Why are human newborns so fat? Relationship between fatness and brain size at birth [retracted article]

The plumpness of the human newborn has long been recognized as a trait in need of explanation among researchers. Using a linear regression analysis, we find that head circumference is significantly and positively associated with BMI at birth, after gestational age and birthlength were controlled for, in a sample of 1,069 healthy liveborn routinely delivered at the University Hospital of Coimbra (partial correlation r = 0.409, P < 0.0001). This significant association is consistent with the idea that newborn fatness is related to the higher need of lipids in newborn humans as an energetic and plastic substrate during its accelerated brain growth period. As birthweight and birth head size are associated with head size and cognitive abilities in childhood and adult life, it could be postulated that these cognitive abilities could have acted as selective pressure responsible for the newborn fatness increase in our lineage. Am. J. Hum. Biol. 16:24–30, 2004. © 2003 Wiley‐Liss, Inc.     

SIGN-R1, a novel C-type lectin expressed by marginal zone macrophages in spleen,mediates uptake of the polysaccharide dextran

The marginal zone macrophages of the spleen are implicated in the clearance of polysaccharides, but underlying mechanisms need to be pinpointed. SIGN-R1 is one of five recently identified mouse genes that are homologous to human DC-SIGN and encode a single, external, C-terminal C-type lectin domain. We find that a polyclonal antibody to a specific SIGN-R1 peptide reacts primarily and strongly with a subset of macrophages in the marginal zone of spleen and lymph node medulla. In both sites, SIGN-R1 exists primarily in an aggregated form, resistant to dissociation into monomers upon boiling in SDS under reducing conditions. Upon transfection into three different cell lines, high-mol.-wt forms bearing SIGN-R1 are expressed, as well as reactivity with ER-TR9, a mAb previously described to react selectively with marginal zone macrophages. SIGN-R1-expressing macrophages preferentially sequester dextrans following i.v. injection. Likewise, when phagocytic cells are enriched from spleen and tested in culture, dextran is selectively endocytosed by a subset of very large SIGN-R1(+) cells representing approximately 5% of total released macrophages. Uptake of FITC-dextran by these macrophages in vivo and in vitro is blocked by ER-TR9 and polyclonal anti-SIGN-R1 antibodies. Following transfection with SIGN-R1, cell lines become competent to endocytose dextrans. The dextran localizes primarily to compartments lacking transferrin receptor and the LAMP-1 CD107a panlysosomal antigen. Therefore, SIGN-R1 mediates the uptake of dextran polysaccharides, and it is predominantly expressed in the macrophages of the splenic marginal zone and lymph node medulla.     

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Invasion into surrounding brain tissue is a fundamental feature of gliomas and the major reason for treatment failure. The process of brain invasion in gliomas is not well understood. Differences in gene expression and/or gene products between invading and noninvading glioma cells may identify potential targets for new therapies. To look for genes associated with glioma invasion, we first employed Affymetrix microarray Genechip technology to identify genes differentially expressed in migrating glioma cells in vitro and in invading glioma cells in vivo using laser capture microdissection. We observed upregulation of a variety of genes, previously reported to be linked to glioma cell migration and invasion. Remarkably, major histocompatiblity complex (MHC) class I and II genes were significantly downregulated in migrating cells in vitro and in invading cells in vivo. Decreased MHC expression was confirmed in migrating glioma cells in vitro using RT-PCR and in invading glioma cells in vivo by immunohistochemical staining of human and murine glioblastomas for beta2 microglobulin, a marker of MHC class I protein expression. To the best of our knowledge, this report is the first to describe the downregulation of MHC class I and II antigens in migrating and invading glioma cells, in vitro and in vivo, respectively. These results suggest that the very process of tumor invasion is associated with decreased expression of MHC antigens allowing glioma cells to invade the surrounding brain in a 'stealth'-like manner.     

Psychological and social effects of orthodontic treatment

Adolescents with commonly occurring forms of malocclusion often are presumed to be at risk for negative self-esteem and social maladjustment. A randomized control group design was used to assess the psychosocial effects of orthodontic treatment for esthetic impairment. Ninety-three participants, 11 to 14 years old, with mild to moderate malocclusions, were randomly assigned to receive orthodontic treatment immediately or after serving as delayed controls. A battery of psychological and social measures was administered before treatment, during treatment, and three times after completion of treatment, the last occurring one year after termination. Repeated measures analyses of variance assessed group differences at the five time points. Parent-, peer-, and self-evaluations of dental-facial attractiveness significantly improved after treatment, but treatment did not affect parent- and self-reported social competency or social goals, nor subjects' self-esteem. In summary, dental-specific evaluations appear to be influenced by treatment, while more general psychosocial responses are not.This research was supported by Grant NIH-NIDR-R01-DE06154 from the National Institute of Dental Research.     

