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Biomedical subjects

D Keeling

Publications and source records attributed to D Keeling.

18 recordsLinked to original sources
PubMed2005

Procedures for the outpatient management of patients with deep venous thrombosis.

Although deep venous thrombosis (DVT) is now widely managed on an outpatient basis, at a practical level there remains a potential for uncertainty as to which patient might prove suitable and in particular in regard to the lines of responsibility of each department involved in the delivery of clinical care. This guideline sets out recommendations for the standardization of the outpatient management of patients with DVT.

Ambulatory Care↗
PubMed2004

The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization.

von Willebrand disease (VWD) is the commonest inherited bleeding disorder. However, despite an increasing understanding of the pathophysiology of VWD, the diagnosis of VWD is frequently difficult because of uncertainty regarding the relationship between laboratory assays and function in vivo. The objective of this guideline is to provide contemporary advice on a rational approach to the diagnosis of VWD. This is the second edition of this UK Haemophilia Centre Doctors' Organisation (UKHCDO) guideline and supersedes the previous edition which was published in 1997.

Hematologic Tests↗
PubMed2003

Review article: Esomeprazole--enhanced bio-availability, specificity for the proton pump and inhibition of acid secretion.

Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor available for clinical use as a single isomer. It demonstrates pharmacological and clinical benefits beyond those seen with the racemic omeprazole. Esomeprazole has higher and more consistent bio-availability than omeprazole, which results in a greater area under the plasma concentration-time curve. It is the area under the plasma concentration-time curve of omeprazole and esomeprazole that determines how much of each reaches the parietal cell, and thus the control of gastric acid secretion that is achieved. Esomeprazole, like other proton pump inhibitors, has a high specificity for the acidic environment of the parietal cell, where it is accumulated, activated and covalently inhibits the proton pump. Proton pumps elsewhere in the body do not achieve the level of acidity needed for accumulation and activation. Esomeprazole, 40 mg once daily, provides more effective control of gastric acid secretion than omeprazole, 20 or 40 mg once daily, and all other proton pump inhibitors given at their standard doses. This translates into greater clinical effect compared with omeprazole, 20 mg once daily, and lansoprazole, 30 mg once daily, in the management of reflux disease. Esomeprazole therapy is well tolerated, with a low adverse events profile, similar to that seen with omeprazole.

Anti-Ulcer Agents↗
PubMed1998

Prevention of central venous catheter associated thrombosis using minidose warfarin in patients with haematological malignancies.

Thrombosis is a well-recognized complication following insertion of central venous catheters and is associated with significant morbidity. In an attempt to reduce line-associated thrombosis, 108 consecutive patients with haematological malignancies were commenced on prophylactic 'minidose' warfarin, 1 mg/d, at the time of line insertion. This group of patients were compared with a historic group of 115 consecutive patients who had not received warfarin. Clinically-suspected venous thrombosis was confirmed by Doppler ultrasound or venography. Patients taking prophylactic warfarin had their prothrombin time measured three times per week with the aim of maintaining an INR <1.6. Five (5%) of the 108 patients who received minidose warfarin developed a thrombosis, at a median of 72 d (range 5-166) from the time of catheter insertion. In the 115 patients who were not anticoagulated 15 (13%) developed a catheter-associated thrombosis at a median of 16 d (range 1-35). There was a significant reduction in line-associated thrombosis in patients receiving warfarin (P=0.03). These data suggest that minidose warfarin reduces the incidence of central venous catheter related thrombosis in patients with haematological malignancies.

Adult↗
PubMed1997

Social support for elderly patients with chronic wounds.

Few attempts have been made to measure the social support received by elderly patients with chronic wounds. To focus research on these issues, an established model integrating the various roles played by social support in the adaptation of patients to stressful situations was applied. Two questionnaires were used to measure perceived social support and coping in a sample of patients with leg ulcers (N = 15, mean age 70.4 years) or diabetic foot ulcers (N = 15, mean age 63.6 years) at two time-points over a four-month period. The results indicate that there were no statistical differences between the groups. The overall levels of social support were low, with emotional support recorded most frequently. The standardised scores for types of coping indicate no unusual patterns, although the scores for logical analysis were low. However, there was considerable variation in the types of coping strategies used by individuals.

Adaptation, Psychological↗
PubMed1995

Properties of the reversible K(+)-competitive inhibitor of the gastric (H+/K+)-ATPase, SK&F 97574. I. In vitro activity.

