McDermott International (United States)

Culture is often seen as the key inhibitor of effective knowledge sharing. A study of companies where sharing knowledge is built into the culture found that they did not change their culture to match their knowledge management initiatives. They adapted their approach to knowledge management to fit their culture. They did this by: linking sharing knowledge to solving practical business problems; tying sharing knowledge to a pre‐existing core value; introducing knowledge management in a way that matches the organization’s style; building on existing networks people use in their daily work; and encouraging peers and supervisors to exert pressure to share.

Plasma lipoprotein(a) [Lp(a)], a low density lipoprotein particle with an attached apolipoprotein(a) [apo(a)], varies widely in concentration between individuals. These concentration differences are heritable and inversely related to the number of kringle 4 repeats in the apo(a) gene. To define the genetic determinants of plasma Lp(a) levels, plasma Lp(a) concentrations and apo(a) genotypes were examined in 48 nuclear Caucasian families. Apo(a) genotypes were determined using a newly developed pulsed-field gel electrophoresis method which distinguished 19 different genotypes at the apo(a) locus. The apo(a) gene itself was found to account for virtually all the genetic variability in plasma Lp(a) levels. This conclusion was reached by analyzing plasma Lp(a) levels in siblings who shared zero, one, or two apo(a) genes that were identical by descent (ibd). Siblings with both apo(a) alleles ibd (n = 72) have strikingly similar plasma Lp(a) levels (r = 0.95), whereas those who shared no apo(a) alleles (n = 52), had dissimilar concentrations (r = -0.23). The apo(a) gene was estimated to be responsible for 91% of the variance of plasma Lp(a) concentration. The number of kringle 4 repeats in the apo(a) gene accounted for 69% of the variation, and yet to be defined cis-acting sequences at the apo(a) locus accounted for the remaining 22% of the inter-individual variation in plasma Lp(a) levels. During the course of these studies we observed the de novo generation of a new apo(a) allele, an event that occurred once in 376 meioses.

Since the publication of the Bass model in 1969, research on the modeling of the diffusion of innovations has resulted in a body of literature consisting of several dozen articles, books, and assorted other publications. Attempts have been made to reexamine the structural and conceptual assumptions and estimation issues underlying the diffusion models of new product acceptance. The authors evaluate these developments for the past two decades. They conclude with a research agenda to make diffusion models theoretically more sound and practically more effective and realistic.

Idiopathic pulmonary fibrosis (IPF) is an adult-onset, lethal, scarring lung disease of unknown etiology. Some individuals with IPF have a familial disorder that segregates as a dominant trait with incomplete penetrance. Here we used linkage to map the disease gene in two families to chromosome 5. Sequencing a candidate gene within the interval, TERT, revealed a missense mutation and a frameshift mutation that cosegregated with pulmonary disease in the two families. TERT encodes telomerase reverse transcriptase, which together with the RNA component of telomerase (TERC), is required to maintain telomere integrity. Sequencing the probands of 44 additional unrelated families and 44 sporadic cases of interstitial lung disease revealed five other mutations in TERT. A heterozygous mutation in TERC also was found in one family. Heterozygous carriers of all of the mutations in TERT or TERC had shorter telomeres than age-matched family members without the mutations. Thus, mutations in TERT or TERC that result in telomere shortening over time confer a dramatic increase in susceptibility to adult-onset IPF.

Lower extremity peripheral artery disease (PAD) affects >230 million adults worldwide and is associated with increased risk of various adverse clinical outcomes (other cardiovascular diseases such as coronary heart disease and stroke and leg outcomes such as amputation). Despite its prevalence and clinical importance, PAD has been historically underappreciated by health care professionals and patients. This underappreciation seems multifactorial (eg, limited availability of the first-line diagnostic test, the ankle-brachial index, in clinics; incorrect perceptions that a leg vascular disease is not fatal and that the diagnosis of PAD would not necessarily change clinical practice). In the past several years, a body of evidence has indicated that these perceptions are incorrect. Several studies have consistently demonstrated that many patients with PAD are not receiving evidence-based therapies. Thus, this scientific statement provides an update for health care professionals regarding contemporary epidemiology (eg, prevalence, temporal trends, risk factors, and complications) of PAD, the present status of diagnosis (physiological tests and imaging modalities), and the major gaps in the management of PAD (eg, medications, exercise therapy, and revascularization). The statement also lists key gaps in research, clinical practice, and implementation related to PAD. Orchestrated efforts among different parties (eg, health care providers, researchers, expert organizations, and health care organizations) will be needed to increase the awareness and understanding of PAD and improve the diagnostic approaches, management, and prognosis of PAD.

Since the publication of the Bass model in 1969, research on the modeling of the diffusion of innovations has resulted in a body of literature consisting of several dozen articles, books, and assorted other publications. Attempts have been made to reexamine the structural and conceptual assumptions and estimation issues underlying the diffusion models of new product acceptance. The authors evaluate these developments for the past two decades. They conclude with a research agenda to make diffusion models theoretically more sound and practically more effective and realistic.

