Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 2002"

Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta.

Abstract: Background A small proportion of patients with chronic myeloproliferative diseases have constitutive activation of the gene for platelet-derived growth factor receptor beta (PDGFRB), which encodes a receptor tyrosine kinase. The gene is located on chromosome 5q33, and the activation is usually caused by a t(5;12)(q33;p13) translocation associated with an ETV6-PDGFRB fusion gene. The tyrosine kinase inhibitor imatinib mesylate specifically inhibits ABL, PDGFR, and KIT kinases and has impressive clinical efficacy in BCR-ABL–positive chronic myeloid leukemia. Methods We treated four patients who had chronic myeloproliferative diseases and chromosomal translocations involving 5q33 with imatinib mesylate (400 mg daily). Three of the four patients presented with leukocytosis and eosinophilia; their leukemia cells carried the ETV6-PDGFRB fusion gene. The fourth patient had leukocytosis, eosinophilia, and a t(5;12) translocation involving PDGFRB and an unknown partner gene; he also had extensive raised, ulcerated...

Localization of major gangliosides in the PNS: implications for immune neuropathies

Abstract: Summary Antibodies targeting major gangliosides that are broadly distributed in the nervous system are some- times associated with clinical symptoms that imply selective nerve damage. For example, anti-GD1a anti- bodies are associated with acute motor axonal neuropa- thy (AMAN), a form of Guillain-Barresyndrome that selectively affects motor nerves, despite reports that GD1a is present in human axons and myelin and is not expressed differentially in motor versus sensory roots. We used a series of high-affinity monoclonal antibodies (mAbs) against the major nervous system gangliosides GM1, GD1a, GD1b and GT1b to test whether any of them bind motor or sensory fibres differentially in rodent and human peripheral nerves. The following observations were made. (i) Some of the anti-GD1a antibodies preferentially stained motor fibres, support- ing the association of human anti-GD1a antibodies with predominant motor neuropathies such as AMAN. (ii) A GD1b antibody preferentially stained the large dorsal root ganglion (DRG) neurones, in keeping with the pro- posed role of human anti-GD1b antibodies in sensory ataxic neuropathies. (iii) Two mAbs with broad struc- tural cross-reactivity bound to both gangliosides and peripheral nerve proteins. (iv) Myelin was poorly stained; all clones stained axons nearly exclusively. Our findings suggest that anti-ganglioside antibody fine specificity as well as differences in ganglioside access- ibility in axons and myelin influence the selectivity of injury to different fibre systems and cell types in human autoimmune neuropathies.

Hyponatraemic states following 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') ingestion.

Abstract: Background: Life‐threatening and fatal hyponatraemic complications following ecstasy use have previously been documented. Aim: To define clinical features of hyponatraemia following the ingestion of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’). Design: Retrospective case series. Methods: All enquiries to the London centre of the National Poisons Information Service (NPIS) between December 1993 and March 1996 were screened for cases of MDMA use associated with hyponatraemia (serum sodium <130 mmol/l). History of fluid consumption, presenting features and subsequent clinical course were recorded. Results: Seventeen patients, aged 15–26 years, were identified. Serum sodium levels ranged between 107 mmol/l and 128 mmol/l. In six patients, biochemical results were consistent with inappropriate secretion of antidiuretic hormone (SIADH). Analytical confirmation of MDMA ingestion was obtained in 10 patients. Ten patients were known to have ingested a large amount of non‐alcoholic or alcoholic fluid. The clinical pattern was remarkably uniform, with initial vomiting and disturbed behaviour, followed in 11 patients by seizures. Drowsiness, a mute state and disorientation were observed for up to 3 days. Two patients died; 14 made a complete recovery. Discussion: MDMA can cause life‐threatening hyponatraemic encephalopathy when accompanied by excessive fluid ingestion. The mechanism involves inappropriate secretion of antidiuretic hormone.

Shuttleworthia satelles gen. nov., sp. nov., isolated from the human oral cavity.

