Biomedical subjects
Publications and source records attributed to E Pereira.
Retrospective studies, based on autopsy findings, indicate that infiltration of the gastrointestinal tract complicates leukemia of all types and may be present from the esophagus to the rectum. This report presents what is believed to be the first reported case of a patient with chronic lymphocytic leukemia with evidence of esophageal, gastric, duodenal bulb, and colonic involvement confirmed by mucosal biopsy at endoscopy.
OBJECTIVES: Limited data have been reported concerning the influence of right ventricular systolic overload on the accuracy of the 2D echocardiographic (echo) determination of left ventricular (LV) ejection fraction (EF). The normal newborn at birth (high pulmonary peak systolic pressure) and just after the fall of pulmonary pressure, represent an in vivo model to study this influence. This study compares the LVEF determined by recommended 2D echocardiographic algorithms with that by 3D echo, in newborns at birth and just after the normal fall of right ventricular systolic pressure. METHODS: 100 echocardiographic studies (50 at 2 to 6 hours after birth--group I; and 50 at 7 to 14 days old--control group) were performed in 82 normal newborns, to determine LVEF by 4 geometric models (cylinder hemiellipsoid; ellipsoid biplane; single plane area length, in 4- and 2-chamber view; biplane method of discs) and visual estimation, using 3D echocardiography as the reference method. RESULTS: In group I, the correlation between 3D echo and cylinder hemiellipsoid was r = 0.62 (SEE = 4.5%); ellipsoid biplane, r = 0.69 (SEE = 4.1%); single plane area length, 4 chambers, r = 0.66 (SEE = 5.1%) and, 2 chambers, r = 0.72 (SEE = 4.0%); biplane method of discs, r = 0.83 (SEE = 3.6%), and, visual estimation, r = 0.78 (SEE = 3.5%). In the control group, the correlation between 3D echo and cylinder hemiellipsoid was r = 0.70 (SEE = 3.4%); ellipsoid biplane, r = 0.63 (SEE = 3.4%); single plane area length, 4 chambers, r = 0.79 (SEE = 3.5%) and, 2 chambers, r = 0.76 (SEE = 4.1%); biplane method of discs, r = 0.90 (SEE = 2.3%), and, visual estimation, r = 0.64 (SEE = 3.9%). IN CONCLUSION: These data suggest that the biplane method of discs and single plane area length using 2-chamber view allows a more accurate LVEF determination when significant right ventricular pressure overload is present.
Cells that overexpress the mdr 1 gene have decreased steady-state accumulation and increased efflux of many anticancer drugs including anthracyclines and vinca alkaloids. The mechanism(s) of P-glycoprotein-mediated efflux of drugs is (are) still poorly understood. In an attempt to identify mechanism(s) by which multidrug resistance can be circumvented, the cellular accumulation has been examined of pirarubicin, doxorubicin and idarubicin alone and in conjunction with four vinca alkaloid derivatives--vinblastine, navelbine, vindesine and vincristine. The present study was performed using a spectrofluorometric method with which it is possible to follow continuously the uptake and release of fluorescent molecules by living cells, as the incubation of the cells with the drug proceeds. Erythroleukemia K562 cell lines were used. It has been shown that the P-glycoprotein-mediated efflux of these three anthracyclines can be inhibited by vinca alkaloids derivatives. At pH 7.2, 50% of the P-glycoprotein-mediated efflux of daunorubicin and idarubicin was inhibited by about 40 +/- 10 microM vinblastine and that of pirarubicin by 10 +/- 2 microM vinblastine. The vinblastine concentration required to inhibit 50% of the active efflux of these anthracyclines did not depend on the anthracycline concentrations used, indicating that the inhibition was non competitive. The ability of navelbine, vincristine and vindesine to inhibit the active efflux of pirarubicin was also checked; 15 +/- 3 microM navelbine are required to inhibit 50% of the active efflux but at concentrations lower than 100 microM, neither vincristine nor vindesine were able to inhibit this efflux, indicating that the vinca alkaloids compounds which are the most efficient are the most lipophilic. For the four vinca alkaloids, the concentration required to inhibit 50% of the efflux was lower as the pH was higher. A detailed kinetics analysis of the P-glycoprotein-mediated efflux of pirarubicin in the presence of vinblastine indicates a non competitive inhibition with K(I) = 12 +/- 2 microM.