Two ATP-binding cassette (ABC) transporters, ABCG5 and ABCG8, have been proposed to limit sterol absorption and to promote biliary sterol excretion in humans. To test this hypothesis, a P1 clone containing the human ABCG5 and ABCG8 genes was used to generate transgenic mice. The transgenes were expressed primarily in the liver and small intestine, mirroring the expression pattern of the endogenous genes. Transgene expression only modestly affected plasma and liver cholesterol levels but profoundly altered cholesterol transport. The fractional absorption of dietary cholesterol was reduced by about 50%, and biliary cholesterol levels were increased more than fivefold. Fecal neutral sterol excretion was increased three- to sixfold and hepatic cholesterol synthesis increased two- to fourfold in the transgenic mice. No significant changes in the pool size, composition, and fecal excretion of bile acids were observed in the transgenic mice. Transgene expression attenuated the increase in hepatic cholesterol content induced by consumption of a high cholesterol diet. These results demonstrate that increased expression of ABCG5 and ABCG8 selectively drives biliary neutral sterol secretion and reduces intestinal cholesterol absorption, leading to a selective increase in neutral sterol excretion and a compensatory increase in cholesterol synthesis.

Two ATP-binding cassette (ABC) transporters, ABCG5 and ABCG8, have been proposed to limit sterol absorption and to promote biliary sterol excretion in humans. To test this hypothesis, a P1 clone containing the human ABCG5 and ABCG8 genes was used to generate transgenic mice. The transgenes were expressed primarily in the liver and small intestine, mirroring the expression pattern of the endogenous genes. Transgene expression only modestly affected plasma and liver cholesterol levels but profoundly altered cholesterol transport. The fractional absorption of dietary cholesterol was reduced by about 50%, and biliary cholesterol levels were increased more than fivefold. Fecal neutral sterol excretion was increased three- to sixfold and hepatic cholesterol synthesis increased two- to fourfold in the transgenic mice. No significant changes in the pool size, composition, and fecal excretion of bile acids were observed in the transgenic mice. Transgene expression attenuated the increase in hepatic cholesterol content induced by consumption of a high cholesterol diet. These results demonstrate that increased expression of ABCG5 and ABCG8 selectively drives biliary neutral sterol secretion and reduces intestinal cholesterol absorption, leading to a selective increase in neutral sterol excretion and a compensatory increase in cholesterol synthesis.

RATIONALE: Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres. OBJECTIVES: To test whether telomere shortening is a frequent mechanism underlying pulmonary fibrosis, we have characterized telomere lengths in subjects with familial or sporadic disease who do not have coding mutations in TERT or TERC. METHODS: Using a modified Southern blot assay, the telomerase restriction fragment length method, and a quantitative polymerase chain reaction assay we have measured telomere lengths of genomic DNA isolated from circulating leukocytes from normal control subjects and subjects with pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS: All affected patients with telomerase mutations, including case subjects heterozygous for newly reported mutations in TERT, have short telomere lengths. A significantly higher proportion of probands with familial pulmonary fibrosis (24%) and sporadic case subjects (23%) in which no coding mutation in TERT or TERC was found had telomere lengths less than the 10th percentile when compared with control subjects (P = 2.6 x 10(-8)). Pulmonary fibrosis affectation status was significantly associated with telomerase restriction fragment lengths, even after controlling for age, sex, and ethnicity (P = 6.1 x 10(-11)). Overall, 25% of sporadic cases and 37% of familial cases of pulmonary fibrosis had telomere lengths less than the 10th percentile. CONCLUSIONS: A significant fraction of individuals with pulmonary fibrosis have short telomere lengths that cannot be explained by coding mutations in telomerase. Telomere shortening of circulating leukocytes may be a marker for an increased predisposition toward the development of this age-associated disease.

