National cancer clinical trials: children have equal access; adolescents do not

PURPOSE: To determine whether adolescents with cancer, who in comparison to younger patients have a higher cancer incidence and lower mortality reduction, have equal access to national cancer clinical trials. METHODS: The ethnic/racial distribution of 29,859 subjects < 20 years of age entered onto National Cancer Institute-sponsored clinical trials between January 1, 1991, and June 30, 1994, was compared with the expected distribution of patients of the same age in the United States. RESULTS: The Children's Cancer Group and Pediatric Oncology Group had 29,134 (97.6%) of the total study entries among < 20-year-old subjects during the 3.5 years of surveillance. The adult cooperative groups accounted for < 3% of the clinical trials entries in the 15-19-year age range. When analyzed nationally by region, the under-representation of the older adolescent subjects was universal. From other analyses, the two pediatric cooperative groups were estimated to have registered > 94% of the children < 15 years of age who were expected to have been diagnosed to have cancer, but only 21% of the cancer patients in the 15-19-year age group. CONCLUSIONS: The national pediatric cancer cooperative groups allow the majority of American children < 15 years of age and their families equal opportunity to access clinical cancer trials, regardless of race or ethnicity. Among patients 15-19 years of age, however, > 75% are not being enrolled by any cooperative group sponsored by the National Cancer Institute. Thus, older adolescents are disadvantaged with respect to access to the national clinical trials, regardless of their race or ethnicity.     

The inactivated plasmid inititator protein RepC/RepC* may have a regulatory role

During replication of the plasmid pT181, the initiator protein RepC is modified by the addition of an oligodeoxynucleotide, giving rise to a new form, RepC*. Here we show that during in vitro replication, RepC* is radioactively labeled, suggesting that the source of the RepC* oligodeoxynucleotide is the newly synthesized pT181 DNA. The RepC/RepC* heterodimer retains its ability to bind the pT181 double-strand origin and, therefore, it may act as a competitive inhibitor of the RepC homodimer during replication.     

Genetic control of differential baseline breathing pattern

The purpose of the present study was to determine the genetic control of baseline breathing pattern by examining the mode of inheritance between two inbred murine strains with differential breathing characteristics. Specifically, the rapid, shallow phenotype of the C57BL/6J (B6) strain is consistently distinct from the slow, deep phenotype of the C3H/HeJ (C3) strain. The response distributions of segregant and nonsegregant progeny were compared with the two progenitor strains to determine the mode of inheritance for each ventilatory characteristic. The BXH recombinant inbred (RI) strains derived from the B6 and C3 progenitors were examined to establish strain distribution patterns for each ventilatory trait. To establish the mode of inheritance, baseline breathing frequency (f), tidal volume, and inspiratory time (TI) were measured five times in each of 178 mature male animals from the two progenitor strains and their progeny by using whole body plethysmography. With respect to f and TI, the two progenitor strains were consistently distinct, and segregation analyses of the inheritance pattern suggest that the most parsimonious genetic model for response distributions of f and TI is a two-loci model. In similar experiments conducted on 82 mature male animals from 12 BXH RI strains, each parental phenotype was represented by one or more of the RI strains. Intermediate phenotypes emerged to confirm the likelihood that parental strain differences in f and TI were determined by more than one locus. Taken together, these studies suggest that the phenotypic difference in baseline respiratory timing between male B6 and C3 mice is best explained by a genetic model that considers at least two loci as major determinants.     

Developmental changes in glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase oxidative and reductive activities in rat Leydig cells

