Short-term estradiol administration in aging ovariectomized rats provides lasting benefits for memory and the hippocampus: a role for insulin-like growth factor-I.

We previously demonstrated that aged ovariectomized rats that had received prior estradiol treatment in middle age exhibited enhanced spatial memory and increased levels of estrogen receptor (ER)-α in the hippocampus long after estradiol treatment was terminated. The implication for cognition of increased levels of ERα resulting from prior estradiol exposure is unknown. In the absence of estrogens, growth factors, including IGF-I, can induce ERα-mediated transcription through ligand-independent mechanisms. Our current goal was to determine whether IGF-I mediates the ability of short-term exposure to estradiol to exert long-term effects on cognition and the hippocampus of aging females. Ovariectomized middle-aged rats were implanted with estradiol or cholesterol vehicle capsules. After 40 days, all capsules were removed and drug treatments were initiated. Half of each hormone treatment group received chronic intracerebroventricular delivery of the IGF-I receptor antagonist JB1, and the other half received artificial cerebrospinal fluid vehicle. Rats were tested on a spatial memory radial-arm maze task and hippocampi were immunostained for proteins of interest by Western blotting. As expected, previous treatment with estradiol enhanced spatial memory and increased levels of ERα in the hippocampus. JB1 reversed these effects. Previous treatment with estradiol resulted in lasting increases in levels of IGF-I receptors and phosphorylation of ERK/MAPK, a downstream signaling molecule of both ERα and IGF-I receptors, and increased levels of the ERα-regulated protein, choline acetyltransferase. JB1 blocked effects on ERK/MAPK and choline acetyltransferase. Results indicate that activation of IGF-I receptors is necessary for prior estradiol exposure to exert lasting impact on the hippocampus and memory.

Unconjugated hyperbilirubinemia and early childhood caries in a diverse group of neonates.

We evaluated if the development of early childhood caries is associated with the severity of unconjugated hyperbilirubinemia during the first 2 weeks after birth. We performed a retrospective case-control study of children less than 6 years of age seen for comprehensive dental examination by pediatric dentists years following a hospital stay in the neonatal intensive care unit. Exclusion criteria included genetic disorders, cleft palate, direct hyperbilirubinemia, and missing information on jaundice. Children with early childhood caries were compared with those without dental caries for a panel of perinatal and neonatal clinical variables. Seventy-six children met study criteria. Of 76 children, 42 children had early childhood caries, while 34 children had healthy primary dentitions. Among clinical variables, only race and peak total serum bilirubin concentration differed significantly between the two groups on bivariate analysis. On logistic regression, peak total serum bilirubin concentration was significantly associated with early childhood caries (adjusted odds ratio 1.17, 95% confidence interval 1.04 to 1.32). Neonatal unconjugated hyperbilirubinemia may be associated with early childhood caries in children.

Cefonicid: an overview of clinical studies in the United States.

Cefonicid, an investigational cephalosporin with a half-life just under 5 hr, was studied by more than 100 investigators in the United States. Of 1,060 cefonicid-treated patients for whom the clinical efficacy of the compound could be evaluated, 91.7% were cured or improved; 95% received a single daily dose. Rates of bacteriologic cure were equal for infections due to gram-positive cocci (89.9%) and gram-negative bacilli (93.2%). Overall rates of favorable response to cefonicid therapy, by disease, were 88.4%, urinary tract infections; 91.4%, lower respiratory tract infections; 95.1%, skin and skin-structure infections; and 91.3%, bone and joint infections. Prophylaxis with cefonicid administered 1 hr before surgery was as effective as that with control antibiotic in reducing the incidence of perioperative infection. For 795 patients who received cefonicid or control drug who underwent gynecologic surgery, prosthetic arthroplasty, cesarean section, or intraabdominal surgery, the reduction in incidence of perioperative infections were equivalent. Resistance to cefonicid developed infrequently (1.3%). Overall safety of cefonicid was comparable with that of control agents except for the frequency of occurrence of diarrhea, which was lower among patients who received cefonicid than among those who received a control drug.

Ceftizoxime treatment of cutaneous and subcutaneous tissue infections.

Forty-seven adults with infected cutaneous lesions including decubitus ulcers, leg ulcers, cellulitis, pyoderma, and infected dermatitis were treated in a randomized single-blind study with ceftizoxime (2 gm/day, administered intravenously) or cefamandole (4 gm/day, administered intravenously). The duration of treatment ranged from five to 17 days with ceftizoxime and from six to 14 days with cefamandole. Both gram-positive cocci (mostly Staphylococcus sp) and gram-negative bacilli were cultured from the infected areas before treatment. Clinical and bacteriological responses to both drugs were excellent. Ceftizoxime at a dosage of 1 gm twice daily proved to be at least as effective as 1 gm of cefamandole given four times daily. Both drugs were well tolerated, effective, and safe in the treatment of skin and skin-structure infections. Neither drug therapy had to be discontinued because of adverse effects.

Nuclear magnetic resonance studies on the structure of the tetrapeptide tuftsin, L-threonyl-L-lysyl-L-prolyl-L-arginine, and its pentapeptide analogue L-threonyl-L-lysyl-L-prolyl-L-prolyl-L-arginine.

Nuclear magnetic resonance spectroscopy has been used to investigate the solution conformation of tuftsin, threonyllysylprolylarginine, as well as a pentapeptide inhibitor of tuftsin, threonyllysylprolylprolylarginine. Both proton and carbon-13 studies were performed. In water, neither peptide gives evidence of a preferred conformation. In dimethyl-d6 sulfoxide, tuftsin appears to prefer a particular conformation, but the inhibitor does not. The conformation of tuftsin is one in which the amide NH proton of arginine is solvent shielded. The conformation does not, however, appear to be such that a normal 4 leads to 1 beta turn exists.

