Inflammatory Markers in Acute Myocardial Infarction Patients: Preliminary Evidence of a Prospective Association With Depressive Symptoms

Inflammatory activity has been associated with both coronary disease and depressive symptoms. We sought to determine whether inflammatory markers in myocardial infarction (MI) patients are prospectively associated with depressive symptomatology. Participants were a convenience sample of MI patients. Depressive symptoms were assessed soon after the MI and again 7 months postdischarge. Inflammatory markers examined were interleukin-6 (IL-6) and interleukin-1β. Results suggest no significant cross-sectional association between inflammatory markers and depressive symptoms at baseline. However, bivariate and multiple regression analyses revealed a significant positive prospective association between baseline IL-6 and depressive symptoms 7 months later ( β  = .57, p  < .01). The results suggest that temporal considerations are important in understanding relationships between inflammation and depressive symptoms following MI.     

Effect of four different types of single-dose treatment with chloroquine and with chloroquine and pyrimethamine on Plasmodium falciparum infections in a semi-immune population in northern Nigeria

The disadvantages to single-dose treatment of malaria are: 1) the drugs used are subject to local availability, 2) the dosages used differ from country to country, and 3) seldom have preliminary trials been carried out under local conditions to evaluate the drugs. The trial described in this paper was undertaken in a savanna area of northern Nigeria where malaria was hyperendemic, from March-May 1969. 522 subjects having plasmodium falciparum trophozoites in their blood were selected and divided into 4 groups, from a total of 3 villages, Tama, Koda, and Fakuwa. In groups 1, 2, and 3 the dosages of chloroquine base administered alone were adjusted to body weight, surface area of subject, and age; in group 4 a combination of chloroquine diphosphate and pyrimethamine was given at a standard dosage related to age. Blood films were taken daily from all subjects on days 1-5, every 5 days from day 5-30, and every 10 days until day 60. 425 subjects were retained throughout the trial. Findings were: 1) in all 4 groups the parasite rates declined to levels of 3.3-7% on day 3 and to only 1.3-3.4% of the original level by day 5, 2) the percentage of recrudescence among subjects with diarrhea (10.8%) at the time of medication is slightly higher than that among those without diarrhea (7.1%) and in the 14 and over age group recrudescence was less in group 1 (4.1%) than group 4 (9.7%), in which the adult dosage was limited to a standard 450 mg of chloroquine base, 3) of the 32 detected cases that became positive again between day 10-60, malaria parasites were found on only 1 occasion in 21 and twice in 2 of them, 4) the gametocyte rates increased in all groups but the rise in the 14 and over age group was less pronounced, 5) no side effects other than vomiting were reported (rate of between 2.5-8%), 6) a single-dose treatment with chloroquine in dosages of 10 mg of base/kg body weight or higher failed to prevent the reappearance of parasites within 2 months of treatment in 6.5-11% of children in the 1-9 year age group, 7) the 4 types of treatment with chloroquine proved to be equally effective in all age groups, and 8) dosages of chloroquine adjusted to body weight range would appear preferable and could be used by health professionals in mass drug administration studies.     

Effects of bacterial superantigens on behavior of mice in the elevated plus maze and light-dark box

Bacterial superantigens, such as staphylococcal enteroxins A and B (SEA/SEB) stimulate T cells to produce high levels of cytokines in blood. Previously it had been shown that these toxins were capable of stimulating increased neuroendocrine activity and enhanced behavioral reactivity to novel gustatory and non-gustatory stimuli. Therefore, it was suggested that these superantigens may promote anxiety-like behavior. In the current set of experiments, BALB/cByJ and C57BL/6J male mice were challenged with either SEB (50 microg) or SEA (5 or 10 microg) and tested for behavior in the elevated plus maze (EPM). Results suggested an absence of increased anxiety-like behavior, with exploration of the open arms being enhanced by SEA or SEB treatment. In another test of anxiety, the light-dark box, SEB challenge of BALB/cByJ mice 90 min prior to testing, did not alter exit latency, activity nor time spent in the dark. However, in a second experiment, it was found that if animals were first tested for consumption, followed by testing in the light-dark box, SEB challenged animals displayed increased exit latency and reduced exploration. These studies suggest that in standard tests of rodent anxiety-like behavior, evidence for the induction of anxiety-like processes subsequent to challenge with SEA or SEB is not patently discernable. However, neurobiological events induced by immunological challenge might synergize with reactivity to psychogenic and/or gustatory stimuli, thereby resulting in increased anxiety-like behavior that could be unmasked by standard behavioral tests such as the light-dark box or EPM.     