The careful clinical characterization of patients with genetic forms of severe hypercholesterolemia has played a critical role in the historic linkage of hypercholesterolemia to atherosclerosis. Elucidation of gene defects that cause severe hypercholesterolemia has provided molecular entrees into the biosynthetic and regulatory pathways that produce and eliminate cholesterol and has led to the development of potent pharmacological agents that dramatically reduce circulating levels of cholesterol. The last decade of the twentieth century culminated in the demonstration that pharmacological reductions in plasma cholesterol levels result in fewer cardiovascular events and reduce total mortality. This review will summarize recent developments in our understanding of the molecular pathogenesis and treatment of monogenic forms of severe hypercholesterolemia, and some implications that these findings have for the management of common forms of hypercholesterolemia. General overview of LDL metabolism. Cholesterol is a rigid, hydrophobic molecule that confers structural integrity to plasma membranes of vertebrate cells. Excess cellular cholesterol is esterified with fatty acids to form cholesteryl esters, which are either stored as lipid droplets in cells or packaged with other apolipoproteins to form VLDL in the liver and and chylomicrons in the intestine (Figure ​(Figure1).1). The two major cholesterol-carrying lipoproteins in humans are LDL and HDL. Approximately 70% of circulating cholesterol is transported as LDL. Figure 1 Overview of LDL metabolism in humans. Dietary cholesterol and triglycerides are packaged with apolipoproteins in the enterocytes of the small intestine, secreted into the lymphatic system as chylomicrons (CM). As chylomicrons circulate, the core triglycerides ... LDL is formed in the circulation from VLDL (Figure ​(Figure1).1). The triglycerides and phospholipids of circulating VLDL are hydrolyzed by lipases anchored to vascular endothelial surfaces, forming cholesterol-enriched VLDL remnant particles. Approximately half of the VLDL remnants are cleared from the circulation by LDL receptor–mediated (LDLR-mediated) endocytosis in the liver, and the remainder undergoes further processing to produce LDL. Most LDL is removed from the circulation after binding to the hepatic LDLR via apoB-100. Plasma levels of LDL-cholesterol (LDL-C) are directly related to the incidence of coronary events and cardiovascular deaths. Approximately 50% of the interindividual variation in plasma levels of LDL-C is attributable to genetic variation (1). The major portion of this genetic variation is polygenic, reflecting the cumulative effects of multiple sequence variants in any given individual. A subset of patients with very high plasma LDL-C levels have monogenic forms of hyper-cholesterolemia, which are associated with the deposition of cholesterol in tissues, producing xanthomas and coronary atherosclerosis. The clinical features, diagnosis, and pathophysiology of the known mendelian disorders of severe hypercholesterolemia will be serially reviewed (Table ​(Table1).1). This will be followed by a discussion of how insights gleaned from the study of these disorders may be extended to the treatment of hypercholesterolemia in the general population. Table 1 Major monogenic diseases that cause severe hypercholesterolemia Familial hypercholesterolemia Historical perspective. Familial hypercholesterolemia (FH), the most common and most severe form of monogenic hypercholesterolemia, was the first genetic disease of lipid metabolism to be clinically and molecularly characterized (2). The disease has an autosomal codominant pattern of inheritance and is caused by mutations in the LDLR gene; individuals with two mutated LDLR alleles (FH homozygotes) are much more severely affected than those with one mutant allele (FH heterozygotes). The plasma levels of LDL-C are uniformly very high in FH homozygotes, irrespective of diet, medications, or lifestyle. For example, FH homozygotes living in China, where the dietary intake of cholesterol and saturated fat is low, have plasma LDL-C levels similar to those of FH homozygotes living in Western countries (3). FH homozygotes develop cutaneous (planar) xanthomas and coronary atherosclerosis in childhood (2). Atherosclerosis develops initially in the aortic root, causing supravalvular aortic stenosis, and then extends into the coronary ostia. The severity of atherosclerosis is proportional to the extent and duration of elevated plasma LDL-C levels (calculated as the cholesterol-year score) (4). If the LDL-C level is not effectively reduced, FH homozygotes die prematurely of atherosclerotic cardiovascular disease. Optimization of other cardiovascular risk factors has little impact on the clinical course of the disease. Patients with homozygous FH are classified into one of two major groups based on the amount of LDLR activity measured in their skin fibroblasts: patients with less than 2% of normal LDLR activity (receptor-negative), and patients with 2–25% of normal LDLR activity (receptor-defective) (2). In general, plasma levels of LDL-C are inversely related to the level of residual LDLR activity. Untreated, receptor-negative patients with homozygous FH rarely survive beyond the second decade; receptor-defective patients have a better prognosis but, with few exceptions, develop clinically significant atherosclerotic vascular disease by age 30, and often sooner (2). The plasma levels of LDL-C in FH heterozygotes are lower (elevated two- to threefold) and much more dependent on other genetic and environmental factors than are those in FH homozygotes. Although the nature of the molecular defect has some impact on the severity of hypercholesterolemia, FH heterozygotes with the same LDLR mutation can have widely different plasma levels of LDL-C (2). The clinical prognosis of FH heterozygotes is related not only to the magnitude of the elevation in plasma LDL-C but also to the presence of other coronary risk factors (5).

Recent advances in the neurosciences offer a wealth of new information about how the brain works, and how the body and mind interact. These findings offer important and surprising implications for work in political science. Specifically, emotion exerts an impact on political decisions in decisive and significant ways. While its importance in political science has frequently been either dismissed or ignored in favor of theories that privilege rational reasoning, emotion can provide an alternate basis for explaining and predicting political choice and action. In this article, I posit a view of decision making that rests on an integrated notion of emotional rationality.Rose McDermott is the author of Risk Taking in International Relations (1998) and Political Psychology in International Relations (2004) and works largely in the areas of political psychology, experimentation, and American foreign policy. The author is grateful to Jennifer Hochschild, Robert Jervis, and Stephen Rosen for generous and constructive advice and encouragement; and to Gerald Clore, Jonathan Cowden, Thomas Kozachek, Jonathan Mercer, Joanne Miller, Philip Zimbardo, the members of the Political Psychology and Behavior Workshop at Harvard, and anonymous reviewers for useful guidance and suggestions.Passion is a sort of fever in the mind, which ever leaves us weaker than it found us.—William Penn, Fruits of Solitude (1693)We consider affective processing to be an evolutionary antecedent to more complex forms of information processing; but higher cognition requires the guidance provided by affective processing.—Ralph Adolphs and Antonio Damasio, “The Interaction of Affect and Cognition” (2001)

Common sense allows that persons unable to handle a difficult problem can be labeled “disabled.” Social analysis shows that being labeled often invites a public response that multiplies the difficulties facing the seemingly unable. Cultural analysis shows that disability refers most precisely to inadequate performances only on tasks that are arbitrarily circumscribed from daily life. Disabilities are less the property of persons than they are moments in a cultural focus. Everyone in any culture is subject to being labeled and disabled.

