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Biomedical subjects

S J Brett

Publications and source records attributed to S J Brett.

At least 19 recordsLinked to original sources
PubMed2005

Long-term survival and residual hazard after in-hospital cardiac arrest.

AIM: The purpose of this study was to determine long-term survival after in-hospital cardiac arrests and to explore if and when the excess mortality risk imposed by the index event reaches that of an age and sex matched general population. METHOD: A retrospective analysis of data from 1,571 in-hospital cardiac arrests between the calendar years 1997 and 2002 inclusive was performed. Two hundred and fifty-nine people survived until hospital discharge, 220 of which were residents in England and included in the study. Kaplan-Meier curves were constructed for the survivors and an age and sex matched comparator population, and survival compared with a one-sample log rank test. Smoothed hazard curves were constructed for the two populations. Differences in outcome from year of index event were also sought. RESULTS: 16.5% of patients survived to hospital discharge. Patients continue to experience a mortality rate greater than that of the comparator population during the first 200 days, with overall 70 deaths versus 18.7 as predicted from life tables (p < 0.0001). The hazard is greatest after resuscitation and falls thereafter until about 2 years where it is not very different to that of the comparator population and then subsequently rises. No evidence was found of a difference in the first year survival between patients resuscitated in different calendar years (p > 0.3 for all tests). CONCLUSION: The residual risk to an individual cardiac arrest survivor's life is greatest during the first year of survival, but declines progressively during the first 2 years after the event, subsequently approaching the risk experienced by the general population.

Aged↗
PubMed2005

Prolonged cognitive dysfunction in survivors of critical illness.

A prospective study using neuropsychological testing explored cognitive performance, and specifically executive function, in survivors of critical illness during the first year of recovery. Fifty-one patients who had survived 3 days or more in the intensive care unit were studied approximately 3 months after discharge; 45 of them were studied again 6 months later. General health was assessed using the Short-Form 36. Cognitive and executive functions were measured using Raven's Progressive Matrices, the Hayling Sentence completion test and the Six-Element Test. Three months after discharge from intensive care, all eight domains of Short-Form 36 were impaired among survivors; by 9 months, four of the eight domains showed significant improvement. At 3 months, 35% of patients scored at or below a level equivalent to the lowest performing 5% of a normal population (i.e. the fifth percentile) on two or more tests of cognitive function; by 9 months only 4% of patients were impaired to this extent. Although cognitive performance improved with time, it remained below normal.

Adult↗
PubMed2002

A survey of physicians' attitudes to transfusion practice in critically ill patients in the UK.

This study aimed to examine the attitudes of intensivists and haematologists to the use of blood and blood products using a scenario-based postal questionnaire. One hundred and sixty-two intensivists and 77 haematologists responded to the survey. In four scenarios, the baseline haemoglobin thresholds for red cell transfusion ranged from 6 to 12 g.dl(-1). There was significant variation between scenarios (p <0.005). Increasing age, high Acute Physiology and Chronic Health Status II score, surgery, acute respiratory distress syndrome, septic shock and lactic acidosis significantly (p <0.005) modified the transfusion threshold. There were greater variations in the baseline threshold for platelet transfusion. The majority of respondents (72.3%) selected a baseline haemoglobin threshold between 9 and 10 g.dl(-1). The thresholds for platelet transfusion were far less consistent.

Adult↗
PubMed2002

Blood component use in critically ill patients.

This prospective observational study was conducted to assess the current transfusion practice in critically ill patients. One thousand two hundred and forty-seven consecutive critically ill patients admitted between February 1999 and October 1999 were included in the study. Overall 666 (53%) patients were administered red cells. Transfused patients had significantly higher intensive care unit mortality but also had higher Acute Physiology and Chronic Health Evaluation II scores and longer durations of stay. The average pretransfusion haemoglobin concentration was < 9 g.dl(-1) in 75% of transfusion episodes. The common indications for transfusion were low haemoglobin (72%) and haemorrhage (25%). Overall, 202 (16%) and 281 (22%) of the patients were transfused platelets and fresh frozen plasma, respectively. The indications for transfusion were haemorrhage, low platelet counts, prolonged prothrombin time or to provide cover for invasive interventions. Most platelet transfusions were given at values in the order of 50-100 x 10(9).l(-1). The pretransfusion platelet count varied according to the indications for transfusion. This study showed that transfusion practice is consistent and that in general there does not seem to be an excessive use of blood components in critically ill patients.

