Search PubMed⌕ Search

Biomedical subjects

M Yacoub

Publications and source records attributed to M Yacoub.

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

Evaluation of human cytomegalovirus gene expression in thoracic organ transplant recipients using nucleic acid sequence-based amplification.

BACKGROUND: Human cytomegalovirus (CMV) infection is a major cause of morbidity in transplant patients. Early diagnosis and treatment have been shown to improve outcome. We evaluated the suitability of CMV immediate early, early, and late gene expression detected by nucleic acid sequence-based amplification (NASBA) as markers of CMV infection. METHODS: Blood samples were taken immediately before transplant and every one to two weeks after transplantation for 12 weeks from 50 patients undergoing thoracic organ transplantation. CMV-NASBA was performed and results compared with serology, CMV pp65 antigenaemia (CMV-AG) and the development of clinical CMV infection. Patients received "preemptive" anti-CMV therapy with ganciclovir based on the CMV-AG results. RESULTS: CMV immediate early and early gene expression were detected in 87 and 47%, respectively, of patients without other evidence of CMV infection. CMV late gene expression had a sensitivity of 97% for infection (compared with 83% for CMV-AG P=0.06) and a specificity of 93% (compared with 100% P=NS). Late gene expression occurred at the same time as CMV antigenaemia but 1.1 weeks earlier than the threshold of antigenaemia (CMV-AG>10) used to initiate preemptive therapy. CONCLUSION: NASBA provided a standardized tool for the detection of CMV transcripts with a greater sensitivity than the standard antigenemia test. Detection of immediate early and early gene transcripts was not specific for subsequent infection. CMV late gene expression determined by NASBA was an accurate and early marker of CMV infection. Detection of CMV late gene expression could be used to trigger "preemptive" anti-CMV therapy.

Adult↗
PubMed2000

Alpha-gal-independent dual recognition and activation of xenogeneic endothelial cells and human naïve natural killer cells.

BACKGROUND: Interaction between vascularized xenograft and host immune system is thought to occur via Galactose alpha (1,3) Galactose (Gala 1,3 gal) structures decorating the xenograft. METHODS: We raised anti-Gala 1,3 gal-BSA polyclonal antibodies in baboons and investigated effect(s) of these antibodies as well as soluble Gala 1,3 gal-BSA on human naive natural killer (NK) cell interactions with porcine aortic endothelial cells. RESULTS: We demonstrate that human naive (unstimulated) NK cells recognize xenogeneic endothelial cells under conditions where binding to the Gala 1,3 gal structures is minimized by the presence of blocking anti-Gala 1,3 gal IgG or soluble Gala 1-3 gal and in the absence of xenoreactive natural antibodies and complement. After xenogeneic encounter both endothelial cells and human NK cells are activated. Endothelial cell activation is rapid and is manifested initially by an intraendothelial calcium transient and subsequently by expression of P-selectin and vascular endothelial cell adhesion molecule-1 on the xenoendothelium surface. NK cell activation is manifested by increased expression of perforin and increased cytotoxicity towards the xenoendothelium. Neither recognition nor activation of the xenoendothelium was affected by the introduction of either anti-Gala 1,3 gal IgG or soluble Gala 1-3 gal. CONCLUSION: Our data provide evidence that innate immune cells, such as NK cells, recognize and activate xenoendothelial cells independently of Gala 1-3 gal structures and raise the possibility of novel interactive sites on both human naive NK cells and discordant xenogeneic endothelium.

Animals↗
PubMed2000

An epithelial cell line that can stimulate alloproliferation of resting CD4+ T cells, but not after IFN-gamma stimulation.

