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Biomedical subjects

G Lucas

Publications and source records attributed to G Lucas.

At least 19 recordsLinked to original sources
PubMed2006

Lack of clinical efficacy of rituximab in the treatment of autoimmune neutropenia and pure red cell aplasia: implications for their pathophysiology.

We describe 11 patients with severe refractory autoimmune cytopenias treated with the anti-CD20 monoclonal antibody rituximab. Six patients had autoimmune neutropenia (AIN), two had pure red cell aplasia (PRCA), one had AIN and autoimmune haemolytic anaemia, one had AIN and immune thrombocytopaenia purpura (ITP) and one had PRCA and ITP. Rituximab was administered at a dose of 375 mg/m(2) as an intravenous infusion weekly for 4 weeks. Six of eight patients with AIN and all three patients with PRCA did not respond. Two patients died: one with resistant AIN and autoimmune haemolytic anaemia died of pneumocytis pneumonia infection, and one with PRCA and ITP died of an acute exacerbation of bronchiectasis. Rituximab in AIN and PRCA appears to be less effective than Campath-1H when compared to historical data from our group. This supports the hypothesis that T cells may be important in the pathophysiology of AIN and PRCA.

Adult↗
PubMed2005

Granulocyte transfusions for treating infections in patients with neutropenia or neutrophil dysfunction.

BACKGROUND: Transfusions of granulocytes have a long history of usage in clinical practice to support and treat severe infection in high risk groups of patients with neutropenia or neutrophil dysfunction. However, there is considerable current variability in therapeutic granulocyte transfusion practice, and uncertainty about the beneficial effect of transfusions given as an adjunct to antibiotics on mortality. OBJECTIVES: To determine the effectiveness of granulocyte transfusions compared to no granulocyte transfusions for treating infections in patients with neutropenia or disorders of neutrophil function in reducing mortality. SEARCH STRATEGY: Randomised controlled trials (RCTs) were searched for in the Cochrane Central Register of Controlled Trials (CENTRAL) in 2003. Searching was also undertaken on the OVID versions of Medline and Embase using an RCT search filter strategy. SELECTION CRITERIA: RCTs involving transfusions of granulocytes, given therapeutically, to patients with neutropenia or disorders of neutrophil dysfunction. DATA COLLECTION AND ANALYSIS: Two reviewers completed data extraction independently. Relative risk (RR) with 95% confidence intervals (CI) using the random effects model were reported for dichotomous outcomes. Pre-specified subgroup analyses were done and reported eg granulocyte dose. MAIN RESULTS: Eight parallel RCTs were included with 310 total analysed patient episodes. Different policies were applied for the schedule of transfusion, method of granulocyte procurement and process of donor selection including leucocyte compatibility. Each study used different criteria for neutropenia (range < 0.1 to < 1.0 x 10(9)/L) and definition of infection requiring treatment. For mortality, which was extracted from six trials, the summary RR = 0.64 in favour of transfusion (95% CI 0.33, 1.26), but with evidence of significant statistical heterogeneity (Chi-square 11.3 and I(2) = 56%). The data for the combined RR for mortality for the four studies transfusing higher granulocyte doses greater than 1x10(10) indicated a significant summary RR= 0.37 (95% CI 0.17, 0.82); Chi-square 3.9, I(2) 23%. Data on rates of reversal of infection could be extracted from four studies, and the combined RR was 0.94 (95% CI 0.71, 1.26), again with evidence of heterogeneity. In addition to the observed clinical diversity between all studies, uncertainty about the quantitative and qualitative analyses for these studies is compounded by methodological deficiencies. AUTHORS' CONCLUSIONS: Currently, there is inconclusive evidence from RCTs to support or refute the generalised use of granulocyte transfusion therapy in the most common neutropenic patient populations, that is caused by myeloablative chemotherapy with or without haematopoietic stem cell support. Contemporary well designed prospective trials are required to evaluate the efficacy of this intervention in these patient populations and to establish definitively whether it has clinical benefit. In such studies, average numbers of collected granulocytes for adults should be (at least) greater than 1x10(10).

