Biomedical subjects
Publications and source records attributed to R P Martin.
TEE played a significant role in the management of 2 patients by defining the extent of cardiac invasion. We believe TEE would be helpful in patients presenting with thoracic tumors believed to be encroaching on cardiac structures, where consideration is being given to surgical resection of the tumor.
Cytoplasmic tRNA(Lys)CUU is the only nuclear-encoded tRNA of Saccharomyces cerevisiae found to be associated with mitochondria. Selective import of this tRNA into isolated organelles requires cytoplasmic factors. Here we identify two of these factors as the cytoplasmic and mitochondrial lysyl-tRNA synthetases. The cytoplasmic enzyme is obligatory for in vitro import of the deacylated, but not of the aminoacylated tRNA. We thus infer that it is needed for aminoacylation of the tRNA, which is a prerequisite for its import. The mitochondrial synthetase, which cannot aminoacylate tRN(Lys)CUU, is required for import of both aminoacylated and deacylated forms. Its depletion leads to a total arrest of tRNA import, in vitro and in vivo. The mitochondrial lysyl-tRNA synthetase is able to form specific and stable RNP complexes with the amino-acylated tRNA. Furthermore, an N-terminal truncated form of the synthetase which cannot be targeted into mitochondria is unable to direct the import of the tRNA. We therefore hypothesize that the cytosolic precursor form of the mitochondrial synthetase has a carrier function for translocation of the tRNA across the mitochondrial membranes. However, cooperation of the two synthetases is not sufficient to direct tRNA import, suggesting the need of additional factor(s).
In Saccharomyces cerevisiae, one of the two cytoplasmic lysine-tRNA isoacceptors, tRNA(LysCUU), is the only nuclear-coded tRNA species to be mitochondrially-imported. Using an in vitro assay of tRNA import, we have studied if the mitochondrial protein translocation machinery is also involved in the mitochondrial targeting of this tRNA. As for protein import, tRNA import also requires the integrity of proteins exposed onto the mitochondrial outer membrane and is dependent upon energy and membrane eletrochemical potential. Furthermore, partial ATP-depletion of the import system leads to stabilization of a translocation intermediate containing the tRNA. In this case, the import of the tRNA can be completed after addition of a new source of energy, even without restoration of the membrane electrochemical potential and without further addition of cytoplasmic proteins. Outer and inner mitochondrial membrane receptors shown to participate in translocation of mitochondrial pre-proteins (MOM19 and MPI1/MIM44, respectively) are also important for import of the tRNA, in vitro as well as in vivo. In contrast, the outer membrane receptor MOM72 is dispensable for the import. Taken together, these results demonstrate that a functional mitochondrial protein translocation apparatus is required for the mitochondrial import of the yeast tRNA(LysCUU).
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Cryopreserved aortic allografts were used for aortic valve replacement in 80 patients between 1986 and 1994 (infracoronary in 46 and complete root replacement in 34). Hospital mortality was 6.3% (5/80) with all deaths occurring in the infracoronary group. Three of five deaths were in patients with endocarditis and valve ring abscess. Left ventricular-aortic mean pressure gradients across the allograft valves were significantly lower for root replacement patients (mean, 9.0 +/- 6.9 mm Hg versus 18.1 +/- 8.7 mm Hg for infracoronary patients) (p = 0.0001). No patient having root allograft replacement had early echocardiographic aortic insufficiency greater than grade 1 versus 28% of those having infracoronary implantations. Late aortic insufficiency of grade 2 or greater was seen in 46% of patients having infracoronary implantation versus 17% of patients having root implantation. Nine patients had explantation of an aortic allograft (eight infracoronary and one root). Reasons for explantation were as follows: endocarditis (three infracoronary, one root), technical (three infracoronary), undiagnosed idiopathic hypertrophic subaortic stenosis (1 patient), and prolapsing infracoronary leaflet (1 patient). Actuarial freedom from grade 3 and 4 aortic insufficiency or explantation was 77% at 7 years for infracoronary implantations. We conclude that the infracoronary aortic allograft has an unacceptable frequency of late insufficiency and its use in this position should be abandoned. The substantial incidence of late endocarditis in the infracoronary (free-hand) aortic allograft was surprising.