Comprehensively evaluating cancer survival in children with birth defects: a population-based assessment

Cancer Causes & Control - Congenital malformations are strong risk factors for childhood cancer. Our objective was to determine whether cancer survival differs by birth defect status among...     

Do longer formula feeding and later introduction of solids increase risk for pediatric acute lymphoblastic leukemia?

Milk formula feeding can elevate insulin-like growth factor-1 levels, possibly impacting leukemogenesis. The intent of the current study is to examine the associations between infant feeding practices and age at introduction of solids on risk of childhood acute lymphoblastic leukemia (ALL). Incident cases of infant and childhood (aged ≤14 years) ALL (n = 142) were enrolled in a case–control study. Cases were frequency matched on age, sex, race, and ethnicity to two sets of controls (n = 284 total). Multivariable logistic regression was used to determine the association between infant feeding practices and age at the introduction of solids and the odds ratio of ALL. In adjusted multivariable analyses, each additional month of formula feeding was associated with a 1.17 (1.09–1.25) odds ratio; each additional month of age at introduction of solids was associated with a 1.18 (1.07–1.30) odds ratio. In this study, longer duration of formula feeding and later age at the introduction of solid foods were independently associated with increased risk of ALL. Additional studies are needed to address the factors influencing duration of formula feeding and delayed introduction of solids. The results support the potential role of energy balance in early life as a contributor to risk for pediatric acute lymphoblastic leukemia.     

Platelets from Munc18c heterozygous mice exhibit normal stimulus-induced release

A critical aspect of hemostasis is the release of clot-forming components from the three intra-platelet stores: dense core granules, alpha-granules and lysosomes. Exocytosis from these granules is mediated by soluble (SNAPs and NSF) and integralmembrane proteins (v- and t-SNAREs). Three SM (Sec1/Munc18) proteins are present in mouse platelets (Munc18a, 18b and 18c) and each potentially regulates exocytosis via modulation of their cognate syntaxin binding partner. To define the molecular machinery required for platelet exocytosis, we analyzed platelets from Munc18c heterozygous knockout mice. These platelets show a decrease in Munc18c but no apparent reduction in other secretory machinery components. No differences in the rates of aggregation or of secretion of [(3)H]-5HT (dense core granules), platelet factor 4 (alpha-granules), or hexosaminidase (lysosomes) were detected between platelets from Munc18c heterozygous knockout or wild-type mice. The platelets also show normal morphology. Contrary to a predicted requirement for Munc18c in platelet secretion, data reported here show that reducing Munc18c levels does not substantially alter platelet function. These data show that despite Munc18c's role in platelet secretion, the lack of a secretion defect may be attributed to compensation by other Munc18 isoforms or that one allele is sufficient to maintain secretion under standard conditions.     

Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum

Aims/hypothesis Adiponectin is an adipocyte-derived secretory factor that is specifically produced in adipocytes. It exerts effects on energy homeostasis via peripheral and central mechanisms. However, it is not clear whether adiponectin crosses the blood–brain barrier in humans. In serum, adiponectin circulates in several different complexes, each of which has distinct functions. Here, we wanted to test whether adiponectin can be found in human cerebrospinal fluid (CSF) and whether specific adiponectin complexes are enriched in CSF compared with peripheral serum samples. We also wanted to establish whether there is a sex-related difference with regard to the distribution of adiponectin oligomers in CSF. Materials and methods We studied 22 subjects (11 men, 11 women) in this study. Their average BMI was 28.0 ± 4.7 kg/m²; average age was 70 ± 7 years. Results Analysis of total adiponectin revealed that adiponectin protein is present in human CSF at approximately 0.1% of serum concentration. The distribution of adiponectin oligomers differs considerably in CSF from that of serum within matched samples from the same patients. Only the adiponectin trimeric and low-molecular-mass hexameric complexes are found in CSF, with a bias towards the trimeric form in most patients. Male subjects have a higher CSF:serum ratio of total adiponectin (p < 0.05; n = 20) and have slightly higher trimer levels in serum and CSF than female subjects. Conclusions/interpretation We conclude that the adiponectin trimer is the predominant oligomer in human CSF.     

