Statins alter oxidant-antioxidant status and lower exercise-induced oxidative stress.

Data on effects of statins on resting oxidant-antioxidant status are contradictory and no study has been published on the effects of statins on exercise-induced oxidative stress. We carried out a 6-month longitudinal study in 10 dyslipidemic patients receiving 10 mg/day atorvastatin and 13 healthy sedentary subjects. Thiobarbituric acid reactive substances (TBARS) and reduced ascorbic acid (RAA) were measured in plasma at rest and every 5 minutes after submaximal isometric thumb adduction and handgrip sustained until exhaustion. At inclusion, resting TBARS and RAA levels in controls and patients did not differ and exercise increased TBARS and decreased RAA. Atorvastatin reduced resting TBARS and RAA levels in a time-dependent but lipid-independent manner. The main effect was a post-exercise increase in TBARS, without affecting the post-exercise RAA levels. The reduction in oxidative stress occurred earlier in oxidative muscles involved in thumb adduction. In conclusion, atorvastatin lowers resting oxidant-antioxidant activity: exercise-induced oxidative stress occurs mainly in muscles having a high oxidative capacity.

Adenosine and hemodialysis in humans.

BACKGROUND: Infections and hypotension are serious complications that develop during hemodialysis (HD) treatment. Adenosine (ADO), a strong hypotensive and immunosuppressive agent, may participate in these two HD complications, because high concentrations of ADO metabolites are found in dialyzed human plasma. ADO, which is released by endothelial cells, is quickly transformed into inosine (INO) by plasmatic ADO deaminase (ADA) and mononuclear cell ADO deaminase (MCADA). In plasma, the degradation of ADO into INO and its uptake by red blood cells (RBC) are both very rapid, resulting in the short half-life of ADO in blood. METHODS: Using liquid chromatography, we evaluated ADO and INO plasma concentrations before and after HD session. RESULTS: Before the HD session, ADO and INO plasma concentrations were higher in hemodialyzed patients than in controls and in peritoneally dialyzed patients. At the end of the HD session, ADO plasma concentration was increased. ADO plasma concentration for the undialyzed patients was in the same range as that of the controls. Before HD, ADA activity was higher in hemodialyzed patients (559 +/- 349 IU) than in controls (219 +/- 48 IU), and the activity rose during the session (665 +/- 135 IU). ADA activity in the undialyzed patients (222 +/- 80 IU) was in the same range as that of the controls (219 +/- 48 IU). Before the HD session, the MCADA activity (247 +/- 144 IU) was lower than in controls (624 +/- 99 IU). HD did not modify ADO RBC uptake. ADO inhibited mononuclear cell proliferation and interferon-gamma production in humans. Finally, as much as 50 microM INO does not inhibit ADO uptake by RBC and does not modify ADA and MCADA activities. CONCLUSIONS: These data indicate that chronic HD inhibited MCADA activity and increased ADO plasma concentration. Both high ADO plasma concentration and low MCADA activity may be involved in dialysis-induced immune system failure and thereby favor infectious diseases.

Adenosine and the nervous system: pharmacological data and therapeutic perspectives.

1. Adenosine acts on a family of G-protein-coupled receptors called purinoreceptors. 2. Four subtypes have been cloned and pharmacologically characterized. 3. The principal pharmacological data and structure-function relations for agonist interactions with P1 receptors are presented. 4. We conclude that the potent role of adenosine in the nervous system may be interesting for the development of drugs targeted at purines and their receptors.

Adenosine and migraine.

BACKGROUND: Adenosine is a powerful natural vasodilator that participates in the control of cerebral and meningeal blood flow. In this context, it could be involved in the pathophysiology of migraine, since it was previously reported that intravenous adenosine can precipitate crises in migraine patients. METHODS: We have investigated circulating adenosine levels in 12 patients suffering from migraine without aura, during crises and in crisis-free periods, and have compared the levels noted to those of a population of 10 controls. To determine if there are interactions between adenosine and serotonin, we examined the effect of adenosine and antagonists on the uptake and the release of (14C) serotonin by platelets. RESULTS AND CONCLUSION: We have reached a dual conclusion: 1) during migraine headaches there is an increase (mean 68%) in circulating adenosine levels and this increase may participate in cephalalgia; 2) activation of A2 receptors by adenosine causes a dose-dependent serotonin uptake by platelets. This inhibition of uptake could participate in the rapid elimination of serotonin in migraine sufferers. As a result of this, the use of adenosine antagonists could be an effective complementary treatment for migraine.

Interactions between cyclosporine A and adenosine in kidney transplant recipients.

