Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity

CCR5, a chemokine receptor expressed on T cells and macrophages, is the principal coreceptor for M-tropic HIV-1 strains. Recently, we described an NH2-terminal modification of the CCR5 ligand regulated on activation, normal T cell expressed and secreted (RANTES), aminooxypentane-RANTES (AOP-RANTES), that showed potent inhibition of macrophage infection by HIV-1 under conditions where RANTES was barely effective. To investigate the mechanism of AOP-RANTES inhibition of HIV infectivity we examined the surface expression of CCR5 using a monoclonal anti-CCR5 antibody, MC-1. We demonstrate that AOP-RANTES rapidly caused >90% decrease in cell surface expression of CCR5 on lymphocytes, monocytes/ macrophages, and CCR5 transfected Chinese hamster ovary (CHO) cells. RANTES also caused a loss of cell surface CCR5, although its effect was less than with AOP-RANTES. Significantly, AOP-RANTES inhibited recycling of internalized CCR5 to the cell surface, whereas RANTES did not. When peripheral blood mononuclear cells are cultured for prolonged periods of time in the presence of RANTES, CCR5 expression is comparable to that seen on cells treated with control medium, whereas there is no CCR5 surface expression on cells cultured in the presence of AOP-RANTES. Immunofluorescence indicated that both AOP-RANTES and RANTES induced downmodulation of cell surface CCR5, and that the receptor was redistributed into endocytic organelles containing the transferrin receptor. When RANTES was removed, the internalized receptor was recycled to the cell surface; however, the receptor internalized in the presence of AOP-RANTES was retained in endosomes. Using human osteosarcoma (GHOST) 34/CCR5 cells, the potency of AOP-RANTES and RANTES to inhibit infection by the M-tropic HIV-1 strain, SF 162, correlated with the degree of downregulation of CCR5 induced by the two chemokines. These differences between AOP-RANTES and RANTES in their effect on receptor downregulation and recycling suggest a mechanism for the potent inhibition of HIV infection by AOP-RANTES. Moreover, these results support the notion that receptor internalization and inhibition of receptor recycling present new targets for therapeutic agents to prevent HIV infection.     

Parathyroid hormone (1-34) increased total body bone mass in aged female rats

Daily subcutaneous administration of bovine parathyroid hormone (PTH)(1-34) stimulates bone formation and increases bone mass in rat tibiae, femora and lumbar spine. However, the effects of PTH on the whole body bone mineral content and density determined by dual energy x-ray absortiometry (DEXA) have not been previously reported in rats. Eighteen-month-old intact female rats were subcutaneously injected daily with 0, 40, 80 or 160 micrograms/kg/day of bovine PTH (1-34) for either 15 or 60 days. Whole body DEXA was performed at 1 day before autopsy, and bone area, bone mineral content (BMC) and bone mineral density (BMD) of the total body were determined. Total femoral, tibial and lumbar spine BMD was also determined ex vivo. Cancellous bone histomorphometry was performed on sections of double-labeled proximal tibial metaphyses. Whole body bone mineral content and density were significantly increased by 60 days, but not by 15 days, of PTH treatment at all dose groups compared with vehicle controls. Lumbar vertebral and total femoral BMD was significantly increased at all doses of PTH by 15 days of administration and further increased by 60 days. All doses of PTH increased trabecular bone area in proximal tibial metaphyses by 15 days and further increased by 60 days. All doses of PTH increased trabecular bone area in proximal tibial metaphyses by 15 days and further increased by 60 days. In proximal tibial cancellous bone, dose-dependent increases in percent labeled perimeter, mineral apposition rate and bone formation rate-bone volume referent were found between 40 and 160 micrograms/kg of PTH treatment by 15 days, and no further increases were found by 60 days. Our results showed that in aged female rats, bovine PTH(1-34) increased bone formation and total body bone mass.     

Balance retraining in a hemiparetic patient using center of gravity biofeedback: a single-case study

A single-subject experimental design was used to evaluate the effects of center of gravity biofeedback on retraining balance control in a 72-yr.-old male hemiparetic patient. For both assessment and training the subject stood on dual force-plates enclosed on three sides by a visual surround. A 4-wk. training period consisted of subject-initiated shifts in body weight to control movement of a real-time computer display of the subject's center of gravity. A Sensory Organization Test and evaluation of weight distribution indicated that biofeedback retraining positively affected balance control during dynamic conditions and when the ground support moved forward.     

