Inclusion body myositis-like phenotype induced by transgenic overexpression of beta APP in skeletal muscle

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger amyloid-beta precursor protein (betaAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of betaAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted betaAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of betaAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for betaAPP mismetabolism in human IBM.     

Complete nucleotide sequence of an infectious clone of human T-cell leukemia virus type II: an open reading frame for the protease gene.

The entire nucleotide sequence of an infectious clone of human T-cell leukemia virus type II provirus was determined. This provirus consists of 8952 nucleotides. In addition to long terminal repeats and gag, pol, env, and X, a protease gene that is responsible for processing the gag precursor protein was found. The protease gene is encoded in a different frame from gag and pol and was located between the gag and pol open reading frames. The 5' region of the protease gene overlaps the 3' gag region. Coding regions of the provirus show about 60% homology with those of human T-cell leukemia virus type I at the nucleotide level. The evolutionary relationship between human T-cell leukemia virus types I and II is discussed.     

Use of spleen organ cultures to monitor hemopoietic progenitor cell regeneration following irradiation and marrow transplantation

After lethal irradiation of C57BL mice followed by the injection of 10(7) marrow cells, total cellularity and progenitor cell levels exceeded pretreatment levels within 12 days in the spleen, but regeneration remained incomplete in the marrow. The exceptional regenerative capacity of progenitor populations in the spleen was observed in organ cultures of spleen slices prepared 24 hr after irradiation and transplantation, excluding continuous repopulation from the marrow as a significant factor in splenic regeneration.     

Hormonal effects on cell proliferation in a human erythroleukemia cell line (K562)

We have investigated the hormonal responsiveness of K562 cells using a serum-substituted in vitro clonogenic assay. Dexamethasone inhibited colony formation by the K562 cells, and the inhibitory effect could be reversed by progesterone (10(-6) M). Fluoxymesterone caused a prominent enhancement of K562 colony growth, whereas estriol had no effect. Stimulation by triiodothyronine was maximal at 10(-7) M, and the thyroid effect could be abrogated by the beta 2-adrenergic antagonist butoxamine in equimolar concentrations. Using standard tissue culture conditions, the beta-adrenergic agent isoproterenol, but not the alpha catecholamine phenylephrine, enhanced the proliferation of K562 cells. When K562 cells were grown under hormone-depleted conditions, they developed responsiveness to phenylephrine and were no longer stimulated by isoproterenol. DbcAMP and prostaglandins of the E series also caused K562 colony enhancement. Prostaglandin F2 alpha had no effect on cell proliferation. Insulin was an effective stimulant of colony formation of K562 cells, as were human growth hormone and ovine prolacin. Bovine growth hormone had no effect. Our results are consistent with the identificaiton of K562 as an erythroid line, and they indicate that K562 cells respond to endocrine hormones in a manner analogous to normal erythroid progenitors.     

Human T-cell leukemia virus type II transforms normal human lymphocytes.

A unique human retrovirus (human T-cell leukemia virus type II, HTLV-II), isolated from a patient with a T-cell variant of hairy-cell leukemia, has been shown to be distinct from the more common isolates of human T-cell leukemia virus. This virus was tested for its ability to transform normal human peripheral blood lymphocytes. The HTLV-II-infected T-cell line Mo-T was lethally x-irradiated and cocultivated with normal human peripheral blood lymphocytes. The cocultivation of normal cells with Mo-T cells resulted in the transformation of the normal cells as evidenced by the establishment of permanent cell lines. The transformed cells are infected with HTLV-II as shown by immunologic tests and molecular hybridization. The cells are of mature T-cell phenotype and constitutively produce lymphokines. An Epstein-Barr virus-transformed lymphoblast B-cell line established from peripheral blood cells of the patient Mo, designated Mo-B, also was found to be infected with HTLV-II. All HTLV-II-infected cells, including the Mo-B cells, were capable of transforming normal cells of T-cell phenotype by transmission of virus by cocultivation. These results indicate that HTLV-II infects both B and T cells but transforms normal human peripheral blood lymphocytes of T-cell phenotype.     

Porcine reproductive and respiratory syndrome (PRRS): an immune dysregulatory pandemic

Porcine reproductive and respiratory disease syndrome (PRRS) is a viral pandemic that especially affects neonates within the “critical window” of immunological development. PRRS was recognized in 1987 and within a few years became pandemic causing an estimated yearly $600,000 economic loss in the USA with comparative losses in most other countries. The causative agent is a single-stranded, positive-sense enveloped arterivirus (PRRSV) that infects macrophages and plasmacytoid dendritic cells. Despite the discovery of PRRSV in 1991 and the publication of >2,000 articles, the control of PRRS is problematic. Despite the large volume of literature on this disease, the cellular and molecular mechanisms describing how PRRSV dysregulates the host immune system are poorly understood. We know that PRRSV suppresses innate immunity and causes abnormal B cell proliferation and repertoire development, often lymphopenia and thymic atrophy. The PRRSV genome is highly diverse, rapidly evolving but amenable to the generation of many mutants and chimeric viruses for experimental studies. PRRSV only replicates in swine which adds to the experimental difficulty since no inbred well-defined animal models are available. In this article, we summarize current knowledge and apply it toward developing a series of provocative and testable hypotheses to explain how PRRSV immunomodulates the porcine immune system with the goal of adding new perspectives on this disease.     

Adult memory for specific instances of a repeated event: a preliminary review

In cases of repeated victimisation, a complainant’s statement of abuse, and therefore memory, is often critical evidence for forensic investigations and legal proceedings. It is therefore important to understand the functioning of adults’ memory for repeated events. As such, the purpose of this paper was to review the extant literature on adult memory for instances of a repeated event. The results of the review revealed a small number of heterogeneous studies on adult repeated-event memory (N = 12). The literature so far shows that while adults might have difficulty in recalling information specific to instances (narrow accuracy), they are capable of remembering information across multiple instances (broad accuracy). It was also found that several factors may impact recall of instances including age, the number of experienced instances, rehearsing an event, repeated retrieval and event distinctiveness. The discussion highlights the forensic implications of this research and future research directions.