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T J Williams

Publications and source records attributed to T J Williams.

At least 55 records · Page 3Linked to original sources
PubMed2000

Basophil responses to chemokines are regulated by both sequential and cooperative receptor signaling.

To investigate human basophil responses to chemokines, we have developed a sensitive assay that uses flow cytometry to measure leukocyte shape change as a marker of cell responsiveness. PBMC were isolated from the blood of volunteers. Basophils were identified as a single population of cells that stained positive for IL-3Ralpha (CDw123) and negative for HLA-DR, and their increase in forward scatter (as a result of cell shape change) in response to chemokines was measured. Shape change responses of basophils to chemokines were highly reproducible, with a rank order of potency: monocyte chemoattractant protein (MCP) 4 (peak at <1 nM) >/= eotaxin-2 = eotaxin-3 >/= eotaxin > MCP-1 = MCP-3 > macrophage-inflammatory protein-1alpha > RANTES = MCP-2 = IL-8. The CCR4-selective ligand macrophage-derived chemokine did not elicit a response at concentrations up to 10 nM. Blocking mAbs to CCR2 and CCR3 demonstrated that responses to higher concentrations (>10 nM) of MCP-1 were mediated by CCR3 rather than CCR2, whereas MCP-4 exhibited a biphasic response consistent with sequential activation of CCR3 at lower concentrations and CCR2 at 10 nM MCP-4 and above. In contrast, responses to MCP-3 were blocked only in the presence of both mAbs, but not after pretreatment with either anti-CCR2 or anti-CCR3 mAb alone. These patterns of receptor usage were different from those seen for eosinophils and monocytes. We suggest that cooperation between CCRs might be a mechanism for preferential recruitment of basophils, as occurs in tissue hypersensitivity responses in vivo.

Basophils↗
PubMed2000

Eotaxin is specifically cleaved by hookworm metalloproteases preventing its action in vitro and in vivo.

Eotaxin is a potent eosinophil chemoattractant that acts selectively through CCR3, which is expressed on eosinophils, basophils, mast cells, and Th2-type T cells. This arm of the immune system is believed to have evolved to control helminthic parasites. We hypothesized that helminths may employ mechanisms to inhibit eosinophil recruitment, to prolong worm survival in the host. We observed that the excretory/secretory products of the hookworm Necator americanus inhibited eosinophil recruitment in vivo in response to eotaxin, but not leukotriene B(4), a phenomenon that could be prevented by the addition of protease inhibitors. Using Western blotting, N. americanus supernatant was shown to cause rapid proteolysis of eotaxin, but not IL-8 or eotaxin-2. N. americanus homogenate was fractionated by gel filtration chromatography, and a FACS-based bioassay measured the ability of each fraction to inhibit the activity of a variety of chemokines. This resulted in two peaks of eotaxin-degrading activity, corresponding to approximately 15 and 50 kDa molecular mass. This activity was specific for eotaxin, as responses to other agonists tested were unaffected. Proteolysis of eotaxin was prevented by EDTA and phenanthroline, indicating that metalloprotease activity was involved. Production of enzymes inactivating eotaxin may be a strategy employed by helminths to prevent recruitment and activation of eosinophils at the site of infection. As such this represents a novel mechanism of regulation of chemokine function in vivo. The existence of CCR3 ligands other than eotaxin (e.g., eotaxin-2) may reflect the evolution of host counter measures to parasite defense systems.

Animals↗
PubMed2000

Delta 32 deletion of CCR5 gene and association with asthma or atopy.

The CCR5-delta32 deletion polymorphism (CCR5-delta32) was investigated for linkage and association to asthma and atopy using two panels of nuclear families containing 1284 individuals. No statistically significant linkage to asthma/wheeze or atopy was observed in either of the two panels of families. Multiallelic transmission disequilibrium tests (TDT) of the combined data found no significant association for atopy (52 independent alleles transmitted, 51 non-transmitted) or asthma/wheeze (39 transmitted, 44 non-transmitted). Although functional evidence might suggest that CCR5 is a good candidate gene for atopic asthma, this study provides no genetic evidence from CCR5-delta32 polymorphism to support this hypothesis.

Alleles↗
PubMed2000

A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry.

