Results of a high-resolution genome screen of 437 Alzheimer's disease families

Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.     

Fine-needle aspiration of a primary mediastinal large B-cell lymphoma: a case report with cytologic, histologic, and flow cytometric considerations

Fine-needle aspiration (FNA) cytology and immunophenotyping by flow cytometry (FCM) are increasingly being used for diagnosing and subclassifying lymphoma in the REAL/WHO classification. Herein, we report a case of primary mediastinal large B-cell lymphoma (PMBL), a subtype of diffuse large B-cell lymphoma in the WHO classification, diagnosed by FNA cytology in conjunction with FCM. This, to our knowledge, has not previously been reported. A 57-yr-old woman presented with bilateral axillary lymphadenopathy and intermittent shortness of breath. CT scan revealed a 5-cm anterior mediastinal mass and mediastinal lymphadenopathy. Endoscopic ultrasound-guided FNA of a 4.5-cm subcarinal lymph node showed medium to large atypical lymphocytes with scant to moderate finely vacuolated cytoplasm. Nuclei were enlarged, cleaved, noncleaved, lobulated, and hyperchromatic. The background showed lymphoglandular bodies. Malignant large cell lymphoma was cytologically diagnosed. FCM, performed on a portion of the FNA specimen, demonstrated large B cells devoid of surface immunoglobulin expression, the characteristic immunophenotype of PMBL. The histologic diagnosis was PMBL. Touch-imprint cytology of the histologic specimen showed large cells with a narrow rim of clear cytoplasm and prominent outer cell border. Nuclear features were similar to the FNA specimen. In the presence of a mediastinal mass, FNA cytology in conjunction with FCM can effectively diagnose PMBL in the appropriate clinical setting.     

Defects in regulation of apoptosis in caspase-2-deficient mice

During embryonic development, a large number of cells die naturally to shape the new organism. Members of the caspase family of proteases are essential intracellular death effectors. Herein, we generated caspase-2-deficient mice to evaluate the requirement for this enzyme in various paradigms of apoptosis. Excess numbers of germ cells were endowed in ovaries of mutant mice and the oocytes were found to be resistant to cell death following exposure to chemotherapeutic drugs. Apoptosis mediated by granzyme B and perforin was defective in caspase-2-deficient B lymphoblasts. In contrast, cell death of motor neurons during development was accelerated in caspase-2-deficient mice. In addition, caspase-2-deficient sympathetic neurons underwent apoptosis more effectively than wild-type neurons when deprived of NGF. Thus, caspase-2 acts both as a positive and negative cell death effector, depending upon cell lineage and stage of development.     

Prevalence and correlates of HIV infection among young injection drug users in San Francisco

OBJECTIVE: We assessed the prevalence of HIV infection and associated risk behaviors among street-recruited young injection drug users (IDUs) in San Francisco. METHODS: In a cross-sectional study, 304 young (age <30 years) IDUs with a history of injecting in the previous 30 days were interviewed and tested for antibodies to HIV. Analyses assessing independent associations with HIV infection were limited to males only, due to the low number of infections in women. RESULTS: The prevalence of HIV infection was 5.3% overall but was highly stratified by gender and sexual preference (15.6% among homosexual/bisexual men vs. heterosexual men) and recruitment neighborhood (18% in the Polk Street area). Of 16 HIV infections, 14 (88%) were in males. Factors independently associated with HIV infection in males included sexual preference (homosexual/bisexual vs. heterosexual: adjusted odds ratio [AOR], 7.5; 95% confidence interval [CI], 1.5-36.6), recruitment neighborhood (Polk Street neighborhood vs. other neighborhoods: AOR, 4.8; 95% CI, 1.4-16.7), and duration of residence in San Francisco (>or=1 year vs. <1 year: AOR, 11.8; 95% CI, 1.4-95.8). CONCLUSIONS: The prevalence of HIV infection was highest among male IDUs who have sex with men. The strong associations between HIV infection and sexual orientation and HIV infection and recruitment locale suggest that risk may be attributable largely to sexual risk. In addition to successful prevention efforts aimed at reducing needle-associated risk, current intervention models aimed at young IDUs should target high-risk neighborhoods and emphasize sexual risk reduction measures, in particular among men who have sex with men.     