Cause of Death↗
PubMed2005

Current products and practices: personal digital assistants in orthodontics.

Personal Digital Assistants (PDAs) have certain advantages over conventional diaries and are thought of as the 'electronic filofax'. They can be backed up, used for personal and professional organization, integrated with mobile phones for email and Internet access, image storage, logbook functions and audit. They are limited when used for desktop functions. This article attempts to highlight the current advantages and disadvantages of PDAs for use in orthodontics, and provides some guidance to those who are considering the purchase of such a device.

Cell Phone↗
PubMed2002

Neonatal alloimmune thrombocytopenia due to HPA-3a antibodies: a case report.

A healthy infant was born at term by elective cesarean section to a 32-year-old para 4, gravida 4, mother. Within 24 hours, the infant was noted to have fairly extensive bruising on the back and shoulders. A full blood count evaluation was remarkable for severe thrombocytopenia (platelet count of 29 x 10(9)/L). Other hematologic parameters were normal. Human leukocyte antigen (HLA) class-1 antibodies but not platelet-specific antibodies were detectable in the maternal serum using a commercial antigen-capture ELISA (GTI-PakPlus kit). Anti-HPA-3a antibodies, while weakly reactive in the monoclonal antibody immobilization of platelet antigens (MAIPA) assay in the immediate postpartum serum, were readily detectable using this assay in a sample taken 4 weeks later. Genotyping for human platelet antigens (HPA) 1-5 by the polymerase chain reaction technique with sequence-specific primers (PCR-SSP) revealed the infant's platelet genotype to be HPA-1a/1a, 3a/3b, while that of the mother was HPA-1a/1a, 3b/ 3b, consistent with a diagnosis of anti-HPA-3a neonatal alloimmune thrombocytopenia (NAIT). This case illustrates the increased sensitivity of the MAIPA technique for the detection of platelet-specific antibodies. We believe this to be the first serologically confirmed case of NAIT due to anti-HPA-3a to be reported in the republic of Ireland.

Journal Article↗
PubMed2001

Reduced antinociception and plasma extravasation in mice lacking a neuropeptide Y receptor.

Neuropeptide Y (NPY) is believed to exert antinociceptive actions by inhibiting the release of substance P and other 'pain neurotransmitters' in the spinal cord dorsal horn. However, the physiological significance and potential therapeutic value of NPY remain obscure. It is also unclear which receptor subtype(s) are involved. To identify a possible physiological role for the NPY Y1 receptor in pain transmission, we generated NPY Y1 receptor null mutant (Y1-/-) mice by homologous recombination techniques. Here we show that Y1-/- mice develop hyperalgesia to acute thermal, cutaneous and visceral chemical pain, and exhibit mechanical hypersensitivity. Neuropathic pain is increased, and the mice show a complete absence of the pharmacological analgesic effects of NPY. In the periphery, Y1 receptor activation is sufficient and required for substance P release and the subsequent development of neurogenic inflammation and plasma leakage. We conclude that the Y1 receptor is required for central physiological and pharmacological NPY-induced analgesia and that its activation is both sufficient and required for the release of substance P and initiation of neurogenic inflammation.

Animals↗
PubMed2001

Neurochemical and electrophysiological evidence that 5-HT4 receptors exert a state-dependent facilitatory control in vivo on nigrostriatal, but not mesoaccumbal, dopaminergic function.