We describe a small molecule chemokine receptor antagonist, UCB35625 (the trans-isomer J113863 published by Banyu Pharmaceutical Co., patent WO98/04554), which is a potent, selective inhibitor of CCR1 and CCR3. Nanomolar concentrations of UCB35625 were sufficient to inhibit eosinophil shape change responses to MIP-1alpha, MCP-4, and eotaxin, while greater concentrations could inhibit the chemokine-induced internalization of both CCR1 and CCR3. UCB35625 also inhibited the CCR3-mediated entry of the human immunodeficiency virus-1 primary isolate 89.6 into the glial cell line, NP-2 (IC(50) = 57 nm). Chemotaxis of transfected cells expressing either CCR1 or CCR3 was inhibited by nanomolar concentrations of the compound (IC(50) values of CCR1-MIP-1alpha = 9.6 nm, CCR3-eotaxin = 93.7 nm). However, competitive ligand binding assays on the same transfectants revealed that considerably larger concentrations of UCB35625 were needed for effective ligand displacement than were needed for the inhibition of receptor function. Thus, it appears that the compound may interact with a region present in both receptors that inhibits the conformational change necessary to initiate intracellular signaling. By virtue of its potency at the two major eosinophil chemokine receptors, UCB35625 is a prototypic therapy for the treatment of eosinophil-mediated inflammatory disorders, such as asthma and as an inhibitor of CCR3-mediated human immunodeficiency virus-1 entry.

Animals↗
PubMed2000

Mechanism underlying acute resident leukocyte disappearance induced by immunological and non-immunological stimuli in rats: evidence for a role for the coagulation system.

OBJECTIVE: To investigate the involvement of the fibrinogen-fibrin system in the acute reduction of the resident leukocyte population following pleural inflammation. METHODS: Sensitized and naive rats were injected intrapleurally (i.pl.) with antigen (ovalbumin) and platelet-activating factor (PAF) or bradykinin, respectively. Heparin (0.25 U/cavity), EDTA (80 microg/cavity) and hirudin (1 U/cavity) were injected locally 5 min before challenge, whereas fucoidin was injected intraperitoneally 30 min before stimulation. RESULTS: Antigen challenge led to a rapid reduction in the number of resident leukocytes 30 min post-challenge (from 7.7 +/- 0.4 x 10(6) cells/cavity to 2.3 +/- 0.2 x 106 cells/cavity, n = 6, p < 0.001). The pleural stimulation of naive rats with either PAF or bradykinin also led to a significant decrease in the pleural leukocyte population, which occurred in parallel with the formation of a fibrin meshwork containing captured cells, as attested by electron microscopy. Heparin prevented the drop in the total leukocyte numbers, without modifying either plasma leakage or histamine release at 30 min or the subsequent neutrophil and eosinophil infiltration noted 4 and 24 h post-challenge, respectively. Similarly, hirudin and EDTA prevented the antigen-induced leukocyte disappearance reaction. Heparin also impaired the drop in the pleural leukocyte numbers evoked by PAF and bradykinin. CONCLUSION: Our data show that the pleural resident cell disappearance phenomenon noted early after inflammatory provocation depends on the activation of the fibrinogen-fibrin system, and is not required for the subsequent leukocyte recruitment.

Animals↗
PubMed2000

Bilateral sequential single lung transplantation for pulmonary hypertension and Eisenmenger's syndrome.

BACKGROUND: Lung transplantation, with and without intracardiac repair for pulmonary hypertension (PH) and Eisenmenger's syndrome (EIS), has become an alternative transplant strategy to combined heart and lung transplantation (HLT). METHODS: Thirty-five patients with PH or EIS underwent either bilateral sequential single lung transplantation (BSSLT, group I, n = 13) or HLT (group II, n = 22). Another 74 patients, who underwent BSSLT for other indications, served as controls (group III). Immediate allograft function, early and medium-term outcomes, lung function, and 2-year survival were compared between the groups. RESULTS: Comparisons between groups I and II showed no significant difference in any variables except percent predicted forced vital capacity. Immediate allograft function was significantly inferior (p < 0.05) and the blood loss was greater (p < 0.01) in group I when compared with those in group III. However, this resulted in no significant difference in early and medium-term outcomes, and 2-year survival between the 2 groups. CONCLUSIONS: BSSLT for PH and EIS can be performed as an alternative procedure to HLT without an increase in early and medium-term morbidity and mortality. Results are comparable with BSSLT performed for other indications.

Adult↗
PubMed2000

Maximizing thoracic organ transplant opportunities: the importance of efficient coordination.