APACHE↗
PubMed1999

Expression of L-selectin on Th1 cells is regulated by IL-12.

L-selectin has become established as a key molecule in the recirculation of naïve T cells from the blood to peripheral lymph nodes, yet little is known about its role in the migration of effector or memory cells. While differentiating naïve CD4+ T cells into Th1 and Th2 subsets in vitro, it was noted that L-selectin levels were maintained on the Th1 subset of cells. The expression of L-selectin on the Th1 cells appeared to be dependent on the presence of IL-12. Th2 cells, differentiated in the absence of IL-12, failed to maintain L-selectin expression. Coculture with IL-12, IL-18, IL-4, TNF-alpha, or IFN-alpha, -beta, or -gamma demonstrated a dependence on IL-12 alone for L-selectin expression. In addition, the inclusion of heat-killed Listeria monocytogenes in the cultures also maintained L-selectin expression on the Th1 cells. In all cultures, the maintenance of L-selectin on the T cell surface could be blocked by the inclusion of anti-IL-12 Abs. Analysis of the mRNA levels for L-selectin in T cells, differentiated in the presence or absence of IL-12, showed that the cytokine appears to exert its effect on L-selectin at the transcriptional level. Given the key role played by IL-12 in the differentiation of naïve T cells into the Th1 subset, the observation that IL-12 can also regulate L-selectin expression has implications for the migration of Th1 effector cells both through the lymphatic system and to sites of inflammation.

Adjuvants, Immunologic↗
PubMed1998

Pulmonary response of normal human subjects to inhaled vasodilator substances.

1. Inhaled vasodilators such as nitric oxide and epoprostenol (prostaglandin I2) are now widely employed as supportive therapies to improve oxygenation and reduce pulmonary vascular resistance in patients with acute and chronic pulmonary hypertension. However, few data exist concerning their effects in normal individuals. The aim of this study was to characterize the response of the pulmonary circulation in normal individuals to inhaled nitric oxide and nebulized prostaglandin I2.2.Eight healthy volunteers were exposed to inhaled nitric oxide (0, 20 and 40 p.p.m.) and nebulized prostaglandin I2 (10 microgram/ml). Changes in effective pulmonary blood flow and diffusing capacity of the lung for carbon monoxide (TLCO) were measured using respiratory mass spectrometry. Bicycle ergometry was used to increase effective pulmonary blood flow as a positive control.3. Exercise produced significant increases in both effective pulmonary blood flow and TLCO, but neither nitric oxide nor prostaglandin I2 produced significant changes in either parameter.4.No significant change in pulmonary haemodynamics was demonstrated in response to inhaled nitric oxide or nebulized prostaglandin I2, using doses known to be effective in patients with acute and chronic pulmonary hypertension. These data suggest that the normal pulmonary vascular bed is not amenable to vasodilatation by inhaled drugs. The study further suggests that the normal pulmonary vasodilatation seen on exercise is not mediated pharmacologically, but is a secondary consequence to the mechanical effects of a rise in pulmonary blood flow. This study thus supports the view that there is no resting vasoconstrictor tone in the pulmonary vascular bed.

Administration, Inhalation↗
PubMed1998

Cross-linking of the CAMPATH-1 antigen (CD52) mediates growth inhibition in human B- and T-lymphoma cell lines, and subsequent emergence of CD52-deficient cells.