Phenotypic analysis of donor cells infiltrating the small intestinal epithelium and spleen during graft-versus-host disease

A pyriform sinus fistula can cause acute thyroiditis or recurrent infection in the neck. This fistula is believed to be a remnant of the branchial apparatus, although its origin has yet to be pinpointed. The spatial distribution of C cells in the thyroid gland was mapped by immunohistologic method in four patients with a pyriform sinus fistula. The C cells were identified immunohistologically with anticalcitonin antibody. The stained calcitonin-positive cells also crossreacted with the antibodies to carcinoembryonic antigen, chromogranin A, and neuron-specific enolase. The C cells were mainly distributed near the end of the fistula, and in three patients their concentration per unit volume of thyroid tissue was found to be inversely proportional to the distance from the end of the fistulas. Comparison of distant locations of the left-sided thyroid lobe in patients and the same region in control subjects showed a similar number of C cells. Thus this limited distribution of C cells suggested that the pyriform sinus fistula was either a remnant of the ultimobranchial body, the result of disturbed migration of the C cell in the fetus, or both.     

In vitro 2,3,7,8-tetrachlorodibenzo-p-dioxin interference with the anterior pituitary hormone adrenocorticortropin

Pharmacological effects of acute treatment with venlafaxine (VEN), a clinically active antidepressant [a noradrenaline (NA) and 5-hydroxytryptamine (5-HT) reuptake inhibitor without any affinity for neurotransmitter receptors] were studied in mice and rats. VEN inhibited the reserpine- or apomorphine-induced hypothermia and enhanced the L-5-HTP-induced head twitches in mice. It reduced the immobility time in Porsolt's test in mice and rats, but either did not change the locomotor activity (mice) or decreased it (rats). VEN reduced the locomotor hyperactivity induced by amphetamine (AMP), apomorphine (APO) and quinpirole (QUI), as well as the APO-induced stereotypy; the stereotypy induced by AMP in rats was prolonged. VEN neither changed the clonidine-induced aggressiveness in mice nor the behavioral syndrome induced by oxotremorine in rats. The obtained results indicate that VEN, given acutely, shows a pharmacological profile similar to that of tricyclic NA and 5-HT reuptake inhibitors. In contrast to the antidepressants mentioned above, VEN does not exhibit an alpha 1-adrenolytic or a cholinolytic activity (in vivo tests).     

Use of the suture anchor in open Bankart reconstruction. A follow-up report

We previously reported early results of a new technique using a suture anchor to perform a modified Bankart reconstruction. That study included patients from two medical centers and had an average followup of only 1 year. This report includes patients from a single center with followup extended to a mean of 42 months (range, 33 to 61). Between April 1988 and August 1991, 53 patients with recurrent anterior glenohumeral instability underwent modified Bankart reconstruction with the use of a suture anchor. Thirty-two patients met inclusion criteria (identifiable Bankart lesion, open repair with suture anchors, and minimum followup of 2 years); 4 patients were lost to followup. There have been no complications as a result of this technique. Ninety-three percent of the patients in the study had objectively excellent or good results. There were 2 failures with recurrent anterior dislocation. The use of a suture anchor can simplify the Bankart reconstruction. At average followup of 3 years, 26 patients have returned to presurgery activity levels without recurrent dislocation or subluxation. However, careful attention to anchor placement at the junction of articular cartilage and the glenoid neck is necessary to avoid technical failure.     

EEG feedback training in the treatment of epilepsy: some questions and some answers

A basic question in EEG feedback training of epileptic patients is whether the decrease in seizures is specifically due to the training or to other factors. Questions may also be raised as to what EEG changes are involved. Preliminary results in five patients suggest that seizure reductions can occur with training which are not due to placebo or nonspecific effects or to changes in medication compliance. These changes occurred rapidly during EEG-contingent feedback training but not when feedback was random in relation to the EEG. Reliable changes in the EEG were also observed, but the question of which mechanism accounts for these results has yet to be answered.     

The extinction of fires in aircraft jet engines — Part I,small-scale simulation of fires

Three modes of combustion are possible in an aircraft engine fire, and these have been simulated separately in a small wind tunnel.     

Transient emission and generation currents in Metal-Insulator-Semiconductor capacitors

The transient current of an MIS (metal-insulator-silicon) capacitor which is subjected to a voltage step (or pulse) has been investigated. It is shown that the different magnitudes and shapes exhibited by the transient current depend on the initial and final biasing conditions. By varying these conditions the three main contributing current components, namely, surface emission, surface generation and bulk generation can be identified.