Expression of the macrophage scavenger receptor, a multifunctional lipoprotein receptor, in microglia associated with senile plaques in Alzheimer's disease.

The macrophage scavenger receptor is a multifunctional receptor whose ligands include oxidized low density lipoprotein (LDL), as well as several other polyanionic macromolecules. Although the capacity of the receptor to bind modified LDL has implicated it in the process of atherosclerosis, its physiological role remains uncertain. We have examined human brain for expression of macrophage scavenger receptor as part of ongoing studies of lipoprotein receptors in the central nervous system. The receptor is expressed on microglia, but not on astrocytes, neurons, or vessel-associated structures. In Alzheimer disease, there is strong expression of the scavenger receptor in association with senile plaques.     

Effect of age on behavioral and enzymatic changes during thiamin deficiency

Open field behavior and whole brain enzymatic activities were determined during thiamin deficiency in two strains of young, as well as in aged mice. In young CD-1 mice, thiamin deficiency reduced total distance traveled and vertical movements after 7 days and the decline was more than 50% by day 9. The behavioral deficit was highly correlated to decreases in 2-oxoglutarate dehydrogenase activity (KGDH). The open field behavior of Balb/c mice was about 40% less than in CD-1 mice and responded in a qualitatively different manner to thiamin deficiency. The activity of the Balb/c mice increased and then decreased with thiamin deficiency. The activity of 3 month old mice peaked on day 6 (126% of initial score), whereas 10 and 30 month mice showed a much greater increase (about 175% of initial scores), but on day 7. Although the activity of the thiamin dependent enzyme transketolase (TK) was affected similarly at all ages, the activity of KGDH in the aged brain was more sensitive to thiamin deficiency than in the young; KGDH activity declined 41%, 57% or 74% at 3, 10, or 30 months, respectively. Thus, the current mouse model is an attractive one to study the interaction of thiamin deficiency with aging.     

Sequence variation and size ranges of CAG repeats in the Machado-Joseph disease, spinocerebellar ataxia type 1 and androgen receptor genes

A subgroup of trinucleotide repeat diseases result from abnormalexpansions of CAG repeats which are translated into polyglutaminestretches. As yet there is little understanding of how the polyglutaminesfunction either normally, or when expanded. We have investigatedthese sequences in the Machado-Joseph disease, androgen receptorand spinocerebellar ataxia type 1 genes in humans and otherprimates. None of the 748 normal chromosomes that were examinedhad more than 34 uninterrupted gluta-mine codons in the Machado-Josephdisease gene. Similarly, no normal alleles with more than 39uninterrupted glutamine codons have been reported for the otherdisease genes associated with polyglutamine expansions. Sequenceanalyses of the repeats in primates revealed shorter polyglutaminestretches in some of the non-human primates at all three lociand marked diversions from the expected polyglutamines in theorang-utan Machado-Joseph gene and in the marmoset spinocerebellarataxia type 1 gene. These data suggest that conservation ofthese polyglutamine stretches may not always be necessary fornormal gene function.     

Changes in peritoneal myeloid populations and their proinflammatory cytokine expression during infection with Listeria monocytogenes are altered in the absence of gamma/delta T cells

Evidence that gamma/delta T cells play a broad, immunoregulatory role has been accumulating steadily. We show here that myeloid cells are disregulated after peritoneal infection with Listeria monocytogenes in mice lacking gamma/delta T cells. Inflammatory populations of neutrophils and monocytes recruited to the site of infection remained longer. Intracellular cytokine analysis showed that frequencies of myeloid cells producing interleukin-12 and tumor necrosis factor alpha were higher and remained elevated longer after infection in mice genetically deficient in gamma/delta T cells. In vivo dye-tracking studies indicated that the majority of inflammatory monocytes differentiated into resident tissue macrophages in situ. In vitro experiments confirmed that monocytes harvested from mice lacking gamma/delta T cells were defective in their maturation process. This evidence suggests that gamma/delta T cells promote differentiation in the monocyte/macrophage lineage. These cells are important for bactericidal activity, inflammatory cytokine production, clearance of inflammatory neutrophils, and ultimately, antigen presentation to T cells. Regulation of monocyte/macrophage differentiation may underlie a broad segment of the phenotypic alterations that have been reported in mice lacking gamma/delta T cells.     

Innovations in curriculum design: A multi-disciplinary approach to teaching statistics to undergraduate medical students

Background  

Statistics is relevant to students and practitioners in medicine and health sciences and is increasingly taught as part of the medical curriculum. However, it is common for students to dislike and under-perform in statistics. We sought to address these issues by redesigning the way that statistics is taught.     

Search for a human leukemia virus

Summary In summary, we examined the bone marrow and blood of 107 leukemic children for the presence of virus or virus-like structures. Material for study included both fresh specimens and cells cultivated over varying periods of time. In four instances in which patients' plasma was inoculated onto human amnion cells and in one instance of cultivated bone marrow, we observed particles morphologically similar to myxoviruses. Indirect immunofluorescence testing for antigens of murine leukemia viruses failed to demonstrate fluorescence in leukemic cells. Studies are in progress on a continuous leukemic bone marrow culture to recover in recognizable form either replicating virus or viral genome.Dedicated to ProfessorJohn F. Enders on the occasion of his 70th birthday.These studies were supported by U.S.P.H.S. Grants CA 05176, CA 08480 and CA 07054, from the National Cancer Institute and by American Lebanese Syrian Associated Charities (ALSAC).     

Escherichia coli and Staphylococcus aureus elicit differential innate immune responses following intramammary infection

Staphylococcus aureus and Escherichia coli are among the most prevalent species of gram-positive and gram-negative bacteria, respectively, that induce clinical mastitis. The innate immune system comprises the immediate host defense mechanisms to protect against infection and contributes to the initial detection of and proinflammatory response to infectious pathogens. The objective of the present study was to characterize the different innate immune responses to experimental intramammary infection with E. coli and S. aureus during clinical mastitis. The cytokine response and changes in the levels of soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP), two proteins that contribute to host recognition of bacterial cell wall products, were studied. Intramammary infection with either E. coli or S. aureus elicited systemic changes, including decreased milk output, a febrile response, and induction of the acute-phase synthesis of LBP. Infection with either bacterium resulted in increased levels of interleukin 1beta (IL-1beta), gamma interferon, IL-12, sCD14, and LBP in milk. High levels of the complement cleavage product C5a and the anti-inflammatory cytokine IL-10 were detected at several time points following E. coli infection, whereas S. aureus infection elicited a slight but detectable increase in these mediators at a single time point. Increases in IL-8 and tumor necrosis factor alpha were observed only in quarters infected with E. coli. Together, these data demonstrate the variability of the host innate immune response to E. coli and S. aureus and suggest that the limited cytokine response to S. aureus may contribute to the well-known ability of the bacterium to establish chronic intramammary infection.