The CAMPATH-1H (CD52) antigen is a 21 000-28 000 MW glycopeptide antigen that is highly expressed on T and B lymphocytes and is coupled to the membrane by a glycosylphosphatidylinositol (GPI) anchoring structure. The humanized CAMPATH-1H anti-CD52 antibody is extremely effective at mediating depletion of both normal and tumorigenic lymphocytes in vivo and has been used in clinical trials for lymphoid malignancy and rheumatoid arthritis. Cross-linking GPI-anchored molecules, including CD52, on the surface of T lymphocytes in the presence of phorbol 12-myristate 13-acetate or anti-CD3, results in cellular activation. In the present study we have investigated the functional effects of cross-linking CD52 on T and B tumour cell lines. Cross-linking CD52 on either a B-cell line, Wien 133, which expresses high levels of endogenous CD52 or Jurkat T cells transfected and selected to express high levels of CD52 resulted in growth inhibition. This effect showed slower kinetics and occurred in a lower percentage of cells than growth inhibition stimulated via T- or B-cell receptors. Growth inhibition of the Wien 133 line was followed by the induction of apoptosis, which appeared independent of the Fas/Fas L pathway. Wien 133 cells surviving anti-CD52 treatment were selected and cloned and found to have down-regulated CD52 expression, with a characteristic biphasic pattern of 10% CD52-positive, 90% negative by fluorescence-activated cell sorter analysis. Interestingly, surface expression of other GPI-linked molecules, such as CD59 and CD55, was also down-regulated, but other transmembrane molecules such as surface IgM, CD19, CD20, HLA-DR were unaffected. The present study and previous work show that this is due to a defect in the synthesis of mature GPI precursors. Separation of CD52-positive and negative populations in vitro resulted in a rapid redistribution to the mixed population. Injection of CD52-negative cells into nude mice to form a subcutaneous tumour resulted in a substantial increase in expression of CD52. These results suggest that the defect in the Wien 133 cells is reversible, although the molecular mechanism is not clear. These observations have relevance to the clinical situation as a similar GPI-negative phenotype has been reported to occur in lymphocytes following CAMPATH-1H treatment in vivo.

Animals↗
PubMed1998

Production of nitric oxide during surgery involving cardiopulmonary bypass.

OBJECTIVES: Surgery involving cardiopulmonary bypass induces an inflammatory response due to the contact of blood with the extracorporeal circuit. In some patients, this inflammatory response leads to multiple organ failure and death. Inflammatory states may increase the production of nitric oxide, either by increasing the activity of constitutive enzyme systems or by inducing of inflammation-specific systems. We hypothesized that surgery involving cardiopulmonary bypass would increase the production of nitric oxide in association with the inflammatory response. DESIGN: Prospective, single center, observational study. SETTING: University-affiliated, tertiary referral cardiothoracic center. PATIENTS: Eleven adult patients undergoing routine myocardial revascularization. INTERVENTIONS: Surgery for myocardial revascularization. MEASUREMENTS AND MAIN RESULTS: Observations were made after induction of anesthesia, before bypass, after completion of the bypass, and on return to the recovery area. Parameters measured included hemodynamics, exhaled nitric oxide concentrations, plasma nitrate/nitrite concentration, plasma and bronchoalveolar lavage myeloperoxidase concentrations, and protein carbonyl conversion. All patients survived surgery. Oxygenation index fell significantly after bypass. Plasma myeloperoxidase increased significantly during the study period. Plasma carbonyl conversion also increased, although not significantly. Plasma nitrate/nitrite and airway nitric oxide concentrations did not change through the course of the study. CONCLUSION: Surgery involving cardiopulmonary bypass induced a demonstrable inflammatory response, but this response was not associated with increased nitric oxide production.

Aged↗
PubMed1998

Reduced mortality in association with the acute respiratory distress syndrome (ARDS).

