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1. Shape preferences for simple Euclidian forms in three age groups [1989]

  • Silver, Annabelle, Combs, Allan, McConnellogue, Janet, Johnson, Robin, Pickering, John, and Hicks, Jacqueline
  • Perceptual and Motor Skills. April 1989, Vol. 68 Issue 2, p522, 1 p.
Subjects
Testing, Research, Age groups -- Testing, Intelligence (Psychology) -- Testing, Form perception (Psychology) -- Research, Age and intelligence -- Testing, and Form perception -- Research

2. Serum lipid response to dietary cholesterol in subjects fed a low-fat, high-fiber diet [1989]

  • Edington, Jacqueline D., Geekie, Moira, Carter, Robin, Benfield, Lisa, Ball, Madeleine, and Mann, Jim
  • American Journal of Clinical Nutrition. July 1989, Vol. 50 Issue 1, p58, 5 p.
Subjects
Health aspects, Physiological aspects, Research, Control, Hyperlipoproteinemia -- Health aspects, Cholesterol -- Physiological aspects, Low cholesterol diet -- Research, Blood cholesterol -- Control, and Low-cholesterol diet -- Research
Abstract
Both cholesterol and saturated fat in the diet have been linked to increased risk of coronary artery disease. Dietary cholesterol and saturated fat appear to contribute to heart disease by raising blood cholesterol. The elevated circulating cholesterol may adhere to the inner walls of the coronary arteries, slowing or blocking blood flow. While dietary cholesterol is only found in animal foods such as meat, eggs and dairy products, saturated fat may be found in animal or vegetable foods. Persons who wish to reduce their risk of heart disease are usually advised to make several changes in their diet: reduce cholesterol, reduce saturated fat, and increase fiber. The 58 participants followed a low-saturated-fat, high-fiber diet throughout the 12 weeks. To this background diet were added nine eggs per week for the first four weeks, zero eggs for the second four weeks and nine eggs per week for the last four weeks. Eggs were used as a source of cholesterol. The participants' blood cholesterol levels did not change significantly when the number of eggs was changed from nine to zero and back to nine. The subjects showed no consistent evidence of 'hyperresponse', defined as a greater than average increase in blood cholesterol in response to a given increase in dietary cholesterol. It is concluded that once a person is eating a low-saturated-fat, high-fiber diet, reducing dietary cholesterol to below 400 mg per day provides little additional benefit in terms of lowering blood cholesterol. A cholesterol intake of 400 mg per day is considered moderate and was provided in the diet containing nine eggs per week. When subjects added zero eggs to the background diet they consumed 90 mg cholesterol per day.

3. Adaptation of an automated assay for determination of beta-hydroxybutyrate in dogs using a random access analyzer. [1992]

  • Christopher MM, Pereira JL, and Brigmon RL
  • Veterinary clinical pathology [Vet Clin Pathol] 1992; Vol. 21 (1), pp. 3-8.
Abstract
An automated method for measuring beta-hydroxybutyrate was adapted to the Ciba-Corning 550 Express trade mark random access analyzer. The assay was based on a kinetic reaction utilizing hydroxybutyrate-dehydrogenase. Beta-hydroxybutyrate concentration (mmol/L) was calculated ratiometrically using a 1.0 mmol/l standard. Canine serum, plasma, and urine were used without prior deproteinization and only a 30-microliter sample was required. The method demonstrated good linearity between 0 to 2 mmol/l of beta-hydroxybutyrate. Analytical recovery (accuracy) within these concentrations ranged from 85.8 to 113.3%. Both within-run and day-to-day precision were determined, as was specificity of the assay in the presence of a variety of interfering substances. The automated assay was rapid and economical, with reagent stability maintained for at least 2 weeks at 4 degrees C. This assay can readily be applied toward the assessment of ketoacidosis in dogs, and with further validation, other species.

4. Nonsteroidal signals originating in the gonads [1992]

  • Ackland, Jacqueline F., Schwartz, Neena B., Mayo, Kelly E., and Dodson, Robin E.
  • Physiological Reviews. July 1992, Vol. 72 Issue 3, p731, 57 p.
Subjects
Physiological aspects, Evaluation, Gonads -- Physiological aspects, Ovaries -- Physiological aspects, Testis -- Physiological aspects, Sex hormones -- Physiological aspects, Peptide hormones -- Evaluation, and Hormones, Sex -- Physiological aspects
Abstract
The various peptide factors produced in the testes and ovaries are reviewed. Chemical isolation, purification, and amino acid and nucleotide sequencing have led to the understanding of the mechanisms of actions of these nonsteroidal agents. Among the gonadal peptides identified are inhibin, relaxin, oocyte meiosis inhibitor and growth factors. The study of the functions of these peptides have led to the identification of other proteins such as luteinizing inhibitor and clusterin. Immunological or molecular probes were also able to detect factors originally identified in other glands such as propiomelanocortin and atrial natriuretic factor.

5. On winning friends and influencing people: action identification and self-presentation success [1992]

  • Vallacher, Robin R., Wegner, Daniel M., McMahan, Susan C., Cotter, Jacqueline, and Larsen, Kathleen A.
  • Social Cognition. Fall, 1992, Vol. 10 Issue 3, p335, 21 p. graph
Subjects
Self-presentation -- Research, Identification (Psychology) -- Research, and Social psychology -- Research
Abstract
Eighty undergraduate students were asked to describe themselves using high-level or low-level terms of action identification theory and self-presentation. The subjects were told that they were trying to impress an easily-impressionable person or a difficult-to-impress person. Ratings made by the subjects and observers showed that low-level terms of action identificationtheory and self-presentation such as smiling when appropriate, were more effective in terms of getting positive first impressions.

6. Characteristics relating to ovarian cancer risk: collaborative analysis of seven U.S. case-control studies. Epithelial ovarian cancer in black women [1993]

  • John, Esther M., Whittemore, Alice S., Harris, Robin, and Itnyre, Jacqueline
  • Journal of the National Cancer Institute. Jan 20, 1993, Vol. 85 Issue 2, p142, 6 p.
Subjects
Risk factors, Health aspects, Research, Ovarian cancer -- Risk factors, African American women -- Health aspects, Oral contraceptives -- Health aspects, Breast feeding -- Health aspects, and Disease susceptibility -- Research
Abstract
Background: Previous epidemiologic studies of ovarian cancer have focused chiefly on White women, who have a higher incidence of ovarian cancer than Black women. No study has previously examined risk factors for ovarian cancer among Black women. Purpose: This study was designed to evaluate the risk of epithelial ovarian cancer in Black women in relation to reproductive characteristics such as pregnancy, oral contraceptive use, and breast-feeding, and to determine whether differences in reproductive factors between Black and White women account for differences in ovarian cancer incidence. Methods: Combining interview data from seven case-control studies, we compared reproductive characteristics of 110 Black case subjects with a diagnosis of epithelial ovarian cancer between 1971 and 1986 with characteristics of 251 Black population control subjects and 114 Black hospital control subjects. We also compared the prevalence of reproductive factors in 246 Black population control subjects and 4378 White population control subjects and estimated the fraction of Black-White differences in ovarian cancer incidence attributable to racial differences in prevalence of these characteristics. Results: Decreased risks of epithelial ovarian cancer in Black women were associated with parity of four or higher (odds ratio [OR] = 0.53; 95% confidence interval [CI] = 0.25-1.1), breast-feeding for 6 months or longer (OR = 0.85; 95% CI = 0.36-2.0), and use of oral contraceptives for 6 years or longer (OR = 0.62; 95% CI = 0.24-1.6). A greater proportion of Black women (48%) than White women (27%) reported four or more term pregnancies, and Black women (62%) were more likely than White women (53%) to have breast-fed their children. Oral contraceptive use was more common among White women (59%) than Black women (51%). Conclusion: Differences in the prevalence of other factors related to ovarian cancer risk or differences in genetic susceptibility must explain most of the Black-White differences in incidence of ovarian cancer. [J Natl Cancer Inst 85:142-147, 1993]

7. Public health interests in trade agreements on alcoholic beverages in North America [1993]

  • Ferris, Jacqueline, Room, Robin, and Giesbrecht, Norman
  • Alcohol Health & Research World. Summer 1993, Vol. 17 Issue 3, p235, 7 p.
Subjects
International trade, Laws, regulations and rules, Alcoholic beverage industry -- International trade, International trade regulation, and International trade -- Laws, regulations and rules
Abstract
Public health often conflicts with economic benefit in trade agreements covering alcoholic beverages. In North America, states and provinces tend to bear the brunt of costs. Several alcohol trade and marketing agreements are discussed.

8. New barriers to ventricular invasion in paraglottic laryngeal cancer [1994]

  • Beitler, Jonathan J., Mahadevia, Panna S., Silver, Carl E., Wadler, Scott, Rubin, John S., Bello, Jacqueline A., Mitnick, Robin J., and Vikram, Bhadrasain
  • Cancer. May 15, 1994, Vol. 73 Issue 10, p2648, 5 p.
Subjects
Physiological aspects, Development and progression, Cancer invasiveness -- Physiological aspects, and Laryngeal cancer -- Development and progression
Abstract
Background. Anatomic barriers to the spread of laryngeal cancer include the conus elasticus, the quadrangular membrane, and the thyroid cartilage. It has been speculated that an elastic barrier surrounds and protects the ventricle. Methods. The authors studied the microanatomic patterns of spread of 17 cases of patients who had laryngeal cancer with paraglottic disease and confirmed their findings by examining normal autopsy specimens. Results. Five patients of the seventeen cases showed no ventricular mucosal involvement despite extensive paraglottic disease. Both an inner, central, subepithelial periventricular elastic barrier, and a more peripheral periventricular elastic membrane barrier were identified; the latter was in continuity with the conus elasticus and quadrangular membrane. Conclusions. Two weak fibroelastic barriers surround the ventricle. The outer, peripheral, fibroelastic membrane is contiguous with the conus elasticus and the quadrangular membrane. Therefore, ventricular involvement is not a sensitive indicator of paraglottic spread. Squamous cell cancer may grow around the periventricular barriers to involve both the true and false cords but may spare the ventricle. The prognostic significance of the violation or preservation of the periventricular elastic barriers is unknown.

9. The Meaning of Illness Questionnaire: further evidence for its reliability and validity. [1994]

  • Weir R, Browne G, Roberts J, Tunks E, and Gafni A
  • Pain [Pain] 1994 Sep; Vol. 58 (3), pp. 377-386.
Subjects
Adaptation, Psychological, Adult, Chronic Disease, Factor Analysis, Statistical, Female, Humans, Male, Regression Analysis, Social Support, Socioeconomic Factors, Surveys and Questionnaires, Life Change Events, Pain psychology, and Quality of Life
Abstract
Cognitive appraisal processes or the meaning a person gives a stressful event are believed to mediate an individual's reaction to an event and, as such, have been demonstrated to explain adjustment to illness. The purpose of this paper is to test this cognitive as well as other social and illness variables to explain the variance in a person's adjustment to chronic pain. Two hundred and twenty-two patients, who were randomly selected from an original sample of referrals to a chronic pain specialty clinic, completed a questionnaire by telephone interview or mail. The questionnaire consisted of psychosocial scales (PAIS-SR; Social Support) and cognitions including the Meaning of Illness Questionnaire (MIQ). Fifty-six percent of the sample had poor psychosocial adjustment to their pain problem. Seventy percent of the variance in adjustment was explained by social and cognitive variables which corroborates their importance. The MIQ 5-factor structure was supported and provides credible evidence of the role of cognitions in differentiating between the poor and well adjusted.

10. Developmental expression of the sea urchin egg receptor for sperm [1994]

  • Ohlendieck, Kay, Partin, Jacqueline S., Stears, Robin L., and Lennarz, William J.
  • Developmental Biology. Sept, 1994, Vol. 165 Issue 1, p53, 10 p. photograph
Subjects
Sea urchins -- Eggs and Spermatozoa -- Analysis
Abstract
Western and Northern blot analyses and immunocytochemistry of the sea urchin egg receptor for sperm to study the receptor expression during oogenesis indicate that in the last two developmental phases of oogenesis the receptor mRNA level exhibits a very high increase despite the absence of receptor glycoprotein or receptor mRNA in the early oocytes. The development of receptor occurs in association with the spatial and temporal formation of cortical granules. Development of the receptor in the late stages and its localization to the cell surface and cortical granules indicates that the receptor mediates attachment of sperm to the surface of the mature egg cell.

11. Ambiguity and underwriter decision processes [1995]

  • Kunreuther, Howard, Meszaros, Jacqueline, Hogarth, Robin M., and Spranca, Mark
  • Journal of Economic Behavior & Organization. May 1995, Vol. 26 Issue 3, p337, 1 p.
Subjects
Ambiguity -- Economic aspects, Decision-making -- Research, Insurance industry -- Psychological aspects, and Risk assessment -- Psychological aspects
Abstract
Research is presented demonstrating the impact of ambiguity and risk on the insurance pricing decisions of underwriters. Premiums are shown to be substantially higher where there is uncertainty about potential loss levels and where the probability of an event occurring is ambiguous.

12. An evaluation of peer and professional trainers in a union-based occupational health and safety training program [1997]

  • Kurtz, Jacqueline R., Robins, Thomas G., and Schork, M. Anthony
  • Journal of Occupational and Environmental Medicine. July 1997, Vol. 39 Issue 7, p661, 11 p.
Subjects
Training, Evaluation, Occupational safety and health -- Training, Employee trainers -- Evaluation, and Occupational health and safety -- Training
Abstract
Social cognitive theory posits that behavior can be changed by observing others perform or describe performance of behaviors. This framework was applied to understanding health behavior change associated with workplace health and safety training. Questionnaires were developed and administered to 426 workers at a United Automobile Worker's Union health and safety training program. Participants received training from one of three trainers: (1) local union discussion leaders (LUDLs), (2) professional staff trainers, or (3) LUDLs with professional staff trainers. Data were collected in three phases: before, after, and three months post-training. Findings show that subjects trained by LUDLs identify most closely with their instructors, whereas subjects trained by staff trainers identify least closely with them. In addition, workers trained by LUDLs reported changing behavior as a result of training more often than workers trained by others.

13. Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines [1997]

  • Boshoff, Chris, Endo, Yoshio, Collins, Paul D., Takeuchi, Yasuhiro, Reeves, Jacqueline D., Schweickart, Vicki L., Siani, Michael A., Sasaki, Takuma, Williams, Timothy J., Gray, Patrick W., Moore, Patrick S., Chang, Yuan, and Weiss, Robin A.
  • Science. Oct 10, 1997, Vol. 278 Issue 5336, p290, 5 p.
Subjects
Physiological aspects, Kaposi's sarcoma -- Physiological aspects, HIV, Virus inactivation, HIV infections -- Physiological aspects, HIV (Viruses) -- Inactivation, and HIV infection -- Physiological aspects
Abstract
Kaposi's sarcoma (KS) is a highly angiogenic multicentric tumor most commonly seen in immunodeficient individuals. Since the acquired immunodeficiency syndrome (AIDS) epidemic, KS has become one of the most common [...]
Unique among known human herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) encodes chemokine-like proteins (vMIP-I and vMIP-II). vMIP-II was shown to block infection of human immunodeficiency virus-type 1 (HIV-1) on a CD4-positive cell line expressing CCR3 and to a lesser extent on one expressing CCR5, whereas both vMIP-I and vMIP-II partially inhibited HIV infection of peripheral blood mononuclear cells. Like eotaxin, vMIP-II activated and chemoattracted human eosinophils by way of CCR3. vMIP-I and vMIP-II, but not cellular MIP-1 [Alpha] or RANTES, were highly angiogenic in the chorioallantoic assay, suggesting a possible pathogenic role in Kaposi's sarcoma.

14. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection [1998]

  • Halsey, Neal A., Coberly, Jacqueline S., Desormeaux, Julio, Losikoff, Phyllis, Atkinson, Joan, Moulton, Lawrence H., Contave, Mireil, Johnson, Michael, Davis, Homer, Geiter, Lawrence, Johnson, Erica, Huebner, Robin, Boulos, Reginald, and Chaisson, Richard E.
  • The Lancet. March 14, 1998, Vol. 351 Issue 9105, p786, 7 p.
Subjects
Prevention, Complications and side effects, Evaluation, Tuberculosis -- Prevention, HIV infections -- Complications, Rifampin -- Evaluation, Pyrazinamide -- Evaluation, Isoniazid -- Evaluation, and HIV infection -- Complications
Abstract
A short course of treatment with rifampicin and pyrazinamide may effectively prevent tuberculosis in HIV-infected people with a positive skin test for the disease. Researchers assigned 750 people in Haiti to six months of treatment with isoniazid or two months of treatment with rifampicin and pyrazinamide. Tuberculosis developed in 3.8% of the people who took isoniazid and 5% of those who took the two-drug combination. Both treatments provided similar levels of tuberculosis prevention, but people were more likely to comply with treatment instructions when the course of therapy was shorter.
Background Tuberculosis is a common complication of HIV-1 infection, especially in developing countries. Practical and effective chemoprophylaxis regimens for HIV-1-related tuberculosis are needed. Our aim was to test the efficacy of isoniazid versus rifampicin with pyrazinamide for prevention of tuberculosis in HIV-1-positive individuals. Methods We compared the efficacy of 6 months of isoniazid with 2 months of rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1-seropositive individuals. Eligible participants were aged 16-77 years, HIV-1 seropositive, had a positive purified-protein derivative (PPD) skin test reaction of at least 5 mm, and had a normal chest radiograph. Participants were randomly assigned partially supervised twice weekly isoniazid for 24 weeks or twice weekly rifampicin and pyrazinamide for 8 weeks. Participants were followed up for up to 4 years for the development of tuberculosis and survival. Findings Tuberculosis developed in 14 (3.8%) of 370 participants assigned isoniazid and 19 (5.0%) of 380 participants assigned rifampicin and pyrazinamide (Cox model rate ratio 1.3 [95% CI 0.7-2.7]). The Kaplan-Meier estimate of the risk of tuberculosis during the first 10 months after entry was 3.7% among participants who received rifampicin and pyrazinamide compared with 1.0% (p=0.03) among participants who received isoniazid, and 5.4% versus 5.1%, respectively (p=0.9) at 36 months after entry. Higher rates of tuberculosis were observed in people with baseline CD4 percentages (of total lymphocytes) of less than 20 (rate ratio 40 [95% CI 1.8-9.0]). There were no significant differences in total mortality at any time. Interpretation Twice-weekly isoniazid preventive therapy for 6 months or rifampicin and pyrazinamide for 2 months provided similar overall protection against tuberculosis in HIV-1-infected. PPD-positive adults. The better protection among recipients of isoniazid during the first 10 months was most likely secondary to the longer duration of chemoprophylaxis. Preventive therapy for HIV-1-seropositive, PPD-positive individuals could be practical in developing countries with a once weekly clinic visit, but optimum duration of chemoprophylaxis has not been determined. Lancet 1998; 351: 786-92

15. Latanoprost treatment for glaucoma: effects of treating for 1 year and of switching from timolol [1998]

  • Camras, Carl B., Wax, Martin B., Ritch, Robert, Weinreb, Robert, Robin, Alan L., Higginbotham, Eve J., Lustgarten, Jacqueline, Stewart, William C., Sherwood, Mark, Krupin, Theodore, Wilensky, Jacob, Cioffi, George A., Katz, L. Jay, Schumer, Robert A., Kaufman, Paul L., Minckler, Don, Zimmerman, Thom, and Stjernschantz, Johan
  • American Journal of Ophthalmology. Sept 1998, Vol. 126 Issue 3, p390, 10 p.

16. Anger-related traits and response to interpersonal conflict among New York City traffic agents [1998]

  • Brondolo, Elizabeth, Masheb, Robin, Stores, Jacqueline, Stockhammer, Tanya, Tunick, Wendy, Melhado, Elizabeth, Karlin, William A., Schwartz, Joseph, Harburg, Ernest, and Contrada, Richard J.
  • Journal of Applied Social Psychology. Nov 16, 1998, Vol. 28 Issue 22, p2089, 3 p. 3
Subjects
Anger -- Research, Interpersonal conflict -- Research, Traffic police -- Psychological aspects, and Social psychology -- Research
Abstract
This study evaluates the psychosocial correlates of anger-related traits. Participants include New York City traffic enforcement agents (TEAs), who issue summonses for vehicular and parking violations and are frequently confronted by angry motorists. This sample of TEAs is 53% African American and 57% female. Participants completed surveys at 2 points, 4 months apart, which measured attitudinal, affective, and expressive components of hostility and anger, as well as dimensions of workplace psychosocial response. Results indicate that trait anger-in was positively associated with frequency of conflict, anger intensity, and burnout in cross-sectional analyses; and positively associated with frequency of conflict in prospective analyses. Trait anger was positively associated with an increase in burnout over a 4-month period. These findings provide support for the transactional model of hostility and health and have implications for worksite interventions promoting cardiovascular health.

17. Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. [2002]

  • Schmidt S, Barcellos LF, DeSombre K, Rimmler JB, Lincoln RR, Bucher P, Saunders AM, Lai E, Martin ER, Vance JM, Oksenberg JR, Hauser SL, Pericak-Vance MA, and Haines JL
  • American journal of human genetics [Am J Hum Genet] 2002 Mar; Vol. 70 (3), pp. 708-17. Date of Electronic Publication: 2002 Feb 11.
Subjects
Adolescent, Adult, Age of Onset, Alleles, Child, Disease Progression, Female, Haplotypes genetics, Heterozygote, Humans, Male, Middle Aged, Molecular Sequence Data, Multiple Sclerosis pathology, Phenotype, Polymorphism, Single Nucleotide genetics, Probability, Survival Analysis, Apolipoproteins E genetics, Genetic Predisposition to Disease, Multiple Sclerosis genetics, Multiple Sclerosis physiopathology, and Polymorphism, Genetic genetics
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, with a complex etiology that includes a strong genetic component. The contribution of the major histocompatibility complex (MHC) has been established in numerous genetic linkage and association studies. In addition to the MHC, the chromosome 19q13 region surrounding the apolipoprotein E (APOE) gene has shown consistent evidence of involvement in MS when family-based analyses were conducted. Furthermore, several clinical reports have suggested that the APOE-4 allele may be associated with more-severe disease and faster progression of disability. To thoroughly examine the role of APOE in MS, we genotyped its functional alleles, as well as seven single-nucleotide polymorphisms (SNPs) located primarily within 13 kb of APOE, in a data set of 398 families. Using family-based association analysis, we found statistically significant evidence that an SNP haplotype near APOE is associated with MS susceptibility (P=.005). An analysis of disease progression in 614 patients with MS from 379 families indicated that APOE-4 carriers are more likely to be affected with severe disease (P=.03), whereas a higher proportion of APOE-2 carriers exhibit a mild disease course (P=.02).

18. Toxic equivalency factors for PAH and their applicability in shellfish pollution monitoring studies. [2002]

  • Law RJ, Kelly C, Baker K, Jones J, McIntosh AD, and Moffat CF
  • Journal of environmental monitoring : JEM [J Environ Monit] 2002 Jun; Vol. 4 (3), pp. 383-8.
Subjects
Animals, Carcinogens, Environmental toxicity, Environmental Monitoring, Gasoline toxicity, Mollusca, Petroleum toxicity, and Polycyclic Aromatic Hydrocarbons toxicity
Abstract
Fish and shellfish are exposed to a wide range of polycyclic aromatic hydrocarbons (PAH) following oil spills at sea, and can become contaminated as a result. Finfish have a more effective mixed-function oxidase enzyme system than shellfish, and are therefore able to metabolise and excrete PAH more effectively than the invertebrates. Thus, contamination by high-molecular weight PAH, including those with carcinogenic potential and so of concern with regard to human consumers, is therefore usually observed in shellfish, and particularly in bivalve molluscs. Oil spills are not the sole source of PAH, however, as parent compounds are also generated by a wide range of combustion processes. In this paper, consideration is given to monitoring data gathered following recent oil spills (both of crude oil and diesel fuel), alongside data from other studies. These include studies conducted around a former gasworks site and downstream of an aluminium smelter in the UK, and from mussel monitoring studies undertaken in the UK and the USA (including the Exxon Valdez oil spill and the National Status and Trends programme), and in other countries in Europe. For comparative purposes the PAH concentrations are summed and also expressed as benzo[a]pyrene equivalents, their relative concentrations being weighted in relation to the carcinogenic potential of individual PAH compounds using toxic equivalency factors (TEF). Our aim was to assess the utility of this approach in fishery resource monitoring and control following oil spills. Certainly this approach seems useful from the data assessed in this study. and the relative ranking of the various studies seems to reflect the relative degree of concern for human consumers due to the differing contamination sources. As a simple tool for control purposes it is equally applicable to PAH derived from oil spills, and from industrial and combustion sources.

19. Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats. [2002]

  • Novak J, Ramirez RJ, Gandley RE, Sherwood OD, and Conrad KP
  • American journal of physiology. Regulatory, integrative and comparative physiology [Am J Physiol Regul Integr Comp Physiol] 2002 Aug; Vol. 283 (2), pp. R349-55.
Subjects
Animals, Dose-Response Relationship, Drug, Drug Administration Schedule, Endothelin Receptor Antagonists, Endothelium, Vascular physiology, Enzyme Inhibitors pharmacology, Female, In Vitro Techniques, Infusion Pumps, Implantable, Nitric Oxide Synthase antagonists inhibitors, Peptides, Cyclic pharmacology, Pregnancy, Rats, Rats, Long-Evans, Receptor, Endothelin B, Vascular Patency drug effects, Vasoconstrictor Agents pharmacology, Vasodilator Agents pharmacology, Vasomotor System physiology, Arteries drug effects, Arteries physiology, Kidney blood supply, Relaxin pharmacology, and Vasomotor System drug effects
Abstract
Administration of the ovarian hormone relaxin to nonpregnant rats vasodilates the renal circulation comparable to pregnancy. This vasodilation is mediated by endothelin (ET), the ET(B) receptor, and nitric oxide. Furthermore, endogenous relaxin mediates the renal vasodilation and hyperfiltration that occur during gestation. The goal of this study was to investigate whether myogenic reactivity of small renal and mesenteric arteries is reduced in relaxin-treated rats comparable to the pregnant condition. Relaxin or vehicle was administered to virgin female Long-Evans rats for 5 days at 4 microg/h, thereby producing midgestational blood levels of the hormone. The myogenic responses of small renal arteries (200-300 microm in diameter) isolated from these animals were evaluated in an isobaric arteriograph system. Myogenic reactivity was significantly reduced in the small renal arteries from relaxin-treated compared with vehicle-treated rats. The reduced myogenic responses were mediated by the ET(B) receptor and nitric oxide since the selective ET(B) receptor antagonist RES-701-1 and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester restored myogenic reactivity to virgin levels. The influence of relaxin was not limited to the renal circulation because myogenic reactivity was also reduced in small mesenteric arteries isolated from relaxin-treated rats. Thus relaxin administration to nonpregnant rats mimics pregnancy, insofar as myogenic reactivity of small renal and mesenteric arteries is reduced in both conditions.

20. Antithrombin 'DREUX' (Lys 114Glu): a variant with complete loss of heparin affinity. [2002]

  • Mushunje A, Zhou A, Huntington JA, Conard J, and Carrell RW
  • Thrombosis and haemostasis [Thromb Haemost] 2002 Sep; Vol. 88 (3), pp. 436-43.
Subjects
Animals, Antithrombin III metabolism, Binding Sites, Brain Ischemia blood, Cattle, DNA Mutational Analysis, Factor Xa Inhibitors, Family Health, Genetic Variation, Humans, Hypercholesterolemia blood, Male, Middle Aged, Mutation, Missense, Protein Binding genetics, Antithrombin III chemistry, Antithrombin III genetics, and Heparin metabolism
Abstract
Here we report the finding of a new natural antithrombin mutation that confirms the critical contribution of lysine 114 to the binding of the core heparin pentasaccharide, with the replacement of lysine 114 by glutamate causing a complete loss in affinity. The variant was identified in a father and son, the father having been investigated for an episode of cerebral ischaemia associated with hypercholesterolaemia. The variant forms SDS-stable complexes with activated factor X (fXa) and its thermal stability and rate of factor Xa inhibition in the absence of heparin are identical to those of normal antithrombin. Normal antithrombin binds to the high affinity heparin pentasaccharide with a Kd of 1nM, as detected by a 45% change in intrinsic fluorescence, resulting in a 230-fold increase in rate of factor Xa inhibition. However, no change in fluorescence was detected for the variant when titrated with heparin or the heparin pentasaccharide, nor was there detectable activation towards factor Xa, indicating a complete loss of heparin binding.

21. Multiple susceptibility loci for multiple sclerosis. [2002]

  • Haines JL, Bradford Y, Garcia ME, Reed AD, Neumeister E, Pericak-Vance MA, Rimmler JB, Menold MM, Martin ER, Oksenberg JR, Barcellos LF, Lincoln R, and Hauser SL
  • Human molecular genetics [Hum Mol Genet] 2002 Sep 15; Vol. 11 (19), pp. 2251-6.
Subjects
Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 6, Chromosomes, Human, Pair 7, Genetic Heterogeneity, HLA-DR2 Antigen genetics, Humans, Lod Score, Multiple Sclerosis etiology, Genetic Linkage, Genetic Predisposition to Disease, and Multiple Sclerosis genetics
Abstract
Multiple sclerosis (MS) is a common and frequently disabling autoimmune disorder mediated by autoaggressive T cells and autoantibodies that target central nervous system myelin. While numerous studies have demonstrated a strong genetic component to MS, it has been difficult to identify the specific genes involved. Several genomic screens have been undertaken to locate such genes, but have not provided consistent gene localization, except for the MHC on chromosome 6p21 and a locus on chromosome 19q13. To determine which of the original genomic locations presented in the US genome screen could be replicated, a more detailed analysis of additional families was performed. The results, derived from a population of 266 affected individuals belonging to 98 multiplex families, continue to support linkage to chromosomes 6p21, 6q27, and 19q13 with LOD scores>3.0, and suggest that regions on chromosomes 12q23-24 and 16p13 may also harbor susceptibility loci for MS. Analysis taking into account the known HLA-DR2 association identified two additional potential linkage regions on chromosomes 7q21-22 and 13q33-34. These regions can now be targeted for detailed study to identify the underlying MS susceptibility genes.

22. Standards for hospital libraries 2002. [2002]

  • Gluck JC, Hassig RA, Balogh L, Bandy M, Doyle JD, Kronenfeld MR, Lindner KL, Murray K, Petersen J, and Rand DC
  • Journal of the Medical Library Association : JMLA [J Med Libr Assoc] 2002 Oct; Vol. 90 (4), pp. 465-72.
Subjects
Consultants, Humans, Librarians, Personnel Staffing and Scheduling standards, Societies, Workforce, Information Management standards, Libraries, Hospital standards, Library Services standards, and Professional Role
Abstract
The Medical Library Association's "Standards for Hospital Libraries 2002" have been developed as a guide for hospital administrators, librarians, and accrediting bodies to ensure that hospitals have the resources and services to effectively meet their needs for knowledge-based information. Specific requirements for knowledge-based information include that the library be a separate department with its own budget. Knowledge-based information in the library should be directed by a qualified librarian who functions as a department head and is a member of the Academy of Health Information Professionals. The standards define the role of the medical librarian and the links between knowledge-based information and other functions such as patient care, patient education, performance improvement, and education. In addition, the standards address the development and implementation of the knowledge-based information needs assessment and plans, the promotion and publicity of the knowledge-based information services, and the physical space and staffing requirements. The role, qualifications, and functions of a hospital library consultant are outlined. The health sciences library is positioned to play a key role in the hospital. The increasing use of the Internet and new information technologies by medical, nursing, and allied health staffs; patients; and the community require new strategies, strategic planning, allocation of adequate resources, and selection and evaluation of appropriate information resources and technologies. The Hospital Library Standards Committee has developed this document as a guideline to be used in facing these challenges.

23. Health effects of World Trade Center site workers. [2002]

  • Levin S, Herbert R, Skloot G, Szeinuk J, Teirstein A, Fischler D, Milek D, Piligian G, Wilk-Rivard E, and Moline J
  • American journal of industrial medicine [Am J Ind Med] 2002 Dec; Vol. 42 (6), pp. 545-7.
Subjects
Air Pollutants analysis, Aircraft, Humans, Musculoskeletal Diseases etiology, Musculoskeletal Diseases psychology, New York City, Occupational Diseases psychology, Occupational Health, Pilot Projects, Respiratory Tract Diseases psychology, Air Pollutants adverse effects, Occupational Diseases etiology, Occupational Exposure adverse effects, Rescue Work, Respiratory Tract Diseases etiology, and Terrorism

24. Efficient production of Arthromyces ramosus peroxidase by Aspergillus awamori. [2003]

  • Lokman BC, Joosten V, Hovenkamp J, Gouka RJ, Verrips CT, and van den Hondel CA
  • Journal of biotechnology [J Biotechnol] 2003 Jun 26; Vol. 103 (2), pp. 183-90.
Subjects
Aspergillus genetics, Aspergillus growth development, Blotting, Northern, Blotting, Southern, Fermentation, Heme metabolism, Mitosporic Fungi genetics, Peroxidase metabolism, Plasmids, Promoter Regions, Genetic, Aspergillus enzymology, Biotechnology methods, Mitosporic Fungi enzymology, and Peroxidase genetics
Abstract
The heterologous production of Arthromyces ramosus peroxidase (ARP) was analysed in the filamentous fungus Aspergillus awamori under control of the inducible endoxylanase promoter. Secretion of active ARP was achieved up to 800 mg l(-1) in shake flask cultures. Western blot analysis showed that an rARP product of the correct molecular weight was produced. In contrast to several other studies about heterologous production of heme containing peroxidases, our results suggest that in A. awamori no heme limitation exists during overproduction of ARP.

25. Prevalence of obsessive compulsive disorder in first- and multi-episode male patients with schizophrenia-spectrum disorders. [2003]

  • Koen L, Oosthuizen PP, Niehaus DJ, Emsley RA, Muller JE, Stein DJ, Keyter N, Lochner C, and Seedat S
  • South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde [S Afr Med J] 2003 Jul; Vol. 93 (7), pp. 517-8.
Subjects
Adult, Comorbidity, Cross-Sectional Studies, Humans, Male, Obsessive-Compulsive Disorder complications, Prevalence, Racial Groups, Schizophrenia complications, South Africa epidemiology, Obsessive-Compulsive Disorder ethnology, and Schizophrenia ethnology

26. Butyrate-treated colonic Caco-2 cells exhibit defective integrin-mediated signaling together with increased apoptosis and differentiation. [2003]

  • Lévy P, Robin H, Bertrand F, Kornprobst M, and Capeau J
  • Journal of cellular physiology [J Cell Physiol] 2003 Dec; Vol. 197 (3), pp. 336-47.
Subjects
Apoptosis drug effects, Butyrates pharmacology, Caco-2 Cells, Carcinoma drug therapy, Carcinoma metabolism, Carcinoma physiopathology, Caspase 3, Caspases drug effects, Caspases metabolism, Cell Adhesion drug effects, Cell Differentiation drug effects, Colonic Neoplasms drug therapy, Colonic Neoplasms metabolism, Colonic Neoplasms physiopathology, Down-Regulation drug effects, Down-Regulation physiology, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, Integrin beta1 drug effects, Integrin beta1 metabolism, Integrins drug effects, Intestinal Mucosa drug effects, NF-kappa B drug effects, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases drug effects, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation drug effects, Protein-Tyrosine Kinases drug effects, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins drug effects, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2 drug effects, Proto-Oncogene Proteins c-bcl-2 metabolism, Signal Transduction drug effects, Signal Transduction physiology, Sucrase drug effects, Sucrase metabolism, Apoptosis physiology, Cell Adhesion physiology, Cell Differentiation physiology, Integrins metabolism, Intestinal Mucosa metabolism, and Protein Serine-Threonine Kinases
Abstract
We previously reported that the enterocytic differentiation of human colonic Caco-2 cells correlated with alterations in integrin signaling. We now investigated whether differentiation and apoptosis of Caco-2 cells induced by the short-chain fatty acid butyrate (NaBT) was associated with alterations in the integrin-mediated signaling pathway with special interest in the expression and activity of focal adhesion kinase (FAK), of the downstream phosphatidylinositol 3'-kinase (PI 3-kinase)-Akt pathway and in the role of the nuclear factor kappaB (NF-kappaB). NaBT increased the level of sucrase. It induced apoptosis as shown by: (1) decreased Bcl-2 and Bcl-X(L) proteins and increased Bax protein; (2) activation of caspase-3; and (3) increased shedding of apoptotic cells in the medium. This effect was associated with defective integrin-mediated signaling as shown by: (1) down-regulation of beta1 integrin expression; 2) decreased FAK expression and tyrosine phosphorylation; (3) concerted alterations in cytoskeletal and structural focal adhesions proteins (talin, ezrin); and (4) decreased FAK ability to associate with PI 3-kinase. However, in Caco-2 cells, beta1-mediated signaling failed to be activated downstream of FAK and PI 3-kinase at the level of Akt. Transfection studies show that NaBT treatment of Caco-2 cells promoted a significant activation of the NF-kappaB which was probably involved in the NaBT-induced apoptosis. Our results indicate that the prodifferentiating agent NaBT induced apoptosis of Caco-2 cells probably through NF-kappaB activation together with a defective beta1 integrin-FAK-PI 3-kinase pathways signaling.

27. Firing patterns of type II spiral ganglion neurons in vitro. [2004]

  • Reid MA, Flores-Otero J, and Davis RL
  • The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2004 Jan 21; Vol. 24 (3), pp. 733-42.
Subjects
Action Potentials physiology, Animals, Cells, Cultured, Cochlear Nerve physiology, Culture Techniques, Electric Stimulation methods, Immunohistochemistry, Kv1.1 Potassium Channel, Mice, Mice, Inbred CBA, Neurons classification, Neurons metabolism, Patch-Clamp Techniques, Potassium Channels biosynthesis, Protein Subunits biosynthesis, Reaction Time physiology, Neurons physiology, Potassium Channels, Voltage-Gated, and Spiral Ganglion cytology
Abstract
Type I and type II spiral ganglion neurons convey auditory information from the sensory receptors in the cochlea to the CNS. The numerous type I neurons have been extensively characterized, but the small population of type II neurons with their unmyelinated axons are undetectable with most recording methods. Despite the paucity of information about the type II neurons, it is clear that they must have a significant role in sound processing because they innervate the large number of outer hair cells that are critical for maintaining normal responses to stimuli. To elucidate the function of type II neurons, we have developed an approach for studying their electrophysiological features in vitro. Type II neurons obtained from postnatal day 6-7 mice displayed distinctly different firing properties than type I neurons. They showed slower accommodation, lower action potential thresholds, and more prolonged responses to depolarizing current injection than the type I neurons. These differences were most evident in neurons from the basal, high-frequency region of the cochlea. The basal type I neurons displayed uniformly fast firing features, whereas the basal type II neurons showed particularly slow accommodation and responses to depolarization. Interestingly, neurons from the apical, low-frequency region of the cochlea showed the opposite trend. These data suggest that the type I and type II neurons have specialized electrophysiological characteristics tailored to their different roles in auditory signal processing. In particular, the type II neuron properties are consistent with cells in other sensory systems that receive convergent synaptic input for high-sensitivity stimulus detection.

28. Investigation of seven proposed regions of linkage in multiple sclerosis: an American and French collaborative study. [2004]

  • Pericak-Vance MA, Rimmler JB, Haines JL, Garcia ME, Oksenberg JR, Barcellos LF, Lincoln R, Hauser SL, Cournu-Rebeix I, Azoulay-Cayla A, Lyon-Caen O, Fontaine B, Duhamel E, Coppin H, Brassat D, Roth MP, Clanet M, Alizadeh M, Yaouanq J, Quelvennec E, Semana G, Edan G, Babron MC, Genin E, and Clerget-Darpoux F
  • Neurogenetics [Neurogenetics] 2004 Feb; Vol. 5 (1), pp. 45-8. Date of Electronic Publication: 2003 Nov 01.
Subjects
Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 3, Cooperative Behavior, France, Genetic Predisposition to Disease, HLA-DR Antigens genetics, HLA-DR Serological Subtypes, Humans, United States, Genetic Linkage genetics, and Multiple Sclerosis genetics
Abstract
Multiple sclerosis (MS) is a demyelinating autoimmune disease with a strong yet complex genetic component. To date only the HLA-DR locus, and specifically the HLA-DR15 allele, has been identified and confirmed as influencing the risk of developing MS. Genomic screens on several datasets have been performed and have identified several chromosomal regions with interesting results, but none have yet been confirmed. We tested seven of the most-promising regions (on chromosomes 1p, 2p, 3p, 3q, 5q, 19q, and Xp) identified from several genomic screens in a dataset of 98 multiplex MS families from the United States and 90 multiplex MS families from France. The results did not confirm linkage to 2p, 3q, 5q, or Xp in the overall dataset, or in subsets defined by geographic origin or HLA-DR15 status. Regions on 1p34, 3p14, and 19q13 produced lod scores >0.90 in at least one subset of the data, suggesting that these regions should be examined in more detail.

