Inadequate levels of essential nutrients in developed nations as a risk factor for disease: a review.

Inadequate levels of essential nutrients is a most important factor in environmental health, leading to an almost monotonic increase in the incidence, morbidity, mortality, and associated costs of 'diseases of affluence' that has persisted for circa a century. Such an unprecedented human tragedy can be explained by the (1) flawed belief that essential nutrients can be replaced by xenobiotic molecules--a fundamental error, (2) failure to recognize that the levels of certain essential nutrients in diets available in the environment are not adequate to produce optimum health, longevity or resistance, and (3) failure to recognize that the refined diet has a lower essential nutrient content. Such beliefs contribute to early death in affluent nations.

Unique properties of fetal lymphoid progenitors identified according to RAG1 gene expression.

RAG1/GFP knockin mice were exploited to isolate and characterize fetal lymphoid progenitors. CD11b and IL-7Ralpha are expressed in a developmental stage-dependent fashion, revealing how substantial numbers of early lymphoid progenitors were discarded or neglected in previous studies. The myeloerythroid potential of fetal progenitors in clonal assays declined in synchrony with activation of the RAG1 locus but was not completely extinguished. Lymphoid differentiation corresponded to patterns of gene expression previously found for adult marrow, but no fraction of fetal liver was enriched with respect to B + T progenitors. Also, unlike adults, fetal lymphoid progenitors transiently expressed endothelial cell markers. These findings help to reconcile discrepancies in previous reports and suggest that the fetal immune system arises via unique mechanisms.

Lymphoid lineage cells in adult murine bone marrow diverge from those of other blood cells at an early, hormone-sensitive stage.

Advances in cell sorting and GFP knock-in technology have made it possible to identify rare hematopoietic cells in murine bone marrow that are undergoing lymphocyte fate specification. Steroid hormones also represent important research tools for investigating relationships between different categories of lympho-hematopoietic precursors. By selectively blocking entry into and progression within lymphoid lineages, the hormones probably have a major influence on numbers of lymphocytes that are produced under normal circumstances. These issues are discussed within the context of developmental age-dependent changes that occur in the lymphopoietic process.

Nature or nurture? Steady-state lymphocyte formation in adults does not recapitulate ontogeny.

Substantial progress has been made in determining developmental relationships between lymphocyte precursors and those corresponding to other blood cell lineages. Indeed, exploitation of RAG1/GFP knock-in mice has recently made it possible to chart the entire sequence of lymphocyte differentiation events in adult bone marrow and thymus. However, the differentiation pathways proposed for fetal life are very different from this model. We review many examples where the results of gene targeting experiments are substantially dependent on developmental age. In mice, adult patterns of gene expression and corresponding properties of lymphocyte precursors are not fully established until several weeks after birth, and the same might be true for humans. Furthermore, examples are cited where fetal hematopoietic cells did not efficiently acquire those properties when transplanted to an adult environment. There are several important implications of these findings. Cognizance of developmental age-related changes might resolve apparent conflicts in the literature. Hematopoietic stem cells and their lymphoid lineage progeny appear in waves, and a direct connection is yet to be established between fetal stem cells and ones that sustain adult blood cell formation. There is the possibility that adult stem cells derive from founders with an unknown origin.

Imaging synapse formation during thymocyte selection: inability of CD3zeta to form a stable central accumulation during negative selection.

TCR signaling can result in cell fates ranging from activation to tolerance to apoptosis. Organization of molecules in an "immunological synapse" between mature T cells and APCs correlates with the strength of TCR signaling. To investigate synapse formation during thymic selection, we have established a reaggregate system in which molecular recruitment of GFP fusion proteins to thymocyte:stromal cell interfaces can be visualized in real time. We demonstrate that negative selection is associated with efficient conjugate formation and rapid recruitment of p56(lck) and CD3zeta to an immunological synapse. Interestingly, CD3zeta-GFP does not accumulate at the center of the synapse, as in mature T cells, but at the periphery across a wide range of ligand densities. This implicates differences in synapse geometry in initiation of alternate signals downstream of the TCR.

Pericardial disease in rheumatoid arthritis.

Six patients with rheumatoid constrictive pericarditis, five seen in a two and one half year period, are described. All patients were male, all had rheumatoid factor, and all had active arthritis. Diagnosis was suspected from careful physical examination and confirmed in five patients by cardiac catheterization. Pericardiectomy was successful in all five patients on whom it was performed. Rheumatoid constrictive pericarditis should be suspected in any patient with rheumatoid arthritis and unexplained signs of right heart failure.

Normal distribution of acetylation phenotypes in systemic lupus erythematosus.

Previous reports have indicated that idiopathic systemic lupus erythematosus (SLE), like drug-induced lupus, is more frequent in "slow" hepatic acetylators. Using dapsone acetylation rate to determine phenotypes, we found that of the 18 SLE patients studied, 9 were fast acetylators, 8 were slow, and 1 was indeterminate. This result (53% fast) is similar to acetylator phenotypes in our normal controls (50% fast) and in the population at large (52%).