Interleukin-5 (IL-5) is a potential candidate gene in the pathogenesis of asthma, as it is the main cytokine controlling eosinophil activity and eosinophils are pivotal in the development of airway inflammation. Mutation detection studies were performed on the IL-5 gene and the alpha-chain of its receptor in 30 asthmatic and 30 nonasthmatic subjects. Single-strand conformational polymorphism (SSCP) and heteroduplex analysis (HA) did not reveal any change from the reported normal sequence in all 4 exons of IL-5 as well as the promoter and 3'-untranslated regions of the gene. No SSCP variations were seen within the complete coding sequence of the IL-5 receptor alpha-chain. Mutations of the IL-5 gene coding region, its promoter and receptor are unlikely to be common causes of an inherited predisposition to asthma.
OBJECTIVE: The aim of this study was to characterize changes in left ventricular morphology and function by conventional echocardiography in a pediatric population after renal transplantation (RT). MATERIAL AND METHODS: This study includes 21 children, 11 female and 10 male, aged 11.8 +/-2.6 years at the time of renal transplantation. Eleven were on regular hemodialysis treatment and two on continuous peritoneal dialysis for 31.8 +/- 31.6 months; eight were transplanted without prior dialysis. Eight children were hypertensive before RT and nine (seven de novo) after RT. The patients were analysed in a prospective follow-up study with echocardiography immediately before and 30.2 +/- 15 months after successful renal transplantation. We measured the following echocardiographic parameters: Left ventricular end diastolic (LVED) and end systolic diameter (LVES), left atrial dimension (LAD), septal thickness (IVST), posterior wall thickness (PWT), shortening fraction (SF) and left ventricular index mass (LVIM). The paired Student's test, Fisher exact test and Pearson's correlation were used for statistical analysis. We analyzed the echocardiographic changes in the total group and separately in the subgroups with and without prior hemodialysis, as well as the influence of the duration of dialysis, anemia and hypertension. RESULTS: 1. After renal transplantation we found a decrease in the LVED LVES, LAD, IVST and PWT measurements (p < 0.05). There was a negligible increase in SF. The LVIM decreased from 139 g/m2 to 104 g/m2, representing a 21% reduction of the initial value, but this reduction was not of statistically significant. 2. The findings were similar in the hemodialysis group-LVIM decreased from 167.6 g/m2 to 94.9 g/m2, representing a 35% reduction in the initial value. 3. In the non dialysis group LVED, LVES, LAD and SVT decreased and LVIM showed a minor increase. There was a negligible increase in SF. 4. We found an increased LVIM in children with prior hemodialysis before RT, especially if dialysis lasted for more than two years. 5. Amelioration of hematocrit correlated with reduction of LVIM. 6. Regression of LV hypertrophy after RT was not dependent on blood pressure levels. CONCLUSIONS: Renal transplantation resulted in a tendency towards normalization of the echocardiographic parameters analysed: Contractility, as assessed by shortening fraction, was normal in this population. Although cardiac hypertrophy and dilation is reversible after RT, it would seem that children may benefit from an earlier transplantation.
Two-dimensional (2D) echocardiographic visual estimation of left ventricular (LV) ejection fraction (EF) in patients with acquired heart disease yields results that are comparable to those obtained by recommended algorithms. However, there is no information concerning its accuracy in congenital heart disease. This study compares applicability, accuracy, and reproducibility of LVEF by visual estimation with that by currently used algorithms (cylinder hemiellipsoid, ellipsoid biplane, and biplane method of disks) in 92 consecutive patients with congenital heart disease but unrepaired complete atrioventricular septal defect, univentricular heart, and hypoplastic left ventricle, using 3D echocardiography as the reference method. Visual estimation of LVEF could be applied in all cases. Because of technically inadequate 2D echocardiographic images for volume measurement, analysis for comparison could be performed in 71 patients (77%), aged 1 day to 47 years. The correlation between 3D echocardiographic and visual estimation was 0.91 (SEE 3.3%), cylinder hemiellipsoid, 0.86 (SEE 3.9%), ellipsoid biplane 0.87 (SEE 3.9%), and biplane method of disks 0.93 (SEE 3.2%). Intraobserver variability was similar for all 2D echo methods. Interobserver variability was greater for visual estimation. In conclusion, visual estimation of LVEF is applicable to most patients with congenital heart disease, yielding results that are comparable to those obtained by currently used 2D echocardiographic algorithms.
