The association of class I and II HLA antigens with rheumatic fever and its manifestations was examined in 72 patients, including 48 blacks and 24 Caucasians. No significant association was found between class I antigens and rheumatic fever. In contrast, HLA-DR2 and HLA-DR4 phenotypes were encountered in a significantly higher frequency in black and Caucasian patients with rheumatic fever, respectively, compared with the control populations (P < 0.005). The most significant association (P < 0.005) of these DR antigens with a major manifestation of rheumatic fever was found for mitral insufficiency. In addition, a significant association was encountered between persistent elevation of antibody to the group A streptococcal carbohydrate and HLA-DR4 in Caucasian patients (P < 0.04) or HLA-DR2 in the black patients (P < 0.001). The frequency of HLA-DR2/ 4 heterozygotes among patients with rheumatic fever did not differ significantly from controls. These findings support the concept of a genetically determined susceptibility to rheumatic fever and, particularly, to rheumatic heart disease. The association of the clinical manifestations of rheumatic fever and the immune hyperresponsiveness to a streptococcal antigen could be ascribed to a disease-associated immune-response gene which is in linkage disequilibrium with the DR2 and DR4 alleles of HLA-DR locus on chromosome six.

The extent of nucleotide variation within the HIV-1 env hypervariable domains serves as a marker of virus genotypes within infected individuals and as a means to track transmission of the virus between individuals. We analyzed env VI and V2 sequences in longitudinal samples from two HIV-1-infected mothers, each with three children infected by maternal transmission of the virus. Sequences in samples that were obtained from two infants at 2 d and 4 wk after birth displayed more variation in V1 and V2 than maternal samples obtained at the same times. Multiple HIV-1 genotypes were identified in each mother. In each family, multiple maternal HIV-1 genotypes were transmitted to the infants. Specific amino acid residues in the hypervariable domains were conserved within sequences from each family producing a family-specific amino acid signature pattern in V1 and V2. Viruses that were highly related to maternal viruses in signature pattern persisted for as long as 4 yr in the older children. Results support a model of transmission involving multiple HIV-1 genotypes with development of genetic variation from differential outgrowth and accumulation of genetic changes within each individual. (J. Clin. Invest. 1994. 93:380-390.) Key words: human immunodeficiency virus 1 genetic variation * maternal transmission

Over the past 20 years, hospitalists have emerged as a distinct group of pediatric practitioners. In August of 2014, the American Board of Pediatrics (ABP) received a petition to consider recommending that pediatric hospital medicine (PHM) be recognized as a distinct new subspecialty. PHM as a formal subspecialty raises important considerations related to: (1) quality, cost, and access to pediatric health care; (2) current pediatric residency training; (3) the evolving body of knowledge in pediatrics; and (4) the impact on both primary care generalists and existing subspecialists. After a comprehensive and iterative review process, the ABP recommended that the American Board of Medical Specialties approve PHM as a new subspecialty. This article describes the broad array of challenges and certain unique opportunities that were considered by the ABP in supporting PHM as a new pediatric subspecialty.

Multiple targets for immune recognition and cellular tropism are localized to the Vi and V2 hypervariable regions in the amino portion of human immunodeficiency virus type 1 (HIV-1) gpl20e`v. We have assessed genetic diversity in env Vl and V2 hypervariable domains in vivo within epidemiologically related strains of HIV-1. Our strategy was to analyze longitudinal samples from two seropositive mothers and multiple children infected by perinatal transmission. Although the Vi and V2 domains are closely linked in the HIV-1 genome, nucleotide sequences in Vl and in V2 evolved independently in maternal-infant viruses in vivo. A high proportion of the nucleotide substitutions would introduce amino acid diversity in Vl and in V2. A significant excess of nonsynonymous over synonymous substitutions was identified in HIV-1 env Vl and V2 peptides in the mothers and in two older children but was not generally apparent in HIV-1 sequences in infants. An excess of nonsynonymous over synonymous substitutions indicated that there is positive selection for independent genetic variation in the Vl and V2 domains in vivo. It is likely that there are host responses to complex determinants in the Vi or V2 hypervariable domain of HIV-1 gpl20. Genetic variability within the human immunodeficiency virus type 1 (HIV-1) genome is most pronounced in env, in which nucleotide substitutions, duplications, and deletions produce extensive amino acid diversity within five hypervariable domains in the envelope glycoprotein (7). The hypervariable domains, designated Vi through V5, are interspersed with conserved regions along the gp120 molecule (42, 44, 70). Sequence variation in env can affect an array of functional parameters of the virus in vivo and in culture (8, 9, 14, 16, 28, 52, 57, 59, 61, 62, 74). Major determinants critical for HIV-1 tropism, for cytopathology in culture, and for host immunological responses to HIV-1 infection have been mapped to the carboxyl half of gp120, where V3, V4, and V5 are localized (14, 15, 24, 35). The V3 hypervariable region in particular encodes the principal neutralizing domain in gp120 (25). Nucleotide variability in the V3 loop is characterized by a high proportion of nonsynonymous substitutions indicative of positive genetic selection (1, 60, 71). A principal mechanism contributing to evolution of genetic variability in the V3 domain of gp120 is the host immune response (6, 21, 30, 39). Complex functional determinants are not restricted to the V3 region of gpl20. Sequences associated with HIV-1 tropism for macrophages (49, 69) or encoding targets for immune recognition (13, 17, 26, 32, 67) are also localized in

The organizational structures of academic health centers (AHCs) vary widely, but they all exist along a continuum of integration--that is, the degree to which the academic and clinical missions operate under a single administrative and governance structure. This author provides a brief overview of the topic of AHC integration, including the pros and cons of more integrated or less integrated models. He then traces the evolution of the University of Florida (UF) Health Science Center, which was created in the 1950s as a fully integrated AHC and which now operates under a more distributed management and governance model. Starting as a completely integrated AHC, UF's Health Science Center reached a time of maximal nonintegration (or dys-integration) in the late 1990s and at the beginning of this decade. Circumstances are now pushing the expanding clinical and academic enterprises to be more together as they face the challenges of market competition, federal research budget constraints, and reengineering clinical operations to reduce costs, enhance access, and improve quality and patient safety. Although formal organizational integration may not be possible or appropriate for any number of legal or political reasons, the author suggests that AHCs should strive for "functional integration" to be successful in the current turbulent environment.

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