BACKGROUND: The bispectral (BIS) index has previously been shown to be a quantifiable measure of the sedative and hypnotic effects of anesthetic drugs. This study was designed to assess the effect of BIS monitoring on the utilization of volatile anesthetics and their recovery profiles after ambulatory surgery. METHODS: Sixty consenting women undergoing outpatient laparoscopic tubal ligation procedures were randomly assigned to one of four treatment groups. After a standardized induction, anesthesia was maintained with either desflurane (Groups I and II) or sevoflurane (Groups III and IV) in combination with nitrous oxide, 65%, and fentanyl. In the control groups (Groups I and III), the anesthesiologists were blinded to the BIS value, and the volatile anesthetics were administered according to standard clinical practice. In Groups II and IV, the volatile anesthetics were titrated to maintain the BIS value at 60. The volatile anesthetic usage and the times from discontinuation of anesthesia to verbal response, orientation, and home-readiness were recorded. RESULTS: During the maintenance period, the BIS values were significantly lower in the control groups (mean, 42) compared with the BIS-titrated groups (mean, 60). The volatile anesthetic usage in the BIS-titrated groups was 30-38% lower (P < 0.05) compared with the control groups. Similarly, the times to verbal responsiveness were 30-55% shorter in the BIS-titrated (vs. control) groups. CONCLUSIONS: Titrating desflurane and sevoflurane using the BIS monitor decreased their utilization and contributed to a faster emergence from anesthesia in outpatients undergoing laparoscopic tubal ligation procedures.

The LMA is a useful airway device for most adult and pediatric patients. It is easy and atraumatic to insert, with minimal somatic and autonomic responses from the patient. It is a suitable alternative to the face mask and to tracheal intubation in a wide variety of clinical situations. In addition, the LMA facilitates blind and fiberoptic techniques of intubation, but its role in the emergency scenario has yet to be established. The preliminary experience gained with this device in Europe and Australasia suggests that it may also transform contemporary anesthetic practice in the United States.