29. Anxiety disorders and schizophrenia. [2004]

  • Muller JE, Koen L, Soraya S, Emsley RA, and Stein DJ
  • Current psychiatry reports [Curr Psychiatry Rep] 2004 Aug; Vol. 6 (4), pp. 255-61.
Subjects
Anxiety Disorders physiopathology, Brain physiopathology, Humans, Obsessive-Compulsive Disorder epidemiology, Panic Disorder epidemiology, Phobic Disorders epidemiology, Schizophrenia physiopathology, Stress Disorders, Post-Traumatic epidemiology, Anxiety Disorders epidemiology, and Schizophrenia epidemiology
Abstract
Anxiety symptoms and disorders have long been described in schizophrenia. This article reviews the epidemiology, phenomenology, and neurobiologic underpinnings of comorbid anxiety symptoms and disorders in schizophrenia. Recent literature was obtained by Medline searches using key words relating to schizophrenia and anxiety symptoms or disorders. There is some evidence that anxiety may be a core symptom dimension in schizophrenia, although further work is required. There is evidence that comorbid obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social anxiety disorder are all more common than expected by chance in schizophrenia, although additional work is needed to determine the mechanisms that underlie these associations and their clinical implications. In the interim, however, the data emphasize the importance of assessing and treating comorbid anxiety symptoms and disorders in schizophrenia.

30. Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35. [2004]

  • Marazita ML, Murray JC, Lidral AC, Arcos-Burgos M, Cooper ME, Goldstein T, Maher BS, Daack-Hirsch S, Schultz R, Mansilla MA, Field LL, Liu YE, Prescott N, Malcolm S, Winter R, Ray A, Moreno L, Valencia C, Neiswanger K, Wyszynski DF, Bailey-Wilson JE, Albacha-Hejazi H, Beaty TH, McIntosh I, Hetmanski JB, Tunçbilek G, Edwards M, Harkin L, Scott R, and Roddick LG
  • American journal of human genetics [Am J Hum Genet] 2004 Aug; Vol. 75 (2), pp. 161-73. Date of Electronic Publication: 2004 Jun 04.
Subjects
Genetic Linkage, Genetic Markers, Genetic Predisposition to Disease, Humans, Lod Score, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 9, Cleft Lip genetics, and Cleft Palate genetics
Abstract
Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD]=6.6). In addition, meta-analyses with the addition of results from 186 more families (six populations; 1,033 genotyped individuals) showed genomewide significance for 10 more regions, including another novel region at 2q32-35 (P=.0004). These are the first genomewide significant linkage results ever reported for CL/P, and they represent an unprecedented demonstration of the power of linkage analysis to detect multiple genes simultaneously for a complex disorder.

31. Positive end-expiratory pressure above lower inflection point minimizes influx of activated neutrophils into lung. [2004]

  • Monkman SL, Andersen CC, Nahmias C, Ghaffer H, Bourgeois JM, Roberts RS, Schmidt B, and Kirpalani HM
  • Critical care medicine [Crit Care Med] 2004 Dec; Vol. 32 (12), pp. 2471-5.
Subjects
Animals, Animals, Newborn, Biopsy, Needle, Cell Movement, Disease Models, Animal, Female, Immunohistochemistry, Lung Compliance, Male, Positron-Emission Tomography, Probability, Pulmonary Ventilation, Random Allocation, Respiratory Distress Syndrome diagnostic imaging, Sensitivity and Specificity, Tidal Volume, Neutrophils physiology, Positive-Pressure Respiration methods, Respiratory Distress Syndrome pathology, and Respiratory Distress Syndrome therapy
Abstract
Objectives: To compare the effects of low vs. high tidal volume (Vt) with three positive end-expiratory pressure (PEEP) strategies on activated neutrophil influx into the lung.
Design: Prospective, randomized controlled animal study.
Setting: Animal laboratory in a university hospital.
Subjects: Newborn piglets.
Interventions: Surfactant-depleted piglets were randomized in littermate pairs; to PEEP of either 0 (zero end-expiratory pressure [ZEEP]; n = 6), 8 cm H2O (PEEP 8; n = 5), or 1 cm H2O above the lower inflection point (LIP) (PEEP>LIP; n = 6). Within each pair piglets were randomized to a low VT (5-7 mL/kg) or high VT strategy (17-19 mL/kg). After 4 hrs of mechanical ventilation, 18-fluorodeoxyglucose (18FDG) was injected and positron emission tomography scanning was performed.
Measurements and Main Results: VT and PEEP changes on influx constants of 18FDG were assessed by analysis of variance. A within-litter comparison of Vt was nonsignificant (p = .50). A between-litter comparison, ordered in linear trend rank, from ZEEP, to PEEP 8, to PEEP>LIP, showed a strong effect of PEEP on influx constant (p = .019).
Conclusions: PEEP set above the LIP on the inspiratory limb of the pressure-volume curve affords a stronger lung protection than VT strategy.

32. Obsessive compulsive disorder--prevalence in Xhosa-speaking schizophrenia patients. [2005]

  • Niehaus DJ, Koen L, Muller J, Laurent C, Stein DJ, Lochner C, Seedat S, Mbanga I, Deleuze JF, Mallet J, and Emsley RA
  • South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde [S Afr Med J] 2005 Feb; Vol. 95 (2), pp. 120-2.
Subjects
Adult, Comorbidity, Ethnicity, Female, Humans, Interview, Psychological, Male, Obsessive-Compulsive Disorder complications, Prevalence, Schizophrenia epidemiology, Schizophrenia ethnology, Schizophrenic Psychology, South Africa epidemiology, Obsessive-Compulsive Disorder epidemiology, and Schizophrenia complications
Abstract
Obsessive compulsive disorder (OCD) has been reported in up to 31% of schizophrenia sufferers. This study evaluated the presence of OCD in a Xhosa-speaking schizophrenia group. Xhosa patients (N = 509, including 100 sibships) with schizophrenia were recruited from hospital and community settings. The patients underwent a structured clinical interview for the presence of lifetime co-morbid schizophrenia and OCD. Only 3 patients (0.5%) fulfilled criteria for OCD. No concordance for OCD was noted in the sibship group. Our findings differ from those in other parts of the world, and if replicated, might suggest unique protective environmental or genetic factors for OCD in certain ethnic groups.

33. The prevalence, correlates, and costs of depression in people living with HIV/AIDS in Ontario: implications for service directions. [2005]

  • Williams P, Narciso L, Browne G, Roberts J, Weir R, and Gafni A
  • AIDS education and prevention : official publication of the International Society for AIDS Education [AIDS Educ Prev] 2005 Apr; Vol. 17 (2), pp. 119-30.
Subjects
Adaptation, Psychological, Adult, Age Distribution, Comorbidity, Female, HIV Infections psychology, Health Care Costs statistics numerical data, Health Care Surveys, Health Expenditures statistics numerical data, Health Services statistics numerical data, Health Status, Health Surveys, Humans, Male, Middle Aged, Ontario epidemiology, Prevalence, Quality of Life, Risk Factors, Sex Distribution, Socioeconomic Factors, Depression economics, Depression epidemiology, HIV Infections economics, and HIV Infections epidemiology
Abstract
As new technologies extend the lives of people living with HIV/AIDS (PHA), the need increases for services that optimize their quality-of-life cost effectively. This study of PHAs (n = 297) in Ontario, Canada, examined the prevalence of depression, and its association with quality-of-life, coping strategies, social support, and use of health and social services. Results showed that depression was widespread (54.2%) and largely unrelated to demographic characteristics, but associated with diminished health status, health-related quality-of-life, and coping strategies. Depressed PHAs used significantly more crisis health care and related services, and community-based HIV/AIDS service organizations (ASOs). Findings suggest quality-of-life of PHAs may be improved by expanding the capacity of ASO workers to recognize and address depression, including helping depressed PHA access appropriate medication and sustain medication regimes.

34. Standards for hospital libraries 2002 with 2004 revisions. [2005]

  • Hassig RA, Balogh L, Bandy M, Doyle JD, Gluck JC, Lindner KL, Reich B, and Varner D
  • Journal of the Medical Library Association : JMLA [J Med Libr Assoc] 2005 Apr; Vol. 93 (2), pp. 282-3.
Subjects
Humans, Information Management standards, Library Associations standards, Professional Role, United States, Information Storage and Retrieval standards, Librarians, Libraries, Hospital standards, and Library Services standards

35. Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. [2005]

  • Woods KS, Cundall M, Turton J, Rizotti K, Mehta A, Palmer R, Wong J, Chong WK, Al-Zyoud M, El-Ali M, Otonkoski T, Martinez-Barbera JP, Thomas PQ, Robinson IC, Lovell-Badge R, Woodward KJ, and Dattani MT
  • American journal of human genetics [Am J Hum Genet] 2005 May; Vol. 76 (5), pp. 833-49. Date of Electronic Publication: 2005 Mar 30.
Subjects
Adolescent, Base Sequence, Child, Child, Preschool, Choristoma genetics, Chromosomes, Human, X, Gene Duplication, Human Growth Hormone deficiency, Humans, Infant, Male, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Pituitary Gland, Anterior, Polymorphism, Genetic, SOXB1 Transcription Factors, DNA-Binding Proteins genetics, High Mobility Group Proteins genetics, Hypopituitarism genetics, Pituitary Gland, Posterior abnormalities, and Transcription Factors genetics
Abstract
Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.

36. Characteristics of people living with HIV who use community-based services in Ontario, Canada: implications for service providers. [2005]

  • Williams P, Narciso L, Browne G, Roberts J, Weir R, and Gafni A
  • The Journal of the Association of Nurses in AIDS Care : JANAC [J Assoc Nurses AIDS Care] 2005 Jul-Aug; Vol. 16 (4), pp. 50-63.
Subjects
Adaptation, Psychological, Chi-Square Distribution, Community Health Services economics, Cross-Sectional Studies, Depression virology, Female, Financing, Personal statistics numerical data, HIV Infections complications, HIV Infections epidemiology, Health Care Surveys, Health Expenditures statistics numerical data, Health Services Needs and Demand, Health Status, Health Surveys, Humans, Karnofsky Performance Status, Male, Ontario epidemiology, Poverty psychology, Poverty statistics numerical data, Quality of Life, Social Work statistics numerical data, Socioeconomic Factors, Surveys and Questionnaires, Community Health Services statistics numerical data, HIV Infections psychology, Patient Acceptance of Health Care psychology, and Patient Acceptance of Health Care statistics numerical data
Abstract
Community-based AIDS service organizations (CBAOs) direct services to multiple-needs people living with HIV/AIDS who are less likely to use mainstream health promotion services. As people live longer with HIV, the potential to enhance quality of life increases, yet little is known about who uses CBAOs or how this use affects other health and social services. This study of people living with AIDS in Ontario, Canada (n = 297) examined the demographic and health-related characteristics of people with AIDS who do and do not use CBAOs and their patterns of mainstream service utilization. It found that users of CBAOs were significantly less healthy, less able to sustain normal activities, and more often depressed. They reported physical disabilities significantly more often. Their quality of life was also lower along certain dimensions. They were significantly poorer and more reliant on government income supports. They consumed significantly more nonhospital health and social services and had significantly higher out-of-pocket costs. These results suggest CBAOs are being accessed appropriately by those most vulnerable. In an effort to strengthen CBAO capacity to recognize and address depression and physical health problems prevalent among their clients, links to other mainstream health promotion and social services is recommended.

37. A high-density screen for linkage in multiple sclerosis. [2005]

  • Sawcer S, Ban M, Maranian M, Yeo TW, Compston A, Kirby A, Daly MJ, De Jager PL, Walsh E, Lander ES, Rioux JD, Hafler DA, Ivinson A, Rimmler J, Gregory SG, Schmidt S, Pericak-Vance MA, Akesson E, Hillert J, Datta P, Oturai A, Ryder LP, Harbo HF, Spurkland A, Myhr KM, Laaksonen M, Booth D, Heard R, Stewart G, Lincoln R, Barcellos LF, Hauser SL, Oksenberg JR, Kenealy SJ, and Haines JL
  • American journal of human genetics [Am J Hum Genet] 2005 Sep; Vol. 77 (3), pp. 454-67. Date of Electronic Publication: 2005 Jul 29.
Subjects
Australia, Chromosome Mapping, Europe, Family, Genetic Markers genetics, Genomics methods, Humans, Middle Aged, United States, Chromosomes, Human genetics, Genetic Linkage, Genetic Predisposition to Disease genetics, Genetic Testing methods, and Multiple Sclerosis genetics
Abstract
To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.

38. Longitudinal study of inpatients admitted to a general activation service: variables that predict discharge to a patient's discharge goal location. [2005]

  • Blackman-Weinberg C, Crook J, Roberts J, and Weir R
  • Archives of physical medicine and rehabilitation [Arch Phys Med Rehabil] 2005 Sep; Vol. 86 (9), pp. 1782-7.
Subjects
Adult, Aged, Cohort Studies, Disability Evaluation, Female, Humans, Inpatients, Longitudinal Studies, Male, Middle Aged, Ontario, Patient Transfer, Predictive Value of Tests, Probability, Prospective Studies, Recovery of Function, Risk Factors, Socioeconomic Factors, Treatment Outcome, Activities of Daily Living, Continuity of Patient Care organization administration, Patient Discharge, Physical Therapy Modalities, and Rehabilitation Centers organization administration
Abstract
Objective: To determine which sociodemographic and clinical characteristics of patients admitted to a general activation service (GAS) are predictive of discharge to patients' discharge goal locations (DGLs).
Design: Prospective cohort study.
Setting: Rehabilitation and complex continuing care hospital in southern Ontario, Canada.
Participants: Patients admitted from January 2000 to December 2002 (N=154).
Intervention: The GAS.
Main Outcome Measure: Patients indicated on their service applications where they wanted to be discharged. This is termed the DGL.
Results: Fifty-three percent of the sample were discharged to their DGLs. Ninety-eight percent of these patients were discharged by 9 months. Eighty-seven percent who were discharged to their DGLs were discharged to their own home. Predictors of being discharged to the DGL were better activities of daily living scores, good vision, and having sufficient help at home. Expert clinician opinion of the likelihood of each patient being discharged to his/her DGL, based on initial assessment, was also predictive of each patient's eventual discharge to his/her DGL.
Conclusions: The GAS has a 53% success rate in discharging patients to their DGLs. Variables have been identified that should be useful in predicting whether patients will be discharged to their DGLs. Our findings are meaningful and informative in determining future admission criteria for the service.

39. A case of "ifufunyane": a xhosa culture-bound syndrome. [2005]

  • Niehaus DJ, Stein DJ, Koen L, Lochner C, Muller JE, Mbanga NI, Emsley RA, and Gorman JM
  • Journal of psychiatric practice [J Psychiatr Pract] 2005 Nov; Vol. 11 (6), pp. 411-3.
Subjects
Adult, Antipsychotic Agents therapeutic use, Humans, Hysteria drug therapy, Male, Religion and Psychology, South Africa, Syndrome, Culture, Hysteria psychology, and Hysteria rehabilitation

40. Positive and negative symptoms in affected sib pairs with schizophrenia: implications for genetic studies in an African Xhosa sample. [2005]

  • Niehaus DJ, Koen L, Laurent C, Muller J, Deleuze JF, Mallet J, Seller C, Jordaan E, and Emsley R
  • Schizophrenia research [Schizophr Res] 2005 Nov 15; Vol. 79 (2-3), pp. 239-49. Date of Electronic Publication: 2005 Jul 01.
Subjects
Adult, Chi-Square Distribution, Demography, Factor Analysis, Statistical, Family Health, Female, Humans, Male, Middle Aged, Schizophrenia complications, Severity of Illness Index, South Africa epidemiology, Psychiatric Status Rating Scales, Schizophrenia diagnosis, Schizophrenia epidemiology, Schizophrenic Psychology, and Sibling Relations
Abstract
Careful phenotyping and the identification of subtypes of schizophrenia can contribute significantly to the success of genetic studies in schizophrenia. The phenomenology of schizophrenia in affected sib pairs has been well-described in Caucasian populations, however a paucity of data exists for African populations. This study therefore investigated symptom dimensions in a sizeable group of affected Xhosa sib pairs as a means of evaluating the role of shared familial factors in the psychosis of schizophrenia. Five hundred and thirteen participants were interviewed with the Diagnostic Interview for Genetic Studies (DIGS), which included the Schedules for the Assessment of Negative and Positive symptoms (SANS/SAPS). One hundred and four sib pairs were then extracted (N = 208) for analysis of concordance for lifetime psychotic symptoms and an exploratory factor analysis of the SANS/SAPS. Concordance analysis of life-time symptoms indicated a significant concordance for olfactory hallucinations, persecutory delusions, jealousy, somatic, reference and control delusions as well as thought insertion and withdrawal. The factor analysis of the global scores of the SAPS and SANS revealed a five factor best-fit model and accounted for 92.5% of variance. The factors included a negative symptom factor, a positive symptom factor, a positive thought disorder and a bizarre behaviour component. The core symptomatology of schizophrenia in this sib pair sample was similar to that reported in Caucasian populations with the exception of higher rates of auditory hallucinations and delusions of persecution. In summary therefore; although the factor analysis only supported the concept of the universality of psychotic symptoms in schizophrenia, the concordance analysis of these symptoms did reveal hallucinations as well as delusions of control as possible candidates relevant for future research into genotype-phenotype relationships.

41. Synthesis and structure-activity relationships of 1,2,4-triazoles as a novel class of potent tubulin polymerization inhibitors. [2005]

  • Ouyang X, Chen X, Piatnitski EL, Kiselyov AS, He HY, Mao Y, Pattaropong V, Yu Y, Kim KH, Kincaid J, Smith L 2nd, Wong WC, Lee SP, Milligan DL, Malikzay A, Fleming J, Gerlak J, Deevi D, Doody JF, Chiang HH, Patel SN, Wang Y, Rolser RL, Kussie P, Labelle M, and Tuma MC
  • Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2005 Dec 01; Vol. 15 (23), pp. 5154-9. Date of Electronic Publication: 2005 Sep 28.
Subjects
Antineoplastic Agents chemical synthesis, Humans, Microtubules drug effects, Molecular Structure, Structure-Activity Relationship, Triazoles chemical synthesis, Tubulin Modulators chemical synthesis, Tumor Cells, Cultured, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Triazoles chemistry, Triazoles pharmacology, Tubulin Modulators chemistry, and Tubulin Modulators pharmacology
Abstract
A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.

42. Community-associated methicillin-resistant Staphylococcus aureus epidemic clone USA300 in isolates from Florida and Washington. [2006]

  • Roberts JC, Krueger RL, Peak KK, Veguilla W, Cannons AC, Amuso PT, and Cattani J
  • Journal of clinical microbiology [J Clin Microbiol] 2006 Jan; Vol. 44 (1), pp. 225-6.
Subjects
Community-Acquired Infections epidemiology, Drug Resistance, Bacterial, Electrophoresis, Gel, Pulsed-Field, Florida epidemiology, Humans, Staphylococcus aureus isolation purification, Washington epidemiology, Wound Infection epidemiology, Wound Infection microbiology, Community-Acquired Infections microbiology, Methicillin pharmacology, Methicillin Resistance, Staphylococcal Infections epidemiology, and Staphylococcus aureus drug effects
Abstract
We examined 299 methicillin-resistant, community-associated Staphylococcus aureus isolates from Florida and Washington State for the presence of the USA300 epidemic clone. Pulsed-field gel electrophoresis demonstrated the epidemic clone in 43% of our S. aureus strains and in isolates from both states. The majority of the USA300 isolates (88%) were from wound infections.

43. Oxadiazole derivatives as a novel class of antimitotic agents: Synthesis, inhibition of tubulin polymerization, and activity in tumor cell lines. [2006]

  • Ouyang X, Piatnitski EL, Pattaropong V, Chen X, He HY, Kiselyov AS, Velankar A, Kawakami J, Labelle M, Smith L 2nd, Lohman J, Lee SP, Malikzay A, Fleming J, Gerlak J, Wang Y, Rosler RL, Zhou K, Mitelman S, Camara M, Surguladze D, Doody JF, and Tuma MC
  • Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2006 Mar 01; Vol. 16 (5), pp. 1191-6. Date of Electronic Publication: 2006 Jan 11.
Subjects
Animals, Antimitotic Agents chemistry, Antimitotic Agents classification, Biopolymers chemistry, Biopolymers metabolism, Cell Line, Tumor, Humans, Inhibitory Concentration 50, Mice, Molecular Structure, Oxadiazoles chemical synthesis, Oxadiazoles classification, Protein Conformation drug effects, Structure-Activity Relationship, Antimitotic Agents chemical synthesis, Antimitotic Agents pharmacology, Oxadiazoles chemistry, Oxadiazoles pharmacology, Tubulin chemistry, and Tubulin metabolism
Abstract
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.