(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVES: To determine normal values for variables of left ventricular diastolic function in children measured by Doppler echocardiography and their relations to body surface area (BSA). BACKGROUND: There is increasing interest in echocardiographic assessment of left ventricular diastolic function in children but normal data for children are limited. METHODS: Assessment of left ventricular diastolic function was performed in 130 normal participants (aged from 2.4 months to 19.6 years) from their transmitral flow patterns obtained by pulsed wave Doppler echocardiography. RESULTS: Centile charts for commonly used left ventricular diastolic functional variables plotted against BSA are presented. Peak early diastolic filling velocity and atrial phase filling velocity integral were independent of BSA. Although most other filling indices showed strong relations with BSA, some had more curvilinear relations with BSA due to additional interactions with heart rate. The increase in left ventricular filling with growth is largely achieved by an increase in the early "passive" contribution to filling. The slower heart rates of older children are associated with lower atrial phase filling velocities but increased filling time, so the atrial contribution to filling remains relatively constant. CONCLUSIONS: Normal values of many left ventricular diastolic function variables change with growth in children and cannot be extrapolated from adult data. The data presented are suitable for use in size matched matched comparative studies of left ventricular function in children. Careful standardisation of echocardiographic protocols is necessary to ensure the validity of any comparisons.
OBJECTIVES: To examine left ventricular (LV) diastolic function in patients previously treated with anthracycline drugs for childhood malignancy. To consider clinical relevance, relations with systolic dysfunction, and the pathophysiology of anthracycline cardiotoxicity. DESIGN: Cross sectional echocardiographic study of LV function. SETTING: Supraregional centre for paediatric cardiology, principal centre for the treatment of childhood malignancy in southwest England. PATIENTS: 226 of 236 patients surviving between 6.5 months and 17 (median 5.3) years from initial anthracycline treatment for childhood malignancy attended for clinical and echocardiographic examination. Cumulative anthracycline doses were between 50 and 750 (median 300) mg/m2. 22 patients had also received cardiac irradiation. METHODS: Detailed assessment of transmitral diastolic pulsed wave Doppler flow patterns along with LV dimensions and systolic function measured by M mode echocardiography. MAIN OUTCOME MEASURES: Peak early (E) and atrial (A) phase filling velocities and EA ratio, time and acceleration and deceleration to and from peak E velocity, velocity integrals and ratio, isovolumic relaxation time (IVRT), and heart rate were measured. Results were examined in relation to LV cavity and posterior wall dimensions and shortening fraction (SF), and compared with paired control data matched for body surface area. RESULTS: Eleven (5%) patients had abnormal effort tolerance. Fifty one (23%) had SF < 30% and SF was inversely correlated with cumulative dose and time from treatment. The relative risk of symptomatic cardiac failure was greatly increased by prior irradiation; > 60% of irradiated patients who received > 400 mg/m2 of anthracycline were symptomatic. Early diastolic filling was relatively normal or enhanced at low anthracycline doses or when SF was preserved, with a shorter IVRT and increased atrial phase filling. Early filling was reduced at higher doses or with reduced SF, with longer IVRT and a further increase in atrial phase filling. A more "restrictive" pattern of diastolic filling (with high E and low A velocities) was seen in some patients, particularly after cardiac irradiation. CONCLUSIONS: Significant abnormalities of diastolic function are associated with anthracycline induced cardiac damage. These are not linearly related to anthracycline dose but appear to reflect the underlying myocardial pathophysiology associated with anthracycline toxicity, which is not demonstrated by the standard M mode echocardiogram. Although the overall clinical significance of such diastolic dysfunction is uncertain, some individual abnormalities may have significant management and therapeutic implications.
