Fish oil supplementation with and without added vitamin E differentially modulates plasma antioxidant concentrations in healthy women

5-[4-(2-Carboxyethylcarbamoyl)phenylazo]salicylic acid disodium salt dihydrate (CAS 80573-04-2, BX661A) is developed as a therapeutic agent for ulcerative colitis. To clarify the mechanisms of action of BX661A, the effects of BX661A and its metabolites 5-aminosalicylic acid (5-ASA) and 4-aminobenzoyl-beta-aline (4-ABA) on polymorphonuclear (PMN) leukocyte chemotaxis and production of reactive oxygen species (ROS) from PMN cells were investigated and compared with the effects of 2-hydroxy-5-[[4-[(2-pyridinylamino)sulfonyl]phenyl]azo]-benzoic acid (CAS 599-79-1, SASP) and its metabolite 4-amino-N-2-pyridinyl-benzenesulfonamide (CAS 144-83-2, SP). 1. BX661A, SASP and SP concentration-dependently inhibited guinea pig PMN cell chemotaxis induced by zymosan-activated serum (IC50 = 1.39, 2.17 mmol/l, respectively) and by N-formyl-methionyl-leucyl-phenylalanine (FMLP) with IC50 values of 0.55, 0.06 and 0.66 mmol/l, respectively. 5-ASA and 4-ABA weakly affected the PMN cell chemotaxis induced by zymosan-activated serum (both IC50 values > or = 10 mmol/l) and by FMLP (IC50 > or = 10 and 8.05 mmol/l, respectively). 2. BX661A, SASP and SP concentration-dependently inhibited human PMN cell chemotaxis induced by FMLP with IC50 values of 0.68, 0.05 and 2.68 mmol/l, respectively, but both IC50 values of 5-ASA and 4-ABA were > 10 mmol/l. 3. BX661A, SASP, 5-ASA, 4-ABA and SP inhibited ROS production from rat PMN cells stimulated by FMLP in a concentration-dependent manner (IC50 = 58.4, 27.5, 0.61, 1242 and 13.9 mmol/l, respectively). 4. BX661A, SASP, 5-ASA, 4-ABA and SP inhibited ROS production from human PMN cells stimulated by FMLP in a concentration-dependent manner (IC50 = 67.4, 46.1, 0.69, 748 and 8.31 mumol/l, respectively). These results suggest that BX661A itself has inhibitory effects against PMN cell chemotaxis and ROS production from PMNs and that 5-ASA, which is the active moiety of BX661A, has a potent inhibitory effect against ROS production from PMNs. Therefore, these effects may be partially involved in the therapeutic effects of BX661A on ulcerative colitis.     

Type I adenylyl cyclase mutant mice have impaired mossy fiber long-term potentiation

Long-term potentiation (LTP) at the mossy fiber-->CA3 pyramidal cell synapse in the hippocampus is an NMDA-independent form of LTP that requires cAMP-dependent protein kinase (PKA) activity and can be induced by forskolin, a general activator of adenylyl cyclases. Presynaptic Ca2+ influx and elevated cAMP may be obligatory for mossy fiber LTP. Because the Ca2+-stimulated type 1 adenylyl cyclase (AC1) is expressed in the dentate gyrus and CA3 pyramidal cells, it is hypothesized that AC1 may be critical for mossy fiber LTP. To test this hypothesis, we examined several forms of hippocampal LTP in wild-type and AC1 mutant mice. Wild-type and AC1 mutant mice exhibited comparable perforant path LTP recorded in the dentate gyrus as well as decremental LTP at the Schaffer collateral-->CA1 pyramidal cell synapse. Although the mutant mice exhibited normal paired pulse facilitation, mossy fiber LTP was impaired significantly in AC1 mutants. High concentrations of forskolin induced mossy fiber LTP to comparable levels in wild-type and AC1 mutant mice, indicating that signaling components downstream from the adenylyl cyclase, including PKA, ion channels, and secretory machinery, were not affected by disruption of the AC1 gene. These data indicate that coupling of Ca2+ to activation of AC1 is crucial for mossy fiber LTP, most likely via activation of PKA and enhancement of excitatory amino acid secretion.     

Biphenylsulfonamide endothelin antagonists: structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1, 1'-biphenyl]-2-sulfonamide (BMS-187308)

Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.     

Prediction of drinking outcomes for male alcoholics after 10 to 14 years

This study reports on the long-term outcomes of 360 men who were hospitalized for alcoholism during 1980 to 1984 and followed at 12 months and again 10 to 14 years later. At the 10/14-year follow-up, 96 (26.7%) men were confirmed as deceased; 255 (70.8%) men participated in the assessment/interview battery completed during baseline hospitalization. The battery consisted of psychosocial, alcohol-related, and psychiatric measures. Two distinct but highly correlated outcome measures were selected: a clinical rating scale and a factor score. Overall, predictors from baseline and 12-month follow-up included age at intake hospitalization, alcoholism severity, social stability, drinking days, and antisocial personality disorder. Approximately 37% of the assessed survivors were either totally abstinent or drinking nonabusively throughout the 10/14-year follow-up, whereas another 37% continued to drink abusively. Men who abstained or reduced alcohol intake reported better physical health at follow-up than those who continued to drink. Although our findings did not directly link alcoholism to death, they strongly indicate that chronic alcohol abuse may lead to premature death.     