It has previously been shown that IFN-gamma-induced up-regulation of HLA class II on the surface of epithelial cells is not sufficient to induce proliferation of allospecific CD4+ T cells in vitro. To further investigate this phenomenon, a human epithelial bladder carcinoma, T24, was induced to constitutively express HLA class II without IFN-gamma stimulation, by permanent transfection with the full-length class II transactivator (CIITA) gene. Proliferation of allospecific T cells to transfected and wild-type cells with and without prior activation with saturating levels of IFN-gamma for 4 days was examined. IFN-gamma-activated T24 did not induce any response from CD4+ T cells. However, T24.CIITA induced significant levels of alloproliferation, which could be abrogated by pretreatment of T24.CIITA with a mAb to LFA-3. Prestimulation of T24. CIITA with saturating levels of IFN-gamma for 4 days also prevented allospecific CD4+ T cell proliferation. These findings suggest that epithelial cells may be intrinsically able to process and present alloantigen and provide adequate costimulation. We propose that IFN-gamma has a secondary, as yet unidentified, effect that acts to negatively regulate this response, at least in some epithelial cells.

CD4-Positive T-Lymphocytes↗
PubMed2000

Left ventricular function and mass after orthotopic heart transplantation: a comparison of cardiovascular magnetic resonance with echocardiography.

OBJECTIVE: We compared the assessment of left ventricular function and mass by M-mode echocardiography (echo) with fast breath-hold cardiovascular magnetic resonance (CMR) in patients who received orthotopic heart transplantation. We also sought to establish the reproducibility of breath-hold CMR in this patient population. METHODS: We prospectively acquired 51 sets of echo and CMR data in 21 patients who had undergone orthotopic heart transplantation. We examined the intraobserver and interobserver reproducibility of breath-hold CMR in this group and compared it with published data. We compared the left ventricular ejection fraction (EF) and mass determined by echo with the CMR data. RESULTS: The average time between CMR and echo was 0 +/- 7 days (mean +/- SD), the time between each set of CMR-echo data acquisition was 5.1 +/- 4.1 months. Cardiovascular magnetic resonance showed good reproducibility in this population, with intraobserver percentage variability of 2.2% +/- 2.4% for EF and 3. 2% +/- 2.7% for mass, and interobserver percentage variability of 2. 4% +/- 1.9% for EF and 2.2% +/- 1.9% for mass. The Bland-Altman limits of agreement between echo and CMR were wide for both EF (-9. 6% to 15%) and mass, irrespective of the formula used (-61.3 to 198 g for the Bennett and Evans formula, -65.4 to 196.8 g for the American Society of Echocardiography (ASE) formula, -65.3 to 181 g for the Devereux formula, and -95.2 to 64.6 g for the Teichholz formula). CONCLUSION: Fast-acquisition CMR is reproducible in recipients of transplanted hearts. We found poor agreement with the results of echo. The choice of technique will depend on local resources as well as the clinical importance of the result. Echo remains readily available and gives rapid assessment of volumes, EF, and mass. However, the good reproducibility of CMR may make it a more suitable technique for long-term follow-up of an individual or of a study population.

Cardiac Volume↗
PubMed2000

A redox-based mechanism for nitric oxide-induced inhibition of DNA synthesis in human vascular smooth muscle cells.

1. The current study explored potential redox mechanisms of nitric oxide (NO)-induced inhibition of DNA synthesis in cultured human and rat aortic smooth muscle cells. 2. Exposure to S-nitrosothiols, DETA-NONOate and NO itself inhibited ongoing DNA synthesis and S phase progression in a concentration-dependent manner, as measured by thymidine incorporation and flow cytometry. Inhibition by NO donors occurred by release of NO, as detected by chemiluminescence and judged by the effects of NO scavengers, haemoglobin and cPTIO. 3. Co-incubation with redox compounds, N-acetyl-L-cysteine, glutathione and L-ascorbic acid prevented NO inhibition of DNA synthesis. These observations suggest that redox agents may alternatively attenuate NO bioactivity extracellularly, interfere with intracellular actions of NO on the DNA synthesis machinery or restore DNA synthesis after established inhibition by NO. 4. Recovery of DNA synthesis after inhibition by NO was similar with and without redox agents suggesting that augmented restoration of DNA synthesis is an unlikely mechanism to explain redox regulation. 5. Study of extracellula interactions revealed that all redox agents potentiated S-nitrosothiol decomposition and NO release. 6. Examination of intracellular NO bioactivity showed that as opposed to attenuation of NO inhibition of DNA synthesis by redox agents, there was no inhibition (potentiation in the presence of ascorbic acid) of soluble guanylate cyclase (sGC) activation judged by cyclic GMP accumulation in rat cells. 7. These data provide evidence that NO-induced inhibition of ongoing DNA synthesis is sensitive to redox environment. Redox processes might protect the DNA synthesis machinery from inhibition by NO, in the setting of augmented liberation of biologically active NO from NO donors.

