Baclofen reestablishes micro-opioid receptor levels modified by morphine withdrawal syndrome in either sex

We have previously shown that the GABA(B) agonist baclofen (BAC) prevents the expression of morphine (MOR) withdrawal syndrome in male as well as female mice. In addition, we have demonstrated that BAC reestablishes the dopamine levels modified by MOR withdrawal syndrome in male mice. The aim of the present study was to evaluate the micro-opioid receptor binding parameters in striatum and frontal cortex of male and female mice during MOR withdrawal and its prevention with BAC. Prepubertal Swiss-Webster mice of either sex were rendered dependent by intraperitoneal (i.p.) injection of MOR (2 mg/kg) twice daily for 9 days. On the tenth day, dependent animals received naloxone (NAL) (6 mg/kg, i.p.) 60 min after the last dose of MOR and another pool of dependent mice received BAC (2 mg/kg, i.p.) previous to NAL injection. Thirty min after NAL or saline injection mice were sacrificed, brains were collected, and the striatum and frontal cortex were dissected in order to perform binding studies with [(3)H][DAMGO]. The density of micro-opioid receptor increased significantly during MOR withdrawal in male and female striatum as well as in male cortex. In addition, in both brain areas the B(max) was higher in male than in female mice during MOR withdrawal. Finally, BAC pretreatment of MOR withdrawn mice reestablished the levels of micro-opioid receptor by significantly decreasing the B(max) in either sex. In conclusion, although there were sex differences in the micro-opioid receptor density during MOR withdrawal syndrome, BAC was able to reestablish the changes in binding parameters induced by the NAL-precipitated withdrawal in female and male mice.     

Cardiac parasympathetic dysfunction related to depression in older adults with acute coronary syndromes

OBJECTIVE: To determine whether depression is associated with cardiac autonomic alterations in elderly patients with recent acute coronary syndromes (ACSs). METHODS: Cross-sectional study on the association between a major depressive episode or isolated depressive symptoms (21-item Hamilton depression score) and heart rate variability abnormalities in 56 adults (31 women, 55%) 60 years of age and older with a recent (24-72 h) myocardial infarction (MI) or unstable angina (UA). RESULTS: Spectral and nonspectral parameters of respiratory sinus arrhythmia, indicative of parasympathetic activity on the heart, were decreased in patients with depression (high-frequency heart rate variability [log ms(2)] 2.12+/-0.4 vs. 2.52+/-0.5, P=.024; pNN50 [%] 1+/-2 vs. 9+/-15, P=.006; and rMSNN [ms] 16+/-6 vs. 28+/-22, P=.009). Also, high-frequency heart rate variability decreased with increasing depressive symptom severity. CONCLUSION: In a sample of older adults suffering from ACSs, depression was associated with impaired parasympathetic control of the heart.     

Potentiation of glucocorticoid release does not modify the long-term effects of a single exposure to immobilization stress

Rationale Previous work has shown that a single exposure of rats to a severe stressor (immobilization, IMO) results, days to weeks later, in a reduced response (desensitization) of the hypothalamic–pituitary–adrenal (HPA) axis to a second exposure to the same stressor.Objectives In the present work, we studied the influence of both length of exposure to IMO and circulating levels of corticosterone on the first day on the degree of desensitization of two sets of physiological variables: HPA hormones and food intake.Methods Rats were given SC saline or ACTH administration and then exposed to IMO for 0, 1 or 20 min. Seven days later, all rats were exposed to 20 min IMO. HPA response was followed on both experimental days by repeated blood sampling and food intake was measured on a 24-h basis.Results Both ACTH administration and IMO activates the HPA axis and IMO reduced food intake for several days. A single previous experience with IMO enhanced the post-IMO return of HPA hormones to basal levels on day 8 and reduced the degree of anorexia. The protective effect of previous IMO on food intake was independent of, whereas that on HPA activation was positively related to, the length of exposure on day 1. Concomitant ACTH administration on day 1 did not modify the observed effects.Conclusions Long-term protective effects of a single exposure to IMO are observed even with a brief exposure, but they are not potentiated by increasing corticosterone levels during the first exposure.     