In vivo effects of beta-endorphin on lymphocyte proliferation and interleukin 2 production

Experiments were undertaken in rats to investigate the effects of in vivo infusion of beta-endorphin (BEP) on subsequent Con A-induced proliferation and interleukin 2 (IL-2) production by spleen cells in vitro. BEP administration induced a dose-dependent enhancement of the proliferative response to Con A. Infusion of the opiate antagonist naloxone (NAL) inhibited the Con A response and infusion of NAL prior to BEP resulted in even further inhibition. None of these treatments resulted in detectable alterations in IL-2 production after 48 h in culture. To demonstrate a direct interaction between BEP and lymphocytes, spleen cells were incubated in vitro with varying concentrations of BEP and/or NAL. Enhanced Con A-induced proliferation was observed following incubation with BEP in the range 10(-12) to 10(-9) M (levels comparable to the effective in vivo doses) and this effect was abrogated by NAL pretreatment (10(-6) M). These data indicate a role for BEP in enhancing lymphocyte reactivity which is to some extent dependent on opiate receptors on the cell surface. This report extends the evidence obtained from in vitro experiments implicating endogenous opioids in modulation of host immunity by demonstrating that these effects can be obtained in vivo.     

Effects of urokinase-type plasminogen activator in the acquisition, expression and reinstatement of cocaine-induced conditioned-place preference

Cocaine and many other psychostimulants strongly induce urokinase-type plasminogen activator (uPA) expression in the mesolimbic dopaminergic pathway, which plays a major role in drug-mediated behavioral plasticity [Bahi A, Boyer F, Gumy C, Kafri T, Dreyer JL. In vivo gene delivery of urokinase-type plasminogen activator with regulatable lentivirus induces behavioral changes in chronic cocaine administration. Eur J Neurosci 2004;20:3473-88; Bahi A, Boyer F, Kafri T, Dreyer JL. Silencing urokinase in the ventral tegmental area in vivo induces changes in cocaine-induced hyperlocomotion. J Neurochem 2006;98:1619-31; Bahi A, Dreyer JL. Overexpression of plasminogen activators in the nucleus accumbens enhances cocaine-, amphetamine- and morphine-induced reward and behavioral sensitization. Genes Brain Behav 2007]. In this study, the role of mesolimbic dopamine (DA) pathways in the development of cocaine reward was examined by conditioned-place preference in rats with bilateral intra-accumbens injections of uPA-expressing lentiviral vectors. We show that overexpression of uPA in the Nac significantly augments cocaine-induced place preference. Furthermore, while this did not affect the ability of preference to be extinguished, reinstatement with a low dose of cocaine produced significantly greater preference to the cocaine-associated context. Once CPP had been established, and the preference extinguished, reinstatement induced by a priming dose of cocaine was facilitated by uPA. Inhibition of this serine protease expression using doxycycline abolished the augmented acquisition produced by overexpression of uPA but not the expression of the cocaine-induced CPP. When uPA is inhibited during the acquisition phase, animals no longer demonstrate place preference for the environment previously paired with cocaine. B428, a specific uPA inhibitor does not affect drug reinstatement after extinction if uPA has been activated during acquisition, a clear indication that uPA is involved in the acquisition phase of conditioned-place preference. Our results suggest that that increased uPA expression with repeated drug exposure produces conditions for enhanced acquisition of cocaine-induced CPP, indicating that cocaine-induced CPP and reinstatement may be dependent on active extracellular uPA.     