SK&F 97574 (3-butyryl-4-(2-methylamino)-8-(2-hydroxyethoxy)quinoline), is a potent inhibitor of the (H+/K+)-ATPase in membrane vesicles isolated from porcine gastric mucosa. It inhibits (H+/K+)-ATPase activity in lyophilised vesicles in a kinetically competitive manner with respect to the activating cation, K+, with an inhibition constant (Ki) of 0.46 +/- 0.003 microM. Inhibition of (H+/K+)-ATPase activity is freely reversible. Binding of SK&F 97574 was shown to be mutually exclusive and the previously reported reversible (H+/K+)-ATPase inhibitors, SCH 28080 and MDPQ. Therefore, despite its structural dissimilarity, SK&F 97574 appears to bind to the same lumenal region of the (H+/K+)-ATPase identified as the binding site for these compounds. SK&F 97574 is a weak base (pKa = 6.86), and would therefore be expected to accumulate in the acidic compartment at the lumenal face of the parietal cell. In intact gastric vesicles (which have the lumenal face of the ATPase on the interior), SK&F 97574 inhibited ATP-dependent H(+)-transport with a similar potency to ATPase activity. SK&F 97574 is therefore relatively membrane permeable, and would be predicted to gain access readily to its site of action in vivo. The effect of pH on inhibition of H+/K(+)-ATPase activity by SK&F 97574 is consistent with its being active only in its protonated form. The selectivity of SK&F 97574 for the gastric (H+/K+)-ATPase was tested by examining its ability to inhibit a closely related p-class pump, the (Na+/K+)-ATPase from dog kidney. SK&F 97574 was found to have a 60-fold greater sensitivity for the former enzyme. The (Na+/K+)-ATPase was not inhibited in a K(+)-competitive manner by SK&F 97574, indicating an entirely different, probably nonspecific, mechanism.

Adenosine Triphosphate↗
PubMed1995

Pharmacological aspects of acid secretion.

The secretion of gastric acid is regulated both centrally and peripherally. The finding that H2-receptor antagonists are able to reduce or abolish acid secretion due to vagal, gastrinergic, and histaminergic stimulation shows that histamine plays a pivotal role in stimulation of the parietal cell. In the rat, the fundic histamine is released from the ECL cell, in response to gastrin, acetylcholine, or epinephrine, and histamine release is inhibited by somatostatin or by the H3-receptor ligand, R-alpha-methyl histamine. The parietal cell has a muscarinic, M3, receptor responsible for [Ca]i regulation. Blockade of muscarinic receptors by atropine can be as effective as H2-receptor blockade in controlling acid secretion. However, general effects on muscarinic receptors elsewhere produce significant side effects. The different receptor pathways converge to stimulate the gastric H+,K(+)-ATPase, the pump responsible for acid secretion by the stomach. This enzyme is an alpha,beta heterodimer, present in cytoplasmic membrane vesicles of the resting cell and in the canaliculus of the stimulated cell. It has been shown that acid secretion by the pump depends on provision of K+Cl- efflux pathway becoming associated with the pump. As secretion occurs only in the canaliculus, this K+Cl- pathway is activated only when the pump inserts into the canalicular membrane. Transport by the enzyme involves reciprocal conformational changes in the cytoplasmic and extracytoplasmic domain. These result in changes in sidedness and affinity for H3O+ and K+, enabling active H+ for K+ exchange. The acid pump inhibitors of the substituted benzimidazole class, such as omeprazole, are concentrated in the canaliculus of the secreting parietal cell and are activated there to form sulfenamides. The omeprazole sulfenamide, for example, reacts covalently with two cysteines in the extracytoplasmic loops between the fifth and sixth transmembrane and the seventh and eighth transmembrane segments of the alpha subunit of the H+,K(+)-ATPase, forming disulfide derivatives. This inhibits ATP hydrolysis and H+ transport, resulting in effective, long-lasting regulation of acid secretion. Therefore, this class of acid pump inhibitor is significantly more effective and faster acting than the H2 receptor antagonists. K+ competitive antagonists bind to the M1 and M2 transmembrane segments of the alpha subunit of the acid pump and also abolish ATPase activity. These drugs should also be able to reduce acid secretion more effectively than receptor antagonists and provide shorter acting but complete inhibition of acid secretion.

Amino Acid Sequence↗
PubMed1994

Benign myocardial uptake of hydroxymethylene diphosphonate.

During 'routine' bone scanning with diphosphonates, 10 elderly men were noted to show prominent myocardial uptake of Tc-hydroxymethylene diphosphonate (HDP) consistently, but no heart activity was seen with Tc-methylene disphosphonate (MDP). None had evidence of recent myocardial injury and the uptake persisted over a period of many months. In some, myocardial uptake defects were noted, analogous to 201Tl- and Tc-methoxyisobutyl isonitrile (MIBI) scans postinfarction. The condition appears to be essentially benign but its aetiology remains obscure. We have not been able to identify its cause; presumably atherosclerosis is one factor.