In this study we investigated, using in vivo microdialysis and single unit recordings, the role of serotonin4 (5-HT4) receptors in the control of nigrostriatal and mesoaccumbal dopaminergic (DA) pathway activity. In freely moving rats, the 5-HT4 antagonist GR 125487 (1 mg/kg, i.p.), without effect on its own, significantly reduced the enhancement of striatal DA outflow induced by 0.01 (-35%) and 0.1 (-66%), but not 1 mg/kg, s.c. haloperidol (HAL). Intrastriatal infusion of GR 125487 (1 microM) had no influence on basal DA outflow, but attenuated (-49%) the effect of 0.01 mg/kg HAL. Systemic administration of GR 125487 modified neither basal nor 0.01 mg/kg HAL-stimulated accumbal DA outflow. In halothane-anaesthetized rats, 1 or 10 mg/kg GR 125487, without effect by itself, failed to modify the changes in accumbal and striatal DA outflow elicited by electrical stimulation (300 microA, 1 ms, 20 Hz, 15 min) of the dorsal raphe nucleus. Finally, GR 125487 (444 microg/kg, i.v.), whilst not affecting basal firing of DA neurons within either the substantia nigra or the ventral tegmental area, reduced HAL-stimulated (1--300 microg/kg, i.v.) impulse flow of nigrostriatal DA neurons only. These results indicate that 5-HT4 receptors exert a facilitatory control on both striatal DA release and nigral DA neuron impulse flow only when nigrostriatal DA transmission is under activated conditions. Furthermore, they indicate that the striatum constitutes a major site for the expression of the control exerted by 5-HT4 receptors on DA release. In contrast, 5-HT4 receptors have no influence on mesoaccumbal DA activity in either basal or activated conditions.

Action Potentials↗
PubMed2001

The effect of treatment with Campath-1H in patients with autoimmune cytopenias.

We describe 21 patients with severe and life-threatening autoimmune cytopenias resistant to standard immunosuppression who were treated with the monoclonal antibody Campath-1H. Four patients had autoimmune neutropenia, four had autoimmune haemolytic anaemia, four had pure red cell aplasia, one had immune thrombocytopenia purpura (ITP), three had autoimmune haemolytic anaemia and ITP (Evan's syndrome), three had autoimmune pancytopenia (ITP, autoimmune neutropenia and autoimmune haemolytic anaemia), one had ITP (associated with acquired Glanzmann's disease) and autoimmune neutropenia, and one had ITP and red cell aplasia. Campath-1H was administered at a dose of 10 mg/d as an intravenous infusion for 10 d. Responses were seen in 15 patients, which were sustained in six. Relapse occurred in eight patients after Campath-1H treatment. Patients entering the study later, received cyclosporine after Campath-1H in an attempt to reduce the incidence of relapse. Three patients received a second course of Campath-1H; all responded but later relapsed. Fourteen patients are alive at a median of 12 months (range 4-61) after Campath-1H. Campath-1H represents an alternative therapeutic option for severe, refractory autoimmune cytopenias.

Adolescent↗
PubMed2001

Recurrent transfusion-related acute lung injury.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare condition that is commonly associated with the transfusion of donor plasma containing WBC antibodies. Biologically active lipids that accumulate during storage of RBCs and platelets may also cause TRALI. There has been only one previously reported case of recurrent TRALI. CASE REPORT: A patient received a transfusion 2 days after undergoing hysterectomy; she developed TRALI after receiving the transfusion. The patient recovered after being on ventilation for 6 days but received an additional transfusion and had a second episode of TRALI, which required further ventilation. RESULTS: Laboratory investigation of the first episode of TRALI suggested the presence of HLA-A2 (N = 1) and granulocyte-specific IgM antibodies (N = 2) in the sera from three of the donors. All three sera reacted in crossmatch studies with the patient's granulocytes and lymphocytes. Lymphocyte-specific IgG antibodies were detected in the patient's serum. There was no evidence to suggest the involvement of WBC antibodies in the second episode of TRALI. Antibody screening of the donors' samples and both forward and reverse crossmatch studies were negative. CONCLUSION: The first episode of TRALI seems to be due to the action of HLA-A2 and granulocyte-specific IgM antibodies. The second episode may have been due to the action of lipid neutrophil-priming agents in the donors' units in association with the patient's underlying pulmonary condition (i.e., recovering from lung injury). TRALI can recur if a patient requires further transfusion support shortly after an initial episode of TRALI.

Acute Disease↗
PubMed2000

Role of cholinergic and GABAergic systems in the feedback inhibition of dorsal raphe 5-HT neurons.

