Induction of CD4 expression and human immunodeficiency virus type 1 replication by mutants of the interferon-inducible protein kinase PKR

Replication of the human immunodeficiency virus type 1 (HIV-1) is inhibited by interferons (IFNs), and the IFN-inducible protein kinase PKR is thought to mediate this effect by regulating protein synthesis. Here we report that ectopic expression of dominant negative PKR mutants in Jurkat cells induces HIV-1 replication. Specifically, expression of CD4 is upregulated by the PKR mutants, and this correlates with an induction of HIV-1 binding and proviral DNA synthesis upon HIV-1 infection. Moreover, activation of NF-kappaB was induced by an RNA binding-defective mutant of PKR. Thus, it appears that PKR, in addition to translational control, is involved in HIV-1 replication by modulating virus binding through the regulation of CD4 expression and virus gene expression through the activation of NF-kappaB.     

Diagnosis of deep vein thrombosis, an overview

This article reviews the role of dendritic cells in cutaneous immunity. Langerhans cells (LC) found in the epidermis are the best-characterized dendritic cell population. They have the ability to process antigen in the periphery, transport it to the draining lymph nodes (DLN) where they are able to cluster with, and activate, antigen-specific naive T cells. During migration LC undergo phenotypic and functional changes which enable them to perform this function. There are other less well-characterized dendritic cells including dendritic epidermal T cells, dermal dendrocytes and dermal "LC-like' cells. Although there is no evidence that dendritic epidermal T cells (DETC) can present antigen or migrate to lymph nodes, they do influence the intensity of cutaneous immune responses to chemical haptens. Antigen-presenting cells (APC) in the dermis may provide alternative routes of antigen presentation which could be important in the regulation of skin immune responses. Therefore, dendritic cells are vital for the induction of immune responses to antigens encountered via the skin. LC are particularly important in primary immune responses due to their ability to activate naive T cells. The faster kinetics of secondary responses, and the ability of nonprofessional APC to induce effector function in previously activated cells, suggest that antigen presentation in the DLN may be less important in responses to previously encountered antigens. In these secondary responses, dendritic and nondendritic APC in the skin may directly induce effector functions from antigen-specific recirculating cells.     

Modulating L-type calcium current affects discontinuous cardiac action potential conduction

We have used pairs of cardiac cells (i.e., one real guinea pig ventricular cell and a real-time simulation of a numerical model of a guinea pig ventricular cell) to evaluate the effects on action potential conduction of a variable coupling conductance in combination with agents that either increase or decrease the magnitude of the L-type calcium current. For the cell pairs studied, we applied a direct repetitive stimulation to the real cell, making it the "leader" cell of the cell pair. We have demonstrated that significant delays in action potential conduction for a cell pair can occur either with a decreased value of coupling conductance or with an asymmetry in size such that the follower cell is larger than the leader cell. In both conditions we have shown that isoproterenol, applied to the real cell at very low concentrations, can reversibly decrease the critical coupling conductance (below which action potential conduction fails) for a cell pair with fixed cell sizes, or, for a fixed value of coupling conductance, increase the maximum allowable asymmetry in cell size for successful conduction. For either of these effects, we were able to show that treatment of the real cell with BayK 8644, which more specifically increases the magnitude of the L-type calcium current, was able to mimic the actions of isoproterenol. Treatment of the leader cell of the cell pair (the real cell) with nifedipine, which selectively lowers the magnitude of the L-type calcium current, had effects opposite those of isoproterenol or BayK 8644. The actions of nifedipine, isoproterenol, and BayK 8644 are all limited to conditions in which the conduction delay is on the order of 5 ms or more, whether this delay is caused by limited coupling conductance or by asymmetry in size of the cells. This limitation is consistent with the time course of the L-type calcium current and suggests that the effects of calcium channel blockers or beta-adrenergic blocking drugs, in addition to being selective for regions of the heart that depend on the L-type calcium current for the upstroke of the action potential, would also be somewhat selective for regions of the heart that have discontinuous conduction, either normally or because of some pathological condition.     

The informal community caregiver: a link between the health care system and local residents

A group of "informal" caregivers, local people to whom residents turn for information and advice, was identified in the east Harlem community and enlisted in a two-month study. Results suggest that formal human services agencies and their intended clientele would benefit by increased efforts on the part of these institutions to locate and work with community caregivers.     

