Pharmacokinetics of hyperimmune anti-human immunodeficiency virus immunoglobulin in persons with AIDS

Hyperimmune anti-human immunodeficiency virus immunoglobulin (HIVIG) is an intravenous immunoglobulin prepared from HIV-infected asymptomatic donors with a CD4 cell count greater than 400 cells/microl and a high titer of antibody to HIV-1 p24 protein. Twelve persons with AIDS received four doses of HMG (two at 50 mg/kg of body weight and then two at 200 mg/kg) every 28 days. Pharmacokinetics were evaluated by measurement of anti-p24 antibody. HIVIG was well tolerated, and all participants completed the study. Three subjects who were not receiving Pneumocystis carinii pneumonia (PCP) prophylaxis developed PCP. The mean value for HIVIG clearance was 3.02 ml/kg/day at 50 mg/kg and 3.65 ml/kg/day at 200 mg/kg (P = 0.027); the mean trough antibody titers (reciprocal units) were 1,442 and 4,428, respectively. This study indicates that high titers of anti-p24 antibody can be maintained with a monthly administration schedule of HIVIG and that short-term safety is acceptable. Comparisons to evaluate the therapeutic potential of HIVIG are justified.     

Protein kinase A activators inhibit agonist induced prostaglandin production in human amnion

Prostaglandin (PG) production by human amnion has been postulated to have a role in the onset of labor. Previous work by ourselves and others has demonstrated that oxytocin, phorbol esters and epidermal growth factor (EGF) increase PGE2 production in human amnion cells by activation of the Phospholipase C/Protein Kinase C (PKC) cascade system. The present study was undertaken to determine the effect of prior activation of the Adenylate Cyclase cascade system upon subsequent stimulation of PGE2 production by oxytocin, phorbol 12-myristate-13-acetate (PMA) or EGF in amnion cells and membrane discs. Isoproterenol, forskolin and dibutyryl cyclic adenosine monophosphate (dbcAMP) were utilized to activate the Adenylate Cyclase system at the receptor, enzyme and second messenger level. In control amnion cells, oxytocin, PMA and EGF each provoked dose dependent increases in PGE2 production. In cells preincubated with dbcAMP, forskolin or isoproterenol, agonist stimulated PGE2 production was markedly (50-90%) inhibited (p < 0.01). Inhibition was dose dependent upon preincubator concentrations. Maximal inhibition by adenylate cyclase activators occurred with 2-4 h of preincubation. In membrane discs, forskolin preincubation also inhibited oxytocin, PMA and EGF stimulation of PGE2 production. Activation of the Adenylate Cyclase system in human amnion cells or membrane discs inhibits the subsequent action of potent stimulators of PGE2 production in human amnion.     

Intrauterine transfusions influence fetal leukocyte counts and subsets

Histamine is an important mediator in allergic reactions, gastric acid secretions, and neurotransmission in the central nervous system. Basophils and mast cells are the main sources of histamine, which is formed from L-histidine by histidine decarboxylase (HDC). However, the regulatory mechanism of HDC in these cells remains unclear. We examined the regulation of HDC activity and gene expression using a unique human mast cell line, HMC-1, after stimulation with phorbol 12-myristate 13-acetate (PMA) or ionomycin. HDC activity was increased from 52.1+/-0.4 (mean+/-standard deviation) to 154+/-6.9, or 105.6+/-6.2 pmol/min/mg protein (n = 3), 4 hours after stimulation with PMA (10 ng/mL) or ionomycin (10[-6] M). Although actinomycin D had no effect on this increase, cycloheximide completely inhibited the increase caused by these stimuli. The population of HMC-1 cells containing HDC protein was increased after stimulation with either PMA or ionomycin as evaluated by immunocytochemical analysis with anti-HDC antibody as a marker. HMC-1 constitutively expressed HDC mRNA, and its level was not increased with these stimuli. These results suggest that the increase of HDC activity in HMC-1 induced by PMA or ionomycin is regulated at the translational level.     

Experimental studies of mechanically-induced articular cartilage defects following implantation of allogeneic embryonal chondrocytes in a collagen-fibrin gel in chickens

Full thickness defects (diameter 1,7 mm; depth 2,5 mm) were created mechanically in articular cartilage and subchondral bone of the condyles of tibiotarsal joints of 9-month old chickens. This full-thickness defects were repaired with cultured allogenic embryonic chick epiphyseal chondrocytes from the tibiae and femura of 10-days-old chicken embryos. The cells were embedded in a collagen-fibrinogen-matrix. Controls were similarly operated, but received either no treatment or implants the delivery substance only. Healing of the defects was observed macroscopically, histologically, histochemically and histomorphometrically after 3, 12 and 24 weeks. This graft was successfully transplanted in mechanically induced defects in 80%. The resulting hyaline cartilage was structurally reorganized according to the host pattern and under the influence of environmental conditions. The articular zone preserved it's cartilaginous phenotype, whereas the subchondral regions were transformed into bone. 12 weeks after the operation the defects in the experimental group were completely filled. In all instances in this group, there was an initial extreme increase of mitotic rate and cell number. After 24 weeks normal and subnormal values were founded. The defects in the control groups healed with fibrocartilage. Our results showed, that only the defects in the experimental group were completely filled with reparative hyaline cartilage tissue. In the present study the mixture of cultured allogenic embryonic chondrocytes and a collagen-fibrinogen-matrix was used successfully as a transplant for repairing defects in articular cartilage of chickens. Thus allogenic transplantation of cultured embryonal chondrocytes appears to be one of the most promising methods for the restoration of articular cartilage.     

