L. George Veasy

Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks

Acute rheumatic fever (ARF), a sequelae of group A Streptococcus (GAS) infection, is the most common cause of preventable childhood heart disease worldwide. The molecular basis of ARF and the subsequent rheumatic heart disease are poorly understood. Serotype M18 GAS strains have been associated for decades with ARF outbreaks in the U.S. As a first step toward gaining new insight into ARF pathogenesis, we sequenced the genome of strain MGAS8232, a serotype M18 organism isolated from a patient with ARF. The genome is a circular chromosome of 1,895,017 bp, and it shares 1.7 Mb of closely related genetic material with strain SF370 (a sequenced serotype M1 strain). Strain MGAS8232 has 178 ORFs absent in SF370. Phages, phage-like elements, and insertion sequences are the major sources of variation between the genomes. The genomes of strain MGAS8232 and SF370 encode many of the same proven or putative virulence factors. Importantly, strain MGAS8232 has genes encoding many additional secreted proteins involved in human–GAS interactions, including streptococcal pyrogenic exotoxin A (scarlet fever toxin) and two uncharacterized pyrogenic exotoxin homologues, all phage-associated. DNA microarray analysis of 36 serotype M18 strains from diverse localities showed that most regions of variation were phages or phage-like elements. Two epidemics of ARF occurring 12 years apart in Salt Lake City, UT, were caused by serotype M18 strains that were genetically identical, or nearly so. Our analysis provides a critical foundation for accelerated research into ARF pathogenesis and a molecular framework to study the plasticity of GAS genomes.

Persistence of acute rheumatic fever in the intermountain area of the United States

We report our 8-year experience with the resurgence of acute rheumatic fever during the years 1985 through 1992. The records of 274 confirmed cases referred to Primary Childrens Medical Center were reviewed. The clinical features including the presence of the Jones criteria, demographic data, preceding streptococcal infection, and the use of echocardiographic studies were tabulated and assessed. Patients came predominantly (84%) from middle-class families with access to medical care. Only 46 patients (17%) sought medical attention for a preceding sore throat. Carditis evident by auscultation was the dominant major manifestation in 68% of the cases. Echocardiography demonstrated mitral regurgitation that was not audible in 15 (47%) of 32 patients who had only polyarthritis at onset and in 30 (57%) of the 53 who had pure chorea. The incidence of acute rheumatic fever has been declining since the peak of the outbreak in 1985 but is continuing in the intermountain area at rates comparable to those of the 1960s.

Molecular Analysis of Group A Streptococcus Type emm18 Isolates Temporally Associated with Acute Rheumatic Fever Outbreaks in Salt Lake City, Utah

ABSTRACT Acute rheumatic fever (ARF) and subsequent rheumatic heart disease are rare but serious sequelae of group A Streptococcus (GAS) infections in most western countries. Salt Lake City (SLC), Utah, and the surrounding intermountain region experienced a resurgence of ARF in 1985 which has persisted. The largest numbers of cases were encountered in 1985-1986 and in 1997-1998. Organisms with a mucoid colony phenotype when grown on blood agar plates were temporally associated with the higher incidence of ARF. To develop an understanding of the molecular population genetic structure of GAS strains associated with ARF in the SLC region, 964 mucoid and nonmucoid pharyngeal isolates recovered in SLC from 1984 to 1999 were studied by sequencing the emm gene. Isolates with an emm18 allele were further characterized by sequencing the spa, covR, and covS genes. Peak periods of ARF were associated with GAS isolates possessing an emm18 allele encoding the protein found in serotype M18 isolates. Among the serotype M18 isolates, the difference in the number of C repeats produced three size variants. Variation was limited in spa, a gene that encodes a streptococcal protective antigen, and covR and covS, genes that encode a two-component regulatory system that, when inactivated, results in a mucoid phenotype and enhanced virulence in mouse infection models. Pulsed-field gel electrophoresis showed a single restriction profile for serotype M18 organisms isolated during both peak periods of ARF. In SLC, the incidence of ARF coresurged with the occurrence of GAS serotype M18 isolates that have very restricted genetic variation.

Current results with intraaortic balloon pumping in infants and children

BACKGROUND Intraaortic balloon pumping (IABP) is useful for support in patients with moderate left ventricular dysfunction. IABP is usually timed with the R wave of the electrocardiogram. We have utilized M-mode echocardiography timed IABP in children with left-side heart failure since 1994. Electrocardiogram timing seems inappropriate for children, who have much higher heart rates. We describe our experience with children who underwent IABP therapy before and after 1994, when echocardiographic timing was instituted. METHODS We reviewed records of 29 children who underwent IABP for all indications at Primary Childrens Medical Center since 1988. RESULTS Overall survival was 62.1% (18 of 29) in this series. Survival was similar for infants (odds ratio = 2.0, 95% confidence interval = 0.29 to 14.31, p = 0.43) and older children. Survival was similar in the echocardiography era when compared with the electrocardiogram era (odds ratio = 2.4, 95% confidence interval = 0.56 to 10.4, p = 0.44). CONCLUSIONS IABP is a useful means of support in children with left ventricular dysfunction. M-mode echocardiography is effective in triggering IABP. The sample size in this study is too small to detect a mortality rate difference.