Adenosine is involved in a large number of physiological processes including immune response and vasomotor function. But its precise involvement in renal physiology is poorly understood. We have investigated the putative relationships between cyclosporine A (CsA) and adenosine (ADO) metabolism in kidney transplant recipients (KTR). We first compared ADO plasma levels in three groups of patients and in 10 controls: the first group (N = 14) was composed of CsA-treated KTR; the second group (N = 5) was KTR not treated with CsA, and the third (N = 6) was chronic kidney failure patients. We also measured ADO plasma level in two KTR treated with FK506, a CsA analog. ADO plasma levels in CsA-treated KTR were significantly higher (mean 0.76 microM +/- 0.27) than in the control group (mean 0.31 +/- 0.13; Mean-Whitney test, S = 8.5; P = 2.1 x 10(-4)) and than in the chronic kidney failure group (0.37 +/- 0.16, Mann-Whitney, S = 5.5; P = 1.6 x 10(-3)). In CsA-treated KTR, CsA and ADO plasma levels were significantly correlated (Spearman's, r = 0.8, P = 1.9 x 10(-3)). No significant differences in ADO plasma levels were found between patients with chronic kidney failure and controls (P < 0.05). ADO plasma levels in KTR not treated with CsA were in the same range as those in controls. Finally, the ADO plasma level was increased in the two FK506-treated patients. We also investigated the action of CsA on ADO plasma degradation and uptake by erythrocytes in vitro. No interaction between adenosine deaminase and CsA was found because CsA, in the presence of adenosine deaminase, did not modify the plasma half-life of ADO. Conversely, in the presence of CsA (500 and 1000 ng/ml), the uptake of ADO by erythrocytes was significantly decreased in adenosine deaminase-free samples (analysis of variance, P = 1.8.10(-3) and 1.2 x 10(-4), respectively). We conclude that ADO plasma levels are significantly elevated and correlate with CsA blood level in CsA-treated KTR, and that these high levels are due to CsA inhibition of ADO uptake by red cells. Since ADO and metabolites have well known immunosuppressive and vascular effects, ADO is likely to participate in the immune defect and in the vasoconstriction induced by CsA.

Is the clinical course of HIV-1 changing? Cohort study.

OBJECTIVE: To assess whether the clinical course of HIV infection has changed from 1985 to 1995. DESIGN: Cohort Study. SETTING: Infectious disease clinic. SUBJECTS: 285 patients recruited from September 1985 to January 1995 with < or = 12 months between the dates of their last seronegative and first seropositive test result and with first follow up visit in the six months after seroconversion and at least 12 months' follow up. Patients were grouped according to the date of seroconversion. MAIN OUTCOME MEASURES: Time to CD4 cell count of < 500, 400, and 200 x 10(6) cells/l, and clinical outcome defining AIDS; variation in cell count per day between consecutive visits, and ratio between this variation and time from estimated date of seroconversion at each visit. RESULTS: The groups were similar in age, number with acute primary HIV infection, CD4 cell count at intake, and cell count at the beginning of antiretroviral treatment; they differed in sex ratio, risk factors for HIV, probability of CD4 cell decline to < 500, 400, and 200 x 10(6) cells/l. and risk of developing AIDS. Acute infection, seroconversion after December 1989, and serum beta 2 microglobulin > 296 nmol/l were independent predictors of poor clinical course. The speed of CD4 cell decline, expressed as cell variation divided by the number of days between consecutive visits, increased with more recent seroconversion (P = 0.02). Ratio between the speed of CD4 cell decline and time from estimated date of seroconversion at each visit was also higher in the patients who seroconverted after December 1989. CONCLUSIONS: The faster disease progression and the higher speed of CD4 cell decline at early stages in the patients with recently acquired HIV infection suggest changes in the clinical course of HIV infection.

The influence of cytomegalovirus on the natural history of HIV infection: evidence of rapid course of HIV infection in HIV-positive patients infected with cytomegalovirus.