Relapsing Cutaneous Alternariosis in a Kidney Transplant Recipient Cured with Liposomal Amphotericin B

An immunosuppressed patient who presented with unusual clinical signs of cutaneous alternariosis, including papular, nodular and verrucous lesions of the forearms, is reported. In spite of continuous treatment with oral itraconazole for 6 months, a large, progressive, necrotic ulcer appeared on the patient's left leg. Liposomal amphotericin B was then administered (total dose, 750 mg) with excellent clinical results. Electronic Publication     

Comparison of the growth and hydrogen peroxide production by vaginal probiotic lactobacilli under different culture conditions

OBJECTIVE: The purpose of this study was to determine the optimal conditions for the growth and hydrogen peroxide production by vaginal lactobacilli. STUDY DESIGN: Two vaginal lactobacillus strains were cultured under different growth conditions (temperature, pH, agitation, and growth media) with a fractional factorial experimental design. RESULTS: The optimal growth conditions of Lactobacillus paracasei CRL (Centro de Referencia para Lactobacilus Culture Collection) 1289 and Lactobacillus crispatus CRL 1266 were temperature 37 degrees C and initial pH 6.5, nonagitated cultures, in autolysat de levure; peptone, tryptone, Tween 80 et glucose (LAPTg) broth for L paracasei or in de Man-Rogosa-Sharpe (MRS) and LAPTg broths for L crispatus. The hydrogen peroxide production, detected only in agitated cultures, was higher at 37 degrees C and pH 6.5. The oxidative metabolite produced the self-inhibition of the lactobacilli growth. In mixed cultures of lactobacilli and Staphylococcus aureus under the optimal conditions of hydrogen peroxide production, the pathogen growth was inhibited. CONCLUSION: The results provided information about the factors that affect the hydrogen peroxide production and about the most favorable conditions with which to obtain the highest biomass in the shortest possible time.     

Nonpeptide antagonists of AT1 receptor for angiotensin II delay the onset of acute respiratory distress syndrome

We have previously reported that losartan, a selective antagonist of AT1 receptors for angiotensin II (AII), strongly suppresses the activation of neutrophils by N-formylmethionyl-leucyl-phenylalanine (fMLP) through a mechanism that does not involve inhibition of AT1 receptors. Herein, we analyze whether losartan would prevent the development of the acute respiratory distress syndrome (ARDS) triggered by lung bacterial infection. We found that losartan (0.2-200 microg/kg/min) delays the onset of ARDS in Wistar rats challenged by i.t. instillation of Bordetella bronchiseptica. Although this effect was associated with a significant inhibition of lung-neutrophil recruitment, lung bacterial clearance was not impaired but rather, it was significantly improved. We also found that another nonpeptide AT1 receptor blocker, irbesartan, exerted similar effects to losartan, i.e., it was also able to inhibit neutrophil activation by fMLP and to delay the onset of ARDS in B. bronchiseptica-challenged rats. Neither the inhibitor of angiotensin-converting enzyme captopril, nor the nonselective peptide inhibitor of AII receptors saralasin reproduced these effects. Our data are consistent with the possibility that nonpeptide AT1 receptor blockers delay the onset of ARDS triggered by bacterial infection through a mechanism dependent, at least in part, on their ability to prevent neutrophil activation by N-formyl-peptides.     

Glucocorticoids are involved in the long-term effects of a single immobilization stress on the hypothalamic-pituitary-adrenal axis

We have previously observed that a single exposure to a severe stressor such as immobilization (IMO) induces long-lasting desensitization of the responsiveness of the hypothalamic–pituitary–adrenal (HPA) axis to the same stressor that enhances rather than dissipates with time (days). As this desensitization of the HPA axis was not observed in response to a novel stressor, we suggested this might be a particular type of learning linked to severe stressful situations. Taking into account the evidence that glucocorticoids are involved in learning and memory, the present study addresses the role of glucocorticoids in the induction of long-term effects of an acute exposure to IMO. Three different experimental approaches were used: (i) blockade of stress-induced corticosterone release by using adrenalectomized rats supplemented with a low dose of corticosterone in the drinking saline (ADX+B); (ii) blockade of corticosterone synthesis during the first exposure to IMO with the 11-β-hydroxylase inhibitor metyrapone (200 mg/kg); and (iii) administration of the glucocorticoid receptor antagonist RU486 (100 mg/kg). Previous exposure to IMO resulted in an enhanced post-stress recovery of the HPA response to the same stressor 1 week later. These long-term effects of IMO were blocked in ADX+B rats, were partially reduced in metyrapone-treated rats and only modestly affected by RU486 administration. These data suggest that glucocorticoids play a partial role in the induction of long-term effects of IMO on the HPA responsiveness to the same stressor, although the weak effect of RU486 suggests that non-classical corticosteroid receptors may be involved. The role of glucocorticoids in the expression of the phenomenon is suggested by the full blockade of the phenomenon in ADX+B rats, but further studies are needed. As blockade of corticosterone synthesis only partially blunted the long-term effect of IMO, it appears that full induction of the long-term effects of acute exposure to IMO on the HPA axis is only achieved by the concerted action of several endocrine (or neurochemical) factors.     