44. Moderate ascorbate deficiency increases myogenic tone of arteries from pregnant but not virgin ascorbate-dependent rats. [2006]

  • Ramirez RJ, Hubel CA, Novak J, DiCianno JR, Kagan VE, and Gandley RE
  • Hypertension (Dallas, Tex. : 1979) [Hypertension] 2006 Mar; Vol. 47 (3), pp. 454-60. Date of Electronic Publication: 2006 Jan 23.
Subjects
Administration, Oral, Animals, Antioxidants administration dosage, Ascorbic Acid administration dosage, Dose-Response Relationship, Drug, Female, Fetal Weight drug effects, Gestational Age, Methacholine Chloride pharmacology, Phenylephrine pharmacology, Pregnancy, Rats, Rats, Mutant Strains, Vasoconstrictor Agents pharmacology, Vasodilator Agents pharmacology, Vasomotor System drug effects, Antioxidants pharmacology, Ascorbic Acid pharmacology, Ascorbic Acid Deficiency physiopathology, Mesenteric Arteries physiopathology, Pregnancy Complications physiopathology, and Vasomotor System physiopathology
Abstract
Plasma ascorbic acid is decreased in women with the pregnancy disorder preeclampsia. We used a mutant strain of rats (Osteogenic Disorder Shionogi), dependent on dietary sources of vitamin C, to investigate whether reduced intake of the vitamin would differentially affect vascular function in late-pregnant (day 19) and age-matched virgin rats. The animals were given either 1 mg/mL of ascorbic acid ad libitum in drinking water [fully supplemented (FS)] or 0.25 mg/mL [marginally supplemented (MS)]. Fetal weights were 21% lower in MS than FS rats, whereas mean maternal weights and pup numbers did not differ. Small mesenteric arteries (diameter, 268+/-7 microm) were mounted in a pressurized arteriograph. Myogenic reactivity (contractile response to step increases in intraluminal pressure) was increased in arteries from MS pregnant compared with FS pregnant rats to levels observed in virgin rats. Ascorbic acid intake did not affect myogenic responses of arteries from virgin rats. Hence, the normal pregnancy-induced reduction in myogenic reactivity was abrogated in MS pregnant animals. Inhibition of nitric oxide synthase had no effect on the myogenicity of arteries from virgin or MS pregnant rats but increased myogenicity of FS pregnant rats to the level of MS pregnant rats. Free radical scavengers reversed the accentuated myogenicity of MS pregnant rats without affecting FS pregnant or virgin rat arteries. These data indicate that moderate ascorbate deprivation increases mesenteric artery myogenic responsiveness during pregnancy. This increase may result from a decrease in nitric oxide-mediated modulation of the myogenic contractile response.

45. Tricyclic azepine derivatives: pyrimido[4,5-b]-1,4-benzoxazepines as a novel class of epidermal growth factor receptor kinase inhibitors. [2006]

  • Smith L 2nd, Piatnitski EL, Kiselyov AS, Ouyang X, Chen X, Burdzovic-Wizemann S, Xu Y, Pan W, Chen X, Wang Y, Rosler RL, Patel SN, Chiang HH, Milligan DL, Columbus J, Wong WC, Doody JF, and Hadari YR
  • Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2006 Mar 15; Vol. 16 (6), pp. 1643-6. Date of Electronic Publication: 2006 Jan 18.
Subjects
Adenosine Triphosphate metabolism, Azepines chemistry, Binding Sites, Cell Proliferation drug effects, Cells, Cultured, Humans, Molecular Structure, Phosphorylation drug effects, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases antagonists inhibitors, Protein-Tyrosine Kinases antagonists inhibitors, Receptor, ErbB-2 antagonists inhibitors, Structure-Activity Relationship, Substrate Specificity, Azepines chemical synthesis, Azepines pharmacology, ErbB Receptors antagonists inhibitors, Protein Kinase Inhibitors chemical synthesis, and Protein Kinase Inhibitors pharmacology
Abstract
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.

46. Health consequences of the September 11 World Trade Center attacks: a review. [2006]

  • Moline J, Herbert R, and Nguyen N
  • Cancer investigation [Cancer Invest] 2006 Apr-May; Vol. 24 (3), pp. 294-301.
Subjects
Anxiety epidemiology, Asbestos adverse effects, Construction Materials adverse effects, Depression epidemiology, Dust, Humans, Inhalation Exposure adverse effects, Mineral Fibers adverse effects, Neoplasms epidemiology, Particle Size, Polycyclic Aromatic Hydrocarbons adverse effects, Respiratory Tract Diseases epidemiology, Respiratory Tract Diseases etiology, Risk Factors, Stress Disorders, Post-Traumatic epidemiology, Stress Disorders, Post-Traumatic etiology, Air Pollutants adverse effects, Environmental Exposure adverse effects, Occupational Exposure adverse effects, and September 11 Terrorist Attacks psychology
Abstract
In the aftermath of the September 11 World Trade Center (WTC) attack, a large number of people sustained potential exposures to smoke, dust, particulate matter, and a variety of toxins, including asbestos, pulverized concrete, glass fibers, polycyclic aromatic hydrocarbons (PAHs), and polychlorinated furans and dioxins. Additionally, many had exposure to psychological traumatogens. The most common effects seen to date are respiratory and mental health consequences. The long-term consequences of exposures are not yet known, and there remains concern about the potential for late-emerging diseases such as cancers. This article reviews WTC-related health effects, the spectrum of exposures and how they were documented, and discusses future preventive efforts.

47. Health promotion for frail older home care clients. [2006]

  • Markle-Reid M, Weir R, Browne G, Roberts J, Gafni A, and Henderson S
  • Journal of advanced nursing [J Adv Nurs] 2006 May; Vol. 54 (3), pp. 381-95.
Subjects
Adaptation, Psychological, Aged, Aged, 80 and over, Depression psychology, Emotions, Female, Health Care Costs, Health Promotion economics, Health Status, Home Nursing economics, Humans, Male, Mental Health, Patient Acceptance of Health Care, Patient Dropouts, Quality of Life, Single-Blind Method, Social Support, Frail Elderly psychology, Health Promotion methods, and Home Nursing methods
Abstract
Aim: This paper reports a study evaluating the comparative effects and costs of a proactive nursing health promotion intervention in addition to usual home care for older people compared with usual home care services alone.
Background: An ageing population, budget constraints and technological advances in many countries have increased the pressure on home care resources. The result is a shift in nursing services from health promotion to meet the more pressing need for postacute care. For frail older people with long-term needs, these changes combine to create a fragmented system of health service delivery, characterized by providing nursing on demand rather than proactively.
Methods: A two-armed, single-blind, randomized controlled trial was carried out with older people > or =75 years and eligible for personal support services through a home care programme in Ontario, Canada. Participants were randomly allocated either to usual home care (control) or to a nursing (experimental) group. In addition to usual home care, the nursing group received a health assessment combined with regular home visits or telephone contacts, health education about management of illness, coordination of community services, and use of empowerment strategies to enhance independence. The data were collected in 2001-2002.
Results: Of the 288 older people who were randomly allocated at baseline, 242 (84%) completed the study (120 nursing group; 122 control group). Proactively providing older people with nursing health promotion, compared with providing nursing services on-demand, resulted in better mental health functioning (P = 0.009), a reduction in depression (P = 0.009), and enhanced perceptions of social support (P = 0.009) at no additional cost from a societal perspective.
Conclusions: Home based nursing health promotion, proactively provided to frail older people with chronic health needs, enhances quality of life while not increasing the overall costs of health care. The results underscore the need to re-invest in nursing services for health promotion for older clients receiving home care.

48. Bipolar disorder: imaging state versus trait. [2006]

  • Friedman JN, Hurley RA, and Taber KH
  • The Journal of neuropsychiatry and clinical neurosciences [J Neuropsychiatry Clin Neurosci] 2006 Summer; Vol. 18 (3), pp. 296-301.
Subjects
Bipolar Disorder diagnostic imaging, Bipolar Disorder physiopathology, Humans, Limbic System physiopathology, Magnetic Resonance Imaging, Mood Disorders physiopathology, Positron-Emission Tomography, Bipolar Disorder pathology, and Bipolar Disorder psychology

49. Novel tricyclic azepine derivatives: Biological evaluation of pyrimido[4,5-b]-1,4-benzoxazepines, thiazepines, and diazepines as inhibitors of the epidermal growth factor receptor tyrosine kinase. [2006]

  • Smith L 2nd, Wong WC, Kiselyov AS, Burdzovic-Wizemann S, Mao Y, Xu Y, Duncton MA, Kim K, Piatnitski EL, Doody JF, Wang Y, Rosler RL, Milligan D, Columbus J, Balagtas C, Lee SP, Konovalov A, and Hadari YR
  • Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2006 Oct 01; Vol. 16 (19), pp. 5102-6. Date of Electronic Publication: 2006 Aug 02.
Subjects
Antineoplastic Agents pharmacology, Azepines chemistry, Cell Line, Tumor, Heterocyclic Compounds, 3-Ring chemistry, Humans, Inhibitory Concentration 50, Neoplasm Proteins antagonists inhibitors, Phosphorylation drug effects, Structure-Activity Relationship, Vascular Endothelial Growth Factor Receptor-2 antagonists inhibitors, Antineoplastic Agents chemical synthesis, Azepines chemical synthesis, Azepines pharmacology, ErbB Receptors antagonists inhibitors, Heterocyclic Compounds, 3-Ring chemical synthesis, and Heterocyclic Compounds, 3-Ring pharmacology
Abstract
Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range).

50. Lessons learned combining N-of-1 trials to assess fibromyalgia therapies. [2006]

  • Zucker DR, Ruthazer R, Schmid CH, Feuer JM, Fischer PA, Kieval RI, Mogavero N, Rapoport RJ, Selker HP, Stotsky SA, Winston E, and Goldenberg DL
  • The Journal of rheumatology [J Rheumatol] 2006 Oct; Vol. 33 (10), pp. 2069-77.
Subjects
Adult, Cross-Over Studies, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Practice Patterns, Physicians', Research Design, Rheumatology trends, Sickness Impact Profile, Surveys and Questionnaires, Treatment Outcome, Amitriptyline therapeutic use, Antidepressive Agents therapeutic use, Fibromyalgia drug therapy, Fluoxetine therapeutic use, and Randomized Controlled Trials as Topic statistics numerical data
Abstract
Objective: Applying population research to individual treatment requires understanding the connections between patient-specific characteristics, population-based studies, and treatment responses. Conducting practice-based research using individual-focused (N-of-1) trials may aid this process. We combined N-of-1 trials to compare fibromyalgia therapies and to assess the feasibility and outcomes of this approach for practice-based effectiveness research.
Methods: Community- and center-based rheumatologists enrolled patients with fibromyalgia syndrome in randomized, double-blind, multi-crossover, N-of-1 trials comparing amitriptyline and the combination amitriptyline and fluoxetine. Fibromyalgia Impact Questionnaire outcomes were used for the individuals' treatment and combined across patients for sample-based analyses. Outcomes were compared with results from more standard trial designs.
Results: Eight rheumatologists enrolled 58 patients in N-of-1 trials. Most physicians and patients had not previously participated in clinical trials. Using several analytic methods, the pooled results showed a better outcome score (mean difference: -6.1 +/- 2.0 to -8.0 +/- 3.7 points) in patients taking combination therapy. These population results are similar to published outcomes from a more traditional crossover trial. Neither practice type nor patient characteristics were significantly associated with the observed treatment-effect variation. Most participants, irrespective of selected treatment, felt their individual N-of-1 trials were helpful.
Conclusion: Implementation of the combined N-of-1 methodology is feasible in rheumatology practices and results confirm greater fibromyalgia improvement with combination therapy. This research approach broadens participation, although our trials' specifics likely influenced enrollment eligibility. In addition to individual benefits, combining N-of-1 trial data provides population research benefits. This patient-focused approach should be further explored to bridge research and practice.

51. The effectiveness and efficiency of home-based nursing health promotion for older people: a review of the literature. [2006]

  • Markle-Reid M, Browne G, Weir R, Gafni A, Roberts J, and Henderson SR
  • Medical care research and review : MCRR [Med Care Res Rev] 2006 Oct; Vol. 63 (5), pp. 531-69.
Subjects
Aged, House Calls, Humans, Randomized Controlled Trials as Topic, Geriatric Nursing, Health Promotion, Home Care Services, and Program Evaluation
Abstract
Despite the large potential role that community nurses have in providing individualized health promotion to older people, there is a lack of consensus in the literature regarding this role's effectiveness and efficiency. This article presents a literature review and synthesis of 12 randomized controlled trials selected from 344 published studies on preventive home visitation programs for older people. The findings suggest that a diversity of home visiting interventions carried out by nurses can favorably affect health and functional status, mortality rates, use of hospitalization and nursing homes, and costs. Further research is needed that focuses on the outcomes of quality of life, mental health, social support, caregiver burden, the acceptability of intervention, and specific subgroups of clients who benefit most. Findings also indicate the need for a theoretical foundation, increased emphasis on health-promotion strategies, and more research using a more complete economic evaluation to establish efficiency.

52. The World Trade Center disaster and the health of workers: five-year assessment of a unique medical screening program. [2006]

  • Herbert R, Moline J, Skloot G, Metzger K, Baron S, Luft B, Markowitz S, Udasin I, Harrison D, Stein D, Todd A, Enright P, Stellman JM, Landrigan PJ, and Levin SM
  • Environmental health perspectives [Environ Health Perspect] 2006 Dec; Vol. 114 (12), pp. 1853-8.
Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Air Pollution adverse effects, Air Pollution analysis, Dust analysis, Female, Humans, Male, Mass Screening methods, Middle Aged, Occupational Diseases etiology, Occupational Diseases physiopathology, Respiratory Tract Diseases etiology, Respiratory Tract Diseases physiopathology, Spirometry, Time Factors, Occupational Diseases diagnosis, Occupational Exposure adverse effects, Respiratory Tract Diseases diagnosis, and September 11 Terrorist Attacks
Abstract
Background: Approximately 40,000 rescue and recovery workers were exposed to caustic dust and toxic pollutants following the 11 September 2001 attacks on the World Trade Center (WTC). These workers included traditional first responders, such as firefighters and police, and a diverse population of construction, utility, and public sector workers.
Methods: To characterize WTCrelated health effects, the WTC Worker and Volunteer Medical Screening Program was established. This multicenter clinical program provides free standardized examinations to responders. Examinations include medical, mental health, and exposure assessment questionnaires; physical examinations; spirometry; and chest X rays.
Results: Of 9,442 responders examined between July 2002 and April 2004, 69% reported new or worsened respiratory symptoms while performing WTC work. Symptoms persisted to the time of examination in 59% of these workers. Among those who had been asymptomatic before September 11, 61% developed respiratory symptoms while performing WTC work. Twenty-eight percent had abnormal spirometry; forced vital capacity (FVC) was low in 21%; and obstruction was present in 5%. Among nonsmokers, 27% had abnormal spirometry compared with 13% in the general U.S. population. Prevalence of low FVC among nonsmokers was 5-fold greater than in the U.S. population (20% vs. 4%). Respiratory symptoms and spirometry abnormalities were significantly associated with early arrival at the site.
Conclusion: WTC responders had exposure-related increases in respiratory symptoms and pulmonary function test abnormalities that persisted up to 2.5 years after the attacks. Longterm medical monitoring is required to track persistence of these abnormalities and identify late effects, including possible malignancies. Lessons learned should guide future responses to civil disasters.

53. WTC five-year assessment: Herbert et al. respond [2007]

  • Herbert, Robin, Skloot, Gwen, Metzger, Kristina, Landrigan, Philip J., Moline, Jacqueline, Stein, Diane, Todd, Andrew, Levin, Stephen M., Baron, Sherry, and Udasin, Iris
  • Environmental Health Perspectives. Feb 2007, Vol. 115 Issue 2, pA72, 2 p.
Abstract
In our article (Herbert et al. 2006), we described the establishment of the World Trade Center (WTC) Worker and Volunteer Medical Screening Program and presented results of screening examinations undertaken [...]

54. Clinical features of the DOK7 neuromuscular junction synaptopathy. [2007]

  • Palace J, Lashley D, Newsom-Davis J, Cossins J, Maxwell S, Kennett R, Jayawant S, Yamanashi Y, and Beeson D
  • Brain : a journal of neurology [Brain] 2007 Jun; Vol. 130 (Pt 6), pp. 1507-15. Date of Electronic Publication: 2007 Apr 23.
Subjects
Adult, Alleles, Amino Acid Sequence, Biopsy, Cholinesterase Inhibitors therapeutic use, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Muscle, Skeletal pathology, Muscular Dystrophies, Limb-Girdle drug therapy, Muscular Dystrophies, Limb-Girdle genetics, Muscular Dystrophies, Limb-Girdle pathology, Myasthenic Syndromes, Congenital drug therapy, Myasthenic Syndromes, Congenital pathology, Pedigree, Polymerase Chain Reaction methods, Sequence Alignment, Treatment Outcome, Muscle Proteins genetics, Mutation, Myasthenic Syndromes, Congenital genetics, and Neuromuscular Junction pathology
Abstract
Mutations in DOK7 have recently been shown to underlie a recessive congenital myasthenic syndrome (CMS) associated with small simplified neuromuscular junctions ('synaptopathy') but normal acetylcholine receptor and acetylcholinesterase function. We identified DOK7 mutations in 27 patients from 24 kinships. Mutation 1124_1127dupTGCC was common, present in 20 out of 24 kinships. All patients were found to have at least one allele with a frameshift mutation in DOK7 exon 7, suggesting that loss of function(s) associated with the C-terminal region of Dok-7 underlies this disorder. In 15 patients, we were able to study the clinical features in detail. Clinical onset was usually characterized by difficulty in walking developing after normal motor milestones. Proximal muscles were usually more affected than distal, leading to a 'limb-girdle' pattern of weakness; although ptosis was often present from an early age, eye movements were rarely involved. Patients did not show long-term benefit from anticholinesterase medication and sometimes worsened, and where tried responded to ephedrine. The phenotype can be distinguished from 'limb-girdle' myasthenia associated with tubular aggregates, where DOK7 mutations were not detected and patients respond to anticholinesterase treatments. CMS due to DOK7 mutations are common within our UK cohort and is likely to be under-diagnosed; recognition of the phenotype will help clinical diagnosis, targeted genetic screening and appropriate management.

55. Genome-wide association study identifies novel breast cancer susceptibility loci [2007]

  • Easton, Douglas F., Pooley, Karen A., Dunning, Alison M., Pharoah, Paul D. P., Thompson, Deborah, Ballinger, Dennis G., Struewing, Jeffery P., Morrison, Jonathan, Field, Helen, Luben, Robert, Wareham, Nicholas, Ahmed, Shahana, Healey, Catherine S., Bowman, Richard, Luccarini, Craig, Conroy, Don, Shah, Mitul, Munday, Hannah, Jordan, Clare, Perkins, Barbara, West, Judy, Redman, Karen, Driver, Kristy, Meyer, Kerstin B., Haiman, Christopher A., Kolonel, Laurence K., Henderson, Brian E., Le Marchand, Loic, Brennan, Paul, Sangrajrang, Suleeporn, Gaborieau, Valerie, Odefrey, Fabrice, Shen, Chen-Yang, Wu, Pei-Ei, Wang, Hui-Chun, Eccles, Diana, Evans, D. Gareth, Peto, Julian, Fletcher, Olivia, Johnson, Nichola, Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Chenevix-Trench, Georgia, Bojesen, Stig E., Nordestgaard, Borge G., Axelsson, Christen K., Garcia-Closas, Montserrat, Brinton, Louise, Chanock, Stephen, Lissowska, Jolanta, Peplonska, Beata, Nevanlinna, Heli, Fagerholm, Rainer, Eerola, Hannaleena, Kang, Daehee, Yoo, Keun-Young, Noh, Dong-Young, Ahn, Sei-Hyun, Hunter, David J., Hankinson, Susan E., Cox, David G., Hall, Per, Wedren, Sara, Liu, Jianjun, Low, Yen-Ling, Bogdanova, Natalia, Schurmann, Peter, Dork, Thilo, Tollenaar, Rob A. E. M., Jacobi, Catharina E., Devilee, Peter, Klijn, Jan G. M., Sigurdson, Alice J., Doody, Michele M., Alexander, Bruce H., Zhang, Jinghui, Cox, Angela, Brock, Ian W., MacPherson, Gordon, Reed, Malcolm W. R., Couch, Fergus J., Goode, Ellen L., Olson, Janet E., Meijers-Heijboer, Hanne, van den Ouweland, Ans, Uitterlinden, Andre, Rivadeneira, Fernando, Milne, Roger L., Ribas, Gloria, Gonzalez-Neira, Anna, Benitez, Javier, Hopper, John L., McCredie, Margaret, Southey, Melissa, Giles, Graham G., Schroen, Chris, Justenhoven, Christina, Brauch, Hiltrud, Hamann, Ute, Ko, Yon-Dschun, Spurdle, Amanda B., Beesley, Jonathan, Chen, Xiaoqing, Aghmesheh, Morteza, Amor, David, Andrews, Lesley, Antill, Yoland, Armes, Jane, Armitage, Shane, Arnold, Leanne, Balleine, Rosemary, Begley, Glenn, Beilby, John, Bennett, Ian, Bennett, Barbara, Berry, Geoffrey, Blackburn, Anneke, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Byron, Keith, Callen, David, Campbell, Ian, Clarke, Christine, Colley, Alison, Cotton, Dick, Cui, Jisheng, Culling, Bronwyn, Cummings, Margaret, Dawson, Sarah-Jane, Dixon, Joanne, Dobrovic, Alexander, Dudding, Tracy, Edkins, Ted, Eisenbruch, Maurice, Farshid, Gelareh, Fawcett, Susan, Field, Michael, Firgaira, Frank, Fleming, Jean, Forbes, John, Friedlander, Michael, Gaff, Clara, Gardner, Mac, Gattas, Mike, George, Peter, Giles, Graham, Gill, Grantley, Goldblatt, Jack, Greening, Sian, Grist, Scott, Haan, Eric, Harris, Marion, Hart, Stewart, Hayward, Nick, Hopper, John, Humphrey, Evelyn, Jenkins, Mark, Jones, Alison, Kefford, Rick, Kirk, Judy, Kollias, James, Kovalenko, Sergey, Lakhani, Sunil, Leary, Jennifer, Lim, Jacqueline, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Maclurcan, Mariette, Mann, Graham, Marsh, Deborah, McKay, Michael, Anne McLachlan, Sue, Meiser, Bettina, Milne, Roger, Mitchell, Gillian, Newman, Beth, O'Loughlin, Imelda, Osborne, Richard, Peters, Lester, Phillips, Kelly, Price, Melanie, Reeve, Jeanne, Reeve, Tony, Richards, Robert, Rinehart, Gina, Robinson, Bridget, Rudzki, Barney, Salisbury, Elizabeth, Sambrook, Joe, Saunders, Christobel, Scott, Clare, Scott, Elizabeth, Scott, Rodney, Seshadri, Ram, Shelling, Andrew, Spurdle, Amanda, Suthers, Graeme, Taylor, Donna, Tennant, Christopher, Thorne, Heather, Townshend, Sharron, Tucker, Kathy, Tyler, Janet, Venter, Deon, Visvader, Jane, Walpole, Ian, Ward, Robin, Waring, Paul, Warner, Bev, Warren, Graham, Watson, Elizabeth, Williams, Rachael, Wilson, Judy, Winship, Ingrid, Young, Mary Ann, Bowtell, David, Green, Adele, deFazio, Anna, Gertig, Dorota, Webb, Penny, Mannermaa, Arto, Kosma, Veli-Matti, Kataja, Vesa, Hartikainen, Jaana, Day, Nicholas E., Cox, David R., and Ponder, Bruce A. J.
  • Nature. June 28, 2007, Vol. 447 Issue 7148, p1087, 7 p.
Subjects
Genetic susceptibility -- Research -- Genetic aspects and Breast cancer -- Genetic aspects -- Risk factors -- Research
Abstract
Author(s): Douglas F. Easton (corresponding author) [1]; Karen A. Pooley [2]; Alison M. Dunning [2]; Paul D. P. Pharoah [2]; Deborah Thompson [1]; Dennis G. Ballinger [3]; Jeffery P. Struewing [...]

56. Tumor-derived mutations in the TRAIL receptor DR5 inhibit TRAIL signaling through the DR4 receptor by competing for ligand binding. [2007]

  • Bin L, Thorburn J, Thomas LR, Clark PE, Humphreys R, and Thorburn A
  • The Journal of biological chemistry [J Biol Chem] 2007 Sep 21; Vol. 282 (38), pp. 28189-94. Date of Electronic Publication: 2007 Jul 31.
Subjects
Binding, Competitive, Cell Line, Tumor, Dose-Response Relationship, Drug, Electroporation, Humans, Ligands, Models, Biological, Protein Binding, Signal Transduction, Subcellular Fractions metabolism, Gene Expression Regulation, Neoplastic, Mutation, Neoplasms metabolism, and Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism
Abstract
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a cytokine that preferentially induces apoptosis in tumor cells compared with normal cells through two receptors (DR4 and DR5). Somatic mutations in these receptors have been found in different kinds of cancer; however, it is poorly understood how the mutations affect signaling. We found that point mutations (L334F, E326K, E338K, and K386N) that were identified in human tumors result in the DR5 receptor losing its ability to form a functional death-inducing signaling complex and induce apoptosis. The mutant receptors also have a "dominant negative" effect whereby they inhibit the ability of TRAIL to induce apoptosis through functional DR4 receptors. This dominant negative mechanism is achieved through competition for TRAIL binding as shown by experiments where the ability of the mutant DR5 receptor to bind with the ligand was abolished, thus restoring TRAIL signaling through DR4. The inhibitory effect on signaling through the wild-type DR4 protein can be overcome if the inhibitory mechanism is bypassed by using a DR4-agonistic antibody that is not subject to this competition. This study provides a molecular basis for the use of specific therapeutic agonists of TRAIL receptors in people whose tumors harbor somatic DR5 mutations.

57. African-Caribbean cancer consortium for the study of viral, genetic and environmental cancer risk factors. [2007]

  • Ragin CC, Taioli E, McFarlane-Anderson N, Avery G, Bennett F, Bovell-Benjamin A, Thompson AB, Carrington A, Campbell-Everett L, Ford J, Hennis A, Jackson M, Lake S, Leske MC, Magai C, Nemesure B, Neugut A, Odedina F, Okobia M, Patrick A, Plummer WB, Reams RR, Roberts R, Scott-Hastings S, Sharma S, Wheeler V, Wu SY, and Bunker C
  • Infectious agents and cancer [Infect Agent Cancer] 2007 Sep 24; Vol. 2, pp. 17. Date of Electronic Publication: 2007 Sep 24.
Abstract
This is a short summary of a meeting of the "African-Caribbean Cancer Consortium", jointly organized by the University of Pittsburgh, Department of Epidemiology and the University of Pittsburgh Cancer Institute, held in Montego Bay, Jamaica as a satellite meeting at the Caribbean Health Research Council, 52nd Annual Council and Scientific meeting on May 4, 2007.

58. Inhibitory activity of cetuximab on epidermal growth factor receptor mutations in non small cell lung cancers. [2007]

  • Doody JF, Wang Y, Patel SN, Joynes C, Lee SP, Gerlak J, Rolser RL, Li Y, Steiner P, Bassi R, Hicklin DJ, and Hadari YR
  • Molecular cancer therapeutics [Mol Cancer Ther] 2007 Oct; Vol. 6 (10), pp. 2642-51. Date of Electronic Publication: 2007 Oct 03.
Subjects
Animals, Antibodies, Monoclonal, Humanized, Apoptosis, Blotting, Western, Cell Line, Tumor, Cetuximab, Dimerization, ErbB Receptors metabolism, Female, Fluorescent Antibody Technique, Humans, Immunoblotting, Immunoprecipitation, Mice, Mice, Nude, Phosphorylation, Protein Kinase Inhibitors pharmacology, Ubiquitin metabolism, Antibodies, Monoclonal pharmacology, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung genetics, ErbB Receptors genetics, Lung Neoplasms genetics, and Mutation drug effects
Abstract
Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) were identified in approximately 15% of all patients with non-small cell lung cancer (NSCLC). These mutations have been established as an indicator of superior response to gefitinib and erlotinib, small molecule inhibitors of the EGFR kinase domain. Whether these mutations would also render patients more susceptible to treatment with cetuximab (Erbitux), an EGFR-neutralizing antibody, is yet to be determined. In this study, we attempted to evaluate the effect of cetuximab on several NSCLC lines harboring some of the more common EGFR mutations (L858R and delL747-T753insS), as well as the recently identified kinase inhibitor-resistant mutation, T790M. We could show that the kinase activity of the abovementioned EGFR mutants was hindered by cetuximab, as detected by both cell-based phosphorylation and proliferation assays. Interestingly, cetuximab also induced enhanced degradation of the EGFR mutants as compared with the wild-type receptor. Most importantly, cetuximab successfully inhibited the growth of NSCLC lines in xenograft models. These results indicate the promising potential of cetuximab as a regimen for patients with NSCLC bearing these mutations.

59. The new University of Colorado medical school curriculum: a pediatric perspective. [2007]

  • Deterding RR, Wong S, Faries G, Glover JJ, Garrington TP, Wang M, Anderson MS, and Krugman RD
  • The Journal of pediatrics [J Pediatr] 2007 Nov; Vol. 151 (5 Suppl), pp. S32-6.
Subjects
Child, Clinical Clerkship methods, Colorado, Faculty, Medical organization administration, Humans, Schools, Medical organization administration, Curriculum, Education, Medical, Undergraduate methods, Pediatrics education, and Program Development methods
Abstract
The University of Colorado School of Medicine has developed an innovative 4-year undergraduate curriculum. As a strong advocate for education and curriculum reform, Dr M. Douglas Jones Jr. created an environment for pediatrics to flourish in this new curriculum. Pediatric content has increased in all years of the curriculum, and pediatric faculty have had greater opportunities to teach and seek career development in medical education. In this report, we review the process that led to curriculum reform, provide an overview of the new curriculum design, and highlight examples of the positive impact this process has had on education in pediatrics. We hope that sharing our experience, may benefit others in medical education.

60. Anti-chromatin antibodies drive in vivo antigen-specific activation and somatic hypermutation of rheumatoid factor B cells at extrafollicular sites. [2007]

  • Herlands RA, William J, Hershberg U, and Shlomchik MJ
  • European journal of immunology [Eur J Immunol] 2007 Dec; Vol. 37 (12), pp. 3339-51.
Subjects
Animals, Autoimmunity genetics, Chromatin immunology, Disease Models, Animal, Genetic Predisposition to Disease, Lupus Erythematosus, Systemic genetics, Lupus Erythematosus, Systemic immunology, Lymphocyte Cooperation, Mice, Mice, Inbred BALB C, Mice, Inbred MRL lpr immunology, Mice, Transgenic, Nucleosomes immunology, Organ Specificity, Particle Size, Specific Pathogen-Free Organisms, Spleen ultrastructure, Toll-Like Receptors immunology, Antibodies, Antinuclear immunology, Autoimmunity immunology, B-Lymphocyte Subsets immunology, Immunoglobulin G immunology, Lymphocyte Activation immunology, Rheumatoid Factor immunology, Somatic Hypermutation, Immunoglobulin immunology, and Spleen immunology
Abstract
A dominant type of spontaneous autoreactive B cell activation in murine lupus is the extrafollicular generation of plasmablasts. The factors governing such activation have been difficult to identify due to the stochastic onset and chronic nature of the response. Thus, the ability to induce a similar autoreactive B cell response with a known autoantigen in vivo would be a powerful tool in deciphering how autoimmune responses are initiated. We report here the establishment and characterization of a system to initiate autoreactive extrafollicular B cell responses, using IgG anti-chromatin antibodies, that closely mirrors the spontaneous response. We demonstrate that exogenously administered anti-chromatin antibody, presumably by forming immune complexes with released nuclear material, drives activation of rheumatoid factor B cells in AM14 Tg mice. Anti-chromatin elicits autoreactive B cell activation and development into antibody-forming cells at the T zone/red pulp border. Plasmablast generation occurs equally in BALB/c, MRL/+ and MRL/lpr mice, indicating that an autoimmune-prone genetic background is not required for the induced response. Importantly, infused IgG anti-chromatin induces somatic hypermutation in the absence of a GC response, thus proving the extrafollicular somatic hypermutation pathway. This system provides a window on the initiation of an autoantibody response and reveals authentic initiators of it.

61. Reciprocal regulation of presynaptic and postsynaptic proteins in bipolar spiral ganglion neurons by neurotrophins. [2007]

  • Flores-Otero J, Xue HZ, and Davis RL
  • The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2007 Dec 19; Vol. 27 (51), pp. 14023-34.
Subjects
Animals, Animals, Newborn, Cells, Cultured, Membrane Proteins ultrastructure, Mice, Mice, Inbred CBA, Nerve Growth Factors ultrastructure, Presynaptic Terminals chemistry, Presynaptic Terminals physiology, Presynaptic Terminals ultrastructure, Spiral Ganglion cytology, Spiral Ganglion physiology, Membrane Proteins physiology, Nerve Growth Factors physiology, Presynaptic Terminals metabolism, and Spiral Ganglion metabolism
Abstract
A unifying principle of sensory system organization is feature extraction by modality-specific neuronal maps in which arrays of neurons show systematically varied response properties and receptive fields. Only beginning to be understood, however, are the mechanisms by which these graded systems are established. In the peripheral auditory system, we have shown previously that the intrinsic firing features of spiral ganglion neurons are influenced by brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). We now show that is but a part of a coordinated package of neurotrophin actions that also includes effects on presynaptic and postsynaptic proteins, thus encompassing the input, transmission, and output functions of the spiral ganglion neurons. Using immunocytochemical methods, we determined that proteins targeted to opposite ends of the neuron were organized and regulated in a reciprocal manner. AMPA receptor subunits GluR2 and GluR3 were enriched in base neurons compared with their apex counterparts. This distribution pattern was enhanced by exposure to BDNF but reduced by NT-3. SNAP-25 and synaptophysin were distributed and regulated in the mirror image: enriched in the apex, enhanced by NT-3 and reduced by BDNF. Moreover, we used a novel coculture to identify potential endogenous sources of neurotrophins by showing that sensory receptors from different cochlear regions were capable of altering presynaptic and postsynaptic protein levels in these neurons. From these studies, we suggest that BDNF and NT-3, which are systematically distributed in complementary gradients, are responsible for orchestrating a comprehensive set of electrophysiological specializations along the frequency contour of the cochlea.

62. Response to early literacy instruction in the United States, Australia, and Scandinavia: A behavioral-genetic analysis. [2008]

  • Samuelsson S, Byrne B, Olson RK, Hulslander J, Wadsworth S, Corley R, Willcutt EG, and Defries JC
  • Learning and individual differences [Learn Individ Differ] 2008; Vol. 18 (3), pp. 289-295.
Abstract
Genetic and environmental influences on early reading and spelling at the end of kindergarten and Grade 1 were compared across three twin samples tested in the United States, Australia, and Scandinavia. Proportions of variance due to genetic influences on kindergarten reading were estimated at .84 in Australia, .68 in the U.S., and .33 in Scandinavia. The effects of shared environment on kindergarten reading were estimated at .09 in Australia, .25 in the U.S., and .52 in Scandinavia. A similar pattern of genetic and environmental influences was obtained for kindergarten spelling. One year later when twins in all three samples had received formal literacy instruction for at least one full school year, heritability was similarly high across country, with estimated genetic influences varying between .79 and .83 for reading and between .62 and .79 for spelling. These findings indicate that the pattern of genetic and environmental influences on early reading and spelling development varies according to educational context, with genetic influence increasing as a function of increasing intensity of early instruction. Longitudinal analyses revealed genetic continuity for both reading and spelling between kindergarten and Grade 1 across country. However, a new genetic factor comes into play accounting for independent variance in reading at Grade 1 in the U.S. and Scandinavia, suggesting a change in genetic influences on reading. Implications for response-to-instruction are discussed.

63. Letter to the editor journal of genetic counseling. When you care enough to do your very best: genetic counselor experiences of compassion fatigue. [2008]

  • Sahhar M, Bogwitz M, Brown E, Forbes R, Greenberg J, Hossack L, and Menezes M
  • Journal of genetic counseling [J Genet Couns] 2008 Feb; Vol. 17 (1), pp. 139-40; author reply 141-2. Date of Electronic Publication: 2007 Oct 18.
Subjects
Humans, Workforce, Burnout, Professional, Genetic Counseling, and Health Personnel psychology

64. WTC medical monitoring and treatment program: comprehensive health care response in aftermath of disaster. [2008]

  • Moline JM, Herbert R, Levin S, Stein D, Luft BJ, Udasin IG, and Landrigan PJ
  • The Mount Sinai journal of medicine, New York [Mt Sinai J Med] 2008 Mar-Apr; Vol. 75 (2), pp. 67-75.
Subjects
Humans, Inhalation Exposure adverse effects, Mass Screening, New York City epidemiology, Occupational Diseases etiology, Occupational Exposure adverse effects, Particulate Matter adverse effects, Monitoring, Physiologic, Occupational Diseases epidemiology, Population Surveillance, Program Development, Relief Work, and September 11 Terrorist Attacks
Abstract
The attack on the World Trade Center (WTC) on September 11th, 2001 exposed thousands of individuals to an unprecedented mix of chemicals, combustion products and micronized building materials. Clinicians at the Mount Sinai Irving Selikoff Center for Occupational and Environmental Medicine, in partnership with affected stakeholder organizations, developed a medical screening program to evaluate the health status of workers and volunteers who spent time at the WTC site and thus sustained exposure in the aftermath of September 11th. Standardized questionnaires were adapted for use in this unique population and all clinicians underwent training to ensure comparability. The WTC Worker and Volunteer Medical Screening Program (MSP) received federal funding in April 2002 and examinations began in July 2002. The MSP and the follow up medical monitoring program has successfully recruited nearly 22,000 responders, and serves as a model for the rapid development of a medical screening program to assess the health of populations exposed to environmental hazards as a result of natural and man-made disasters. The MSP constitutes a successful screening program for WTC responders. We discuss the challenges that confronted the program; the absence of a prior model for the rapid development of a program to evaluate results from mixed chemical exposures; little documentation of the size of the exposed population or of who might have been exposed; and uncertainty about both the nature and potential severity of immediate and long-term health effects.
(Copyright (c) 2008 Mount Sinai School of Medicine)

65. Epidemiologic research on man-made disasters: strategies and implications of cohort definition for World Trade Center worker and volunteer surveillance program. [2008]

  • Savitz DA, Oxman RT, Metzger KB, Wallenstein S, Stein D, Moline JM, and Herbert R
  • The Mount Sinai journal of medicine, New York [Mt Sinai J Med] 2008 Mar-Apr; Vol. 75 (2), pp. 77-87.
Subjects
Air Pollution adverse effects, Epidemiologic Methods, Humans, Inhalation Exposure adverse effects, New York City epidemiology, Occupational Diseases etiology, Occupational Health, Particulate Matter adverse effects, Program Evaluation, Relief Work, Disaster Planning, Occupational Diseases epidemiology, Occupational Exposure adverse effects, Population Surveillance, Public Health, September 11 Terrorist Attacks, and Volunteers
Abstract
Studies of long-term health consequences of disasters face unique methodologic challenges. The authors focused on studies of the health of cleanup and recovery workers, who are often poorly enumerated at the outset and difficult to follow over time. Comparison of the experience at the World Trade Center disaster with 4 past incidents of chemical and radiation releases at Seveso, Italy; Bhopal, India; Chernobyl, Ukraine; and Three Mile Island, USA, provided useful contrasts. Each event had methodologic advantages and disadvantages that depended on the nature of the disaster and the availability of records on area residents, and the emergency-response and cleanup protocol. The World Trade Center Worker Monitoring Program has well-defined eligibility criteria but lacks information on the universe of eligible workers to characterize response proportions or the potential for distortion of reported health effects. Nonparticipation may result from lack of interest, lack of awareness of the program, availability of another source of medical care, medical conditions precluding participation, inability to take time off from work, moving out of the area, death, or shift from initially ineligible to eligible status. Some of these considerations suggest selective participation by the sickest individuals, whereas others favor participation by the healthiest. The greatest concern with the validity of inferences regarding elevated health risks relative to external populations is the potential for selective enrollment among those who are affected. If there were a large pool of nonparticipating workers and those who suffered ill health were most motivated to enroll, the rates of disease among participants would be substantially higher than among all those eligible for the program. Future disaster follow-up studies would benefit substantially by having access to accurate estimates of the number of workers and information on the individuals who contributed to the cleanup and recovery effort.
(Copyright (c) 2008 Mount Sinai School of Medicine)

66. Mental health of workers and volunteers responding to events of 9/11: review of the literature. [2008]

  • Bills CB, Levy NA, Sharma V, Charney DS, Herbert R, Moline J, and Katz CL
  • The Mount Sinai journal of medicine, New York [Mt Sinai J Med] 2008 Mar-Apr; Vol. 75 (2), pp. 115-27.
Subjects
Humans, New York City epidemiology, Stress Disorders, Post-Traumatic epidemiology, United States epidemiology, Mental Health, Mental Health Services organization administration, Relief Work, September 11 Terrorist Attacks, Stress Disorders, Post-Traumatic diagnosis, and Volunteers psychology
Abstract
Background: Disaster workers responding to the events of September 11th were exposed to traumatic events. No study has systematically investigated the diverse mental health status and needs of the heterogeneous population of disaster workers responding to the events of September 11th.
Methods: Using PubMed and Medline and the search terms of "September 11, 2001" or "September 11" or "9/11"or "WTC" or "World Trade Center", the authors reviewed all articles that examined the mental health outcomes of workers at one of the three September 11th crash sites or the Fresh Kills landfill in New York City.
Results: In total, 25 articles met study inclusion criteria, often using different methodologies. The articles described varying degrees of mental health symptomatology, risk factors for adverse mental health outcomes, and utilization of mental health services.
Conclusions: The mental health needs of workers exposed to the events of September 11th ranged from little to no care to pharmacotherapy. A range of risk factors, including exposures at the WTC site and occupational activities, impacted on these needs but the role of specific mental health interventions was less clear. These findings suggest the need for a future program for disaster workers consisting of an accessible mental health treatment service supported by comprehensive postdisaster surveillance and emphasis on pre-disaster mental wellness. A number of areas for further consideration and study were identified, including the need for a more diverse exploration of involved responder populations as well as investigation of potential mental health outcomes beyond post-traumatic stress disorder (PTSD).
(Copyright (c) 2008 Mount Sinai School of Medicine)

67. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. [2008]

  • Emery S, Neuhaus JA, Phillips AN, Babiker A, Cohen CJ, Gatell JM, Girard PM, Grund B, Law M, Losso MH, Palfreeman A, and Wood R
  • The Journal of infectious diseases [J Infect Dis] 2008 Apr 15; Vol. 197 (8), pp. 1133-44.
Subjects
AIDS-Related Opportunistic Infections immunology, AIDS-Related Opportunistic Infections mortality, Adult, CD4 Lymphocyte Count, Cohort Studies, Drug Administration Schedule, Female, HIV Infections immunology, HIV Infections mortality, HIV Infections virology, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Treatment Outcome, Anti-HIV Agents administration dosage, HIV immunology, and HIV Infections drug therapy
Abstract
Background: The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral suppression [VS] group). In the DC group, participants started ART when the CD4+ cell count was <250 cells/microL. Clinical outcomes in participants not receiving ART at entry inform the early use of ART.
Methods: Patients who were either ART naive (n=249) or who had not been receiving ART for >or= 6 months (n=228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths; and (iv) the composite of outcomes (ii) and (iii).
Results: A total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for >or= 6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for 6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56; p=.02); outcome (ii), 3.26 (95% CI, 1.04-10.25; p=.04); outcome (iii), 7.02 (95% CI, 1.57-31.38; p=.01); and outcome (iv), 4.19 (95% CI, 1.69-10.39; p=.002 ).
Conclusions: Initiation of ART at CD4+ cell counts >350 cells/microL compared with <250 cells/microL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial.

68. Activation of oligodendroglial Fyn kinase enhances translation of mRNAs transported in hnRNP A2-dependent RNA granules. [2008]

  • White R, Gonsior C, Krämer-Albers EM, Stöhr N, Hüttelmaier S, and Trotter J
  • The Journal of cell biology [J Cell Biol] 2008 May 19; Vol. 181 (4), pp. 579-86.
Subjects
Animals, Cell Adhesion Molecules, Neuronal metabolism, Cell Line, Contactins, Enzyme Activation, Genes, Reporter, Luciferases metabolism, Mice, Neural Cell Adhesion Molecules metabolism, Phosphorylation, Protein Binding, RNA, Messenger genetics, RNA, Messenger metabolism, Recombinant Fusion Proteins metabolism, Response Elements genetics, Cytoplasmic Granules metabolism, Heterogeneous-Nuclear Ribonucleoprotein Group A-B metabolism, Oligodendroglia enzymology, Protein Biosynthesis, Proto-Oncogene Proteins c-fyn metabolism, and RNA Transport
Abstract
Central nervous system myelination requires the synthesis of large amounts of myelin basic protein (MBP) at the axon-glia contact site. MBP messenger RNA (mRNA) is transported in RNA granules to oligodendroglial processes in a translationally silenced state. This process is regulated by the trans-acting factor heterogeneous nuclear ribonucleoprotein (hnRNP) A2 binding to the cis-acting A2 response element (A2RE). Release of this repression of MBP mRNA translation is thus essential for myelination. Mice deficient in the Src family tyrosine kinase Fyn are hypomyelinated and contain reduced levels of MBP. Here, we identify hnRNP A2 as a target of activated Fyn in oligodendrocytes. We show that active Fyn phosphorylates hnRNP A2 and stimulates translation of an MBP A2RE-containing reporter construct. Neuronal adhesion molecule L1 binding to oligodendrocytes results in Fyn activation, which leads to an increase in hnRNP A2 phosphorylation. These results suggest that Fyn kinase activation results in the localized translation of MBP mRNA at sites of axon-glia contact and myelin deposition.

69. External beam boost for cancer of the cervix uteri when intracavitary therapy cannot be performed. [2008]

  • Barraclough LH, Swindell R, Livsey JE, Hunter RD, and Davidson SE
  • International journal of radiation oncology, biology, physics [Int J Radiat Oncol Biol Phys] 2008 Jul 01; Vol. 71 (3), pp. 772-8. Date of Electronic Publication: 2008 Jan 22.
Subjects
Adult, Aged, Aged, 80 and over, Brachytherapy, Female, Humans, Middle Aged, Radiotherapy Dosage, Retrospective Studies, Treatment Outcome, Radiotherapy, Conformal methods, and Uterine Cervical Neoplasms radiotherapy
Abstract
Purpose: To assess the outcome of patients treated with radical radiotherapy for cervical cancer who received an external beam boost, in place of intracavitary brachytherapy (ICT), after irradiation to the whole pelvis.
Methods and Materials: Case notes were reviewed for all patients treated in this way in a single center between 1996 and 2004. Patient and tumor details, the reasons why ICT was not possible, and treatment outcome were documented.
Results: Forty-four patients were identified. The mean age was 56.4 years (range, 26-88 years). Clinical International Federation of Gynecology and Obstetrics or radiologic stage for Stages I, II, III, and IV, respectively, was 16%, 48%, 27%, and 7%. A total radiation dose of 54-70 Gy was given (75% received > or =60 Gy). Reasons for ICT not being performed were technical limitations in 73%, comorbidity or isolation limitations in 23%, and patient choice in 4%. The median follow-up was 2.3 years. Recurrent disease was seen in 48%, with a median time to recurrence of 2.3 years. Central recurrence was seen in 16 of the 21 patients with recurrent disease. The 5-year overall survival rate was 49.3%. The 3-year cancer-specific survival rate by stage was 100%, 70%, and 42% for Stages I, II, and III, respectively. Late Grades 1 and 2 bowel, bladder, and vaginal toxicity were seen in 41%. Late Grade 3 toxicity was seen in 2%.
Conclusion: An external beam boost is a reasonable option after external beam radiotherapy to the pelvis when it is not possible to perform ICT.

70. Additional EFNB1 mutations in craniofrontonasal syndrome. [2008]

  • Wallis D, Lacbawan F, Jain M, Der Kaloustian VM, Steiner CE, Moeschler JB, Losken HW, Kaitila II, Cantrell S, Proud VK, Carey JC, Day DW, Lev D, Teebi AS, Robinson LK, Hoyme HE, Al-Torki N, Siegel-Bartelt J, Mulliken JB, Robin NH, Saavedra D, Zackai EH, and Muenke M
  • American journal of medical genetics. Part A [Am J Med Genet A] 2008 Aug 01; Vol. 146A (15), pp. 2008-12.
Subjects
DNA genetics, Female, Humans, Male, Polymerase Chain Reaction, Sequence Analysis, DNA, Syndrome, Chromosomes, Human, X, Craniosynostoses genetics, Ephrin-B1 genetics, and Mutation

71. Enduring mental health morbidity and social function impairment in world trade center rescue, recovery, and cleanup workers: the psychological dimension of an environmental health disaster. [2008]

  • Stellman JM, Smith RP, Katz CL, Sharma V, Charney DS, Herbert R, Moline J, Luft BJ, Markowitz S, Udasin I, Harrison D, Baron S, Landrigan PJ, Levin SM, and Southwick S
  • Environmental health perspectives [Environ Health Perspect] 2008 Sep; Vol. 116 (9), pp. 1248-53.
Subjects
Adult, Depression epidemiology, Female, Humans, Male, Middle Aged, Panic Disorder epidemiology, Prevalence, Stress Disorders, Post-Traumatic epidemiology, Surveys and Questionnaires, United States epidemiology, Depression diagnosis, Mental Health, Occupational Exposure, Panic Disorder diagnosis, September 11 Terrorist Attacks, and Stress Disorders, Post-Traumatic diagnosis
Abstract
Background: The World Trade Center (WTC) attacks exposed thousands of workers to hazardous environmental conditions and psychological trauma. In 2002, to assess the health of these workers, Congress directed the National Institute for Occupational Safety and Health to establish the WTC Medical Monitoring and Treatment Program. This program has established a large cohort of WTC rescue, recovery, and cleanup workers. We previously documented extensive pulmonary dysfunction in this cohort related to toxic environmental exposures.
Objectives: Our objective in this study was to describe mental health outcomes, social function impairment, and psychiatric comorbidity in the WTC worker cohort, as well as perceived symptomatology in workers' children.
Methods: Ten to 61 months after the WTC attack, 10,132 WTC workers completed a self-administered mental health questionnaire.
Results: Of the workers who completd the questionnaire, 11.1% met criteria for probable post-traumatic stress disorder (PTSD), 8.8% met criteria for probable depression, 5.0% met criteria for probable panic disorder, and 62% met criteria for substantial stress reaction. PTSD prevalence was comparable to that seen in returning Afghanistan war veterans and was much higher than in the U.S. general population. Point prevalence declined from 13.5% to 9.7% over the 5 years of observation. Comorbidity was extensive and included extremely high risks for impairment of social function. PTSD was significantly associated with loss of family members and friends, disruption of family, work, and social life, and higher rates of behavioral symptoms in children of workers.
Conclusions: Working in 9/11 recovery operations is associated with chronic impairment of mental health and social functioning. Psychological distress and psychopathology in WTC workers greatly exceed population norms. Surveillance and treatment programs continue to be needed.

72. Ovarian status in healthy postmenopausal women. [2008]

  • Healy DL, Bell R, Robertson DM, Jobling T, Oehler MK, Edwards A, Shekleton P, Oldham J, Piessens S, Teoh M, Mamers P, Taylor N, and Walker F
  • Menopause (New York, N.Y.) [Menopause] 2008 Nov-Dec; Vol. 15 (6), pp. 1109-14.
Subjects
Adult, Aged, Aged, 80 and over, CA-125 Antigen blood, Cohort Studies, Female, Humans, Inhibins blood, Mass Screening, Middle Aged, Ovarian Neoplasms blood, Ovarian Neoplasms prevention control, Ovary pathology, Ultrasonography, Ovarian Neoplasms diagnostic imaging, Ovary diagnostic imaging, and Postmenopause
Abstract
Objective: There are currently no programs to assess ovarian health in postmenopausal women. The aim of this study was to describe the ovaries in healthy women at least 5 years after menopause by questionnaire, transvaginal ultrasonography, and blood ovarian cancer markers.
Design: A total of 515 women who were asymptomatic and at the Stages of Reproductive Aging Workshop +2 stage of menopause (>5 y postmenopause) were recruited by advertisement. Clinical history was obtained by questionnaire, and biophysical assessment by a transvaginal ultrasound investigation and biochemical assessment by serum CA-125 and inhibin were performed. Abnormal findings were confirmed and then reviewed.
Results: Both ovaries were identified by transvaginal ultrasonography in 71% of women. The right ovary was visualized in 86.3% of these volunteers, and the left ovary was visualized in 78%. The presence of small unilocular cysts and echogenic foci facilitated identification of the ovary in some women. Ovarian/paraovarian lesions were present in 12.6% of women. Abnormalities of the endometrium and uterus were also common, prompting surgery in 7.2% of the women. Total serum inhibin concentrations were normal for postmenopausal women, whereas serum CA-125 was elevated in two women.
Conclusions: We find that the description and detection of postmenopausal ovaries by transvaginal ultrasonography allows the identification of both ovaries in most postmenopausal women. Ultrasonography-detected abnormalities of the ovary and/or the uterus/endometrium are common in women at this stage of life. The potential need for surgical intervention after the detection of such abnormalities needs to be carefully evaluated when considering transvaginal ultrasonography as a screening tool for ovarian cancer.

73. Enhancing the antilisterial effect of Lactobacillus curvatus CWBI-B28 in pork meat and cocultures by limiting bacteriocin degradation. [2008]

  • Kouakou P, Ghalfi H, Destain J, Duboisdauphin R, Evrard P, and Thonart P
  • Meat science [Meat Sci] 2008 Nov; Vol. 80 (3), pp. 640-8. Date of Electronic Publication: 2008 Feb 26.
Abstract
This work focused on Listeria monocytogenes growth inhibition and growth rebound in raw and cooked pork meat inoculated with Lactobacillus curvatus strains. During storage of raw meat homogenates in the presence of the bacteriocin-producing strain Lactobacillus curvatus CWBI-B28wt, the Listeria monocytogenes cfu count was initially reduced to an undetectable level, but a growth rebound occurred after two weeks, coinciding with loss of 70% of the bacteriocin activity present at the end of week 2. The Listeria growth rebound was suppressed when proteolysis of bacteriocin was countered by the absence of proteases (bacteriocin addition to cooked meat) or the presence of 1% soy flour (added to provide competing substrates). Further experiments confirmed that bacteriocin is sensitive to the action of proteolytic enzymes isolated from both Lactobacillus curvatus CWBI-B28wt and the meat matrix. Bacteriocin proteolysis thus emerges as a cause of Listeria growth rebound.

74. Arylphthalazines as potent, and orally bioavailable inhibitors of VEGFR-2. [2009]

  • Duncton MA, Piatnitski Chekler EL, Katoch-Rouse R, Sherman D, Wong WC, Smith LM 2nd, Kawakami JK, Kiselyov AS, Milligan DL, Balagtas C, Hadari YR, Wang Y, Patel SN, Rolster RL, Tonra JR, Surguladze D, Mitelman S, Kussie P, Bohlen P, and Doody JF
  • Bioorganic & medicinal chemistry [Bioorg Med Chem] 2009 Jan 15; Vol. 17 (2), pp. 731-40. Date of Electronic Publication: 2008 Nov 24.
Subjects
Administration, Oral, Animals, Biological Availability, Female, Isoquinolines chemical synthesis, Isoquinolines pharmacokinetics, Mice, Mice, Inbred Strains, Phthalazines administration dosage, Phthalazines chemical synthesis, Piperidines, Quinazolines, Vascular Endothelial Growth Factor Receptor-1 antagonists inhibitors, Phthalazines pharmacokinetics, and Vascular Endothelial Growth Factor Receptor-2 antagonists inhibitors
Abstract
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.

75. Genomic screening identifies novel linkages and provides further evidence for a role of MYH9 in nonsyndromic cleft lip and palate. [2009]

  • Chiquet BT, Hashmi SS, Henry R, Burt A, Mulliken JB, Stal S, Bray M, Blanton SH, and Hecht JT
  • European journal of human genetics : EJHG [Eur J Hum Genet] 2009 Feb; Vol. 17 (2), pp. 195-204. Date of Electronic Publication: 2008 Aug 20.
Subjects
Female, Humans, Male, Pedigree, Polymorphism, Single Nucleotide, Cleft Lip genetics, Cleft Palate genetics, Molecular Motor Proteins genetics, and Myosin Heavy Chains genetics
Abstract
Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth anomaly that requires prolonged multidisciplinary rehabilitation. Although variation in several genes has been identified as contributing to NSCLP, most of the genetic susceptibility loci have yet to be defined. To identify additional contributory genes, a high-throughput genomic scan was performed using the Illumina Linkage IVb Panel platform. We genotyped 6008 SNPs in nine non-Hispanic white NSCLP multiplex families and a single large African-American NSCLP multiplex family. Fourteen chromosomal regions were identified with LOD>1.5, including six regions not previously reported. Analysis of the data from the African-American and non-Hispanic white families revealed two likely chromosomal regions: 8q21.3-24.12 and 22q12.2-12.3 with LOD scores of 2.98 and 2.66, respectively. On the basis of biological function, syndecan 2 (SDC2) and growth differentiation factor 6 (GDF6) in 8q21.3-24.12 and myosin heavy-chain 9, non-muscle (MYH9) in 22q12.2-12.3 were selected as candidate genes. Association analyses from these genes yielded marginally significant P-values for SNPs in SDC2 and GDF6 (0.01

76. 2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: design and synthesis of a potent and isoform selective PKC-zeta inhibitor. [2009]

  • Trujillo JI, Kiefer JR, Huang W, Thorarensen A, Xing L, Caspers NL, Day JE, Mathis KJ, Kretzmer KK, Reitz BA, Weinberg RA, Stegeman RA, Wrightstone A, Christine L, Compton R, and Li X
  • Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2009 Feb 01; Vol. 19 (3), pp. 908-11. Date of Electronic Publication: 2008 Dec 06.
Subjects
Benzimidazoles pharmacology, Crystallography, X-Ray, Cyclin A chemistry, Cyclin-Dependent Kinase 2 metabolism, Drug Design, Humans, Imidazoles pharmacology, Inhibitory Concentration 50, Models, Chemical, Models, Molecular, Molecular Conformation, Protein Isoforms, Benzimidazoles chemical synthesis, Chemistry, Pharmaceutical methods, Enzyme Inhibitors pharmacology, Imidazoles chemical synthesis, Protein Kinase C chemistry, and Protein Kinase C isolation purification
Abstract
The inhibition of PKC-zeta has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-zeta). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH(2) derivative. The analog displays good selectivity over other PKC isoforms (alpha, betaII, gamma, delta, epsilon, mu, theta, eta and iota/lambda) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).

77. Longitudinal assessment of spirometry in the World Trade Center medical monitoring program. [2009]

  • Skloot GS, Schechter CB, Herbert R, Moline JM, Levin SM, Crowley LE, Luft BJ, Udasin IG, and Enright PL
  • Chest [Chest] 2009 Feb; Vol. 135 (2), pp. 492-498. Date of Electronic Publication: 2009 Jan 13.
Subjects
Adult, Air Pollutants analysis, Analysis of Variance, Epidemiological Monitoring, Female, Forced Expiratory Volume, Humans, Longitudinal Studies, Male, Mass Screening organization administration, Monitoring, Physiologic, Multivariate Analysis, New York City, Occupational Diseases diagnosis, Occupational Diseases etiology, Reference Values, Respiratory Tract Diseases etiology, Risk Factors, Sensitivity and Specificity, Smoking epidemiology, Time Factors, Vital Capacity, Environmental Monitoring statistics numerical data, Mass Screening statistics numerical data, Respiratory Tract Diseases diagnosis, September 11 Terrorist Attacks, and Spirometry
Abstract
Background: Multiple studies have demonstrated an initial high prevalence of spirometric abnormalities following World Trade Center (WTC) disaster exposure. We assessed prevalence of spirometric abnormalities and changes in spirometry between baseline and first follow-up evaluation in participants in the WTC Worker and Volunteer Medical Monitoring Program. We also determined the predictors of spirometric change between the two examinations.
Methods: Prebronchodilator and postbronchodilator spirometry, demographics, occupational history, smoking status, and respiratory symptoms and exposure onset were obtained at both examinations (about 3 years apart).
Results: At the second examination, 24.1% of individuals had abnormal spirometry findings. The predominant defect was a low FVC without obstruction (16.1%). Between examinations, the majority of individuals did not have a greater-than-expected decline in lung function. The mean declines in prebronchodilator FEV(1) and FVC were 13 mL/yr and 2 mL/yr, respectively (postbronchodilator results were similar and not reported). Significant predictors of greater average decline between examinations were lack of bronchodilator responsiveness at examination 1 and weight gain [corrected].
Conclusions: Elevated rates of spirometric abnormalities were present at both examinations, with reduced FVC most common. Although the majority had a normal decline in lung function, lack of bronchodilator response at examination 1 and weight gain were significantly associated with greater-than-normal lung function declines [corrected]. Due to the presence of spirometric abnormalities > 5 years after the disaster in many exposed individuals, longer-term monitoring of WTC responders is essential.