Acetylcysteine↗
PubMed2000

Long-term results after aortic valve replacement in patients with congestive heart failure. Homografts vs prosthetic valves.

OBJECTIVES: The aim of this study was to assess the influence of valve substitute (homograft vs prosthetic valve) on the long-term survival and late valve-related complication rates following aortic valve replacement in patients with aortic valve disease and congestive heart failure. BACKGROUND: The effect of choice of valve substitute on outcome after aortic valve replacement in patients with pre-operative heart failure is unknown. The superior haemodynamic profile of homografts may be of particular benefit. METHODS: We retrospectively analysed pre-operative, operative and follow-up data on 518 adults in functional classes III and IV, who, over the 25 years 1969-1993, had their initial aortic valve replacement at Harefield hospital. Follow-up conducted during 1996 to April 1997 and totalling 4439 patient-years was 96.1% complete. Using multivariate analysis, independent risk factors for different complications and mortality were defined. RESULTS: Overall 5-, 10- and 20-year survival was 80+/-2%, 62+/-2% and 30+/-3%, respectively, with no significant difference between valve types. However, homografts (n=381) independently reduced the rate of serious complications and cardiac death, whereas mechanical valves were an independent adverse risk factor for late mortality. The rates of anticoagulant-related bleeding and thromboembolism were increased by mechanical valves, whereas primary tissue failure was the main complication of homografts. CONCLUSIONS: Long-term outcome of homograft aortic valve replacement in patients with congestive heart failure is acceptable, with a reduced rate of serious complications and cardiac death. Further improvements would be expected if the rate of primary tissue failure could be reduced.

Adolescent↗
PubMed2000

Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family.

BACKGROUND: Primary pulmonary hypertension (PPH), resulting from occlusion of small pulmonary arteries, is a devastating condition. Mutations of the bone morphogenetic protein receptor type II gene (BMPR2), a component of the transforming growth factor beta (TGF-beta) family which plays a key role in cell growth, have recently been identified as causing familial PPH. We have searched for BMPR2 gene mutations in sporadic PPH patients to determine whether the same genetic defect underlies the more common form of the disorder. METHODS: We investigated 50 unrelated patients, with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension, by direct sequencing of the entire coding region and intron/exon boundaries of the BMPR2 gene. DNA from available parent pairs (n=5) was used to assess the occurrence of spontaneous (de novo) mutations contributing to sporadic PPH. RESULTS: We found a total of 11 different heterozygous germline mutations of the BMPR2 gene in 13 of the 50 PPH patients studied, including missense (n=3), nonsense (n=3), and frameshift (n=5) mutations each predicted to alter the cell signalling response to specific ligands. Parental analysis showed three occurrences of paternal transmission and two of de novo mutation of the BMPR2 gene in sporadic PPH. CONCLUSION: The sporadic form of PPH is associated with germline mutations of the gene encoding the receptor protein BMPR-II in at least 26% of cases. A molecular classification of PPH, based upon the presence or absence of BMPR2 mutations, has important implications for patient management and screening of relatives.

Adolescent↗
PubMed2000

Features selection and architecture optimization in connectionist systems.