We studied a cohort of 299 HIV-positive individuals with known date of seroconversion to evaluate the role of Cytomegalovirus (CMV) in the natural history of HIV. The study population consisted of 236 initially CMV-positive patients, 55 CMV-negative subjects and 8 CMV seroconverters. The study endpoints were the decline to CD4+ < 200 x 10(6) cells/l, AIDS, and death. The cumulative risk of CMV disease and the survival after CMV disease were also investigated. At intake, there was no inter-group difference in sex, age, risk behaviours, history of hairy leucoplakia or herpes zoster and antiretroviral treatment. During the follow-up, 108 patients fell below 200 CD4+ x 10(6) cells/l, 72 developed AIDS and 63 died. Twenty-one subjects had CMV disease. The cumulative incidence of CMV disease in the cohort was 18.9%, and 23.3% within 8 and 9 years for the initially CMV-positive patients and 33.3% and 66.7% for the CMV seroconverters (log-rank test: p = 0.101). The median survival after CMV disease was 153 days (range: 28-855, interquartile range: 261), with a cumulative survival of 45.1%, 16.9% and 4.3% within 6, 12 and 18 months, respectively. On Cox's regression, the acute HIV seroconversion was an independent predictor of each endpoint, history of hairy leucoplakia or herpes zoster being associated only with CD4+ cell decline. Baseline CMV seropositivity was related to short survival (p = 0.037) and 2 x 2 inter-group comparison showed that older individuals with sexually acquired HIV who seroconverted to CMV had higher rates of progression to the study endpoints. Our data suggest that CMV infection influences the natural history of HIV disease and that CMV disease strongly affects the survival of the HIV-positive patients.

Adenosine and the nervous system: clinical implications.

After a review of the metabolism and pharmacology of adenosine, this work will examine the various therapeutic possibilities involving the use of agonists or antagonists of adenosine A1 or A2 receptors in neurological disorders. Promising preclinical results have been obtained with epilepsy, cerebral ischemia, alcoholism, and pain.

Adenosine and neuropathic pain.

Recent studies have reported the possibilities of relieving neuropathic pain by administering adenosine or its analogs. In order to determine if there exists a metabolic anomaly of this nucleoside in patients with neuropathic pain, circulating adenosine levels were compared in three patient groups. The first was composed of individuals suffering from neuropathic pain, the second of patients with nervous system lesions in the absence of pain, and the third was composed of patients suffering from pain resulting from excessive nociception. The adenosine blood levels of these patients were compared to those of a control group. Finally, adenosine in the cerebrospinal fluid (CSF) of some patients was also assayed. The results show that there are reduced levels of blood and CSF adenosine in patients with neuropathic pain. This adenosine deficiency could explain the potential therapeutic effects of administering adenosine or its analogs.

Tracheobronchial aspergillosis in a patient with AIDS treated with aerosolized amphotericin B combined with itraconazole.

The clinical features of a tracheobronchial infection due to Aspergillus flavus in an AIDS patient with a normal neutrophil count is described. Diagnosis was made by culture and microscopic examination of biopsies obtained from bronchial vegetations seen at bronchoscopy. Radiographic examination of the neck revealed the presence of large endoluminal fungal masses. Initially the patient was treated with a combination of itraconazole, flucytosine and aerosolized amphotericin B, then only with itraconazole plus aerosolized amphotericin B. A good therapeutic response was observed.

beta-Endorphin and blood pressure in multiple trauma victims.

In addition to pain and stress, endogenous opiates and in particular beta-endorphin could be involved in the modulation of cardiovascular parameters. Several studies have thus shown increases in plasma beta-endorphin levels in the course of septic or hypovolemic shock. Our study involving 44 multiple trauma patients indicates that even in the absence of any hemodynamic disorders, there is a correlation between systolic blood pressure and plasma beta-endorphins. These results argue in favor of the existence of feedback between systolic blood pressure and plasma beta-endorphins.

Use of dantrolene in experimental scorpion envenomation by Androctonus australis hector.

Hyperthermia and profuse perspiration are rarely absent in severe cases of scorpion envenomation. Based on these observations, the aim of this study was to determine the therapeutic effects of dantrolene, on experimental poisoning by the venom of Androctonus australis hector. Dantrolene is a directly acting muscle relaxant which lowers the body temperature in malignant hyperthermia. The results indicate that the early use of this drug raises the LD50 in experimentally poisoned mice. If these results are transposable to humans, dantrolene could be a useful therapeutic adjuvant.

The use of HPLC to evaluate the variations of blood coronary adenosine levels during percutaneous transluminal angioplasty.

Although it is well established that adenosine is released during acute ischemia, little is known of the behaviour of adenosine levels following treatment of coronary lesion by percutaneous transluminal coronary angioplasty (PTCA). Using high performance liquid chromatography, we measured intracoronary adenosine levels before and 5 min after PTCA in ten patients with one-vessel disease and a significant (> 70%) coronary stenosis. Adenosine levels decrease in all patients after PTCA. Nevertheless, more studies are now necessary to evaluate the possible predictive value (with regard to restenosis) of coronary adenosine levels after PTCA.

Use of HPLC to measure circulating adenosine levels in migrainous patients.