A novel method for selection of invasive tumor cells: Derivation and characterization of highly metastatic K1735 melanoma cell lines based onin vitro andin vivo invasive capacity

Tumor cell invasion of basement membranes is required at several steps in the process of metastasis. To study the genetic and biochemical events mediating invasion, a variant cell line (TK) was selected from the metastatic M2 K1735 murine melanoma cell line. A novel selection procedure was used, based onin vitro andin vivo invasion and growth upon basement membrane and stroma. Additionally, two extrapulmonary metastases of the TK cell line, TK-Eve and TK-Liver, were established as cell lines and characterized. The TK cell line demonstrates greater metastatic potentialin vivo and invasive abilityin vitro than the parent M2 cell line, confirming the validity of the selection procedure. In addition, the M2 and TK cell lines were examined for other cell functions involved in the metastatic process. Cellular growth rates and sensitivity to T lymphocyte and natural killer cell lysis were not determining factors in the metastatic potentials of the M2 and selected cell lines; possible macrophage contribution to metastatic behavior was noted. [³⁵S]methionine pulse labeling of protein synthesis and karyotypic analysis confirm the close relationship of parental and selected cell lines.Supported by contract NDI-23910.Supported by ACS Institution Grant IN-15-Y and NIH Grant MRC-5T34-GM08037.Was a fellow of the Jane Coffin Childs Memorial Fund for Medical Research. This investigation has been aided by a grant from the Jane Coffin Childs Memorial Fund for Medical Research. Also supported by NIH Postdoctoral Fellowship #HD06423.     

Human anti-acetylcholine receptor antibodies use variable gene segments analogous to those used in autoantibodies of various specificities

The production of autoantibodies to the nicotinic acetylcholine receptor are responsible for many of the neurological symptoms observed in myasthenia gravis. An understanding of the structural organization of the anti-receptor antibodies may help to define the role of these antibodies in the pathogenesis of this disease. The nucleotide sequences of the heavy and light chains of three human monoclonal anti-receptor antibodies isolated from peripheral blood lymphocytes from two patients with myasthenia gravis were analyzed. In addition, the structure of an anti-idiotypic antibody was studied. The V_H and V_L gene segments used in the anti-receptor antibodies appear to be derived from the same repertoire as gene segments that have been found in other autoantibodies isolated from patients with various autoimmune diseases. The IgM anti-receptor antibodies are direct copies of germline gene segments, while the structures of the IgG anti-receptor antibody and the anti-idiotypic antibody appear to be mutated suggesting that they have undergone antigenic selection.     

Prevalences, genotypes, and risk factors for HIV transmission in South America

HIV cross-sectional studies were conducted among high-risk populations in 9 countries of South America. Enzyme-linked immunosorbent assay screening and Western blot confirmatory testing were performed, and env heteroduplex mobility assay genotyping and DNA sequencing were performed on a subset of HIV-positive subjects. HIV prevalences were highest among men who have sex with men (MSM; 2.0%-27.8%) and were found to be associated with multiple partners, noninjection drug use (non-IDU), and sexually transmitted infections (STIs). By comparison, much lower prevalences were noted among female commercial sex workers (FCSWs; 0%-6.3%) and were associated mainly with a prior IDU and STI history. Env subtype B predominated among MSM throughout the region (more than 90% of strains), whereas env subtype F predominated among FCSWs in Argentina and male commercial sex workers in Uruguay (more than 50% of strains). A renewed effort in controlling STIs, especially among MSM groups, could significantly lessen the impact of the HIV epidemic in South America.     

The incorporation of iodine in thyroid hormone may stem from its role as a prehistoric signal of ecologic opportunity: an evolutionary perspective and implications for modern diseases

To optimize fitness under conditions of varying Darwinian opportunity, organisms demonstrate tremendous plasticity in their life-history strategies based on their perception of available resources. Higher-energy environments generally promote more aggressive life-history strategies, such as faster growth, larger adult size, greater genetic variation, shorter lifespan, larger brood sizes, and offspring ratio skewed towards the larger-sized gender. While numerous mechanisms regulate life-history plasticity including genetic imprinting, methylation, and growth factors, evidence suggests that thyroid hormone plays a central role. Given the pivotal adaptive role of thyroid hormone, the teleology of its dependence on dietary iodine for production remains unexplained. We hypothesize that iodine may have emerged as a substrate for production of thyroid hormone in prehistoric ecosystems because the former represented a reliable proxy for ecologic potential that enabled the latter to modulate growth, reproduction, metabolic rate, and lifespan. Such a scenario may have existed in early marine ecosystems where ocean-surface vegetation, which concentrates iodine for its antimicrobial and antioxidant properties, formed the basis of the food chain. Teleologic parallels can be drawn to the food-chain accumulation of antimicrobials that also exhibit antioxidant properties and promote adult size, brood size, and offspring quality by modulating central hormonal axes. As each higher species in the food chain tunes its life-history strategy based on iodine intake, the coupling of this functional role of iodine with its value as a resource signal to the next member of the food-chain may promote runaway evolution. Whereas predators in prehistoric ecosystems successfully tuned their life-history strategy using iodine as a major input, the strategy may prove maladaptive in modern humans for whom the pattern of iodine intake is decoupled from resource availability. Iodine acquired through sodium iodide supplementation may independently contribute to some biologic dysfunctions currently attributed to sodium.