Several observations indicate that 5-HT1A receptors found on a long neuronal feedback loop, originating from the medial prefrontal cortex, regulate 5-HT neuronal firing. In the present study, the muscarinic (M) receptor antagonists atropine and scopolamine as well as the M2 receptor antagonist AF-DX 116, but not the preferential M1 receptor antagonist pirenzepine, reduced the suppressant effect of the 5-HT1A receptor agonist 8-OH-DPAT on the spontaneous firing activity of rat dorsal raphe 5-HT neurons. Moreover, AF-64A-induced lesions of cholinergic neurons directly in the medial prefrontal cortex and after its i.c.v. injection attenuated the effect of 8-OH-DPAT. Finally, the NMDA receptor antagonist (+)MK-801 and the GABA(B) receptor antagonist SCH-50911, but not the GABA(A) receptor antagonist (-)bicuculline, dampened the latter response. The present study unveiled a key role for the cholinergic and GABAergic systems in the feedback inhibition of dorsal raphe 5-HT neurons.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2000

[Epidemiology and etiology of acquired heart valve diseases in adults].

Acquired valvular heart disease remains common. Their causes have changed during the past 30 years with the increase in life expectancy and with the decrease in the incidence of rheumatic fever. Calcific aortic stenosis is currently the predominant cause, followed by left heart valvular regurgitations due to degenerative disease and infective endocarditis. Post-radiation valvular disease might become more frequent in the future. More recently, left heart valvular diseases were observed in the United States in patients treated by anorexigen treatment.

Adult↗
PubMed2000

Endogenous serotonin enhances the release of dopamine in the striatum only when nigro-striatal dopaminergic transmission is activated.

In this study, we use in vivo microdialysis to investigate the influence of endogenous serotonin (5-HT) on striatal dopamine (DA) and 5-hydroxyidoleacetic acid (5-HIAA) efflux in both basal and activated conditions. The selective serotonin reuptake inhibitors citalopram and fluoxetine were used to mobilize endogenous 5-HT. In halothane-anaesthetized rats, citalopram (5 mg/kg, i.p.), administered either alone or in combination with the 5-HT(1A) receptor antagonist WAY 100635 (0.1 mg/kg, s.c.), while reducing striatal 5-HIAA outflow (-25 and -15%, respectively), had no effect on basal DA output. When locally applied into the striatum, citalopram had no effect at 1 microM concentration, but enhanced DA release after its perfusion at 25 and 100 mircroM concentrations (+27% and +67%, respectively). However, the injection of the neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, failed to modify the effect of 25 microM citalopram. In freely-moving rats, the intrastriatal infusion of citalopram or fluoxetine (1 microM each), had no effect on its own, but significantly enhanced the increase in DA outflow induced by the subcutaneous administration of 0.01 mg/kg haloperidol (+31% and +30% for citalopram and fluoxetine, respectively). These findings indicate that, in the striatum, endogenous 5-HT has no influence on DA release under basal conditions, but positively modulates DA outflow when nigro-striatal DA transmission is activated.

5,7-Dihydroxytryptamine↗
PubMed2000

The effect of serotonergic agents on haloperidol-induced striatal dopamine release in vivo: opposite role of 5-HT(2A) and 5-HT(2C) receptor subtypes and significance of the haloperidol dose used.

This study investigated, using microdialysis in freely-moving rats, the role of serotonin (5-HT) and 5-HT(2) receptor subtypes in the enhancement of striatal dopamine (DA) release induced by various doses of haloperidol. The subcutaneous injection of 0.01, 0.1 or 1 mg/kg haloperidol dose-dependently increased DA outflow (160, 219 and 230% of baseline, respectively). The effect of 0.01 mg/kg haloperidol was, respectively, potentiated by the 5-HT uptake inhibitor citalopram (1 mg/kg, s.c.; +35%) and reduced by the 5-HT(1A) receptor agonist 8-OH-DPAT (0.025 mg/kg, s.c.; -32%). Also, it was reduced by the 5-HT(2A) antagonist SR 46349B (0.5 mg/kg, s.c. ; -40%) or by the 5-HT(2A/2B/2C) antagonist ritanserin (1.25 mg/kg, i.p.; -34%), and potentiated by the 5-HT(2B/2C) antagonist SB 206553 (5 mg/kg, i.p; +78%). Further, only this latter compound significantly modified basal dopamine release by itself (+26%). Dopamine released by 0.1 mg/kg haloperidol was enhanced (+100%) by citalopram, decreased (-61%) by SR 4634B, but unaltered by SB 206553. Finally, none of the compounds used were able to modify the enhancement of dopamine release induced by 1 mg/kg haloperidol. These results show that central 5-HT(2A) and 5-HT(2C) receptors exert an opposite (respectively excitatory and inhibitory) influence on DA release. Moreover, they suggest that the 5-HT(2A)-dependent modulation depends on the degree of central DA receptor blockade.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2000