Evidence for lack of myocardial injury in children with acute rheumatic carditis.

Despite pathologic evidence of myocardial inflammation, the significance of myocarditis in children with acute rheumatic carditis remains controversial. Elevations in cardiac troponin I have been demonstrated in other forms of myocarditis. The purpose of our study was to determine if levels of cardiac troponin I are elevated, suggesting myocardial injury, in patients with acute rheumatic carditis. We identified all those patients with acute rheumatic fever, presenting between July 1998 and December 2000, who had clinical evidence of carditis, such as a new murmur of mitral or aortic regurgitation, and who had an echocardiogram, measurements of levels of cardiac troponin I, erythrocyte sedimentation rate, and/or C-reactive protein performed at the time of presentation. Their charts were reviewed for demographic and clinical data. Echocardiograms were reviewed for severity of aortic and mitral regurgitation, and measurements made of left ventricular ejection fraction, fractional shortening, and end-diastolic dimension. We found 16 patients with acute rheumatic carditis, ranging in age from 2.0 to 16.1 years, with just over one-third having symptoms of congestive heart failure. All patients had evidence of acute inflammation. There was a significant relationship between symptoms and severity of mitral regurgitation. No patient had elevated levels of cardiac troponin I level. The fact that levels of cardiac troponin I are not elevated in the serum of children with acute rheumatic carditis suggests that there is minimal myocytic necrosis in this setting. This supports the concept that acute valvar regurgitation is the major hemodynamic abnormality in these patients.

Antibody responses to group A streptococcal infections in acute rheumatic fever.

Acute rheumatic fever (ARF) is a nonsuppurative sequela of group A streptococcal pharyngitis. It is a multifocal inflammatory disease, affecting primarily the joints, heart, central nervous system and skin, occurring in 0.1%–3% of individuals after untreated group A streptococcal pharyngitis. Although the exact pathogenesis of this process remains unknown, there is considerable evidence indicating that it is initiated by an autoimmune response to untreated group A streptococcal pharyngitis. Onset of ARF may occur anytime from early childhood through adult life, but peak incidence is in children between the ages of 5 and 15 years. Arthritis, carditis, Sydenham chorea, and the less frequently occurring skin manifestations (erythema marginatum and subcutaneous nodules) make up the 5 major manifestations in the Jones criteria for the diagnosis of ARF. These manifestations may be present in the patient either alone or in any combination. Rheumatic fever and its clinically significant sequela, rheumatic heart disease, continue to be a major health problem in developing countries, which are occupied by two thirds of the world’s population. Additionally, a disturbing resurgence of ARF has occurred in several areas of the United States in the mid 1980s and continues to present a significant health problem today. With persistence of the resurgence of ARF in Utah, we have seen over 600 cases of ARF since 1985. This review will focus primarily on host antibody responses to the extracellular and somatic antigenic components of group A streptococcus and their cross-reactivity to human tissues believed to be involved in the pathogenesis of ARF.

A thermodilution method for quantification of bidirectional shunts

Abstract A method for measurement of bidirectional cardiovascular shunt fractions from single indicator dilution curves is presented. Linear system models corresponding to four basic shunt configurations are devised to represent the indicator dilution response of the cardiopulmonary circulation. The congenital heart defects in which bidirectional shunts exist are discussed in terms of the four anatomic configurations. Computer algorithms and digital processing techniques used for analyses of the indicator dilution curves are presented in detail. Forty-one thermodilution curves recorded during 13 pediatric cardiac catheterization procedures were analyzed and the results compared to simultaneous oximetric determinations. Comparison of L-R shunts, expressed as fractions of pulmonary plus R-L shunt flows, calculated by the two methods gave a standard error of 0.083 and a maximum difference of 0.15. Error analysis of the indicator dilution method predicted a standard deviation of 0.06. Multiple determinations were reproducible within a standard deviation of 0.051. Comparison of the right-to-left shunts, expressed as fractions of systemic plus left-to-right shunt flows gave a standard error of 0.083 and a maximum difference of 0.13. The standard deviation of multiple determinations was 0.029.

Using a dedicated small computer in conjunction with a time-shared system in a hospital intensive care unit.

Abstract The digital computer has become a valuable tool for monitoring critically ill patients. Large computer systems, e.g., the time-shared system ( 1 ) at the Latter-Day Saints Hospital, offer the advantages of (1) base of programming, (2) central record keeping, (3) flexibility and (4) computing capability; whereas small dedicated computers offer the advantages of (1) simplicity, (2) stand-alone capability, and (3) reliability. This paper describes a system which uses a small computer (PDP-8) in conjunction with a large time-shared computer (CDC-3200) for automation of blood analysis in the pediatric intensive care unit of the Primary Childrens Hospital in Salt Lake City.