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R Guerra

Publications and source records attributed to R Guerra.

At least 37 records · Page 2Linked to original sources
PubMed1998

Statistically robust approaches for sib-pair linkage analysis.

Many traits that distinguish one individual from another, such as height or weight, are clearly heritable and yet vary continuously in populations. Continuous, heritable variation in trait levels presumably reflects the segregation of multiple genes, but elucidation of the genetic architecture of quantitative traits has been limited. Haseman & Elston (1972) developed a genetically robust method (HE) for detecting linkage to quantitative trait loci using sib-pairs. The method is based on a simple linear regression of the squared sib-pairs trait difference on the proportion of alleles shared identical by descent at a marker locus. Linkage is detected by a negative slope which has been traditionally assessed by a standard t-test. Wan, Cohen & Guerra (1997) have shown that the standard t-test is robust to the violations of the stochastic assumptions underlying the test. In practice, however, the standard t-test, based on least-squares regression, is sensitive to outliers. The presence of outliers in the data can lead to false positive and false negative linkage results. Accordingly we have developed and evaluated a statistically robust procedure for the HE approach to linkage. The procedure is based on robust regression. Simulation studies show that this robust procedure has greater power than the standard t-test in the presence of outliers, and has similar power to the standard t-test in the absence of outliers. This robust procedure also shows greater power than rank-based approaches either in the absence or presence of outliers. To illustrate the methods using real data we reanalyse data from two lipoprotein systems that motivated this work.

Adult↗
PubMed1998

Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1.

Turner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.

Adolescent↗
PubMed1998

Ultrastructural localization of gelsolin in lattice corneal dystrophy type I.

In the light of recent studies into lattice corneal dystrophies, with particular reference to gelsolin immunoreactivity, the authors set out to determine the ultrastructural localization of gelsolin molecules in lattice corneal dystrophy type I. Immunoelectron microscopy with a monoclonal antibody against the COOH-terminal of the native gelsolin molecule (clone GS-2C4) was used to compare antigelsolin reactivity in normal and dystrophic corneas. A gelsolin-like protein was observed at the level of the rough endoplasmic reticulum in both epithelial and endothelial cells, together with mild positive staining in stromal keratocytes of normal corneas; increased keratocytic immunoreactivity with positive staining within and/or around corneal amyloid deposits was revealed in dystrophic corneas. Observed intra- and extracellular immunoreactivity suggests that amyloid deposition may induce gelsolin synthesis; this actin-related protein could be involved in the rearrangement of corneal stroma in lattice corneal dystrophy.

Amyloid↗
PubMed1998

The health care reform in Italy: transition or turmoil.

Health care reform in Italy is transforming its centrally planned, vertically integrated National Health Service into a market-oriented system in which public funders contract directly with individual providers. A model is envisaged in which a plurality of public and private care providers compete for contracts with capitated health agencies responsible for assuring uniform levels of services for geographically defined populations. The ultimate goal of the reform is to guarantee universal coverage and secure global spending limits while, at the same time, promoting efficiency in the delivery of care and enhancing responsiveness to consumers. The emphasis upon incentives for the individual provider which will be introduced should, however, be considered against the quest for equity in health care which was the central tenet of the 1978 reform and is yet to be attained. The fragmentation of the National Health Service into many separate, competing delivery units might well damage the ability to plan strategically for addressing the substantial inequities in health status, health care utilization, and health service availability which still exist across the country. Competition between a plurality of providers and fee-for-service payment schemes add additional concerns about unnecessary care and supplier-induced demand. It creates the need for developing rules to make competition manageable and providing sound clinical and financial information that make enforcement possible. The poor record scored in managing the contractual relationships between the LHUs and the strong private health sector suggests that massive investment in promoting managerial skills and developing appropriate clinical and financial information systems are required. Careful experimentation in implementing the reform and continuous monitoring of its impact on the health care system are, therefore, the imperatives of the next two years.

Capitation Fee↗
PubMed1997

A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol.

