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Biomedical subjects

S Brett

Publications and source records attributed to S Brett.

At least 19 recordsLinked to original sources
PubMed2006

Silent myocardial ischaemia and haemoglobin concentration: a randomized controlled trial of transfusion strategy in lower limb arthroplasty.

BACKGROUND AND OBJECTIVES: Red cell transfusion is commonly used in orthopaedic surgery. Evidence suggests that a restrictive transfusion strategy may be safe for most patients. However, concern has been raised over the risks of anaemia in those with ischaemic cardiac disease. Perioperative silent myocardial ischaemia (SMI) has a relatively high incidence in the elderly population undergoing elective surgery. This study used Holter monitoring to compare the effect of a restrictive and a liberal red cell transfusion strategy on the incidence of SMI in patients without signs or symptoms of ischaemic heart disease who were undergoing lower limb arthroplasty. MATERIALS AND METHODS: We performed a multicentre, controlled trial in which 260 patients undergoing elective hip and knee replacement surgery were enrolled and randomized to transfusion triggers that were either restrictive (8 g/dl) or liberal (10 g/dl). Participants were monitored with continuous ambulatory electrocardiogram (ECG) (Holter monitoring), preoperatively for 12 h and postoperatively for 72 h. The tapes were analysed for new ischaemia by technicians blinded to treatment. The total ischaemia time in minutes was divided by the recording time in hours and an ischaemic load in min/h was calculated. Haemoglobin levels were measured preoperatively, postoperatively in the recovery room, and on days one, three and five after surgery. RESULTS: The mean postoperative haemoglobin concentration was 9.87 g/dl in the restrictive group and 11.09 g/dl in the liberal group. In the restrictive group, 34% were transfused a total of 89 red cell units, and in the liberal group 43% were given a total of 119 red cell units. A postoperative episode of silent ischaemia was experienced by 21/109 (19%) patients in the restrictive group and by 26/109 (24%) patients in the liberal group [mean difference -4.6%; 95% confidence interval (CI): -15.5% to 6%, P = 0.41). There was no significant difference (P = 0.53) between the overall ischaemic load in the restrictive group (median 0 min/h, range 0-4.18) and the liberal group (median 0 min/h, range 0-19.48). In those patients who did experience postoperative SMI, the mean ischaemic load was 0.48 min/h in the restrictive group and 1.51 min/h in the liberal group (ratio 0.32, 95% CI: 0.14-0.76, P = 0.011). The median postoperative length of hospital stay in the restrictive group was 7.3 days [range 5-11; interquartile range (IQR) 6-8] compared with 7.5 days (range 5-13; IQR 7-8) in the liberal group. The numbers were not large enough to conclude equivalence. CONCLUSIONS: In patients without preoperative evidence of myocardial ischaemia undergoing elective hip and knee replacement surgery, a restrictive transfusion strategy seems unlikely to be associated with an increased incidence of SMI. A proportion of these patients experience moderate SMI, regardless of the transfusion trigger. Use of a restrictive transfusion strategy did not increase length of hospital stay, and use of this strategy would lead to a significant reduction in red cell transfusion in orthopaedic surgery. Our data did not indicate any potential for harm in employing such a strategy in patients with no prior evidence of cardiac ischaemia who were undergoing elective orthopaedic surgery.

Aged↗
PubMed2005

Increased incidence of cancer in adult Gaucher disease in Western Europe.

The adult form of Gaucher disease (type I GD) is associated with a high prevalence of hypergammaglobulinemia and monoclonal gammopathy of undetermined significance (MGUS). A significantly increased risk of cancer, especially of hematological types, has been found in Ashkenazi-Jewish GD type 1 patients. In this study, incidence and mortality of cancer were assessed in a total of 131 GD patients of mixed ancestry in a population from Western Europe, i.e. 2 Gaucher referral centers in Germany (Düsseldorf) and the Netherlands (Amsterdam). Standardized rate ratios were determined by indirect standardization, using age- and sex-specific incidence and mortality rates of the Dutch population. A total of 14 GD patients of non-Ashkenazi-Jewish descent were identified of whom 5 had a hematologic malignancy. These numbers correspond to an increased risk of cancer of 2.5 (95% CI 1.1-4.7) and an increased risk of hematologic cancer of 12.7 (95% CI 2.6-37.0) among GD patients compared to the general population. In particular, the incidences of multiple myeloma and hepatocellular carcinoma in absence of preexisting cirrhosis were highly elevated, with standardized rate ratios of 51.1 (95% CI 6.2-184) and 141.3 (95% CI 17.1-510.5), respectively. These strongly increased risks on developing cancer suggest that measures for early detection and prevention of hematological and hepatic malignancies in patients with Gaucher type I disease are mandatory.