Adenosine is a powerful natural vasodilator that could be involved in migraine. It is difficult to assay this nucleoside, however, because it has a short half-life. We have used HPLC to compare the concentrations of blood adenosine sampled in crisis-free intervals and during crisis periods in ten patients with common migraine and have compared these levels to those noted in a control population. Our sampling technique uses vacuum suction and enables rapid mixing of the blocking solution and whole venous blood. This results in reproducible HPLC assays. We also show that, during a migraine crisis, mean blood adenosine levels increase by 47%. However, the origin of this adenosine release is difficult to define.

Purification and chemical and biological characterizations of seven toxins from the Mexican scorpion, Centruroides suffusus suffusus.

Seven polypeptides highly toxic to mice were isolated from the venom of the scorpion, Centruroides suffusus suffusus (Css), and their chemical and toxic properties were characterized. It was shown that the most active toxins by intracerebroventricular injection are less active when injected subcutaneously. The complete amino acid sequence (66 residues) of toxin II (Css II) has been determined. The C-terminal end is amidated as found for most other scorpion toxins. Css II is a beta-type toxin, previously used to define the binding site for activation of the sodium channel. Using rat brain synaptosomes, we demonstrated that all Css toxins compete with 125I-Css II to bind to site 4 and should be considered as beta-scorpion toxins. Specific binding parameters for Css VI, one of the most active toxins, were determined: KD = 100 pM; capacity in binding sites, 2.2 pmol of toxin/mg of synaptosomal protein. Css VI was shown to inhibit gamma-aminobutyric acid uptake by synaptosomes: K 0.5 = 100 pM, which agrees with its KD. Competition experiments between the seven Css toxins and 125I-Css II for antiserum raised against Css II demonstrated that all these toxins have common antigenic properties.

Amino acid sequence of toxin VII, a beta-toxin from the venom of the scorpion Tityus serrulatus.

The sequence of the 61 amino acids of toxin VII, a beta-toxin from the venom of the South American scorpion Tityus serrulatus, has been determined by automatic sequencing of the reduced and S-[14C] carboxymethylated protein and of tryptic peptides obtained before or after citraconylation of this protein. This toxin, the most active beta-toxin from this venom, is the first Tityus toxin to be fully sequenced. The results clearly show that toxin VII belongs to the structural group of scorpion toxins originating from Central and North America.

Evidence for the existence of procolipase in chicken pancreas and pancreatic juice.

Purified antibodies raised against chicken colipase were coupled to Sepharose 4B and colipase was isolated in a single step by immunoaffinity chromatography from an extract of chicken pancreas prepared under conditions where trypsin activation is avoided. The purified protein has a single amino terminal residue of alanine and its biochemical properties are similar to those of the precursor form of colipase (procolipase) previously isolated from porcine and equine pancreas or pancreatic juice. Further evidence for the existence of procolipase was obtained from kinetic studies of the hydrolysis of the Intralipid emulsion by untreated and trypsin-treated chicken pancreatic juice.

Immunochemistry of scorpion alpha-neurotoxins. Determination of the antigenic site number and isolation of a highly enriched antibody specific to a single antigenic site of toxin II of Androctonus australis Hector.

Scorpion neurotoxins active on mammals, i.e. alpha- and beta-toxins, have been divided into several groups according to structural and also immunological criteria. A study of the alpha-toxins has been performed in order to determine the number of antigenic sites; a minimum of four Fab fragments were found to bind simultaneously to toxins I and II of Androctonus australis Hector, and toxin I of Buthus occitanus tunetanus. Taking advantage of the loss of one common antigenic site between toxin II of Androctonus australis Hector and toxin III of Buthus occitanus tunetanus, a highly purified antibody population towards a single site of toxin II of Androctonus australis Hector was isolated and characterized. This result is discussed in terms of sequence homologies between the two proteins as the amino acid sequence of toxin III of Buthus occitanus tunetanus has been determined using standard procedures: the two proteins differ at three positions, two of which (positions 10 and 64) are in the vicinity of the disulfide bridge Cys 12-Cys 63, the third (position 51) is the only one to be conservative.

Isolation and partial structural characterization of chicken pancreatic colipase.

Colipase has been isolated from acidic extracts of chicken pancreatic tissue homogenized with Triton X-100. The cofactor fully activates bile salt inhibited mammalian lipases. The amino terminal sequence of the avian protein has been determined up to position 39 and compared to the homologous region of the mammalian colipases (pig, horse, man) previously studied. From this comparison, it appears that a high degree of homology exists between the proteins.