (-)20.92), P=0.02); rho=-0.26, P=0.057). Increased maternal high-school education, as indicated by a high-school diploma or additional education beyond high school, was also associated with longer TL, by ~500 base pairs (adjusted ß-coefficient for high-school diploma or greater=505.68 (95% confidence interval, 151.69 to 859.68), P<0.01); rho=0.36, P<0.01). Increasing head circumference trended towards statistical significance in association with longer TL (adjusted ß-coefficient = 7.33; 95% confidence interval -0.52 to 15.18; P=0.07). When we removed all infants who had been exposed to high oxidative stress in pregnancy including those exposed to maternal hypertension, preeclampsia, gestational diabetes, and those who were low birth weight or preterm birth (n=7), increasing birth weight percentile was associated with longer TL (adjusted ß-coefficient=8.04 (95% confidence interval 0.07 to 16.00), P=0.048). CONCLUSION: Shorter TL at birth is associated with being male, low maternal education (less than a high school degree), and a trend towards lower birth weight and head circumference. Given the critical role of long TL in predicting health and disease, these findings contribute to the growing literature attempting to understand determinants of TL.

Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study.

UNLABELLED: ESSENTIALS: Children with acute lymphoblastic leukemia (ALL) are at risk of thromboembolism (TE). This is a prospective evaluation of the incidence, risk factors and outcomes of TE in 1038 children with ALL. TE occurred in 6.1% of children, with the highest incidence (20.5%) among those aged 15-17 years. A TE-associated case fatality of 6.4% indicates that TE is a severe complication of ALL treatment. BACKGROUND: Thromboembolism (TE) is a major toxicity in children with acute lymphoblastic leukemia (ALL) and may have a negative impact on ALL treatment. OBJECTIVES: To examine the cumulative incidence, outcomes and risk factors associated with TE in children with leukemia. PATIENTS/METHODS: We prospectively evaluated TE in 1038 Nordic children and adolescents (≥ 1 and < 18 years) diagnosed with ALL during 2008-2013 and treated according to the NOPHO (Nordic Society of Pediatric Hematology and Oncology)-ALL 2008 protocol. The cohort was followed until December 2014. Cox proportional regression was used to compute hazard ratios (HRs). RESULTS: TE events (n = 63) occurred most frequently in conjunction with asparaginase (ASP) administration (52/63). The cumulative incidence of TE was 6.1% (95% confidence interval [CI], 4.8-7.7). Being aged 15-17 years was associated with an increased risk of TE (adjusted HR of 4.0; 95% CI, 2.1-7.7). We found a TE-associated 30-day case fatality of 6.4% (95% CI, 1.8-15.5) and TE-related truncation of ASP therapy in 36.2% (21/58). Major hemorrhage occurred in 3.5% (2/58) of anticoagulated patients. Minor hemorrhage was reported in two out of 58 patients. No major bleeds occurred in children who received low-molecular-weight heparin. CONCLUSIONS: Methods to identify children and adolescents who will benefit from thromboprophylaxis during ALL treatment are called for. The truncation of ASP should be avoided. The long-term survival outcomes for ALL patients with TE require close monitoring in the future.

Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence.

Little is known about the molecular background to senescence in T-lymphocytes. In fibroblast systems replicative senescence has been shown to correlate with a number of changes in the expression of the proteins normally regulating progression through the G1 phase of the cell cycle, and recently the Ink4 inhibitor p16 was implicated as a central regulator of replicative senescence in human fibroblasts. It has, however, been claimed that p16 is not expressed in T-lymphocytes. In the present study we have analysed G1 regulating proteins in ageing human T-lymphocytes. We show that PHA and IL-2 stimulated T-lymphocytes cease to proliferate after around 20 population doublings, these cells can not thereafter be restimulated to growth, and were also found to exhibit markers for senescence. We found that T-lymphocytes accumulate p16 and p15 protein during successive population doublings and display high levels of these proteins as they enter into replicative senescence. There was also an increased binding of p16 to the Cdk6 kinase in senescent cells, and a decreased Cdk6 as well as Cdk2 kinase activity. The levels of other G1 regulating proteins were also altered in the senescent cells, such as slightly elevated levels of p21/WAF1, and downregulation of Cdk2 and cyclinD3. The levels of p27/ Kip1 is down regulated in proliferating cells but rise to approximately 15% of the levels in un-stimulated quiescent cells. As a high proportion of T-cell childhood acute lymphoblastic leukaemias have deletions of both p15 and p16, our data suggest that inactivation of these genes makes it possible for leukemic cells to avoid senescence.