A Vulnerable Age for the Introduction of Solid Foods in Pediatric Acute Lymphoblastic Leukemia

Background: There is little research concerning infant formula or the age at introduction to solid foods and pediatric acute lymphoblastic leukemia (ALL). The purpose of this case-control study was to estimate the association of age at introduction of solids and pediatric ALL. Methods: 171 ALL cases aged 0–14 years were recruited at Texas Children's Cancer Center and matched on sex, age, and ethnicity to 342 population-based controls. Data were collected on infant feeding and known risk factors for ALL. Multivariable logistic regression was used to model the odds ratio of ALL by quartile of age at introduction of solids with the first/earliest quartile (0–4 months) as the reference group. Results: In adjusted models, the odds ratio of ALL among children in quartile 3 (7–9 months) was 4.08, 95% confidence interval (CI) 1.42–11.71; for children in quartile 4 (≥10 months) the odds ratio (OR) was 6.03, 95% CI 2.06–17.72. For each additional month of milk formula feeding, the OR of ALL was 1.16, 95% CI 1.08–1.25. Conclusions: These results suggest a window when later introduction to solids is positively associated with ALL and recommend compliance with the American Academy of Pediatrics guidelines.     

PANIC-ATTAC: a mouse model for inducible and reversible beta-cell ablation

OBJECTIVE—Islet transplantations have been performed clinically, but their practical applications are limited. An extensive effort has been made toward the identification of pancreatic β-cell stem cells that has yielded many insights to date, yet targeted reconstitution of β-cell mass remains elusive. Here, we present a mouse model for inducible and reversible ablation of pancreatic β-cells named the PANIC-ATTAC (pancreatic islet β-cell apoptosis through targeted activation of caspase 8) mouse.RESEARCH DESIGN AND METHODS—We efficiently induce β-cell death through apoptosis and concomitant hyperglycemia by administration of a chemical dimerizer to the transgenic mice. In contrast to animals administered streptozotocin, the diabetes phenotype and β-cell loss are fully reversible in the PANIC-ATTAC mice, and we find significant β-cell recovery with normalization of glucose levels after 2 months.RESULTS—The rate of recovery can be enhanced by various pharmacological interventions with agents acting on the glucagon-like peptide 1 axis and agonists of peroxisome proliferator–activated receptor-γ. During recovery, we find an increased population of GLUT2⁺/insulin⁻ cells in the islets of PANIC-ATTAC mice, which may represent a novel pool of potential β-cell precursors.CONCLUSIONS—The PANIC-ATTAC mouse may be used as an animal model of inducible and reversible β-cell ablation and therefore has applications in many areas of diabetes research that include identification of β-cell precursors, evaluation of glucotoxicity effects in diabetes, and examination of pharmacological interventions.Diabetes is an epidemic affecting 180 million people worldwide with rising prevalence (1). Successful islet transplantation with the Edmonton protocol was considered a significant step toward a cure (2). However, because of the scarcity of available islets and limited viability of transplanted islets, this procedure has not yet found widespread application. Extensive efforts have been directed toward identifying pancreatic β-cell stem cells for transplantation and approaches to stimulate β-cell regeneration.In the past, the potential β-cell precursors have been identified among embryonic stem cells, ductal cells, acinar cells, and nonendocrine epithelial cells (3–7). More recently, the proliferation of pre-existing β-cells has been shown to be the major source of β-cell regeneration in lineage tracing studies (8). The mechanisms of β-cell regeneration therefore remain controversial, and different methodologies and animal models may be at the source of these inconsistent observations.Both in vitro islet culture and diabetic animal models have been used extensively in characterization of pancreatic β-cell death and regeneration and identification of β-cell precursors. However, the findings gained from islet cultures in vitro cannot always be extrapolated to the in vivo situation because of the complexity of β-cell physiology. Current in vivo pancreas injury models include toxin administration, pancreatectomy, and ductal ligation. Studies using these models have provided valuable insights for physiological and pathophysiological regulation of β-cells. However, these animal models use acute, extreme, and nonphysiological insults, and none of them show significant β-cell recovery after injury.In the present study, we describe a pancreas injury model with inducible and reversible β-cell ablation. In the current transgenic mouse model, the PANIC-ATTAC (pancreatic islet β-cell apoptosis through targeted activation of caspase 8) mouse, β-cell death is induced in a specific and well-defined manner through treatment of a chemical dimerizer. Importantly, the PANIC-ATTAC mice show extensive β-cell regeneration and normalization of glucose levels after treatment. We found an increased population of GLUT2⁺/insulin⁻ cells, which may serve as β-cell precursors. The PANIC-ATTAC mouse model has the potential to be highly informative in many areas of diabetes research and provides an opportunity to characterize β-cell pathophysiology during diabetes progression.     

Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies

Total plasma adiponectin and high-molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. However, we have recently reported paradoxical hyperadiponectinemia in patients with severe insulin resistance due to genetically defective insulin receptors. This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction and to refine the previous observations by determining adiponectin complex distribution. Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12-54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3-54.2] vs. 8.9 mg/l [1.5-28.5 for BMI <25 kg/m(2)]), which was accounted for largely by HMW polymers. Hyperadiponectinemia resolved in parallel with reduction of insulin receptor antibodies and clinical resolution of insulin resistance. Although the well-established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated.