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Biomedical subjects

M Green

Publications and source records attributed to M Green.

At least 91 records · Page 5Linked to original sources
PubMed2001

Pediatric solid-organ transplant recipients carry chronic loads of Epstein-Barr virus exclusively in the immunoglobulin D-negative B-cell compartment.

Solid-organ transplant recipients are at risk for development of lymphoproliferative diseases. The purpose of this study was to examine the distribution of Epstein-Barr virus (EBV) load in the peripheral blood of pediatric transplant recipients who had become chronic viral load carriers (>8 copies/10(5) lymphocytes for >2 months). A total of 19 patients with viral loads ranging from 20 to 5,000 viral genome copies/10(5) lymphocytes were studied. Ten patients had no previous diagnosis of posttransplant lymphoproliferative disease (PT-LPD), while nine had recovered from a diagnosed case of PT-LPD. No portion of the peripheral blood viral load was detected in the cell-free plasma fraction. Viral DNA was found in a population of cells characterized as CD19(hi) and immunoglobulin D negative, a phenotype that is consistent with the virus being carried exclusively in the memory B-cell compartment of the peripheral blood. There was no difference in the compartmentalization based upon either the level of the viral load or the past diagnosis of an episode of PT-LPD. These results have implications for the design of tests to detect EBV infection and for the interpretation and use of positive EBV PCR assays in the management of transplant recipients.

Adolescent↗
PubMed2001

Inspiratory muscle relaxation rate slows during exhaustive treadmill walking in patients with chronic heart failure.

Exercise intolerance is a feature of chronic heart failure (CHF). We hypothesized that excessive loading of the respiratory muscle pump might contribute to exertional breathlessness. One marker of excessive muscle-loading is slowing of maximum relaxation rate (MRR) and, therefore, to test our hypothesis, we investigated the effect of exhaustive treadmill walking on inspiratory muscle MRR in patients with CHF. We studied eight stable patients with mild-moderate CHF walking on a treadmill until termination because of severe dyspnea. Inspiratory muscle MRR was determined from esophageal pressure (Pes) change during submaximal sniffs (Sn) before and immediately after exercise to a mean (SD) minute ventilation of 77 () L/min. For comparison, nine healthy subjects performed a similar protocol; exercise was terminated either by severe dyspnea or when minute ventilation reached 100 L/min. There were no significant differences in terms of heart rate, respiratory rate, tidal volume, or inspiratory duty cycle at cessation of exercise. The mean slowing of Sn Pes MRR in the first minute after termination of exercise in the CHF group was 22.4% and in the normal control group it was 2.8% (p < 0.01). Our data show that slowing of inspiratory muscle relaxation rate occurs in patients with CHF walking to severe breathlessness. We conclude that severe loading of the inspiratory muscles is a feature of exertional dyspnea in CHF.

Adult↗
PubMed2001

Inspiratory muscle strength in acute asthma.

STUDY OBJECTIVES: The aim of this study was to measure inspiratory pressure-generating capacity in patients presenting with acute asthma, as it has been suggested that inspiratory muscle fatigue may contribute to breathlessness and acute respiratory failure. DESIGN: Descriptive study. SETTING: Emergency departments of two inner-city hospitals. PATIENTS: Fifty-one patients with acute asthma, and 45 patients without respiratory disease who served as control subjects. MEASUREMENTS AND RESULTS: Maximum inspiratory pressure-generating capacity was measured soon after presentation by the sniff nasal inspiratory pressure (SNIP) method. The mean (SD) SNIP was 110 cm H(2)O (23 cm H(2)O) in men with asthma (mean for control subjects, 126 cm H(2)O [25 cm H(2)O]; p < 0.05) and 80 cm H(2)O [24 cm H(2)O] in women with asthma (mean for control subjects, 105 cm H(2)O (26 cm H(2)O); p < 0.01). In a second study of simultaneous SNIP and intrathoracic pressure measurements in a group of patients with acute asthma (n = 10) and control subjects (n = 11), the effect of airways obstruction on SNIP was assessed. The measurement of sniff esophageal pressure was more negative than SNIP by approximately 16% in asthmatic patients and by 4% in control subjects. Taking account of the likely effect of airways obstruction on SNIP, the reduction in inspiratory pressure-generating capacity that was observed in these patients with moderately severe acute asthma was minor and was consistent with the modest hyperinflation observed. CONCLUSIONS: This study did not find evidence of inspiratory muscle weakness or fatigue in patients with moderately severe acute asthma presenting to the emergency department.

Adolescent↗
PubMed2001

Advances in the treatment of non-small cell lung cancer: molecular markers take the stage.

Increasing evidence that non-small cell lung cancer is a systemic disease from the outset confirms the rationale for adjuvant chemotherapy. However, clinical trial evidence of benefit is still awaited. The position is clearer in the case of neoadjuvant therapy because long-term follow up of two trials now shows that patients randomized to chemotherapy before surgery were significantly more likely to survive to 5 years than patients treated with surgery alone. Early data suggest that neoadjuvant chemotherapy based on docetaxel (Taxotere; Aventis, Antony, France) (possibly used sequentially with other agents) may be as effective as older regimens and better tolerated. Because p53 status influences the expression of microtubule-associated proteins and hence the sensitivity of a tumor to taxanes, it is possible that molecular markers could be used to customize chemotherapy to individual patients. Generally, it is becoming clearer that molecular staging is a more sensitive means of demonstrating tumor dissemination than light microscopy. The Cancer and Leukemia Group B is undertaking a prospective study using reverse transcriptase-polymerase chain reaction to detect MUC-1 RNA in bone marrow and hilar and mediastinal lymph nodes removed at resection with the aim of distinguishing between stage I patients likely to remain disease-free for long periods and those at high risk of relapse. A study of small cell lung cancer is using automated fluorescence microscopy to detect keratin-positive cells in the marrow and blood of patients who have a complete response to initial therapy but are nevertheless at high overall risk of relapse. The identification of genetic lesions in a high proportion of patients with non-small cell lung cancer may guide the development of new therapies aimed at increasing rates of apoptosis among tumor cells.

Antineoplastic Agents↗
PubMed2001

Improved pharmacokinetic properties of a polyethylene glycol-modified form of interferon-beta-1a with preserved in vitro bioactivity.

Interferon therapies suffer from a relatively short half-life of the products in circulation. To address this issue we investigated the effects of polyethylene glycol modification (PEGylation) on the pharmacokinetic properties of human interferon (IFN)-beta-1a. PEGylation with a linear 20-kDa PEG targeted at a single site on the N-terminal amine had no deleterious effect on its specific activity in an in vitro antiviral assay. In monkeys, PEG IFN-beta-1a treatment induced neopterin and beta2-microglobulin expression (pharmacodynamic markers of activity). Systemic clearance values in monkeys, rats, and mice decreased, respectively, from 232, 261, and 247 ml/h/kg for the unmodified IFN-beta-1a to 30.5, 19.2, and 18.7 ml/h/kg for the PEGylated form, while volume of distribution values decreased from 427, 280, and 328 ml/kg to 284, 173, and 150 ml/kg. The decreased clearance and volume of distribution resulted in higher serum antiviral activity in the PEG IFN-beta-1a-treated animals. In the rat, a more extensive set of dosing routes was investigated, including intraperitoneal, intratracheal, and oral administration. Bioavailability for the PEG IFN-beta-1a was similar to the unmodified protein for each of the extravascular routes examined. For the intraperitoneal route, bioavailability was almost 100%, whereas for the oral and intratracheal routes absorption was low (<5%). In rats, subcutaneous bioavailability was moderate (28%), whereas in monkeys it was approximately 100%. In all instances an improved pharmacokinetic profile for the PEGylated IFN-beta-1a was observed. These findings demonstrate that PEGylation greatly alters the pharmacokinetic properties of IFN-beta-1a, resulting in an increase in systemic exposure following diverse routes of administration.

Animals↗
PubMed2001

BK virus infection in renal transplant recipients.

BK virus (BKV) is increasingly being recognized as an important pathogen among renal transplant recipients. To date, only limited information is known about BKV infections in this population; definitive data regarding the epidemiology, diagnosis, treatment, and outcome of BKV infection are lacking. Therefore, further investigations are needed. This article reviews our current understanding of BKV infections among renal transplant patients.

BK Virus↗
PubMed2001

Management of Epstein-Barr virus-induced post-transplant lymphoproliferative disease in recipients of solid organ transplantation.

The optimal management of Epstein-Barr virus (EBV)-induced post-transplant lymphoproliferative diseases (PTLD) remains controversial. While withdrawal or reduction of immunosuppression is widely accepted as the strategy for the treatment of EBV/PTLD, the role of additional therapeutic interventions remains less clear. Newer strategies, including anti-B-cell monoclonal antibodies and adoptive immunotherapy offer the promise of impaired efficacy and outcome against EBV disease, but lack data demonstrating how and when to use these approaches. The current review provides an overview of potential strategies and presents guidelines for the management of EBV/PTLD in solid-organ transplant recipients.

B-Lymphocytes↗
PubMed2000

SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity.

The IL-1 receptor-associated kinase (IRAK/mPLK) is linked to the regulation of nuclear factor-kappaB (NF-kappaB)-dependent gene expression. Here we describe a novel binding partner of IRAK/mPLK that we term SIMPL (signaling molecule that associates with the mouse pelle-like kinase). Overexpression of SIMPL leads to the activation of NF-kappaB-dependent promoters, and inactivation of SIMPL inhibits IRAK/mPLK as well as tumor necrosis factor receptor type I-induced NF-kappaB activity. Dominant inhibitory alleles of IkappaB kinase (IKKalpha or IKKbeta) block the activation of NF-kappaB by IRAK/mPLK and SIMPL. Furthermore, SIMPL binds IRAK/mPLK and the IKKs in vitro and in vivo. In the presence of antisense mRNA to SIMPL, the physical association between IRAK/mPLK and IKKbeta but not IRAK/mPLK and IKKalpha is greatly diminished. Moreover, dominant-negative SIMPL blocks IKKalpha- or IKKbeta-induced NF-kappaB activity. These results lead us to propose a model in which SIMPL functions to regulate NF-kappaB activity by linking IRAK/mPLK to IKKbeta/alpha-containing complexes.

Amino Acid Sequence↗
PubMed2000

A single dose sub-unit vaccine protects against pneumonic plague.

In this study, the protection afforded against aerosolised Yersinia pestis by injection of a single dose of an alhydrogel-adsorbed sub-unit vaccine has been compared with that given by an existing killed whole cell vaccine licensed for human use. The sub-unit vaccine, prepared by admixing F1 antigen derived from a Y. pestis cell culture supernatant with recombinant V antigen derived from an E. coli cell lysate, fully protected an outbred strain of mouse against exposure to 10(6) CFU of virulent plague organisms (10(4) mouse lethal doses, MLD). In contrast, the whole cell vaccine provided only 16% protection against the same level of challenge. Furthermore, sub-unit vaccinees were able to clear the bacteria from their lungs post-challenge whereas bacteria were cultured from the lungs of a surviving KWC vaccinee post-challenge. In killed whole cell vaccinees, physiologically significant levels of IgG to F1 only were detectable and the levels of F1-specific IgG in serum and in broncho-alveolar washings were significantly lower (p<0.05) compared with sub-unit vaccinees. In sub-unit vaccinees, an IgG titre to the F1 and V antigens was detected in serum where it was significantly higher (p<0.05) compared with broncho-alveolar washings suggesting that, at the time of challenge, protection is attributable mainly to the combined circulating IgG titre to the F1 and V sub-units. The enhanced protective efficacy of this sub-unit vaccine administered as a single dose compared with an existing vaccine has been demonstrated in an outbred animal model of pneumonic plague.

Animals↗
PubMed2000

Epstein-Barr virus gene expression in the peripheral blood of transplant recipients with persistent circulating virus loads.

Pediatric solid organ transplant recipients are at risk for Epstein-Barr virus (EBV)-driven lymphoproliferative disease. The expression of 5 sentinel EBV genes (EBNA1, EBNA2a, LMP1, LMP2a, and ZEBRA) was examined in solid organ transplant recipients who developed persistent virus loads in their peripheral blood lymphocytes after transplantation. Two distinct groups were identified. LMP2a gene expression alone was detected among 12 of 14 patients carrying EBV loads < or =100 copies/10(5) lymphocytes. The other 2 low-load carriers made LMP2a RNA but also expressed LMP1 RNA. In contrast, LMP2a and LMP1 gene expression was detected among 11 of 13 patients carrying a virus load >100 copies/10(5) lymphocytes. Two high-load carriers made LMP1 RNA but not the RNA for LMP2a or any of the other viral genes. Therefore, persistent low-load carriers appear to maintain an apparently normal state of latent viral infection, whereas high-load carriers display a unique LMP1:LMP2a pattern of viral gene expression that has not been previously described.

Adolescent↗
PubMed2000

Predictive negative value of persistent low Epstein-Barr virus viral load after intestinal transplantation in children.

BACKGROUND: The correlation between an elevated Epstein-Barr virus (EBV) viral load in the peripheral blood and the subsequent development of EBV-associated posttransplant lymphoproliferative disease (PTLD) is the basis for strategies using serial measurements of the EBV viral load to guide preemptive therapy (PT). Neither the frequency, duration of monitoring, nor the predictive negative value of viral load monitoring for asymptomatic patients with persistent low or nondetectable viral loads against the development of PTLD has been established. METHODS: Since April 1994, children undergoing intestinal transplantation (ITx) underwent serial monitoring of the EBV viral load in their peripheral blood using a quantitative competitive EBV polymerase chain reaction assay (PCR). Samples were obtained every 2 weeks for the first 3 months and then every 1-3 months depending on the patients clinical condition. EBV viral loads > or =40 (for patients who were EBV seronegative pre-ITx) and > or =200 (for those who were seropositive) genome copies/10(5) peripheral blood lymphocytes were felt to identify patients at increased risk for PTLD and generally prompted PT. RESULTS: A total of 30 ITx recipients were compliant with our monitoring protocol; 23/30 are alive 6-59 months post-ITx. A total of 12/30 never had a viral load >40 and did not receive PT. In contrast, 18/30 had > or =1 high viral load (> or =200); the first high viral load was measured a median of 59 days post-ITx (range 1-440). A late rise (>6 months post-ITx) was seen in only 2/18 children. A total of 0/12 patients with persistently low viral loads received PT and none developed PTLD. In contrast, 5/18 with > or =1 one high viral load (including 2/14 who received and 3/4 who did not receive PT) developed PTLD. All five children with PTLD were EBV seropositive pre-ITx and experienced their first high EBV PCR within the first 3 months after ITx. CONCLUSIONS: The predictive negative value of persistently low or nondetectable EBV viral loads was 100% in this study. Patients with nondetectable or low viral loads for the first 6 months after ITx did not develop PTLD regardless of their pretransplant EBV serological status. The frequency of viral load monitoring can be safely decreased for patients whose viral loads remain low for the first 6 months ITx.

Antiviral Agents↗
PubMed2000

Comparative long-term evaluation of tacrolimus and cyclosporine in pediatric liver transplantation.

BACKGROUND: In this report, we compare the long-term outcome of pediatric liver transplantation (LTx) patients maintained with tacrolimus-based and with cyclosporine (CsA)-based immunosuppressive therapy. We examine long-term patient and graft survival, the incidence of rejection, and immunosuppression-related complications. METHOD: There were 233 consecutive primary LTx in children (ages <18 years) performed between October 1989 and December 1994 with tacrolimus-based immunosuppressive therapy (Group I). These were compared with 120 consecutive primary LTx performed with CsA-based immunosuppressive therapy between January 1988 and October 1989(Group II). Children in both groups were followed until July 1999. Mean follow-up was 91.41+/-17.7 months (range 55.6-117.8) for Group I, and 128+/-6.1 months (range 116.7-138.6) for Group II. RESULTS: At 9 years of follow-up, actuarial patient and graft survival were significantly improved (patient survival 85.41% in Group I vs. 63.8% in Group II, P=0.0001; graft survival Group I 78.9% vs. 60.8% Group II, P=0.0003) and the rate of re -transplantation was significantly lower among patients in Group I (12% in Group I vs. 22.5% in Group II P=0.01). Children in Group I also experienced a significantly reduced incidence of acute rejection (0.97 per patient Group I vs. 1.5 per patient Group II P=0.002) and significantly less steroid resistant acute rejection episodes (3.1% in Group I vs. 8.6% in Group II P=0.0001). The mean steroid dose was significantly lower in Group I compared with Group II at all time points (P=0.0001) after LTx. Freedom from steroid was also significantly higher in Group I compared with Group II at all time points after LTx (ranging from 78% to 84% in Group I and 9% to 32% in Group II during a 1- to 7-year posttransplant period P=0.0001). The rate of hypertension was significantly lower in Group I than Group II (P=0.0001), and the severity of hypertension (need for more than one anti-hypertensive medication) was also significantly lower in Group I than Group II (P=0.0001). Although the rate of posttransplant lymphoproliferative disorder (PTLD) was not significantly different (13.7% Group I vs.8.3% Group II, P=0.13), the survival after PTLD was significantly better for Group I at 81.2% than for Group II at 50% after 5 years (P=0.034). Conclusion. The results suggest that tacrolimus-based therapy provides significant long-term benefit to pediatric LTx patients, evidenced by significantly improved patient and graft survival, reduced rate of rejection, and hypertension with lower steroid doses.

Cause of Death↗
PubMed2000

Selective inhibition of nuclear steroid receptor function by a protein from a human tumorigenic poxvirus.

The poxvirus molluscum contagiosum (MC) has a worldwide distribution and its prevalence is on the rise. Here we report that the MCV MC013L protein inhibits glucocorticoid and vitamin D, but not retinoid or estrogen, nuclear receptor transactivation. A direct interaction of MC013L with glucocorticoid and vitamin D receptor is supported by yeast two-hybrid, GST pull-down, and far Western blot analyses. Glucocorticoids act as potent inhibitors of keratinocyte proliferation, while vitamin D and retinoids promote and block terminal differentiation, respectively. Therefore, MC013L may promote efficient virus replication by blocking the differentiation of infected keratinocytes. MC013L may be the first member of a new class of poxvirus proteins that directly modulate nuclear receptor-mediated transcription.

Amino Acid Sequence↗
PubMed2000

The use of interprofessional peer examiners in an objective structured clinical examination: can dental students act as examiners?

OBJECTIVE: To assess whether final year dental students could act as reliable examiners within an Objective Structured Clinical Examination (OSCE) by comparison with results obtained by an experienced member of staff. DESIGN: A station testing examination of the mouth was included in the second year medical undergraduate summative OSCE examination. SETTING: Concurrently run in three different examination venues on the Ninewells Hospital campus. SUBJECTS: 147 medical students and 3 pairs (A, B, C) of examiners. Each examining pairing consisted of one member of staff and one dental student (blind to each other's marking). METHOD: A checklist of 13 tasks to be performed was provided to the examiners. One mark awarded for a completed task, no mark for no attempt at the task, and half a mark for attempt at task. RESULTS: Paired results were available for 125 medical students. Using Mann-Witney analysis, the non-parametric 95% confidence intervals for the difference in scores between the 3 paired teams were group A (-0.5, 0), group B (-0.5, 0.5), group C (-0.5, 0). In only 4 students (out of 125) did the difference between the individual pair differ by 2 or more marks. CONCLUSION: On the basis of this pilot study final year dental students may be used as examiners in OSCEs where basic technical skills are to be evaluated. This development from peer group teaching provides further evidence supportive of interprofessional education.

Clinical Competence↗