Glucocorticoids directly regulate testosterone production in Leydig cells through a glucocorticoid receptor (GR)-mediated repression of the genes that encode testosterone biosynthetic enzymes. The extent of this action is determined by the numbers of GR within the Leydig cell, the intracellular concentration of glucocorticoid, and 11beta-hydroxysteroid dehydrogenase (11betaHSD) activities that interconvert corticosterone (in the rat) and its biologically inert derivative, 11-dehydrocorticosterone. As glucocorticoid levels remain stable during pubertal development, GR numbers and 11betaHSD activities are the primary determinants of glucocorticoid action. Therefore, in the present study, levels of GR and 11betaHSD messenger RNA (mRNA) and protein were measured in rat Leydig cells at three stages of pubertal differentiation: mesenchymal-like progenitors (PLC) on day 21, immature Leydig cells (ILC) that secrete 5alpha-reduced androgens on day 35, and adult Leydig cells (ALC) that are fully capable of testosterone biosynthesis on day 90. Numbers of GR, measured by [3H]dexamethasone binding, in purified cells were 6.34 +/- 0.27 (x 10(3) sites/cell; mean +/- SE) for PLC, 30.45 +/- 0.74 for ILC, and 32.54 +/- 0.84 for ALC. Although GR binding was lower in PLC, steady state levels for GR mRNA were equivalent at all three stages (P > 0.05). Oxidative and reductive activities of 11betaHSD were measured by assaying the conversion of radiolabeled substrates in incubations of intact Leydig cells. Both oxidative and reductive activities were barely detectable in PLC, intermediate in ILC, and highest in ALC. The ratio of the two activities favored reduction in PLC and ILC and oxidation in ALC (oxidation/reduction, 0.33 +/- 0.33 for PLC, 0.43 +/- 0.05 for ILC, and 2.12 +/- 0.9 for ALC, with a ratio of 1 indicating equivalent rates for both activities). The mRNA and protein levels of type I 11betaHSD in Leydig cells changed in parallel with 11betaHSD reductive activity, which increased gradually during the transition from PLC to ALC, compared with the sharp rise that was seen in oxidative activity. We conclude that Leydig cells at all developmental stages have GR and that their ability to respond to glucocorticoid diminishes as net 11betaHSD activity switches from reduction to oxidation. This provides a mechanism for the Leydig cell to regulate its intracellular concentration of corticosterone, thereby varying its response to this steroid during pubertal development.     

Relation between the level of E. coli gene expression and the structure of translation initiation region (TIR). III. Sites of complementary interaction of TIR with 16S rRNA

The addition of vertebral disc degeneration to the job-related disease register raises the question of vertebral disc degeneration patterns according to loading strain. The readings of the lumbar vertebra of construction workers and nurses were compared with those of a group without workload. In the groups examined, aged 35 to 50, monosegmental damage was found in only 17% of the patients with high workload, as opposed to 29% of those with no workload, mostly with monosegmental damage at level L5/S1. Damage to the upper segments of the lumbar spine with intact discs in between was found exclusively in patients with high workload. Multiple segment damage in the age range examined was found in subjects with activities that add to the load of the spinal column. The value of MRI in assessing and evaluating illness originating from the vertebral discs is currently being discussed.     

Role of fever in infection: has induced fever any therapeutic potential in HIV infection?

Ancient societies had no rational understanding of fever. The Greeks were the first to recognise that it may be part of nature's method of effecting cure in some diseases. How best to assist nature went through many trials and errors. Appreciation of the prognostic value of fever and how it may be controlled was slow to appear. That there was a place in the therapeutic arsenal for induced fever came only with the 20th century. Finding a suitable, safe, and satisfactory means came slowly. The curative power of well controlled and reproducible levels of fever was proved by the arrest of one deadly and incurable complication of a sexually transmitted disease in the first half of this century. The purpose of this review is to promote discussion and, hopefully, well ordered laboratory and clinical trials aimed at learning whether or not induced fevers have a place in the care of patients with HIV/AIDS.     

An animal model of Peyronie's-like condition associated with an increase of transforming growth factor beta mRNA and protein expression

PURPOSE: Transforming growth factor beta (TGF-beta) is involved in numerous vital processes including tissue fibrosis. Our objective was to study the role of TGF-beta in the induction of a Peyronie's-like condition and to produce an animal model for the further study of Peyronie's disease. MATERIALS AND METHODS: Twenty-four adult male Sprague-Dawley rats were divided into two groups. Different concentrations of cytomodulin, a synthetic heptopeptide with TGF-beta-like activity, were injected into the tunica of each rat from the first group (n = 18). Rats in the second group (n = 6) received saline injections as a control. The tunical tissues were taken after 3 days, 2 weeks, and 6 weeks and were examined using Hart and Trichrome stains. In the same tissue samples, TGF-beta mRNA and protein expression were studied. RESULTS: Histological alterations were observed in 15 out of 18 cytomodulin-injected rats, especially in tissue examined after 6 weeks. The most prominent changes were chronic cellular infiltration, focal and diffuse elastosis, thickening, disorganization and clumping of the collagen bundles. Results from immunoblot revealed remarkable TGF-beta1 protein expression in all the cytomodulin-injected rats only after 2 and 6 weeks. No remarkable TGF-beta2 or TGF-beta3 protein expression was observed. TGF-beta1 mRNA expression in the cytomodulin-injected rats was noticed in rats injected with higher concentrations after 3 days, while it was expressed in all rats after 2 weeks. There was no expression in the control group after either 3 days or 2 weeks. CONCLUSIONS: Cytomodulin can induce Peyronie's-like condition in the rat penis, which may explain the role of TGF-beta in the pathogenesis of Peyronie's disease.     