Improvement in liver fibrosis, functionality and hemodynamics in CCI4-cirrhotic rats after injection of the Liver Growth Factor.

BACKGROUND/AIMS: Most substances used in experimental models of cirrhosis are chosen either as protectors of lipid peroxidation, as antifibrogenic agents or as vitamins, among others. In this report, we analyze the improvement produced, in established cirrhosis (CCl4 plus phenobarbital) in rats, by intraperitoneal injection of Liver Growth Factor, a hepatic mitogen with activity both in vivo and in vitro. METHODS: Following confirmation of CCl4-induced cirrhosis, Liver Growth Factor (4.5 microg per ratx2 injections/week for 3 weeks) was administered to one group of rats (Cirr+LGF). The remaining rats (Cirr) received saline. The groups were compared in terms of serum enzymes, tissue damage, total liver collagen, collagenase activity, microsomal enzyme activities, splanchnic and systemic hemodynamics and portosystemic shunting. RESULTS: Treatment of rats presenting CCl4-induced cirrhosis with Liver Growth Factor decreased serum aminotransferase levels and increased levels of serum albumin and total protein. The Liver collagen content was lower in rats treated with Liver Growth Factor (2.96 vs. 4.32 mg/g liver, p<0.01). Microscopic studies revealed that the livers of rats receiving Liver Growth Factor showed decreases in fibrosis, necrosis and inflammatory infiltration, as well as a recovery of architectural integrity. Liver function was improved after treatment with Liver Growth Factor, as indicated by the rate constant for elimination of aminopyrine, which increased from 0.0063 to 0.0170 (p<0.05). This increase was accompanied by a higher total amount of cytochrome P-450 as well as of certain P-450 isoenzymes, especially those that are hormone-dependent, such as P-450 3A. The improved liver histology and function observed in Cirr+LGF rats was associated with decreases in portal pressure (14.4 vs. 9.4 mm Hg, p<0.01) and portosystemic shunting (55.8 vs. 11.5%, p<0.01), as well as increases in mean arterial pressure and systemic vascular resistance, and a reduction in ascites. CONCLUSIONS: Administration of the hepatic mitogen, Liver Growth Factor, to CCl4-cirrhotic rats decreased liver collagen and reorganized the hepatic extracellular matrix, resulting in an improvement in liver function, reduced portal pressure and amelioration of ascites.     

Shift from biliary to urinary elimination of acetaminophen-glucuronide in acetaminophen-pretreated rats

Despite its toxicity, acetaminophen (APAP) is used increasingly as an analgesic, antipyretic, and anti-inflammatory agent. We examined the effect of prior exposure to APAP on its biliary and urinary elimination. The biliary and urinary elimination of a test dose of APAP (150 mg/kg i.v.) was determined in male Wistar rats 24 h after pretreatment with vehicle, a single dose (1.0 g/kg i.p.), or increasing daily doses (0.2, 0.3, 0.6, and 1.0 g/kg/day i.p.) of APAP. Although elimination of the parent APAP was minimally affected, biliary excretion of APAP glucuronide was significantly decreased 70 and 80%, whereas urinary excretion was significantly increased 90 and 100% in the groups pretreated with single and repeated doses of APAP, respectively, relative to vehicle controls. Western analysis and confocal immunofluorescent microscopy indicated a marked increase in hepatic expression of multidrug resistance-associated protein 3 (Mrp3) in both groups pretreated with APAP, relative to expression of Mrp2. ATP-dependent transport of [3H]taurocholate, an Mrp3 substrate, was significantly increased in basolateral liver plasma membrane vesicles from rats pretreated with repeated doses of APAP relative to controls. Enterohepatic recirculation of APAP glucuronide after administration of the same test dose of the drug was significantly decreased in rats pretreated with repeated doses of APAP. These data indicate that APAP pretreatment induced a shift from biliary to urinary elimination of APAP glucuronide, consistent with the increased expression of Mrp3 in the basolateral domain of the hepatocyte. We postulate that decreased enterohepatic recirculation contributes to decreased APAP hepatotoxicity by reducing liver exposure.