Interleukin-1 dysregulation is an intrinsic defect in macrophages from MRL autoimmune-prone mice

Macrophages (M?) from pre-diseased autoimmune-prone MRL mice (both MRL/+ and MRL/1pr) dramatically underproduce the cytokine interleukin-1 (IL-1) in comparison to M? from a number of normal strains. In this study we show that IL-1 dysregulation by MRL M? is fully expressed at birth, and that this defect does not change with time or the development of disease. We also constructed adult irradiation chimeras (consisting of A/J → MRL and MRL → A/J mice), and show that M? isolated from these chimeras display a pattern of IL-1 production indistinguishable from that of the donor strain controls. Moreover, when we constructed a mixed chimera (A/J + MRL → A/J), the A/J and MRL M? coexisting within the same animal retained their individual patterns of IL-1 production when isolated by negative selection. Taken together, these results provide the first substantive evidence for an intrinsic defect (IL-1 dysregulation) in M? from MRL autoimmune-prone mice.     

Behavioral and hormonal effects of attachment object separation in surrogate-peer-reared and mother-reared infant rhesus monkeys

Mother-reared and surrogate-peer-reared rhesus monkeys were separated from their respective attachment objects at 6 months of age and tested for the following 9 weeks to determine their home cage behavior and their pituitary-adrenocortical responses to stress. Both groups displayed a strong immediate behavioral response to separation which was characterized by increases vocalization, increased locomotion, and decreased self-play. However, the surrogate-peer-reared infants showed a subsequent recovery in their levels of self-play whereas the mother-reared infants instead developed stereotypic behavior patterns such as repetitive pacing. The 2 groups displayed similar plasma cortisol responses to weekly sessions in an apparatus equipped with animated toy “monsters.” Mother-reared but not surrogate-peer-reared subjects, however, also manifested elevated cortisol levels when an animal in an adjacent cage was captured and removed for stress testing. Mother-reared infant monkeys thus responded in a stronger and more prolonged manner to the loss of their attachment object than surrogate-peer-reared infants. These results suggest that infant rhesus monkeys form stronger attachments to monkey mothers than to inanimate surrogate mothers, a phenomenon which has not been as clearly demonstrated using other indices of attachment strength.     

Anxiety psychopathology predictive of outcome in patients with panic disorder and depression treated with imipramine, alprazolam and placebo

This study examines clinical predictors of outcome for patients with panic disorder and depression in a 16 week, placebo-controlled trial of alprazolam and imipramine (n = 126). Baseline global severity of illness and phobic avoidance were differentially predictive of acute response to treatment. Patients in the mild to moderate range of global distress experienced smaller degrees of improvement on alprazolam than on imipramine at week 4. At endpoint, the relative effectiveness of the active medication versus placebo was diminished in patients with higher levels of phobic avoidance. This relationship was not evident for completers, suggesting that the adverse effects of avoidance on outcome after sustained treatment was reduced.     

Altered IL-1 Expression and Compartmentalization in Monocytes from Patients with AIDS Stimulated with Mycobacterium avium Complex

The pathophysiologic basis for the exuberant intracellular growth of Mycobacterium avium complex (MAC) in AIDS patients is unclear but may relate to altered expression of modulatory cytokines. Interleukin (IL)-1, IL-6, and TNF- expression by monocytes from AIDS patients and healthy subjects (HS) stimulated with isogeneic MAC strains (SmT, smooth-transparent, virulent; SmD, smooth-domed, avirulent) was examined. Spontaneous cytokine production was not observed in patients with AIDS. MAC strains induced less IL-1 and IL-1 release in AIDS patients than HS (P < 0.05). The ratio of cell-associated to supernatant IL-1 also was increased in AIDS patients (P = 0.03). IL-1 mRNA expression paralleled protein release in either group of subjects. In both HS and AIDS patients, stimulation with SmD induced more IL-1 and TNF- release by monocytes compared to SmT. In AIDS patients, SmD also induced greater IL-6 release than SmT (P < 0.01). Alterations in monocyte expression and compartmentalization of the regulatory cytokines IL-1 and IL-6 may enhance bacterial replication and contribute to the patho-genesis of MAC infection in AIDS.     

Aluminum welding fume-induced pneumoconiosis

Chronic exposure to high concentrations of fumes during aluminum arc welding causes a severe pneumoconiosis characterized by diffuse pulmonary accumulation of aluminum metal and a corresponding reduction in lung function. Aluminum fume-induced pneumoconiosis is a rarely reported entity, of which the true incidence is unknown. We report the clinical, radiographic, microscopic, and microanalytic results of 2 coworkers, employed by the same aluminum shipbuilding facility, who died of complications from this disease. Scanning electron microscopy and energy dispersive x-ray analysis of the exogenous particle content in the lung tissue of these cases revealed the highest concentrations of aluminum particles (average of 9.26 billion aluminum particles per cm(3) of lung tissue) among the 812 similar analyses in our pneumoconiosis database. One patient had an original clinical diagnosis of sarcoidosis but no evidence of granulomatous inflammation.     

Differential contribution of chemotaxins and opsonins to neutrophil-mediated killing of Schistosoma mansoni larvae.