Hexokinase 2 from Saccharomyces cerevisiae: regulation of oligomeric structure by in vivo phosphorylation at serine-14

Homodimeric hexokinase 2 from Saccharomyces cerevisiae is known to have two sites of phosphorylation: for serine-14 the modification in vivo increases with glucose exhaustion [Kriegel et al. (1994) Biochemistry 33, 148-152], while for serine-157 it occurs in vitro with ATP in the presence of nonphosphorylateable five-carbon analogues of glucose [Heidrich et al. (1997) Biochemistry 36, 1960-1964]. We show now by site-directed mutagenesis and sedimentation analysis that serine-14 phosphorylation affects the oligomeric state of hexokinase, its substitution by glutamate causing complete dissociation; glutamate exchange for serine-157 does not. Phosphorylation of wild-type hexokinase at serine-14 likewise causes dissociation in vitro. In view of the higher glucose affinity of monomeric hexokinase and the high hexokinase concentration in yeast [Womack, F., and Colowick, S. P. (1978) Arch. Biochem. Biophys. 191, 742-747; Mayes, E. L., Hoggett, J. G., and Kellett, G. L. (1983) Eur. J. Biochem. 133, 127-134], we speculate that the in vivo phosphorylation at serine-14 as transiently occurring in glucose derepression might provide a mechanism to improve glucose utilization from low level and/or that nuclear localization of the monomer might be involved in the signal transduction whereby glucose causes catabolite repression.     

Clinical predictors of HIV-1 infection among preschool children in Dar es Salaam, Tanzania

Seroprevalence of HIV-1 infection was determined in children aged between eighteen months and five years, attending maternal and child health (MCH) clinics in Dar es Salaam, Tanzania. A total of 889 children were eligible for the study, however seven children could not be enrolled because their mothers/guardians absconded and blood could not be drawn from 21 children due to refusal of mothers/guardians and from another 12 children due to technical reasons. Therefore, the participation rate was 95.5%. Of the 849 children screened, 14 (1.65%) were found to have IgG anti HIV-1 antibodies in their sera. The main clinical features found in children with symptomatic HIV-1 disease were weight loss, generalized lymphadenopathy, recurrent fevers, and prolonged diarrhoea. The utility of clinical features suggestive of HIV-1 infection (according to CDC classification) in identifying HIV-1 infection in children was evaluated and found to have high sensitivity (100%), specificity (96.9%) and negative predictive value (100%), but a low positive predictive value (35%). Marked variations in progression to symptomatic phase were noted, whereby some relatively young children had progressed to symptomatic phase (CDC class P-2A), while some older children were still in the asymptomatic stage (CDC class P-1 C). None of the symptomatic HIV-1 infected children presented with neurological disease, severe opportunistic infections, or malignancies. Although reduced mid-upper arm circumference and weight-for-age were associated with HIV seropositivity, these clinical parameters had low positive predictive values compared to the CDC classification.     

Critical pharmacologic management in the emergency department

PURPOSE: Starting from a status hypercoagulability previous to substitutive hip and knee surgery, the aim of this work was to investigate the influence of different osteoarthropatic pictures for which arthroplasty is indicated in the activation of the clotting cascade, rheumatoid arthritis (RA) being one of such pictures. PATIENTS AND METHODS: Of 79 patients suitable for prosthetic surgery of hip (53) and knee (26), the preoperative values of several markers, namely, D dimers (D-D), thrombin-antithrombin (TAT) complex, and F1 + 2 prothrombin fragment (F1 + F2) were assessed by enzymoimmunoasay. The mean age of the patients was 65.5 years, and their sex distribution was 50 women and 29 men. The indications for arthroplasty were as follows: osteoarthrosis (62), aseptic necrosis (11), RA (9), articular gout (2), previous fracture (2), more than one diagnosis overlapped in some cases. The results attained were compared with a control group comprised of 33 subjects (16 women and 17 men) with mean age similar to the patient's group (68.06 years). RESULTS: The D-D values in the patients suitable for hip arthroplasty and the TAT values in patients suitable for both types of surgery were significantly higher than those found in the control group (p = 0.012 and 0.01, respectively). The preoperative TAT levels of the RA patients were significantly higher (p = 0.025) than those found in the patients with the other surgical indications. CONCLUSIONS: Previously to the performance of arthroplasty, the patients show hypercoagulative marker values higher than those of age-matched controls. The significant rising of TAT found in RA patients is concordant with the literature, and this fact makes it advisable to include RA among the pathologic situations associated with hypercoagulability, as this is a common indication for substitutive hip and knee surgery with high risk of venous thromboembolic disease.