Aged↗
PubMed1993

Anti-DNA antibodies in the primary antiphospholipid syndrome (PAPS)

Primary antiphospholipid syndrome (PAPS) is considered a distinct entity from SLE and patients with PAPS are generally regarded as being dsDNA antibody negative. Levels of IgG and IgM ss and ds DNA antibodies were measured by ELISA in 30 patients who fulfilled the criteria for the diagnosis of PAPS. We compared these patients with 20 normal controls and seven patients with idiopathic SLE. We also examined all the sera for anti-nuclear antibodies by Hep-2 cells and for dsDNA antibodies by Crithidia. We found that 16 patients with PAPS had antibodies to ss and/or dsDNA. Only three of the 16 positive patients had both IgG and IgM anti-DNA antibodies. Twelve patients had anti-nuclear antibodies, but only two were weakly positive for dsDNA antibodies by Crithidia immunofluorescence. Eleven out of 30 patients with PAPS had IgM anti-dsDNA antibodies compared to two out of the seven SLE patients. The PAPS patients with anti-DNA antibodies were clinically indistinguishable from the PAPS patients without antibodies against DNA. Our results show that 53% of patients with PAPS had antibodies to DNA which supports the view that PAPS and SLE are probably overlapping disorders.

Antibodies, Antinuclear↗
PubMed1992

A K+ competitive, conformational probe of the H,K-ATPase.

The H,K-ATPase was noncovalently labelled with a fluorescent quinoline derivative, 1-(2-methylphenyl)-4-methylamino-6-methyl-2,3-dihydropyrrolo [3,2-c]quinoline, (MDPQ). MDPQ competitively inhibited the K+ stimulated ATP hydrolysis with a Ki of 0.22 microM but did not inhibit the MgATP-dependent phosphoenzyme to an extent greater than 10% of control. Inhibitor binding to the H,K-ATPase enhanced MDPQ fluorescence. This fluorescence was quenched by lumenal K+ with a K0.5 of 1.8 mM. MDPQ binding to the H,K-ATPase shifted the fluorescence Ex/Em maxima from 342/478 nm to 342/453 nm. Phosphorylation of the H,K-ATPase by MgATP further enhanced fluorescence with a difference spectra [MgATP-(MgATP+KCl)] emission peak at 446 nm. Trypsin dependent proteolysis of the H,K-ATPase stabilized within the E2K conformation eliminated the phosphoenzyme response, but enhanced the K+ specific dephosphoenzyme response. These observations show that MDPQ is a fluorescent, competitive inhibitor of the H,K-ATPase that interacts with a lumenal cation binding site. Under specific conditions, both the cation and MDPQ binding sites remain intact within trypsin produced cleavage peptides of the H,K-ATPase.

Aminoquinolines↗
PubMed1991

A K(+)-competitive fluorescent inhibitor of the H,K-ATPase.

The interactions of a novel fluorescent compound, 1-(2-methylphenyl)-4-methylamino-6-methyl-2,3-dihydropyrrolo[3,2-c ]quinoline (MDPQ) with the gastric H,K-ATPase were determined. MDPQ was shown to inhibit the H,K-ATPase and its associated K(+)-phosphatase competitively with K+, with Ki values of 0.22 and 0.65 microM, respectively. It also inhibited H+ transport with an IC50 of 0.29 microM, but at a concentration of 3.5 microM, reduced the steady-state level of phosphoenzyme by only 28%. The fluorescence of the inhibitor increased upon binding to the enzyme. 70% of this increment was quenched by K+, independently of Mg2+. The binding of MgATP to a high affinity site (K0.5(ATP) less than 1 microM) markedly increased the fluorescence due to the formation of an inhibitor-phosphoenzyme complex saturating with a K0.5(MDPQ) of 0.94 microM. The K(+)-dependent fluorescent quench (K0.5(K+) = 1.8 mM) required the ionophore, nigericin, indicating that K+ and MDPQ were competing at an extracytosolic site on the enzyme. Formation also of an enzyme-vanadyl-inhibitor complex was shown by the fact that Mg2+ plus vanadate enhanced MDPQ fluorescence in the absence of MgATP and decreased fluorescence in the presence of MgATP. The minimal stoichiometry of bound MDPQ determined by fluorescence titrations in the presence of MgATP was 1.4 mol/mol phosphoenzyme. The data suggest that this compound can serve as a probe of conformation at an extracytosolic site of the H,K-ATPase.

Adenosine Triphosphatases↗