A brief history of health care quality assessment and improvement in the United States.

We review the history and current efforts to assess and improve health care in the United States. This process has involved a host of government agencies and commissions, professional organizations, insurance underwriters, corporations, and more recently, market forces. Traditional approaches to quality control have stressed case-by-case analysis and identifying outliers. Newer approaches include creating practice guidelines and profiles of hospitals and physicians. The joint goals of quality improvement and cost control can best be realized if institutions and practitioners embrace these new approaches and use them to enhance their performances.     

Escherichia coli α-Hemolysin Counteracts the Anti-Virulence Innate Immune Response Triggered by the Rho GTPase Activating Toxin CNF1 during Bacteremia

The detection of the activities of pathogen-encoded virulence factors by the innate immune system has emerged as a new paradigm of pathogen recognition. Much remains to be determined with regard to the molecular and cellular components contributing to this defense mechanism in mammals and importance during infection. Here, we reveal the central role of the IL-1β signaling axis and Gr1+ cells in controlling the Escherichia coli burden in the blood in response to the sensing of the Rho GTPase-activating toxin CNF1. Consistently, this innate immune response is abrogated in caspase-1/11-impaired mice or following the treatment of infected mice with an IL-1β antagonist. In vitro experiments further revealed the synergistic effects of CNF1 and LPS in promoting the maturation/secretion of IL-1β and establishing the roles of Rac, ASC and caspase-1 in this pathway. Furthermore, we found that the α-hemolysin toxin inhibits IL-1β secretion without affecting the recruitment of Gr1+ cells. Here, we report the first example of anti-virulence-triggered immunity counteracted by a pore-forming toxin during bacteremia.     

Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis

Hypokalemic periodic paralysis type 2 (hypoPP2) is an inherited skeletal muscle disorder caused by missense mutations in the SCN4A gene encoding the alpha subunit of the skeletal muscle Na+ channel (Nav1.4). All hypoPP2 mutations reported so far target an arginine residue of the voltage sensor S4 of domain II (R672/G/H/S). We identified a novel hypoPP2 mutation that neutralizes an arginine residue in DIII-S4 (R1132Q), and studied its functional consequences in HEK cells transfected with the human SCN4A cDNA. Whole-cell current recordings revealed an enhancement of both fast and slow inactivation, as well as a depolarizing shift of the activation curve. The unitary Na+ conductance remained normal in R1132Q and in R672S mutants, and cannot therefore account for the reduction of Na+ current presumed in hypoPP2. Altogether, our results provide a clear evidence for the role of R1132 in channel activation and inactivation, and confirm loss of function effects of hypoPP2 mutations leading to muscle hypoexcitability.     

Significance of ecological vicariance and long-distance dispersal in the diversification of Carex sect. Spirostachyae (Cyperaceae)

Plant disjunctions have provided one of the most intriguing distribution patterns historically addressed by biogeographers. Carex sect. Spirostachyae (Cyperaceae) displays an interesting pattern of disjunction to evaluate these scenarios, with species occurring in the main continental landmasses and in oceanic islands of the two hemispheres. Internal transcribed spacer and 5'-trnK intron plastid gene sequences were analyzed to determine (1) the times of diversification using penalized likelihood, and (2) reconstructions of the regions using maximum likelihood and Bayesian approaches of origin of sect. Spirostachyae and internal main lineages. The times for the diversification of sect. Spirostachyae are dated to between the end of the Eocene and the Oligocene, whereas the two main lineages are dated to between the end of the Oligocene and the beginning of Miocene. The phylogenetic analyses reveal a Mediterranean-Eurasian center of differentiation for sect. Spirostachyae and subsection Spirostachyae, whereas no clear, single ancestral area could be inferred for subsection Elatae. Both long-distance dispersal and ecological vicariance appear to have been involved in the evolutionary history of the disjunct distribution of the main lineages of sect. Spirostachyae. These organisms appear to have a special ability to colonize remote areas (through transoceanic and interhemispherical colonizations), but special long-distance dispersal mechanisms are not evident.     

