Volume 4 Issue 7, July 1998

Several neurodegenerative disorders are characterized by intracellular protein accumulations or inclusions, such as the Lewy bodies of Parkinson's disease. Although little is know about the origin of these accumulations and their specific affect on neurons, it seems likely that as they grow they prove fatal to the cell. Here Michael Brownstein and colleagues speculate on a broad role for alpha synuclein in the development of Lewy bodies and the other protein inclusions associated with neurodegeneration.

With the identification of several Alzheimer disease (AD)-associated genes, genetic testing for AD is possible. However, as for some other-late onset disorders, the ethical and social implications of such tests are considerable. In response to the commercial availability and the likely increased use of AD genetic tests, The Stanford Program in Genomics, Ethics, and Society formed a broad-based working group to examine the pros and cons of testing. Here they present their recommendations.

New clinical reports demonstrate that targeting the biological pathways of hormone and peptide growth factor receptors holds promise for the prevention and treatment of breast cancer.

In the second Leverhulme lecture, David Nabarro (Department for International Development) discusses the lessons learnt from health issues of the last 20 years and the challenges facing health care in the 21st century.

New evidence identifies γδ T cells as key players in both epithelial defense and the regulation of innate and acquired immune responses.

New evidence shows that the interstitial cells of Cajal are the intestinal pacemaker cells that regulate gut motility (pages 848–851).

A new high-throughput tissue microarray technology is capable of simultaneously testing hundreds of tumor samples for a number of different molecular markers (pages 848–847).

Catecholamine-induced release of the immunosuppressive cytokine IL-10 is associated with an increase in infection and sepsis among patients with acute brain injury (803–813).

Evidence emerges that Coxsackie virus-induced autoimmune insulin-dependent diabetes mellitus in mice may be caused by bystander activation of T cells or other mechanisms distinct from molecular mimicry (pages 781–785).

The development of a primate model, a potential diagnostic test and a novel therapeutic strategy contribute to our understanding of the role of amyloid β in Alzheimer's disease (pages 822–834).

A new generation of NSAIDs selectively and irreversibly inhibits cyclooxygenase-2—an enzyme that regulates several cellular processes involved in colon cancer development including angiogenesis.

Allelic variants for the HIV-1 co-receptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the co-receptor CXCR4, stromal-derived factor (SDF-1), have been associated with a delay in disease progression. We began this study to test whether polymorphisms in the CCRS regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals. Here we describe the evolutionary relationships between the phenotypically important CCRS alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-Δ32 and CCR2-64I polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression. The disease-retarding effects of the CCR2-64I allele were found in African Americans but not in Caucasians, and the SDF1-3′A/3′A genotype was associated with an accelerated progression to death. In contrast, the CCR5-Δ32 allele and a CCR5 promoter mutation with which it is tightly linked were associated with limited disease-retarding effects. Collectively, these findings draw attention to a complex array of genetic determinants in the HIV-host interplay.

We show that the fraction of proliferating CD4⁺ lymphocytes is similar in HIV-infected subjects in the early stage of disease and in HIV-negative subjects, whereas the fraction of proliferating CD8+ lymphocytes is increased 6.8-fold in HIV-infected subjects. After initiation of antiviral therapy, there is a late increase in proliferating CD4⁺ T cells associated with the restoration of CD4⁺ T-cell counts. These results provide strong support for the idea of limited CD4⁺ T-cell renewal in the early stage of HIV infection and indicate that after effective suppression of virus replication, the mechanisms of CD4⁺ T-cell production are still functional in early HIV infection.

Components of the transforming growth factor-β (TGF-β) signal pathway function as classic tumor suppressors, but the role of the TGF-βs themselves is less clear. Here we show that mice heterozygous for deletion of the TGF-β1 gene express only 10–30% of wild-type TGF-β1 protein levels. Although grossly normal, these mice have a subtly altered proliferative phenotype, with increased cell turnover in the liver and lung. Treatment of these mice with chemical carcinogens resulted in enhanced tumorigenesis when compared with wild-type littermates. However, tumors in the heterozygous mice did not lose the remaining wild-type TGF-β1 allele, indicating that the TGF-β1 ligand is a new form of tumor suppressor that shows true haploid insufficiency in its ability to protect against tumorigenesis.