Genetic factors strongly influence interindividual variation in plasma high density lipoprotein cholesterol (HDL-C) levels, but the specific genetic polymorphisms that confer heritable variation in HDL-C levels have not been identified. In this study we examined the relationship between polymorphism in LIPC, the gene encoding hepatic lipase, and plasma HDL-C concentrations using a sequential approach comprising linkage analysis, DNA sequencing, and association studies. Linkage studies in 1465 American white subjects from 218 nuclear families indicated that allelic variation at, or closely linked to, the hepatic lipase gene accounts for a significant fraction ( approximately 25%) of the variation in plasma HDL-C concentrations. The hepatic lipase gene was then sequenced in selected individuals, and four novel polymorphisms were identified in the 5' flanking region of the gene. These polymorphisms were in complete linkage disequilibrium and thus identified a single novel allele. Association studies indicated that heterozygosity for the rare allele was associated with modestly increased concentrations of plasma HDL-C (41 +/- 11 vs. 37 +/- 10 mg/dl, P < 0.05) and apolipoprotein AI in men (131 +/- 23 vs. 122 +/- 21 mg/dl, P < 0.05) but not in women. Homozygosity for the rare allele was associated with markedly higher plasma HDL-C (63 +/- 3 mg/dl) and apolipoprotein AI (153 +/- 9 mg/dl) concentrations in men. The results of the association study were replicated in a second, independently ascertained sample. Taken together, the results of the linkage and association studies provide strong evidence that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-C levels.

Analysis of Variance↗
PubMed1997

A permutation test for the robust sib-pair linkage method.

The robust sib-pair method introduced by Haseman & Elston (1972) is one of the most widely circulated allele-sharing methods for linkage analysis. The procedure evaluates linkage by significance testing of a regression coefficient and, hence, a standard t-test has traditionally been applied despite known violations of the statistical assumptions underlying the test. We present a permutation based reference distribution for the estimate of the regression coefficient that is motivated by genetic principles rather than by standard regression testing procedures. The permutation test approximates Mendelian co-segregation under the null hypothesis of no linkage, making it a very natural approach. Theory and simulations show that the conventional t-test approximates the permutation test quite well, even when dependent sib pairs are used for analysis. These results thus indirectly address concerns over the t-test. To illustrate the permutation test using real data we applied the procedure to two lipoprotein systems that have been well characterized.

Animals↗
PubMed1997

Extension of the Haseman-Elston method to multiple alleles and multiple loci: theory and practice for candidate genes.

The Haseman & Elston (1972) sibling-pair regression method has been used to detect and estimate the variance contribution to observed values of a quantitative trait by allelic variation in specific candidate genes. The procedure was developed under a model with a single biallelic trait locus. This assumption does not hold for several known systems. In this paper we prove that for candidate gene analysis the Haseman-Elston procedure extends to the case of multiple trait loci, each possibly having more than two alleles. Simulation experiments comparing single-locus to two-locus models show that fitting the extended regression equations maintains nominal significance levels, but the power to detect linkage to trait variation is not improved by including additional loci. These results indicate that the original proposal is statistically robust to violations of the underlying genetic model. Practical issues associated with quantifying the relative variance contribution by individual loci are also discussed. Applications of the extended regression equations to lipoprotein(a) and high density lipoprotein cholesterol are given for illustration.

Alleles↗
PubMed1997

The Apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African Americans.

The distributions of plasma lipoprotein(a), or Lp(a), levels differ significantly among ethnic groups. Individuals of African descent have a two- to threefold higher mean plasma level of Lp(a) than either Caucasians or Orientals. In Caucasians, variation in the plasma Lp(a) levels has been shown to be largely determined by sequence differences at the apo(a) locus, but little is known about either the genetic architecture of plasma Lp(a) levels in Africans or why they have higher levels of plasma Lp(a). In this paper we analyze the plasma Lp(a) levels of 257 sibling pairs from 49 independent African American families. The plasma Lp(a) levels were much more similar in the sibling pairs who inherited both apo(a) alleles identical by descent (IBD) (r = .85) than in those that shared one (r = .48) or no (r = .22) parental apo(a) alleles in common. On the basis of these findings, it was estimated that 78% of the variation in plasma Lp(a) levels in African Americans is attributable to polymorphism at either the apo(a) locus or sequences closely linked to it. Thus, the apo(a) locus is the major determinant of variation in plasma Lp(a) levels in African Americans, as well as in Caucasians. No molecular evidence was found for a common "high-expressing" apo(a) allele in the African Americans. We propose that the higher plasma levels of Lp(a) in Africans are likely due to a yet-to-be-identified trans-acting factor(s) that causes an increase in the rate of secretion of apo(a) or a decrease in its catabolism.