BACKGROUND: Reduced levels of interferon gamma (IFNgamma) mRNA and protein have been detected in the bronchoalveolar lavage fluid of atopic asthmatics. IFNgamma is secreted by TH1 cells while IL-4 and IL-5 are secreted by TH2 cells and an imbalance in the TH1/TH2 response may be responsible for atopic asthma. The gene for IFNgamma is located on chromosome 12; a region of the genome which has been shown in linkage studies to be associated with asthma. OBJECTIVE: To determine if there are any mutations present in the coding exons and 5' flanking region of the IFNgamma gene in atopic asthmatic subjects compared with controls to explain the lower levels of this cytokine as an inherited, rather than acquired, factor in the asthmatic subjects. METHODS: The four exons and 5' flanking region of the IFNgamma gene were amplified by polymerase chain reaction (PCR) from genomic DNA of 265 individuals from a Western Australian and a Venezuelan population. The PCR products were examined by single strand conformational polymorphism and heteroduplex analyses to see if there were any changes in the DNA migration patterns which would suggest the presence of a sequence variation. RESULTS: The four exons and the 5' flanking region of the IFNgamma gene were amplified from 265 individuals from two populations. Single strand conformational polymorphism and heteroduplex analyses did not reveal any mutations in the regions examined. CONCLUSION: The gene for IFNgamma appears to be highly conserved as no sequence variations were detected in 265 individuals. These results suggest that mutations of the IFNgamma gene are unlikely to be a significant cause of an inherited asthma diathesis.
Fifty episodes of oropharyngeal candidiasis in HIV-infected patients were analyzed prospectively in order to evaluate the clinical response to fluconazole. The minimum inhibitory concentrations (MICs) of fluconazole for the Candida strains isolated from the pharynx were correlated with the clinical response. Treatment with fluconazole (100 mg/day) was successful in 86% of the cases. A good clinical outcome followed in 97% of the cases when a strain sensitive to fluconazole was isolated. This figure fell to 22% when the strain was resistant to fluconazole (p < 0.001). The rate of post-treatment colonization was high (87%), and selection of non-albicans Candida species occurred in 23% of the cases. In conclusion, fluconazole treatment for oropharyngeal candidiasis of HIV-infected patients was useful in most cases, but less sensitive non-albicans species can be selected. Most treatment failures were associated with increased MICs of fluconazole for the strains isolated before treatment; therefore, susceptibility testing is recommended as an aid in clinical decision-making for the use of the azole group of drugs.
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PURPOSE: To determine early and late results of surgical myocardial revascularization (SMR) in young patients. METHODS: We studied retrospectively 73 patients aging less than 40 years and submitted to SMR between 1975 and 1989. The method used was patient card review and thelephone contact with the patient or his physician. RESULTS: Follow-up was obtained in all cases in a period of 2 to 185 (59.9 +/- 41.0) months. Of the coronary risk factors smoking was the most frequent. One vessel coronary artery disease was observed in 16 (21.9%) patients, 2 and 3 vessel coronary artery disease in 26 (35.6%) and 32 (43.8%) patients respectively. SMR was considered complete in 68 (93.2%) patients. An associated procedure was performed on 10 cases: Left ventricular aneurysm repair in 9 (12.3%) and mitral valve replacement in one (1.4%). Perioperative myocardial infarction occurred in 7 (9.5%) patients and one of them died (operative mortality: 1.4%). During follow-up, 6 (8.3%) patients died with an actuarial survival rate of 89.1% at 15 years. An event free survival rate of 68.3% was observed at 10 years. From 66 survivors, 53 (80.3%) were asymptomatic at late follow-up and 48 (72.7%) patients returned to work. CONCLUSION: Surgical myocardial revascularization in young patients associated with medical treatment, has good early and late results with a high percentage of patients asymptomatic and reemployed at a late follow-up.
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The basic distinguishing feature of multidrug resistant (MDR) cells is a decrease in steady-state drug levels as compared to drug-sensitive controls. It is well-known that verapamil increases the sensitivity of MDR cells to drugs, thus reverting drug resistance. A limiting factor for its clinical use is the pronounced cardiovascular effects of the calcium channel antagonist which occur at the high plasma concentrations required to block P-glycoprotein transport efficiently. From a clinical point of view, it is important to find verapamil derivatives with low calcium channel blocking activity and high reverting activity. This was the aim of the present study. In this context we have investigated the ability of 20 verapamil analogues with restricted molecular flexibility to increase cellular accumulation of anticancer drugs and overcome resistance, and their inotropic, chronotropic, and slow calcium channel antagonistic activity. In this study an anthracycline derivative 4'-O-tetrahydropyranyl adriamycin, and an erythroleukaemia K562 cell line were used. Three of the 20 derivatives checked were completely devoid of calcium channel blocking activity while exhibiting MDR reverting ability comparable to that of verapamil. These derivatives could be useful for the treatment of MDR in cancer patients and for the design and development of other verapamil derivatives.