78. Enteral nutrition practice recommendations. [2009]

  • Bankhead R, Boullata J, Brantley S, Corkins M, Guenter P, Krenitsky J, Lyman B, Metheny NA, Mueller C, Robbins S, and Wessel J
  • JPEN. Journal of parenteral and enteral nutrition [JPEN J Parenter Enteral Nutr] 2009 Mar-Apr; Vol. 33 (2), pp. 122-67. Date of Electronic Publication: 2009 Jan 26.
Subjects
Consumer Product Safety, Drug Administration Routes, Enteral Nutrition adverse effects, Humans, Refeeding Syndrome prevention control, Enteral Nutrition standards, Nutrition Disorders prevention control, Nutrition Disorders therapy, and Practice Guidelines as Topic

79. The costs and effects of addressing the needs of vulnerable populations: results of 10 years of research. [2009]

  • Browne G, Roberts J, Byrne C, Gafni A, Weir R, and Majumdar B
  • The Canadian journal of nursing research = Revue canadienne de recherche en sciences infirmieres [Can J Nurs Res] 2009 Mar; Vol. 41 (1), pp. 193-203.

80. Comprehensive analysis of expression, subcellular localization, and cognate pairing of SNARE proteins in oligodendrocytes. [2009]

  • Feldmann A, Winterstein C, White R, Trotter J, and Krämer-Albers EM
  • Journal of neuroscience research [J Neurosci Res] 2009 Jun; Vol. 87 (8), pp. 1760-72.
Subjects
Animals, Cell Compartmentation physiology, Cell Membrane ultrastructure, Cells, Cultured, Central Nervous System ultrastructure, Dimerization, Female, Golgi Apparatus metabolism, Golgi Apparatus ultrastructure, Male, Membrane Fusion physiology, Mice, Myelin Sheath ultrastructure, Oligodendroglia ultrastructure, Protein Transport physiology, Qa-SNARE Proteins metabolism, Qb-SNARE Proteins metabolism, Qc-SNARE Proteins metabolism, R-SNARE Proteins metabolism, Transport Vesicles metabolism, Transport Vesicles ultrastructure, Vesicle-Associated Membrane Protein 3 metabolism, Cell Membrane metabolism, Central Nervous System metabolism, Myelin Sheath metabolism, Oligodendroglia metabolism, and SNARE Proteins metabolism
Abstract
Oligodendrocytes form the central nervous system myelin sheath by spiral wrapping of their plasma membrane around axons, necessitating a high rate of exocytic membrane addition to the growing myelin membrane. Membrane fusion is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins (SNAREs), which act by specific pairing of vesicle (R)- and target (Q)-SNAREs. To characterize oligodendroglial SNAREs and their trafficking pathways, we performed a detailed expression analysis of SNAREs in differentiating cultured oligodendrocytes and myelin and determined their subcellular localization. Expression of the plasma membrane Q-SNAREs syntaxin 3, syntaxin 4, SNAP23, and the endosomal R-SNARE VAMP3/cellubrevin increased with oligodendroglial maturation, while the expression of SNAP29 decreased. Interestingly, syntaxin 3, syntaxin 4, and VAMP7/tetanustoxin-insensitive VAMP accumulated in myelin during development, suggesting a role in myelin membrane fusion. Coimmunoprecipitation from oligodendroglial cell lysates elucidated interactions between SNAREs: for example, Golgi-localized VAMP4 associated with syntaxin 6 and SNAP29. Furthermore, we identified a cognate core complex composed of VAMP3, syntaxin 4, and SNAP23, which may mediate fusion of endosome-derived vesicles with the plasma membrane. This study provides a comprehensive analysis of SNARE proteins in oligodendrocytes and assigns defined SNAREs to putative vesicle trafficking pathways in myelinating oligodendrocytes, thus facilitating future functional analysis of distinct SNAREs in oligodendroglial membrane traffic and myelination.
((c) 2009 Wiley-Liss, Inc.)

81. Impact of thyroid function and polymorphisms in the type 2 deiodinase on blood pressure: the Rotterdam Study and the Rotterdam Scan Study. [2009]

  • van der Deure WM, Peeters RP, Uitterlinden AG, Hofman A, Breteler MM, Witteman J, and Visser TJ
  • Clinical endocrinology [Clin Endocrinol (Oxf)] 2009 Jul; Vol. 71 (1), pp. 137-44. Date of Electronic Publication: 2008 Oct 16.
Subjects
Aged, Aged, 80 and over, Cohort Studies, Female, Genetic Predisposition to Disease, Humans, Hypertension blood, Hypertension physiopathology, Male, Middle Aged, Netherlands, Risk Factors, Thyroid Function Tests, Thyroid Hormones blood, Blood Pressure, Hypertension genetics, Iodide Peroxidase genetics, Polymorphism, Genetic, Receptors, Thyrotropin genetics, and Thyroid Gland physiology
Abstract
Introduction: Thyroid function and genetic variation in the hypothalamus-pituitary-thyroid axis have been implicated in blood pressure regulation and susceptibility to hypertension. However studies conducted thus far were small with controversial results.
Objective: To examine whether serum thyroid parameters and polymorphisms in the type 2 deiodinase and the TSH receptor are associated with blood pressure and the presence of hypertension in two large cohorts of elderly subjects.
Design and Participants: We studied a random sample of 1444 subjects of the Rotterdam study, and 997 subjects of the Rotterdam Scan study, two population-based cohort studies among elderly individuals aged 55-90 years. Outcome measurements Data on blood pressure and hypertension were obtained, and serum thyroid parameters, D2-Thr92Ala, D2-ORFa-Gly3Asp and TSHR-Asp727Glu polymorphisms were determined.
Results: In contrast to previous findings, no consistent and/or significant associations were found between serum TSH and FT4 and blood pressure in both cohorts. In addition, the D2-Thr92Ala, D2-ORFa-Gly3Asp and TSHR-Asp727Glu polymorphisms were not associated with blood pressure or the risk of hypertension.
Conclusions: In two large populations of elderly subjects, neither serum thyroid parameters nor polymorphisms in the type 2 deiodinase and the TSH receptor, were associated with blood pressure or the presence of hypertension. Our data suggest that thyroid function is not an important determinant of hypertension in elderly Dutch subjects.

82. Multiple myeloma in World Trade Center responders: a case series. [2009]

  • Moline JM, Herbert R, Crowley L, Troy K, Hodgman E, Shukla G, Udasin I, Luft B, Wallenstein S, Landrigan P, and Savitz DA
  • Journal of occupational and environmental medicine [J Occup Environ Med] 2009 Aug; Vol. 51 (8), pp. 896-902.
Subjects
Adult, Aged, Female, Humans, Male, Middle Aged, New York City epidemiology, Allied Health Personnel, Multiple Myeloma epidemiology, and September 11 Terrorist Attacks
Abstract
Objectives: We report on cases of multiple myeloma (MM) observed in World Trade Center (WTC) responders registered in the WTC Medical Program.
Methods: Possible cases of MM diagnosed between September 11, 2001, and September 10, 2007, in responders were confirmed if they met the World Health Organization and Mayo Clinic diagnostic criteria.
Results: Among 28,252 responders of known sex and age, eight cases of MM were observed (6.8 expected). Four of these cases were observed in responders younger than 45 years at the time of diagnosis (1.2 expected). A slight deficit of MM cases was observed in responders older than 45 years (4 observed, 5.6 expected).
Conclusion: In this case series, we observe an unusual number of MM cases in WTC responders under 45 years. This finding underscores the importance of maintaining surveillance for cancer and other emerging diseases in this highly exposed population.

83. Use of a nisin-producing starter culture of Lactococcus lactis subsp, lactis to improve traditional fish fermentation in Senegal. [2009]

  • Diop MB, Dubois-Dauphin R, Destain J, Tine E, and Thonart P
  • Journal of food protection [J Food Prot] 2009 Sep; Vol. 72 (9), pp. 1930-4.
Subjects
Animals, Colony Count, Microbial, Fermentation, Food Microbiology, Food Preservation standards, Humans, Hydrogen-Ion Concentration, Senegal, Consumer Product Safety, Food Preservation methods, Lactococcus lactis metabolism, Nisin biosynthesis, and Seafood microbiology
Abstract
Lactococcus lactis subsp. lactis strain CWBI B1410, which produces various antibacterial compounds including organic acids and nisin, was used as a starter culture to improve the traditional Senegalese fish fermentation in which fish are mostly transformed to guedj by spontaneous fermentation for 24 to 48 h at ambient temperatures near 30 degrees C followed by salting (with NaCl) and sun drying. Assays were performed on lean fish (Podamasys jubelini) and fat fish (Arius heudelotii) purchased at a local market. The total viable microbial counts in raw fillets of P. jubelini and A. heudelotii were 5.78 and 5.39 log CFU/g, respectively. Populations of enteric bacteria (which can include pathogenic bacteria) in P. jubelini and A. heudelotii were 4.08 and 4.12 log CFU/g, respectively. Spontaneous fermentation of raw fillets at 30 degrees C led to the proliferation of enteric bacteria to 9 log CFU/g after 24 h in fermented P. jubelini and A. heudelotii fillets with pH values of 6.83 and 7.50, respectively. When raw fish fillets were supplemented with glucose (1%, wt/wt) and inoculated with Lactococcus lactis (10(7) CFU/g), the pH decreased to about 4.60 after 10 h at 30 degrees C, and nisin activity was detected in juice from the fillets. Traditionally fermented fillets of P. jubelini and A. heudelotii contained enteric bacteria at higher levels of 4 and 2 log CFU/g, respectively, than did fillets of the same fish supplemented with glucose and fermented with the starter culture. These data suggest that this new fish fermentation strategy combined with salting and drying can be used to enhance the safety of guedj.

84. Stories behind the symptoms: a qualitative analysis of the narratives of 9/11 rescue and recovery workers. [2009]

  • Bills CB, Dodson N, Stellman JM, Southwick S, Sharma V, Herbert R, Moline JM, and Katz CL
  • The Psychiatric quarterly [Psychiatr Q] 2009 Sep; Vol. 80 (3), pp. 173-89. Date of Electronic Publication: 2009 Jul 08.
Subjects
Adult, Disasters, Female, Humans, Male, Interview, Psychological, Rescue Work, and September 11 Terrorist Attacks psychology
Abstract
A qualitative study of the experiences of rescue and recovery workers/volunteers at Ground Zero following the terrorist attacks of 9/11/01 is reported. Information was extracted from a semi-structured clinical evaluation of 416 responders who were the initial participants in a large scale medical and mental health screening and treatment program for 9/11 responders. Qualitative analysis revealed themes that spanned four categories- occupational roles, exposures, attitudes/experiences, and outcomes related to the experience of Ground Zero. Themes included details regarding Ground Zero roles, grotesque experiences such as smells, the sense of the surreal nature of responding, and a turning to rituals to cope after leaving Ground Zero. These findings personalize the symptom reports and diagnoses that have resulted from the 9/11 responders' exposure to Ground Zero, yielding richer information than would otherwise be available for addressing the psychological dimensions of disasters. This work shows that large scale qualitative surveillance of trauma-exposed populations is both relevant and feasible.

85. ASPAN's evidence-based clinical practice guideline for the promotion of perioperative normothermia. [2009]

  • Hooper VD, Chard R, Clifford T, Fetzer S, Fossum S, Godden B, Martinez EA, Noble KA, O'Brien D, Odom-Forren J, Peterson C, and Ross J
  • Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses [J Perianesth Nurs] 2009 Oct; Vol. 24 (5), pp. 271-87.
Subjects
Humans, Infant, Newborn, Body Temperature Regulation, Evidence-Based Nursing, Practice Guidelines as Topic, and Societies, Nursing

86. Ovarian status in healthy postmenopausal women: follow-up 12 months after transvaginal ultrasound. [2009]

  • Bell RJ, Healy DL, Robertson DM, Jobling T, Oehler MK, Edwards A, Shekleton P, Oldham J, Piessens S, Teoh M, Mamers P, Taylor N, and Walker F
  • Menopause (New York, N.Y.) [Menopause] 2009 Nov-Dec; Vol. 16 (6), pp. 1149-55.
Subjects
Adult, Aged, Aged, 80 and over, CA-125 Antigen blood, Cohort Studies, Female, Humans, Inhibins blood, Middle Aged, Ovarian Diseases blood, Ovarian Diseases surgery, Ovarian Neoplasms blood, Ovarian Neoplasms diagnostic imaging, Reproducibility of Results, Time Factors, Ultrasonography, Ovarian Diseases diagnostic imaging, Ovary diagnostic imaging, and Postmenopause
Abstract
Objective: We have previously reported on the point prevalence of ovarian lesions detected by transvaginal ultrasound (TVU) in 515 asymptomatic women at least 5 years postmenopause. The aims of this study were to report, in the same women, on the repeatability of visualization of the ovaries (TVU) and the natural history of ovarian lesions seen at baseline but not treated surgically and to assess whether any women developed new ovarian abnormalities 12 months later.
Methods: The study involved a cohort of 515 postmenopausal women recruited from the community, at least 5 years past their last period. They were assessed at baseline and again after 12 months with TVU and serum levels of inhibin and CA-125.
Results: The right and left ovaries were seen on both occasions in 80% and 68% of women, respectively. Of the 49 women who had an ovarian lesion at baseline, did not undergo surgery at that time, and had a follow-up TVU, the lesion was unchanged 12 months later in 30 women. Four women developed a new ovarian lesion within the 12 months. None of the 14 women who underwent surgery on the basis of the ovarian appearance at baseline, or the 2 who had surgery on the basis of the ovarian appearance at follow-up, had an ovarian malignancy.
Conclusions: The use of TVU in women at least 5 years after menopause is problematic because the ovaries cannot be visualized in all women and because TVU has the potential to identify many benign lesions that would otherwise remain undetected. These are important considerations in weighing up the risks and benefits of using TVU as a screening tool.

87. World Trade Center multiple myeloma: police responders only? [2009]

  • Miller, Albert, Moline, Jacqueline M., Herbert, Robin, Crowley, Laura, Troy, Kevin, Hodgman, Erica, Shukla, Gauri, Udasin, Iris, Luft, Benjamin, and Wallenstein, Sylvan
  • Journal of Occupational and Environmental Medicine. Dec 2009, Vol. 51 Issue 12, p1357, 2 p.
Subjects
World Trade Center and Pentagon Attacks, 2001, Risk factors, Demographic aspects, Health aspects, Multiple myeloma -- Risk factors, Multiple myeloma -- Demographic aspects, and First responders -- Health aspects

88. The association of serum testosterone levels and ventricular repolarization. [2010]

  • van Noord C, Dörr M, Sturkenboom MC, Straus SM, Reffelmann T, Felix SB, Hofman A, Kors JA, Haring R, de Jong FH, Nauck M, Uitterlinden AG, Wallaschofski H, Witteman JC, Völzke H, and Stricker BH
  • European journal of epidemiology [Eur J Epidemiol] 2010; Vol. 25 (1), pp. 21-8. Date of Electronic Publication: 2009 Dec 03.
Subjects
Adult, Aged, Cross-Sectional Studies, Electrocardiography, Germany, Humans, Linear Models, Male, Middle Aged, Netherlands, Prospective Studies, Testosterone physiology, Testosterone blood, and Ventricular Function physiology
Abstract
Unlabelled: It is assumed that testosterone is an important regulator of gender-related differences in ventricular repolarization. Therefore, our aim was to study whether serum levels of testosterone are associated with QTc, QT and RR interval variation.
Setting: two independent population-based cohort studies.
Participants: 445 male participants (> or =55 years) from the Rotterdam study cohort and 1,428 male participants from the study of health in Pomerania (SHIP) with an electrocardiogram who were randomly sampled for assessment of serum testosterone at baseline, after exclusion of participants with testosterone altering drugs, QTc prolonging drugs or dig(it)oxin, left ventricular hypertrophy and left and right bundle branch block.
Endpoints: length of the QTc, QT and RR intervals.
Analysis: linear regression model, adjusted for the two individual studies and a pooled analysis of both studies. The pooled analysis of the Rotterdam study and SHIP showed that the QTc interval gradually decreased among the tertiles (P value for trend 0.024). The third tertile of serum testosterone was associated with a lower QTc interval compared to the first tertile [-3.4 ms (-6.5; -0.3)]. However, the third tertile of serum testosterone was not associated with a lower QT interval compared to the first tertile [-0.7 ms (-3.1; 1.8)]. The RR interval gradually increased among the tertiles (P value for trend 0.002) and the third tertile of serum testosterone showed an increased RR interval compared to the first tertile [33.5 ms (12.2; 54.8)]. In the pooled analysis of two population-based studies, serum testosterone levels were not associated with the QT interval, which could be due to a lack of power. Lower QTc intervals in men with higher serum testosterone levels could be due to the association of serum testosterone with prolongation of the RR interval.

89. Expression, purification, characterization and crystallization of non- and phosphorylated states of JAK2 and JAK3 kinase domain. [2010]

  • Hall T, Emmons TL, Chrencik JE, Gormley JA, Weinberg RA, Leone JW, Hirsch JL, Saabye MJ, Schindler JF, Day JE, Williams JM, Kiefer JR, Lightle SA, Harris MS, Guru S, Fischer HD, and Tomasselli AG
  • Protein expression and purification [Protein Expr Purif] 2010 Jan; Vol. 69 (1), pp. 54-63. Date of Electronic Publication: 2009 Sep 23.
Subjects
Amino Acid Sequence, Biocatalysis, Chromatography, High Pressure Liquid, Crystallization, Electrophoresis, Polyacrylamide Gel, Fermentation, Humans, Kinetics, Molecular Sequence Data, Phosphorylation, Protein Structure, Tertiary, Janus Kinase 2 chemistry, Janus Kinase 2 isolation purification, Janus Kinase 3 chemistry, and Janus Kinase 3 isolation purification
Abstract
Janus-associated kinases (JAKs) play critical roles in cytokine signaling, and have emerged as viable therapeutic targets in inflammation and oncology related diseases. To date, targeting JAK proteins with highly selective inhibitor compounds have remained elusive. We have expressed the active kinase domains for both JAK2 and JAK3 and devised purification protocols to resolve the non-, mono- (Y1007) and diphosphorylated (Y1007 and Y1008) states of JAK2 and non- and monophosphorylated states of JAK3 (Y980). An optimal purified protein yield of 20, 29 and 69mg per 20L cell culture was obtained for the three JAK2 forms, respectively, and 12.2 and 2.3mg per 10L fermentation for the two JAK3 forms allowing detailed biochemical and biophysical studies. To monitor the purification process we developed a novel HPLC activity assay where a sequential order of phosphorylation was observed whereby the first tyrosine residue was completely phosphorylated prior to phosphorylation of the tandem tyrosine residue. A Caliper-based microfluidics assay was used to determine the kinetic parameters (K(m) and k(cat)) for each phosphorylated state, showing that monophosphorylated (Y1007) JAK2 enzyme activity increased 9-fold over that of the nonphosphorylated species, and increased an additional 6-fold for the diphosphorylated (Y1007/Y1008) species, while phosphorylation of JAK3 resulted in a negligible increase in activity. Moreover, crystal structures have been generated for each isolated state of JAK2 and JAK3 with resolutions better than 2.4A. The generation of these reagents has enabled kinetic and structural characterization to inform the design of potent and selective inhibitors of the JAK family.

90. Biomarkers of organophosphorus nerve agent exposure: comparison of phosphylated butyrylcholinesterase and phosphylated albumin after oxime therapy. [2010]

  • Read RW, Riches JR, Stevens JA, Stubbs SJ, and Black RM
  • Archives of toxicology [Arch Toxicol] 2010 Jan; Vol. 84 (1), pp. 25-36. Date of Electronic Publication: 2009 Oct 28.
Subjects
Animals, Biomarkers, Butyrylcholinesterase analysis, Callitrichinae, Central Nervous System Agents administration dosage, Central Nervous System Agents toxicity, Cholinesterase Inhibitors administration dosage, Humans, Injections, Intramuscular, Lethal Dose 50, Organophosphorus Compounds administration dosage, Phosphorylation, Serum Albumin analysis, Time Factors, Tyrosine analogs derivatives, Tyrosine analysis, Butyrylcholinesterase chemistry, Cholinesterase Inhibitors toxicity, Cholinesterase Reactivators therapeutic use, Environmental Exposure, Organophosphorus Compounds toxicity, Oximes therapeutic use, and Serum Albumin chemistry
Abstract
Organophosphorus nerve agents inhibit the activity of cholinesterases by phosphylation of the active site serine. In addition, sarin, cyclosarin, soman and tabun have been shown to phosphylate a tyrosine residue in albumin. Therapies against nerve agent poisoning include the use of oximes to reactivate inhibited cholinesterases by displacement of the phosphyl moiety and hence detectable levels of adducts with cholinesterases may be reduced. Adducts with tyrosine have been shown to be persistent in the guinea pig in the presence of oxime therapy. Plasma samples obtained from an animal study aimed at improving therapy against nerve agent poisoning were used to compare the suitability of tyrosine and butyrylcholinesterase (BuChE) adducts as biomarkers of nerve agent exposure after treatment with therapeutic oximes. Under the terms of the project licence, these samples could be collected only on death of the animal, which occurred within hours of exposure or when culled at 23 or 24 days. Tyrosine adducts were detected in all samples collected following intra-muscular administration of twice the LD50 dose of the respective nerve agent. Aged BuChE adducts were detected in samples collected within a few hours after administration of soman and tabun, but not after 23 or 24 days. No BuChE adducts were detected in animals exposed to sarin and cyclosarin where samples were collected only after 23 or 24 days.