Adolescent↗
PubMed1997

Determinants of plasma platelet-activating factor acetylhydrolase: heritability and relationship to plasma lipoproteins.

Plasma platelet-activating factor acetylhydrolase (PAF-AH) is the enzyme that inactivates PAF (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine). We determined the relative contributions of genetic and environmental factors to variation in plasma PAF-AH activity in 240 individuals from 60 nuclear families. Regression of mean-offspring PAF-AH activity on the mid-parent value indicated that 62% of the variation in plasma PAF-AH activity was heritable. Spousal values were weakly negatively correlated, indicating that familial aggregation of PAF-AH activity is due to genetic rather than to environmental factors. Among normolipidemic individuals, plasma PAF-AH activity was strongly correlated with the plasma concentration of low density lipoprotein cholesterol (LDL-C), and treatment with lovastatin resulted in proportional decreases in plasma PAF-AH activity and LDL-C concentrations. To further elucidate the relationship between PAF-AH and plasma concentrations of LDL, plasma PAF-AH activity was measured in families with well-defined, monogenic disorders of LDL metabolism. Plasma PAF-AH activity cosegregated with plasma LDL-C concentrations in familial hypercholesterolemia, but not in familial hypobetalipoproteinemia. We speculate that the rate of removal of LDL from the circulation may determine the clearance rate of PAF-AH, thereby modulating the activity of PAF-AH in blood.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1996

Identification of viable myocardium by nitrate echocardiography after myocardial infarction: comparison with planar thallium reinjection scintigraphy.

BACKGROUND: The aim of this study was to validate a new diagnostic tool, nitrate echocardiography (NE), for the identification of viable noncontracting myocardium in patients with a history of prior myocardial infarction (MI). Nitroglycerin (NTG) may be useful for this purpose for its peculiar pharmacodynamic action and may represent an option other than dobutamine echocardiography for the detection of hibernating segments in the presence of severely reduced coronary reserve. METHODS: Twenty selected patients (pts) with an old MI were studied with NE and planar thallium scintigraphy with reinjection. NE was performed by administering i.v. NTG starting at 0.4 mcg/kg/minute with equal increments every five minutes up to 2 mcg/kg/minute or to early interruption of the test (decrease of systolic blood pressure > or = 20% or improvement of previously akinetic segments). Left ventricular wall motion was analyzed by dividing the left ventricle (LV) into 16 segments, and a wall motion score index (WMSI) was calculated. Thallium images were obtained at peak exercise, at four hours, and after reinjection. Myocardial viability was defined as an improvement in thallium uptake after reinjection in fixed defects. RESULTS: Basal echo demonstrated 74 akinetic segments; of these 21 (28%, 11 pts) showed improved contractility during NTG infusion at a mean dose of 0.87 +/-0.33 mcg/kg/minute. WMSI decreased from 1.69 +/- 0.29 to 1.46 +/- 0.31 (P = .001). The only hemodynamic response was a drop in systolic blood pressure (136 mmHg to 124; P = .02). Thallium studies showed 29 segments with a four-hour reversible defect and 79 segments with a four-hour fixed defect; of the latter, 14 regions demonstrated improvement in tracer uptake after reinjection (17.7%; 10 pts). Nine pts had a positive echo and thallium study, while 8 showed no improvement either during NE or after thallium reinjection. Two pts had a false-positive nitrate echocardiogram. Therefore, according to an echo/thallium study match, sensitivity, specificity, and accuracy are 90%, 80%, 85%, respectively. CONCLUSION: NE is a reliable and low-cost method for the detection of viable noncontracting myocardium in selected patients with CAD but needs further validation for widespread application.

Aged↗
PubMed1996

Allelic variation in the gene encoding the cholesteryl ester transfer protein is associated with variation in the plasma concentrations of cholesteryl ester transfer protein.

The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from high density lipoproteins (HDL) to triglyceride-rich lipoproteins. Mutations that abolish CETP function are associated with very high levels of HDL cholesterol, but the effect of more common allelic variation at this locus is less clear. In this study, we have measured plasma CETP concentration and plasma HDL cholesterol concentrations in 694 individuals from 106 nuclear families. Robust sibling-pair methods indicated linkage between the CETP locus and inter-individual variation in plasma CETP concentrations. Allelic variation at the CETP locus accounted for 20% of the variation in plasma CETP concentration. No relation between allelic variation at the CETP locus and plasma HDL cholesterol levels was detected. These data indicate that polymorphism in the CETP gene confers variation in plasma CETP concentration. However, this degree of variation in CETP function is not systematically associated with variation in plasma HDL-C concentrations.

Alleles↗
PubMed1995

Improving skills and utilization of community health volunteers in Nepal.

The study analyses the effects of a Nutrition Education Intervention (NEI), specifically designed to reduce vitamin A deficiency, on skills and utilization of Community Health Volunteers (CHVs) in rural Nepal. The intervention, which included preventive and curative activities, was carried out through the existing Primary Health Care (PHC) structure, utilizing CHVs trained by the Ministry of Health and already working in the villages. At the end of two years implementation, the CHVs associated with the NEI showed an improved ability to detect and treat a range of common diseases (diarrhoea, night blindness, malnutrition and acute respiratory infections) as compared with the CHVs not associated with the intervention program. Community utilization of CHVs increased significantly while the use of traditional healers and consultations at private pharmacies decreased. The utilization of health posts and referral to hospitals remained constant. Coverage for all activities carried out by the CHVs was higher among the population within the NEI area. The intervention did not utilize cash incentives. Its operational input consisted mainly of more frequent training, added supervision and increased and regular drug supply. The inclusion of curative activities among the CHVs' responsibilities seems to be a key factor in increasing motivation of volunteers and their acceptance within the community. This study indicated some possible adjustments to improve productivity and utilization of health volunteers in rural communities of Nepal, with a positive return for all PHC activities.

Adult↗
PubMed1995

Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma.

Most of the interindividual variations in plasma levels of lipoprotein(a) [Lp(a)] can be attributed to sequence differences linked to the apolipoprotein(a) [apo(a)] locus. Plasma levels of Lp(a) tend to be inversely related to the number of kringle 4 (K4)-encoding sequences in the apo(a) gene, but there are several exceptions to this general trend. Other aspects of the apo(a) gene, in addition to the number of K4 repeats, affect plasma levels of Lp(a). To identify sequences in the apo(a) gene that contribute to plasma Lp(a) levels, we characterized the relationship between a length polymorphism [(TTTTA)n] located 1.3 kb 5' of the first exon of the apo(a) gene, the number of K4 repeats in the gene, and the plasma levels of Lp(a). There was significant linkage disequilibrium between the number of TTTTA repeats and the number of K4 repeats. All of the apo(a) alleles with 11 TTTTA repeats contained fewer than 24 K4 repeats and were paradoxically associated with low plasma Lp(a) levels (< or = mg/dl). To determine whether this association was due to the effect of the 11 TTTTA copies on apo(a) gene transcription, we measured the ability of fragments containing 11 or eight TTTTA repeats to promote transcription when introduced into cultured human hepatocarcinoma cells. No difference was found in the transcriptional activity of the two fragments. The TTTTA repeat constitutes the first sequence polymorphism at the apo(a) locus, other than the number of K4 repeats, which is associated with plasma concentrations of Lp(a).

Alleles↗
PubMed1995

Sequence microheterogeneity in apolipoprotein(a) gene repeats and the relationship to plasma Lp(a) levels.

Lipoprotein(a) [Lp(a)] is a cholesterol ester-rich atherogenic lipoprotein that is composed of a particle of low density lipoprotein and a large glycoprotein, apolipoprotein(a) [apo(a)]. Apolipoprotein(a) varies in size over a approximately 500 kDa range due to inter-allelic differences in the number of tandemly repeated kringle 4 (K4)-encoding 5.5 kb sequences in the apo(a) gene. Only one of the 10 different types of K4 repeats in the apo(a) gene, the so-called type 2 K4 repeats, vary in number between apo(a) alleles. In this paper, we show that there is microheterogeneity within the sequence of the type 2 K4 repeat. DraIII restriction digestion and genomic blotting revealed that a subset of the type 2 K4-encoding sequences contained a DraIII site (K4-D). The proportion of apo(a) alleles that had at least one K4-D repeat ranged from 25% in Caucasians to 50% in the Chinese. K4-D repeats were clustered at the end(s) of the type 2 K4 tandem array and the number and patterns of the K4-D repeats were in linkage disequilibrium with flanking sequence polymorphisms; these features are remarkably similar to the minisatellite variant repeats (MVRs) found in variable number of tandem repeat sequences (VNTRs). In addition, a DraIII pattern that comprised 9% of the sample was invariably associated with low plasma levels of Lp(a) in Caucasians.

Apolipoproteins↗
PubMed1995

Acute myocardial infarction shortly after a normal exercise stress test. Case reports.

The authors describe 3 cases of AMI occurring shortly after a negative bicycle ergometer stress test. These cases represent an unfortunate but extremely rare complication of a relatively safe diagnostic procedure. The authors also focus on the pathogenesis of the ischemic event, which may be attributed either to intraplaque hemorrhage or to platelet aggregation, both exercise-induced. The prevalence of AMI in this paper (0.06%) is similar to the data described in literature.

Adult↗
PubMed1995

Rapid surveys in support of district health information systems: an experience from Uganda.

The role of rapid health assessment in generating data other than routine reporting for a multi-element primary health care information system is presented. Rapid surveys, based on the adaptation of the WHO/EPI cluster survey methodology, may generate reliable and valid results useful for the support of a managerial PHC information system. However, because of the limitations inherent to the method, so far, only few studies have investigated more than few PHC related issues. The experience of a household rapid survey conducted in Arua District, Uganda, using a modified EPI cluster survey methodology, is reported. Rapid appraisal methods were used to prioritize the information requirement and to identify the survey items. Fully supervised teams of primary school teachers were used as interviewers. Data processing, check and analysis were speeded up by a lap-top computer, in spite of problems of erratic power. Within a 10-day time span between the start of the survey and the publishing of results, data on health services' utilization, health seeking behaviour, coverage of PHC services, including immunization, and anthropometric data on the nutritional status of under-five children were obtained. Standard errors and 95% confidence intervals were calculated taking into account the variability of the parameters under investigation and true design effects were computed. The findings were utilized for the identification of health priorities and the monitoring of effectiveness of programmes, as well as to validate routine reporting. The methodological package was built up looking at the local context, so that it could become an operational tool for the district health management team.

Adolescent↗
PubMed1994

Post-emergency epidemiological surveillance in Iraqi-Kurdish refugee camps in Iran.

In 1991 a computerized, comprehensive epidemiological surveillance system was developed to monitor health trends in approximately 25,000 acutely displaced Kurds in Nowsood and Saryas refugee camps, Bakhtaran region, Northwestern Iran. In addition, community-based surveys offered information unobtainable from health facilities. Weekly population movements, attack rates, point-prevalence estimates, and case fatality ratios were calculated, and the data were analysed and compared. The overall crude mortality rate (CMR) in the camps under study was still 9 times higher than the reported CMR for Iraq. Health problems with very low rates (less than 1.0/1,000 population/week) included the triad of measles, meningitis and tetanus. However, morbidity for the most common conditions (acute respiratory infections, diarrhoea, skin infections, eye diseases and, finally, typhoid fever) was shown to increase at the end of the intervention, highlighting that the pressure of repatriation on refugees made them progressively worse. This article concludes that epidemiological surveillance systems should be implemented during mass-migrations in developing countries also in post-emergency settings. Furthermore, surveillance appears to be indispensable in order for the international agencies to keep abreast of events and to safeguard human rights when international attention subsides.

Epidemiology↗