Expression of the imprinted tumour-suppressor gene H19 is tightly regulated during normal haematopoiesis and is reduced in haematopoietic precursors of patients with the myeloproliferative disease polycythaemia vera.

cDNA subtraction was employed to uncover differences in gene expression between myeloproliferative polycythaemia vera (PV) and normal haematopoietic precursors. Following cDNA subtraction using mRNAs isolated from PV and normal CD34+/CD33- bone-marrow cells, expression of the tumour suppressor H19 was found to be low or absent in the PV sample. Low levels of H19 expression in PV patients were confirmed by in situ hybridization. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to examine expression in the pluripotent haematopoietic cell line FDCP-mix and single bone-marrow precursors, unambiguous IGF2 and H19 expression was demonstrated in normal haematopoietic precursors. Examination of individual bone-marrow precursors revealed that all IGF2-expressing haematopoietic precursors also co-expressed H19, indicating that H19 and IGF2 may be co-ordinately regulated during haematopoiesis. Analysis of FDCP-mix undergoing differentiation and single pluripotent and committed bone-marrow precursors revealed that the pattern of H19 expression coincided with the commitment to a single lineage. Taken together, these observations demonstrate that H19 and IGF2 are specifically expressed during haematopoiesis and that low levels of H19 expression are associated with PV and may contribute to the pathology of the disease.

Animals↗
PubMed2000

IgA myeloma of donor origin arising 7 years after allogeneic renal transplant.

We report the case of a 38-year-old man who developed IgA myeloma of donor origin 7 years after allogeneic renal transplant. The diagnosis of multiple myeloma was unequivocal and based on positive results from serum electrophoresis, skeletal survey and bone marrow investigations. The donor origin of the myeloma cells was confirmed by DNA fingerprinting. We believe this is the first reported case of disseminated multiple myeloma of donor origin developing after allogeneic renal transplant and, as such, gives some insight into the natural history and biology of the disease.

Adult↗
PubMed2000

Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum.

This study investigated, using in vivo microdialysis in the striatum of freely moving rats, the role of striatal serotonin2A (5-HT2A) and 5-HT2C receptor subtypes in the modulation of dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) outflow, both in basal conditions and under activation induced by subcutaneous administration of 0.01 mg/kg haloperidol. The different 5-HT2 agents used were applied intrastriatally at a 1 microM concentration through the microdialysis probe. Basal DA efflux was enhanced (27%) by the 5-HT2A/2B/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) and reduced (-30%) by the 5-HT2B/2C antagonist SB 206553. It was unaffected by infusion of the 5-HT2A antagonist SR 46349B. The effect of DOI was abolished by SB 206553 but not modified by SR 46349B. Haloperidol-stimulated DA efflux (65-70%) was reduced by both SR 46349B (-32%) and the 5-HT2A/2B/2C antagonist ritanserin (-30%) but not affected by SB 206553. Conversely, the effect of haloperidol was potentiated (22%) when DOI was coperfused with SB 206553. Also, haloperidol-stimulated DOPAC outflow (40-45%) was reduced (-20%) by SR 46349B and potentiated (25%) by the combination of SB 206553 with DOI. These results indicate that striatal 5-HT2A receptors, probably through activation of DA synthesis, positively modulate DA outflow only under activated conditions. In contrast, striatal 5-HT2C receptors exert a facilitatory control on basal DA efflux, which appears to be both tonic and phasic.

3,4-Dihydroxyphenylacetic Acid↗