Adolescent↗
PubMed2003

White cell count and intensive care unit outcome.

A high white cell count on admission to the intensive care unit (ICU) is generally perceived to be associated with severe illness and poor outcome, but the implications of a low white cell count are less well recognised. We retrospectively analysed data on 4,165 patients. The white cell count on admission was split into four categories, leucopenic (< 4.0 x 10(9).l(-1)), normal (4.001-10.0 x 10(9).l(-1)), leucemoid (10.001-25.0 x 10(9).l(-1)) and an exaggerated leucemoid response (> 25.001 x 10(9).l(-1)). The mortality of patients with leucopenia on admission to the intensive care unit was higher than those with normal or moderately raised white cell count (37.5% vs. 18.9% and 23.9%, respectively). A leucopenic response, as well as an exaggerated leucemoid response, is associated with an increased mortality.

APACHE↗
PubMed2001

Lipoprotein access to MHC class I presentation during infection of murine macrophages with live mycobacteria.

Following uptake by macrophages, live mycobacteria initially reside within an immature phagosome that resists acidification and retains access to recycling endosomes. Glycolipids are exported from the mycobacterial phagosome and become available for immune recognition by CD1-restricted T cells. The aim of this study was to explore the possibility that lipoproteins might similarly escape from the phagosome and act as immune targets in cells infected with live mycobacteria. We have focused on a 19-kDa lipoprotein from Mycobacterium tuberculosis that was previously shown to be recognized by CD8(+) T cells. The 19-kDa Ag was found to traffic separately from live mycobacteria within infected macrophages by a pathway that was dependent on acylation of the protein. When expressed as a recombinant protein in rapid-growing mycobacteria, the 19-kDa Ag was able to deliver peptides for recognition by MHC class I-restricted T cells by a TAP-independent mechanism. Entry into the class I pathway was rapid, dependent on acylation, and could be blocked by killing the mycobacteria by heating before infection. Although the pattern of 19-kDa trafficking was similar with different mycobacterial species, preliminary experiments suggest that class I presentation is more efficient during infection with rapid-growing mycobacteria than with the slow-growing bacillus Calmette-Guérin vaccine strain.

Animals↗
PubMed2001

The impact of organisational change on outcome in an intensive care unit in the United Kingdom.

OBJECTIVES: To study the change in outcome for patients admitted to an intensive care unit following the establishment of a team of resident medical staff and a change from an "open" to a "closed" organisational format. DESIGN: Database review of prospectively collected data. SETTING: Intensive care unit of a postgraduate teaching hospital. SUBJECTS: 1134 admissions to the intensive care unit over a 3-year period, of whom 476 (42%) followed elective surgery. MAIN OUTCOME MEASURE: Hospital mortality corrected for illness severity by using the APACHE II scoring system. RESULTS: Crude hospital mortality fell from 28% before the changes to 20% afterwards (P = 0.01). With correction for case-mix factors, the probability of death after the changes was reduced by almost half (OR 0.51; CI 0.32, 0.82, P = 0.005). CONCLUSION: A "closed" format of organisation of the delivery of care may result in improved outcomes for patients admitted to intensive care units.

APACHE↗
PubMed1997

Antibody selection against CD52 produces a paroxysmal nocturnal haemoglobinuria phenotype in human lymphocytes by a novel mechanism.

The CD52 antigen is a lymphocyte glycoprotein with an extremely short polypeptide backbone and a single N-linked glycan, and it is attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor. Treatment of rheumatoid arthritis patients with CAMPATH-1H, a humanized monoclonal antibody against CD52, resulted, in a small number of cases, in the appearance and persistence of CD52-negative T cells. Similarly, CD52-negative B cells emerged following in vitro treatment of a CD52-positive human B cell line with CAMPATH-1H. Both the B and T CD52-negative cells were also found to be defective in surface expression of other GPI-anchored proteins. Biochemical analysis revealed a severe defect in the synthesis of a mature GPI precursor in both the B and T cell lines. Therefore the phenotype of these CD52-negative B and T cells closely resembles that of lymphocytes from patients with paroxysmal nocturnal haemoglobinuria (PNH), in which the first step of the GPI-biosynthetic pathway, i.e. synthesis of GlcNAc-phosphatidylinositol, is blocked. In all cases studied to date, this defect maps to a mutation of the phosphatidylinositolglycan class A (PIG-A) structural gene. We therefore amplified the PIG-A gene from both the GPI-negative B and T cells by PCR and determined the nucleotide sequence. No differences from the wild-type sequence were detected; therefore a classical PNH mutation cannot be responsible for the GPI-biosynthesis defect in these cell lines. Significantly, the GPI-negative phenotype of the B cells was reversible upon separation of the positive and negative cells, resulting in a redistribution to a mixed population with either CD52-positive or -negative cells, whereas populations of 100% CD52-negative T cells were stably maintained during culture. Therefore, whereas the GPI-biosynthesis deficiency in the T cell lines may be due to a mutation in another gene required by the GPI-biosynthetic pathway, the reversible nature of this block in the B cell lines suggests a less direct cause, possibly an alteration in a regulatory factor. Overall, these data demonstrate that the PNH phenotype can be generated without a mutation in the PIG-A structural gene, and thereby identify a novel mechanism for the development of GPI deficiency.

Alemtuzumab↗
PubMed1997

Concrete induced cardiac contusion.

A previously fit 22 year old man was struck in the chest by a concrete block dropped through the windscreen of his car while he was driving on the motorway. He suffered extensive chest wall trauma and lung contusion, which subsequently precipitated acute respiratory distress. On admission ECG showed right bundle branch block and left axis deviation. Three days later QRS duration was normal but there was anterior ST segment elevation and subsequent T wave change. There was a large rise in creatine kinase, and echocardiography revealed septal and apical hyokinesis as well as a mobile mass attached to the left side of the interventricular septum, which had the echogenic texture of myocardium. The patient had fixed perfusion defects in the areas of hypokinesis on thallium scanning but the coronary arteries were unobstructed at angiography. He was treated with warfarin in the short term and an angiotensin converting enzyme inhibitor in the longer term and has made an asymptomatic recovery. Outpatient echocardiography two months after the injury demonstrated some recovery in overall left ventricular systolic function and no evidence of the intracardiac mass. This case illustrates some of the typical features of non-fatal cardiac contusion associated with non-penetrating cardiac trauma, and was complicated by partial thickness avulsion of a strip of the myocardium in the interventricular septum.

Accidents, Traffic↗
PubMed1996

Repopulation of blood lymphocyte sub-populations in rheumatoid arthritis patients treated with the depleting humanized monoclonal antibody, CAMPATH-1H.

Patients with severe rheumatoid arthritis who had failed treatment with conventional therapies were treated with a course of five or 10 daily intravenous infusions of CAMPATH-1H, a humanized antibody against the CD52 antigen, resulting in profound depletion of peripheral blood mononuclear cells. During the subsequent 18 months, lymphocytes were analysed for sub-populations by fluorescence-activated cell sorter (FACS) and for proliferation in response to polyclonal T-cell stimulation with anti-CD3 or staphylococcal enterotoxin B (SEB). Treatment resulted in almost complete depletion of lymphocytes from the blood followed by gradual repopulation. CD16+ natural killer (NK) cells and CD14+ monocytes returned to pretreatment levels within 1-2 months. CD19+ B cells returned to within 50% of pre-treatment levels by day 66 and to within normal range by day 150, whereas CD8+ T cells recovered to 50% of pretreatment levels by day 66, but did not show any further increase during the rest of the study period. The most profound effects were on the CD4+ T lymphocyte sub-population, as the mean CD4+ count did not increase above 20% of pre-treatment level at any time during the study period (550 days), at all the doses tested. The T cells which initially repopulated the blood 1-2 months after treatment, nearly all expressed the activation markers human leucocyte antigen (HLA)-DR and CD45RO, although the percentage of T cells expressing these molecules gradually declined to normal levels over time. Proliferative responses to polyclonal T-cell stimulation (anti-CD3 and SEB) were also significantly reduced in the first few months after treatment, but recovered to pre-treatment levels by day 250. The relationship between these observations and the clinical response is discussed.