Evidence for a tyrosine residue at the active site of phosphoglucomutase and its interaction with vanadate.

The rate of transfer of [32P]phosphate from [32P]-labeled phosphoglucomutase (alpha-D-glucose-1,6-bisphosphate:alpha-D-glucose-1-phosphate phosphotransferase, EC 2.7.5.1) to glucose increases dramatically between pH 8.5 and 10.5 with a half maximal rate at pH 9.8. This suggests the participation of a residue containing an ionizable group with a pK close to 10. The inhibition of enzyme activity obtained with tyrosine-derivatizing reactions--iodination, nitration, acetylation, and diazo coupling--is strongly indicative of tyrosine participation. Thiol reagents, p-hydroxymercuribenzoate and ethyleneimine, were without effect. Vanadate and arsenate augmented the transfer reaction 200- and 2.5-fold, respectively, and lowered the pH optimum of the reaction.

The structural requirements of glucose for phosphorylation by phosphoglucomutase.

During catalysis, the phosphoryl group of phosphoglucomutase (alpha-D-glucose-1,6-bisphosphate:alpha-D-glucose-1-phosphate phosphotransferase, EC 2.7.5.1) is transferred through a nucleophilic displacement reaction to the monophosphate substrates to form the diphosphate. Some non-phosphorylated analogs of glucose have been shown to serve as effective acceptors of the active phosphate albeit at a much reduced rate. Several other analogs exhibit little or no reactivity. The relative reaction rates of the reactive analogs follow the order: thioglucose greater than alpha- or beta-D-glucose greater than D-xylose, greater than L-arabinose greater than myo-inositol. The rate of transfer increased with the increased concentration of glucose or its analogs. The products of the reaction may be acid stable ester phosphate or acid labile glycosyl phosphate as well as inorganic phosphate. S-phosphoryl (hemiacetal) thioglucose was identified as a product of the 1-thioglucose reaction. It was possible to define certain steric requirements for the orientation of the hydroxyl groups in all the reacting sugars. These requirements are limited to 3 hydroxyl groups and pertain to loci or receptors on the active site of the enzyme. These would correspond in topography to carbons 2, 3 and 4 of the glucose molecule in the enzyme substrate complex. These hydroxyl groups should be oriented equatorially and project below, above and below the plane of the pyranose ring for C-2, C-3 and C-4, respectively.

Amplitude/frequency differences in single-lead ECG of normal versus coronary heart diseased males.

A resting "normal" ECG can coexist with known coronary heart disease (CHD). Combined sensitivity and specificity errors of at least 10% in exercise ECGs are not unusual. Improved screening for CHD was attempted using amplitude/frequency analysis of ECG recordings. Thirty normal males and 30 with documented CHD were selected. The ECGs were recorded on electromagnetic tape during supine rest. Analysis provided digital conversion, selection of four ECG segments, time-normalization and amplitude/frequency analysis. Analyses provided one digital, plot per each segment and one per each 30-subject average. The results from one ECG lead are presented. Significant differences (p less than or equal to 0.05) appeared in the comparisons between the normal and CHD groups. Retrospectively, amplitude criteria individually screened normal from CHD males to an improved degree compared with exercise ECGs.

The dephosphorylation of phosphoglucomutase by nucleophilic reagents.

The phosphoryl group on the serine residue at the active site of phosphoglucomutase is presumed to undergo nucleophilic attack by the monophosphate substrates glucose 1- and glucose 6-phosphate to form glucose 1,6-diphosphate. Fluoride, hydroxylamine, and several thiol compounds have now been shown to serve as effective nucleophiles toward the active phosphate and result in the dephosphorylation of phosphoglucomutase. The more extensively studied nucleophiles, cysteine, hydroxylamine, and fluoride, are effective at a concentration as low as 1 mM with a relative reactivity of 40, 2, and 1, respectively. The reaction proceeds as long as the catalytic activity of the enzyme is maintained. Inactivation of the enzyme abolishes dephosphorylation by all nucleophilic reagents thus far studied. The dephosphorylation reaction shows optimal activity of pH 6.5. The rate of dephosphorylation exhibits saturation kinetics. With fluoride the Km is 534 mM. Dephosphorylation by fluoride is stimulated by some but not all bivalent cations. Cu+ and Co2+ are the most effective. Cu2+ not only augments the reaction with fluoride but also facilitates a nucleophilic attack by water, in the absence of the halogen, to yield inorganic phosphate. No augmentation of the rate of dephosphorylation by bivalent cations can be elicited with either cysteine or hydroxylamine. The products of the fluoride reaction are phosphorofluoridate, a small but variable amount of inorganic phosphate, and a fully active dephosphoenzyme. By constrast, cysteine and hydroxylamine yield inorganic phosphate and a partially inactive enzyme. The dephosphorylation rate varies with temperature. Arrhenius plots for the fluoride reaction reveal two distinct slopes. The heat of activation between 5-37 degrees was found to be 10.2 Cal per mol. Between 0-5 degrees, however, it was considerably greater amounting to 24.3 Cal per mol.

Extrachromosomal nature of hydrogen sulfide production in Escherichia coli.

Two strains of Escherichia coli which produce hydrogen sulfide appear to have acquired this ability via transfer of genetic material from another genus.