Is Oligomeris (Resedaceae) indigenous to North America? Molecular evidence for a natural colonization from the Old World

Oligomeris linifolia constitutes one of the few examples of intercontinental disjunctions at the species level between the arid regions of the Old World and SW North America. The status of the American populations has been obscure, with some authors considering the populations to be introduced, whereas others believe them to be native. To clarify these conflicting opinions, we performed phylogeographic analyses using nuclear ribosomal ITS and plastid trnL-F and rps16 sequences to infer the origin of the disjunct American populations. Two independent molecular clock approaches based on ITS and cpDNA sequences (rbcL, matK, trnL-F) were used to estimate a divergence time of O. linifolia. Low levels of sequence divergence and estimates of relatively recent splits of Oligomeris lineages disagree with the vicariance hypotheses traditionally suggested to account for New-Old World disjunctions. In addition, significant genetic differentiation of American populations does not indicate a recent anthropogenic introduction. Morphological uniformity and the sharing of haplotypes between disjunct populations, together with the molecular clock results, suggest that a long-distance dispersal event from the Old Word to SW North America may have taken place during the Quaternary, in spite of limited dispersal mechanisms in Oligomeris.     

Evolution of Iris subgenus Xiphium based on chromosome numbers, FISH of nrDNA (5S, 45S) and trnL–trnF sequence analysis

The subgenus Xiphium is one of the six infrageneric divisions of the genus Iris. Chromosome numbers of six of the seven Xiphium species are known. Here the aim was to infer genetic and phylogenetic relationships based on chromosome numbers, chromosome markers and plastid sequences. Chromosomal locations of 5S and 45S rDNA loci were determined in 19 populations of the 7 species by fluorescence in situ hybridization (FISH). Additionally, the trnL–trnF plastid spacer was sequenced and a phylogenetic analysis performed. Based on chromosome markers, subgenus Xiphium species were classified into four groups that differed in the number and locations of both types of nrDNA: (1) I. tingitana (2n = 28), I. filifolia (2n = 30, 34) and I. xiphium (2n = 34), (2) I. juncea (2n = 32) and I. boissieri (2n = 36), (3) I. serotina (2n = 34) and (4) I. latifolia (2n = 42). Although the trnL–trnF phylogeny was not fully resolved, the sequence analysis showed a well-supported subgroup of I. filifolia, I. tingitana and I. xiphium, as well as I. juncea. FISH physical maps of the Iris subgenus Xiphium taxa are species dependent. I. filifolia, I. tingitana and I. xiphium are very closely related species and share cytogenetic characteristics. Disploidy appears to have been central in the evolution of this subgenus, given a series of chromosome numbers (2n = 28, 30, 32, 34, 36, 42) and our phylogenetic results. Clear differences were found among European and African populations of I. filifolia. A different taxonomic treatment of I. filifolia is supported for populations on both sides of the Strait of Gibraltar.     

The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis

The protein tyrosine phosphatase SHP-1 is a well-known inhibitor of activation-promoting signaling cascades in hematopoietic cells but its potential role in insulin target tissues is unknown. Here we show that Ptpn6(me-v/me-v) (also known as viable motheaten) mice bearing a functionally deficient SHP-1 protein are markedly glucose tolerant and insulin sensitive as compared to wild-type littermates, as a result of enhanced insulin receptor signaling to IRS-PI3K-Akt in liver and muscle. Downregulation of SHP-1 activity in liver of normal mice by adenoviral expression of a catalytically inert mutant of SHP-1, or after small hairpin RNA-mediated SHP-1 silencing, further confirmed this phenotype. Tyrosine phosphorylation of CEACAM1, a modulator of hepatic insulin clearance, and clearance of serum [125I]-insulin were markedly increased in SHP-1-deficient mice or SHP-1-deficient hepatic cells in vitro. These findings show a novel role for SHP-1 in the regulation of glucose homeostasis through modulation of insulin signaling in liver and muscle as well as hepatic insulin clearance.     

A new peptidic vector for molecular imaging of apoptosis, identified by phage display technology

Phosphatidylserine (PS) exposure on the cell surface is an early marker of apoptosis. To select PS binding peptides as vectors of contrast agents to image apoptosis, a phage library has been exposed to perfused mouse livers. Phages not retained on control livers during the first perfusions were used for selections on apoptotic livers in a second series of perfusions. Four selected phages were further evaluated for binding to PS-coated enzyme-linked immunosorbent assay (ELISA) plates. They presented an apparent affinity constant (Ka app) for PS ranging from 6.08x10(10) M to 1.62x10(11)M. These phages did not bind to phosphatidylcholine, and competition with annexin V confirmed their specific interaction with PS. The phage with the highest affinity-bound PS in ELISA with a Ka app=(1.6+/-0.2)x10(11)M. It carried the TLVSSL peptide that was synthesized. Specific competition with annexin V and with the synthetic peptide was performed and confirms the specificity of the interaction.