BACKGROUND: A study was undertaken to investigate possible reductions in mortality and/or changes in outcome predictive factors in patients with the acute respiratory distress syndrome (ARDS) managed in a single centre. METHODS: The study was a prospective observational cohort study of two patient populations with ARDS. Group 1 comprised 41 patients enrolled between May 1990 and April 1993, and group 2 consisted of 78 patients enrolled between June 1993 and March 1997. The end points of the study were mortality and various factors predictive of death. RESULTS: There was a marked reduction in mortality between groups 1 and 2 (66% versus 34%; relative risk 1.77; CI 1.23 to 2.55). There were no significant differences between the groups in terms of age (40.6 (3.3) versus 45.5 (2.2) years), APACHE score (14.5 (0.72) versus 13.6 (0.1)), lung injury score (2.95 (0.07) versus 2.8 (0.1)), incidence of multi-organ failure (29% versus 32%), incidence of sepsis (31% versus 39%), or PaO2/FIO2 (kPa) ratio (11.8 (0.67) versus 12.0 (0.6)). There was a significantly lower proportion of men in group 1 (51% versus 74%). The case mix of the two groups was closely matched: following elective surgery 48% versus 48%, trauma 17% versus 16%, primary lung injury 12% versus 24%. Patients in group 1 were supported using several ventilatory and other modes (volume preset, non-inverse ratio ventilation, n = 15; pressure controlled inverse ratio ventilation (PC-IRV), n = 11; ultra high frequency jet ventilation (UHFJV), n = 13; an intravascular oxygenation device (IVOX) and extracorporeal gas exchange (ECGE), n = 2). Within group 1 no significant difference in mortality was observed between the patients on volume controlled ventilation and the remainder. In group 2 all patients received PC-IRV (n = 78) but, in addition, some received other support techniques (UHFJV n = 4, ECGE n = 2). In group 1 only sepsis on admission (21% (survivors) versus 56% (non-survivors)) predicted death. In group 2 age of survivors and non-survivors (41.2 (2.6) versus 52.6 (3.5)), APACHE score (12.2 (0.6) versus 15.8 (0.9)), and PaO2/FIO2 (12.8 (0.86) versus 10.5 (0.72)) predicted survival, but not the incidence of sepsis or multi-organ failure. CONCLUSIONS: In recent years a highly significant reduction in mortality associated with ARDS has been observed between two groups of patients well matched for disease severity and case mix. Changes in ICU organisation rather than specific interventions may account for this reduction, although different ventilatory and other management strategies used in the two groups may also be relevant.

Adult↗
PubMed1998

Measurement of endogenous nitric oxide in the lungs of patients with the acute respiratory distress syndrome.

Elevated levels of nitric oxide (NO) are detectable in the exhaled breath of patients suffering from a number of inflammatory lung diseases. We hypothesized that NO would be detectable in the exhaled air of patients with the acute respiratory distress syndrome (ARDS) undergoing mechanical ventilation and that the concentration would be greater than that from a control group of ventilated subjects. The concentration of NO in the lower airways of 13 patients with ARDS and 18 patients anesthetized and ventilated prior to cardiac surgery was measured by chemiluminescence. The NO concentration was 1.13 +/- 0.36 (mean +/- SEM) parts per billion (ppb) in the ARDS group and 5.5 +/- 0.8 ppb in the control group (2 p < 0.0001). NO is detectable in the exhaled air of patients with ARDS and is at a lower concentration than in control subjects.

Adolescent↗
PubMed1998

Clinical correlates in acute lung injury: response to inhaled nitric oxide.

STUDY OBJECTIVES: The use of inhaled nitric oxide (NO) in the management of patients with ARDS has become widespread, although not all patients respond to this form of support. The aim of this study was to examine the relationship of responsiveness to inhaled NO and features of underlying disease. DESIGN: Prospective observational study. SETTING: The ICU of a university-affiliated, tertiary referral hospital. PATIENTS: Twenty-six adult patients with established ARDS. INTERVENTIONS: Conventional support for multiple organ failure, plus inhaled NO. MEASUREMENTS AND RESULTS: Response to inhaled NO was assessed, and ARDS was characterized in terms of pulmonary morphology (scoring of high-resolution CT); inflammation (BAL neutrophil count and plasma myeloperoxidase concentration); and markers of lung injury severity (oxygenation deficit and pulmonary vascular resistance [PVR]). Fourteen patients responded to NO and 12 did not. There were no differences between the two groups in terms of CT score, inflammatory status, baseline oxygenation deficit, lung injury score, or PVR. Additionally, there was no difference in survival between responders and nonresponders. Patients who developed ARDS after thoracic surgery were significantly more likely to die than other patients (relative risk 4.1, p < 0.01). The oxygenation deficit and lung injury score correlated better with the extent of ground-glass opacification than with the volume of consolidated lung tissue. CONCLUSION: We were unable to identify features of disease likely to be associated with a clinically useful response to inhaled NO therapy using the parameters studied.

Acute Disease↗
PubMed1997

Quantitative but not qualitative variation in MHC class II alters CD4 interaction and influences T cell repertoire formation.