Genomic organization and allelic polymorphism of the human killer cell inhibitory receptor gene KIR103

Killer cell inhibitory receptors (KIR) belong to the immunoglobulin superfamily of molecules and are expressed on natural killer (NK) cells. The KIRs of the p58/p50 family have two immunoglobulin domains and are ligands for HLA-Cw antigens, whereas the p70/p70 delta family has three immunoglobulin domains and comprises ligands for HLA-B antigens and possibly some HLA-A antigens. Members of a third KIR family, KIR103, have two immunoglobulin domains but have highest nucleotide sequence homology to the p70 family. The ligands for KIR103 on target cells are currently unknown. We here report the complete genomic organization of KIR103. It spans about 12 kb of DNA and consists of eight exons of which exon 1 and exon 2 encode the leader sequence. Exon 3 encodes the first immunoglobulin domain (gamma 1), and exon 4 encodes the main part of the second immunoglobulin domain (gamma 3), which also contains sequences contributed by exon 5 and exon 6. Exon 6 encodes the transmembrane domain, whereas exons 7 and 8 encode most of the cytoplasmic domain. KIR103 is polymorphic, and two alleles, 103AS and 103LP, are defined in this study. Additional full-length cDNA clones for KIR103 have been isolated and are shown to be formed by alternative mRNA splicing with exon skipping. Some of these truncated KIR103 cDNA could encode shorter transmembrane molecules, whereas others lack the transmembrane domain and are candidate genes for secreted KIR products. KIR103 is localized to the KIR genetic region on chromosome 19q13.4.     

Examining a paradox in the pathogenesis of human pulmonary tuberculosis: immune activation and suppression/anergy

Protective immunity against Mycobacterium tuberculosis (MTB) in animal models is based on cell-mediated immunity (CMI), involving bi-directional interactions between T cells and cells of the monocyte/macrophage (MO/MA) lineage. Key factors include MO-derived interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha as well as T cell derived IL-2 and interferon (IFN)-gamma. These cytokines appear particularly crucial in the induction of MA-mediated elimination of mycobacteria. Several lines of evidence indicate that similar mechanisms are operating in humans. During active pulmonary tuberculosis (PTB), signs of both immune depression and immune activation are concomitantly present. Decreased tuberculin skin test reactivity in vivo and deficient IFN-gamma production by MTB-stimulated mononuclear cells in vitro are observed. On the other hand, the serum levels of several cytokines, including TNF, and other inflammatory mediators are increased and circulating MO and T cell show phenotypic and functional evidence of in vivo activation. In this review, we will discuss the evidence for three models, which could explain this apparent paradox: 1. Stimulation of the T cell-suppressive function from MO/MA; 2. Intrinsic T cell refractoriness, possibly associated with tendency to apoptosis (programmed cell death), and 3. Compartmentalization and redistribution of immune responses to the site of disease. The opportunistic behavior of MTB during human immunodeficiency virus (HIV) infection can be explained by suppression of type-1 responses at the level of antigen-presenting cells, CD4 T cells and effector macrophages. The ominous prognostic significance of intercurrent PTB during HIV infection seems primarily due to prolonged activation of HIV replication in macrophages. Supportive immune therapy during PTB could aim at correcting the type-1 deficiency either by IFN-gamma inducers (e.g. IL-12, IL-18) or by neutralizing the suppressive cytokines transforming growth factor beta (TGF-beta) and IL-10. Alternatively, inflammatory over-activity could be reduced by neutralizing TNF. Finally, anti-apoptotic therapies (e.g. IL-15) might be considered.     

Intra-amniotic infection and premature rupture of the membranes

Antiphospholid antibodies (APL) have a notable association with recurrent miscarriages, arterial and venous thrombosis and thrombocytopenia. Analysis of the potential pathogenic effects of such human antibodies has been hampered by the considerable difficulty in producing IgG as opposed to IgM monoclonal immunoglobulins. We have developed four human monoclonal IgG APL (LJ1, AH2, DA3 and UK4) by fusing the peripheral blood lymphocytes of three patients with SLE with a mouse human heteromyeloma cell line, CB-F7. These antibodies bind to a variety of anionic phospholipids, two (LJ1 and AH2) bind total histones but none binds to ssDNA or dsDNA. Binding to beta 2 GPI is non-specific. UK4 alone demonstrates lupus anticoagulant activity. All four have lambda light chains, two are IgG1 (AH2 and UK4) and two are IgG3 (LJ1 and DA3). These APL utilize VH genes present in the fetally restricted repertoire and multiple somatic mutations in the CDR suggest an antigen-driven process. In contrast, there is no restriction in V lambda gene usage and only one lambda chain is extensively mutated. Two clonally related hybridomas were isolated from a single patients. This supports the theory that clonal expansion is the mechanism whereby antigen selects high affinity mutations.