In silico identification of putative metal binding motifs.

Metal ion binding domains are found in proteins that mediate transport, buffering or detoxification of metal ions. In this study, we have performed an in silico analysis of metal binding proteins and have identified putative metal binding motifs for the ions of cadmium, cobalt, zinc, arsenic, mercury, magnesium, manganese, molybdenum and nickel. A pattern search against the UniProtKB/Swiss-Prot and UniProtKB/TrEMBL databases yielded true positives in each case showing the high-specificity of the motifs.

The analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery.

Background: As optimal pain relief after surgery is difficult to achieve with the use of just one drug, many pain experts advocate the use of two or more classes of medications so as to reduce the side effects from any one drug. In this trial, we assessed the analgesic efficacy of administering perioperative celecoxib, pregabalin, or both after spinal fusion surgery.

Methods: Eighty patients scheduled to undergo elective decompressive lumbar laminectomy with posterior spinal fusion were randomized to receive oral medications: placebo 1 h before and 12 h after surgery, celecoxib 400 mg 1 h before and celecoxib 200 mg 12 h after surgery, pregabalin 150 mg 1 h before and 12 h after surgery, or a pregabalin/celecoxib combination of 400 mg/150 mg 1 h before and 200 mg/150 mg 12 h after surgery.

Paradoxical bronchospasm: a potentially life threatening adverse effect of albuterol.

We report a case of paradoxical bronchospasm to both levalbuterol and albuterol. While the exact mechanism for this known adverse effect of albuterol is not known, awareness of this adverse effect can be life saving to the patient. To our knowledge, this is the first reported case of paradoxical bronchospasm to levalbuterol inhalation solution.

Lemierre syndrome complicating a subcutaneous neck abscess.

Lemierre syndrome is septic thrombophlebitis of the internal jugular vein caused typically by an oropharyngeal infection. We report a case of Lemierre syndrome complicating a subcutaneous neck abscess. Lemierre syndrome should be considered in the differential diagnosis of septic emboli and sepsis, especially in a patient with tenderness along the sternomastoid muscle.

The effect of cyclooxygenase-2 inhibition on acute and chronic donor-site pain after spinal-fusion surgery.

Background And Objectives: The development of chronic pain after spinal-fusion surgery represents a significant source of morbidity. One of the predictive factors for the development of chronic postsurgical pain is inadequate acute postoperative pain management. Further, the up-regulation of cyclooxygenase-2 (COX-2) after surgery may result in neuro-plastic changes that may contribute to a progression from acute to chronic pain.

Role of hydrophobic interactions and salt-bridges in beta-hairpin folding.

Beta-hairpins are the simplest form of beta-sheets which, due to the presence of long-range interactions, can be considered as tertiary structures. Molecular dynamics simulation is a powerful tool that can unravel whole pathways of protein folding/unfolding at atomic resolution. We have performed several molecular dynamics simulations, to a total of over 250 ns, of a beta-hairpin peptide in water using GROMACS.

Evidence of a double-lid movement in Pseudomonas aeruginosa lipase: insights from molecular dynamics simulations.

Pseudomonas aeruginosa lipase is a 29-kDa protein that, following the determination of its crystal structure, was postulated to have a lid that stretched between residues 125 and 148. In this paper, using molecular dynamics simulations, we propose that there exists, in addition to the above-mentioned lid, a novel second lid in this lipase. We further show that the second lid, covering residues 210-222, acts as a triggering lid for the movement of the first.

Modulation of fluorouracil antitumor activity by folic acid in a murine model system.

The biochemical basis for modulation of fluorouracil (FU) activity by leucovorin is elevation of the metabolite methylenetetrahydrofolate, which stabilizes the inhibitory ternary complex formed between thymidylate synthase and the active metabolite of FU, 5-fluorodeoxyuridylate. Folic acid, because it can also potentially be metabolized to methylenetetrahydrofolate, was evaluated for its ability to potentiate FU antitumor activity in a dietary folic acid restricted murine model. The plasma pharmacokinetics and tissue distribution of folic acid and all stable metabolites thereof were determined in the model to establish administration schedules.

Effects of antisense-based folypoly-gamma-glutamate synthetase down-regulation on reduced folates and cellular proliferation in CCRF-CEM cells.

The effect of down-regulation of folylpoly-gamma-glutamate synthetase (FPGS) activity on intracellular reduced folate accumulation and cellular proliferation was examined, using an inducible antisense expression system in the human T-lymphoblastic leukemia cell line CCRF-CEM. FPGS catalyzes the addition of gamma-glutamyl residues to natural folates and classical antifolates, which results in their enhanced cellular retention and increased cytotoxicity. As such, this enzyme has become a focus as a potential anticancer drug target.

Impact of schedule on leucovorin potentiation of fluorouracil antitumor activity in dietary folic acid deplete mice.

A dietary folic acid depleted mouse model was established and used to evaluate the relationship between elevation of reduced folates after leucovorin (LV) administration and potentiation of fluorouracil (FU) response of an implanted tumor. C3H mouse mammary adenocarcinomas from mice maintained on a folic acid deplete diet had modestly decreased methylenetetrahydrofolate and tetrahydrofolate levels, and were somewhat less responsive to FU alone compared with replete animals. LV administration resulted in a substantial increase in tumor folate by 1 hr that returned to near basal levels by 12 hr.

Disposition of leucovorin and its metabolites in dietary folic acid-deplete mice - comparison between tumor, liver, and plasma.

Purpose: A comprehensive pharmacokinetic study of leucovorin (5-formyltetrahydrofolate, 5-HCO-FH4) and its metabolites was conducted in plasma, liver and implanted tumor tissue from mice maintained on a low folic acid diet. While it has been previously demonstrated that the antitumor activity of fluorouracil (FU) can be potentiated by 5-HCO-FH4, the optimum time for administration of FU after 5-HCO-FH4, to maximally elevate the active folate metabolite methylenetetrahydrofolate in tumor has not been established. Human plasma studies have defined the pharmacokinetics of circulating 5-HCO-FH4 and its metabolites, but comparison with human tumor accumulation has not been practicable because of sampling difficulties.