BACKGROUND: In Australia, despite large distances and one of the world's lowest multiorgan donor rates (11.4/million population/year), the thoracic organ transplant (TOTx) rate of 9.6/million population/year is one of the world's highest. METHODS: As an example of the Australian approach, a system of transplant coordination and organ allocation has evolved at the Alfred Hospital. Donor organs are assigned locally, or between the 4 major TOTx units on rotation. The recipient team then selects appropriate recipients, matching by blood group, size, cytomegalovirus (CMV) status, prospective cross matching and clinical status. An experienced recipient coordinator takes responsibility for organization of the retrieval and transplant process, including all operating room staff, all medical personnel, and transport for the donor team and the potential TOTx recipients. RESULTS: Between February 1989 and February 1999, 307 hearts, 48 heart/ lung, 124 single and 116 bilateral lung transplants were performed from 452 donor offers (52% beyond 500 miles). This represents 1.74 organs transplanted/thoracic donor and compares favourably to American United Network for Organ Sharing (1.43) and European (1.3) figures. CONCLUSIONS: The Australia TOTx model has enabled high transplant rates by efficiently using the available donor organs. This has been achieved through an enlarged, experience TOTx team, the optimizing of donor acceptance criteria and improving coordination logistics to allow multiple thoracic procedures simultaneously.

Australia↗
PubMed2000

Outcomes from paired single-lung transplants from the same donor.

BACKGROUND AND METHODS: Simultaneous, paired single-lung transplants from a single organ donor is one way to maximize lung transplant opportunities. Paired transplants allow comparison between left and right single-lung transplants and also provide insight into the relevance of donor vs recipient factors in rejection outcomes. RESULTS: Of 76 paired transplants (38 pairs) performed at the Alfred Hospital, 68 patients have survived >30 days. We observed no significant differences between left and right single-lung transplants in ICU stay (median, 3.1 vs 3.0 days; range, 0.5 to 83 vs 0.5 to 76 days), hospital stay (median, 19.5 vs 24.0 days; range, 1 to 118 vs 11 to 144 days), airway complications (5 vs 3), and 5-year survival (60% vs 50%). The 6 month, and 1- and 2-year survivals were lower in left single-lung transplant recipients, primarily related to increased mortality from airway complications. In 28 pairs, both recipients survived 90 days, and the incidence, frequency, and time of onset of acute rejection and chronic rejection (bronchiolitis obliterans syndrome [BOS]) were not significantly different. When sequentially performed lung transplants were separately analyzed, the incidence of acute rejection was not related to graft ischemic time. CONCLUSIONS: The general outcomes of right and left transplants are similar, although we observed increased 6-month to 2-year mortality associated with left lung transplantation. The lack of correlation between the incidence of acute rejection episodes or the severity of BOS in paired allograft recipients suggests that "donor factors" are not the dominant cause.

Adolescent↗
PubMed2000

Eotaxin and eosinophil recruitment: implications for human disease.

Eosinophils have been implicated in a broad range of diseases, notably allergic conditions (for example, asthma, rhinitis and atopic dermatitis) and other inflammatory disorders (for example, inflammatory bowel disease, eosinophilic gastroenteritis and pneumonia). These disease states are characterized by an accumulation of eosinophils in tissues. Severe tissue damage ensues as eosinophils release their highly cytotoxic granular proteins. Defining the mechanisms that control recruitment of eosinophils to tissues is fundamental to understanding these disease processes and provides targets for novel drug therapy. An important discovery in this context was the identification of an eosinophil-specific chemoattractant, eotaxin. Over the past six years there has been intensive investigation into the biological effects of eotaxin and its role in specific disease processes and this is the subject of this review.

Animals↗
PubMed2000

A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives.

