Hemoglobin Levels and iron Intakes in Infants Attending Selected Child Health Centres in the City of Toronto

An investigation of the hemoglobin levels of infants in potentially high-risk categories demonstrated the possibilities of a public health program of screening and referral for anemia. Blood samples for hemoglobin determinations and particulars of 24-hour dietary intakes were obtained for 252 infants between the ages of 6 and 18 months at seven child health centres in the City of Toronto. Twenty-nine percent of the infants had hemoglobin levels below 10 g./100 ml. of blood. Problems in the collection and analysis of dietary data limited the interpretation of iron intakes.     

Type 5 acid phosphatase. Sequence, expression and chromosomal localization of a differentiation-associated protein of the human macrophage

The purple acid phosphatases and uteroferrin belong to a diverse multifunctional class of binuclear iron-containing proteins that includes haemerythrin and ribonucleotide reductase. In the pig, uteroferrin has been implicated in the delivery of iron to the foetus, but the role of the related human type 5 acid phosphatase that is principally found in resident tissue macrophages is not yet clear. To define further the function of this metalloenzyme, we have isolated and sequenced a cDNA clone for type 5 acid phosphatase and investigated expression of its gene in human tissues. The phosphatase clone contains an open reading frame of 975 bp and encodes a protein of 325 amino acids, including a signal peptide of 19 residues and two potential sites for N-glycosylation. The type 5 acid phosphatase gene mapped to the short arm of human chromosome 19 and was found to have a restriction fragment length polymorphism on digestion with XbaI. Expression of phosphatase mRNA was restricted to mononuclear phagocytes and the enzyme was induced greater than 20-fold on transformation of normal human monocytes to macrophages by culture in serum-supplemented medium. Type 5 acid phosphatase thus represents a tightly regulated system for the study of molecular events in the differentiation programme of the normal macrophage.     

On the magnetic properties of cobalt substituted bovine superoxide dismutase derivatives.

We have measured the magnetic susceptibility in the temperature range 1.4–77°K of three derivatives of bovine superoxide dismutase in which Co²⁺ was substituted for Zn²⁺: (1) 2Co²⁺ — in which Co²⁺ binds to the normal Zn²⁺ site and the Cu²⁺ site is unoccupied, (2) 2Co²⁺2Cu²⁺ — in which the Zn²⁺ site is occupied by Co²⁺ and the copper sites contains Cu²⁺ and (3) 2Co²⁺2Cu⁺ — which is the reduced form of the second derivative. The 2Co²⁺ protein exhibits Curie paramagnetism indicating $\text{S′}\text{=}\text{1}\text{2}$ and the zero-field splitting must be greater than ?20 cm^?1. The same propeties have been observed with the 2Co²⁺2Cu⁺-protein. By contrast, the 2Co²⁺2Cu²⁺-derivative exhibits relatively little paramagnetism, some of which arises from non-specifically associated metal ions. The lower susceptibility is due to antiferromagnetic coupling between Co²⁺ and Cu²⁺, and the magnitude of the coupling constant is probably ?5 cm^?1.     

Structure of a C. perfringens Enterotoxin Mutant in Complex with a Modified Claudin-2 Extracellular Loop 2

CPE (Clostridium perfringens enterotoxin) is the major virulence determinant for C. perfringens type-A food poisoning, the second most common bacterial food-borne illness in the UK and USA. After binding to its receptors, which include particular human claudins, the toxin forms pores in the cell membrane. The mature pore apparently contains a hexamer of CPE, claudin and, possibly, occludin. The combination of high binding specificity with cytotoxicity has resulted in CPE being investigated, with some success, as a targeted cytotoxic agent for oncotherapy. In this paper, we present the X-ray crystallographic structure of CPE in complex with a peptide derived from extracellular loop 2 of a modified, CPE-binding Claudin-2, together with high-resolution native and pore-formation mutant structures. Our structure provides the first atomic-resolution data on any part of a claudin molecule and reveals that claudin's CPE-binding fingerprint (NPLVP) is in a tight turn conformation and binds, as expected, in CPE's C-terminal claudin-binding groove. The leucine and valine residues insert into the binding groove while the first residue, asparagine, tethers the peptide via an interaction with CPE's aspartate 225 and the two prolines are required to maintain the tight turn conformation. Understanding the structural basis of the contribution these residues make to binding will aid in engineering CPE to target tumor cells.     

Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy

The KCC2 cotransporter establishes the low neuronal Cl⁻ levels required for GABA_A and glycine (Gly) receptor-mediated inhibition, and KCC2 deficiency in model organisms results in network hyperexcitability. However, no mutations in KCC2 have been documented in human disease. Here, we report two non-synonymous functional variants in human KCC2, R952H and R1049C, exhibiting clear statistical association with idiopathic generalized epilepsy (IGE). These variants reside in conserved residues in the KCC2 cytoplasmic C-terminus, exhibit significantly impaired Cl⁻-extrusion capacities resulting in less hyperpolarized Gly equilibrium potentials (E_Gly), and impair KCC2 stimulatory phosphorylation at serine 940, a key regulatory site. These data describe a novel KCC2 variant significantly associated with a human disease and suggest genetically encoded impairment of KCC2 functional regulation may be a risk factor for the development of human IGE.     

Non-coding RNA's: lightning strikes twice

A second case has been found of a nematode gene involved in developmental timing that encodes a short, non-coding RNA. Both RNAs are expressed at specific times and appear to repress target genes by interacting with their 3' untranslated regions. A coincidence? Or does this pathway attract small RNA regulators?     

Measles: immune suppression and immune responses

Measles is a highly contagious viral disease that remains the leading vaccine-preventable cause of child mortality worldwide. Deaths from measles are due largely to an increased susceptibility to secondary bacterial and viral infections, attributed to a prolonged state of immune suppression. Several abnormalities of the immune system have been described, including changes in lymphocyte number and function, shifts in cytokine responses, immunomodulatory effects of interleukin-10, down regulation of interleukin-12, impaired antigen presentation, and altered interferon alpha/beta signaling pathways. Although the current vaccine is very effective, knowledge of the molecular basis of the immune responses to measles virus could contribute to the development of a safer, more immunogenic measles vaccine. However, the safety of new measles vaccines must be carefully investigated, as two measles vaccines have resulted in unintended immunologic consequences: atypical measles following administration of the formalin-inactivated measles vaccine and increased mortality in girls following administration of high-titer measles vaccines.     

Novel (4-piperazin-1-ylquinolin-6-yl) arylsulfonamides with high affinity and selectivity for the 5-HT(6) receptor

The discovery of (4-piperazin-1-ylquinolin-6-yl) arylsulfonamides and their binding affinities for a selection of 5-HT and dopamine subreceptors is described. Many compounds show high affinity (pK(i)>8) for the 5-HT(6) receptor and >100-fold selectivity against a range of other receptors. Structure-activity relationships of these compounds are discussed.