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Biomedical subjects

A McCluskey

Publications and source records attributed to A McCluskey.

At least 19 recordsLinked to original sources
PubMed2002

Effect of rescuer fatigue on performance of continuous external chest compressions over 3 min.

Guidelines for the performance of cardiopulmonary resuscitation (CPR) have been revised recently and now advocate that chest compressions are performed without interruption for 3 min in patients during asystole and pulseless electrical activity. The aim of the present study was to determine if rescuer fatigue occurs during 3 min of chest compressions and if so, the effects on the rate and quality of compressions. Forty subjects competent in basic life support (BLS) were studied. They performed continuous chest compressions on a Laerdal Skillmeter Resusci-Anne manikin for two consecutive periods of 3 min separated by 30 s. The total number of compressions attempted was well maintained at approximately 100 min(-1) throughout the period of study. However, the number of satisfactory chest compressions performed decreased progressively during resuscitation (P < 0.001) as follows: first min, 82 min(-1); second, 68 min(-1); third, 52 min(-1); fourth, 70 min(-1); fifth, 44 min(-1); sixth, 27 min(-1). We observed significant correlations between the number of satisfactory compressions performed and both height and weight of the rescuer. Female subjects achieved significantly fewer satisfactory compressions compared with males (P = 0.03). Seven subjects (five female, two male) were unable to complete the second 3-min period because of exhaustion. We conclude that rescuer fatigue adversely affects the quality of chest compressions when performed without interruption over a 3-min period and that this effect may be greater in females due to their smaller stature. Consideration should be given to rotating the rescuer performing chest compressions after 1 min intervals.

Adult↗
PubMed2001

Cantharimides: a new class of modified cantharidin analogues inhibiting protein phosphatases 1 and 2A.

Cantharidin and its analogues have been of considerable interest as potent inhibitors of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A). However, limited modifications to the parent compounds is tolerated. As part of an on-going study we have developed a new series of cantharidin analogues, the cantharimides. Inhibition studies indicate that cantharimides possessing a D- or L-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC(50)=3.22+/-0.7 microM; PP2A IC(50)=0.81+/-0.1 microM and PP1 IC(50)=2.82+/-0.6 microM; PP2A IC(50)=1.35+/-0.3 microM, respectively) than norcantharidin (PP1 IC(50)=5.31+/-0.76 microM; PP2A IC(50)=2.9+/-1.04 microM) and essentially equipotent with cantharidin (PP1 IC(50)=3.6+/-0.42 microM; PP2A IC(50)=0.36+/-0.08 microM). Cantharimides with non-polar or acidic amino acid residues are only poor inhibitors of PP1 and PP2A.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2001

A highly atom efficient, solvent promoted addition of tetraallylic, tetraallenic, and tetrapropargylic stannanes to carbonyl compounds.

Tetraallylic, tetraallenic, and tetrapropargylic stannanes (0.25 equiv) react with aldehydes in methanol to provide unsaturated alcohols in good to excellent yields (56-99%). These reactions proceed exclusively with allylic rearrangement for tetra(2-butenyl)tin 2b and tetra(1,2-butadienyl)tin 16c and predominantly with allylic rearrangement for tetrapropadienyltin 16a and tetra(2-butynyl)tin 6e. Allylation reactions also proceeded smoothly with reactive ketones such as ethyl pyruvate (9a) and cyclohexanone (9b). The corresponding TFA-catalyzed reactions of dimethyl acetals 4d and 4e are regiospecific with allylic rearrangement.

Journal Article↗
PubMed2001

Oral midazolam premedication for day case breast surgery, a randomised prospective double-blind placebo-controlled study.

We conducted a randomised prospective double-blind placebo-controlled study to assess the efficacy of oral midazolam premedication in 50 ASA I and II female patients scheduled to undergo day case breast surgery. Anxiety was assessed using 100-mm visual analogue scales (VAS) and The State-Trait Anxiety Inventory (STAI) psychometric questionnaire. Midazolam premedication did not significantly reduce either VAS or STAI score, although heart rate and systolic arterial pressure immediately before induction of anaesthesia were significantly lower in patients who received midazolam (p = 0.006 and 0.039, respectively). Induction of anaesthesia was achieved with a lower dose of propofol (p = 0.0009) and excellent (Grade I) conditions for insertion of a laryngeal mask airway were achieved more often after midazolam premedication (p = 0.038). Arterial desaturation during induction of anaesthesia and insertion of a laryngeal mask airway occurred more often in patients who received placebo (p = 0.022). There was a good correlation between VAS and STAI used to assess the anxiolytic effects of premedication. (Spearman coefficient 0.58, p < 0.0001).