Abstract: Nine strains of anaerobic, non-spore-forming, gram-positive bacilli, isolated from the human oral cavity and provisionally identified as belonging to the genus Eubacterium, were subjected to a comprehensive range of phenotypic and genetic tests. Biochemically, they were found to comprise a homogeneous group, and phylogenetic analysis of their 16S rRNA sequences indicated that they constitute a unique branch within the Clostridium-Bacillus subphylum of the phylum Firmicutes. All of the isolates displayed an unusual colonial morphology after extended incubation. This resembled a contaminated culture in that small, secondary colonies were seen to arise around and from within the primary colony form, and a third, independent, colony type was also seen. However, inspection of the colonies by Gram-staining and scanning electron microscopy together with protein profile analysis and 16S rRNA gene sequence comparison of the two independent colony types revealed that only a single organism was present. A new genus, Shuttleworthia, and the species Shuttleworthia satelles gen. nov., sp. nov., are proposed. The cells are saccharolytic, and acetate, butyrate and lactate are produced as end products of glucose fermentation. Aesculin is hydrolysed and indole is produced. The G+C content of the DNA of the type strain is 51 mol%. The type strain is strain DSM 14600T (= CCUG 45864T = VPI D143K-13T).

Limited antifibrillatory effectiveness of clinically relevant concentrations of class I antiarrhythmics in isolated perfused rat hearts.

Abstract: The Langendorff-perfused rat heart with regional ischemia is increasingly used for evaluating drugs for prevention of phase-1, ischemia-induced ventricular fibrillation (VF). Surprisingly, the effectiveness of Class I antiarrhythmics has not been characterized in this model. One lower and one higher concentration of quinidine (0.79 and 7.90 microM), lidocaine (3.88 and 12.93 microM), and flecainide (0.74 and 1.48 microM), representing the peak unbound plasma and total blood concentrations, respectively, at "therapeutic" dosage, were evaluated. The left main coronary artery was occluded for 30 min to elicit phase-1 VF, after which reperfusion-induced VF was examined. In hearts perfused with Krebs' solution containing 3 mM K(+), the higher concentrations of quinidine and lidocaine reduced the incidence of phase-1 VF from 92% to 0% and 17% respectively, (each p < 0.05). The lower drug concentrations were ineffective. Flecainide was equi-effective at low and high concentrations, with VF incidence reduced from 92% to 17% (p < 0.05). Neither low nor high concentrations of any of the drugs affected the incidence of reperfusion-induced VF. Using hearts perfused with Krebs' containing 5 mM K(+), sufficient to substantially reduce control phase-1 VF incidence, the experiment was repeated to test for possible proarrhythmic activity. None of the three drugs increased arrhythmia incidence. In this model, it was not possible to suppress ischemia-induced and reperfusion-induced VF with flecainide, lidocaine, or quinidine at concentrations equivalent to peak unbound plasma levels after clinical administration. This may explain the lack of clinical benefit with these drugs against sudden cardiac death. Because none of the drugs were proarrhythmic in ischemic hearts in which arrhythmia susceptibility had been lowered by high K(+), it would seem that clinical proarrhythmia seen with these drugs may not be related to exacerbation of phase-1, ischemia-induced VF.

Treatment of Parkinson's disease and restless legs syndrome with cabergoline, a long-acting dopamine agonist.

Abstract: Dopamine agonists have diverse chemical and physical properties that can directly stimulate the dopamine receptors, unlike levodopa which undergoes presynaptic breakdown to dopamine before dopaminergic effects in Parkinson's disease (PD). Cabergoline, a dopamine agonist effective given once daily, is being used as treatment for PD. In theory, therapy with cabergoline provides striatal intrasynaptic dopamine replacement of PD in a physiological manner because of its long half-life and the resultant sustained rather than pulsatile dopaminergic stimulation. Several placebo-controlled trials using cabergoline as adjunctive therapy in PD have shown that cabergoline significantly reduces 'off' time, improves motor function and reduces levodopa requirement. Cabergoline has also been used as monotherapy in PD and has been shown to be as effective as other dopamine agonists in improving motor function and to be superior to levodopa in reducing dyskinesias over a five-year period. Work from our group and others have also demonstrated the efficacy of cabergoline in PD patients with nocturnal disabilities and those with restless legs syndrome (RLS). More recently we have reported that cabergoline is a well-tolerated dopamine agonist in both young and elderly patients and has an acceptable side-effect profile.