Liver X receptor (LXR) is a nuclear receptor that plays a crucial role in orchestrating the trafficking of sterols between tissues. Treatment of mice with a potent and specific LXR agonist, T0901317, is associated with increased biliary cholesterol secretion, decreased fractional cholesterol absorption, and increased fecal neutral sterol excretion. Here we show that expression of two target genes of LXRα, the ATP-binding cassette (ABC) transportersAbcg5 and Abcg8, is required for both the increase in sterol excretion and the decrease in fractional cholesterol absorption associated with LXR agonist treatment. Mice expressing no ABCG5 and ABCG8 (G5G8 −/− mice) and their littermate controls were treated for 7 days with T0901317. In wild type animals, treatment with the LXR agonist resulted in a 3-fold increase in biliary cholesterol concentrations, a 25% reduction in fractional cholesterol absorption, and a 4-fold elevation in fecal neutral sterol excretion. In contrast, the LXR agonist did not significantly affect biliary cholesterol levels, fractional cholesterol absorption, or neutral fecal sterol excretion in the G5G8 −/−mice. Thus Abcg5 and Abcg8 are required for LXR agonist-associated changes in dietary and biliary sterol trafficking. These results establish a central role for ABCG5 and ABCG8 in promoting cholesterol excretion in vivo. Liver X receptor (LXR) is a nuclear receptor that plays a crucial role in orchestrating the trafficking of sterols between tissues. Treatment of mice with a potent and specific LXR agonist, T0901317, is associated with increased biliary cholesterol secretion, decreased fractional cholesterol absorption, and increased fecal neutral sterol excretion. Here we show that expression of two target genes of LXRα, the ATP-binding cassette (ABC) transportersAbcg5 and Abcg8, is required for both the increase in sterol excretion and the decrease in fractional cholesterol absorption associated with LXR agonist treatment. Mice expressing no ABCG5 and ABCG8 (G5G8 −/− mice) and their littermate controls were treated for 7 days with T0901317. In wild type animals, treatment with the LXR agonist resulted in a 3-fold increase in biliary cholesterol concentrations, a 25% reduction in fractional cholesterol absorption, and a 4-fold elevation in fecal neutral sterol excretion. In contrast, the LXR agonist did not significantly affect biliary cholesterol levels, fractional cholesterol absorption, or neutral fecal sterol excretion in the G5G8 −/−mice. Thus Abcg5 and Abcg8 are required for LXR agonist-associated changes in dietary and biliary sterol trafficking. These results establish a central role for ABCG5 and ABCG8 in promoting cholesterol excretion in vivo. ATP-binding cassette wild type forAbcg5 and Abcg8 allele homozygous for an allele with inactivated Abcg5 and Abcg8 liver X receptor high density lipoprotein low density lipoprotein sterol regulatory element-binding protein gas chromatography fast protein liquid chromatography Cholesterol is an important structural component of animal cell membranes. The cholesterol required to maintain membrane integrity can be synthesized de novo from acetyl-CoA or can be obtained from cholesterol-containing foods in the diet. The typical Western diet includes ∼400 mg of cholesterol per day, of which 40–50% is absorbed in the proximal small intestine. The major pathway by which cholesterol is eliminated from the body is by excretion into bile either as free cholesterol or after conversion to bile acids. A variety of noncholesterol sterols are also present in the diet. The most plentiful of these are the two plant sterols, sitosterol and campesterol. The levels of these sterols in tissues are very low, because plant sterols are poorly absorbed from the intestine and are preferentially secreted into the bile by hepatocytes (1Schoenheimer R. Science. 1931; 74: 579-584Crossref PubMed Scopus (43) Google Scholar, 2Gould R.G. Jones R.J. LeRoy G.V. Wissler R.W. Taylor C.B. Metabolism. 1969; 18: 652-662Abstract Full Text PDF PubMed Scopus (121) Google Scholar, 3Salen G. Ahrens Jr., E.H. Grundy S.M. J. Clin. Invest. 1970; 49: 952-967Crossref PubMed Scopus (386) Google Scholar). One mechanism by which excess cholesterol and other sterols are eliminated from the body involves the action of two ATP-binding cassette (ABC)1half-transporters, ABCG5 and ABCG8 (4Berge K.E. Tian H. Graf G.A. Yu L. Grishin N.V. Schultz J. Kwiterovich P. Shan B. Barnes R. Hobbs H.H. Science. 2000; 290: 1771-1775Crossref PubMed Scopus (1351) Google Scholar, 5Lee M.H. Lu K. Hazard S. 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Invest. 2002; 110: 671-680Crossref PubMed Scopus (607) Google Scholar). Plant sterol levels are more than 50% lower in these mice than in their wild type littermates. Disruption of the mouseAbcg5 and Abcg8 genes has the opposite effect on dietary sterol trafficking. The G5G8 −/− mice have 30-fold higher plasma levels of sitosterol than do their wild type littermates due to increased fractional absorption of dietary plant sterols and impaired biliary sterol excretion (12Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (608) Google Scholar). Abcg5 and Abcg8 are expressed predominantly in the liver and small intestine (4Berge K.E. Tian H. Graf G.A. Yu L. Grishin N.V. Schultz J. Kwiterovich P. Shan B. Barnes R. Hobbs H.H. Science. 2000; 290: 1771-1775Crossref PubMed Scopus (1351) Google Scholar) and are coordinately up-regulated at the transcriptional level by dietary cholesterol. The response ofAbcg5 and Abcg8 to cholesterol requires the liver X receptor α (LXRα) (13Repa J.J. Berge K.E. Pomajzl C. Richardson J.A. Hobbs H. Mangelsdorf D.J. J. Biol. Chem. 2002; 277: 18793-18800Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar), a nuclear receptor that regulates the expression of many key genes in lipid metabolism, includingABCA1 (14Repa J.J. Turley S.D. Lobaccaro J.A. Medina J. Li L. Lustig K. Shan B. Heyman R.A. Dietschy J.M. Mangelsdorf D.J. Science. 2000; 289: 1524-1529Crossref PubMed Scopus (1150) Google Scholar, 15Costet P. Luo Y. Wang N. Tall A.R. J. Biol. Chem. 2000; 275: 28240-28245Abstract Full Text Full Text PDF PubMed Scopus (851) Google Scholar), the gene mutated in Tangier disease (16Brooks-Wilson A. Marcil M. Clee S.M. Zhang L.H. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O. Loubser O. Ouelette B.F. Fichter K. Ashbourne-Excoffon K.J. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. 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Mice accumulate of cholesterol in the liver a high cholesterol diet D.J. Turley S.D. Ma W. Janowski B.A. Lobaccaro J.M. Hammer R.E. Mangelsdorf D.J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), wild type mice treated with an LXR agonist have decreased fractional absorption of dietary cholesterol (14Repa J.J. Turley S.D. Lobaccaro J.A. Medina J. Li L. Lustig K. Shan B. Heyman R.A. Dietschy J.M. Mangelsdorf D.J. Science. 2000; 289: 1524-1529Crossref PubMed Scopus (1150) Google Scholar) and increased biliary cholesterol excretion A.K. R. G. J. Clin. Invest. 2001; PubMed Scopus Google Scholar). The mechanism by which the of dietary cholesterol has not been The decreased fractional absorption of dietary cholesterol associated with LXR agonist treatment to the action of because levels of increased dramatically in the small intestine of the LXR (14Repa J.J. Turley S.D. Lobaccaro J.A. Medina J. Li L. Lustig K. Shan B. Heyman R.A. Dietschy J.M. Mangelsdorf D.J. Science. 2000; 289: 1524-1529Crossref PubMed Scopus (1150) Google Scholar). of mice expressing no −/− mice) no in biliary cholesterol secretion or fecal neutral sterol excretion A.K. R. G. J. Clin. Invest. 2001; PubMed Scopus Google Scholar, T. T. R. G. A.K. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). In the we the that ABCG5 and ABCG8 the LXR agonist-associated increase in biliary and fecal excretion of cholesterol and reduction in cholesterol The LXR agonist from were obtained either from or from Mice homozygous for a and Abcg8 allele (G5G8 were as (12Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (608) Google Scholar). The mice in these were mice of The mice were in in a with a from to and a diet containing cholesterol and animal were with of the and at the of containing of were by diet with T0901317. The in at for no more than mice were of the and for with either the or the diet from a The and of treatment were on (14Repa J.J. Turley S.D. Lobaccaro J.A. Medina J. Li L. Lustig K. Shan B. Heyman R.A. Dietschy J.M. Mangelsdorf D.J. Science. 