Maternal efforts to prevent type 1 diabetes in at-risk children

OBJECTIVE: The aim of this study was to assess maternal diabetes prevention efforts aimed at children identified as at risk through newborn genetic screening. RESEARCH DESIGN AND METHODS: A total of 192 mothers of children identified as at risk for type 1 diabetes through newborn genetic screening were administered a structured interview 3.6 +/- 0.8 years after risk notification. The interview assessed possible diabetes prevention behaviors across six domains: health surveillance, diet, physical activity, illness prevention, medications, and stress reduction. A mother's cognitive (diabetes risk perception and perceived control), affective (anxiety), and coping responses to the child's at-risk status were assessed. RESULTS: A total of 67% of mothers reported one or more diabetes prevention behaviors. Monitoring behaviors (e.g., watching for signs of diabetes and checking blood glucose) were the most common, reported in 59%, followed by modifications in the child's diet in 34% and physical activity in 14%. Potentially harmful prevention behaviors (e.g., limiting contact with other children, delaying immunizations, and giving medications including insulin) were rare. Mothers who engaged in diabetes prevention behaviors reported higher diabetes risk perception, greater anxiety, and more use of certain coping styles. Infants of these mothers were more likely to have a first-degree relative with diabetes. CONCLUSIONS: In the absence of known methods of preventing type 1 diabetes, most mothers of at-risk children report diabetes prevention behaviors. Such behaviors must be more carefully assessed to ensure accurate interpretation of data obtained from natural history studies and prevention trials.     

Effects of copper on A-type potassium currents in acutely dissociated rat hippocampal CA1 neurons

The effects of copper on voltage-gated A-type potassium currents were investigated in acutely dissociated rat hippocampal CA1 neurons using the whole-cell patch-clamp technique. Extracellular application of various concentrations of copper (1-1000 microM) reversibly reduced the amplitude of voltage-gated A-type potassium currents in a dose-dependent manner with a 50% inhibitory concentration value of 130 microM. Copper (300 microM) increased the V1/2 of the activation curve and state-inactivation curve by 17.2 and 9.0 mV, respectively. Thus, copper slowed down the activation and inactivation process of voltage-gated A-type potassium currents. This study indicated that copper reversibly inhibits the hippocampal CA1 neuronal voltage-gated A-type potassium current in a dose-dependent and voltage-dependent manner, and such actions are likely involved in the regulation of the neuronal excitability and the pathophysiology of Wilson's disease.     

Effects of chronic lead exposure on 1H MRS of hippocampus and frontal lobes in children

The authors performed IQ testing and magnetic resonance spectroscopy on six lead-exposed and six control children. Levels of N-acetyl aspartate (neuronal density and mitochondrial metabolism), creatine + phosphocreatine (phosphate metabolism), and choline (membrane turnover) were decreased in four brain regions (left and right frontal, left and right hippocampus) in lead-exposed children vs controls. The reductions were right frontal > left frontal > hippocampus but were the same bilaterally in the hippocampus.     

Autoimmunity to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease

The pathogenic mechanisms underlying Batten disease are unclear. Patients uniformly possess autoantibodies against glutamic acid decarboxylase (GAD) that are predominantly reactive with a region of GAD (amino acids 1 to 20) distinct from subjects with autoimmune type 1 diabetes or stiff-person syndrome. Batten patients did not possess autoantibodies against other type 1 diabetes-associated autoantigens and human leukocyte antigen genotypes revealed no specific associations with this disease.     

Synergy between anti-endoglin (CD105) monoclonal antibodies and TGF-beta in suppression of growth of human endothelial cells

Endoglin (CD105) is a proliferation-associated cell membrane antigen of endothelial cells and strongly expressed in the angiogenic vasculature of solid tumors. Endoglin is essential for angiogenesis/vascular development and an ancillary transforming growth factor beta (TGF-beta) receptor. Certain anti-endoglin monoclonal antibodies (mAbs), termed SN6 series mAbs, inhibited angiogenesis, tumor growth and metastasis in mice. We investigated the mechanisms by which anti-endoglin mAbs suppress growth of proliferating endothelial cells. We found that 4 SN6 series mAbs suppressed growth of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner in the absence of any effector cells or complement. Significant differences in the growth suppression between the 4 anti-endoglin mAbs defining different epitopes were observed. These differences were not determined by antigen-binding avidities of the mAbs. Combination of TGF-beta1 and each of the 4 anti-endoglin mAbs exerted synergistic growth suppression of HUVECs. Binding of anti-endoglin mAbs to endoglin-expressing cells did not block the subsequent binding of TGF-beta1. Conversely, preincubation of HUVECs with TGF-beta1 did not change cell surface expression of endoglin. The present results suggest that direct suppression of the endothelial cell growth by SN6 series mAbs is one of the underlying mechanisms by which anti-endoglin mAbs exert antiangiogenic and tumor-suppressive activity in vivo. The results further suggest that TGF-beta1 plays an important role in the in vivo antiangiogenic efficacy of anti-endoglin mAbs by synergistically enhancing the activity of these mAbs. Further studies of the present novel findings may provide valuable information about the functional roles of endoglin and anti-endoglin mAbs in the TGF-beta-mediated cell regulation.     

