Citations

Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) ɛ4 allele, a common Alzheimer's susceptibility gene, have abnormally low measurements of the cerebral metabolic rate for glucose (CMRgl) in the same regions as patients with Alzheimer's dementia. In this article, we characterize longitudinal CMRgl declines in cognitively normal ɛ4 heterozygotes, estimate the power of PET to test the efficacy of treatments to attenuate these declines in 2 years, and consider how this paradigm could be used to efficiently test the potential of candidate therapies for the prevention of Alzheimer's disease. We studied 10 cognitively normal ɛ4 heterozygotes and 15 ɛ4 noncarriers 50–63 years of age with a reported family history of Alzheimer's dementia before and after an interval of approximately 2 years. The ɛ4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus, and these declines were significantly greater than those in the ɛ4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal ɛ4 heterozygotes are needed per active and placebo treatment group to detect a 25% attenuation in these CMRgl declines with 80% power and P = 0.005 in 2 years. Assuming these CMRgl declines are related to the predisposition to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study thousands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.

T helper 1 cells play a major role in protective immunity against mycobacterial pathogens. Since the antigen (Ag) specificity of CD4 + human T cells is strongly controlled by HLA class II polymorphism, the immunogenic potential of candidate Ags needs to be defined in the context of HLA polymorphism. We have taken advantage of class II-deficient (Ab 0 ) mice, transgenic for either HLA-DRA/B1*0301 (DR3) or HLA-DQB1*0302/DQA*0301 (DQ8) alleles. In these animals, all CD4 + T cells are restricted by the HLA molecule. We reported previously that human DR3-restricted T cells frequently recognize heat shock protein (hsp)65 of Mycobacterium tuberculosis , and only a single hsp65 epitope, p1–20. DR3.Ab 0 mice, immunized with bacillus Calmette–Guérin or hsp65, developed T cell responses to M. tuberculosis , and recognized the same hsp65 epitope, p1–20. Hsp65-immunized DQ8.Ab 0 mice mounted a strong response to bacillus Calmette–Guérin but not to p1–20. Instead, we identified three new DQ8-restricted T cell epitopes in the regions 171–200, 311–340, and 411–440. DR3.Ab 0 mice immunized with a second major M. tuberculosis protein, Ag85 (composed of 85A, 85B, and 85C), also developed T cell responses against only one determinant, 85B p51–70, that was identified in this study. Importantly, subsequent analysis of human T cell responses revealed that HLA-DR3+, Ag85-reactive individuals recognize exactly the same peptide epitope as DR3.Ab 0 mice. Strikingly, both DR3-restricted T cell epitopes represent the best DR3-binding sequences in hsp65 and 85B, revealing a strong association between peptide-immunodominance and HLA binding affinity. Immunization of DR3.Ab 0 with the immunodominant peptides p1–20 and p51–70 induced T cell reactivity to M. tuberculosis . Thus, for two different Ags, T cells from DR3.Ab 0 mice and HLA-DR3+ humans recognize the same immunodominant determinants. Our data support the use of HLA-transgenic mice in identifying human T cell determinants for the design of new vaccines.

Ectomesenchymomas (EM) are rare malignant neoplasms usually consisting of rhabdomyosarcoma (RMS) with a neural component. Only 21 cases have been previously reported. Here we extend the clinicopathologic spectrum of EM by describing our findings in 15 cases. Only 5 patients were infants; 10 were ≤3 years old and 5 were ≥6 years old. No male predilection was observed; 7 were female. The originating institutional diagnoses were; RMS (12), undifferentiated sarcoma (1), or EM (2), suggesting underdiagnosis of this entity. The primary tumor sites included external genital (5), pelvis/abdomen (6), head and neck (3), and extremity (1). The size of the primary neoplasm was usually ≥5 cm at diagnosis but dissemination only occurred in a minority. Local infiltration was not uncommon. These neoplasms were typically multilobate, thinly encapsulated, hemorrhagic, and necrotic. Light microscopic features were highly variable, but embryonal RMS with scattered or clustered ganglion cells, often in lacunae, was characteristic. In some cases, primitive neuroblastic or neuroectodermal areas were found and/or a component of alveolar RMS was seen. Focal anaplasia was occasionally observed. Mitotic activity appears higher than previously appreciated and some necrosis was invariably present. Electron microscopy was performed in 11 cases, which confirmed skeletal muscle ± neural differentiation. Cytogenetic studies performed in five cases revealed no specific abnormality. Monoclonal neuron-specific enolase was the best marker of ganglion cells and primitive neural elements. MIC-2 (CD99) membrane expression was not definitively present in any of the six cases examined. A number of the above parameters appear to be of some prognostic significance, but overall, these neoplasms appear to have a similar outcome as would be predicted for their RMS element alone (exclusive of any neural component), with respect to the RMS subtype, age of the patient, and anatomic location of the neoplasm.