Antibodies, Monoclonal↗
PubMed1995

Functional analysis of the effects of a fully humanized anti-CD4 antibody on resting and activated human T cells.

A fully humanized anti-CD4 antibody was studied for its effects on resting and activated CD4 T cells. Whereas the antibody was poorly lytic, it induced dramatic down-modulation of CD4 expression on both types of cell. In order to down-modulate CD4 on resting, normal CD4 T cells there was an absolute requirement for FcR-mediated cross-linking of the anti-CD4 antibody, and only CD4 levels were affected. When activated cloned T-cell lines were studied there was no requirement for cross-linking and several other cell surface markers were also affected. Although the total cellular CD4 was reduced in the down-modulated cells, as judged by Western blot analysis, that CD4 which remained was associated with p56lck. The results are discussed in relation to the potential use of humanized anti-CD4 antibodies in the therapy of autoimmune disease and the choice of antibody isotype for such a therapeutic antibody.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1994

The invariant chain inhibits presentation of endogenous antigens by a human fibroblast cell line.

The human fibroblast cell line, M1, expressing the products of transfected DRA and DRB1*0101 genes (M1-DR1) was unable to present intact influenza antigens to a series of DR1-restricted human T cell lines and clones, but was fully able to present synthetic peptides for T cell recognition. In contrast, M1-DR1 cells infected with live influenza virus were recognized by two polyclonal hemagglutinin- or whole virus-specific T cell lines and one of four T cell clones. This difference could not be accounted for simply by the ability of infectious virus to overcome a defect in antigen uptake by the M1-DR1 cells, in that direct studies of endocytosis showed that the M1 cells were more efficient than human B cells in the internalization of exogenous protein. These data suggested that the M1 cells were unable to present exogenous antigens but were capable of loading major histocompatibility complex (MHC) class II molecules with peptides derived from endogenous antigens. To investigate this further, the M1-DR1 cells were super-transfected with a cDNA encoding the p33 and p35 forms of the human invariant chain (Ii). Expression of the Ii chain was detected by intracytoplasmic staining of transfectants, and by metabolic labeling. Equimolar amounts of the p33 and p35 forms were detected, and the high level of p35 Ii was reflected by extensive retention of Ii protein in the endoplasmic reticulum. Addition of the Ii chain led to no recovery of presentation of intact antigens with DR1, but inhibited the presentation of live virus. These data indicate that MHC class II molecules in the M1-DR1 cells can be loaded with peptides derived from endogenous proteins, possibly in the biosynthetic pathway, and that the Ii chain has a role in limiting this route of class II antigen presentation.

Antigen Presentation↗
PubMed1994

Mellow and frenetic antecedent music during athletic performance of children, adults, and seniors.

Previous research has yielded a contradictory picture of the effects of music on athletic performance. While athletes frequently report using music while training or during or before an event, laboratory studies have generally not detected a beneficial effect of music. The influence of music, judged mellow and frenetic, played before exercise was assessed by measuring stationary bicycle mileage. 60 volunteers from three age groups (child, adult, and senior) and with two levels of prior activity (high and low) were subjects. Each participant received three randomized 2-min. exercise trials, each preceded by 1-min. exposure to mellow music, frenetic music, or white noise. Mileage in both music conditions was significantly higher than that during the white-noise control trial except among the senior subjects. No significant differences between frenetic and mellow music were noted.

Adolescent↗
PubMed1994

Comparison of expression of a humanized monoclonal antibody in mouse NSO myeloma cells and Chinese hamster ovary cells.

