Intrathoracic pressure fluctuations move blood during CPR: Comparison of hemodynamic data with predictions from a mathematical model

Whether blood flow during cardiopulmonary resuscitation (CPR) results from intrathoracic pressure fluctuations or direct cardiac compression remains controversial. We developed a mathematical model that predicts that blood flow due to intrathoracic pressure fluctuations should be insensitive to compression rate over a wide range but dependent on the applied force and compression duration. If direct compression of the heart plays a major role, however, the model predicts that flow should be dependent on compression rate and force, but above a threshold, insensitive to compression duration. These differences in hemodynamics produced by changes in rate and duration form a basis for determining whether blood flow during CPR results from intrathoracic pressure fluctuations or from direct cardiac compression. The model was validated for direct cardiac compression by studying the hemodynamics of cyclic cardiac deformation following thoracotomy in four anesthetized, 21–32-kg dogs. As predicted by the model, there was no change in myocardial or cerebral perfusion pressures when the duration of compression was increased from 15% to 45% of the cycle at a constant rate of 60/min. There was, however, a significant increase in perfusion pressures when rate was increased from 60 to 150/min at a constant duration of 45%. The model was validated for intrathoracic pressure changes by studying the hemodynamics produced by a thoracic vest (vest CPR) in eight dogs. The vest contained a bladder that was inflated and deflated. Vest CPR changed intrathoracic pressure without direct cardiac compression, since sternal displacement was <0.8 cm. As predicted by the model and opposite to direct cardiac compression, there was no change in perfusion pressures when the rate was increased from 60 to 150/min at a constant duration of 45% of the cycle. Manual CPR was then studied in eight dogs. There was no surgical manipulation of the chest. Myocardial and cerebral blood flows were determined with radioactive microspheres and behaved as predicted from the model of intrathoracic pressure, not direct cardiac compression. At nearly constant peak sternal force (378–426 N), flow was significantly increased when the duration of compression was increased from short (13%–19% of the cycle) to long (40%–47%), at a rate of 60/min. Flow was unchanged, however, for an increase in rate from 60 to 150/min at constant compression duration. In addition, myocardial and cerebral flow correlated with their respective perfusion pressures. Thus vital organ perfusion pressures and flow for manual external chest compression are dependent on the duration of compression, but not on rates of compression of 60 and 150/min. These data are of course similar to those produced by vest CPR, where intrathoracic pressure is manipulated without sternal displacement, and to those predicted for movement of blood by intrathoracic pressure changes. These data are, however, opposite to those produced by cardiac deformation and to those predicted for movement blood by direct cardiac compression. We conclude that intrathoracic pressure fluctuations generate blood flow during manual CPR.     

HLA alleles and haplotypes among the Lakota Sioux: report of the ASHI minority workshops, part III

Human leukocyte antigen (HLA) class I and II alleles were defined for 302 Lakota Sioux American Indians as part of the American Society for Histocompatibility and Immunogenetics coordinated studies on minority populations. The study group was comprised of adult volunteers from the Cheyenne River and Ogala Sioux tribes residing, respectively, on the Cheyenne River and Pine Ridge Reservations in South Dakota. Of the participants, 263 (87%) claimed full American Indian ancestry through both maternal and paternal grandparents. The study group included 25 nuclear families that were informative for genotyping. HLA phenotypes from 202 adults with no other known first-degree relative included in the study were used for calculation of allele and haplotype frequencies by maximum likelihood estimation. HLA-A, -B, and -Cw alleles were found to be in Hardy Weinberg equilibrium. Deviation from equilibrium was observed for DRB1 alleles (p=0.01), but could be attributed to the sample size and the occurrence of some genotypes with low expected frequencies. Polymorphism among the Sioux was limited with four to seven alleles comprising >80% of those observed at each locus. Several alleles were found at high frequency (0.05-0.30) among the Sioux that are also prevalent in other Native Americans and Alaska Natives, including: A*2402, *3101, and *0206; B*3501,*3901, *5101, and *2705; Cw*0702, *0404, and *03041; DRB1*0407, *0404, *1402, and *16021; and DQB1*0301, *0302, and *0402. DRB1*0811, which has been only previously described in Navajo and Tlingit Indians, was found to occur at a frequency of 0.119 among the Sioux. Two new alleles were defined among the Sioux: Cw*0204 and DRB1*040703, which were found in two and four individuals, respectively. In the haplotype analyses, significant linkage disequilibrium (p<0.00001) was seen in all pairwise comparisons of loci and numerous two and three locus haplotypes were found to have strong, positive linkage disequilibrium values. The two most common extended haplotypes among the Sioux, determined by maximum likelihood estimation and genotyping were: A*31012, B*3501, Cw*0404, DRB1*0407; and A*24021, B*3501, Cw*0404, DRB1*0404.     

Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model

Human adenocarcinoma (AC) is the most frequently diagnosed human lung cancer, and its absolute incidence is increasing dramatically. Compared to human lung AC, the A/J mouse-urethane model exhibits similar histological appearance and molecular changes. We examined the gene expression profiles of human and murine lung tissues (normal or AC) and compared the two species' datasets after aligning approximately 7500 orthologous genes. A list of 409 gene classifiers (P value <0.0001), common to both species (joint classifiers), showed significant, positive correlation in expression levels between the two species. A number of previously reported expression changes were recapitulated in both species, such as changes in glycolytic enzymes and cell-cycle proteins. Unexpectedly, joint classifiers in angiogenesis were uniformly down-regulated in tumor tissues. The eicosanoid pathway enzymes prostacyclin synthase (PGIS) and inducible prostaglandin E(2) synthase (PGES) were joint classifiers that showed opposite effects in lung AC (PGIS down-regulated; PGES up-regulated). Finally, tissue microarrays identified the same protein expression pattern for PGIS and PGES in 108 different non-small cell lung cancer biopsies, and the detection of PGIS had statistically significant prognostic value in patient survival. Thus, the A/J mouse-urethane model reflects significant molecular details of human lung AC, and comparison of changes in orthologous gene expression may provide novel insights into lung carcinogenesis.     

Diagnosis of gastrointestinal stromal tumors: A consensus approach

As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GISTs), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and the development of novel and effective therapy for GISTs using the receptor tyrosine kinase inhibitor STI-571, these tumors have become the focus of considerable attention by pathologists, clinicians, and patients. Stromal/mesenchymal tumors of the gastrointestinal tract have long been a source of confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication. Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity in diagnosis and a proposed scheme for estimating metastatic risk in these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term "benign" for any GIST, at least at the present time.     

Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome

Completion of the Rattus norvegicus genome sequence enabled a global inventory and analysis of the nuclear receptors (NRs) in three mammalian species. Forty-nine NR members were found in mouse, 48 in human. Forty-seven were found in the rat, with gaps at the locations expected for the other two. Pairwise comparisons of their distribution in rat, mouse, and human identified 11 syntenic NR gene blocks, including three small clusters of two or three closely related genes, each spanning 40 kb to 1700 kb. The exon structure of the ligand-binding domain suggests that exon shuffling has played a role in the evolution of this family. An invariant splice junction in all members of the NR family except LXRbeta suggests a functional role for the intron. The ligand-binding domains of PXR and CAR are among the most divergent in the family. Their higher nucleotide substitution rates may be related to the central role played by these two NRs in the metabolism of the foreign compounds and may have resulted from limited positive selection.     

Assessment of the epidemic potential of a new strain of rotavirus associated with the novel G9 serotype which caused an outbreak in the United States for the first time in the 1995-1996 season

Rotavirus causes severe morbidity in developed countries and frequent deaths (> or = 500,000 per year) in less-developed countries. Historically, four serotypes--G1, G2, G3, and G4-have predominated; they are distinguished by one of two surface neutralization antigens (VP7). However, in 1983 and 1984 we described a new rotavirus serotype, designated G9, in five children hospitalized for diarrhea in Philadelphia, Pa. G9 rotavirus was not identified again in the Western Hemisphere until it caused ca. 50% of the rotavirus disease detected in Philadelphia in the 1995-1996 season. This outbreak allowed us to question whether a rotavirus strain completely new to a well-studied community would target either very young infants or older children, cause especially severe disease, or completely displace previously extant serotypes. We observed a significant excess of G9 infections in younger infants (especially in those < 6 months old) that might be attributed to the lack of G9-specific antibodies in mothers. Of further note, six of the seven oldest patients with rotavirus diarrhea were infected with the G9 strains (not significant). However, the age distribution of children with rotavirus did not differ over a 5-year study period regardless of the infecting serotype. Patients with diarrhea associated with G9 strains did not have disease more severe than that caused by the G1, G2, or G3 serotype. G9 strains did not displace the other serotypes but were virtually completely replaced by G1 or G2 serotypes in the three subsequent rotavirus seasons. We conclude that the abrupt appearance of this novel rotavirus serotype did not present a special threat to public health in the community.     

Engineered cellular response to scaffold architecture in a rabbit trephine defect

Tight control of pore architecture in porous scaffolds for bone repair is critical for a fully elucidated tissue response. Solid freeform fabrication (SFF) enables construction of scaffolds with tightly controlled pore architecture. Four types of porous scaffolds were constructed using SFF and evaluated in an 8-mm rabbit trephine defect at 8 and 16 weeks (n = 6): a lactide/glycolide (50:50) copolymer scaffold with 20% w/w tri-calcium phosphate and random porous architecture (Group 1); another identical design made from poly(desaminotyrosyl-tyrosine ethyl ester carbonate) [poly(DTE carbonate)], a tyrosine-derived pseudo-polyamino acid (Group 2); and two poly(DTE carbonate) scaffolds containing 500 microm pores separated by 500-microm thick walls, one type with solid walls (Group 3), and one type with microporous walls (Group 4). A commercially available coralline scaffold (Interpore) with a 486-microm average pore size and empty defects were used as controls. There was no significant difference in the overall amount of bone ingrowth in any of the devices, as found by radiographic analysis, but patterns of bone formation matched the morphology of the scaffold. These results suggest that controlled scaffold architecture can be superimposed on biomaterial composition to design and construct scaffolds with improved fill time.