2000; 289: 1524-1529Crossref PubMed Scopus (1150) Google Scholar, H. A. J.J. Medina J.C. Li L. S. Wang S. M. Mangelsdorf D.J. Lustig Shan B. 2000; PubMed Scopus Google Scholar). levels in plasma and liver were by gas chromatography as M. Dietschy J.M. Turley S.D. J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar, S.D. Dietschy J.M. J. Lipid Res. Full Text PDF PubMed Google Scholar) with plasma and tissues were in at for after of as a were and The were in for by levels were were fast protein liquid chromatography and the sterol in from the of mice a The of cholesterol, and bile were as S.D. Dietschy J.M. Metabolism. Full Text PDF PubMed Scopus Google Scholar). Mice were either the or for days to to containing The were for an days which the were The were and to a of of to fecal neutral and sterol excretion (11Yu L. Li-Hawkins J. Hammer R.E. Berge K.E. Horton J.D. Cohen J.C. Hobbs H.H. J. Clin. Invest. 2002; 110: 671-680Crossref PubMed Scopus (607) Google Scholar, M. Dietschy J.M. Turley S.D. J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar). Mice were either the or for days to an containing cholesterol and by (12Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (608) Google Scholar). Mice were in containing The were and the were for days and for sterol absorption as (12Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (608) Google Scholar). from tissues the and to the of as J. J.L. Hammer R.E. Horton J.D. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, G. J. Horton J.D. Hammer R.E. J.L. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). are as the The between the were for by the levels of sitosterol and were 30-fold higher −/− than in G5G8 mice a diet. of to the diet for 7 days resulted in a of plasma plant sterol levels to levels in wild type plasma sitosterol levels increased from to in the LXR an increase of in the plasma level of the other major dietary plant plasma levels of cholesterol were lower in −/− mice than in wild type as (12Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (608) Google Scholar) The levels of plasma cholesterol increased by 50% and by in the wild type mice −/− mice with treatment. to the of sterols in the plasma of these in the of sterols in the and wild type The increase in plasma sterol levels due to of sterols in both of mice Treatment with associated with of the sterol and a into the as has been T. T. R. G. A.K. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, H. A. J.J. Medina J.C. Li L. S. Wang S. M. Mangelsdorf D.J. Lustig Shan B. 2000; PubMed Scopus Google Scholar). treatment increased biliary cholesterol levels of wild type mice by 3-fold to as T. T. R. G. A.K. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) In to wild type no increase in biliary cholesterol level in the G5G8 −/− mice after treatment with to These are with Abcg5 and Abcg8 the target genes for the increase in biliary cholesterol levels associated with LXR levels were significantly lower in the than in the wild type A in biliary levels in not −/− mice (12Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (608) Google Scholar). and bile levels after treatment in mice not in −/− mice in biliary lipid levels were in wild type mice treated with an LXR agonist T. T. R. G. A.K. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). of plant sterols were significantly higher in G5G8 −/− mice than in wild type G5G8 −/− mice have increased fractional absorption of dietary plant sterols and a decrease in the biliary excretion of sterols, which to the higher levels of plant sterols in these mice (12Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (608) Google Scholar). Treatment of −/− mice with resulted in a reduction in sitosterol and levels The cholesterol level by in the wild type mice after treatment with T0901317, in due to the increase in biliary cholesterol secretion In to the wild type no in cholesterol levels in the mice after LXR agonist from the of increase in biliary cholesterol secretion in these mice levels were in the and G5G8 −/−mice. Treatment with associated with an increase in in both of mice as H. A. J.J. Medina J.C. Li L. S. Wang S. M. Mangelsdorf D.J. Lustig Shan B. 2000; PubMed Scopus Google Scholar). These results are to the which the expression of genes in the pathway and is an LXR target gene J.J. G. J. Y. Lobaccaro J.M. I. Shan B. J.L. Mangelsdorf D.J. 2000; PubMed Scopus Google Scholar). The fractional absorption of dietary cholesterol from to in the wild type mice treated with T0901317, which is to that by (14Repa J.J. Turley S.D. Lobaccaro J.A. Medina J. Li L. Lustig K. Shan B. Heyman R.A. Dietschy J.M. Mangelsdorf D.J. Science. 2000; 289: 1524-1529Crossref PubMed Scopus (1150) Google Scholar). In to wild type the fractional absorption of cholesterol increased to in G5G8 −/− mice fractional cholesterol absorption and increased biliary cholesterol secretion both to the increase in fecal neutral sterol excretion that with LXR agonist treatment (14Repa J.J. Turley S.D. Lobaccaro J.A. Medina J. Li L. Lustig K. Shan B. Heyman R.A. Dietschy J.M. Mangelsdorf D.J. Science. 2000; 289: 1524-1529Crossref PubMed Scopus (1150) Google Scholar, T. T. R. G. A.K. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The level of neutral sterols into the the lower in the G5G8 −/− mice than in the G5G8 and level to increase with treatment ABCG5 and ABCG8 are required for the of fecal neutral sterol excretion by the LXR agonist T0901317. bile excretion in and G5G8 and did not significantly with treatment The levels of LXR target including were to that the in the tissues of the treated The expression levels of LXR target genes were increased with treatment in both of mice with the ofAbcg5 and Abcg8 −/− The levels which is not a target gene of did not increase significantly with treatment in either wild type −/− mice The major of is that ABCG5 and ABCG8 are required in mice for the of biliary and fecal cholesterol excretion by the LXR agonist, T0901317. Disruption ofAbcg5 and Abcg8 the increase in biliary cholesterol levels, the reduction in fractional cholesterol absorption, and the increase in fecal neutral sterol excretion associated with LXR (14Repa J.J. Turley S.D. Lobaccaro J.A. Medina J. Li L. Lustig K. Shan B. Heyman R.A. Dietschy J.M. Mangelsdorf D.J. Science. 2000; 289: 1524-1529Crossref PubMed Scopus (1150) Google Scholar, T. T. R. G. A.K. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). These with the of mice expressing either no ABCG5 and ABCG8 or higher levels of both (11Yu L. Li-Hawkins J. Hammer R.E. Berge K.E. Horton J.D. Cohen J.C. Hobbs H.H. J. Clin. Invest. 2002; 110: 671-680Crossref PubMed Scopus (607) Google Scholar, 12Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (608) Google Scholar), that LXR the excretion of sterols by Abcg5 In wild type treatment with the LXR agonist associated with significantly lower plasma levels of both sitosterol and in plasma plant sterol levels were in mice containing copies of the human ABCG5 andABCG8 (11Yu L. Li-Hawkins J. Hammer R.E. Berge K.E. Horton J.D. Cohen J.C. Hobbs H.H. J. Clin. Invest. 2002; 110: 671-680Crossref PubMed Scopus (607) Google Scholar). In to wild type plasma levels of sitosterol and increased with treatment in the G5G8 −/− mice These that increased expression of Abcg5 is both and for the LXR agonist-associated reduction in plasma plant sterol levels in the wild type In the of ABCG5 and plant sterols accumulate in the liver due to an to sterols into the bile and an increased absorption of dietary plant sterols (12Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. 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The of fecal cholesterol by the LXR agonist from an increase in biliary cholesterol secretion by hepatocytes the decreased fractional absorption of dietary cholesterol by ofAbcg5 and Abcg8 be required to the of these in the liver and small intestine. cholesterol transport involves the of cholesterol from tissues to the the secretion of cholesterol into and the excretion of sterols in The that cholesterol transport has not been The in are with the that two ABCG5 and the in and for also M. and for in and tissues. W. for

