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B O'Keeffe

Publications and source records attributed to B O'Keeffe.

9 recordsLinked to original sources
PubMed2000

Requirement for a kinase-specific chaperone pathway in the production of a Cdk9/cyclin T1 heterodimer responsible for P-TEFb-mediated tat stimulation of HIV-1 transcription.

Tat activation of HIV-1 transcription is mediated by human transcription elongation factor P-TEFb, which interacts with Tat and phosphorylates the C-terminal domain of RNA polymerase II. The catalytic subunit of the P-TEFb complex, Cdk9, has been shown to interact with cyclin T and several other proteins of unknown identity. Consequently, the exact subunit composition of active P-TEFb has not been determined. Here we report the affinity purification and identification of the Cdk9-associated proteins. In addition to forming a heterodimer with cyclin T1, Cdk9 interacted with the molecular chaperone Hsp70 or a kinase-specific chaperone complex, Hsp90/Cdc37, to form two separate chaperone-Cdk9 complexes. Although the Cdk9/cyclin T1 dimer was exceptionally stable and produced slowly in the cell, free and unprotected Cdk9 appeared to be degraded rapidly. Several lines of evidence indicate the heterodimer of Cdk9/cyclin T1 to be the mature, active form of P-TEFb responsible for phosphorylation of the C-terminal domain of RNA polymerase II interaction with the Tat activation domain, and mediation of Tat activation of HIV-1 transcription. Pharmacological inactivation of Hsp90/Cdc37 function by geldanamycin revealed an essential role for the chaperone-Cdk9 complexes in generation of Cdk9/cyclin T1. Our data suggest a previously unrecognized chaperone-dependent pathway involving the sequential actions of Hsp70 and Hsp90/Cdc37 in the stabilization/folding of Cdk9 as well as the assembly of an active Cdk9/cyclin T1 complex responsible for P-TEFb-mediated Tat transactivation.

Benzoquinones↗
PubMed1994

Comparative crossover assessment of serum bactericidal activity and pharmacokinetics of ciprofloxacin and ofloxacin.

The study compared the pharmacokinetics and pharmacodynamics of ciprofloxacin and ofloxacin in 12 healthy male volunteers with normal renal function. Each volunteer received oral ciprofloxacin 500 mg, intravenous (i.v.) ciprofloxacin 400 mg, oral ofloxacin 400 mg, or i.v. ofloxacin 400 mg in a randomized, double-blind, crossover design with a one-week 'washout' period between doses. Mean peak serum concentrations were 4.48 and 5.44 mg/L for i.v. ciprofloxacin and ofloxacin, respectively. For the oral regimens, mean peak serum concentrations were 2.45 mg/L for ciprofloxacin and 4.44 mg/L for ofloxacin. Minimum bactericidal concentrations (MBC) and serum bactericidal activity (SBA) for each drug were measured against five strains of each of the following species: Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Pseudomonas aeruginosa, Acinetobacter anitratus, Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae, using the microdilution method of the National Committee for Clinical Laboratory Standards (NCCLS). Ciprofloxacin was more active in vitro than ofloxacin against the tested species of Enterobacteriaceae and P. aeruginosa, while ofloxacin was slightly more active against A. anitratus. MBCs for the two drugs were similar for H. influenzae and S. aureus. Oral and i.v. ciprofloxacin in the doses given resulted in nearly equivalent SBA. Similarly, oral and i.v. ofloxacin had nearly equivalent SBA. For the i.v. and oral regimens of both agents, peak SBA was > or = 2 throughout the 12-hour test period against the Enterobacteriaceae and H. influenzae. At peak concentrations, both drugs had modest SBA against P. aeruginosa, A. anitratus, and S. aureus but little or no activity 8 and 12 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Family care in the coronary care unit: an analysis of clinical nurse specialist intervention.

A sudden and life-threatening illness requiring hospitalization and admission to the coronary care unit (CCU) can result in serious disorganization for the patient's family. This disorganization can become obvious to staff when family members are too anxious to hear important information about the patient or when families are unable to make decisions about the patient's treatment or disposition. Although CCU care is highly technical, it is not exclusively technical. Patients and their families need care that is considerate of the family group. In a case report, the Lazarus stress and coping framework is used to assess, intervene in, and evaluate care given to one family during an admission of a family member to the CCU. Although this framework is individually oriented and is particularly dependent on individual cognition, it proved useful for work with the described family.

Adaptation, Psychological↗
PubMed1980

Successful management of serious disopyramide poisoning.

A case of deliberate disopyramide overdosage is described. Circulatory collapse was treated by means of a large dose of isoprenaline, and charcoal haemoperfusion was used in an attempt to enhance the elimination of disopyramide. The suitability of this treatment regime is discussed in the light of findings from animal studies and the implications for the management of the disopyramide-poisoned patient are considered.

Adult↗
PubMed1979

Cardiac consequences and treatment of disopyramide intoxication: experimental evaluation in dogs.

A slow (1.18 mumol.kg-1.mm-1) intravenous infusion of disopyramide (mol.wt 339) was given to 8 adult Beagle dogs. An initial phase of slow decline in cardiac output and broadening of the QRS complex on the ECG, with systolic blood pressure maintained above 13.5 kPa (100 mmHg), was followed by a phase of rapid circulatory failure without a correspondingly dramatic change in ECG appearances. Underventilation and cardiac arrhythmias were observed only in the agonal phase after several minutes of circulatory arrest. They were not therefore the primary cause of death, which was due to failure of myocardial contractility. Three positively inotropic drugs (isoprenaline, dopamine, and glucagon) are shown to be capable of restoring the failing circulation, provided they are given before the phase of complete circulatory standstill. In this respect isoprenaline appears superior to dopamine and glucagon.

Animals↗