We report a detailed comparison of two commonly used stable, amplifiable mammalian expression systems (Chinese Hamster Ovary cells/dihydrofolate reductase and Mouse NSO myeloma/glutamine synthetase) used to express a humanized IgG1 monoclonal antibody. We compare copy number and steady state mRNA levels of both the selectable marker and heavy chain of the antibody throughout the selection and amplification process. In both cell lines, copy number and steady state levels of heavy chain and selectable marker increased during selection and were further increased during amplification. As expected, an increase in steady state mRNA levels of heavy chain correlated with an increase in expression of antibody whilst an increase in the steady state levels of mRNA of the selectable marker correlated with increased resistance to the selective agent. In NSO and CHO cells producing equivalent amounts of antibody, the copy number of the antibody genes and selectable marker was significantly higher in the CHO cells than in the NSO cells. However, the steady state mRNA levels of the heavy chain of the antibody were virtually identical. Rates of protein secretion in the two cell lines were also compared and found to be very similar. When the antibody purified from both systems was compared in a number of functional assays they behaved identically.

Animals↗
PubMed1993

A humanized CD18 antibody can block function without cell destruction.

Leukocyte integrins are intimately involved in transient adherence of leukocytes to endothelium and to each other in the processes of extravasation and cell activation. In this study, seven mAb directed against human CD11a and two mAb directed against human CD18, the alpha- and beta-chains of the leukocyte functional Ag-1 molecule, respectively, were analyzed for their ability to inhibit several leukocyte functional Ag-1-mediated interactions. The best blocking mAb in these studies, a rat anti-human CD18, YFC51.1, was subsequently humanized by complementarily-determining region grafting, associated with human C regions and expressed. The humanized mAb was shown to maintain binding for human CD18. Even though the humanized mAb was an IgG1 isotype it still retained the functional blocking characteristics of the rat mAb while failing to mediate cell killing. The IgG1 mAb was unable to bind human Clq and could block but did not mediate antibody-dependent cellular cytotoxicity.

Animals↗
PubMed1992

Influence of H-2 genes on growth of Mycobacterium tuberculosis in the lungs of chronically infected mice.

Mice infected by intraperitoneal injection of Mycobacterium tuberculosis were studied over a 23-week period. They showed progressive infection in the lung (with increasing microbial count and granuloma size) whereas viable bacillary counts remained largely stationary in the spleen and in the liver. The influence of H-2 genes on the progression of the lung infection was studied in four congenic strains of animals with B10 and three congenic strains of animals with BALB backgrounds. H-2k mice had significantly higher bacterial counts in the lung than H-2b mice on both B10 and BALB backgrounds, BALB. K (H-2k) mice were also more susceptible than BALB/c (H-2d) mice. Results with recombinant strains showed that bacillary counts and granulomatous infiltration were lower in the B10 (KbAbE-Db) compared with B10.A(3R) (KbAbEbDd) strain and in B10.A(4R) (KkAkE-Db) compared with B10.BR (KkAkEkDk) mice. This resistance to the late expansion of tuberculous infection in the lungs may be associated with the lack of an expressed I-E molecular or with the expression of the Db molecule.

Animals↗
PubMed1991

Priming of influenza virus-specific cytotoxic T lymphocytes vivo by short synthetic peptides.

Influenza virus-specific CTL were primed in vivo by immunization with short synthetic peptides representing major CTL epitopes from the nucleoprotein of type A influenza virus. The resultant CTL after in vitro boosting of primed spleen cells recognized both virus-infected and peptide-pulsed target cells. The requirement of CD4+ T cell activation was investigated in several ways. First the addition of helper epitopes to the CTL epitope did not enhance CTL generation, suggesting that helper activity was either not limiting or not required. However, in vivo depletion of CD4+ T cells completely inhibited the generation of CTL by peptide immunization. The inclusion of anti-CD4 in the in vitro restimulation with peptide also prevented the generation of CTL, whereas in vitro reactivation of virus immune spleen cells with peptide was not inhibited by anti-CD4. Thus there appears to be heterogeneity in the requirement of CD4+ T cell proliferation in CTL generation. One possibility is that virus infected cells can stimulate higher affinity T cells that are less helper T cell dependent.

Animals↗