Interleukin-12 redirects murine immune responses to soluble or aluminum phosphate adsorbed HSV-2 glycoprotein D towards Th1 and CD4+ CTL responses

The type of immune response elicited against HSV-2 infection may be a factor in the frequency and severity of recurrent disease, with non-recurrent status being associated with a Th1-like response. As administration of glycoprotein D subunit formulated with an aluminum-based adjuvant induces predominantly Th2-like immune responses, we sought to assess the ability of IL-12 to redirect anti-HSV immunity towards a Th1 response. Co-administration of gD with IL-12 resulted in gD-specific antibody subclass switching from predominantly IgG1 observed in mice immunized with either gD or gD/AlPO4 to a more balanced combination of IgG1 and IgG2a, and enhanced virus neutralizing activity. Spleen cells from mice immunized with gD and IL-12, and restimulated in vitro with HSV-2, developed into effector cells capable of secreting IFN-gamma and lysing HSV-2 infected targets, while those obtained from gD or gD/ALPO4 immunized mice did not express lytic activity. In vitro studies determined that these CTLs were CD4+ and that the cytotoxicity was primarily perforin dependent. Vaginal challenge with HSV-2 demonstrated that IL-12 co-administration with gD resulted in increased efficacy of this vaccine as compared to administration of gD antigen alone. This acquired protection persisted up to 1 year. Finally, adsorbing gD and IL-12 to AlPO4 decreased the optimal dose of IL-12 required to enhance gD immunogenicity and shift responses towards a Th1-like profile.     

Lessons from the polybrominated diphenyl ethers (PBDEs): precautionary principle,primary prevention,and the value of community-based body-burden monitoring using breast milk

Levels of chemicals in humans (body burdens) are useful indicators of environmental quality and of community health. Chemical body burdens are easily monitored using breast milk samples collected from first-time mothers (primiparae) with infants 2-8 weeks of age. Currently, there is no body-burden monitoring program using breast milk in the United States, although ad hoc systems operate successfully in several European countries. In this article we describe the value of such monitoring and important considerations of how it might be accomplished, drawing from our experiences with pilot monitoring projects. Breast milk has several advantages as a sampling matrix: It is simple and noninvasive, with samples collected by the mother. It monitors body burdens in reproductive-age women and it estimates in utero and nursing-infant exposures, all important to community health. Time-trend data from breast milk monitoring serve as a warning system that identifies chemicals whose body burdens and human exposures are increasing. Time trends also serve as a report card on how well past regulatory actions have reduced environmental chemical exposures. Body-burden monitoring using breast milk should include educational programs that encourage breast-feeding. Finally, and most important, clean breast milk matters to people and leads to primary prevention--the limiting of chemical exposures. We illustrate these advantages with polybrominated diphenyl ethers (PBDEs), a formerly obscure group of brominated flame retardants that rose to prominence and were regulated in Sweden when residue levels were found to be rapidly increasing in breast milk. A community-based body-burden monitoring program using breast milk could be set up in the United States in collaboration with the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). WIC has a large number of lactating first-time mothers: It has 6,000 clinics nationwide and serves almost half (47%) the infants born in the United States. Educational programs (e.g., those run by WIC) are needed that encourage breast-feeding, especially in lower-income communities where breast-feeding rates are low and where breast-feeding may help protect the infant from the effects of environmental chemical exposures. Education is also needed about reducing chemical body burdens. A body-burden monitoring program would provide valuable data on time trends, background levels, and community hot spots in need of mitigation and follow-up health studies; develop analytic methods for new chemicals of concern; and archive breast milk samples for future analyses of other agents.