We report here the sequence of RPK1 (for Regulatory cell Proliferation Kinase), a new Saccharomyces cerevisiae gene coding for a protein with sequence similarities to serine/threonine protein kinases. The protein sequence of 764 amino acids includes an amino-terminal domain (residues 1-410), which may be involved in regulation of the kinase domain (residues 411-764). The catalytic domain of Rpk1 is not closely related to other known yeast protein kinases but exhibits strong homology to a newly discovered group of mammalian kinases (PYT, TTK, esk) with serine/threonine/tyrosine kinase activity. Null alleles of RPK1 are lethal and thus this gene belongs to the small group of yeast protein kinase genes that are essential for cell growth. In addition, eliminating the expression of RPK1 gives rise to the accumulation of non-viable cells with less than a 1 N DNA content suggesting that cells proceed into mitosis without completion of DNA synthesis. Therefore, the Rpk1 kinase may function in a checkpoint control which couples DNA replication to mitosis. The level of the RPK1 transcript is extremely low and constant throughout the mitotic cycle. However it is regulated during cellular differentiation, being decreased in alpha-factor-treated a cells and increased late in meiosis in a/alpha diploids. Taken together, our results suggest that Rpk1 is involved in a pathway that coordinates cell proliferation and differentiation.
OBJECTIVES: We sought to determine the incidence of late perfusion defects attributable to coronary artery mobilization in patients undergoing anatomic correction for complete transposition of the great arteries. BACKGROUND: Anatomic correction (arterial switch procedure) is currently the surgical treatment of choice for complete transposition. From its conception, there has been concern about the impact on myocardial perfusion of the coronary artery mobilization and reimplantation involved in the correction. Previous studies have demonstrated myocardial perfusion defects in patients after correction, although a causal relation between coronary mobilization, and perfusion abnormality has not been established. METHODS: In a case-comparison study designed to test this hypothesis, 29 children underwent imaging with technetium-99m 2-methoxy isobutyl isonitrile (technetium-99m mibi). Ten had undergone anatomic correction (arterial switch group; interval from operation 6.9 +/- 1.42 years [range 4.9 to 9.1]); 9 had required noncoronary open heart surgery for other cardiac lesions (post-bypass group; interval from operation 5.6 +/- 3.6 years [range 1.0 to 13.25]); and 10 had had no surgical procedure (control group). The latter group comprised children with atrial or ventricular septal defects who required a radionuclide study for shunt calculation. Planar studies were performed in all 29 children, and additional tomographic acquisition was achieved in 25. To assess reversibility of perfusion defects both an exercise and a rest planar study were performed in the arterial switch group. RESULTS: Perfusion abnormalities were observed in seven of the nine children in the postbypass group and in all 10 children in the arterial switch group. The frequency of perfusion defects in these two groups was similar, with at least 25% of the tomographic segments reported being abnormal. The control group had significantly fewer defects than the other two groups (p = 0.02), with only 8% of the tomographic segments judged to be abnormal. In all except one patient in the arterial switch group, the segments reported as abnormal on the planar exercise study were either abnormal or equivocal on the rest study, indicating a fixed abnormality. CONCLUSIONS: Although the precise etiology of these perfusion abnormalities cannot be defined from this study, these data suggest that their origin is related more to the insult of open heart surgery itself than to the coronary manipulation involved in the arterial switch procedure. The functional importance requires further study.
Much of the research and thinking in the area of childhood temperament has been guided by the structural and measurement model of Thomas, Chess, and colleagues. Recently, researchers have called into question this structural conception and have explored the factor structure of the instruments based on the Thomas and Chess model. A review of the literature indicates that there are few studies at any one age level, and that much of the research is limited by small samples. The results of a large sample factor analysis of parent and teacher ratings of preschool children are reported. A five-factor solution was judged most appropriate for parent ratings, and a three-factor solution seemed most appropriate for teacher ratings. Relations of these factors to the Big Five personality factors found in adult personality research are discussed.