91. The resistance to freeze-drying and to storage was determined as the cellular ability to recover its survival rate and acidification activity. [2010]

  • Coulibaly I, Dubois-Dauphin R, Destain J, Fauconnier ML, Lognay G, and Thonart P
  • International journal of microbiology [Int J Microbiol] 2010; Vol. 2010, pp. 625239. Date of Electronic Publication: 2010 Jun 16.
Abstract
The protective effects of the fatty acid composition and membrane action of the acidification activity of two strains of Lactobacillus kept at 20 degrees C were studied. The addition of sorbitol, monosodium glutamate and glycerol during storage is causing the decline of acidification and increased concentrations of unsaturated fatty acids observed in both strains. The addition of sorbitol and monosodium glutamate does not alter the fatty acid composition, whatever the strain, but increases the resistance to freeze-drying of L. plantarum CWBI-B1419 and improves survival during storage. The addition of these preservatives and decreased activity of acidification improves the ratio unsaturated. These results indicate that the survival during storage and freeze-drying resistance are closely related to the composition of membrane fatty acids. This behaviour can be interpreted as an adaptation of L. plantarum B1419-CWBI supplemented by cryoprotectant additives such as sorbitol or monosodium glutamate sorbitol and monosodium glutamate as an additive. L. plantarum CWBI-B1419 presents a greater adaptation to culture conditions than L. paracasei ssp. paracasei LMG9192(T).

92. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. [2010]

  • Sofat R, Hingorani AD, Smeeth L, Humphries SE, Talmud PJ, Cooper J, Shah T, Sandhu MS, Ricketts SL, Boekholdt SM, Wareham N, Khaw KT, Kumari M, Kivimaki M, Marmot M, Asselbergs FW, van der Harst P, Dullaart RP, Navis G, van Veldhuisen DJ, Van Gilst WH, Thompson JF, McCaskie P, Palmer LJ, Arca M, Quagliarini F, Gaudio C, Cambien F, Nicaud V, Poirer O, Gudnason V, Isaacs A, Witteman JC, van Duijn CM, Pencina M, Vasan RS, D'Agostino RB Sr, Ordovas J, Li TY, Kakko S, Kauma H, Savolainen MJ, Kesäniemi YA, Sandhofer A, Paulweber B, Sorli JV, Goto A, Yokoyama S, Okumura K, Horne BD, Packard C, Freeman D, Ford I, Sattar N, McCormack V, Lawlor DA, Ebrahim S, Smith GD, Kastelein JJ, Deanfield J, and Casas JP
  • Circulation [Circulation] 2010 Jan 05; Vol. 121 (1), pp. 52-62. Date of Electronic Publication: 2009 Dec 21.
Subjects
Anticholesteremic Agents administration dosage, Biomarkers, Blood Pressure drug effects, Blood Pressure genetics, Cholesterol Ester Transfer Proteins blood, Dose-Response Relationship, Drug, Electrolytes blood, Genotype, Humans, Lipoproteins, HDL blood, Polymorphism, Single Nucleotide, Quinolines administration dosage, Randomized Controlled Trials as Topic statistics numerical data, Risk Factors, White People statistics numerical data, Anticholesteremic Agents adverse effects, Cholesterol Ester Transfer Proteins antagonists inhibitors, Cholesterol Ester Transfer Proteins genetics, Hypercholesterolemia drug therapy, Hypercholesterolemia epidemiology, Hypercholesterolemia genetics, Hypertension chemically induced, Hypertension epidemiology, Hypertension genetics, and Quinolines adverse effects
Abstract
Background: Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target.
Methods and Results: We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI -0.28 to 0.60 mm Hg) and diastolic blood pressure (-0.04 mm Hg, 95% CI -0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib.
Conclusions: Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

93. Microfabricated planar glass gas chromatography with photoionization detection. [2010]

  • Lewis AC, Hamilton JF, Rhodes CN, Halliday J, Bartle KD, Homewood P, Grenfell RJ, Goody B, Harling AM, Brewer P, Vargha G, and Milton MJ
  • Journal of chromatography. A [J Chromatogr A] 2010 Jan 29; Vol. 1217 (5), pp. 768-74. Date of Electronic Publication: 2009 Dec 04.
Subjects
Equipment Design, Glass chemistry, Temperature, Chromatography, Gas instrumentation, Chromatography, Gas methods, Photochemistry instrumentation, Photochemistry methods, and Volatile Organic Compounds analysis
Abstract
We report the development of a microfabricated gas chromatography system suitable for the separation of volatile organic compounds (VOCs) and compatible with use as a portable measurement device. Hydrofluoric acid etching of 95x95mm Schott B270 wafers has been used to give symmetrical hemi-spherical channels within a glass substrate. Two matching glass plates were subsequently cold bonded with the channels aligned; the flatness of the glass surfaces resulted in strong bonding through van der Waals forces. The device comprised gas fluidic interconnections, injection zone and 7.5 and 1.4m long, 320microm internal diameter capillaries. Optical microscopy confirmed the capillaries to have fully circular channel profiles. Direct column heating and cooling could be achieved using a combination of resistive heaters and Peltier devices. The low thermal conductivity of glass allowed for multiple uniform temperature zones to be achieved within a single glass chip. Temperature control over the range 10-200 degrees C was achieved with peak power demand of approximately 25W. The 7.5m capillary column was static coated with a 2microm film of non-polar dimethylpolysiloxane stationary phase. A standard FID and a modified lightweight 100mW photoionization detector (PID) were coupled to the column and performance tested with gas mixtures of monoaromatic and monoterpene species at the parts per million concentration level. The low power GC-PID device showed good performance for a small set of VOCs and sub ng detection sensitivity to monoaromatics.
(Copyright (c) 2009 Elsevier B.V. All rights reserved.)

94. A cross-sectional study of the prevalence, correlates, and costs of falls in older home care clients 'at risk' for falling. [2010]

  • Markle-Reid M, Browne G, Gafni A, Roberts J, Weir R, Thabane L, Miles M, Vaitonis V, Hecimovich C, Baxter P, and Henderson S
  • Canadian journal on aging = La revue canadienne du vieillissement [Can J Aging] 2010 Mar; Vol. 29 (1), pp. 119-37.
Subjects
Aged, Aged, 80 and over, Canada, Cognition Disorders epidemiology, Cross-Sectional Studies, Environment, Female, Health Status, Humans, Male, Parkinson Disease epidemiology, Risk Factors, Vision Disorders epidemiology, Accidental Falls economics, Accidental Falls statistics numerical data, Health Services for the Aged standards, and Home Care Services standards
Abstract
This study examined the six-month prevalence, risk factors, and costs of falls in older people using home support services who are at risk of falling. Of the 109 participants, 70.6 per cent reported >or= one fall in the previous six months, and 27.5 per cent experienced multiple falls. Although there was no statistically significant difference in any fall-related risk factor between fallers (1+ falls) and non-fallers (0 falls), fallers had clinically important trends towards lower levels of physical, social, and psychological functioning. There was no statistically significant difference between fallers and non-fallers in the total per-person costs of use of health services in the previous six months; however, there were significant differences between groups in specific types of health services. The multivariate analysis revealed the presence of five risk factors for falls: neurological disorder (e.g., cognitive impairment, Parkinson's disease), age >or= 85 years, environmental hazards, previous slip or trip, and visual impairment.

95. The effects and costs of a multifactorial and interdisciplinary team approach to falls prevention for older home care clients 'at risk' for falling: a randomized controlled trial. [2010]

  • Markle-Reid M, Browne G, Gafni A, Roberts J, Weir R, Thabane L, Miles M, Vaitonis V, Hecimovich C, Baxter P, and Henderson S
  • Canadian journal on aging = La revue canadienne du vieillissement [Can J Aging] 2010 Mar; Vol. 29 (1), pp. 139-61.
Subjects
Aged, Aged, 80 and over, Animals, Emotions, Evidence-Based Medicine, Fear, Female, Health Services for the Aged organization administration, Health Status, Home Care Services standards, Humans, Male, Pain, Patient Care Team, Perception, Risk Factors, Sex Characteristics, Accidental Falls prevention control, Health Services for the Aged standards, and Home Care Services organization administration
Abstract
This study determined the effects and costs of a multifactorial, interdisciplinary team approach to falls prevention. Randomized controlled trial of 109 older adults who are at risk for falls. This was a six-month multifactorial and evidence-based prevention strategy involving an interdisciplinary team. The primary outcome was number of falls during the six-month follow-up. At six months, no difference in the mean number of falls between groups. Subgroup analyses showed that the intervention effectively reduced falls in men (75-84 years old) with a fear of falling or negative fall history. Number of slips and trips was greatly reduced; and emotional health had a greater improvement in role functioning related to emotional health in the intervention group. Quality of life was improved, slips and trips were reduced, as were falls among males (75-84 years old) with a fear of falling or negative fall history.

96. The effects and costs of a multifactorial and interdisciplinary team approach to falls and prevention for older home care clients 'at risk' for falling: a randomized controlled trial [2010]

  • Markle-Reid, Maureen, Browne, Gina, Gafni, Amiram, Roberts, Jacqueline, Weir, Robin, Thabane, Lehana, Miles, Melody, Vaitonis, Vida, Hecimovich, Catherine, Baxter, Pamela, and Henderson, Sandra
  • Canadian Journal on Aging. March 2010, Vol. 29 Issue 1, p139, 23 p.
Subjects
Prevention, Risk factors, Economic aspects, Research, Accidental falls -- Prevention, Accidental falls -- Risk factors, Accidental falls -- Economic aspects, Accidental falls -- Research, Falls (Accidents) -- Prevention, Falls (Accidents) -- Risk factors, Falls (Accidents) -- Economic aspects, and Falls (Accidents) -- Research

97. Case report: Lung disease in World Trade Center responders exposed to dust and smoke: carbon nanotubes found in the lungs of World Trade Center patients and dust samples. [2010]

  • Wu M, Gordon RE, Herbert R, Padilla M, Moline J, Mendelson D, Litle V, Travis WD, and Gil J
  • Environmental health perspectives [Environ Health Perspect] 2010 Apr; Vol. 118 (4), pp. 499-504.
Subjects
Adult, Environmental Exposure, Female, Humans, In Vitro Techniques, Lung ultrastructure, Male, Middle Aged, Dust analysis, Lung chemistry, Lung Diseases chemically induced, Nanotubes, Carbon analysis, September 11 Terrorist Attacks, and Smoke analysis
Abstract
Context: After the collapse of the World Trade Center (WTC) on 11 September 2001, a dense cloud of dust containing high levels of airborne pollutants covered Manhattan and parts of Brooklyn, New York. Between 60,000 and 70,000 responders were exposed. Many reported adverse health effects.
Case Presentation: In this report we describe clinical, pathologic, and mineralogic findings in seven previously healthy responders who were exposed to WTC dust on either 11 September or 12 September 2001, who developed severe respiratory impairment or unexplained radiologic findings and underwent video-assisted thoracoscopic surgical lung biopsy procedures at Mount Sinai Medical Center. WTC dust samples were also examined. We found that three of the seven responders had severe or moderate restrictive disease clinically. Histopathology showed interstitial lung disease consistent with small airways disease, bronchiolocentric parenchymal disease, and nonnecrotizing granulomatous condition. Tissue mineralogic analyses showed variable amounts of sheets of aluminum and magnesium silicates, chrysotile asbestos, calcium phosphate, and calcium sulfate. Small shards of glass containing mostly silica and magnesium were also found. Carbon nanotubes (CNT) of various sizes and lengths were noted. CNT were also identified in four of seven WTC dust samples.
Discussion: These findings confirm the previously reported association between WTC dust exposure and bronchiolar and interstitial lung disease. Long-term monitoring of responders will be needed to elucidate the full extent of this problem. The finding of CNT in both WTC dust and lung tissues is unexpected and requires further study.

98. Expression, purification, and characterization of TYK-2 kinase domain, a member of the Janus kinase family. [2010]

  • Korniski B, Wittwer AJ, Emmons TL, Hall T, Brown S, Wrightstone AD, Hirsch JL, Gormley JA, Weinberg RA, Leone JW, Day JE, Chrencik JE, Sommers CD, Fischer HD, and Tomasselli AG
  • Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2010 May 28; Vol. 396 (2), pp. 543-8. Date of Electronic Publication: 2010 May 08.
Subjects
Animals, Catalysis, Humans, Janus Kinase 2 antagonists inhibitors, Janus Kinase 3 antagonists inhibitors, Mice, Phosphorylation, Protein Structure, Tertiary, TYK2 Kinase antagonists inhibitors, Janus Kinase 2 biosynthesis, Janus Kinase 2 isolation purification, Janus Kinase 3 biosynthesis, Janus Kinase 3 isolation purification, TYK2 Kinase biosynthesis, and TYK2 Kinase isolation purification
Abstract
The Janus kinase family consists of four members: JAK-1, -2, -3 and TYK-2. While JAK-2 and JAK-3 have been well characterized biochemically, there is little data on TYK-2. Recent work suggests that TYK-2 may play a critical role in the development of a number of inflammatory processes. We have carried out a series of biochemical studies to better understand TYK-2 enzymology and its inhibition profile, in particular how the TYK-2 phosphorylated forms differ from each other and from the other JAK family members. We have expressed and purified milligram quantities of the TYK-2 kinase domain (KD) to high purity and developed a method to separate the non-, mono- (pY(1054)) and di-phosphorylated forms of the enzyme. Kinetic studies (k(cat(app))/K(m(app))) indicated that phosphorylation of the TYK-2-KD (pY(1054)) increased the catalytic efficiency 4.4-fold compared to its non-phosphorylated form, while further phosphorylation to generate the di-phosphorylated enzyme imparted no further increase in activity. These results are in contrast to those obtained with the JAK-2-KD and JAK-3-KD, where little or no increase in activity occurred upon mono-phosphorylation, while di-phosphorylation resulted in a 5.1-fold increase in activity for the JAK-2-KD. Moreover, ATP-competitive inhibitors demonstrated 10-30-fold shifts in potency (K(i(app))) as a result of the TYK-2-KD phosphorylation state, while the shifts for JAK-3-KD were only 2-3-fold and showed little or no change for JAK-2-KD. Thus, the phosphorlyation state imparted differential effects on both activity and inhibition within the JAK family of kinases.
(Copyright (c) 2010 Elsevier Inc. All rights reserved.)

99. Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. [2010]

  • Chrencik JE, Patny A, Leung IK, Korniski B, Emmons TL, Hall T, Weinberg RA, Gormley JA, Williams JM, Day JE, Hirsch JL, Kiefer JR, Leone JW, Fischer HD, Sommers CD, Huang HC, Jacobsen EJ, Tenbrink RE, Tomasselli AG, and Benson TE
  • Journal of molecular biology [J Mol Biol] 2010 Jul 16; Vol. 400 (3), pp. 413-33. Date of Electronic Publication: 2010 May 15.
Subjects
Binding Sites, Calorimetry, Humans, Janus Kinase 3 metabolism, Kinetics, Models, Molecular, Piperidines, Protein Binding, Protein Structure, Tertiary, TYK2 Kinase metabolism, Benzimidazoles metabolism, Enzyme Inhibitors metabolism, Janus Kinase 3 chemistry, Pyridones metabolism, Pyrimidines metabolism, Pyrroles metabolism, and TYK2 Kinase chemistry
Abstract
Janus kinases (JAKs) are critical regulators of cytokine pathways and attractive targets of therapeutic value in both inflammatory and myeloproliferative diseases. Although the crystal structures of active JAK1 and JAK2 kinase domains have been reported recently with the clinical compound CP-690550, the structures of both TYK2 and JAK3 with CP-690550 have remained outstanding. Here, we report the crystal structures of TYK2, a first in class structure, and JAK3 in complex with PAN-JAK inhibitors CP-690550 ((3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile) and CMP-6 (tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one), both of which bind in the ATP-binding cavities of both JAK isozymes in orientations similar to that observed in crystal structures of JAK1 and JAK2. Additionally, a complete thermodynamic characterization of JAK/CP-690550 complex formation was completed by isothermal titration calorimetry, indicating the critical role of the nitrile group from the CP-690550 compound. Finally, computational analysis using WaterMap further highlights the critical positioning of the CP-690550 nitrile group in the displacement of an unfavorable water molecule beneath the glycine-rich loop. Taken together, the data emphasize the outstanding properties of the kinome-selective JAK inhibitor CP-690550, as well as the challenges in obtaining JAK isozyme-selective inhibitors due to the overall structural and sequence similarities between the TYK2, JAK1, JAK2 and JAK3 isozymes. Nevertheless, subtle amino acid variations of residues lining the ligand-binding cavity of the JAK enzymes, as well as the global positioning of the glycine-rich loop, might provide the initial clues to obtaining JAK-isozyme selective inhibitors.
(2010 Elsevier Ltd. All rights reserved.)

100. Genetic variation at the phospholipid transfer protein locus affects its activity and high-density lipoprotein size and is a novel marker of cardiovascular disease susceptibility. [2010]

  • Vergeer M, Boekholdt SM, Sandhu MS, Ricketts SL, Wareham NJ, Brown MJ, de Faire U, Leander K, Gigante B, Kavousi M, Hofman A, Uitterlinden AG, van Duijn CM, Witteman JC, Jukema JW, Schadt EE, van der Schoot E, Kastelein JJ, Khaw KT, Dullaart RP, van Tol A, Trip MD, and Dallinga-Thie GM
  • Circulation [Circulation] 2010 Aug 03; Vol. 122 (5), pp. 470-7. Date of Electronic Publication: 2010 Jul 19.
Subjects
Adult, Aged, Atherosclerosis metabolism, Case-Control Studies, Female, Genetic Markers, Genetic Predisposition to Disease epidemiology, Genetic Variation, Humans, Lipoproteins, HDL chemistry, Male, Middle Aged, Particle Size, Polymorphism, Single Nucleotide, Predictive Value of Tests, Risk Factors, Atherosclerosis genetics, Lipoproteins, HDL metabolism, Phospholipid Transfer Proteins genetics, and Phospholipid Transfer Proteins metabolism
Abstract
Background: In contrast to clear associations between variants in genes participating in low-density lipoprotein metabolism and cardiovascular disease risk, such associations for high-density lipoprotein (HDL)-related genes are not well supported by recent large studies. We aimed to determine whether genetic variants at the locus encoding phospholipid transfer protein (PLTP), a protein involved in HDL remodeling, underlie altered PLTP activity, HDL particle concentration and size, and cardiovascular disease risk.
Methods and Results: We assessed associations between 6 PLTP tagging single nucleotide polymorphisms and PLTP activity in 2 studies (combined n=384) and identified 2 variants that show reproducible associations with altered plasma PLTP activity. A gene score based on these variants is associated with lower hepatic PLTP transcription (P=3.2x10(-18)) in a third study (n=957) and with an increased number of HDL particles of smaller size (P=3.4x10(-17)) in a fourth study (n=3375). In a combination of 5 cardiovascular disease case-control studies (n=4658 cases and 11 459 controls), a higher gene score was associated with a lower cardiovascular disease risk (per-allele odds ratio, 0.94; 95% confidence interval, 0.90 to 0.98; P=1.2x10(-3); odds ratio for highest versus lowest gene score, 0.69; 95% confidence interval, 0.55 to 0.86; P=1.0x10(-3)).
Conclusions: A gene score based on 2 PLTP single nucleotide polymorphisms is associated with lower PLTP transcription and activity, an increased number of HDL particles, smaller HDL size, and decreased risk of cardiovascular disease. These findings indicate that PLTP is a proatherogenic entity and suggest that modulation of specific elements of HDL metabolism may offer cardiovascular benefit.

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