Does the security of women influence the security and behavior of states? Existing evidence linking the situation of women to state-level variables such as economic prosperity and growth, health, and corruption is fairly conclusive. Questions remain, however, concerning the degree to which state security and state security-related behavior is linked to the security of women. The “women and peace” thesis draws upon evolutionary biology/psychology for ultimate causes of this linkage, and sociological theories of social diffusion and psychological theories of social learning for more proximate causal mechanisms. Together, a new data resource—the WomanStats Database—and conventional methodology find a robust, positive relationship between the physical security of women and three measures of state security and peacefulness. In addition, a comparison of this proposition to alternative explanations involving level of democracy, level of economic development, and civilizational identity shows that the physical security of women is a better predictor of state security and peacefulness. Although these results are preliminary, it is still possible to conclude that the security of women must not be overlooked in the study of state security, especially given that the research questions to be raised and the policy initiatives to be considered in the promotion of security will differ markedly if the security of women is seriously considered as a significant influence on state security.

Familial hypercholesterolemia (FH) has a frequency of 0.2% in most populations of the world. In selected populations such as the Afrikaners in South Africa, the Christian Lebanese, and the French Canadians, the disease is more frequent due to the founder effect. Previous studies demonstrated that a single mutation at the LDL receptor locus, the so-called French Canadian deletion, makes up 60% of the mutant genes responsible for FH in the French Canadian population. In this study, efforts were directed to determine if there were other common LDL receptor mutations in this population. Three missense mutations were identified and each mutation was reproduced and expressed in vitro. Two of the three mutations result in the production of an LDL receptor protein that is not processed to its mature form at a normal rate. Molecular assays were developed to detect the mutations directly, and the LDL receptor genes of 130 French Canadian FH heterozygotes were screened for the presence of the three missense mutations as well as two deletions. LDL receptor mutations were detected in 76% of individuals and 14% had one of the three missense mutations.