SH3 binding domains in the dopamine D4 receptor

The dopamine D4 receptor is a G protein-coupled receptor (GPCR) that belongs to the dopamine D2-like receptor family. Functionally, the D2-like receptors are characterized by their ability to inhibit adenylyl cyclase. The dopamine D4 receptor as well as many other catecholaminergic receptors contain several putative SH3 binding domains. Most of these sites in the D4 receptor are located in a polymorphic repeat sequence and flanking sequences in the third intracellular loop. Here we demonstrate that this region of the D4 receptor can interact with a large variety of SH3 domains of different origin. The strongest interactions were seen with the SH2-SH3 adapter proteins Grb2 and Nck. The repeat sequence itself is not essential in this interaction. The data presented indicate that the different SH3 domains in the adapter proteins interact in a cooperative fashion with two distinct sites immediately upstream and downstream from the repeat sequence. Removal of all the putative SH3 binding domains in the third intracellular loop of the dopamine D4 receptor resulted in a receptor that could still bind spiperone and dopamine. Dopamine could not modulate the coupling of these mutant receptors to adenylyl cyclase and MAPK, although dopamine modulated receptor-G protein interaction appeared normal. The receptor deletion mutants show strong constitutive internalization that may account for the deficiency in functional activation of second messengers. The data indicates that the D4 receptor contains SH3 binding sites and that these sites fall within a region involved in the control of receptor internalization.     

HIV arthritis

Whether reexposure of varicella-immune persons to varicella-zoster virus would protect against or predispose to development of zoster was analyzed. The rate of zoster in 511 leukemic recipients of varicella vaccine who had 1 or > 1 dose of varicella vaccine and in those who did or did not have a household exposure to varicella was determined. A Kaplan-Meier life-table analysis revealed that the incidence of zoster was lower in those given > 1 dose of vaccine (P < .05). A Cox proportional hazards analysis showed that both household exposure to varicella and receipt of > 1 dose of vaccine were highly protective (P < .01) against zoster. Thus, the risk of zoster is decreased by reexposure to varicella-zoster virus, either by vaccination or by close exposure to varicella.     

Muscle-ligament interactions at the knee during walking.

A two-dimensional mathematical model of the knee is used with gait analysis to calculate muscle, cruciate ligament and tibio-femoral contact forces developed at the knee during normal level walking. Ten normal adult subjects--four females and six males--participated. The knee model is based upon a four-bar linkage comprising the femur, tibia and two cruciate ligaments. It takes account of the rolling and sliding of the femur on the tibia during flexion/extension and the changes in direction of the ligaments and muscle tendons. We considered forces transmitted by six elements: quadriceps, hamstrings, gastrocnemius, anterior and posterior cruciate ligaments, and tibio-femoral contact. The equations of mechanics can be used to determine the absolute values of only three of the knee forces simultaneously, so that twenty limiting solutions of three of the six forces were considered. A limiting solution was rejected if any of the three forces were negative, corresponding to compressive muscle or ligament forces, or tensile contact forces. These constraints always reduced and at times removed the redundancy of the knee structures. The high incidence of predicted single muscle activity, supported by electromyography, suggested that the ligaments play a significant role in load transmission during gait. The temporal patterns of muscle and ligament activity and ligament force magnitudes were sensitive to the choice of model parameters. The analysis showed that each of four possible minimum principles of muscle selection--minimal muscle force, muscle stress, ligament force and contact force--was unlikely to be valid throughout the walking cycle.     

Motion Planning for Redundant Manipulators Using a Floating Point Genetic Algorithm

This paper deals with the trajectory planning problem for redundant manipulators. A genetic algorithm (GA) using a floating point representation is proposed to search for the optimal end-effector trajectory for a redundant manipulator. An evaluation function is defined based on multiple criteria, including the total displacement of the end-effector, the total angular displacement of all the joints, as well as the uniformity of Cartesian and joint space velocities. These criteria result in minimized, smooth end-effector motions. Simulations are carried out for path planning in free space and in a workspace with obstacles. Results demonstrate the effectiveness and capability of the proposed method in generating optimized collision-free trajectories.     

Transient Response and Fixed Pattern Noise in Logarithmic CMOS Image Sensors

Logarithmic CMOS image sensors are appealing for their high-contrast and high-speed response but they require postprocessing to achieve high-quality images. Previously published work has explained the fixed pattern noise (FPN) in these image sensors using a steady-state analysis. This paper explains how the transient response of the readout circuit may also contribute to FPN. Thus, the performance of these CMOS cameras may be optimized with a proper understanding of the transient response, which is explained here through modeling and simulation with some experimental validation. In particular, the gain variation of a logarithmic camera is shown to be caused primarily by premature digitization. As logarithmic and linear active pixel sensors use similar circuits, some results in this paper, e.g., an analysis of readout capacitance, apply equally to the latter.