Astigmatism, accommodation, the oblique effect and meridional amblyopia

Agonist binding to GABAB receptors modulates the activity of the guanine nucleotide binding proteins, Go and Gi. These G proteins are ADP-ribosylated by pertussis toxin and this prevents them from coupling to the GABAB receptor resulting in a reduction in high-affinity GABAB binding. GTP, which binds to a different site on the G protein alpha subunit, also reduces the affinity of the receptor for the G protein, and this can be used as a "marker" for G protein-GABAB receptor linkage. We have examined GABAB binding site distribution in rat brain after unilateral intrahippocampal pertussis toxin injection in vivo, and after incubating brain slices in pertussis toxin in vitro, using the technique of receptor autoradiography. The effect of pertussis toxin was compared with that of GTP gamma S on GABAB binding. Intrahippocampal pertussis toxin administration reduced GABAB but not GABAA receptor binding and the effects appeared to be limited by pertussis toxin diffusion. More widespread reductions in GABAB binding were seen after incubation of brain slices in vitro but the extent varied in different brain regions. No reduction was detected in the corpus striatum. GABAB binding was also reduced in membranes prepared from cerebral cortex, hippocampus and cerebellum but there was no significant reduction in the corpus striatum after pertussis toxin treatment. GTP gamma S reduced GABAB binding to a similar extent in all areas studied irrespective of their sensitivity to pertussis toxin suggesting that while GABAB binding sites are linked to G proteins throughout the rat brain, those in the corpus striatum may be predominantly pertussis toxin insensitive.     

Serotonin modulates spike backpropagation and associated [Ca2+]i changes in the apical dendrites of hippocampal CA1 pyramidal neurons

The effect of serotonin (5-HT) on somatic and dendritic properties was analyzed in pyramidal neurons from the CA1 region in slices from the rat hippocampus. Bath-applied 5-HT (10 microM) hyperpolarized the soma and apical dendrites and caused a conductance increase at both locations. In the dendrites (200-300 microm from the soma) trains of antidromically activated, backpropagating action potentials had lower peak potentials in 5-HT than in normal artificial cerebrospinal fluid. Spike amplitudes were about the same in the two solutions. Similar results were found when the action potentials were evoked synaptically with stimulation in the stratum oriens. In the soma, spike amplitudes increased in 5-HT, with only a small decrease in the peak potential. Calcium concentration measurements, made with bis-fura-2 injected through patch electrodes, showed that the amplitude of the [Ca2+]i changes was reduced at all locations in 5-HT. The reduction of the [Ca2+]i change in the soma was confirmed in slices where cells were loaded with fura-2-AM. The reduction at the soma in 5-HT, where the spike amplitude increased, suggests that the reduction is due primarily to direct modulation of Ca2+ channels. In the dendrites, the reduction is due to a combination of this channel modulation and the lowering of the peak potential of the action potentials.     

The economic costs associated with body mass index in a workplace

This study was undertaken to determine if a progressive correlation exists between body mass index (BMI), health care costs, and absenteeism and to identify an economically optimal BMI. We studied 3,066 First Chicago NBD employees by using health risk appraisals and personnel data. Analysis was completed for those employees with and without a risk for BMI. People at risk for BMI are more likely to have additional health risks, short-term disability and illness absence, and higher health care costs than those not at risk for BMI. A "J-shaped" curve between health care costs and BMI exists, with the low point occurring at about 25 to 27 kg/m2. We concluded that indirect and direct costs to an employer increase with increasing BMI. Employers may benefit from helping employees achieve a healthy weight. The initial target population should be those who are at highest risk of complications from obesity.     

Idiopathic perforation of a porcine aortic bioprosthesis in the aortic position

The report of a failure of glutaraldehyde-preserved porcine aortic xenograft bioprosthesis in the aortic position after 13 months is presented. Severe aortic regurgitation resulted from three "idiopathic" perforations in one of the cusps, and a linear tear in another cusp. Light and electron microscopy showed generalized degeneration of collagen thoughout the faulty valve. The absence of a platelet-fibrin coat on edges of the tear suggested a recent origin, compatible with cardiac catheter manipulation during unsuccessful attempts to cross the valve. The histopathologic data from this valve correlate with previously reported failures with formaldehyde preserved xenograft valves.