BACKGROUND: The electroencephalogram (EEG) has been used to study the effects of anesthetic and analgesic drugs on central nervous system function. A prospective study was designed to evaluate the accuracy of various EEG parameters for assessing midazolam-induced sedation during regional anesthesia. METHODS: Twenty-six consenting adult patients were administered 4.5-20 mg intravenous midazolam (in increments of 0.5-1 mg bolus doses every 6-10 min) until they became unresponsive to tactile stimulation (i.e., mild prodding or shaking). The EEG was continuously recorded from a bifrontal montage (FP1-Cz and FP2-Cz) to obtain the bispectral index (BI), 95% spectral edge frequency (SEF), median frequency (MF), and delta, theta, alpha, and beta power bands. Sedation was assessed clinically at 6-10-min intervals using the Observers' Assessment of Alertness/Sedation (OAA/S) scale, with 1 = no response (unconsciousness) to tactile stimulation to 5 = wide awake. The EEG parameters were correlated with the OAA/S scores using nonparametric Spearman's rank-correlation analysis. Kruskal-Wallis analysis of variance was used to determine significant changes in EEG parameters during the onset of and recovery from midazolam-induced sedation. RESULTS: Of the EEG parameters studied, the BI exhibited the best correlation with OAA/S scores during both the onset (Spearman's Rho = 0.815) and recovery (Spearman's Rho = 0.596) phases. With increasing sedation, there was a progressive decrease in the BI (OAA/S score of 5: BI = 95.4 +/- 2.3; 4: 90.3 +/- 4.5; 3:86.6 +/- 4.6; 2:75.6 +/- 9.7; 1:69.2 +/- 13.9). A similar pattern was found for the 95% SEF as the OAA/S score decreased from 4 to 1. Similarly, EEG-BI increased with recovery from the sedative effects of midazolam (OAA/S score = 2:BI = 75.2 +/- 10.2; 3:82.3 +/- 7.3; 4:90.8 +/- 6). However, no consistent changes were found with the other EEG parameters. The mean EEG values between OAA/S scores 3 and 2 and between OAA/S scores 2 and 1 during the onset and recovery phases from midazolam-induced sedation, defined as EEG50 values for response to verbal command (EEG50-VC) and to shaking of the head (EEG50-SH), were 79.3 +/- 8 and 70.8 +/- 14.3, respectively, for EEG-BI. The EEG-BI displayed the smallest coefficients of variation for the EEG50-VC and EEG50-SH values. CONCLUSIONS: The EEG-BI appears to be a useful parameter for assessing midazolam-induced sedation and can predict the likelihood of a patient responding to verbal commands or to shaking of the head during midazolam-induced sedation.

Mutations in either ATP-binding cassette (ABC) G5 or ABCG8 cause sitosterolemia, an autosomal recessive disorder of sterol trafficking.To determine the site of action of ABCG5 and ABCG8, we expressed recombinant, epitope-tagged mouse ABCG5 and ABCG8 in cultured cells.Both ABCG5 and ABCG8 underwent N-linked glycosylation.When either protein was expressed individually in cells, the N-linked sugars remained sensitive to Endoglycosidase H (Endo H).When ABCG5 and ABCG8 were coexpressed, the attached sugars were Endo H-resistant and neuraminidase-sensitive, indicating that the proteins were transported to the trans-Golgi complex.The mature, glycosylated forms of ABCG5 and ABCG8 coimmunoprecipitated, consistent with heterodimerization of these two proteins.The Endo H-sensitive forms of ABCG5 and ABCG8 were confined to the endoplasmic reticulum (ER), whereas the mature forms were present in non-ER fractions in cultured hepatocytes.Immunoelectron microscopy revealed ABCG5 and ABCG8 on the plasma membrane of these cells.In polarized WIF-B cells, recombinant ABCG5 localized to the apical (canalicular) membrane when coexpressed with ABCG8, but not when expressed alone.To our knowledge this is the first direct demonstration that trafficking of an ABC half-transporter to the cell surface requires the presence of its dimerization partner.

BACKGROUND: We determined whether patients with lower-extremity peripheral arterial disease (PAD) who are more physically active during daily life have lower mortality rates than PAD patients who are less active. METHODS AND RESULTS: Participants were 460 men and women with PAD (mean age 71.9+/-8.4 years) followed up for 57 months (interquartile range 36.6 to 61.9 months). At baseline, participants were interviewed about their physical activity. Vertical accelerometers measured physical activity continuously over 7 days in 225 participants. Analyses were adjusted for age, sex, race, body mass index, hypertension, smoking, comorbidities, total cholesterol, HDL cholesterol, leg symptoms, and ankle-brachial index. At 57-month follow-up, 134 participants (29%) had died, including 75 participants (33%) who wore accelerometers. Higher baseline physical activity levels measured by vertical accelerometer were associated with lower all-cause mortality (P(trend)=0.003). Relative to PAD participants in the highest quartile of accelerometer-measured physical activity, those in the lowest quartile had higher total mortality (hazard ratio 3.48, 95% confidence interval 1.23 to 9.87, P=0.019). Similar results were observed for the combined outcome of cardiovascular events or cardiovascular mortality (P(trend)=0.005). Higher numbers of stair flights climbed during 1 week were associated with lower total mortality (P(trend)=0.035). CONCLUSIONS: PAD patients with higher physical activity during daily life have reduced mortality and cardiovascular events compared with PAD patients with the lowest physical activity, independent of confounders. Further study is needed to determine whether interventions that increase physical activity during daily life are associated with improved survival in patients with PAD.