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OBJECTIVE: A pilot study to assess the efficacy of ICRF187 as a protective agent against the cardiotoxic effects of anthracycline drugs used to treat childhood malignancies. DESIGN: A study of cardiac function in children treated receiving ICRF187 ((s)-(+)-1,2 bis (3,5-dioxopiperazenyl) propane) in addition to anthracycline therapy compared with contemporary controls selected retrospectively on the basis of anthracycline dose matching. PATIENTS: Five children in whom recurrence of malignant disease was re-treated with chemotherapy containing anthracycline drugs and additional ICRF187 (supplied on a compassionate-use basis) (cumulative anthracycline doses 550-1650 mg/m2). Five more children with recurrence of malignant disease were re-treated to similar cumulative anthracycline doses (600-1150 mg/m2) without ICRF187. METHODS: Cardiac function was assessed clinically and echocardiographically throughout treatment. Clinical and echocardiographic state were compared before treatment and after completion of therapy within and between groups treated with and without ICRF187. RESULTS: Two patients treated without ICRF187 developed symptomatic congestive cardiac failure from which one died. Another developed considerable but as yet asymptomatic left ventricular dysfunction. No patient receiving additional ICRF187 developed cardiac failure or left ventricular dysfunction. There were no significant differences in cumulative anthracycline dose, dose increase, type of anthracycline used, survival rate, or length of survival between groups. Left ventricular shortening fraction fell by a mean of 1.0% in patients receiving ICRF187 and by a mean of 11% in the patients treated without it (p = 0.04). CONCLUSIONS: ICRF187 seems to have provided highly effective cardioprotection to this small group of children with end-stage malignancy. Severe cardiotoxicity was seen in a similar group treated with comparable anthracycline doses but without ICRF187.
OBJECTIVE: To assess the results of balloon dilatation of the aortic valve as first line treatment for infants presenting in the first two months of life with cardiac failure caused by severe aortic stenosis. DESIGN: A prospective study of all such infants presenting to a single centre over a three year period. PATIENTS: Of 14 consecutive infants aged < 2 months presenting with heart failure due to severe stenosis of the aortic valve, 12 underwent balloon dilatation of the valve. Two infants with hypoplastic left heart syndrome were excluded. Six patients had other significant cardiac malformations, nine had endocardial fibroelastosis. Four infants were moribund at presentation. INTERVENTIONS: Balloon dilatation was performed through the femoral artery under general anaesthetic, with heparin and antibiotic prophylaxis. Maximum inflated balloon size was selected as equal to or slightly less than the diameter of the aortic valve measured echocardiographically. In two infants balloon dilatation of coexistent severe coarctation was performed at the same time. RESULTS: Dilatation was achieved in all cases. Early survival rate (up to one month) was 75%; 50% survive up to three years. The two deaths occurring < 24 hours after dilatation probably related to the infants' poor condition at presentation and the presence of significant left ventricular hypoplasia. The other early death was due to severe mitral regurgitation from papillary muscle dysfunction. All later deaths were related to associated malformations. The difference in left ventricular size (diameter and length) measured echocardiographically at presentation between survivors and those that died is significant (p < or = 0.002). 83% of deaths occurred in infants with associated malformations. Cusp perforation occurred in one infant, which may have contributed to this patient's death. Left ventricular perforation and cardiac tamponade were treated successfully by prompt pericardiocentesis in another. CONCLUSIONS: Balloon dilatation of the aortic valve is an acceptable first line treatment for neonates with severe symptomatic stenosis of the aortic valve. Outcome depends principally on left ventricular size and on the presence, severity, and timing of treatment of associated malformations. Severe endocardial fibroelastosis was not a risk factor for early death but may have implications for long term survival. The survival rate for this high risk group might be improved by a stratified approach where patients with adequate left ventricular size have balloon dilatation whereas those with severe ventricular hypoplasia are managed like patients with the hypoplastic left heart syndrome.