The influence of the interaction between CD4 and MHC class II molecules on selection of the T cell repertoire was studied in transgenic mice expressing human or human/mouse hybrid MHC class II beta chains. Either wild-type DR beta chains (DR1 beta) or hybrid beta chains comprising the beta1 domain of DR and the beta2, transmembrane, and intracytoplasmic domains of I-E (DRbeta 1Ebeta2) were introduced into and expressed in transgenic mice as a heterodimer with endogenous I-E alpha. Mice expressing low levels of DR1beta:I-E alpha or those expressing low or higher levels of the hybrid DRbeta 1Ebeta2:I-E alpha were studied. Immunization with a suboptimal dose of influenza nucleoprotein peptide exposed a fivefold lower frequency of DR-restricted, peptide-specific, IL-2-secreting T cells in the mice with low-level expression of DRbeta1 Ebeta2:I-E alpha when compared to mice expressing the same molecule at higher levels. The frequency in DRbeta wild-type mice was only twofold lower than that measured in mice with comparable levels of expression of DRbeta 1Ebeta2. These results suggest that positive selection is sensitive to quantitative variation in MHC class II density, unmasked when antigen is limiting, but is relatively insensitive to qualitative variation in the MHC class II: CD4 interaction.

Animals↗
PubMed1997

Differential functional effects of a humanized anti-CD4 antibody on resting and activated human T cells.

A fully humanized immunoglobulin G1 (IgG1) anti-CD4 monoclonal antibody is currently being evaluated in phase I/II clinical trials for rheumatoid arthritis. In order to understand the mode of action of this antibody in vivo, we have carried out a detailed functional analysis in vitro of the effects of this antibody on T-cell activation. The anti-CD4 antibody was found to inhibit both antigen-specific responses involving recognition of human leucocyte antigen (HLA) class II and processed antigenic peptides as well as non-class II dependent responses via anti-CD3 antibodies. The antibody did not cause total blockade of T-cell proliferation, but rather induced a shift in the dose-response curve, decreasing the sensitivity of cells to antigen or anti-CD3-mediated stimulation. The antibody appears to allow at least a partial early signal into the T cell as it does not inhibit the increase in tyrosine phosphorylation induced by anti-CD3 antibodies. A comparison of the intact antibody with that of either the F(ab')2 fragment or an engineered non-Fc receptor (FcR) binding form revealed that the intact antibody was the most effective at inhibiting proliferation of resting peripheral blood CD4+ T cells. However, this difference was only apparent when excess antibody was removed from culture prior to antigen or anti-CD3 mediated stimulation. The intact antibody induced both CD4 down-modulation and increases in CD4-associated tyrosine phosphorylation of resting CD4+ T cells, which were not seen with the non-FcR binding versions, which may account for the enhanced potency of the intact antibody at inhibiting T-cell activation. Interestingly, the anti-CD4 antibody induced a differential effect on activated CD4+ T cell clones compared with resting CD4+ T cells with respect to degree of CD4 cross-linking required to induce functional effects in the T cell. Both intact and non-FcR binding antibodies were equally effective at inhibiting T-cell proliferation of activated T-cell clones. In addition CD4 down-modulation and increased CD4-associated tyrosine phosphorylation were observed with T-cell clones in the absence of secondary cross-linking. Such observations may be of relevance when studying the effects of the antibody at sites of inflammation, where there will be CD4+ T cells of differing activation states as well as varying numbers of FcR positive cells.

Antibodies, Monoclonal↗
PubMed1996

Emergence of CD52-, glycosylphosphatidylinositol-anchor-deficient lymphocytes in rheumatoid arthritis patients following Campath-1H treatment.