In neutrophil-mediated killing of schistosomula, antibody and serum complement serve two functions: (i) opsonization of the target pathogen and (ii) generation of cell-activating, chemotactic peptides. We studied neutrophil-mediated schistosomulum killing in experiments designed to isolate these functions of antibody and complement in the cell activation response of neutrophils to external pathogens. Schistosomula opsonized by antibody or antibody plus complement induced neutrophil-mediated killing, while complement-opsonized larvae did not. Antibody enhancement of cell-mediated killing correlated with increased cell-to-parasite adherence, while cell-mediated killing in the presence of fresh normal human serum (providing chemotactic factor stimulation and complement opsonization of larvae) demonstrated a dissociation between neutrophil adhesive and killing responses. Exogenous chemotactic stimuli were found to enhance significantly neutrophil-mediated killing of both opsonized and unopsonized larvae. Experiments involving parabiotic chambers confirmed that chemotactic-factor-stimulated neutrophils may cause significant parasite mortality without direct cell-parasite contact. In further analysis of the neutrophil response to surface and fluid-phase stimulation, release of neutrophil cytotoxic mediators was found to vary according to the type of stimulus provided: cell exposure to either larvae opsonized by antibody plus complement or to chemotactic factors provoked low-to-moderate cell release of superoxide anion, granule enzymes, and arginase; when opsonic and chemotactic stimuli were combined, a greater-than-additive secretory response was noted. Under such maximal stimulation, oxidative and nonoxidative mediators were synergistic in effecting neutrophil-mediated parasite killing. The primary function of complement in cell-mediated parasite killing appears to be to promote chemotactic-factor-mediated cellular release of toxic agents and not cell-target linkage, whereas antibody-mediated adherence is associated with concurrent cellular activation. Both neutrophils adherent to the antibody-opsonized schistosomulum and chemotactic-factor-stimulated cells (adherent and not adherent to the parasite) appear to contribute significantly to its demise.     

Fenfluramine challenge, self-injurious behavior, and aggression in rhesus monkeys

Self-injurious behavior (SIB) and aggression have been linked to reduced serotonergic (5-HT) functioning in both humans and nonhuman primates. The present study examined serum prolactin and cortisol responses to the 5-HT releasing agent D,L-fenfluramine (FEN) in 24 individually housed rhesus monkeys (Macaca mulatta), 15 of which carried a veterinary record of self-wounding (SW). Subjects received two doses of FEN, 4 and 2 mg/kg, separated by an interval of at least 2 months. For control purposes, monkeys were given an intramuscular saline injection 1 week prior to each FEN challenge. The relationship between the hormonal responses to FEN, wounding history, the rates of self-directed biting and aggression were determined for each animal based on 100 five-minute observations conducted over a period of 12 months surrounding the challenge procedures. Prolactin and cortisol responses to FEN were unrelated either to wounding history or to rates of self-directed biting. However, there were significant inverse correlations between levels of aggression and the prolactin response to both doses of FEN. The present findings provide no evidence for reduced 5-HT system function in rhesus monkeys with SIB under the present challenge conditions. However, the results are consistent with a previously reported inverse relationship between serotonergic activity and aggression. Moreover, a dose-dependent response to FEN was observed only for prolactin, suggesting that this variable is more appropriate than cortisol as an endpoint for FEN challenge in monkeys.     

Evaluation of the latex slide agglutination test for identification of Staphylococcus aureus.

This study evaluated the reliability of the latex slide agglutination test for identifying Staphylococcus aureus. A total of 806 clinical isolates of staphylococci were tested for latex agglutination, clumping factor, and free coagulase. Positive latex tests occurred in 98.3% of coagulase-positive strains, whereas 99.6% of coagulase-negative strains gave negative latex tests. It is concluded that in most instances, the latex slide agglutination test is a reliable method for identifying S. aureus in the clinical laboratory.     

The effect of ageing in spinal cord injured humans on the blood pressure and heart rate responses during fatiguing isometric exercise

Groups of 50 healthy male controls and 50 subjects suffering from paraplegia (aged 20–65 years) were examined as to the inter-relationships between age, paraplegia and the strength, endurance, blood pressure and heart rate responses to fatiguing isometric exercise. Contractions were maintained in both groups under voluntary effort and through a contraction induced by electrical stimulation in the paraplegic group. All contractions were maintained to fatigue at a tension of 40% of the maximal muscle strength in either the handgrip or quadriceps muscles. Muscle strength of the handgrip was higher in the paraplegic subjects than in the controls, averaging 589 N and 463 N, respectively for the two groups. In contrast, quadriceps leg extension strength averaged 696 N in the controls and 190 N in the paraplegic groups; for both groups, ageing was associated with a reduction in muscle strength. While leg endurance was less in the paraplegic group than the control group, handgrip endurance was similar in the two groups, endurance increasing with ageing in both the controls and paraplegics. Both systolic and diastolic blood pressures increased at rest in paraplegic and control subjects with age. The magnitude of the pressor response to exercise also increased with age. This was true during both voluntary exercise and exercise induced through electrical stimulation in the paraplegic groups. The heart rate response (change in heart rate during exercise) to a fatiguing isometric handgrip contraction decreased by about 50% between the ages of 20 and 60 years in both the controls and paraplegics for isometric handgrip exercise. In contrast, heart rate changed little with age during contractions of the quadriceps muscle in paraplegics which were induced by electrical stimulation. Electronic Publication