CDC42 and Rac1 are implicated in the activation of the Nef-associated kinase and replication of HIV-1

BACKGROUND: The negative factor (Nef) of human and simian immunodeficiency viruses (HIV-1, HIV-2 and SIV) is required for high levels of viremia and progression to AIDS. Additionally, Nef leads to cellular activation, increased viral infectivity and decreased expression of CD4 on the cell surface. Previously, we and others demonstrated that Nef associates with a cellular serine kinase (NAK) activity. Recently, it was demonstrated that NAK bears structural and functional similarity to p21-activated kinases (PAKs). RESULTS: In this study, we demonstrate that Nef not only binds to but also activates NAK via the small GTPases CDC42 and Rac1. First, the dominant-negative PAK (PAKR), via its GTPase-binding domain, and dominant-negative GTPases (CDC42Hs-N17 and Rac1-N17) block the ability of Nef to associate with and activate NAK. Second, constitutively active small GTPases (CDC42Hs-V12 and Rac1-V12) potentiate the effects of Nef. Third, interactions between Nef and NAK result in several cellular effector functions, such as activation of the serum-response pathway. And finally, PAKR, CDC42Hs-N17 and Rac1-N17 decrease levels of HIV-1 production to those of virus from which the nef gene is deleted. CONCLUSIONS: By activating NAK via small GTPases and their downstream effectors, Nef interacts with regulatory pathways required for cell growth, cytoskeletal rearrangement and endocytosis. Thus, NAK could participate in the budding of new virions, the modification of viral proteins and the increased endocytosis of surface molecules such as CD4. Moreover, blocking the activity of these GTPases could lead to new therapeutic interventions against AIDS.     

Vegetational association of host-seeking adult blacklegged ticks, Ixodes scapularis Say (Acari: Ixodidae), on dairy farms in northwestern Wisconsin

Non-obese diabetic NOD/SCID mice have been used to grow human leukaemia as a systemic disease. The animals were inoculated with leukaemic cells obtained from a 36-year-old male with early B-cell precursor acute lymphoblastic leukaemia and on day 15 were given the first of three weekly injections of 1 mg/kg vincristine or equimolar liposomal vincristine. The development of leukaemia in the mice was monitored by taking weekly blood samples and measuring the cell content by flow cytometry. The median time to 50% human cells in the peripheral blood of mice treated with free vincristine was 41 d from the start of treatment compared with 49 d for mice treated with liposomal vincristine (P < 0.01). The median day of death for mice treated with free vincristine was 47 d from the start of treatment and 57 d for mice receiving liposomal vincristine (P<0.01), thus providing a 21% increase in lifespan for animals treated with the liposomal preparation. There was slightly greater weight loss in mice treated with free vincristine than those given liposomal vincristine. Measurement of in vitro colony forming bone marrow progenitor cells in similarly treated, tumour-free mice, showed no difference in progenitor cell survival between mice that received either type of vincristine. We conclude that encapsulating vincristine in liposomes improves the therapeutic index of this drug measured in mice bearing human leukaemia. This may lead to use of the drug in conventional combination chemotherapy with greater safety or, in this setting, at higher dosage.     

Selection of task-dependent diffusion filters for the post-processing of SPECT images

Iterative reconstruction from single photon emission computed tomography (SPECT) data requires regularization to avoid noise amplification and edge artefacts in the reconstructed image. This is often accomplished by stopping the iteration process at a relatively low number of iterations or by post-filtering the reconstructed image. The aim of this paper is to develop a method to automatically select an optimal combination of stopping iteration number and filters for a particular imaging situation. To this end different error measures between the distribution of a phantom and a corresponding filtered SPECT image are minimized for different iteration numbers. As a study example, simulated data representing a brain study are used. For post-reconstruction filtering, the performance of 3D linear diffusion (Gaussian filtering) and edge preserving 3D nonlinear diffusion (Catté scheme) is investigated. For reconstruction methods which model the image formation process accurately, error measures between the phantom and the filtered reconstruction are significantly reduced by performing a high number of iterations followed by optimal filtering compared with stopping the iterative process early. Furthermore, this error reduction can be obtained over a wide range of iteration numbers. Only a negligibly small additional reduction of the errors is obtained by including spatial variance in the filter kernel. Compared with Gaussian filtering, Catté diffusion can further reduce the error in some cases. For the examples considered, using accurate image formation models during iterative reconstruction is far more important than the choice of the filter.     

Mental disorders in elderly suicide

The purpose of this study was to investigate the prevalence and comorbidity of current mental disorders defined by DSM-III-R among elderly suicide victims and to compare them with the mental disorders among younger victims. Using a psychological autopsy method, we collected comprehensive data on all suicides in Finland during 1 year. Retrospective Axis I-III consensus diagnoses were assigned to a random sample consisting of 43 victims aged 60 years or over and 186 victims aged under 60 from the nationwide suicide population. At least one Axis I diagnosis was made for 91% of the elderly victims. Major depression as the principal diagnosis was more common among the elderly victims. Almost all elderly female victims were major depressives. Psychiatric comorbidity was more common among elderly male than among elderly female victims. More of the elderly victims (88%) than the younger (36%) received Axis III diagnoses. Suicide among the elderly without a diagnosable mental disorder and somatopsychiatric comorbidity seems to be rare.     

Study of the phlebotomines (Diptera, Psychodidae), in area of cutaneous leishmaniasis in the State of Mato Grosso do Sul, Brazil

Interleukin-1 beta (IL-1 beta) significantly inhibits insulin secretion from glucose stimulated islet cells. The mechanism for this inhibition has been hypothesized to be due to stimulation of the inducible form of nitric oxide synthase and a resulting increase in nitric oxide (NO) concentration. Ways to block the effect of IL-1 beta have focused on blocking the binding of IL-1 beta to the IL-1 receptor and the use of antioxidants to neutralize increases in NO. This report focuses on a 33 residue peptide synthesized based on the C-terminal region of the IL-1 beta molecule, a reported binding site of the IL-1 beta molecule, and the redoxcycling antioxidant pyrroloquinoline quinone (PQQ). The 33 residue peptide did not function as an antagonist, but as a weak agonist. High concentrations of PQQ itself inhibited glucose-dependent insulin release while low concentrations did not. PQQ had no effect on the actions of IL-1 beta. Three isosteric and isomeric analogues of PQQ were also investigated. One of the PQQ isomers had an inhibitory effect on insulin secretion at low concentrations where PQQ had no effect. These results reflect the sensitivity of islets to oxidative stress.     

Bovine mastitis due to algae of the genus Prototheca

A survey of the prevention of disability policy and activities in a random sample of 200 ILEP assisted projects was conducted in 1995. This was followed by a workshop of field experts in different aspects of prevention of disability who work in different geographical regions. The survey findings and state of current knowledge on prevention of disability were reviewed during the workshop and recommendations on the planning, implementation, and evaluation of simple and effective prevention of disability developed. Prevention of disability includes complex activities, such as nerve decompression and reconstructive surgery, however these recommendations focus on the simple techniques and approaches which can be implemented through leprosy control programmes, primary health care and community-based rehabilitation. These recommendations have been approved by the ILEP Medical Commission, and reported in the ILEP Medical Bulletin (N degree 8, December 1995).