Prognostic importance of p15INK4B and p16INK4 gene inactivation in childhood acute lymphocytic leukemia.

PURPOSE: The present study explores the prognostic importance of p16INK4/p15INK4B gene inactivation in childhood acute lymphocytic leukemia (ALL). MATERIALS AND METHODS: Cells from 79 pediatric ALL patients were investigated for inactivation of the p15INK4B and p16INK4 genes or loss of heterozygosity (LOH) for chromosome 9p markers by use of Southern hybridization, restriction fragment length polymorphism (RFLP) analysis, microsatellite analysis as well as single-strand conformation polymorphism (SSCP) analysis, and nucleotide sequencing of the p15INK4B and p16INK4 genes. Genetic data were correlated to clinical outcome and established prognostic factors. RESULTS: Inactivation of the p15INK4B and/or p16INK4 genes by homozygous deletion or loss of one allele and mutation of the other was detected in 24 cases (30%). Another 12 patients (15%) showed loss of one allele. A statistically significant correlation was found between inactivation of the p15INK4B/p16INK4 genes and poor prognosis (P < .01). Furthermore, inactivation proved to be an independent factor that predicted relapse, ranking second to WBC count. The trend toward overrepresentation of treatment failure was strongest in the high-risk (HR) group patients with p16INK4/p15INK4B gene inactivation. Patients with deletion of genetic material on 9p21 and normal coding sequence of the remaining p16INK4 and p15INK4B genes had a similar prognosis to that of nondeleted cases. CONCLUSION: The data suggest that analysis of p15INK4B/p16INK4 genes may contribute prognostic information in pediatric ALL.

Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.

PURPOSE: The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies. PATIENTS AND METHODS: This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses. RESULTS: From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient. CONCLUSION: The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.

Interferon system defects in malignant T-cells.

Deletions of chromosome 9p21-22 occur in acute lymphocytic leukemia (ALL), melanoma and glioma. With some exceptions, these deletions include the alpha- and beta-interferon (IFN) genes. In this study, the frequency of alpha- and beta-IFN gene deletions was investigated in 17 T-cell lines, and losses of IFN genes were related to other aspects of the IFN system. Deletions of alpha-/beta-IFN genes were observed in 7/17 cell lines. In two cases the deletions were homozygous for both loci. In most cases aberrations of chromosome 9 were also apparent on cytogenetic analysis. An increased proportion (40% as compared to the expected 13%) of the remaining ten cell lines showed homozygosity for all five common polymorphic alpha-/beta-IFN markers, possibly implicating allelic deletion by loss of heterozygosity (LOH) in some of these clones. The cell lines showed a large variability in IFN production, IFN-alpha receptor number, susceptibility to IFN measured as induction of the enzyme 2',5' oligoadenylate synthetase and cell growth inhibition. No correlations between loss of IFN genes and IFN-producing capacity, or susceptibility to IFN, were found. Of the seven cell lines with a normal IFN-gene dosage and heterozygosity for the alpha- and beta-IFN genes, three had a deficiency in their IFN-producing capacity and one was also insensitive to growth inhibition by IFN. All IFN-producing cell lines predominantly produced beta-IFN.

Deletion of the Ink4-locus (the p16ink4a, p14ARF and p15ink4b genes) predicts relapse in children with ALL treated according to the Nordic protocols NOPHO-86 and NOPHO-92.