AIMS: In October 1995 in response to the results of three studies, the Committee on the Safety of Medicines advised doctors and pharmacists that oral contraceptives containing desogestrel (DSG) and gestodene (GST) were associated with around a two-fold increase in the risk of thromboembolism compared with those containing other progestogens. The objective of this study was to estimate the risk of idiopathic venous thromboembolic disease (VTE) in users of combined oral contraceptives (COCs), to compare the risk between formulations and to examine the effect of using age banding as opposed to matching by exact year of birth. METHODS: A nested case control study was conducted using the General Practice Research Database. Women with a VTE event recorded between 1992 and 1997, who were treated with an anticoagulant, from consideration of their prescription records were likely to have been using a COC prescription on the day of the event and also had no exclusion factors, were deemed cases. For comparison with the previous studies, two nested case control studies were undertaken. Study 1 used controls matched by practice and year of birth. Study 2 used controls matched by practice and within 5 years age bands. RESULTS: We found an incidence of idiopathic VTE amongst users of combined oral contraceptives of 3.8 per 10 000 exposed women years. Incidence rates increased markedly after 35 years of age. The nested case-control study using controls matched by year of birth showed no significant difference in risk between the major COC formulations. With levonorgestrel (LNG) 150 microgram and ethinyloestradiol (EE) 30 microgram as the reference, the adjusted ORs for GST 75 microgram and EE 30 microgram was 1.3 (95% CI 0.8, 2.1), for DSG 150 microgram and EE 30 microgram it was 1.0 (95% CI 0.7, 1.7) and for DSG 150 microgram and EE 20 microgram it was 0.8 (95% CI 0.4, 1.6). Using less rigorous matching criteria, matching controls to cases within 5 years age bands, the ORs increased. When a mixed group of COCs, characterized by having LNG as the progestogen component was used as the reference category, there was an elevation in the ORs for the newer products. We found a significant association between idiopathic VTE and current smoking (OR 2.0 (1.4, 2.7)), BMI over 35 (OR 3.8 (1.8, 8.0)) and asthma (OR 1.9 (1.3, 2.9)). The OR for women who had proxy evidence of general ill health (indicated by the number of prescriptions issued) was 2.2 (1.7, 3.7). CONCLUSIONS: The results of this study indicate that a number of the characteristics of the women taking COCs affect the risk of VTE. There is no evidence to support the hypothesis that there is any difference in risk between COC formulations containing under 50 microg ethinyloestradiol.

Adolescent↗
PubMed2000

Validation of the diagnosis of venous thromboembolism in general practice database studies.

AIMS: The study was conducted to determine whether the method for selecting cases of venous thromboembolism (VTE) from general practice databases significantly affected the findings of an epidemiological study. METHODS: Cases of VTE were identified from the UK General Practice Research Database (GPRD) by searching for codes for deep vein thrombosis (DVT) and pulmonary embolism (PE). These had to be supported by evidence of anticoagulation and be exposed to a combined oral contraceptive (COC) at the time of the event. Additional information about the event was sought from general practitioners who were requested to complete a questionnaire and to supply anonymised copies of hospital letters and discharge summaries. RESULTS: Of the 285 cases identified from the GPRD, additional information was available for 177 VTE events. This information showed that 84% of those events were supported by hospital investigations or a death certificate. Using only verified cases, rather than all GPRD identified events, did not alter the results of the epidemiological study. CONCLUSIONS: The GPRD provides information of sufficiently high quality to allow valid epidemiological research of VTE events. Excluding cases without a database record of hospital admission would lead to valid events being overlooked, and an under-estimate of the disease incidence.

Adult↗
PubMed2000

Fetal and neonatal IL-13 production during pregnancy and at birth and subsequent development of atopic symptoms.

BACKGROUND: Cytokine production at the materno-fetal interface may influence the development of atopy-predisposing immune responses. Because IL-13 possesses IL-4-like activity and may regulate the immune responses observed in atopy, it may contribute to the expression of the atopic phenotype initiated during intrauterine life. OBJECTIVE: We sought to examine IL-13 expression by fetal and neonatal cells and the placenta. METHODS: The production of IL-13 by neonatal and fetal T cells was examined by culturing the cells in the presence or absence of PHA. Production of IL-13 at term was considered in the context of the later development of atopic disease in the child. IL-13 expression in the placenta was assessed by using immunohistochemistry. RESULTS: IL-13 immunoreactivity within the placenta was restricted to 16 to 27 weeks' gestation (6/6 positive vs 0/10 at >27 weeks' gestation). In contrast, spontaneous release of IL-13 by fetal mononuclear cells was first observed from 27 weeks' gestation but was undetectable after 37 weeks' gestation. PHA-stimulated mononuclear cells showed increased IL-13 levels in 80% of samples. Term babies (>37 weeks' gestation) with a parental history of atopy with atopic symptoms by 3 years of age produced significantly lower concentrations of PHA-induced IL-13 when compared with babies with no parental history of atopy (P =.034). CONCLUSION: Thus babies at risk of atopic disease in infancy display defective IL-13 production at birth. This may represent an inherent immaturity in the development of T cell-cytokine responses in babies at genetic risk for atopy or could be a consequence of downregulation of responses by other factors. Normal pregnancy, irrespective of atopic status, is associated with the production of appreciable quantities of IL-13 initially by the placenta and subsequently by the fetus. The regulation of this production and its consequences for the mother and fetus remains to be elaborated.

Female↗
PubMed2000

The effects of age, body mass index, smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives.