Adolescent↗
PubMed2001

Evaluation of the Pneupac Ventipac portable ventilator in critically ill patients.

We assessed adequacy of ventilation in 20 critically ill patients with multiple organ failure using a Pneupac Ventipac portable ventilator and the effects on patients' haemodynamic stability. Baseline data were recorded over 15 min for a range of respiratory, haemodynamic and oxygen transport variables during ventilation with a standard intensive care ventilator (Engström Erica). Patients were then ventilated for 40 min using the portable ventilator. Finally, they were ventilated for a further 40 min using the standard intensive care ventilator. Heart rate, arterial and pulmonary artery pressures were recorded at 5-min intervals throughout the study period. Cardiac index and other haemodynamic data derived from a pulmonary artery catheter were recorded at 20-min intervals. Blood gas analysis was performed and oxygen transport data (oxygen delivery, oxygen consumption and physiological shunt) were calculated at the end of each of the three periods of ventilation. In general, no significant adverse effects of ventilation using the portable ventilator were observed for any of the variables studied. Arterial PO(2) increased significantly during ventilation with the portable ventilator, reflecting the use of a higher inspired oxygen fraction during this part of the study. Oxygen consumption decreased significantly in one patient during ventilation by the portable ventilator although none of the other variables measured in this patient was altered. We conclude that ventilation of critically ill patients using the Pneupac Ventipac portable ventilator was safe, satisfactory and associated with minimal adverse effects on respiratory, haemodynamic and oxygen transport variables.

Aged↗
PubMed2001

Auto-inhibition of Ca(2+)/calmodulin-dependent protein kinase II by its ATP-binding domain.

Ca(2+)/calmodulin dependent protein kinase (CaMPK) II is a key enzyme in many physiological processes. The enzyme is inactive unless Ca(2+)/CaM binds to it. In this inactive form CaMPK-II does not bind ATP suggesting that the ATP-binding domain is involved in an intramolecular interaction. We show here that F12, a 12 amino acid long peptide fragment of the ATP-binding domain (CaMPK-II(23-34), GAFSVVRRCVKV) can inhibit the Ca(2+)/CaM-dependent activity (IC(50) of 3 microM) but has no effect on the Ca(2+)/CaM-independent activity of CaMPK-II. Kinetic analysis exhibited mixed inhibition with respect to autocamtide-2 and ATP. The inhibition by F12 showed specificity towards CaMPK-II, but also inhibited CaMPK-I (IC(50) = 12.5 microM), while CaMPK-IV (IC(50) = 85 microM) was inhibited poorly and cAMP-dependent protein kinase (PKA) was not inhibited. Substitution of phenylalanine at position 25 to alanine (A12), had little effect on the inhibition of different Ca(2+)/CaM-dependent protein kinases, suggesting that phenylalanine 25 does not play a crucial role in the interactions involving F12. Thus the molecular interactions involving the ATP-binding domain appears to play a role in the regulation of nonphosphorylated CaMPK-II activity.

Adenosine Triphosphate↗
PubMed2001

Small molecule inhibitors of serine/threonine protein phosphatases.

Serine/threonine protein phosphatases have long been ignored as potential therapeutic targets for two reasons, one the biochemical significance of these proteins has not been appreciated and two, many natural protein phosphatase inhibitors are potent toxins and are considered unsuitable for clinical use. This review outlines the biochemical role of this protein family in cancer, cystic fibrosis, immunosuppression and, cardiac and neurological disorders. Particular emphasis is also given to the synthesis of selective small molecule inhibitors and their clinical exploitation.

Animals↗
PubMed2001

The inhibition of protein phosphatases 1 and 2A: a new target for rational anti-cancer drug design?