In this paper, we propose a features selection measure and an architecture optimization procedure for Multi-Layer Perceptrons (MLP). The algorithm presented in this contribution employs a heuristic measure named HVS (Heuristic for Variable Selection). This new measure allows us to identify and select important variables in the features space. This can be achieved by eliminating redundant features and those which do not contain enough relevant information. The proposed measure is used in a new procedure aimed at selecting the "best" MLP architecture given an initial structure. Application results for two generic problems: regression and discrimination, demonstrates the proposed selection algorithm's effectiveness in identifying optimized connectionist models with higher accuracy. Finally, an extension of HVS, named epsilonHVS, is proposed for discriminative features detection and architecture optimization for Time Delay Neural Networks models (TDNN).

Algorithms↗
PubMed2000

Rathke's cleft cyst abscess.

Pituitary abscesses are rare. Occasionally they will arise in pre-existing pituitary pathology. We report such an occurrence within a Rathke's cleft cyst. On the basis of history and imaging, this was indistinguishable from more commonly encountered pituitary pathology.

Acinetobacter Infections↗
PubMed2000

Plant poisonings from herbal medication admitted to a Tunisian toxicologic intensive care unit, 1983-1998.

To collect data on Tunisian herbal toxicity we analysed 56 medical records of patients admitted to the toxicological intensive care unit from 1983 to 1998 following the ingestion of plants. The sex ratio of patients was 1:2, the mean age of patients was 26y (2 to 75y) and II species of plants were involved with Atractylis gummifera (32%), Datura stramonium (25%), Ricinus communis (9%), Nerium oleander (7%) and Peganum harmala (7%) most commonly infested. Poisonings involved neurological (91%), gastrointestinal (73%) and cardiovascular systems (18%). Treatment was mainly symptomatic. The only lethal cases of liver failure involved 16 Atractylis gummifera poisonings.

Adolescent↗
PubMed1999

[Acute self-induced poisoning with carbamazepine].

OBJECTIVE: We report the epidemiological, clinical, toxicological and therapeutic aspects of acute voluntary intoxication with carbamazepine. PATIENTS AND METHODS: The study included 17 cases of acute carbamazepine intoxication in patients hospitalized in our toxicology unit. RESULTS: Neurological signs predominated at admission, mainly agitation or coma associated with seizures. Mydriasis and cardiovascular signs were frequent. Blood chemistry most frequently showed hyponatremia. Mean serum carbamazepine level admission was 24 mg/l (range 4 ñ 12 mg/l). Ten patient required respiratory assistance for 28 +/- 17 hours. Symptomatic treatment and gastric lavage (+activated carbon) provided favorable outcome. CONCLUSION: Acute carbamazepine intoxication is seen with increasing frequency. Severity is related to the degree and duration of the coma, respiratory depression, seizures, cardiovascular disorders, and metabolic abnormalities. Symptomatic and specific treatment with activated carbon are required.

Acute Disease↗
PubMed1999

Ligation of ICAM-1 on endothelial cells leads to expression of VCAM-1 via a nuclear factor-kappaB-independent mechanism.

ICAM-1 is an Ig-like cell adhesion molecule expressed by several cell types, including the endothelium. Cross-linking of ICAM-1 on the surface of different cell types has previously been shown to cause an increase in cellular activation within the cytoplasm. In this study, we have compared signaling events following ligation of ICAM-1 by cross-linking with mAbs with events after activation of HUVEC by TNF. ICAM-1 cross-linking caused activation of Erk-1 and the AP-1 transcription factor complex, without any increase in NF-kappaB activity, in contrast to TNF stimulation. Transcription of VCAM-1 mRNA was observed by reverse-transcriptase PCR after ICAM-1 cross-linking, with no associated transcription of E-selectin. This was reflected by the presence of VCAM-1 protein after immunoprecipitation, without E-selectin expression, in ICAM-1 cross-linked cells. In contrast, mRNA and protein for both VCAM-1 and E-selectin were observed in TNF-treated HUVEC, as expected. Addition of the MEK (MAP/Erk kinase) inhibitor PD98059 reduced expression of VCAM-1 after ICAM-1 cross-linking, suggesting that the Erk pathway is involved in ICAM-1-mediated VCAM-1 expression. In conclusion, ICAM-1-induced expression of VCAM-1 represents a pathway for adhesion molecule up-regulation that is distinct from the TNF-induced pathway. It may be similar to the IL-4 pathway or it may represent a novel pathway.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Clenbuterol increases stroke power and contractile speed of skeletal muscle for cardiac assist.