OBJECTIVES: To investigate the factors associated with idiopathic venous thromboembolism in combined oral contraceptive users and to estimate the crude and age-specific incidence rates ofidiopathic venous thromboembolism among this population. METHODS: The UK MediPlus Database and the General Practice Research Database were searched to identify women with evidence of venous thromboembolism while exposed to combined oral contraceptives. Cohort and nested case-control studies were carried out using the same methodology on both databases. We conducted a meta-analysis using the individual data for the cases and controls from the two case-control studies to identify factors associated with idiopathic venous thromboembolism in women using combined oral contraceptives. RESULTS: The incidence rate of idiopathic venous thromboembolism among oral contraceptive users was 39.4 per 100,000 exposed woman-years. The age-specific incidence rates were found to rise sharply after the age of 39 years. Factors identified as being significantly associated with idiopathic venous thromboembolism in women using combined oral contraceptives were: body mass index of 25 kg/m2 and over, the association rising dramatically in women with a body mass index of 35 kg/m2 or more; smoking; general ill health; and asthma. CONCLUSION: We believe that, before prescribing combined oral contraceptives, the venous as well as the arterial factors need to be considered and, in addition, age, obesity and smoking are all relevant when assessing an individual patient's risk.

Adolescent↗
PubMed2000

Pharmacokinetic assessment of oral ganciclovir in lung transplant recipients with cystic fibrosis.

Oral ganciclovir has been used as prophylaxis and therapy against cytomegalovirus in patients with HIV infection and following organ transplantation. Oral ganciclovir has clear practical advantages over intravenous ganciclovir but has a relatively low bioavailability and this may be problematic in at-risk patients with malabsorption. The bioavailability and therefore therapeutic potential of oral ganciclovir in cystic fibrosis (CF) patients post-lung transplant (LT) might be expected to be inadequate given the high incidence of malabsorption in these patients. An 8 h pharmacokinetic study was performed in 12 CF patients 160 +/- 122 days post-transplant who had been taking 1 g oral ganciclovir tds for 3 days with food (plus normal enzyme supplements). Mean (range) serum creatinine was 150 Imol/L (70-280). Blood was sampled at 0.5, 1, 2, 3, 4, 6 and 8 h post-final dose. Plasma was stored at -20 degrees C and later analysed by highperformance liquid chromatography. Mean peak concentration (C(max)) was 4.8 mg/L (0. 96-12.8), mean minimum concentration (C(min)) was 3.6 mg/L (0.78-11. 7) and mean area under the curve (AUC) was 35.4 mg.8 h/L (8-99). C(max), C(min) and AUC correlated significantly with one another (P < 0.001) as well as with serum creatinine and creatinine clearance (P < 0.01). When corrected for alterations in renal function, plasma oral ganciclovir levels are as predicted for other transplant populations. Three days of oral ganciclovir results in therapeutically useful plasma drug levels in the CF LT population, despite a background of general malabsorption. C(max), C(min) and AUC are highly correlated, allowing for the possibility of steady-state drug monitoring to confirm that the recommended dosing algorithm produces appropriate plasma levels.

Adult↗
PubMed2000

Airway neutrophilia in stable and bronchiolitis obliterans syndrome patients following lung transplantation.

BACKGROUND: The bronchiolitis obliterans syndrome (BOS) remains the major constraint on the long term success of lung transplantation. Neutrophils have been associated with fibrosing lung conditions and have been noted to be increased in the bronchoalveolar lavage (BAL) fluid of patients with BOS. METHODS: This study was undertaken to examine neutrophil accumulation in the BAL fluid, airway wall and lung parenchyma, as well as levels of interleukin (IL)-8 in the BAL fluid, in normal controls and lung transplant recipients with and without BOS. Bronchoscopic examination included endobronchial biopsy (EBB), BAL fluid, and transbronchial biopsy (TBB) sampling. Tissue neutrophils were identified by neutrophil elastase staining on 3 microm paraffin biopsy sections and quantified by computerised image analyser. IL-8 levels were measured in unconcentrated BAL fluid by ELISA. RESULTS: Compared with controls, airway wall neutrophilia was increased in both stable lung transplant recipients and those with BOS (p<0.05). BAL neutrophils and IL-8 levels were also increased in both groups of transplant recipients compared with controls (p<0.01), the levels being significantly higher in the BOS group (p<0.01). Neutrophil numbers in the lung parenchyma were not significantly different between the two groups of lung transplant recipients. CONCLUSION: Increased levels of neutrophils are present in the airway wall and BAL fluid of lung transplant recipients with and without BOS. BAL fluid levels of IL-8 are also increased, raising the possibility that neutrophils and/or IL-8 may play a part in the pathogenesis of BOS following lung transplantation.

Adult↗