Inactivation of the Ink4 gene locus locus on 9p comprising the tumour suppressor gene p16ink4a and its neighbours p14ARF and p15ink4b is common in childhood acute lymphoblastic leukaemia (ALL), but the prognostic significance is controversial. DNA from 230 patients was retrospectively analysed by Southern blotting, single strand conformation polymorphism (SSCP) and sequencing techniques. The results were correlated with clinical characteristics and outcome. One hundred and ninety-four fully analysed patients, similarly treated using the Nordic NOPHO-86 or the current NOPHO-92 protocols, were included in the outcome analysis. Deletions approached a minimally deleted region between the p16ink4a and p15ink4b genes, making the p14ARF gene the most commonly deleted coding sequence. Bi-allelic deletion was associated with high white blood cell count (WBC) (P < 0.001), T cell phenotype (P < 0.001) and mediastinal mass (P < 0.001). Patients with Ink4 locus bi-allelic deletions had an inferior pEFS (P < 0.01) and multivariate analysis indicated that bi-allelic deletion of the p16ink4a and the p14ARF genes was an independent prognostic risk factor (P < 0.05). Sub-group analysis revealed a pronounced impact of deletion status for high-risk patients, ie with high WBC. Deletion-status and clinical risk criteria (WBC) could thus be combined to further differentiate risk within the high-risk group. The analysis of the Ink4 locus adds independent prognostic information in childhood ALL treated by Nordic protocols and may help in selection of patients for alternative treatment.

Telomere length is associated with oppositional defiant behavior and maternal clinical depression in Latino preschool children.

Exposure to psychological stress and depression are associated with shorter white blood cell telomere length (TL) in adults, possibly via associated lifelong oxidative stressors. Exposure to maternal depression increases risk for future depression and behavior problems in children, and Latino youth are at high risk. Few studies have evaluated the role of exposure to maternal depression or child behavior in relation to TL in children. We assessed early-childhood exposures to maternal depression from birth to the age of 5 years and child behavior from ages 3-5 years in a cohort of Latino children in relation to child leukocyte TL at ages 4 and 5 years. Children who had oppositional defiant behavior at 3, 4 or 5 years had shorter TL than those without by ~450 base pairs (P < 0.01). In multivariate analyses, independent predictors for shorter TL at 4 and 5 years of age included oppositional defiant disorder at 3, 4 or 5 years (ß = -359.25, 95% CI -633.84 to 84.66; P = 0.01), exposure to maternal clinical depression at 3 years of age (ß = -363.99, 95% CI -651.24 to 764.74; P = 0.01), shorter maternal TL (ß = 502.92, 95% CI 189.21-816.63) and younger paternal age at the child's birth (ß = 24.63, 95% CI 1.14-48.12). Thus, exposure to maternal clinical depression (versus depressive symptoms) in early childhood was associated with deleterious consequences on child cellular health as indicated by shorter TL at 4 and 5 years of age. Similarly, children with oppositional defiant behavior also had shorter TL, possibly related to early exposures to maternal clinical depression. Our study is the first to link maternal clinical depression and oppositional defiant behavior with shorter TL in the preschool years in a relatively homogenous population of low-income Latino children.

Elevated fasting breath hydrogen and abnormal hydrogen breath tests in children with sickle cell disease: a preliminary report.

Hydrogen breath tests were performed in eight children with sickle cell disease (Hgb S-S), four of whom were growth retarded. Average base-line breath H2 values after an overnight fast were elevated (22.4 +/- 10.8 ppm; normal = 7.1 +/- 5.0). Breath H2 concentrations increased significantly above base line within 30-40 min after lactulose ingestion in the four growth-retarded children whereas a negligible rise was observed in the four with normal growth indices. Breath H2 production for each time interval in the first 120 min was greater in all Hgb S-S then in normal children (p less than 0.01 for each time interval measured before 60 min). The results indicate that children with sickle cell disease have intestinal abnormalities favoring excess production of H2 in the fasted state combined with early elevations in postlactulose breath H2 in those with growth retardation. The possible role of disordered gastrointestinal motility and/or anomalously distributed intestinal flora in growth retardation of children with Hgb S-S requires further investigation.

Influence of age on energy requirements.

The effects of aging on energy requirements and energy expenditure were investigated in 35 healthy young men (mean +/- SE age, 22.7 +/- 0.6 y) and elderly men (68.0 +/- 1.5 y). Over a 10-d metabolic balance study, measurements were made of metabolizable energy intake for weight maintenance, total energy expenditure, resting energy expenditure, and thermic effect of feeding. Values for both metabolizable energy intake and total energy expenditure were significantly higher than the current recommended dietary allowance for energy in both age groups (P < 0.01). Total energy expenditures were 14.48 +/- 0.65 and 11.26 +/- 5.40 MJ/d in young and elderly men, respectively. The difference in total energy expenditure between the groups was accounted for by a significant decrease in all the major components of expenditure. These results suggest that the current recommended dietary allowances for energy may underestimate the usual energy needs of healthy adult men.