IgG anti-tetanus toxoid antibody synthesis by human bone marrow. I. Two distinct populations of marrow B cells and functional differences between marrow and peripheral blood B cells

This investigation uses a system for inducing and detecting anti-tetanus toxoid antibody (anti-TT) synthesis to study specific antibody (Ab) synthesis by bone marrow mononuclear cells (MC). We measured the amounts of anti-TT secreted and the number of B cells secreting antibody (Ab). The ELISA plaque detects single B cells secreting specific Ab. The results show that (1) spontaneous anti-TT secretion by MC is higher than spontaneous anti-TT secretion by peripheral blood lymphocytes (PBL) using an ELISA plaque (P<0.01); (2) spontaneous anti-TT production by MC correlated with the serum anti-TT titers as measured by an ELISA (r=0.75,P=0.005); (3) two types of marrow B cells were identified—one that spontaneously secretes anti-TT and another that produces anti-TT after TT-stimulation; (4) the frequency of anti-TT-secreting B cells is higher in MC than in PBL; (5) the amount of Ab secreted per marrow B cell is not different from that secreted by a peripheral B cell; and (6) marrow B cells could be induced to produce anti-TTin vitro up to 10 months without added cytokines. These results show that bone marrow is a major repository for differentiated B cells that spontaneously produce Abs to maintain circulating Abs titers and for memory B cells that can be induced to produce specific Ab.     

Use of interleukin 15 to enhance interferon-gamma production by antigen-specific stimulated lymphocytes from rhesus macaques

The enzyme-linked immune spot (ELISPOT) assay is receiving increased attention as a means for quantifying antigen-specific CD8 T-cell responses in rhesus macaques. Further improving the sensitivity of this assay could aid in the evaluation of vaccine candidates and/or immune therapeutic candidates. Interleukin (IL)-15 has been demonstrated to stimulate expansion of human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) and to regulate homeostatic proliferation of CD8+ memory cells. We evaluated the in vitro effect of IL-15 to increase the detection of interferon-gamma (IFN-gamma) production by antigen-specific stimulated lymphocytes from a group of rhesus macaques exposed to simian-human immunodeficiency virus (SHIV) and a second group infected with SIVmac251, before and after antiretroviral treatment (ART). Results from these studies demonstrate that the presence of IL-15 during stimulation in a peptide-based ELISPOT assay greatly enhanced IFN-gamma production in both SHIV and simian immunodeficiency virus (SIV)-infected macaques. IFN-gamma production was mainly mediated by CD8 lymphocytes. The optimal concentrations of IL-15 that give enhancement of IFN-gamma production to specific antigen, without a significant increase in the spontaneous IFN-gamma release, ranged from 0.5 to 2.5 ng/ml. The mean number of IFN-gamma spots was increased 3.1- to 3.6-fold in response to SIV gag or HIV env peptide pools, respectively, in peripheral blood mononuclear cells (PBMC) from SHIV-infected macaques. Similarly, in SIV-infected macaques, IL-15 increased the mean number of IFN-gamma spots 2.7-fold in response to both SIV gag and env peptide pools. In samples obtained after ART in the same macaques, the increase factor was 2.5 for SIV gag and 1.8 for the env peptide pools. Thus, the sensitivity of the ELISPOT assay can be enhanced by addition of IL-15. This modified assay will be useful for detection of low frequencies of IFN-gamma producing cells in rhesus macaques.     

Association study of a SNAP‐25 microsatellite and attention deficit hyperactivity disorder

Several lines of evidence implicate synaptosomal‐associated protein of 25 kDa (SNAP‐25) in the etiology of attention deficit hyperactivity disorder (ADHD). Most notably, the coloboma mouse mutant, considered to be a good animal model of hyperactivity, has a deletion spanning this gene. Introducing a SNAP‐25 transgene into these animals alleviates hyperlocomotion. We have identified a novel microsatellite repeat in SNAP‐25 located between the 5′UTR and the first coding exon, and tested for association with ADHD. Case‐control analyses suggest there may be a role of this polymorphism in ADHD, with one allele over‐represented in controls and another over‐represented in probands. Within‐family tests of linkage and association confirmed these findings. Further work is needed to ascertain the role of SNAP‐25 in ADHD and assess the functional significance of this polymorphism. © 2002 Wiley‐Liss, Inc.     

Expression of cyclooxygenase-2 in osteosarcoma of bone.

Several studies indicate that cyclooxygenase-2 (COX-2) is overexpressed in human malignancies, where it produces high levels of prostaglandins and contributes to tumor growth. In this study we have analyzed the expression of COX-2 in a series of 48 skeletal osteosarcomas of different subtypes by immunohistochemistry. In addition, we examined the effects of the specific COX-2 inhibitor Celecoxib on the growth of the human osteosarcoma cell line SaOS-2. Immunoreactivity for COX-2 was observed in 39 out of 48 tumors (81.2%), 30 (76.9%) of which showed a moderate or diffuse immunostaining. Considering the group of 42 primary osteosarcomas, COX-2 immunoreactivity was significantly higher in high grade osteosarcomas, where moderate or diffuse expression was detected in 23 out of 32 cases (71.8%), than in low grade osteosarcomas, where moderate or diffuse expression was detected in 2 out of 10 cases (20%) (P = 0.008, Fisher exact test). In addition, low COX-2 expression was always associated with a good response to chemotherapy (5 out of 5 cases), whereas moderate or diffuse COX-2 expression was associated with a good response in 11 out of 20 cases (55%) (P = 0.12, Fisher exact test). In SaOS-2 osteosarcoma cells, which express COX-2, treatment with Celecoxib determined inhibition of cell proliferation and induction of apoptosis. These results indicate that COX-2 is expressed at high levels in high grade osteosarcomas and support the use of COX-2 inhibitors to improve both the tumor response to chemotherapy and the outcome of osteosarcoma patients.