OBJECTIVES: The objective of this study was to determine whether guided three-dimensional echocardiography could improve the reproducibility of left atrial and left ventricular anteroposterior measurements over that of standard unguided two-dimensional echocardiography. BACKGROUND: Although these measurements are standard indexes for evaluating chamber size, their use is limited by significant interobserver variability largely due to variable image plane positioning. To improve measurement accuracy and reproducibility, we have developed a three-dimensional echocardiograph that displays the line of intersection of the real-time image with a previously saved orthogonal reference image. This display shows the relation of the real-time image to anatomic landmarks in its third, nonvisualized dimension and may be used to guide image positioning. METHODS: Three pairs of operators independently performed unguided two-dimensional and guided three-dimensional examinations on three groups of 10 patients each. The left atrium was measured in a plane through the inferior surface of the aortic cusps and the left ventricle in a plane perpendicular to its long axis 1 cm below the mitral leaflet tips. Interobserver variability of these measurements on unguided parasternal long-axis images and on guided short-axis images was assessed. RESULTS: The standard unguided two-dimensional examination was associated with an interobserver variability of 14.6% and 9.1% for atrial and ventricular measurements, respectively. Guided three-dimensional echocardiography significantly reduced interobserver variability to 5.0% and 3.1%, respectively, for the same measurements (p < 0.005 by McNemar's test). CONCLUSIONS: Significant interobserver variability occurs with standard unguided two-dimensional echocardiographic measurement of left atrial and left ventricular dimensions. Guided three-dimensional echocardiography achieves a nearly threefold improvement of reproducibility of these measurements and provides the basis for improved serial evaluation and comparison of atrial and ventricular size by different operators.
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Satisfactory function of the arteriovenous fistula (AVF) is essential for adequate haemodialysis in patients with chronic renal failure. Existing methods to assess AVF function are imprecise (eg, clinical examination) or invasive (eg, angiography). We assessed the value of colour flow-doppler ultrasound (CFDU) in the investigation of clinically suspected AVF dysfunction. 51 patients with suspected impairment of AVF function were studied by CFDU, and 28 also underwent angiography. The findings were compared with the reference standard of the findings at reoperation. CFDU showed AVF stenoses in 18 patients, which were all confirmed at reoperation; the results of angiography in 13 of these 18 patients showed complete agreement with the findings of CFDU and surgery. CFDU showed partial or complete AVF thrombosis in 33 patients, confirmed in all patients at reoperation; 15 patients also underwent angiography, and thrombi were not found in 6 (in 4 because of technical failure). 7 patients had aneurysms on CFDU that were confirmed by surgery in all patients and by angiography in 2 of the 3 patients studied. CFDU enables reliable non-invasive assessment of AVF morphology and function and may become the procedure of choice for AVF assessment in patients with suspected AVF abnormalities.
Actin, a major cytoskeletal component of all eukaryotic cells, is one of the most highly conserved proteins. It is involved in various cellular processes such as motility, cytoplasmic streaming, chromosome segregation and cytokinesis. The actin from the yeast Saccharomyces cerevisiae, encoded by the essential ACT1 gene, is 89% identical to mouse cytoplasmic actin and is involved in the organization and polarized growth of the cell surface. We report here the characterization of ACT2, a previously undescribed yeast split gene encoding a putative protein (391 amino acids, relative molecular mass (Mr) 44,073) that is 47% identical to yeast actin. The requirement of the ACT2 gene for vegetative growth of yeast cells and the existence of related genes in other eukaryotes indicate an important and conserved role for these actin-like proteins. Superimposition of the Act2 polypeptide onto the three-dimensional structure of known actins reveals that most of the divergence occurred in loops involved in actin polymerization, DNase I and myosin binding, leaving the core domain mainly unaffected. To our knowledge, the Act2 protein from S. cerevisiae is the first highly divergent actin molecule described. Structural and physiological data suggest that the Act2 protein might have an important role in cytoskeletal reorganization during the cell cycle.