BACKGROUND: Skeletal muscle assist (SMA) may be limited by loss of power, slowing of contraction and relaxation, and atrophy of the transformed latissimus dorsi muscle (LD). Clenbuterol (clen), a beta2-adrenergic receptor agonist, was used to improve the performance of trained skeletal muscle in sheep. METHODS AND RESULTS: The following 4 groups were used: A (n=6), untrained controls; B (n=6), left LD progressively transformed toward a slow-twitch and fatigue-resistant phenotype by electrical stimulation over 12 weeks (2.5 to 5 V, 240- microsec pulse duration, 35 Hz, 3 to 6 pulses per burst, and up to 40 bursts per minute); C (n=6), clen-treated (0.5 mg/kg SC) for 12 weeks; and D (n=6), clen+trained. In a terminal experiment, the mobilized LD was wrapped around a rubber aorta of a mock circulation and stimulated to contract 40 times per minute. Group A had an initial mean pressure augmentation (DeltaP) of 24.6 mm Hg and stroke power of 2.28 W/kg, but both fell to <20% of their original values by 15 minutes because of fatigue (P<0.005). Group B was fatigue-resistant, with a DeltaP and stroke power at 60 minutes of 13 mm Hg (70% of initial) and 0.34 W/kg (39% of initial), respectively. The performance of group C was similar to that of controls. In group D, however, the muscles were stronger at all time points than in B, with a DeltaP of 23 mm Hg and stroke power of 2.66 W/kg at 60 minutes (P<0.01). The speeds of contraction (+dP/dt:DeltaP) and relaxation (-dP/dt:DeltaP) were significantly greater in group D than B. Protein analyses showed group D to have only a trend toward greater abundance of the fast isoforms of myosin heavy chain and sarcoplasmic reticulum Ca2+-ATPase (P>0.1). CONCLUSIOINS: ++Clen improves the performance of trained skeletal muscle in a model of aortomyoplasty by unknown mechanisms. These findings may have important implications in SMA.

Adrenergic beta-Agonists↗
PubMed1999

Mobilization of the left and right fibrous trigones for relief of severe left ventricular outflow obstruction.

BACKGROUND: There is still no agreement about the optimal method of surgical relief of fixed subaortic stenosis, particularly the severe forms. OBJECTIVES: The purpose of this study was to describe a new technique for the relief of subaortic stenosis based on analysis of the functional anatomy of the left ventricular outflow tract and pathophysiologic features of subaortic stenosis. METHODS AND PATIENTS: We propose that one of the basic abnormalities in subaortic stenosis is interference with the hinge mechanism provided by the 2 fibrous trigones with progressive deposition of fibrous tissue in these angles. The technique described in this paper consists of excision of all components of the fibrous "ring," with mobilization of the left and right fibrous trigones. This results in the restoration of the normal dynamic behavior of the left ventricular outflow tract with maximal widening of the outflow tract as the result of backward displacement of the subaortic curtain and anterior leaflet of the mitral valve. This technique has been used in 57 consecutive patients who ranged in age between 5 months and 56 years (mean, 15.5 +/- 10.6 years). Gradients across the left ventricular outflow tract were between 45 and 200 mm Hg (mean, 86.7 mm Hg). Additional lesions were present in 10 patients, and 7 patients had had 8 previous operations on the left ventricular outflow tract. At operation, in addition to resection of subaortic stenosis, 3 patients had aortic valvotomy, 2 patients had homograft replacement of the aortic valve, 7 patients had patch closure of a ventricular septal defect, and 1 patient had open mitral valvotomy. RESULTS: There were 2 early deaths and 1 late sudden death during the follow-up period that ranged from 1 month to 25 years (mean, 15. 2 years). One patient experienced the development of endocarditis on the aortic valve 7 years after operation, which was successfully treated by homograft replacement. Postoperative gradients across the left ventricular outflow tract varied from no gradient to 30 mm Hg (mean, 8 mm Hg). There were no instances of recurrence of a gradient across the left ventricular outflow tract. CONCLUSION: It is concluded that mobilization of the left and right fibrous trigones results in durable relief of subaortic stenosis.