Behaviorally conditioned suppression of mitogen-induced proliferation and immunoglobulin production: effect of time span between conditioning and reexposure to the conditioning stimulus

Rats were subjected to taste aversion conditioning using the immunosuppressive drug cyclophosphamide (CY) as the unconditioned stimulus (UCS) paired with saccharin, the conditioned stimulus (CS), and were reexposed to the CS at 2, 5, or 10 days after a single conditioning trial. Twenty-four hours after reexposure the rats were sacrificed and spleen cells assayed for mitogen-induced proliferation and immunoglobulin production. A robust conditioned taste aversion (CTA) was observed irrespective of the day of CS reexposure. However, only conditioned rats reexposed to the CS 2 days after training displayed a conditioned reduction in proliferative responses to PHA and PWM. These rats also exhibited a reduction in the synthesis of IgM, but not IgG or IgA, by spleen cells cultured with PWM. These effects were not observed in conditioned rats reexposed 5 or 10 days after conditioning. In another experiment, rats were subjected to a backward conditioning (UCS prior to CS) training trial, tested 2 days later for the presence of CTA, and sacrificed 24 h later for assessment of immune function as described above. The results of this experiment demonstrated that rats do not develop an aversion to saccharin when it is first presented 4 h after CY, and no alterations in spleen cell proliferation and immunoglobulin production were noted. The data show that the CTA response established by explicit association between CY and saccharin depresses in vitro spleen cell proliferation and IgM production only when elicited shortly after the conditioning trial.     

Role of opioid receptor like-1 receptor in modulation of endocrine,immunological, and behavioral responses to the T-cell superantigen staphylococcal enterotoxin A

Opioid receptor like-1 receptor (ORL₁) is selective for orphaninFQ/nociceptin (OFQ/N), a peptide linked to stress. Since immunologic stimuli exert stressor-like effects, the neuroendocrine and behavioral effects of the T-cell superantigen staphylococcal enterotoxin A (SEA) were tested in ORL₁^?/? and ORL₁^+/+ wildtype 129S6 mice. Within 2 h of SEA challenge both genotypes showed elevated corticosterone, but only wildtypes were elevated after 4 h, and had altered hypothalamic CRH mRNA. Although amygdaloid CRH and TNFα mRNA was increased by SEA, this did not vary with genotype. Interestingly, gustatory neophobia due to SEA challenge was augmented in ORL₁^?/? mice, although object neophobia tested 4 days later was abrogated. These results suggest differential requirements for ORL₁ in the mediation of neuroimmune effects exerted at different times after an immune challenge.     

Relationship of varying patterns of cytokine production to the anorexic and neuroendocrine effects of repeated Staphylococcal enterotoxin A exposure

Staphylococcal enterotoxin A (SEA) is a superantigen that stimulates T cells and induces the production of multiple cytokines. Previous studies have shown that SEA augments gustatory neophobia and activates the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to determine if the cytokine response, behavioral effects, and HPA axis activation persisted after repeated SEA treatment. Male C57BL/6J mice were given 1-4 intraperitoneal injections of 5 microg SEA, after which food intake, corticosterone, or peripheral cytokines were measured. In a series of experiments, it was found that secondary exposure to SEA two or three days after priming increased corticosterone, but attenuated splenic TNFalpha, while augmenting IL-1beta, IL-2, and IFNgamma. The anorexic response was intact after secondary exposure, but absent after a third injection, which was still able to elevate corticosterone. It is unlikely that IL-1 mediated the persistent effects on corticosterone, since this was increased in groups lacking corticosterone elevations. Similarly, TNFalpha was only modestly elevated under repeated SEA conditions that elevated plasma corticosterone. This attenuation appeared to be inversely related to the levels of IL-10, the production of which incrementally rose with each successive injection. In conclusion, repeated exposure to SEA activates the HPA axis and alters behavior. However, there may be dissociation between the behavioral and endocrine effects of SEA with increased SEA exposure. Furthermore, it is possible that while TNFalpha was previously shown to be important in response to acute SEA-induced HPA axis activation, further exposure to SEA elicits other cytokines that may exert neuromodulatory effects through sensitization and/or synergistic mechanisms.