Recent investigations in our laboratories have highlighted that the inhibition of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A) is an excellent target for the development of novel anti-cancer agents. Using a combination of the known crystal structure of PP1 and the modelled structure of PP2A, we have rationally designed a new class of protein phosphatase inhibitors, cantharimides, which exhibit broad-spectrum anti-cancer activity. Synthetic modifications of the simplest known PP1 and PP2A inhibitor, norcantharidin, has led to the development of potent PP1 and PP2A inhibitors.

Antineoplastic Agents↗
PubMed2000

Anhydride modified cantharidin analogues: synthesis, inhibition of protein phosphatases 1 and 2A and anticancer activity.

Two series of anhydride modified cantharidin analogues were synthesised and screened for their phosphatase inhibition (PP1 and PP2A) and cytotoxicity in various cancer cell lines (Ovarian A2780, ADDP; Osteosarcoma 143B; and Colon HCT116 and HT29). One series was synthesised by a novel, high yielding one-pot hydrogenation-ring-opening-esterification procedure, the other by acid catalysed acetal formation. Analogues 5-7 and 9 displayed moderate PP2A selectivity (ca. 5- to 20-fold) and inhibition typically in the low microM range (comparable, in some cases to cantharidin). The anticancer activity of these analogues varied with the cell line under study; however, many of them showed selective cytotoxicity for the colon tumour cell lines.

Anhydrides↗
PubMed2000

A gene therapy approach to enhance the targeted radiotherapy of neuroblastoma.

BACKGROUND: The aims of this study were to determine whether the introduction and expression of the noradrenaline transporter (NAT) gene into NAT-negative neuroblastoma cell lines would make them amenable to targeted radiotherapy using [(131)I]MIBG. PROCEDURE: Neuroblastoma cell lines were transfected with a eukaryotic expression vector containing the bovine noradrenaline transporter cDNA under the expression of the CMV promoter. Stable transfectants were created by selection in geneticin (G418) and were characterised for their MIBG uptake ability and susceptibility to [(131)I]MIBG therapy. RESULTS: The cell line SK-N-MC, which normally shows no ability to take up MIBG, was successfully transfected with bNAT. SK-N-MC.bNAT transfectants exhibited uptake and release kinetics similar to those of the natural NAT-expressing cell line SK-N-BE(2c). Levels of [(131)I]MIBG uptake were 33% of those of the highest naturally NAT-expressing cell line SK-N-BE(2c). Growth delay assays using multicellular spheroids indicated that this degree of [(131)I]MIBG uptake was sufficient to inhibit growth at radioactive concentrations of 4 Mbq/ml. CONCLUSIONS: These results demonstrate the feasibility of combining gene therapy with targeted radiotherapy to enhance uptake, and hence radiation dose, to neuroblastoma tumours using [(131)I]MIBG. With the appropriate delivery vehicle and tumour-specific control of expression, the introduction of noradrenaline transporter molecules may be a viable means of enhancing the response of neuroblastoma tumours to [(131)I]MIBG therapy.

Carrier Proteins↗
PubMed2000

Corticotropin releasing hormone: therapeutic implications and medicinal chemistry developments.

Corticotropin releasing hormone (CRH, sometimes known as CRF) is an endogenous 41 amino acid peptide that has been implicated in the onset of pregnancy, the 'fight or flight' response, in addition to a large number of physiological disorders. Recently, medicinal chemists have developed a number of potent and selective compounds that show promise in a vast array of therapeutic uses. Herein we review the current status of research.

Amino Acid Sequence↗
PubMed2000

Inspiratory vocal cord dysfunction, a new approach in treatment.

Vocal cord dysfunction is a well recognized respiratory condition in which adduction of the vocal cords during either inspiration or expiration, or both, causes functional airways obstruction. Diagnosis is usually made by laryngofibreoscopy, however treatment of this condition has generally been unsatisfactory, requiring a multi-disciplinary approach consisting of speech therapy, psychological counselling, sedatives and anaesthetic agents. Here we use an innovative approach which requires relatively inexpensive and simple anaesthetic equipment in order to manipulate airways resistance and thus reduce any vocal cord dysfunction as it occurs. The patient involved found instant relief when using this simple device which is easy to use and is portable.

Adult↗