The molecular basis of familial hypercholesterolemia (FH) in three families of Spanish descent from La Habana was investigated by the candidate gene approach. The Arg3500Gln mutation of apolipoprotein B-100 was not found. Identification of low density lipoprotein receptor (LDLR) gene haplotypes segregating with FH guided the characterisation of three point mutations by automated sequencing. One, a Val408-->Met missense mutation, a founder mutation in Afrikaner FH patients, was recurrent, being associated with a distinct DNA haplotype. The other two, Glu256-->Lys and Val776-->Met missense mutations, were novel and modified highly conserved residues. These mutations were absent in normolipidemic subjects and were associated in heterozygous carriers with twice the cholesterol levels observed in non-carriers. Noticeably, cardiovascular complications were rarely observed in older heterozygotes, even in those with the Afrikaner FH-2 mutation. These findings confirm the molecular heterogeneity of LDLR gene mutations causing FH and the variability of their expression across different populations.
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PURPOSE: To evaluate in the late post-operative period (PO) the chronotropic response to exercise of patients submitted to orthotopic cardiac transplantation (CT) and the implant of a cardiac pacemaker (PM). METHODS: A rate response ventricular PM (VVI+R) which uses minute ventilation (MV) as a sensor was implanted in five patients in the early PO of CT due to chronotropic incompetence. The patients were 31 to 64 years old and the indication to implant of PM was low ventricular escape rhythm following atrial taquicardia/bradycardia (one case) or sinus bradycardia (4 cases). The study was performed by means of paired exercise tests using Naughton protocol in order to compare the heart rate in VVI (prefixed heart rate) and VVIR+MV (rate response) mode. The duration of the exercise was compared between the two modes of stimulation. RESULTS: In VVI mode the heart rate was significantly lower than in VVIR+MV mode for comparable periods of exercise (101 +/- 12 ppm vs 132 +/- 4 ppm; p < 0.05); in VVIR+MV mode the patients had a prolonged time of exercise as compared to VVI mode (15 +/- 7 min vs 12 +/- 7 min; NS). CONCLUSION: The MV rate response PM provided patients with satisfactory heart during exercise and may be an adequate option to patients submitted to CT who present chronotropic incompetence.
Previous studies have indicated that there may be uncleavable TaqI sites (TCGA) within the mouse myogenic gene, Myo-D1. Fragments of DNA bearing most of the presumed insensitive TaqI sites have been reproduced using PCR. The presence of each of the originally uncleavable TaqI sites has been confirmed and each TaqI site has been shown to be sensitive to TaqI hydrolysis in PCR-synthesized genomic DNA. Since TaqI is inhibited by methylation of the adenine residue within its recognition sequence (but not by cytosine methylation), it is suggested that specific adenine bases are methylated in the coding region of Myo-DI and maintained throughout cell division. The same TaqI recognition sequences are insensitive to digestion in genomic DNA isolated from various mouse tissues including fetus, regenerating skeletal muscle and a myogenic cell line, all of which express Myo-D1. Thus, adenine methylation is not a modification of DNA following gametic fusion nor does it appear to play a major role in regulation of Myo-D1 expression.
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The decrease of the intracellular concentration of drug in resistant cells compared to sensitive cells is, in most cases, correlated with the presence, in the membrane of resistant cells, of a 170-kDa P-glycoprotein responsible for an active efflux of the drug. In an attempt to identify mechanism(s) by which multidrug resistance can be circumvented, we have examined the cellular accumulation of 4'-O-tetrahydropyranyl-adriamycin, alone and in conjunction with various ionophores on the one hand and with cyclosporin A on the other hand. The present study was performed using a spectrofluorometric method with which it is possible to follow continuously the uptake and release of fluorescent molecules by living cells, as the incubation of the cells with the drug proceeds. Erythroleukemia K562 cell lines were used. Using experimental conditions in which these ionophores were unable to modify either the intracellular pH, or the transmembrane potential, or to induce an intracellular ATP depletion, we have shown that mobile ionophores as well as cyclosporin inhibit the P-glycoprotein-mediated efflux of 4'-O-tetrahydropyranyl-adriamycin in K562 resistant cells, whereas gramicidin, a channel-forming ionophore, does not. The concentration that must be used to inhibit 50% of the efflux was 0.7 microM for valinomycin, 0.4 microM for nonactin, 0.2 microM for nigericin, 1.1 microM for monensin, 0.4 microM for lasalocid, 1.2 microM for calcimycin and 0.4 microM for cyclosporin. Due to the high toxicity of the ionophores, the observation that they increased 4'-O-tetrahydropyranyl-adriamycin accumulation in the multidrug-resistant cells is not correlated with an effect of these compounds on drug resistance. However, the correlation exists in the case of cyclosporin. From our data showing that lipophilic neutral complexes, formed between carboxylic ionophores and metal ions, are both able to inhibit the P-glycoprotein-mediated efflux of anthracycline we can infer that the lipophilicity but not the cationic charge is an important physical property.