CD52 is a glycosylphosphatidyl-inositol (GPI)-linked glycoprotein expressed at high levels on normal T and B lymphocytes and at lower levels on monocytes, while being absent on granulocytes and bone marrow stem cell precursors. The emergence of CD52- lymphocytes of both T and B cell lineages was observed in three out of 25 rheumatoid arthritis patients treated with teh humanized antibody Campath-1H in phase II clinical trial. Whereas the majority of CD52- B cells had disappeared from the peripheral blood by 3 months post-treatment, both CD52- CD4+ and CD8+ T cells persisted in the circulation for at least 20 months. In the two patients that were tested, the GPI-anchored surface molecules CD55 and CD59 were also absent on the CD52- cells, although expression of other cell surface transmembrane, proteins (CD3, CD4 and CD2) was unaffected. The CD52- cells maintained a stable phenotype in vitro despite repeated re-stimulation in culture. Both CD52- and C52+ clones, established from one of the patients, responded to a similar extent to several T cell mitogens, as assessed by proliferation, suggesting that a general defect in expression of GPI-linked molecules does not impair T cell activation. These data show that an immune attack against a GPI-anchored surface molecule can result in the selection of a GPI-anchor-deficient cell population. Despite the persistence of CD52- T cells in the peripheral blood, no adverse reactions associated with the presence of these cells were noted in any of the patients; in fact they responded with longer remission times after Campath-1H treatment than the other patients in the trial.

Adult↗
PubMed1996

Impairment of endothelium-dependent pulmonary vasodilation in patients with primary pulmonary hypertension.

BACKGROUND: Pulmonary vascular tone may be modulated by endothelium-derived vasoactive mediators. Endothelial dysfunction is thought to occur in primary pulmonary hypertension. The aim of this study was to evaluate the vascular responses of patients with severe primary pulmonary hypertension to endothelium-dependent vasodilators (for example, substance P) and non-endothelium-dependent vaasodilators (for example, adenosine). METHODS: Six patients with primary pulmonary hypertension (mean (SE) systolic, diastolic, and pulmonary artery pressures 91.1 (7), 45.2 (3), and 62 (4.2) mm Hg, respectively, and baseline total pulmonary vascular resistance (TPVR) 1949 (164) dynes.s.cm-5) underwent sequential infusions of substance P (5-100 pmol/min) and adenosine (5-50 micrograms/kg/min) in random order. Pulmonary and systemic haemodynamics were monitored by indwelling radial and pulmonary arterial catheters. RESULTS: Substance P caused a marked fall in systemic vascular resistance (SVR) but minimal pulmonary vasodilation (mean maximal percentage change from baseline in TPVR:SVR ratio 27.85 (6.5)%, p < 0.01). Adenosine caused TPVR to fall, but resulted in no change in SVR (mean maximum percentage change from baseline in TPVR:SVR ratio -9.85 (3.5)%, p < 0.05). CONCLUSION: Endothelium-dependent vasodilation is deficient in the pulmonary circulation of patients with primary pulmonary hypertension and may contribute to the abnormalities of pulmonary vascular tone and reactivity seen in that condition.

Adenosine↗
PubMed1996

Both H-2- and non-H-2-linked genes influence influenza nucleoprotein epitope recognition by CD4+ T cells.

The specificity of the influenza nucleoprotein-induced T-cell proliferative response by mouse strains differing in either H-2- or non-H-2-linked background genes was compared by using a panel of synthetic peptides covering 90% of the nucleoprotein molecule. The results showed, as expected, that H-2 genes strongly influenced the major regions of the molecules recognized by T cells, as the response was focused on different peptides in mice of different H-2 haplotypes. However, some regions of the molecule (e.g. 260-283) were recognized by several different haplotypes, with overlapping but distinct minimal determinants. The lymph node proliferative response appeared to be predominantly restricted by the I-A molecule, as expression of I-E in mice did not result in any detectable recognition of additional epitopes. In the majority of cases the same T-cell epitopes were recognized by mouse strains sharing the same H-2 haplotype but differing in many background genes. Low responsiveness was however observed to p55-77 by DBA/2 and p127-141 by AKR mice to which other H-2d or H-2k strains were high responders. Low responsiveness is therefore unlikely to be a consequence of failure of these peptides to bind to the relevant major histocompatibility complex class II molecule. In addition antigen-presenting cells from the DBA/2 low responder strain was able to process and present whole influenza virus or nucleoprotein as well as antigen-presenting cells from the high responder BALB/c strain. It is therefore suggested that low responsiveness to the peptide p55-77 may be due to a 'hole in the T-cell repertoire', caused perhaps by expression of Mls-1a in the DBA/2 strain. This is supported by the observation that low responsiveness to this epitope appears to be dominant in F1 (low x high) mice.

Animals↗