Adolescent↗
PubMed1999

Incidence and clinical relevance of coronary calcification detected by electron beam computed tomography in heart transplant recipients.

BACKGROUND: Patients treated by cardiac transplantation who survive beyond one year are at significant risk from fatal coronary artery disease. The development of coronary artery calcification in these patients is discussed and methods available to detect it are reviewed. OBJECTIVES: To assess the clinical importance of coronary artery calcium in heart transplant recipients. METHODS: In a cohort of 102 cardiac transplant recipients, electron beam computed tomography was used to measure calcium in the coronary arterial wall 63 days to 9.1 years (median 4.6 years) after transplantation. The results were compared with angiographic findings and with conventional coronary disease risk factors. The patients were followed for a mean of 2.12 years (1.2-4.02 years) to assess the relationship between these findings and future cardiac events. RESULTS: Forty-one (40.2%) had a stenosis of > 24% in one or more major coronary artery at angiography. Forty-six (45%) had a coronary calcium score > 0. The absence of calcium had a negative predictive value with respect to angiographic disease in any vessels of 87.5%. Logistic regression revealed that dyslipidaemia, systemic hypertension and organ ischaemic time were significant predictors of calcification. At follow-up, both an abnormal coronary angiogram and coronary calcium were found to be the only significant predictors of late events. Multivariate analysis suggested that the detection of coronary calcium did not offer any additional predictive information over that provided by the angiogram itself. CONCLUSION: Electron beam computed tomography is well suited to the assessment of calcium in the coronary arteries of heart transplant recipients, although the mechanisms of this calcification remain poorly understood. Calcium is detected more frequently than would be suggested by studies using intravascular ultrasound. It is associated with the presence of angiographic disease, and with some conventional risk factors for coronary disease. At follow-up the presence of coronary calcium was associated with an adverse clinical outcome, as it is in conventional ischaemic heart disease.

Adult↗
PubMed1999

Differential regulation of DNA synthesis by nitric oxide and hydroxyurea in vascular smooth muscle cells.

We investigated the influence of nitrovasodilators on DNA synthesis in cultured human aortic smooth muscle cells and explored the hypothesis that nitric oxide (NO) is directly involved in mediating the inhibitory effects of hydroxyurea on DNA synthesis. Both NO and hydroxyurea inhibited ongoing DNA synthesis and S phase progression in our cells. Exogenous deoxynucleosides partially reversed this inhibition, suggesting that ribonucleotide reductase is a primary target for both NO and hydroxyurea. Nitrovasodilators inhibited DNA synthesis by releasing NO, as detected by chemiluminescence and as shown by the reversal of DNA synthesis inhibition by NO scavengers. This inhibition appears to occur via a cGMP-independent mechanism. In contrast, hydroxyurea did not produce a detectable NO signal, and NO scavengers had no influence on its inhibition of DNA synthesis, suggesting that NO does not mediate the inhibitory action of hydroxyurea in our system. Furthermore, the action of nitrovasodilators and hydroxyurea on DNA synthesis differed according to redox sensitivity. The redox agents N-acetyl-L-cysteine and ascorbate reversed NO inhibition of DNA synthesis and had no effect on DNA synthesis inhibition caused by hydroxyurea.

Antioxidants↗